Formation of cysts by principal-like MDCK cells depends on the synergy of cAMP- and ATP-mediated fluid secretion - Buchholz, Björn; Teschemacher, Barbara; Schley, Gunnar; Schillers, Hermann; Eckardt, Kai-Uwe (Journal of Molecular Medicine, 2011)
It has been suggested that more than 70% of the renal cysts in patients with autosomal dominant polycystic kidney disease (ADPKD) arise from the collecting duct and that within this segment cysts originate almost exclusively from principal rather than intercalated cells. The mechanisms for this predisposition of principal cells have so far remained elusive. We, therefore, used Madin-Darby canine kidney (MDCK) subclones resembling principal cells and alpha-intercalated cells in a three-dimensional in vitro model to determine differences in cystogenesis and cyst growth, including the response to cyclic adenosine monophosphate (cAMP) elevation and the dependence on ATP signaling. We found that in vitro cysts developed only from principal-like but not from intercalated-like MDCK cell clones. This specificity could be verified in mixed MDCK cultures enriched for principal- or intercalated-like cells. In vitro cyst growth upon elevation of intracellular cAMP was mainly driven by fluid secretion, rather than increased cell proliferation. The cAMP-dependent fluid secretion was found to depend on extracellular adenosine-5'-triphosphate (ATP) and to act synergistically with purinergic signaling, as the use of the ATP scavenger apyrase, as well as the P2 receptor inhibitor suramin, reduced cAMP-driven fluid secretion, while increasing extracellular ATP potentiated cAMP-mediated cyst growth. In conclusion, we provide in vitro evidence for the ability of principal rather than intercalated cells to form cysts, based on a synergism of cAMP and ATP signaling in enhancing apical fluid secretion.
Keywords: ATP; cAMP; Collecting duct cells; Cystogenesis; Intercalated cells; Principal cells

Frailty as clinically relevant Parameters in elderly Patients with arterial Hypertension - the FOHYP Study: Rationale and Study Design - Ritt, M.; Schwarz, C.; Bollheimer, Cornelius; Schmieder, Roland; Gaßmann, Karl-Günter; Sieber, Cornel (Zeitschrift für Gerontologie und Geriatrie, 2013)

Frequency and impact of enteric hyperoxaluria in pediatric short bowel syndrome: a retrospective single centre study - Schaefer, Jan Thomas; Schulz-Heise, Susanne; Rueckel, Aline; Rauh, Manfred; Jüngert, Jörg; Galiano, Matthias; Meier, Norbert; Wölfle, Joachim; Schiffer, Mario; Hörning, André (Frontiers in Pediatrics, 2023)
Objectives: The survival of pediatric patients with short bowel syndrome has improved in recent years. Enteric hyperoxaluria as a pathophysiological consequence has been hardly addressed so far. It can be associated with nephrolithiasis, nephrocalcinosis or even renal insufficiency. We assessed the prevalence of hyperoxaluria and its pathogenic consequences in a retrospective single centre study over the last 12 years. Methods: We conducted an internal database search for all pediatric patients suffering from short bowel syndrome treated from 2010 to 2022 in the department of pediatric gastroenterology as well as the pediatric nephrology and dialysis unit. Out of 56 patients identified, 26 patients were analysed for etiology of short bowel syndrome, renal excretion of oxalate (24/26), remaining short bowel and large intestinal length as well as further clinical parameters such as eGFR, nephrocalcinosis/urinary stone formation or stool frequency. Results: Hyperoxaluria was detected in 14/26 patients (54%). Nephrocalcinosis was present in four patients. Out of these four patients, hyperoxaluria could be proven (21% of all hyperoxaluric patients) in three cases, one hyperoxaluric patient had nephrolithiasis (7%). In one patient hyperoxaluria lead to end stage renal disease. We found that 80% of patients with volvulus developed enteric hyperoxaluria. None of the investigated factors had an effect on oxalate excretion. Conclusion: Enteric hyperoxaluria is a relevant pathophysiological finding in patients with short bowel syndrome occurring in about 50% of our cohort with multiple pathogenic complications. Regular screening for hyperoxaluria may be implemented in medical care for patients with short bowel syndrome. If necessary, prophylaxis, e.g., dietary advice or metaphylaxis should be initiated.
CRIS-Team Scopus Importer:2023-08-11
Keywords: enteric hyperoxaluria; hyperoxaluria; intestinal failure; kidney stone; nephrolithiasis; pediatric; short bowel syndrome

Frequency of the necessity of dentoalveolar surgery or conservative treatment in patients before kidney transplantation depending on the duration of dialysis and causative nephrological disease - Möst, Tobias; Lutz, Rainer; Jahn, Arne Eric; Heller, Katharina M.; Schiffer, Mario; Adler, Werner; Deschner, James; Weber, Manuel; Kesting, Marco Rainer (Clinical Oral Investigations, 2021)
Objectives: This retrospective study evaluates intraoral surgical and conservative treatment need in patients with a chronic kidney end-stage disease, depending on the duration of dialysis treatment and the causative nephrological disease. Material and methods: This study is based on data of patients referred to the Department of Oral and Maxillofacial Surgery of the University Hospital Erlangen, Germany, prior to kidney transplantation between January 2015 and March 2020. The necessity for oral surgical or dental therapy was determined by clinical and radiological examinations. Data on renal replacement therapy, cause of underlying renal disease, lifestyle, and general health were collected. Results: Data of N = 89 patients demonstrated that surgical treatment need depends on dialysis duration (p = 0.042). Patients, who had been dialyzing for 2 to 3 years showed the highest need for surgical intervention (80.0%; p = 0.024), followed by dialysis patients with a dialysis time of more than 3 years (48.1%). Similarly, dialysis patients in the second or third year of dialysis had the highest need for conservative treatment (73.3%; p > 0.05), followed by 55.6% of dialysis patients in the third year of dialysis. Conclusions: Operative and conservative treatment is essential to optimize subsequent kidney transplantation. The greatest necessity could be detected for patients in the second and third years of dialysis. Clinical relevance: Oral health addressing surgical and conservative treatment need depends on the duration of dialysis in patients with a chronic kidney end-stage disease.
CRIS-Team Scopus Importer:2021-10-22
Keywords: Immunosuppression; Kidney; Oral health; Organ transplantation

Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease - Schachtl-Riess, Johanna F.; Kheirkhah, Azin; Grüneis, Rebecca; Di Maio, Silvia; Schoenherr, Sebastian; Streiter, Gertraud; Losso, Jamie Lee; Paulweber, Bernhard; Eckardt, Kai-Uwe; Köttgen, Anna; Lamina, Claudia; Kronenberg, Florian; et al. (Journal of the American College of Cardiology, 2021)
Background: Lipoprotein(a) (Lp(a)) concentrations are a major independent risk factor for coronary artery disease (CAD) and are mainly determined by variation in LPA. Up to 70% of the LPA coding sequence is located in the hypervariable kringle IV type 2 (KIV-2) region. It is hardly accessible by conventional technologies, but may contain functional variants. Objectives: This study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD. Methods: We genotyped 4733G>A in the GCKD (German Chronic Kidney Disease) study (n = 4,673) by allele-specific polymerase chain reaction, performed minigene assays, identified proxy single nucleotide polymorphisms and used them to characterize its effect on CAD by survival analysis in UK Biobank (n = 440,234). Frequencies in ethnic groups were assessed in the 1000 Genomes Project. Results: The 4733G>A variant (38.2% carrier frequency) was found in most isoform sizes. It reduces allelic expression without abolishing protein production, lowers Lp(a) by 13.6 mg/dL (95% CI: 12.5-14.7; P < 0.0001) and is the strongest variance-explaining factor after the smaller isoform. Splicing of minigenes was modified. Compound heterozygosity (4.6% of the population) for 4733G>A and 4925G>A, another KIV-2 splicing mutation, reduces Lp(a) by 31.8 mg/dL and most importantly narrows the interquartile range by 9-fold (from 42.1 to 4.6 mg/dL) when compared to the wild type. In UK Biobank 4733G>A alone and compound heterozygosity with 4925G>A reduced HR for CAD by 9% (95% CI: 7%-11%) and 12% (95% CI: 7%-16%) (both P < 0.001). Frequencies in ethnicities differ notably. Conclusions: Functional variants in the previously inaccessible LPA KIV-2 region cooperate in determining Lp(a) variance and CAD risk. Even a moderate but lifelong genetic Lp(a) reduction translates to a noticeable CAD risk reduction.
CRIS-Team Scopus Importer:2021-07-30
Keywords: cardiovascular disease; cohort study; copy number variation; genetic variability; lipoprotein(a); Mendelian randomization

From SYMPLICITY HTN-3 to the Renal Denervation Global Registry: where do we stand and where should we go? - Pathak, Atul; Ewen, Sebastian; Fajadet, Jean; Honton, Benjamin; Mahfoud, Felix; Marco, Jean; Schlaich, Markus; Schmieder, Roland; Tsioufis, Konstantinos; Ukena, Christian; Zeller, Thomas (EuroIntervention, 2014)
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Functional inhibitors of acid sphingomyelinase (FIASMAS): A novel pharmacological group of drugs with broad clinical applications - Kornhuber, Johannes; Tripal, Philipp; Reichel, Martin; Mühle, Christiane; Rhein, Cosima; Muehlbacher, Markus; Groemer, Teja W.; Gulbins, Erich (Cellular Physiology and Biochemistry, 2010)
Acid sphingomyelinase (ASM) is an important lipid-metabolizing enzyme cleaving sphingomyelin to ceramide, mainly within lysosomes. Acid ceramidase (AC) further degrades ceramide to sphingosine which can then be phosphorylated to sphingosine-1-phosphate. Ceramide and its metabolite sphingosine-1-phosphate have been shown to antagonistically regulate apoptosis, cellular differentiation, proliferation and cell migration. Inhibitors of ASM or AC therefore hold promise for a number of new clinical therapies, e.g. for Alzheimer's disease and major depression on the one hand and cancer on the other. Inhibitors of ASM have been known for a long time. Cationic amphiphilic substances induce the detachment of ASM protein from inner lysosomal membranes with its consecutive inactivation, thereby working as functional inhibitors of ASM. We recently experimentally identified a large number of hitherto unknown functional inhibitors of ASM and determined specific physicochemical properties of such cationic amphiphilic substances that functionally inhibit ASM. We propose the acronym "FIASMA" (Functional Inhibitor of Acid SphingoMyelinAse) for members of this large group of compounds with a broad range of new clinical indications. FIASMAs differ markedly with respect to molecular structure and current clinical indication. Most of the available FIASMAs are licensed for medical use in humans, are minimally toxic and may therefore be applied for disease states associated with increased activity of ASM. Copyright © 2010 S. Karger AG, Basel.
Created from Fastlane, Scopus look-up
Keywords: Acid ceramidase; Acid sphingomyelinase; Acid trapping; Cationic amphiphilic drugs; Desipramine; Lysosomotropism

GENERATION OF NOVEL 3D CO-CULTURE SYSTEMS TO STUDY PODOCYTOPATHIES EX VIVO IN A PERSONALIZED MANNER - Rose, Victoria; Sopel, Nina; Ohs, Alexandra; Warnecke, Christina; Schiffer, Mario; Müller-Deile, Janina (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Generation of Patient-Derived Podocytes from Skin Biopsies - Rose, Victoria; Müller-Deile, Janina (Journal of Visualized Experiments, 2023)
Podocytes are epithelial cells sitting on the urinary site of the glomerular filtration barrier that contribute to the selective filter function of the glomerulus. Mutations in podocyte-specific genes can cause focal segmental glomerulosclerosis (FSGS), and podocytes are also affected in many other primary and secondary nephropathies. Due to their differentiated nature, primary cell culture models are limited for podocytes. Therefore, commonly conditionally immortalized cells are used. However, these conditionally immortalized podocytes (ciPodocytes) have several limitations: the cells can dedifferentiate in culture, especially when they reach confluency, and several podocyte-specific markers are either only slightly or not expressed at all. This brings the use of ciPodocytes and their applicability for physiological, pathophysiological, and clinical reach into question. Here, we describe a protocol for the generation of human podocytes-including patient-specific podocytes-from a skin punch biopsy by episomal reprogramming of dermal fibroblasts into hiPSCs and subsequent differentiation into podocytes. These podocytes resemble in vivo podocytes much better in terms of morphological characteristics, like the development of foot processes and the expression of the podocyte-specific marker. Finally, yet importantly, these cells maintain patients' mutations, resulting in an improved ex vivo model to study podocyte diseases and potential therapeutic substances in an individualized approach.
CRIS-Team Scopus Importer:2023-06-30

GENERATION OF PATIENT-SPECIFIC HIPSC-PODOCYTES TO STUDY PHENOTYPE-SPECIFIC ALTERATIONS AND TEST THERAPEUTIC TARGETS EX VIVO - Rose, Victoria; Sopel, Nina; Ohs, Alexandra; Warnecke, Christina; Schiffer, Mario; Müller-Deile, Janina (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2022)
CRIS-Team WoS Importer:2022-07-22

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies - Gorski, Mathias; Rasheed, Humaira; Teumer, Alexander; Thomas, Laurent F.; Graham, Sarah E.; Sveinbjornsson, Gardar; Winkler, Thomas W.; Günther, Felix; Stark, Klaus J.; Chai, Jin Fang; Tayo, Bamidele O.; Wuttke, Matthias; et al. (Kidney International, 2022)
Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
CRIS-Team Scopus Importer:2022-08-05
Keywords: acute kidney injury; chronic kidney disease; diabetes; gene expression

Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies - Sekula, Peggy; Li, Yong; Stanescu, Horia C.; Wuttke, Matthias; Ekici, Arif Bülent; Bockenhauer, Detlef; Walz, Gerd; Powis, Stephen H.; Kielstein, Jan T.; Brenchley, Paul; Eckardt, Kai-Uwe; Kronenberg, Florian; et al. (Nephrology Dialysis Transplantation, 2016)
Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Previous genome-wide association studies (GWAS) of 300 000 genotyped variants identified MN-associated loci at HLA-DQA1 and PLA2R1.We used a combined approach of genotype imputation, GWAS, human leucocyte antigen (HLA) imputation and extension to other aetiologies of chronic kidney disease (CKD) to investigate genetic MN risk variants more comprehensively. GWAS using 9 million high-quality imputed genotypes and classical HLA alleles were conducted for 323 MN European-ancestry cases and 345 controls. Additionally, 4960 patients with different CKD aetiologies in the German Chronic Kidney Disease (GCKD) study were genotyped for risk variants at HLA-DQA1 and PLA2R1.In GWAS, lead variants in known loci [rs9272729, HLA-DQA1, odds ratio (OR) = 7.3 per risk allele, P = 5.9 × 10(-27) and rs17830558, PLA2R1, OR = 2.2, P = 1.9 × 10(-8)] were significantly associated with MN. No novel signals emerged in GWAS of X-chromosomal variants or in sex-specific analyses. Classical HLA alleles (DRB1*0301-DQA1*0501-DQB1*0201 haplotype) were associated with MN but provided little additional information beyond rs9272729. Associations were replicated in 137 GCKD patients with MN (HLA-DQA1: P = 6.4 × 10(-24); PLA2R1: P = 5.0 × 10(-4)). MN risk increased steeply for patients with high-risk genotype combinations (OR > 79). While genetic variation in PLA2R1 exclusively associated with MN across 19 CKD aetiologies, the HLA-DQA1 risk allele was also associated with lupus nephritis (P = 2.8 × 10(-6)), type 1 diabetic nephropathy (P = 6.9 × 10(-5)) and focal segmental glomerulosclerosis (P = 5.1 × 10(-5)), but not with immunoglobulin A nephropathy.PLA2R1 and HLA-DQA1 are the predominant risk loci for MN detected by GWAS. While HLA-DQA1 risk variants show an association with other CKD aetiologies, PLA2R1 variants are specific to MN.
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Genetics of osteopontin in patients with chronic kidney disease: The German chronic kidney disease study - Cheng, Yurong; Li, Yong; Scherer, Nora; Grundner-Culemann, Franziska; Lehtimäki, Terho; Mishra, Binisha H.; Raitakari, Olli T.; Nauck, Matthias; Eckardt, Kai-Uwe; Sekula, Peggy; Schultheiss, Ulla T. (PLoS Genetics, 2022)
Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho) physiology.
CRIS-Team Scopus Importer:2022-04-22

Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine - Schlosser, Pascal; Scherer, Nora; Grundner-Culemann, Franziska; Monteiro-Martins, Sara; Haug, Stefan; Steinbrenner, Inga; Uluvar, Burulça; Wuttke, Matthias; Cheng, Yurong; Ekici, Arif Bülent; Gyimesi, Gergely; Karoly, Edward D.; et al. (Nature Genetics, 2023)
The kidneys operate at the interface of plasma and urine by clearing molecular waste products while retaining valuable solutes. Genetic studies of paired plasma and urine metabolomes may identify underlying processes. We conducted genome-wide studies of 1,916 plasma and urine metabolites and detected 1,299 significant associations. Associations with 40% of implicated metabolites would have been missed by studying plasma alone. We detected urine-specific findings that provide information about metabolite reabsorption in the kidney, such as aquaporin (AQP)-7-mediated glycerol transport, and different metabolomic footprints of kidney-expressed proteins in plasma and urine that are consistent with their localization and function, including the transporters NaDC3 (SLC13A3) and ASBT (SLC10A2). Shared genetic determinants of 7,073 metabolite–disease combinations represent a resource to better understand metabolic diseases and revealed connections of dipeptidase 1 with circulating digestive enzymes and with hypertension. Extending genetic studies of the metabolome beyond plasma yields unique insights into processes at the interface of body compartments.
CRIS-Team Scopus Importer:2023-06-16

Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans - Schlosser, Pascal; Li, Yong; Sekula, Peggy; Raffler, Johannes; Grundner-Culemann, Franziska; Pietzner, Maik; Cheng, Yurong; Wuttke, Matthias; Steinbrenner, Inga; Schultheiss, Ulla T.; Kotsis, Fruzsina; Kacprowski, Tim; et al. (Nature Genetics, 2020)
The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite–locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research.
CRIS-Team Scopus Importer:2020-02-04

Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer. - Grampp, Steffen; Platt, James L.; Lauer, Victoria; Salama, Rafik; Kranz, Franziska; Neumann, Viviana K.; Wach, Sven; Stoehr, Christine; Hartmann, Arndt; Eckardt, Kai-Uwe; Ratcliffe, Peter J.; Mole, David R.; et al. (Nature Communications, 2016)
Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation - Teumer, Alexander; Chaker, Layal; Groeneweg, Stefan; Li, Yong; Di Munno, Celia; Barbieri, Caterina; Schultheiss, Ulla T.; Traglia, Michela; Ahluwalia, Tarunveer S.; Akiyama, Masato; Appel, Emil Vincent R.; Arking, Dan E.; et al. (Nature Communications, 2018)
Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
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Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria - Teumer, Alexander; Li, Yong; Ghasemi, Sahar; Prins, Bram P.; Wuttke, Matthias; Hermle, Tobias; Giri, Ayush; Sieber, Karsten B.; Qiu, Chengxiang; Kirsten, Holger; Tin, Adrienne; Chu, Audrey Y.; et al. (Nature Communications, 2019)
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
CRIS-Team Scopus Importer:2019-09-20

Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms - Li, Yong; Sekula, Peggy; Wuttke, Matthias; Wahrheit, Judith; Hausknecht, Birgit; Schultheiss, Ulla T.; Gronwald, Wolfram; Schlosser, Pascal; Tucci, Sara; Ekici, Arif Bülent; Spiekerkoetter, Ute; Kronenberg, Florian; et al. (Journal of the American Society of Nephrology, 2018)
Background The kidneys have a central role in the generation, turnover, transport, and excretion of metabolites, and these functions can be altered in CKD. Genetic studies of metabolite concentrations can identify proteins performing these functions.Methods We conducted genome-wide association studies and aggregate rare variant tests of the concentrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and fractional excretions in up to 1168 patients with CKD.Results After correction for multiple testing, genome-wide significant associations were detected for 25 serum metabolites, two urine metabolites, and 259 serum and 14 urinary metabolite ratios. These included associations already known from population-based studies. Additional findings included an association for the uremic toxin putrescine and variants upstream of an enzyme catalyzing the oxidative deamination of polyamines (AOC1, P-min=2.4×10-12), a relatively high carrier frequency (2%) for rare deleterious missense variants in ACADM that are collectively associated with serum ratios of medium-chain acylcarnitines (P-burden=6.6×10-16), and associations of a common variant in SLC7A9 with several ratios of lysine to neutral amino acids in urine, including the lysine/glutamine ratio (P=2.2×10-23). The associations of this SLC7A9 variant with ratios of lysine to specific neutral amino acids were much stronger than the association with lysine concentration alone. This finding is consistent with SLC7A9 functioning as an exchanger of urinary cationic amino acids against specific intracellular neutral amino acids at the apical membrane of proximal tubular cells.Conclusions Metabolomic indices of specific kidney functions in genetic studies may provide insight into human renal physiology.
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Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases - Li, Yong; Cheng, Yurong; Consolato, Francesco; Schiano, Guglielmo; Chong, Michael R.; Pietzner, Maik; Nguyen, Ngoc Quynh H.; Scherer, Nora; Biggs, Mary L.; Kleber, Marcus E.; Haug, Stefan; Goecmen, Burulca; et al. (JCI Insight, 2022)
Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin???s complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.
CRIS-Team WoS Importer:2022-06-17

Genome-wide studies to identify risk factors for kidney disease with a focus on patients with diabetes - Regele, Florina; Jelencsics, Kira; Shiffman, Dov; Pare, Guillaume; Mcqueen, Matthew J.; Mann, Johannes; Oberbauer, Rainer (Nephrology Dialysis Transplantation, 2015)
Chronic kidney disease (CKD) affects 10-13% of the general population and diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). In addition to known demographic, biochemical and lifestyle risk factors, genetics is also contributing to CKD risk. In recent years, genome-wide association studies (GWAS) have provided a hypothesis-free approach to identify common genetic variants that could account for the genetic risk component of common diseases such as CKD. The identification of these variants might reveal the biological processes underlying renal impairment and could aid in improving risk estimates for CKD. This review aims to describe the methods as well as strengths and limitations of GWAS in CKD and to summarize the findings of recent GWAS in DN. Several loci and SNPs have been found to be associated with distinct CKD traits such as eGFR and albuminuria. For diabetic kidney disease, several loci were identified in different populations. Subsequent functional studies provided insights into the mechanism of action of some of these variants, such as UMOD or CERS2. However, overall, the results were ambiguous, and a few of the variants were not consistently replicated. In addition, the slow progression from albuminuria to ESRD could limit the power of longitudinal studies. The typically small effect size associated with genetic variants as well as the small portion of the variability of the phenotype explained by these variants limits the utility of genetic variants in improving risk prediction. Nevertheless, identifying these variants could give a deeper understanding of the molecular pathways underlying CKD, which in turn, could potentially lead to the development of new diagnostic and therapeutic tools.
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Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy - Levin, Adeera; Tonelli, Marcello; Bonventre, Joseph; Coresh, Josef; Donner, Jo Ann; Fogo, Agnes B.; Fox, Caroline S.; Gansevoort, Ron T.; Heerspink, Hiddo J.L.; Jardine, Meg; Kasiske, Bertram; Köttgen, Anna; et al. (Lancet, 2017)
The global nephrology community recognises the need for a cohesive plan to address the problem of chronic kidney disease (CKD). In July, 2016, the International Society of Nephrology hosted a CKD summit of more than 85 people with diverse expertise and professional backgrounds from around the globe. The purpose was to identify and prioritise key activities for the next 5-10 years in the domains of clinical care, research, and advocacy and to create an action plan and performance framework based on ten themes: strengthen CKD surveillance; tackle major risk factors for CKD; reduce acute kidney injury-a special risk factor for CKD; enhance understanding of the genetic causes of CKD; establish better diagnostic methods in CKD; improve understanding of the natural course of CKD; assess and implement established treatment options in patients with CKD; improve management of symptoms and complications of CKD; develop novel therapeutic interventions to slow CKD progression and reduce CKD complications; and increase the quantity and quality of clinical trials in CKD. Each group produced a prioritised list of goals, activities, and a set of key deliverable objectives for each of the themes. The intended users of this action plan are clinicians, patients, scientists, industry partners, governments, and advocacy organisations. Implementation of this integrated comprehensive plan will benefit people who are at risk for or affected by CKD worldwide.
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Glomerular Endothelial Cell-Derived microRNA-192 Regulates Nephronectin Expression in Idiopathic Membranous Glomerulonephritis. - Müller-Deile, Janina; Sopel, Nina; Ohs, Alexandra; Rose, Victoria; Gröner, Marwin; Wrede, Christoph; Hegermann, Jan; Daniel, Christoph; Amann, Kerstin Ute; Zahner, Gunther; Schiffer, Mario (Journal of the American Society of Nephrology, 2021)
BACKGROUND: Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is size selective and almost impermeable for antibodies. METHODS: Kidney biopsies from patients with iMGN, cell culture, zebrafish, and mouse models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the GFB. RESULTS: Glomerular endothelial cell (GEC)-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in urine and glomeruli of patients with iMGN, whereas glomerular NPNT is reduced. Overexpression of miR-192-5p and morpholino-mediated npnt knockdown induced edema, proteinuria, and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Structural changes of the glomerular basement membrane (GBM) with increased lucidity, splitting, and lamellation, especially of the lamina rara interna, similar to ultrastructural findings seen in advanced stages of iMGN, were found. IgG-size nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt-knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte-specific Npnt knockout mice. GECs downregulate podocyte NPNT by transfer of miR-192-5p-containing exosomes in a paracrine manner. CONCLUSIONS: Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by GEC-derived miR-192-5p and podocyte-derived miR-378a-3p. We hypothesize that loss of NPNT in the GBM is an important part of the initial pathophysiology of iMGN and enables autoantigenicity of podocyte antigens and subepithelial immune complex deposition in iMGN.
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Glomerular Endothelial Cell-Derived miR-200c Impairs Glomerular Homeostasis by Targeting Podocyte VEGF-A - Ursu, Raluca; Sopel, Nina; Ohs, Alexandra; Tati, Ramesh; Buvall, Lisa; Nyström, Jenny; Schiffer, Mario; Müller-Deile, Janina (International Journal of Molecular Sciences, 2022)
Deciphering the pathophysiological mechanisms of primary podocytopathies that can lead to end-stage renal disease and increased mortality is an unmet need. Studying how microRNAs (miRs) interfere with various signaling pathways enables identification of pathomechanisms, novel biomarkers and potential therapeutic options. We investigated the expression of miR-200c in urine from patients with different renal diseases as a potential candidate involved in podocytopathies. The role of miR-200c for the glomerulus and its potential targets were studied in cultured human podocytes, human glomerular endothelial cells and in the zebrafish model. miR-200c was upregulated in urine from patients with minimal change disease, membranous glomerulonephritis and focal segmental glomerulosclerosis and also in transforming growth factor beta (TGF-β) stressed glomerular endothelial cells, but not in podocytes. In zebrafish, miR-200c overexpression caused proteinuria, edema, podocyte foot process effacement and glomerular endotheliosis. Although zinc finger E-Box binding homeobox 1/2 (ZEB1/2), important in epithelial to mesenchymal transition (EMT), are prominent targets of miR-200c, their downregulation did not explain our zebrafish phenotype. We detected decreased vegfaa/bb in zebrafish overexpressing miR-200c and could further prove that miR-200c decreased VEGF-A expression and secretion in cultured human podocytes. We hypothesize that miR-200c is released from glomerular endothelial cells during cell stress and acts in a paracrine, autocrine, as well as context-dependent manner in the glomerulus. MiR-200c can cause glomerular damage most likely due to the reduction of podocyte VEGF-A. In contrast, miR-200c might also influence ZEB expression and therefore EMT, which might be important in other conditions. Therefore, we propose that miR-200c-mediated effects in the glomerulus are context-sensitive.
CRIS-Team Scopus Importer:2022-12-23
Keywords: endotheliosis; glomerulus; miR-200c; podocytopathies; proteinuria; VEGF-A; zebrafish

Glucose promotes secretion-dependent renal cyst growth. - Kraus, Andre; Schley, Gunnar; Kunzelmann, Karl; Schreiber, Rainer; Peters, Dorien J. M.; Stadler, Ruth; Eckardt, Kai-Uwe; Buchholz, Björn (Journal of Molecular Medicine, 2016)
Polycystic kidney diseases are characterized by the development of numerous bilateral renal cysts that continuously enlarge resulting in a decline of kidney function due to compression of intact nephrons. Cyst growth is driven by transepithelial chloride secretion which depends on both intracellular cAMP and calcium. Mechanisms that are involved in the regulation of the underlying secretory pathways remain incompletely understood. Here we show that glucose concentration has a strong impact on cyst growth of renal tubular cells within a collagen matrix as well as in embryonic kidneys deficient or competent for Pkd1. Glucose-dependent cyst growth correlates with the transcriptional induction of the calcium-activated chloride channel anoctamin 1 (ANO1) and its increased expression in the apical membrane of cyst-forming cells. Inhibition of ANO1 with the specific inhibitor CaCCinh-AO1 significantly decreases glucose-dependent cyst growth in both models. Ussing chamber analyses revealed increased apical chloride secretion of renal tubular cells upon exposure to high glucose medium which can also be inhibited by the use of CaCCinh-AO1. These data suggest that glycemic control may help to reduce renal cyst growth in patients with polycystic kidney disease.Renal cyst growth depends on glucose concentration in two in vitro cyst models. High glucose leads to upregulation of the calcium-activated chloride channel ANO1. High glucose promotes calcium-activated chloride secretion via ANO1. Glucose-dependent secretion can be inhibited by a specific inhibitor of ANO1.
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Keywords: Polycystic kidney disease; Cyst growth; Chloride secretion; Glucose; Diabetes mellitus type 2; Anoctamin 1

Glycaemic control and antidiabetic therapy in patients with diabetes mellitus and chronic kidney disease - cross-sectional data from the German Chronic Kidney Disease (GCKD) cohort - Busch, Martin; Nadal, Jennifer; Schmid, Matthias; Paul, Katharina; Titze, Stephanie; Huebner, Silvia; Koettgen, Anna; Schultheiss, Ulla T.; Baid-Agrawal, Seema; Lorenzen, Johan; Schlieper, Georg; Sommerer, Claudia; et al. (BMC Nephrology, 2016)
Diabetes mellitus (DM) is the leading cause of end-stage renal disease. Little is known about practice patterns of anti-diabetic therapy in the presence of chronic kidney disease (CKD) and correlates with glycaemic control. We therefore aimed to analyze current antidiabetic treatment and correlates of metabolic control in a large contemporary prospective cohort of patients with diabetes and CKD.The German Chronic Kidney Disease (GCKD) study enrolled 5217 patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) between 30-60 mL/min/1.73 m(2) or proteinuria >0.5 g/d. The use of diet prescription, oral anti-diabetic medication, and insulin was assessed at baseline. HbA1c, measured centrally, was the main outcome measure.At baseline, DM was present in 1842 patients (35 %) and the median HbA1C was 7.0 % (25(th)-75(th) percentile: 6.8-7.9 %), equalling 53 mmol/mol (51, 63); 24.2 % of patients received dietary treatment only, 25.5 % oral antidiabetic drugs but not insulin, 8.4 % oral antidiabetic drugs with insulin, and 41.8 % insulin alone. Metformin was used by 18.8 %. Factors associated with an HbA1C level >7.0 % (53 mmol/mol) were higher BMI (OR = 1.04 per increase of 1 kg/m(2), 95 % CI 1.02-1.06), hemoglobin (OR = 1.11 per increase of 1 g/dL, 95 % CI 1.04-1.18), treatment with insulin alone (OR = 5.63, 95 % CI 4.26-7.45) or in combination with oral antidiabetic agents (OR = 4.23, 95 % CI 2.77-6.46) but not monotherapy with metformin, DPP-4 inhibitors, or glinides.Within the GCKD cohort of patients with CKD stage 3 or overt proteinuria, antidiabetic treatment patterns were highly variable with a remarkably high proportion of more than 50 % receiving insulin-based therapies. Metabolic control was overall satisfactory, but insulin use was associated with higher HbA1C levels.
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Good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient: Importance of early detection and rapid immune reconstitution - Sauer, Rolf; Gölitz, Philipp; Jacobi, Johannes; Schwab, Stefan; Linker, Ralf; Lee, De-Hyung (Journal of the Neurological Sciences, 2017)
Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis.
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H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway - Eberhard, Miriam; Dux, Maria; Namer, Barbara; Miljkovic, Jan; Cordasic, Nada; Will, Christine; Kichko, Tetyana; de la Roche, Jeanne; Fischer, Michael Jochen Marco; Suarez, Sebastian A.; Bikiel, Damian; Dorsch, Karola; et al. (Nature Communications, 2014)
Nitroxyl (HNO) is a redox sibling of nitric oxide (NO) that targets distinct signalling pathways with pharmacological endpoints of high significance in the treatment of heart failure. Beneficial HNO effects depend, in part, on its ability to release calcitonin gene-related peptide (CGRP) through an unidentified mechanism. Here we propose that HNO is generated as a result of the reaction of the two gasotransmitters NO and H 2 S. We show that H 2 S and NO production colocalizes with transient receptor potential channel A1 (TRPA1), and that HNO activates the sensory chemoreceptor channel TRPA1 via formation of amino-terminal disulphide bonds, which results in sustained calcium influx. As a consequence, CGRP is released, which induces local and systemic vasodilation. H 2 S-evoked vasodilatatory effects largely depend on NO production and activation of HNO-TRPA1-CGRP pathway. We propose that this neuroendocrine HNO-TRPA1-CGRP signalling pathway constitutes an essential element for the control of vascular tone throughout the cardiovascular system. © 2014 Macmillan Publishers Limited. All rights reserved.

Haemoglobin and vascular function in the human retinal vascular bed - Ritt, Martin; Harazny, Joanna M.; Schmidt, Stefan; Raff, Ulrike; Ott, Christian; Michelson, Georg; Schmieder, Roland (Journal of Hypertension, 2013)
: Haemoglobin is a potential nitric oxide (NO) scavenger. Haemoglobin is associated with blood viscosity and the red blood cell free layer width of microvessels that impact on shear stress in the microcirculation. We hypothesized that haemoglobin modulates retinal vascular function.: In 139 nondiabetic male patients with haemoglobin levels within the normal range, the vasodilatatory response of retinal capillary blood flow (RCF) to flicker light exposure and the vasoconstrictor response of RCF to infusion of NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) were assessed. The latter, because of the selective nature of L-NMMA, reflects a parameter of basal NO activity of retinal vasculature. Examinations of retinal parameters were performed noninvasively and in vivo using scanning laser Doppler flowmetry.: Patients with haemoglobin greater or equal the median revealed reduced increase of RCF to flicker light exposure (2.83 ± 12 vs. 9.52 ± 14 (%), P adjusted = 0.002), and greater decrease of RCF to L-NMMA infusion (-7.35 ± 13 vs. -0.92 ± 14 (%), P adjusted = 0.008), compared with patients with haemoglobin below the median. Haemoglobin was negatively related to the percentage change of RCF to flicker light exposure (r = -0.249, P = 0.004) and to L-NMMA infusion (r = -0.201, P = 0.018). In multiple linear regression analysis haemoglobin was an independent determinant of the percentage change of RCF to flicker light exposure (model 1: ß = -0.278, P = 0.003 and model 2: ß = -0.283, P = 0.002) and to L-NMMA infusion (model 1: ß = -0.256, P = 0.005 and model 2: ß = -0.269, P = 0.004).: Haemoglobin emerged as an independent determinant of vascular function in the human retinal vascular bed.
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Health-related quality of life in people with type 2 diabetes participating in the LEADER trial - Nauck, Michael A.; Buse, John B.; Mann, Johannes; Pocock, Stuart; Bosch-Traberg, Heidrun; Frimer-Larsen, Helle; Ye, Qing; Gray, Alastair (Diabetes Obesity & Metabolism, 2019)
Aims To assess health-related quality of life (HRQoL) in people with type 2 diabetes (T2D) participating in the LEADER cardiovascular outcomes trial using the five-dimension European Quality of Life questionnaire (EQ-5D). Materials and methods The EQ-5D was administered every 12 months in a subset of patients from Canada, Denmark, Germany, Ireland, Italy, Netherlands, Spain, Sweden, the United Kingdom and the United States. We compared changes in utility index scores and visual analogue scale (VAS) scores from baseline to 36 months in participants treated with liraglutide and placebo. We also assessed which complications had the greatest impact on quality of life. Results At 36 months, less deterioration in EQ-5D utility index score was seen in the liraglutide group (-0.058) than in the placebo group (-0.082; estimated treatment difference [ETD] 0.023, 95% confidence interval [CI] 0.004;0.043; P = 0.020). A smaller decrease in EQ-5D VAS score was also demonstrated in the liraglutide group (-3.51) vs. the placebo group (-5.45; ETD 1.94, 95% CI 0.32;3.57; P = 0.019). The benefits of liraglutide treatment compared with placebo were driven primarily by shifts in the domains of mobility and self-care. The most influential events contributing to poorer HRQoL were stroke, heart failure, malignant neoplasm and confirmed hypoglycaemia. Conclusions Liraglutide demonstrated a modest but significant benefit in patient-reported health status using the EQ-5D, compared with placebo. This benefit may be of clinical relevance and requires further study.
CRIS-Team WoS Importer:2019-02-21

Heart Failure in a Cohort of Patients with Chronic Kidney Disease: The GCKD Study - Beck, Hanna; Titze, Stephanie I.; Huebner, Silvia; Busch, Martin; Schlieper, Georg; Schultheiss, Ulla T.; Wanner, Christoph; Kronenberg, Florian; Krane, Vera; Eckardt, Kai-Uwe; Koettgen, Anna (PLoS ONE, 2015)
Chronic kidney disease (CKD) is a risk factor for development and progression of heart failure (HF). CKD and HF share common risk factors, but few data exist on the prevalence, signs and symptoms as well as correlates of HF in populations with CKD of moderate severity. We therefore aimed to examine the prevalence and correlates of HF in the German Chronic Kidney Disease (GCKD) study, a large observational prospective study.We analyzed data from 5,015 GCKD patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73m² or with an eGFR >=60 and overt proteinuria (>500 mg/d). We evaluated a definition of HF based on the Gothenburg score, a clinical HF score used in epidemiological studies (Gothenburg HF), and self-reported HF. Factors associated with HF were identified using multivariable adjusted logistic regression. The prevalence of Gothenburg HF was 43% (ranging from 24% in those with eGFR >90 to 59% in those with eGFR<30 ml/min/1.73m2). The corresponding estimate for self-reported HF was 18% (range 5%-24%). Lower eGFR was significantly and independently associated with the Gothenburg definition of HF (p-trend <0.001). Additional significantly associated correlates included older age, female gender, higher BMI, hypertension, diabetes mellitus, valvular heart disease, anemia, sleep apnea, and lower educational status.The burden of self-reported and Gothenburg HF among patients with CKD is high. The proportion of patients who meet the criteria for Gothenburg HF in a European cohort of patients with moderate CKD is more than twice as high as the prevalence of self-reported HF. However, because of the shared signs, symptoms and medications of HF and CKD, the Gothenburg score cannot be used to reliably define HF in CKD patients. Our results emphasize the need for early screening for HF in patients with CKD.
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Heart rate and blood pressure interactions in the development of erectile dysfunction in high-risk cardiovascular patients - Kratz, Mario T.; Schumacher, Helmut; Sliwa, Karen; Schmieder, Roland; Poess, Janine; Mahfoud, Felix; Unger, Thomas; Lonn, Eva; Koon, Teo; Mancia, Guiseppe; Sleight, Peter; Yusuf, Salim; et al. (European Journal of Preventive Cardiology, 2014)
Erectile dysfunction (ED) is associated with cardiovascular risk factors as elevated systolic blood pressure (SBP), resting high heart rate (HR), and endothelial dysfunction and predicts cardiovascular events. However, the interaction between high HR and SBP and the development of ED remains unclear.We evaluated 1015 male patients enrolled in the ED substudy of ONTARGET and TRANSCEND, examining the influence of mean HR and mean SBP obtained over all study visits (mean 10.9±1.4 study visits) and their interaction with ED. In patients without pre-existing ED, new onset ED was detected in 29% of patients below, and 41% of patients above, the median of mean HR (OR 1.72, 95% CI 1.8-2.5, p = 0.0047). In patients with pre-existing ED, high HR had no add-on effect. With or without pre-existing ED, high SBP had no influence after adjustment for covariates (OR 1.03, 95% CI 0.66-1.59, p = 0.91). In a continuous model, it was shown that effects of high HR were prominent at low Kölner (Cologne) Evaluation of Erectile Function (KEED) score baseline values and in the presence of SBP above the median.In patients at risk for cardiovascular events, high HR is associated with ED, whereas the effect of high SBP was not significant. High resting HR might represent a cardiovascular risk indicator. Whether HR represents a potential treatment target to improve ED in high-risk individuals must be scrutinized in prospective trials.
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Heart-Type Fatty Acid Binding Protein, Cardiovascular Outcomes, and Death: Findings From the German CKD Cohort Study - Schneider, Markus; Schmid, Matthias; Nadal, Jennifer; Wanner, Christoph; Krane, Vera; Floege, Jürgen; Saritas, Turgay; Busch, Martin; Sitter, Thomas; Friedrich, Nele; Stockmann, Helena; Meiselbach, Heike; et al. (American Journal of Kidney Diseases, 2022)
Rationale & Objective: Heart-type fatty acid binding protein (H-FABP) is a biomarker that has been shown to provide long-term prognostic information in patients with coronary artery disease independently of high-sensitivity troponin T (hs-TNT). We examined the independent associations of H-FABP with cardiovascular outcomes in patients with chronic kidney disease (CKD). Study Design: Prospective cohort study. Setting & Participants: 4,951 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73 m2 or overt proteinuria (urinary albumin-creatinine ratio > 300 mg/g or equivalent). Exposure: Serum levels of H-FABP and hs-TNT were measured at study entry. Outcome: Noncardiovascular (non-CV) death, CV death, combined major adverse CV events (MACE), and hospitalization for congestive heart failure (CHF). Analytical Approach: Hazard ratios (HRs) for associations of H-FABP and hs-TNT with outcomes were estimated using Cox regression analyses adjusted for established risk factors. Results: During a maximum follow-up of 6.5 years, 579 non-CV deaths, 190 CV deaths, 522 MACE, and 381 CHF hospitalizations were observed. In Cox regression analyses adjusted for established risk factors, H-FABP was associated with all 4 outcomes, albeit with lower HRs than those found for hs-TNT. After further adjustment for hs-TNT levels, H-FABP was found to be associated with non-CV death (HR, 1.57 [95% CI, 1.14-2.18]) and MACE (HR, 1.40 [95% CI, 1.02-1.92]) but with neither CV death (HR, 1.64 [95% CI, 0.90-2.99]) nor CHF hospitalizations (HR, 1.02 [95% CI, 0.70-1.49]). Limitations: Single-point measurements of H-FABP and hs-TNT. Uncertain generalizability to non-European populations. Conclusions: In this large cohort of patients with CKD, H-FABP was associated with non-CV death and MACE, even after adjustment for hs-TNT. Whether measurement of H-FABP improves cardiovascular disease risk prediction in these patients warrants further studies.
CRIS-Team Scopus Importer:2022-05-20
Keywords: Biomarkers; cardiac death; cardiac diseases; cardiovascular disease (CVD); chronic kidney disease (CKD); heart failure; heart type fatty acid binding protein (H-FABP); high-sensitivity troponin T (hs-TNT); kidney diseases; prognosis; renal function

Hemodialysis Patients with Cardiovascular Disease Reveal Increased Tissue Na+ Deposition - Friedrich, Anna Carolina; Linz, Peter; Nagel, Armin Michael; Rosenhauer, Daniela; Horn, Stephan; Schiffer, Mario; Uder, Michael; Kopp, Christoph; Dahlmann, Anke (Kidney & Blood Pressure Research, 2022)
BACKGROUND: The relationship between Na+ balance and cardiovascular disease (CVD) in hemodialysis (HD) patients is not yet fully understood. We hypothesized that HD patients co-diagnosed with CVD show increased tissue Na+ accumulation compared to HD patients without CVD. METHODS: In our observational study, 52 HD patients were divided into a group with (23 subjects) or without (29 subjects) a positive history of cardiovascular events. We used 23Na-magnetic resonance imaging (23Na-MRI) at 3.0 Tesla to quantify Na+ content in skin and muscle of both groups directly before and after HD. Additionally, total body fluid distribution was determined by bioimpedance spectroscopy (BIS) and laboratory parameters were assessed. RESULTS: Compared to HD patients without CVD, 23Na-MRI detected an increased Na+ content in skin (21.7 ± 7.3 vs. 30.2 ± 9.8 arbitrary units (a.u.), p < 0.01) and muscle tissue (21.5 ± 3.6 vs. 24.7 ± 6.0 a.u., p < 0.05) in patients with previous CVD events. Simultaneously measured fluid amount by BIS, includingexcess extracellular water (1.8 ± 1.7 vs. 2.2 ± 1.7 L, p = 0.44), was not significantly different between both groups. Tissue Na+ accumulation in HD-CVD patients was paralleled by a higher plasma concentration of the inflammation marker interleukin-6 (5.1, IQR 5.8 vs. 8.5, IQR 7.9 pg/mL, p < 0.05). CONCLUSION: In our cohort, HD patients with CVD showed higher tissue Na+ content than HD patients without CVD, while no difference in body water distribution could be detected between both groups. Our findings provide evidence that the history of a cardiovascular event is associated with disturbances in tissue Na+ content in HD patients.
CRIS-Team Scopus Importer:2022-03-25
Keywords: 23Na-magnetic resonance imaging; Cardiovascular disease; Hemodialysis; Tissue Na+

Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease - Wagner, Martin; Ashby, Damien R.; Kurtz, Caroline; Alam, Ahsan; Busbridge, Mark; Raff, Ulrike; Zimmermann, Josef; Heuschmann, Peter U.; Wanner, Christoph; Schramm, Lothar (PLoS ONE, 2015)
Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25–the key hormone of iron-metabolism–on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels.249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003-2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models.Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05).We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define "high risk" populations in CKD.
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Hepcidin Response to Iron Therapy in Patients with Non-Dialysis Dependent CKD: An Analysis of the FIND-CKD Trial - Gaillard, Carlo A.; Bock, Andreas H.; Carrera, Fernando; Eckardt, Kai-Uwe; Van Wyck, David B.; Bansal, Sukhvinder S.; Cronin, Maureen; Meier, Yvonne; Larroque, Sylvain; Roger, Simon D.; Macdougall, Iain C. (PLoS ONE, 2016)
Hepcidin is the key regulator of iron homeostasis but data are limited regarding its temporal response to iron therapy, and response to intravenous versus oral iron. In the 56-week, open-label, multicenter, prospective, randomized FIND-CKD study, 626 anemic patients with non-dialysis dependent chronic kidney disease (ND-CKD) and iron deficiency not receiving an erythropoiesis stimulating agent were randomized (1:1:2) to intravenous ferric carboxymaltose (FCM), targeting higher (400-600?g/L) or lower (100-200?g/L) ferritin, or to oral iron. Serum hepcidin levels were measured centrally in a subset of 61 patients. Mean (SD) baseline hepcidin level was 4.0(3.5), 7.3(6.4) and 6.5(5.6) ng/mL in the high ferritin FCM (n = 17), low ferritin FCM (n = 16) and oral iron group (n = 28). The mean (SD) endpoint value (i.e. the last post-baseline value) was 26.0(9.1),15.7(7.7) and 16.3(11.0) ng/mL, respectively. The increase in hepcidin from baseline was significantly smaller with low ferritin FCM or oral iron vs high ferritin FCM at all time points up to week 52. Significant correlations were found between absolute hepcidin and ferritin values (r = 0.65, p<0.001) and between final post-baseline increases in both parameters (r = 0.70, p<0.001). The increase in hepcidin levels over the 12-month study generally mirrored the cumulative iron dose in each group. Hepcidin and transferrin saturation (TSAT) absolute values showed no correlation, although there was an association between final post-baseline increases (r = 0.42, p<0.001). Absolute values (r = 0.36, p = 0.004) and final post-baseline increases of hepcidin and hemoglobin (p = 0.30, p = 0.030) correlated weakly. Baseline hepcidin levels were not predictive of a hematopoietic response to iron therapy. In conclusion, hepcidin levels rose in response to either intravenous or oral iron therapy, but the speed and extent of the rise was greatest with intravenous iron targeting a higher ferritin level. However neither the baseline level nor the change in hepcidin was able to predict response to therapy in this cohort.
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HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting - Neubert, Patrick; Weichselbaum, Andrea; Reitinger, Carmen; Schatz, Valentin; Schröder, Agnes; Ferdinand, John R.; Simon, Michaela; Bär, Anna Lorena; Brochhausen, Christoph; Gerlach, Roman G.; Tomiuk, Stefan; Hammer, Karin; et al. (Autophagy, 2019)
Infection and inflammation are able to induce diet-independent Na + -accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na + -boosted host defense against the protozoan parasite Leishmania major is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na + (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against E. coli was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular E. coli to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na + -modulated cell autonomous innate immunity. Abbreviations: ACT: actins; AKT: AKT serine/threonine kinase 1; ATG2A: autophagy related 2A; ATG4C: autophagy related 4C, cysteine peptidase; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BMDM: bone marrow-derived macrophages; BNIP3: BCL2/adenovirus E1B interacting protein 3; CFU: colony forming units; CM-H 2 DCFDA: 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester; CTSB: cathepsin B; CYBB: cytochrome b-245 beta chain; DAPI: 4,6-diamidino-2-phenylindole; DMOG: dimethyloxallyl glycine; DPI: diphenyleneiodonium chloride; E. coli: Escherichia coli; FDR: false discovery rate; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GO: gene ontology; HIF1A: hypoxia inducible factor 1, alpha subunit; HUGO: human genome organization; HS: high salt (+ 40 mM of NaCl to standard cell culture conditions); HSP90: heat shock 90 kDa proteins; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Lyz2/LysM: lysozyme 2; NFAT5/TonEBP: nuclear factor of activated T cells 5; MΦ: macrophages; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MIC: minimum inhibitory concentration; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NaCl: sodium chloride; NES: normalized enrichment score; n.s.: not significant; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; NS: normal salt; PCR: polymerase chain reaction; PGK1: phosphoglycerate kinase 1; PHOX: phagocyte oxidase; RFP: red fluorescent protein; RNA: ribonucleic acid; ROS: reactive oxygen species; sCFP3A: super cyan fluorescent protein 3A; SBFI: sodium-binding benzofuran isophthalate; SLC2A1/GLUT1: solute carrier family 2 (facilitated glucose transporter), member 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H + -ATPase; WT: wild type.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Autophagy; cell-autonomous immunity; E. coli; macrophage; salt; sodium

HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease - Kraus, Andre; Peters, Dorien J. M.; Klanke, Bernd; Weidemann, Alexander; Willam, Carsten; Schley, Gunnar; Kunzelmann, Karl; Eckardt, Kai-Uwe; Buchholz, Björn (Kidney International, 2018)
Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations of the PKD1 gene and characterized by growth of bilateral renal cysts. Cyst growth is accompanied by regional hypoxia and induction of hypoxia-inducible factor (HIF)-1α in cyst-lining epithelial cells. To determine the relevance of HIF-1α for cyst growth in vivo we used an inducible kidney epithelium-specific knockout mouse to delete Pkd1 at postnatal day 20 or 35 to induce polycystic kidney disease of different severity and analyzed the effects of Hif-1α co-deletion and HIF-1α stabilization using a prolyl-hydroxylase inhibitor. HIF-1α expression was enhanced in kidneys with progressive cyst growth induced by early Pkd1 deletion, but unchanged in the milder phenotype induced by later Pkd1 deletion. Hif-1α co-deletion significantly attenuated cyst growth in the severe, but not in the mild, phenotype. Application of a prolyl-hydroxylase inhibitor resulted in severe aggravation of the mild phenotype with rapid loss of renal function. HIF-1α expression was associated with induction of genes that mediate calcium-activated chloride secretion. Thus, HIF-1α does not seem to play a role in early cyst formation, but accelerates cyst growth during progressive polycystic kidney disease. This novel mechanism of cyst growth may qualify as a therapeutic target.
EVALuna2:215684
Keywords: hypoxia; hypoxia-inducible factor-1 alpha; polycystic kidney disease; prolyl-hydroxylase inhibitors

HIF activation protects from acute kidney injury - Weidemann, Alexander; Bernhardt, Wanja M.; Klanke, Bernd; Daniel, Christoph; Buchholz, Björn; Campean, Valentina; Amann, Kerstin Ute; Warnecke, Christina; Wiesener, Michael S.; Eckardt, Kai-Uwe; Willam, Carsten (Journal of the American Society of Nephrology, 2008)
The contribution of hypoxia to cisplatin-induced renal tubular injury is controversial. Because the hypoxia-inducible factor (HIF) pathway is a master regulator of adaptation to hypoxia, we measured the effects of cisplatin on HIF accumulation in vitro and in vivo, and tested whether hypoxic preconditioning is protective against cisplatin-induced injury. We found that cisplatin did not stabilize HIF-1 alpha protein in vitro or in vivo under normoxic conditions. However, hypoxic preconditioning of cisplatin-treated proximal tubular cells in culture reduced apoptosis in an HIF-1 alpha-dependent fashion and increased cell proliferation as measured by BrdU incorporation. In vivo, rats preconditioned with carbon monoxide before cisplatin administration had significantly better renal function than rats kept in normoxic conditions throughout. Moreover, the histomorphological extent of renal damage and tubular apoptosis was reduced by the preconditional treatment. Therefore, development of pharmacologic agents to induce renal HIF might provide a new approach to ameliorate cisplatin-induced nephrotoxicity.

HIF is not essential for suppression of experimental tumor growth by mTOR inhibition - Knaup, Karl; Günther, Regina; Stoeckert, Johanna; Monti, Juliana M.; Eckardt, Kai-Uwe; Wiesener, Michael S. (Journal of Cancer, 2017)
The Hypoxia Inducible Transcription Factor (HIF) is the master regulator of cellular response to hypoxic adaptation. Solid tumors inevitably harbour hypoxic regions with subsequent stabilization and activation of HIF and HIF target genes due to poor vascularization and rapid growth. The mammalian target of rapamycin (mTOR) is a global regulator of cellular growth and proliferation, which can also regulate HIF expression independantly of hypoxia via specific activation of cellular translation and transcription. An effective blockade of mTOR results in attenuation of HIF under hypoxic conditions in vitro. This mechanism could enable a simultaneous inhibition of both the mTOR- and the HIF-pathway, resulting in an effective tool for cancer targeting. We set out to analyze the effect of mTOR inhibition and the involvement of mTOR regulation on HIF in vivo in a subcutaneous xenograft model in nude mice. Our results demonstrate that mTOR inhibition in our model leads to a clear reduction in tumor growth of various cellular origins, most likely due to inhibition of cellular proliferation. Moreover, these effects can also be achieved independently of the HIF status of the tumor cells. The HIF levels per se seem to remain unaffected by mTOR inhibition, probably due to the profound hypoxic environment in these threedimensional structures, consequently leading to a strong HIF stabillization. Therefore, treatment of these experimental tumors with mTOR inhibitors is an effective tool to achieve size regression. The involvement of and the effect on HIF in this in vivo setting is nevertheless negligible.
EVALuna2:3992

HIF meets NF-?B signaling - Willam, Carsten (Kidney International, 2014)
An inflammatory stimulus prior to an ischemic insult can be protective in acute kidney injury (AKI) as well as other acute organ injury models, an effect called cross-tolerance. He et al. investigated mechanisms of cross-tolerance whereby pretreatment with lipopolysaccharide (LPS) protects from a subsequent ischemic insult of the kidney. The protection was mediated by LPS-induced nuclear factor-?B and hypoxia-inducible factor-2? (HIF-2?) signaling. These results link two central cellular pathways and give new insight into HIF-mediated renoprotection in AKI models.
EVALuna2:3689

HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond - Maxwell, Patrick H.; Eckardt, Kai-Uwe (Nature Reviews Nephrology, 2016)
Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler - and potentially cheaper - production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial - for instance by reducing the need for parenteral iron - but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury.
EVALuna2:3824

High cardiovascular event rates occur within the first weeks of starting hemodialysis - Eckardt, Kai-Uwe; Gillespie, Iain A.; Kronenberg, Florian; Richards, Sharon; Stenvinkel, Peter; Anker, Stefan D.; Wheeler, David C.; De Francisco, Angel L.; Marcelli, Daniele; Froissart, Marc; Floege, Juergen (Kidney International, 2015)
Early mortality is high in hemodialysis (HD) patients, but little is known about early cardiovascular event (CVE) rates after HD initiation. To study this we analyzed data in the AROii cohort of incident HD patients from over 300 European Fresenius Medical Care dialysis centers. Weekly rates of a composite of CVEs during the first year and monthly rates of the composite and its constituents (coronary artery, cerebrovascular, peripheral arterial, congestive heart failure, and sudden cardiac death) during the first 2 years after HD initiation were assessed. Of 6308 patients that started dialysis within 7 days, 1449 patients experienced 2405 CVEs over the next 2 years. The first-year CVE rate (30.2/100 person-years; 95% CI, 28.7-31.7) greatly exceeded the second-year rate (19.4/100; 95% CI, 18.1-20.8). Composite CVEs were highest during the first week with increased risk compared with the second year, persisting until the fifth month. Except for sudden cardiac death, temporal patterns of rates for all CVE categories were very similar, with highest rates during the first month and a high-risk period extending to 4 months. Higher or lower cumulative weekly dialysis dose, lower blood flow, and lower net ultrafiltration during dialysis were associated with CVE during the high-risk period, but not during the post high-risk period. Thus, the incidence of CVE in the first weeks after HD initiation is much higher than during subsequent periods which raises concerns that HD initiation may trigger CVEs.
EVALuna2:3778

High cholesterol absorption is associated with increased cardiovascular risk in haemodialysis patients: insights from the AURORA study - Silbernagel, Gunther; Duarte, Kevin; Sadiku, Samir; Fauler, Gunter; Maerz, Winfried; Schmieder, Roland; Jardine, Alan G.; Massy, Ziad A.; Girerd, Nicolas; Fellstrom, Bengt; Rossignol, Patrick; Scharnagl, Hubert; et al. (European Journal of Preventive Cardiology, 2022)
Aims Statin treatment did not reduce the risk of cardiovascular events in haemodialysis patients in the 4D and AURORA trials. Post hoc analyses in the 4D study suggested that high cholesterol absorption was associated with increased cardiovascular risk and that atorvastatin would reduce cardiovascular risk in haemodialysis patients with low cholesterol absorption but not in those with high cholesterol absorption. Methods and results AURORA is a randomized, double-blind, placebo-controlled, multi-centre trial in haemodialysis patients. The participants were randomly assigned to receive either rosuvastatin, 10 mg daily, or a matching placebo. There was a follow-up for cardiovascular death with a median duration of 3.9 years. The cholestanol and lathosterol to cholesterol ratios were used to estimate cholesterol absorption and synthesis, respectively. Measurement of non-cholesterol sterols was available in 2332 participants of the 2733 patients included in the primary analysis of the AURORA study. A total of 598 participants died from cardiovascular diseases. The 3rd vs. the 1st tertile of the cholestanol-to-cholesterol ratio was significantly associated with increased risk of cardiovascular death [hazard ratio, HR (95% confidence interval, CI) = 1.36 (1.11-1.65)] in univariate (P = 0.002) and multivariate models (P = 0.034). In contrast, the 3rd vs. the 1st tertile of the lathosterol-to-cholesterol ratio was significantly associated with decreased risk of cardiovascular death [HR (95% CI) = 0.81 (0.67-0.99)] in univariate (P = 0.041) and multivariate (P = 0.019) models. There was no significant interaction between the cholestanol and lathosterol to cholesterol tertiles and treatment group in predicting cardiovascular death. Conclusion The present data from the AURORA study confirm that high cholesterol absorption is associated with increased cardiovascular risk in haemodialysis patients. Assessment of the individual cholesterol absorption rate to guide initiation of statin treatment is not supported by the findings in the AURORA study.
CRIS-Team WoS Importer:2022-05-20

HIGH CHOLESTEROL ABSORPTION IS ASSOCIATED WITH INCREASED CARDIOVASCULAR RISK IN HEMODIALYSIS PATIENTS: INSIGHTS FROM THE AURORA STUDY - Silbernagel, G.; Duarte, K.; Sadiku, S.; Fauler, G.; Maerz, W.; Schmieder, Roland; Jardine, A. G.; Massy, Z. A.; Girerd, N.; Fellstrom, B.; Scharnagl, H.; Zannad, F. (ATHEROSCLEROSIS, 2022)
CRIS-Team WoS Importer:2022-10-14

HIGHLY FREQUENT VARIANTS HIDDEN IN THE KIV-2 REGION OF LPA REGULATE LIPOPROTEIN(A) CONCENTRATIONS AND LOWER CORONARY ARTERY DISEASE RISK - Schachtl-Riess, J. F.; Kheirkhah, A.; Gruneis, R.; Di Maio, S.; Schoenherr, S.; Streiter, G.; Losso, J. L.; Paulweber, B.; Eckardt, Kai-Uwe; Kottgen, A.; Lamina, C.; Kronenberg, F.; et al. (ATHEROSCLEROSIS, 2021)
CRIS-Team WoS Importer:2021-09-24

High oxalate concentrations correlate with increased risk for sudden cardiac death in dialysis patients - Pfau, Anja; Ermer, Theresa; Coca, Steven G.; Tio, Maria Clarissa; Genser, Bernd; Reichel, Martin; Finkelstein, Fredric O.; März, Winfried; Wanner, Christoph; Waikar, Sushrut S.; Eckardt, Kai-Uwe; Aronson, Peter S.; et al. (Journal of the American Society of Nephrology, 2021)
Background The clinical significance of accumulating toxic terminal metabolites such as oxalate in patients with kidney failure is not well understood. Methods To evaluate serum oxalate concentrations and risk of all-cause mortality and cardiovascular events in a cohort of patients with kidney failure requiring chronic dialysis, we performed a post-hoc analysis of the randomized German Diabetes Dialysis (4D) Study; this study included 1255 European patients on hemodialysis with diabetes followed-up for a median of 4 years. The results obtained via Cox proportional hazards models were confirmed by competing risk regression and restricted cubic spline modeling in the 4D Study cohort and validated in a separate cohort of 104 US patients on dialysis after a median follow-up of 2.5 years. Results A total of 1108 patients had baseline oxalate measurements,with a median oxalate concentration of 42.4 μM.During follow-up, 548patients died, including139 (25.4%) fromsudden cardiac death.Atotal of 413 patients reached the primary composite cardiovascular end point (cardiac death, nonfatalmyocardial infarction, and fatal or nonfatal stroke). Patients in the highest oxalate quartile (≥59.7 μM) had a 40%increased risk for cardiovascular events (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [95% CI], 1.08 to 1.81) and a 62% increased risk of sudden cardiac death (aHR, 1.62; 95% CI, 1.03 to 2.56), compared with those in the lowest quartile ( ≤ 29.6 mM). The associations remained when accounting for competing risks and with oxalate as a continuous variable. Conclusions Elevated serumoxalate is a novel risk factor for cardiovascular events and sudden cardiac death inpatients ondialysis. Further studies arewarranted to testwhether oxalate-lowering strategies improve cardiovascular mortality in patients on dialysis.
CRIS-Team Scopus Importer:2021-09-17

High-Salt Diet Causes Osmotic Gradients and Hyperosmolality in Skin Without Affecting Interstitial Fluid and Lymph - Nikpey, Elham; Karlsen, Tine V.; Rakova, Natalia; Titze, Jens; Tenstad, Olav; Wiig, Helge (Hypertension, 2017)
The common notion is that the body Na+ is maintained within narrow limits for fluid and blood pressure homeostasis. Several studies have, however, shown that considerable amounts of Na+ can be retained or removed from the body without commensurate water loss and that the skin can serve as a major salt reservoir. Our own data from rats have suggested that the skin is hypertonic compared with plasma on salt storage and that this also applies to skin interstitial fluid. Even small electrolyte gradients between plasma and interstitial fluid would represent strong edema-generating forces. Because the water accumulation has been shown to be modest, we decided to reexamine with alternative methods in rats whether interstitial fluid is hypertonic during salt accumulation induced by high-salt diet (8% NaCl and 1% saline to drink) or deoxycorticosterone pellet implantation. These treatments resulted both in increased systemic blood pressure, skin salt, and water accumulation and in skin hyperosmolality. Interstitial fluid isolated from implanted wicks and lymph draining the skin was, however, isosmotic, and Na+ concentration in fluid isolated by centrifugation and in lymph was not different from plasma. Interestingly, by eluting layers of the skin, we could show that there was an osmolality and urea gradient from epidermis to dermis. Collectively, our data suggest that fluid leaving the skin as lymph is isosmotic to plasma but also that the skin can differentially control its own electrolyte microenvironment by creating local gradients that may be functionally important.
EVALuna2:35439

High salt reduces the activation of IL-4- and IL-13-stimulated macrophages - Binger, Katrina J.; Gebhardt, Matthias; Heinig, Matthias; Rintisch, Carola; Schröder, Agnes; Neuhofer, Wolfgang; Hilgers, Karl Friedrich; Manzel, Arndt; Schwartz, Christian; Kleinewietfeld, Markus; Voelkl, Jakob; Schatz, Valentin; et al. (Journal of Clinical Investigation, 2015)
A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.
EVALuna2:3819

High Sodium Diet - Role in Renal Sympathodepression - Rodionova, Kristina; Ditting, Tilmann; Fahrmeier, Franziska; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland (FASEB JOURNAL, 2020)
CRIS-Team WoS Importer:2020-10-16

How can you be adherent if you don't know how? - Bertram, Anna; Pabst, Selma; Zimmermann, Tanja; Schiffer, Mario; De Zwaan, Martina (Transplant International, 2016)
EVALuna2:34556

How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? - Bosch, A.; Ott, Christian; Jung, Susan; Striepe, Kristina; Karg, M. V.; Kannenkeril, D.; Dienemann, T.; Schmieder, Roland (EUROPEAN HEART JOURNAL, 2018)
CRIS-Team WoS Importer:2019-03-15

How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial - Bosch, Agnes; Ott, Christian; Jung, Susan; Striepe, Kristina; Karg, Marina V.; Kannenkeril, Dennis; Dienemann, Thomas; Schmieder, Roland (Cardiovascular Diabetology, 2019)
BackgroundEmpagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness.MethodsOur analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial (http://www.ClinicalTrials.gov: NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System (AtCor Medical). Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis.ResultsAs previously reported, therapy with empagliflozin improved arterial stiffness as indicated by reduced central systolic blood pressure (113.612.1 vs 118.612.9mmHg, p<0.001), central pulse pressure (39.1 +/- 10.2 vs 41.9 +/- 10.7mmHg, p=0.027) forward (27.1 +/- 5.69 vs 28.7 +/- 6.23mmHg, p=0.031) as well as reflected wave amplitude (18.9 +/- 5.98 vs 20.3 +/- 5.97mmHg, p=0.045) compared to placebo. The multivariate regression analysis included age, sex and change between empagliflozin and placebo therapy of the following parameters: HbA1c, copeptin, hematocrit, heart rate, LDL-cholesterol, uric acid, systolic 24-h ambulatory blood pressure and high sensitive CRP (hsCRP). Besides the influence of age (beta=-0.259, p=0.054), sex (beta=0.292, p=0.040) and change in systolic 24-h ambulatory blood pressure (beta=0.364, p=0.019), the change of hsCRP (beta=0.305, p=0.033) emerged as a significant determinant of the empagliflozin induced reduction in arterial stiffness (placebo corrected). When replacing HbA1c with fasting plasma glucose in the multivariate regression analysis, a similar effect of the change in hsCRP (beta=0.347, p=0.017) on arterial stiffness parameters was found.Conclusion Besides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism and volume status had no significant influence. Our analysis suggests that empagliflozin exerts, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms.
CRIS-Team WoS Importer:2019-04-18

How long should aHUS be treated? Wie lange sollte aHUS behandelt werden? - Wiesener, Michael (Nephrologe, 2021)
CRIS-Team Scopus Importer:2021-08-20

How to measure retinal microperfusion in patients with arterial hypertension - Szulc, Urszula; Dąbrowska, Edyta; Pieczyński, Janusz; Białkowski, Paweł; Narkiewicz, Krzysztof; Schmieder, Roland; Harazny, Joanna (Blood Pressure, 2020)
Purpose: Assessment and monitoring of changes in microcirculatory perfusion, perfusion dynamic, vessel structure and oxygenation is crucial in management of arterial hypertension. Constant search for non-invasive methods has led the clinical focus towards the vasculature of the retina, which offers a large opportunity to detect the early phase of the functional and structural changes in the arterial hypertension and can reflect changes in brain vasculature. We review all the available methods of retinal microcirculation measurements including angiography, oximetry, retinal vasculature assessment software, Optical Coherence Tomography Angiography, Adaptive Optics and Scanning Laser Doppler Flowmetry and their application in clinical research. Materials and methods: To further analyse the applicability of described methods in hypertension research we performed a systematic search of the PubMed electronic database (April 2020). In our analysis, we included 111 articles in which at least one of described methods was used for assessment of microcirculation of the retina in hypertensive individuals. Results: Up to this point, the methods most commonly published in studies of retinal microcirculation in arterial hypertension were Scanning Laser Doppler Flowmetry followed shortly by Optical Coherence Tomography Angiography and retinal vasculature assessment software. Conclusions: While none of described methods enables the simultaneous measurement of all microcirculatory parameters, certain techniques are widely used in arterial hypertension research, while others gain popularity in screening.
CRIS-Team Scopus Importer:2020-10-02
Keywords: Arterial hypertension; microperfusion; retinal microvasculature

How to Retard Progression of Chronic Kidney Disease - Schneider, Markus; Hilgers, Karl Friedrich (Deutsche Medizinische Wochenschrift, 2017)
End stage chronic kidney disease (CKD) requiring renal replacement therapy is related to poor quality of life and high mortality. Thus, slowing the progression of CKD is an important purpose of therapy. Some general therapeutic approaches aim to slow the decline of renal function and they can be applied in all patients with CKD - irrespective of the underlying cause of CKD. A key intervention is lowering blood pressure (target: <= 140/90 mmHg, and in patients with albuminuria <= 130/80 mmHg). Inhibitors of the renin angiotensin system preferentially should be used in case of albuminuria, depending on the diabetic status and the level of albuminuria: in diabetics with albuminuria >= 30 mg/d, in non-diabetics with albuminuria > 300 mg/d. Mineralocorticoid receptor blockers and endothelin receptors blockers promise novel anti-proteinuric strategies - but still validation of their positive effects on retarding CKD progression is necessary. In patients with diabetic kidney disease, glycemic control aiming for an HbA1c of ? 7.0 % has been established to slow CKD progression. Furthermore, SGLT-2 inhibition with empagliflozin may be considered as a new therapeutic approach that provides additional cardiovascular and renal protection. Finally, recent studies suggest: correction of metabolic acidosis and avoidance of episodes of acute renal failure may provide protection against the progression of CKD.
EVALuna2:4025

Hypercalcemia mimicking myocardial infarction - Schmidt-Lauber, Christian; Anneken, Lars; Schödel, Johannes (Kidney International, 2019)
CRIS-Team Scopus Importer:2019-11-19

Hypertension and kidney disease Bluthochdruck und Nierenerkrankungen - Striepe, Kristina; Schmieder, Roland (Tägliche Praxis, 2020)
The association between kidney disease and hypertension is bidirectional and complex. The kidney could be actor and victim of arterial hypertension. Autoregulatory processes protect the kidney in subjects with mild to moderate arterial hypertension. Above a certain threshold autoregulatory processes fail and glomerular pressure increases, resulting in kidney damage. In contrast, renal disease could cause arterial hypertension via diverse mechanisms, for example increased activity of the sympathetic system, impaired vascular/endothelial function, extracellular sodium overload, extracellular volume overload, increased activity of the renin angiotensin system and vascular stiffening of large arteries. Since arterial hypertension is the most predominant factor for progression of chronic kidney failure, in subjects with arterial hypertension and kidney disease an office blood pressure value of 130-140/70-80 mmHg is advocated. In cases of overt proteinuria the recommended value is lower (systolic 120-130 mmHg). A blood pressure lower than 120/70 mmHg should be avoided because of an increasing cardiovascular mortality. Subjects with comorbid kidney disease and hypertension should be treated with a renin-angiotensin system inhibitor (RAS-inhibitor), this is recommended worldwide in several guidelines. The RAS-inhibitor should be combined with a diuretic or calcium antagonist or both. For patients with still uncontrolled hypertension, there is the option to get an interventional treatment, in particular renal denervation.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Blood pressure; Blood pressure targets; Kidney disease; Renal denervation; Renin-angiotensin system

Hypertension: How should data from SYMPLICITY HTN-3 be interpreted? - Schmieder, Roland (Nature Reviews Cardiology, 2014)
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Hypertension urgencies in the SPYRAL HTN-OFF MED Pivotal trial - Weber, Michael A.; Schmieder, Roland; Kandzari, David E.; Townsend, Raymond R.; Mahfoud, Felix; Tsioufis, Konstantinos; Kario, Kazuomi; Pocock, Stuart; Tatakis, Fotis; Ewen, Sebastian; Choi, James W.; East, Cara; et al. (Clinical Research in Cardiology, 2022)
The SPYRAL HTN-OFF MED Pivotal trial (https://clinicaltrials.gov/ct2/show/NCT02439749) demonstrated significant reductions in blood pressure (BP) after renal denervation (RDN) compared to sham control in the absence of anti-hypertensive medications. Prior to the 3-month primary endpoint, medications were immediately reinstated for patients who met escape criteria defined as office systolic BP (SBP) >= 180 mmHg or other safety concerns. Our objective was to compare the rate of hypertensive urgencies in RDN vs. sham control patients. Patients were enrolled with office SBP >= 150 and < 180 mmHg, office diastolic BP (DBP) >= 90 mmHg and mean 24 h SBP >= 140 and < 170 mmHg. Patients had been required to discontinue any anti-hypertensive medications and were randomized 1:1 to RDN or sham control. In this post-hoc analysis, cumulative incidence curves with Kaplan-Meier estimates of rate of patients meeting escape criteria were generated for RDN and sham control patients. There were 16 RDN (9.6%) and 28 sham control patients (17.0%) who met escape criteria between baseline and 3 months. There was a significantly higher rate of sham control patients meeting escape criteria compared to RDN for all escape patients (p = 0.032), as well as for patients with a hypertensive urgency with office SBP >= 180 mmHg (p = 0.046). Rate of escape was similar between RDN and sham control for patients without a measured BP exceeding 180 mmHg (p = 0.32). In the SPYRAL HTN-OFF MED Pivotal trial, RDN patients were less likely to experience hypertensive urgencies that required immediate use of anti-hypertensive medications compared to sham control.
CRIS-Team WoS Importer:2022-07-29

Hypertrophic remodelling of retinal arterioles in patients with congestive heart failure - Jung, Susanne; Kolwelter, Julie; Bosch, Agnes; Cífková, Renata; Harazny, Joanna M.; Ott, Christian; Achenbach, Stephan; Schmieder, Roland (ESC Heart Failure, 2021)
Aims: Analysis of microvascular parameters in the retinal circulation—known to reflect those in the systemic circulation—allows us to differentiate between eutrophic and hypertrophic remodelling of small arteries. This study aimed to examine microvascular changes in patients with congestive heart failure (CHF) and reduced as well as mid-range ejection fraction. Methods and results: Forty subjects with CHF underwent measurement of retinal capillary flow (RCF), wall-to-lumen ratio (WLR), vessel and lumen diameter, wall thickness, and wall cross-sectional area (WCSA) of retinal arterioles of the right eye by scanning laser Doppler flowmetry (SLDF). Applying a matched pair approach, we compared this group with reference values of age-matched controls from a random sample in the population of Pilsen, Czech Republic. There was no significant difference in RCF and WLR between the groups (RCF: P = 0.513; WLR: P = 0.106). In contrast, wall thickness and WCSA, indicators of hypertrophic remodelling, were higher in CHF subjects (WT: 15.0 ± 4.2 vs. 12.7 ± 4.2 μm, P = 0.021; WCSA: 4437.6 ± 1314.5 vs. 3615.9 ± 1567.8 μm2, P = 0.014). Similarly, vessel (109.4 ± 11.1 vs. 100.5 ± 14.4 μm, P = 0.002) and lumen diameter (79.0 ± 7.9 vs. 75.2 ± 8.5 μm, P = 0.009) were increased in CHF. Conclusions: In CHF subjects, we observed hypertrophic remodelling of retinal arterioles indicative of similar changes of small resistance arteries in the systemic circulation. Microvascular structure and function assessed by SLDF may thereby represent a useful, non-invasive method for monitoring of microvascular damage in patients with CHF and may offer innovative treatment targets for new CHF therapies.
CRIS-Team Scopus Importer:2021-04-09
Keywords: Heart failure; Hypertrophic remodelling; Microvasculature; Retina

Hypoxia and hypoxia-inducible factors in myeloid cell-driven host defense and tissue homeostasis - Jantsch, Jonathan; Schoedel, Johannes (Immunobiology, 2015)
The impact of tissue oxygenation and hypoxia on immune cells has been recognized as a major determinant of host defense and tissue homeostasis. In this review, we will summarize the available data on tissue oxygenation in inflamed and infected tissue and the effect of low tissue oxygenation on myeloid cell function. Furthermore, we will highlight effects of the master regulators of the cellular hypoxic response, hypoxia-inducible transcription factors (HIF), in myeloid cells in antimicrobial defense and tissue homeostasis.
EVALuna2:3744

Hypoxia controls expression of kidney-pathogenic MUC1 variants - Naas, Stephanie; Krüger, René; Knaup, Karl; Naas, Julia; Grampp, Steffen; Schiffer, Mario; Wiesener, Michael; Schödel, Johannes (Life Science Alliance, 2023)
The interplay between genetic and environmental factors influences the course of chronic kidney disease (CKD). In this context, genetic alterations in the kidney disease gene MUC1 (Mucin1) predispose to the development of CKD. These variations comprise the polymorphism rs4072037, which alters splicing of MUC1 mRNA, the length of a region with variable number of tandem repeats (VNTR), and rare autosomal-dominant inherited dominant-negative mutations in or 59 to the VNTR that causes autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1). As hypoxia plays a pivotal role in states of acute and chronic kidney injury, we explored the effects of hypoxia-inducible transcription factors (HIF) on the expression of MUC1 and its pathogenic variants in isolated primary human renal tubular cells. We defined a HIF-binding DNA regulatory element in the promoter-proximal region of MUC1 from which hypoxia or treatment with HIF stabilizers, which were recently approved for an anti-anemic therapy in CKD patients, increased levels of wild-type MUC1 and the disease-associated variants. Thus, application of these compounds might exert unfavorable effects in patients carrying MUC1 risk variants.
CRIS-Team Scopus Importer:2023-08-11

Hypoxia drives glucose transporter 3 expression through hypoxia-inducible transcription factor (HIF)-mediated induction of the long noncoding RNA NICI - Lauer, Victoria; Grampp, Steffen; Platt, James; Lafleur, Veronique; Lombardi, Olivia; Choudhry, Hani; Kranz, Franziska; Hartmann, Arndt; Wullich, Bernd; Yamamoto, Atsushi; Coleman, Mathew L.; Ratcliffe, Peter J.; et al. (Journal of Biological Chemistry, 2020)
Hypoxia-inducible transcription factors (HIFs) directly dictate the expression of multiple RNA species including novel and as yet uncharacterized long noncoding transcripts with unknown function. We used pan-genomic HIF-binding and transcriptomic data to identify a novel long noncoding RNA Noncoding Intergenic Co-Induced transcript (NICI) on chromosome 12p13.31 which is regulated by hypoxia via HIF-1 promoter-binding in multiple cell types. CRISPR/Cas9-mediated deletion of the hypoxia-response element revealed co-regulation of NICI and the neighboring protein-coding gene, solute carrier family 2 member 3 (SLC2A3) which encodes the high-affinity glucose transporter 3 (GLUT3). Knockdown or knockout of NICI attenuated hypoxic induction of SLC2A3, indicating a direct regulatory role of NICI in SLC2A3 expression, which was further evidenced by CRISPR/Cas9-VPR-mediated activation of NICI expression. We also demonstrate that regulation of SLC2A3 is mediated through transcriptional activation rather than posttranscriptional mechanisms because knockout of NICI leads to reduced recruitment of RNA polymerase 2 to the SLC2A3 promoter. Consistent with this we observe NICI-dependent regulation of glucose consumption and cell proliferation. Furthermore, NICI expression is regulated by the von Hippel-Lindau (VHL) tumor suppressor and is highly expressed in clear cell renal cell carcinoma (ccRCC), where SLC2A3 expression is associated with patient prognosis, implying an important role for the HIF/NICI/SLC2A3 axis in this malignancy.
CRIS-Team Scopus Importer:2020-04-07
Keywords: ChIP; ChIP-sequencing (ChIP-Seq); glucose transport; GLUT3; hypoxia; hypoxia-inducible factor (HIF); long noncoding RNA (long ncRNA; lncRNA)

Hypoxia hits APOL1 in the kidney - Grampp, Steffen; Krüger, René; Lauer, Victoria; Uebel, Sebastian; Knaup, Karl; Naas, Julia; Höffken, Verena; Weide, Thomas; Schiffer, Mario; Naas, Stephanie; Schödel, Johannes (Kidney International, 2023)
Individuals of African ancestry carrying two pathogenic variants of apolipoprotein 1 (APOL1) have a substantially increased risk for developing chronic kidney disease. The course of APOL1 nephropathy is extremely heterogeneous and shaped by systemic factors such as a response to interferon. However, additional environmental factors operating in this second-hit model have been less well defined. Here, we reveal that stabilization of hypoxia-inducible transcription factors (HIF) by hypoxia or HIF prolyl hydroxylase inhibitors activates transcription of APOL1 in podocytes and tubular cells. An active regulatory DNA-element upstream of APOL1 that interacted with HIF was identified. This enhancer was accessible preferentially in kidney cells. Importantly, upregulation of APOL1 by HIF was additive to the effects of interferon. Furthermore, HIF stimulated expression of APOL1 in tubular cells derived from the urine of an individual carrying a risk variant for kidney disease. Thus, hypoxic insults may serve as important modulators of APOL1 nephropathy.
CRIS-Team Scopus Importer:2023-05-26
Keywords: chronic kidney disease; hypoxia; podocyte; transcription regulation

Hypoxia induces polycystin-1 expression in the renal epithelium - Grampp, Steffen; Kraus, Andre; Skoczynski, Kathrin; Schiffer, Mario; Krüger, René; Naas, Stephanie; Schödel, Johannes; Buchholz, Björn (Royal Society Open Science, 2023)
Mutations in polycystin-1 which is encoded by the PKD1 gene are the main causes for the development of autosomal dominant polycystic kidney disease. However, only little is known about the physiological function of polycystin-1 and even less about the regulation of its expression. Here, we show that expression of PKD1 is induced by hypoxia and compounds that stabilize the hypoxia-inducible transcription factor (HIF) 1α in primary human tubular epithelial cells. Knockdown of HIF subunits confirms HIF-1α-dependent regulation of polycystin-1 expression. Furthermore, HIF ChIP-seq reveals that HIF interacts with a regulatory DNA element within the PKD1 gene in renal tubule-derived cells. HIF-dependent expression of polycystin-1 can also be demonstrated in vivo in kidneys of mice treated with substances that stabilize HIF. Polycystin-1 and HIF-1α have been shown to promote epithelial branching during kidney development. In line with these findings, we show that expression of polycystin-1 within mouse embryonic ureteric bud branches is regulated by HIF. Our finding links expression of one of the main regulators of accurate renal development with the hypoxia signalling pathway and provides additional insight into the pathophysiology of polycystic kidney disease.
CRIS-Team Scopus Importer:2023-06-30
Keywords: hypoxia; hypoxia-inducible factor; kidney development; PKD1; polycystic kidney disease; transcription regulation

Hypoxia-inducible factor-1α causes renal cyst expansion through calcium-activated chloride secretion - Willam, Carsten; Eckhardt, Kai-Uwe; Buchholz, Björn; Schley, Gunnar; Faria, Diana; Kroening, Sven; Willam, Carsten; Schreiber, Rainer; Klanke, Bernd; Burzlaff, Nicolai; Jantsch, Jonathan; Kunzelmann, Karl; et al. (Journal of the American Society of Nephrology, 2014)
Polycystic kidney diseases are characterized by numerous bilateral renal cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in kidney function over time. We previously showed that cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1α (HIF-1α) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1α-target gene, glucose transporter 1, and report that HIF-1α promotes renal cyst growth in two in vitro cyst models - principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse kidneys stimulated with forskolin. In both models, augmenting HIF-1α levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate enhanced cyst growth. In addition, inhibition of HIF-1α degradation through tubule-specific knockdown of the von Hippel-Lindau tumor suppressor increased cyst size in the embryonic kidney cyst model. In contrast, inhibition of HIF-1α by chetomin and knockdown of HIF-1α both decreased cyst growth in these models. Consistent with previous reports, plMDCK cyst enlargement was driven largely by transepithelial chloride secretion, which consists, in part, of a calcium-activated chloride conductance. plMDCKs deficient for HIF-1α almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal cysts contributes to cyst growth, primarily due to HIF-1α-dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of cyst growth. Copyright © 2014 by the American Society of Nephrology.

Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease - Meng, Xianyi; Groetsch, Bettina; Luo, Yubin; Knaup, Karl; Wiesener, Michael Sean; Chen, Xiao-Xiang; Jantsch, Jonathan; Fillatreau, Simon; Schett, Georg; Bozec, Aline (Nature Communications, 2018)
Hypoxia-inducible factors (HIFs) are key elements for controlling immune cell metabolism and functions. While HIFs are known to be involved in T cells and macrophages activation, their functions in B lymphocytes are poorly defined. Here, we show that hypoxia-inducible factor-1? (HIF-1?) contributes to IL-10 production by B cells. HIF-1? regulates IL-10 expression, and HIF-1?-dependent glycolysis facilitates CD1dhiCD5+ B cells expansion. Mice with B cell-specific deletion of Hif1a have reduced number of IL-10-producing B cells, which result in exacerbated collagen-induced arthritis and experimental autoimmune encephalomyelitis. Wild-type CD1dhiCD5+ B cells, but not Hif1a-deficient CD1dhiCD5+ B cells, protect recipient mice from autoimmune disease, while the protective function of Hif1a-deficient CD1dhiCD5+ B cells is restored when their defective IL-10 expression is genetically corrected. Taken together, this study demonstrates the key function of the hypoxia-associated transcription factor HIF-1? in driving IL-10 expression in CD1dhiCD5+ B cells, and in controlling their protective activity in autoimmune disease.
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Hypoxia inducible factor stabilization improves defective ischemia-induced angiogenesis in a rodent model of chronic kidney disease - Schellinger, Isabel Nahal; Cordasic, Nada; Panesar, Julian; Buchholz, Björn; Jacobi, Johannes; Hartner, Andrea; Klanke, Bernd; Jakubiczka-Smorag, Joanna; Burzlaff, Nicolai; Heinze, Eva; Warnecke, Christina; Raaz, Uwe; et al. (Kidney International, 2017)
Chronic kidney disease (CKD) is associated with increased risk and worse prognosis of cardiovascular disease, including peripheral artery disease. An impaired angiogenic response to ischemia may contribute to poor outcomes of peripheral artery disease in patients with CKD. Hypoxia inducible factors (HIF) are master regulators of angiogenesis and therefore represent a promising target for therapeutic intervention. To test this we induced hind-limb ischemia in rats with CKD caused by 5/6 nephrectomy and administered two different treatments known to stabilize HIF protein in vivo: carbon monoxide and a pharmacological inhibitor of prolyl hydroxylation 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate (ICA). Expression levels of pro-angiogenic HIF target genes (Vegf, Vegf-r1, Vegf-r2, Ho-1) were measured by qRT-PCR. Capillary density was measured by CD31 immunofluorescence staining and HIF expression was evaluated by immunohistochemistry. Capillary density in ischemic skeletal muscle was significantly lower in CKD animals compared to sham controls. Rats with CKD showed significantly lower expression of HIF and all measured pro-angiogenic HIF target genes, including VEGF. Both HIF stabilizing treatments rescued HIF target gene expression in animals with CKD and led to significantly higher ischemia-induced capillary sprouting compared to untreated controls. ICA was effective regardless of whether it was administered before or after induction of ischemia and led to a HIF expression in skeletal muscle. Thus, impaired ischemia-induced angiogenesis in rats with CKD can be improved by HIF stabilization, even if started after onset of ischemia.
EVALuna2:3925
Keywords: cardiovascular disease; chronic kidney disease; hypoxia

Hypoxia-inducible lipid droplet-associated induces DGAT1 and promotes lipid storage in hepatocytes - de la Rosa Rodriguez, Montserrat A.; Deng, Lei; Gemmink, Anne; van Weeghel, Michel; Aoun, Marie Louise; Warnecke, Christina; Singh, Rajat; Borst, Jan Willem; Kersten, Sander (Molecular Metabolism, 2021)
Objective: Storage of triglycerides in lipid droplets is governed by a set of lipid droplet-associated proteins. One of these lipid droplet-associated proteins, hypoxia-inducible lipid droplet-associated (HILPDA), was found to impair lipid droplet breakdown in macrophages and cancer cells by inhibiting adipose triglyceride lipase. Here, we aimed to better characterize the role and mechanism of action of HILPDA in hepatocytes. Methods: We performed studies in HILPDA-deficient and HILPDA-overexpressing liver cells, liver slices, and mice. The functional role and physical interactions of HILPDA were investigated using a variety of biochemical and microscopic techniques, including real-time fluorescence live-cell imaging and Förster resonance energy transfer-fluorescence lifetime imaging microscopy (FRET-FLIM). Results: Levels of HILPDA were markedly induced by fatty acids in several hepatoma cell lines. Hepatocyte-specific deficiency of HILPDA in mice modestly but significantly reduced hepatic triglycerides in mice with non-alcoholic steatohepatitis. Similarly, deficiency of HILPDA in mouse liver slices and primary hepatocytes reduced lipid storage and accumulation of fluorescently-labeled fatty acids in lipid droplets, respectively, which was independent of adipose triglyceride lipase. Fluorescence microscopy showed that HILPDA partly colocalizes with lipid droplets and with the endoplasmic reticulum, is especially abundant in perinuclear areas, and mainly associates with newly added fatty acids. Real-time fluorescence live-cell imaging further revealed that HILPDA preferentially localizes to lipid droplets that are being remodeled. Overexpression of HILPDA in liver cells increased the activity of diacylglycerol acyltransferases (DGAT) and DGAT1 protein levels, concurrent with increased lipid storage. Confocal microscopy coupled to FRET-FLIM analysis demonstrated that HILPDA physically interacts with DGAT1 in living liver cells. The stimulatory effect of HILPDA on lipid storage via DGAT1 was corroborated in adipocytes. Conclusions: Our data indicate that HILPDA physically interacts with DGAT1 and increases DGAT activity. Our findings suggest a novel regulatory mechanism by which fatty acids promote triglyceride synthesis and storage.
CRIS-Team Scopus Importer:2021-03-26
Keywords: DGAT1; Fluorescence microscopy; HILPDA; Lipid droplets; Liver; Triglyceride synthesis

Hypoxia-inducible protein 2 Hig2/Hilpda mediates neutral lipid accumulation in macrophages and contributes to atherosclerosis in apolipoprotein E-deficient mice - Maier, Anja; Wu, Hao; Cordasic, Nada; Oefner, Peter; Dietel, Barbara; Thiele, Christoph; Weidemann, Alexander; Eckardt, Kai-Uwe; Warnecke, Christina (The FASEB Journal, 2017)
Recently we identified hypoxia-inducible protein 2 (HIG2)/hypoxia-inducible lipid droplet associated (HILPDA) as lipid droplet (LD) protein. Because HILPDA is highly expressed in atherosclerotic plaques, we examined its regulation and function in murine macrophages, compared it to the LD adipose differentiation-related protein (Adrp)/perilipin 2 (Plin2), and investigated its effects on atherogenesis in apolipoprotein E-deficient (ApoE(-/-)) mice. Tie2-Cre-driven Hilpda knockout (cKO) did not affect viability, proliferation, and ATP levels in macrophages. Hilpda proved to be a target of hypoxia-inducible factor 1 (Hif-1) and peroxisome proliferator-activated receptors. In contrast, Adrp/Plin2 was not induced by Hif-1. Hilpda localized to the endoplasmic reticulum-LD interface, the site of LD formation. Hypoxic lipid accumulation and storage of oxidized LDL, cholesteryl esters and triglycerides were abolished in Hilpda cKO macrophages, independent of the glycolytic switch, fatty acid or lipoprotein uptake. Hilpda depletion reduced resistance against lipid overload and increased production of reactive oxygen species after reoxygenation. LPS-stimulated prostaglandin-E2 production was dysregulated in macrophages, demonstrating the substrate buffer and reservoir function of LDs for eicosanoid production. In ApoE(-/-) Hilpda cKO mice, total aortic plaque area, plaque macrophages and vascular Vegf expression were reduced. Thus, macrophage Hilpda is crucial to foam-cell formation and lipid deposition, and to controlled prostaglandin-E2 production. By these means Hilpda promotes lesion formation and progression of atherosclerosis.-Maier, A., Wu, H., Cordasic, N., Oefner, P., Dietel, B., Thiele, C., Weidemann, A., Eckardt, K.-U., Warnecke, C. Hypoxia-inducible protein 2 Hig2/Hilpda mediates neutral lipid accumulation in macrophages and contributes to atherosclerosis in apolipoprotein E-deficient mice.
EVALuna2:4018

Hypoxia inhibits nephrogenesis through paracrine Vegfa despite the ability to enhance tubulogenesis - Schley, Gunnar; Scholz, Holger; Kraus, Andre; Hackenbeck, Thomas; Klanke, Bernd; Willam, Carsten; Wiesener, Michael S.; Heinze, Eva; Burzlaff, Nicolai; Eckardt, Kai-Uwe; Buchholz, Björn (Kidney International, 2015)
Reduced nephron number predisposes to hypertension and kidney disease. Interaction of the branching ureteric bud and surrounding mesenchymal cells determines nephron number. Since oxygen supply may be critical for intrauterine development, we tested whether hypoxia and hypoxiainducible factor-1 alpha (HIF-1 alpha) influence nephrogenesis. We found that HIF-1 alpha is required for branching of MDCK cells. In addition, culture of metanephric mouse kidneys with ureteric bud cell-specific stabilization or knockout of HIF-1 alpha revealed a positive impact of HIF-1 alpha on nephrogenesis. In contrast, widespread stabilization of HIF-1 alpha in metanephric kidneys through hypoxia or HIF stabilizers impaired nephrogenesis, and pharmacological HIF inhibition enhanced nephrogenesis. Several lines of evidence suggest an inhibitory effect through the hypoxia response of mesenchymal cells. HIF-1 alpha was expressed in mesenchymal cells during nephrogenesis. Expression of the anti-branching factors Bmp4 and Vegfa, secreted by mesenchymal cells, was increased upon HIF stabilization. The conditioned medium from hypoxic metanephric kidneys inhibited MDCK branching, which was partially rescued by Vegfa antibodies. Thus, the effect of HIF-1 alpha on nephrogenesis appears context dependent. While HIF-1 alpha in the ureteric bud is of importance for proper branching morphogenesis, the net effect of hypoxia-induced HIF activation in the embryonic kidney appears to be mesenchymal cell-dependent inhibition of ureter branching.
EVALuna2:3775
Keywords: hypoxia; hypoxia-inducible factor-1 alpha; kidney development; metanephric mesenchyme; nephrogenesis; Vegfa

Hypoxia regulates the sperm associated antigen 4 (SPAG4) via HIF, which is expressed in renal clear cell carcinoma and promotes migration and invasion in vitro - Knaup, Karl; Monti, Juliana; Hackenbeck, Thomas; Jobst-Schwan, Tilman; Klanke, Bernd; Schietke, Ruth Elisabeth; Wacker, Ingrid; Behrens, Jürgen; Amann, Kerstin Ute; Eckardt, Kai-Uwe; Warnecke, Christina; Wiesener, Michael (Molecular Carcinogenesis, 2014)
Hypoxia leads to the upregulation of a variety of genes mediated largely via the hypoxia inducible transcription factor (HIF). Prominent HIF-regulated target genes such as the vascular endothelial growth factor (VEGF), the glucose transporter 1 (Glut-1), or erythropoietin (EPO) help to assure survival of cells and organisms in a low oxygenated environment. Here, we are the first to report the hypoxic regulation of the sperm associated antigen 4 (SPAG4). SPAG4 is a member of the cancer testis (CT) gene family and to date little is known about its physiological function or its involvement in tumor biology. A number of CT family candidate genes are therefore currently being investigated as potential cancer markers, due to their predominant testicular expression pattern. We analyzed RNA and protein expression by RNAse protection assay, immunoflurescent as well as immunohistological stainings. To evaluate the influence of SPAG4 on migration and invasion capabilities, siRNA knockdown as well as transient overexpression was performed prior to scratch or invasion assay analysis. The hypoxic regulation of SPAG4 is clearly mediated in a HIF-1 and VHL dependent manner. We furthermore show upregulation of SPAG4 expression in human renal clear cell carcinoma (RCC) and co-localization within the nucleolus in physiological human testis tissue. SPAG4 knockdown reduces the invasion capability of RCC cells in vitro and overexpression leads to enhancement of tumor cell migration. Together, SPAG4 could possibly play a role in the invasion capability and growth of renal tumors and could represent an interesting target for clinical intervention. © 2013 Wiley Periodicals, In
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Identification of cell and disease specific microRNAs in glomerular pathologies - Müller-Deile, Janina; Dannenberg, Jan; Liu, Peidi; Lorenzen, Johan; Nyström, Jenny; Thum, Thomas; Schiffer, Mario (Journal of Cellular and Molecular Medicine, 2019)
MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression in physiological processes as well as in diseases. Currently miRs are already used to find novel mechanisms involved in diseases and in the future, they might serve as diagnostic markers. To identify miRs that play a role in glomerular diseases urinary miR-screenings are a frequently used tool. However, miRs that are detected in the urine might simply be filtered from the blood stream and could have been produced anywhere in the body, so they might be completely unrelated to the diseases. We performed a combined miR-screening in pooled urine samples from patients with different glomerular diseases as well as in cultured human podocytes, human mesangial cells, human glomerular endothelial cells and human tubular cells. The miR-screening in renal cells was done in untreated conditions and after stimulation with TGF-β. A merge of the detected regulated miRs led us to identify disease-specific, cell type-specific and cell stress-induced miRs. Most miRs were down-regulated following the stimulation with TGF-β in all cell types. Up-regulation of miRs after TGF-β was cell type-specific for most miRs. Furthermore, urinary miRs from patients with different glomerular diseases could be assigned to the different renal cell types. Most miRs were specifically regulated in one disease. Only miR-155 was up-regulated in all disease urines compared to control and therefore seems to be rather unspecific. In conclusion, a combined urinary and cell miR-screening can improve the interpretation of screening results. These data are useful to identify novel miRs potentially involved in glomerular diseases.
EVALuna2:118627

Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model - Kornhuber, Johannes; Tripal, Philipp; Reichel, Martin; Terfloth, Lothar; Bleich, Stefan; Wiftfang, Jens; Gulbins, Erich (Journal of Medicinal Chemistry, 2008)
Some organic weak bases induce a detachment from inner lysosomal membranes and subsequent inactivation of acid sphingomyelinase (ASM) and thus work as functional ASM inhibitors. The aim of the present investigation was to develop a structure-property-activity relation (SPAR) model in order to specify the structural and physicochemical characteristics of probes capable of functionally inhibiting ASM. High pKa and high log P values are necessary but not sufficient preconditions for functional inhibition of ASM. The experimental data supported the requirement of an additional factor, which is necessary for functional inhibition of ASM. This factor k is related to the steric hindrance of the most basic nitrogen atom and presumably modulates the free presentation of a protonated nitrogen atom at the inner lysosomal surface. During the course of the study, we characterized 26 new functional ASM inhibitors, including doxepine 63, fluoxetine 104, maprotiline 109, nortriptyline 114, paroxetine 118, sertraline 124, suloctidil 125, and terfenadine 127. © 2008 American Chemical Society.
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Identification of novel functional inhibitors of acid sphingomyelinase - Kornhuber, Johannes; Muehlbacher, Markus; Trapp, Stefan; Pechmann, Stefanie; Friedl, Astrid; Reichel, Martin; Mühle, Christiane; Terfloth, Lothar; Groemer, Teja W.; Spitzer, Gudrun M.; Liedl, Klaus R.; Gulbins, Erich; et al. (PLoS ONE, 2011)
We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 μM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans. © 2011 Kornhuber et al.
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Identification of Plasma Metabolites Prognostic of Acute Kidney Injury after Cardiac Surgery with Cardiopulmonary Bypass - Zacharias, Helena U.; Hochrein, Jochen; Vogl, Franziska C.; Schley, Gunnar; Mayer, Friederike; Jeleazcov, Christian; Eckardt, Kai-Uwe; Willam, Carsten; Oefner, Peter J.; Gronwald, Wolfram (Journal of Proteome Research, 2015)
Acute kidney injury (AKI) is a frequent complication after cardiopulmonary bypass, but early detection of postoperative AKI remains challenging. Protein biomarkers predict AKI excellently in homogeneous cohorts but are less reliable in patients suffering from various comorbidities. We employed nuclear magnetic resonance spectroscopy in a prospective study of 85 adult cardiac surgery patients to identify metabolites prognostic of AKI in plasma specimens collected 24 h after surgery. Postoperative AKI of stages 1-3, as defined by the Acute Kidney Injury Network (AKIN), developed in 33 cases. A random forests classifier trained on the NMR spectra prognosticated AKI across all stages, with an average accuracy of 80 ± 0.9% and an area under the receiver operating characteristic curve of 0.87 ± 0.01. Prognostications were based, on average, on 24 ± 2.8 spectral features. Among the set of discriminative ions and molecules identified were Mg(2+), lactate, and the glucuronide conjugate of propofol. Using creatinine, Mg(2+), and lactate levels to derive an AKIN index score, we found AKIN 1 disease to be largely indistinguishable from AKIN 0, in concordance with the rather mild nature of AKIN 1 disease.
EVALuna2:3784

Identifying Isolated Systolic Hypertension From Upper-Arm Cuff Blood Pressure Compared With Invasive Measurements - Picone, Dean S.; Schultz, Martin G.; Armstrong, Matthew K.; Black, J. Andrew; Bos, Willem Jan W.; Chen, Chen Huan; Cheng, Hao Min; Cremer, Antoine; Dwyer, Nathan; Hughes, Alun D.; Kim, Hack Lyoung; Lacy, Peter S.; et al. (Hypertension, 2021)
Isolated systolic hypertension (ISH) is the most common form of hypertension and is highly prevalent in older people. We recently showed differences between upper-arm cuff and invasive blood pressure (BP) become greater with increasing age, which could influence correct identification of ISH. This study sought to determine the difference between identification of ISH by cuff BP compared with invasive BP. Cuff BP and invasive aortic BP were measured in 1695 subjects (median 64 years, interquartile range [55-72], 68% male) from the INSPECT (Invasive Blood Pressure Consortium) database. Data were recorded during coronary angiography among 29 studies, using 21 different cuff BP devices. ISH was defined as ≥130/<80 mm Hg using cuff BP compared with invasive aortic BP as the reference. The prevalence of ISH was 24% (n=407) according to cuff BP but 38% (n=642) according to invasive aortic BP. There was fair agreement (Cohen κ, 0.36) and 72% concordance between cuff and invasive aortic BP for identifying ISH. Among the 28% of subjects (n=471) with misclassification of ISH status by cuff BP, 20% (n=96) of the difference was due to lower cuff systolic BP compared with invasive aortic systolic BP (mean, -16.4 mm Hg [95% CI, -18.7 to -14.1]), whereas 49% (n=231) was from higher cuff diastolic BP compared with invasive aortic diastolic BP (+14.2 mm Hg [95% CI, 11.5-16.9]). In conclusion, compared with invasive BP, cuff BP fails to identify ISH in a sizeable portion of older people and demonstrates the need to improve cuff BP measurements.
CRIS-Team Scopus Importer:2021-02-05
Keywords: aorta; blood pressure; coronary angiography; hypertension; prevalence

Imaging of the musculoskeletal system using low-field magnetic resonance imaging - Pogarell, Tobias; May, Matthias; Nagel, Armin Michael; Uder, Michael; Heiß, Rafael (Radiologe, 2022)
Background Magnetic resonance imaging (MRI) plays a crucial role in musculoskeletal imaging. The high prevalence and pain-related suffering of patients pose a particular challenge concerning availability and turnover times, respectively. Low-field (<= 1.0 T) MRI has the potential to fulfill these needs. However, during the past three decades, high field systems have increasingly replaced low field systems because of their limitations in image quality. Recent technological advancements in high-performance hard- and software promise musculoskeletal imaging with adequate quality at lower field strengths for several regions and indications. Objectives The goal is to provide insight into the advantages and disadvantages of low-field musculoskeletal imaging, discuss the current literature, and include our first experiences with a modern 0.55 T MRI. Materials and methods This review is based on research in various literature databases and our own musculoskeletal imaging experiences with a modern 0.55 T scanner. Conclusion Most publications pertaining to musculoskeletal imaging at low-field strength MRI are outdated, and studies regarding the diagnostic performance of modern low-field MRI systems are needed. These new systems may complement existing high-field systems and make MRI more accessible, even in low-income countries. From our own experience, modern low-field MRI seems to be adequate in musculoskeletal imaging, especially in acute injuries.
CRIS-Team WoS Importer:2022-04-29
Keywords: Field strength; Musculoskeletal injuries; Image quality; Cost; Sustainability

Immune cells control skin lymphatic electrolyte homeostasis and blood pressure - Wiig, Helge; Schröder, Agnes; Neuhofer, Wolfgang; Jantsch, Jonathan; Kopp, Christoph; Karlsen, Tine V.; Boschmann, Michael; Goss, Jennifer; Bry, Maija; Rakova, Natalia; Dahlmann, Anke; Brenner, Sven; et al. (Journal of Clinical Investigation, 2013)
The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.
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IMPACT OF BLOOD PRESSURE AND AGEING ON RETINAL NEURODEGENERATION ASSESSED BY SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY - Jung, Susan; Bosch, Agnes; Kohler, N.; Ott, Christian; Kannenkeril, D.; Dienemann, T.; Harazny, J. M.; Michelson, Georg; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

IMPACT OF DONOR HYPERTENSION AND HISTOLOGIC CHANGES IN LIVING DONOR KIDNEY TRANSPLANTATION: A SINGLE CENTER RETROSPECTIVE STUDY - Dienemann, Thomas; Schellenberg, J.; Heller, K.; Daniel, Christoph; Amann, Kerstin Ute; Weidemann, A. (2018)
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Impact of microvascular disease on cardiorenal outcomes in type 2 diabetes: an analysis from the LEADER and SUSTAIN 6 clinical trials - Zinman, B.; Verma, S.; Bain, S. C.; Honore, J. B.; Mann, Johannes; Nauck, M. A.; Pratley, R.; Rasmussen, S.; Ripa, M. Sejersten; Buse, J. B. (DIABETOLOGIA, 2019)
CRIS-Team WoS Importer:2019-10-11

Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: Results from the LEADER and SUSTAIN 6 clinical trials - Verma, Subodh; Bain, Stephen C.; Honoré, Julie Broe; Mann, Johannes; A. Nauck, Michael; E. Pratley, Richard; Rasmussen, Søren; Sejersten Ripa, Maria; Zinman, Bernard; Buse, John B. (Diabetes Obesity & Metabolism, 2020)
The randomized, double-blind, cardiovascular outcomes trials LEADER (NCT01179048) and SUSTAIN 6 (NCT01720446) showed cardiovascular risk reduction in patients with type 2 diabetes treated with liraglutide and semaglutide, respectively, compared with placebo. This post hoc analysis examined the impact of microvascular disease at baseline on cardiovascular outcomes in these trials, and the efficacy of liraglutide (1.8 mg) and once-weekly semaglutide (0.5-1.0 mg) in patients with and without microvascular disease. In total, 9340 patients from LEADER and 3297 patients from SUSTAIN 6 were included in this analysis; of these, 5761 and 2356 had a history of microvascular disease at baseline and 3835 and 1640 had a history of both microvascular and macrovascular disease, respectively. Patients with microvascular disease were shown to have an increased risk of major adverse cardiovascular events compared with patients without microvascular disease (hazard ratio [95% confidence interval] in LEADER: 1.15 [1.03; 1.29], P =.0136; SUSTAIN 6: 1.56 [1.14; 2.17], P =.0064). Liraglutide and semaglutide consistently reduced cardiovascular risk in patients with and without microvascular disease.
CRIS-Team Scopus Importer:2020-08-21
Keywords: cardiovascular disease; diabetic nephropathy; diabetic neuropathy; diabetic retinopathy; macrovascular disease; type 2 diabetes

Impact of Renal Denervation on Plasma Renin Activity and Relationship of Baseline Plasma Renin Activity to Blood Pressure Lowering Response to Renal Denervation in the SPYRAL HTN-OFF MED Pivotal trial - Mahfoud, Felix; Townsend, Raymond; Kandzari, David; Kario, Kazuomi; Schmieder, Roland; Tsioufis, Konstantinos; Boehm, Michael; Pocock, Stuart; Cohen, Sidney; Fahy, Martin; Weber, Michael (JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2020)
CRIS-Team WoS Importer:2020-12-25

Impact of renal denervation on tissue Na(+) content in treatment-resistant hypertension - Ott, Christian; Kopp, Christoph; Dahlmann, Anke; Schmid, Andrea; Linz, Peter; Hammon, Matthias; Ditting, Tilmann; Veelken, Roland; Uder, Michael; Titze, Jens; Schmieder, Roland; Cavallaro, Alexander Josef (Clinical Research in Cardiology, 2017)
Renal denervation (RDN) has been introduced for reducing blood pressure (BP) in treatment-resistant hypertension (TRH). The precise mechanism how RDN exerts its BP-lowering effects are not yet fully understood. It is widely accepted that sodium (Na(+)) plays a crucial role in the pathogenesis of hypertensive disease. However, there is increasing evidence of osmotically inactive Na(+) storage. We investigated the impact of RDN on Na(+) homeostasis using estimation of salt intake, and measurement of tissue Na(+) content.In a study 41 patients with TRH (office BP >=140/90 mmHg and diagnosis confirmed by 24-h ambulatory BP monitoring) underwent RDN. Tissue Na(+) content was assessed non-invasively with 3.0 T magnetic resonance imaging before and 6 months after RDN. In addition, 24-h urinary Na(+) excretion as an estimate of salt intake and spot urine Na(+)/K(+) excretion were assessed. The study was registered at http://www.clinicaltrials.gov (ID: NCT01687725).There was a significant fall in BP (office: -17 ± 20/-10 ± 12 mmHg; 24-h: -11 ± 13/-6 ± 9 mmHg, all p < 0.001) 6 months after RDN. In contrast, tissue Na(+) content of the muscle (20.1 ± 3.9 vs. 20.7 ± 4.0 mmol/L, p = 0.229) and skin (24.4 ± 6.5 vs. 24.8 ± 6.6 mmol/L, p = 0.695) did not change after RDN. Moreover, there was also no change in salt intake after RDN, whereas Na(+)/K(+) ratio only acutely increased.Although RDN resulted in a substantial reduction of BP, tissue Na(+) content of the muscle and skin was not mobilized and reduced. These data indicate that the BP reduction after RDN is unrelated to Na(+) homeostasis.
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Impact of telmisartan on cardiovascular outcome in hypertensive patients at high risk: a Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease subanalysis - Foulquier, Sebastien; Boehm, Michael; Schmieder, Roland; Sleight, Peter; Teo, Koon; Yusuf, Salim; Schumacher, Helmut; Unger, Thomas (Journal of Hypertension, 2014)
In the Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease, all patients were at high cardiovascular risk, and a substantial proportion were hypertensive. We performed a post-hoc analysis to explore the hypothesis that telmisartan has a differential action in hypertensive vs. nonhypertensive patients.The primary four-fold endpoint (composite of cardiovascular death, myocardial infarction (MI), stroke, or hospitalization for heart failure), the secondary three-fold endpoint (cardiovascular death, MI, and stroke), the individual components, new onset of left ventricular hypertrophy (LVH), and new onset of albuminuria were analyzed.There was no evidence for a significantly differential treatment effect of telmisartan in hypertensive and nonhypertensive patients for any endpoints, although the occurrence of the secondary three-fold endpoint was significantly lower in the telmisartan group (13.0%) compared with placebo (15.0%, P < 0.05) only in hypertensive patients. Moreover, data from this post-hoc analysis suggest that MI may be less frequent in hypertensive patients treated with telmisartan (3.8 vs. 5.1%; P < 0.05). Telmisartan may also reduce new onset of LVH (nonhypertensive patients P < 0.05; hypertensive patients P < 0.001) in both subgroups, and new onset of microalbuminuria and macroalbuminuria in hypertensive patients (P < 0.001 and P < 0.01, respectively).The effect of telmisartan in hypertensive and nonhypertensive patients at high cardiovascular risk was not different. This post-hoc analysis suggests that MI may be further reduced by telmisartan in hypertensive patients. Further investigations are needed to study the hypotheses raised by this explanatory analysis.
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Impact of type 1 diabetes and its duration on wall-to-lumen ratio and blood flow in retinal arterioles - Stefański, Adrian; Wolf, Jacek; Harazny, Joanna M.; Miszkowska-Nagórna, Eliza; Wolnik, Bogumił; Murawska, Joanna; Narkiewicz, Krzysztof; Schmieder, Roland (Microvascular Research, 2023)
Background: Subclinical damage to both the small and large vessels may contribute to the development and progression of cardiovascular disease. Scanning laser Doppler flowmetry (SLDF), an established method used to measure retinal microcirculation, has been successfully applied in hypertensive and post-stroke patients. Methods: Retinal microcirculation was assessed in 158 patients with type 1 diabetes and 38 age-matched healthy controls. The diabetics were divided into 3 groups: group A with diabetes duration <12 months, group B with diabetes with 1–10 years, and group C >10 years of diabetes. Retinal capillary structure and perfusion were evaluated using a Heidelberg retina flowmeter and automatically analyzed with full-field perfusion imaging. Results: Age and BMI were comparable in all the diabetic patients and the controls (mean age 24.8 ± 4.7 years, mean BMI 22.9 ± 4.1). In the univariate analyses, RCF (retinal capillary flow) was significantly higher in group A (297 ± 121 arbitrary units [AU]) vs group B (236 ± 52 AU; p = 0.007) and group C (236 ± 70 AU; p = 0.008) and comparable to that of the controls (p = 0.46). Additionally, the WLR (Wall-to-Lumen Ratio) was highest in group C compared to the other diabetic subgroups and controls (p = 0.001). Multivariate regression analyses including age, BMI, sex, HbA1c, smoking, systolic blood pressure, and diabetes duration as covariates, showed, that only diabetes duration was significantly associated with WLR variations, whereas HbA1c was significantly linked to retinal capillary flow levels. Conclusions: New-onset diabetes is associated with an increase in RCF, which then gradually decreased with the duration of the disease. Structural changes of the retinal arterioles estimated via WLR are evident later in the course of diabetes, especially when the disease duration exceeded 10 years.
CRIS-Team Scopus Importer:2023-02-17
Keywords: Arterioles remodeling; Cardiovascular disease; Retinal microcirculation; Scanning laser Doppler Flowmetry; SLDF; Subclinical organ damage; Type 1 diabetes; Wall-to-lumen ratio

Impaired excitability of renal afferent innervation after exposure to the inflammatory chemokine CXCL1 - Ditting, Tilmann; Freisinger, Wolfgang; Rodionova, Kristina; Schatz, Johannes; Lale, Nena; Heinlein, Sonja; Linz, Peter; Ott, Christian; Schmieder, Roland; Scrogin, Karie E.; Veelken, Roland (American Journal of Physiology-Renal Physiology, 2016)
Recently, we showed that renal afferent neurons exhibit a unique firing pattern, i.e., predominantly sustained firing, upon stimulation. Pathological conditions such as renal inflammation likely alter excitability of renal afferent neurons. Here, we tested whether the proinflammatory chemokine CXCL1 alters the firing pattern of renal afferent neurons. Rat dorsal root ganglion neurons (Th11-L2), retrogradely labeled with dicarbocyanine dye, were incubated with CXCL1 (20 h) or vehicle before patch-clamp recording. The firing pattern of neurons was characterized as tonic, i.e., sustained action potential (AP) firing, or phasic, i.e., <5 APs following current injection. Of the labeled renal afferents treated with vehicle, 58.9% exhibited a tonic firing pattern vs. 7.8%, in unlabeled, nonrenal neurons (P < 0.05). However, after exposure to CXCL1, significantly more phasic neurons were found among labeled renal neurons; hence the occurrence of tonic neurons with sustained firing upon electrical stimulation decreased (35.6 vs. 58.9%, P < 0.05). The firing frequency among tonic neurons was not statistically different between control and CXCL1-treated neurons. However, the lower firing frequency of phasic neurons was even further decreased with CXCL1 exposure [control: 1 AP/600 ms (1-2) vs. CXCL1: 1 AP/600 ms (1-1); P < 0.05; median (25th-75th percentile)]. Hence, CXCL1 shifted the firing pattern of renal afferents from a predominantly tonic to a more phasic firing pattern, suggesting that CXCL1 reduced the sensitivity of renal afferent units upon stimulation.
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Impaired increase of retinal capillary blood flow to flicker light exposure in arterial hypertension - Ritt, Martin; Harazny, Joanna M.; Ott, Christian; Raff, Ulrike; Bauernschubert, Philipp; Lehmann, Marina; Michelson, Georg; Schmieder, Roland (Hypertension, 2012)
We hypothesized that the increase of retinal capillary blood flow (RCF) to flicker light exposure is impaired in subjects with arterial hypertension. In 146 nondiabetic untreated male subjects with (n=50) or without (n=96) arterial hypertension, RCF was measured before and after flicker light exposure noninvasively and in vivo using scanning laser Doppler flowmetry. In addition, in a subgroup of 28 subjects, the change of RCF to flicker light exposure was again assessed during parallel infusion of nitric oxide synthase inhibitor N-monomethyl-l-arginine (L-NMMA). The increase of RCF to flicker light exposure was lower in patients with untreated hypertension compared with normotensive subjects when expressed in absolute terms (7.69±54 versus 27.2±44 AU; P adjusted=0.013) or percent changes (2.95±14 versus 8.33±12%; P adjusted=0.023). Systolic (?=-0.216; P=0.023) but not diastolic blood pressure (?=-0.117; P=0.243) or mean arterial pressure (?=-0.178; P=0.073) was negatively related to the percent change of RCF to flicker light exposure, independently of other cardiovascular risk factors. In the subgroup of 28 subjects, the increase of RCF to flicker light exposure was similar at baseline and during parallel infusion of L-NMMA when expressed in absolute terms (20.0±51 versus 22.6±56 AU; P=0.731) or percent changes (7.12±16 versus 8.29±18%; P=0.607). The increase of RCF to flicker light exposure is impaired in arterial hypertension. In the subgroup of the total study cohort, nitric oxide was not a major determinant of the increase of RCF to flicker light exposure.
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Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction - Menendez-Castro, Carlos; Toka, Okan; Fahlbusch, Fabian; Cordasic, Nada; Wachtveitl, Rainer; Hilgers, Karl Friedrich; Rascher, Wolfgang; Hartner, Andrea (Pediatric Research, 2014)
Intrauterine growth restriction (IUGR) is an important risk factor for cardiovascular disease. Previous studies revealed altered myocardial matrix composition after IUGR. We hypothesized that IUGR is accompanied by compromised myocardial performance independently from arterial hypertension.IUGR was induced in Wistar rats by maternal protein restriction, and hearts of male offspring were studied using echocardiography, immunohistochemistry, real-time PCR, and western blot analysis.At day 70 of life, in the absence of arterial hypertension (mean arterial blood pressure: 101.3 ± 7.1 mmHg in IUGR vs. 105.3 ± 4.6 mmHg in controls, not significant (NS)), echocardiography showed a reduced contractility (ejection fraction: 65.4 ± 1.8% in IUGR vs. 82.2 ± 1.5% in controls, P < 0.001) of a more distensible myocardium in IUGR rats. Altered expression patterns of myosin chains and titin isoforms and increased expression levels of atrial natriuretic peptide, Na/K-ATPase, and ?-adrenergic receptor 1 were detected. A higher number of cardiac fibroblasts and vascular cross-sections were observed in IUGR rats, accompanied by elevated expression of hypoxia inducible factor 1 target genes, such as vascular endothelial growth factor and its receptors.We observed a blood pressure-independent impairment of myocardial function after IUGR, which possibly favors cardiovascular disease later in life. Some IUGR-induced myocardial changes (e.g., sarcomeric components) may partly explain the compromised cardiac performance, whereas others (e.g., elevated vascular supply) reflect compensatory mechanisms.
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Impaired Neovascularization and Reduced Capillary Supply in the Malignant vs. Non-malignant Course of Experimental Renovascular Hypertension - Jagusch, Lisa Gudrun; Cordasic, Nada; Amann, Kerstin Ute; Veelken, Roland; Jacobi, Johannes; Hilgers, Karl Friedrich; Hartner, Andrea (Frontiers in Physiology, 2016)
Malignant hypertension develops in some cases of hypertension but not in others. We hypothesized that an impaired neovascularization and a reduced capillary supply characterizes the malignant course of experimental hypertension. Two-kidney, one-clip renovascular hypertension was induced in rats; controls (sham) were sham operated. To distinguish malignant hypertension from non-malignant hypertension, we considered two factors: weight loss, and the number of typical vascular lesions (onion skin lesions and fibrinoid necroses) per kidney section of the nonclipped kidney. Animals in the upper half for both criteria were defined as malignant hypertensives. After 5 weeks, mean arterial blood pressure was elevated to the same degree in malignant hypertension and non-malignant hypertension whereas plasma renin and aldosterone were significantly higher in malignant hypertensives. The expression of plasminogen activator inhibitor-1 was elevated (up to 14-fold) in non-malignant but significantly more increased (up to 36-fold) in malignant hypertensive rats, compared to sham. As a bioassay for neovascularization, the area of granulation tissue ingrowth in polyvinyl discs (implanted subcutaneously) was reduced in malignant hypertension compared to non-malignant hypertension and sham, while there was no difference between non-malignant hypertension and sham. The number of renal and left ventricular capillaries was significantly lower in malignant hypertension compared to non-malignant hypertension, as was the number of proliferating endothelial cells. We conclude that an impaired neovascularization and capillarization occurs in malignant renovascular hypertension but not in the non-malignant course of the disease despite comparable blood pressure levels. This might contribute to the unique vascular lesions and progressive target organ damage observed in malignant hypertension.
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Implementation of Bayesian Study Design in the SPYRAL HTN-OFF MED Pivotal Trial - Boehm, Michael; Townsend, Raymond; Weber, Michael; Kandzari, David; Mahfoud, Felix; Kario, Kazuomi; Schmieder, Roland; Tsioufis, Konstantinos; Debruin, Vanessa; Hickey, Graeme; Fahy, Martin; Pocock, Stuart (JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Implementation of the KDIGO guideline on lipid management requires a substantial increase in statin prescription rates - Schneider, Markus P.; Hübner, Silvia; Titze, Stephanie I.; Schmid, Matthias; Nadal, Jennifer; Schlieper, Georg; Busch, Martin; Baid-Agrawal, Seema; Krane, Vera; Wanner, Christoph; Kronenberg, Florian; Eckardt, Kai-Uwe (Kidney International, 2015)
The KDIGO guideline on lipid management in adult patients with chronic kidney disease (CKD) reflects a paradigm shift as proposals for statin use are based on cardiovascular risk rather than cholesterol levels. Statin use is now universally recommended in CKD patients 50 years and older, assuming a 10-year risk of coronary heart disease (CHD) of over 10%. Specific comorbidities or formal risk calculation are required for younger patients. It is unknown to which extent these new guidelines differ from previous practice. Here we analyzed statin use in the German Chronic Kidney Disease study of 5217 adult patients with moderately severe CKD under nephrological care enrolled shortly before publication of the new guideline. Accordingly, 407 patients younger than 50 years would be eligible for statins compared with the 277 patients treated so far, and all 4224 patients 50 years and older would be eligible compared with the 2196 already treated. Overall, guideline implementation would almost double statin prescription from 47 to 88%. Among patients 50 years and older currently not on a statin, an estimated 10-year CHD and atherosclerotic event risks over 10% were present in 68% and 82%, respectively. Thus, implementation of the new lipid guideline requires a substantial change in prescription practice, even in CKD patients under nephrological care. Based on comorbidities and risk estimates, the universal recommendation for statin use in CKD patients 50 years and older appears justified.
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Improved blood pressure control via a novel chronic disease management model of care in sub-Saharan Africa: Real-world program implementation results - Otieno, Harun A.; Miezah, Charles; Yonga, Gerald; Kueffer, Fred; Guy, Molly; Lang'At, Chemuttaai; Hettrick, Douglas A.; Schmieder, Roland (Journal of Clinical Hypertension, 2021)
A chronic disease management model of care (Empower Health) was launched in rural and urban areas of Ghana and Kenya in 2018. The goal was to improve disease awareness, reduce the burden of disease, and improve the clinical effectiveness and efficiency of managing hypertension. Leveraging the model, clinicians provide patients with tailored management plans. Patients accessed regular blood pressure checks at home, at the clinic, or at community-partner locations where they received real-time feedback. On the mobile application, clinicians viewed patient data, provided direct patient feedback, and wrote electronic prescriptions accessible through participating pharmacies. To date, 1266 patients had been enrolled in the "real-world" implementation cohort and followed for an average of 351 +/- 133 days across 5 facilities. Average baseline systolic blood pressure (SBP) was 145 +/- 21 mmHg in the overall cohort and 159 +/- 16 mmHg in the subgroup with uncontrolled hypertension (n = 743) as defined by baseline SBP >= 140 mmHg. SBP decreased significantly through 12 months in both the overall cohort (-9.4 mmHg, p < .001) and in the uncontrolled subgroup (-17.6 mmHg, p < .001). The proportion patients with controlled pressure increased from 46% at baseline to 77% at 12 months (p < .001). In summary, a new chronic disease management model of care improved and sustained blood pressure control to 12 months, especially in those with elevated blood pressure at enrollment.
CRIS-Team WoS Importer:2021-02-12

Improved cardiovascular risk prediction in patients with end-stage renal disease on hemodialysis using machine learning modeling and circulating microribonucleic acids - De Gonzalo-Calvo, David; Martinez-Camblor, Pablo; Baer, Christian; Duarte, Kevin; Girerd, Nicolas; Fellstrom, Bengt; Schmieder, Roland; Jardine, Alan G.; Massy, Ziad A.; Holdaas, Hallvard; Rossignol, Patrick; Zannad, Faiez; et al. (Theranostics, 2020)
Rationale: To test whether novel biomarkers, such as microribonucleic acids (miRNAs), and nonstandard predictive models, such as decision tree learning, provide useful information for medical decision-making in patients on hemodialysis (HD).
CRIS-Team WoS Importer:2020-07-31

Improved Persistence to Medication, Decreased Cardiovascular Events and Reduced All-Cause Mortality in Hypertensive Patients with Use of Single-Pill Combinations: Results from the START-Study - Schmieder, Roland; Wassmann, Sven; Predel, Hans Georg; Weisser, Burkhard; Blettenberg, Jörg; Gillessen, Anton; Randerath, Olaf; Mevius, Antje; Wilke, Thomas; Böhm, Michael (Hypertension, 2023)
Background: Single-pill combination improves adherence and persistence to medication in hypertension. It remains unclear whether this also reduces cardiovascular outcomes and all-cause mortality. We analyzed whether single-pill combinations are superior to identical multiple pills on persistence to medication, cardiovascular outcomes, and all-cause mortality. Methods: This was a retrospective claims data (German AOK PLUS) analysis. Data from hypertensive patients ≥18 years treated with renin-angiotensin system combinations given as single pill or identical multipills covering the years 2012 to 2018 were analyzed and followed up to at least 1 year. After 1:1 propensity score matching, persistence to medication, cardiovascular events, and all-cause mortality were compared using non-parametric tests. Results were reported as incidence rate ratios and hazard ratios. Results: After propensity score matching data from 57 998 patients were analyzed: 10 801 patients received valsartan/amlodipine, 1026 candesartan/amlodipine, 15 349 ramipril/amlodipine, and 1823 amlodipine/valsartan/hydrochlorothiazide as single pill or identical multipill. No relevant differences in patient characteristics were observed within the 4 groups. In all groups, a significant lower all-cause mortality, a significant a higher persistence to medication, a significant lower event rate in 15 out of 20 comparisons, and a tendency in the remaining 5 comparisons was observed under single pills compared with multipill combinations. Conclusions: Antihypertensive combination therapy reduces all-cause mortality and cardiovascular when provided as single pill compared to identical drugs as multipills. This strongly supports the European Society of Cardiology/European Society of Hypertension and International Society of Hypertension guidelines recommending the use of a single-pill combination and thus should be more rigorously implemented into daily clinical practice.
CRIS-Team Scopus Importer:2023-05-05
Keywords: antihypertensive agents; cardiovascular diseases; hypertension; medication adherence; mortality; prognosis; risk factors

Improved visualization of peripherally inserted central catheters on chest radiographs of neonates using fractional multiscale image processing - Hammon, Rebecca A.; Seuß, Hannes; Hammon, Matthias; Grillhoesl, Christian; Heiß, Rafael; Zeilinger, Martin; Bayerl, Nadine; Vuylsteke, Pieter; Wanninger, Friedrich; Schroth, Michael; Uder, Michael; Rompel, Oliver (BMC Medical Imaging, 2019)
BACKGROUND: Peripherally inserted central catheters (PICCs) provide secure intravenous access for the delivery of life-sustaining medications and nutrition. They are commonly used in pediatrics. Confirmation of correct central catheter tip position is crucial. Verification is usually done by a radiograph. The aim of this study is to evaluate the ability of Fractional Multiscale image Processing (FMP) to detect PICC tips on the digital chest radiographs of neonates. METHODS: A total of 94 radiographs of 47 patients were included in the study. 29 patients were male, 18 were female. The mean age of all examined children was 9.2 days (range 0-99 days). In total, six readers (two radiologists, two residents in radiology, one last year medical student, one neonatologist) evaluated 94 unprocessed and catheter-enhanced radiographs using a 5-point Likert scale (1 = poor catheter tip visualization, 5 = excellent catheter tip visualization). Additionally, the two radiologists evaluated the diagnostic confidence for chest pathologies using a 5-point Likert scale (1 = poor diagnostic confidence, 5 = excellent diagnostic confidence). Radiographs were evaluated on a dedicated workstation. RESULTS: In all cases, the catheter-enhanced radiograph rated higher than (n = 471), or equal (n = 93) to, the unprocessed radiograph when visualizing catheter tips. 87% of the catheter-enhanced radiographs obtained a rating of 4 or higher, while only 42% of unprocessed radiographs received 4 or more points. Regarding diagnostic confidence for chest pathologies one radiologist rated two catheter-enhanced radiographs higher than the unprocessed radiographs, while all other 186 evaluations rated the catheter-enhanced radiographs equal to (n = 78) or lower than (n = 108) the unprocessed radiographs. Only 60% of the catheter-enhanced radiographs yielded a diagnostic confidence of 4 or higher, while 90% of the unprocessed images received 4 or more points. CONCLUSION: Catheter-enhanced digital chest radiographs demonstrate improved visualization of low contrast PICC tips in neonates compared to unprocessed radiographs. Furthermore, they enable detection of accompanying chest pathologies. However, definitive diagnosis of chest pathologies should be made on unprocessed radiographs.
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Improvement in Retinal Capillary Rarefaction After Valsartan Treatment in Hypertensive Patients - Jumar, Agnes; Harazny, Joanna M.; Ott, Christian; Kistner, Iris; Friedrich, Stefanie; Schmieder, Roland (Journal of Clinical Hypertension, 2016)
Decreased capillary density influences vascular resistance and perfusion. The authors aimed to investigate the influence of the renin-angiotensin receptor blocker valsartan on retinal capillary rarefaction in hypertensive patients. Retinal vascular parameters were measured noninvasively and in vivo by scanning laser Doppler flowmetry before and after 4 weeks of treatment with valsartan in 95 patients with hypertension stage 1 or 2 and compared with 55 healthy individuals. Retinal capillary rarefaction was determined with the parameters intercapillary distance (ICD) and capillary area (CapA). In hypertensive patients, ICD decreased (23.4±5.5 ?m vs 21.5±5.6 ?m, P<.001) and CapA increased (1564±621 vs 1776±795, P=.001) after valsartan treatment compared with baseline. Compared with healthy normotensive controls (ICD 20.2±4.2 ?m, CapA 1821±652), untreated hypertensive patients showed greater ICD (P<.001) and smaller CapA (P=.019), whereas treated hypertensive patients showed no difference in ICD (P=.126) and CapA (P=.728). Therapy with valsartan for 4 weeks diminished capillary rarefaction in hypertensive patients.
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Improvement of albuminuria after renal denervation - Ott, Christian; Mahfoud, Felix; Schmid, Axel; Ditting, Tilmann; Veelken, Roland; Ewen, Sebastian; Ukena, Christian; Uder, Michael; Boehm, Michael; Schmieder, Roland (International Journal of Cardiology, 2014)
The primary objective of this study was the effect of renal denervation (RDN) on elevated urinary albumin-to-creatinine ratio (UACR) in treatment-resistant hypertensive patients. In addition, patients were stratified according their UACR at baseline into micro- (30-300 mg/g, n=37) and macroalbuminuria (>= 300 mg/g, <2,200 mg/g, n=22).Increased albuminuria indicates cardiovascular and renal damage in hypertension. RDN emerged as an innovative interventional approach to reduce blood pressure (BP) and may thus reduce albumin urinary excretion.Fifty-nine treatment-resistant hypertensive patients with elevated UACR at baseline underwent catheter-based RDN using the Symplicity Flex(TM) catheter (Medtronic Inc., Santa Rosa, CA).In the whole and pre-specified subgroups both office and 24-h ambulatory BP were significantly reduced 6 months after RDN. In parallel, a significant reduction in UACR occurred in all patients (160 (65-496) versus 89 (29-319) mg/g creatinine, p<0.001) and in both subgroups (microalbuminuria: 83 (49-153) versus 58 (17-113) mg/g creatinine, p=0.001; macroalbuminuria: (536 (434-1483) versus 478 (109-1080) mg/g creatinine, p<0.001). In accordance, the prevalence of micro- and macroalbuminuria decreased significantly. Regression analysis revealed a modest positive relationship between the decrease of UACR and the fall of systolic BP (?=0.340, p=0.039) independent of renal function. Renal function remained unchanged after RDN.In summary, following RDN, the magnitude of albuminuria as well as the prevalence of micro- and macroalbuminuria decreased in treatment-resistant hypertensive patients. Since albuminuria is an independent renal and cardiovascular risk factor, our findings suggest a reduction of renal and cardiovascular risk in these patients.
EVALuna2:3681

Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling - Distler, Alfiya; Ziemer, Clara; Beyer, Christian; Lin, Neng-Yu; Chen, Chih-Wei; Palumbo-Zerr, Katrin; Dees, Clara; Weidemann, Alexander; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2014)
Canonical as well as non-canonical Wnt signalling pathways have emerged as core pathways of fibrosis. Their profibrotic effects are mediated via distinct intracellular cascades independently of each other. Thus, inhibition of both pathways may have additive antifibrotic effects. Here, we knocked down evenness interrupted (EVI) to simultaneously target for the first time canonical and non-canonical Wnt signalling in experimental fibrosis.The antifibrotic effects of siRNA-mediated knockdown of EVI were evaluated in the mouse models of bleomycin-induced skin fibrosis and in fibrosis induced by adenoviral overexpression of a constitutively active TGF-? receptor I (AdTBRI).Knockdown of EVI decreased the release of canonical and non-canonical Wnt ligands by fibroblasts and reduced the activation of canonical and non-canonical Wnt cascades in experimental fibrosis with decreased accumulation of ?-catenin and phosphorylated JNK and cJun. Inactivation of EVI exerted potent antifibrotic effects and reduced dermal thickening, myofibroblast differentiation and accumulation of collagen in the mouse models of bleomycin-induced and AdTBR-induced fibrosis.Inhibition of Wnt secretion by knockdown of EVI inhibits canonical and non-canonical Wnt signalling and effectively reduces experimental fibrosis in different preclinical models. Inhibition of Wnt secretion may thus be an interesting approach for the treatment of fibrosis.
EVALuna2:3691

Incorporating kidney disease measures into cardiovascular risk prediction: Development and validation in 9 million adults from 72 datasets - Matsushita, Kunihiro; Jassal, Simerjot K.; Sang, Yingying; Ballew, Shoshana H.; Grams, Morgan E.; Surapaneni, Aditya; Arnlov, Johan; Bansal, Nisha; Bozic, Milica; Brenner, Hermann; Brunskill, Nigel J.; Chang, Alex R.; et al. (EClinicalMedicine, 2020)
Background: Chronic kidney disease (CKD) measures (estimated glomerular filtration rate [eGFR] and albuminuria) are frequently assessed in clinical practice and improve the prediction of incident cardiovascular disease (CVD), yet most major clinical guidelines do not have a standardized approach for incorporating these measures into CVD risk prediction. “CKD Patch” is a validated method to calibrate and improve the predicted risk from established equations according to CKD measures. Methods: Utilizing data from 4,143,535 adults from 35 datasets, we developed several “CKD Patches” incorporating eGFR and albuminuria, to enhance prediction of risk of atherosclerotic CVD (ASCVD) by the Pooled Cohort Equation (PCE) and CVD mortality by Systematic COronary Risk Evaluation (SCORE). The risk enhancement by CKD Patch was determined by the deviation between individual CKD measures and the values expected from their traditional CVD risk factors and the hazard ratios for eGFR and albuminuria. We then validated this approach among 4,932,824 adults from 37 independent datasets, comparing the original PCE and SCORE equations (recalibrated in each dataset) to those with addition of CKD Patch. Findings: We confirmed the prediction improvement with the CKD Patch for CVD mortality beyond SCORE and ASCVD beyond PCE in validation datasets (Δc-statistic 0.027 [95% CI 0.018–0.036] and 0.010 [0.007–0.013] and categorical net reclassification improvement 0.080 [0.032–0.127] and 0.056 [0.044–0.067], respectively). The median (IQI) of the ratio of predicted risk for CVD mortality with CKD Patch vs. the original prediction with SCORE was 2.64 (1.89–3.40) in very high-risk CKD (e.g., eGFR 30–44 ml/min/1.73m2 with albuminuria ≥30 mg/g), 1.86 (1.48–2.44) in high-risk CKD (e.g., eGFR 45–59 ml/min/1.73m2 with albuminuria 30–299 mg/g), and 1.37 (1.14–1.69) in moderate risk CKD (e.g., eGFR 60–89 ml/min/1.73m2 with albuminuria 30–299 mg/g), indicating considerable risk underestimation in CKD with SCORE. The corresponding estimates for ASCVD with PCE were 1.55 (1.37–1.81), 1.24 (1.10–1.54), and 1.21 (0.98–1.46). Interpretation: The “CKD Patch” can be used to quantitatively enhance ASCVD and CVD mortality risk prediction equations recommended in major US and European guidelines according to CKD measures, when available. Funding: US National Kidney Foundation and the NIDDK.
CRIS-Team Scopus Importer:2020-11-06
Keywords: cardiovascular disease; Chronic kidney disease; meta-analysis; risk prediction

Increased acid sphingomyelinase activity in peripheral blood cells of acutely intoxicated patients with alcohol dependence - Reichel, Martin; Greiner, Elisabeth; Richter-Schmidinger, Tanja; Yedibela, Oezlem; Tripal, Philipp; Jacobi, Andrea; Bleich, Stefan; Gulbins, Erich; Kornhuber, Johannes (Alcoholism-Clinical and Experimental Research, 2010)
Background: Acid sphingomyelinase (ASM; EC 3.1.4.12) hydrolyses membrane sphingomyelin into the bioactive lipid ceramide and is thus involved in different cellular processes such as differentiation, immunity, or cell death. Activation of ASM has been reported in particular in conjunction with the cellular stress response to several external stimuli, and increased ASM activity was observed in a variety of human diseases. Ethanol-induced activation of ASM has been observed in different cell culture systems, thus raising the question about the effect of alcohol intoxication in human subjects on ASM activity in vivo. Methods: We determined ASM activity in peripheral blood mononucleated cells of 27 patients suffering from alcohol dependence. Patients were classified according to their blood alcohol concentration at admission, and ASM activity was determined repeatedly from all patients during alcohol withdrawal. Results: Acutely intoxicated patients displayed significantly higher ASM activity than patients in early abstinence (Mann-Whitney U test: Z = - 2.6, p = 0.009). ASM activity declined in acutely intoxicated patients to normal values with the transition from the intoxicated state to early abstinence (Wilcoxon test: Z = -2.7, p = 0.007). At the end of withdrawal, ASM activity was significantly increased again compared to the early phase of abstinence in both patient groups (Wilcoxon test: Z = -2.691, p = 0.007 and Z = -2.275, p = 0.023, respectively). Conclusions: Alcohol-induced activation of ASM occurs in human subjects and might be responsible for deleterious effects of ethanol intoxication. Chronic alcohol abuse may induce deregulation of sphingomyelin metabolism in general, and this impairment may cause side effects during withdrawal from alcohol. © 2009 by the Research Society on Alcoholism.
Created from Fastlane, Scopus look-up
Keywords: Alcohol Dependence; Ceramide; Sphingomyelin; Sphingomyelin Phosphodiesterase; Sphingomyelinase

Increased Aldosterone Release During Head-Up Tilt in Early Primary Hypertension - Reinold, Annemarie; Schneider, Andreas; Kalizki, Tatjana; Raff, Ulrike; Schneider, Markus P.; Schmieder, Roland; Schmidt, Bernhard M. W. (American Journal of Hypertension, 2017)
EVALuna2:3924

Increased Expression of Secreted Frizzled-Related Protein 4 in Polycystic Kidneys - Romaker, Daniel; Puetz, Michael; Teschner, Sven; Donauer, Johannes; Geyer, Marcel; Gerke, Peter; Rumberger, Brigitta; Dworniczak, Bernd; Pennekamp, Petra; Buchholz, Björn; Neumann, H. P. H.; Kumar, Rajiv; et al. (Journal of the American Society of Nephrology, 2009)
Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disease associated with progressive renal failure. Although cyst growth and compression of surrounding tissue may account for some loss of renal tissue, the other factors contributing to the progressive renal failure in patients with ADPKD are incompletely understood. Here, we report that secreted frizzled-related protein 4 (sFRP4) is upregulated in human ADPKD and in four different animal models of PKD, suggesting that sFRP4 expression is triggered by a common mechanism that underlies cyst formation. Cyst fluid from ADPKD kidneys activated the sFRP4 promoter and induced production of sFRP4 protein in renal tubular epithelial cell lines. Antagonism of the vasopressin 2 receptor blocked both promoter activity and tubular sFRP4 expression. In addition, sFRP4 selectively influenced members of the canonical Writ signaling cascade and promoted cystogenesis of the zebrafish pronephros. sFRP4 was detected in the urine of both patients and animals with PKD, suggesting that sFRP4 may be a potential biomarker for monitoring the progression of ADPKD. Taken together, these observations suggest a potential role for SFRP4 in the pathogenesis of ADPKD.

Increased pulse wave velocity in patients with an orthostatic blood pressure rise independent of other cardiovascular risk factors - Nolde, Janis M.; Lugo-Gavidia, Leslie Marisol; Kannenkeril, Dennis; Chan, Justine; Matthews, Vance B.; Carnagarin, Revathy; Azzam, Omar; Kiuchi, Márcio Galindo; Schlaich, Markus P. (Journal of Hypertension, 2021)
BACKGROUND: Positional changes in blood pressure (BP) have been shown to have effects on long-term outcomes. Although a BP drop with upright posture is frequently observed, an orthostatic rise in BP can also occur. Here, we aimed to investigate whether the phenotype of orthostatic hypertension is associated with more pronounced vascular hypertension-mediated organ damage (HMOD) and whether this is associated with other cardiovascular risk factors. METHODS: In a cohort of 200 patients referred to our tertiary hypertension clinic, we prospectively assessed unattended seated automated office BP and the response to 1 min of upright posture. The difference in BP after standing up was calculated and pulse wave velocity (PWV) was assessed as a marker of vascular HMOD. Routine clinical cardiovascular risk markers were also assessed. Regression models were used to assess the association between orthostatic BP changes and pulse wave velocity. RESULTS: Baseline characteristics and clinic cardiovascular risk factors were similar between orthostatic BP response groups. A U-shaped association was evident between PWV and orthostatic BP changes with elevated PWV in patients with either a fall or a rise in BP in response to upright posture. The regression models remained significant after adjusting for other cardiovascular risk factors, including 24 h ambulatory BP. CONCLUSION: Both an orthostatic BP drop and rise were associated with elevated PWV. Although standing BP is commonly measured in elderly hypertensive patients to exclude significant orthostatic hypotension, this simple measurement may provide an additional independent risk factor for vascular HMOD at any age.
CRIS-Team Scopus Importer:2021-06-18

Increased salt consumption induces body water conservation and decreases fluid intake - Rakova, Natalia; Kitada, Kento; Lerchl, Kathrin; Dahlmann, Anke; Birukov, Anna; Daub, Steffen; Kopp, Christoph; Pedchenko, Tetyana; Zhang, Yahua; Beck, Luis; Johannes, Bernd; Marton, Adriana; et al. (Journal of Clinical Investigation, 2017)
BACKGROUND: The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living under ultra-long-term controlled conditions. METHODS: Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance. RESULTS: A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion. CONCLUSION: Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion. FUNDING: Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.
EVALuna2:34240

Incretin-based drugs and the kidney in type 2 diabetes: choosing between DPP-4 inhibitors and GLP-1 receptor agonists - Mann, Johannes; Muskiet, Marcel H. A. (Kidney International, 2021)
CRIS-Team WoS Importer:2021-03-19

Individualised treatment targets in patients with type-2 diabetes and hypertension - Schmieder, Roland; Tschoepe, Diethelm; Koch, Cornelia; Ouarrak, Taoufik; Gitt, Anselm K. (Cardiovascular Diabetology, 2018)
AIM: Patients with type-2 diabetes mellitus (T2DM) are at high risk of cardiovascular events, accentuated in the presence of hypertension. At present, it is unclear to what extent the guidelines for the management of T2DM, advocating reduction in HbA1c levels to below target levels, are being adhered to in clinical practice. METHODS: DIALOGUE was a prospective, observational, non-interventional registry performed across multiple centres in Germany. Patients aged 18 years or older who had T2DM and hypertension for whom the treating physician considered blood glucose lowering medication as inadequate and/or not safe/tolerable and chose to add a further oral drug or switch drug treatment were included. Patients were assigned a treatment target HbA1c value (≤ 6.5% [strict]; > 6.5 to ≤ 7.0% [intermediate]; > 7.0 to ≤ 7.5% [lenient]). RESULTS: 8568 patients with T2DM and hypertension were enrolled. 6691 (78.1%) had 12-month follow-up. Patients who were assigned a strict HbA1c treatment target (n = 2644) were younger, had shorter diabetes duration, and less comorbidity in comparison to those with intermediate (n = 2912) or lenient targets (n = 1135). Only 53.1% of patients achieved their HbA1c treatment target (46.2% [strict], 56.8% [intermediate], 59.4% [lenient]). There was little sign of treatment intensification for patients that had not achieved their HbA1c target. CONCLUSIONS: Achievement of treatment targets was poor, leaving many patients with sub-optimal blood glucose levels. The apparent reluctance of physicians to intensify antidiabetic drug therapy is alarming, especially considering the evidence pointing to an association of hyperglycaemia and microvascular complications in patients with T2DM.
EVALuna2:33737

Infection and Predictors of Outcome of Cirrhotic Patients after Emergency Care Hospital Admission - Safi, Wajima; Elnegouly, Mayada; Schellnegger, Raphael; Umgelter, Katrin; Geisler, Fabian; Reindl, Wolfgang; Saugel, Bernd; Hapfelmeier, Alexander; Umgelter, Andreas (Annals of Hepatology, 2018)
Introduction and aims. We aimed to explore the impact of infection diagnosed upon admission and of other clinical baseline parameters on mortality of cirrhotic patients with emergency admissions. Material and methods. We performed a prospective observational monocentric study in a tertiary care center. The association of clinical parameters and established scoring systems with short-term mortality up to 90 days was assessed by univariate and multivariable Cox regression analysis. Akaike's Information Criterion (AIC) was used for automated variable selection. Statistical interaction effects with infection were also taken into account. Results. 218 patients were included. 71.2% were male, mean age was 61.1 +/- 10.5 years. Mean MELD score was 16.2 +/- 6.5, CLIF-consortium Acute on Chronic Liver Failure-score was 34 +/- 11. At 28, 90 and 365 days, 9.6%, 26.0% and 40.6% of patients had died, respectively. In multivariable analysis, respiratory organ failure [Hazard Ratio (HR) = 0.15], albumin substitution (HR = 2.48), non-HCC-malignancy (HR = 4.93), CLIF-C-ACLF (HR = 1.10), HCC (HR = 3.70) and first episode of ascites (HR = 0.11) were significantly associated with 90-day mortality. Patients with infection had a significantly higher 90-day mortality (36.3 vs. 20.1%, p = 0.007). Cultures were positive in 32 patients with resistance to cephalosporins or quinolones in 10, to ampicillin/sulbactam in 14 and carbapenems in 6 patients. Conclusion. Infection is common in cirrhotic ED admissions and increases mortality. The proportion of resistant microorganisms is high. The predictive capacity of established scoring systems in this setting was low to moderate.
CRIS-Team WoS Importer:2019-03-22

Inflammation Modifies the Paradoxical Association between Body Mass Index and Mortality in Hemodialysis Patients - Stenvinkel, Peter; Gillespie, Iain A.; Tunks, Jamie; Addison, Janet; Kronenberg, Florian; Drueke, Tilman B.; Marcelli, Daniele; Schernthaner, Guntram; Eckardt, Kai-Uwe; Floege, Juergen; Froissart, Marc; Anker, Stefan D. (Journal of the American Society of Nephrology, 2016)
High body mass index (BMI) is paradoxically associated with better outcome in hemodialysis (HD) patients. Persistent inflammation commonly features in clinical conditions where the obesity paradox is described. We examined the relationship between BMI and mortality in HD patients, accounting for inflammation, in a historic cohort study of 5904 incident HD patients enrolled in 2007-2009 (312 facilities; 15 European countries) with >=3 months of follow-up. Patients were classified by presence (n=3231) or absence (n=2673) of inflammation (C-reactive protein >=10 mg/l and/or albumin <=35 g/l). Patients were divided into quintiles by BMI (Q1-Q5: <21.5, 21.5-24.0, >24.0-26.4, >26.4-29.8, and >29.8 kg/m(2), respectively). Noninflamed patients in BMI Q5 formed the reference group. During a median follow-up period of 36.7 months, 1929 deaths occurred (822 cardiovascular), with 655 patients censored for renal transplantation and 1183 for loss to follow-up. Greater mortality was observed in inflamed patients (P<0.001). In fully adjusted time-dependent analyses, the all-cause mortality risk in noninflamed patients was higher only in the lowest BMI quintile (hazard ratio [HR, 1.80; 95% confidence interval [95% CI], 1.26 to 2.56). No protective effect was associated with higher BMI quintiles in noninflamed patients. Conversely, higher BMI associated with lower all-cause mortality risk in inflamed patients (HR [95% CI] for Q1: 5.63 [4.25 to 7.46]; Q2: 3.88 [2.91 to 5.17]; Q3: 2.89 [2.16 to 3.89]; Q4: 2.14 [1.59 to 2.90]; and Q5: 1.77 [1.30 to 2.40]). Thus, whereas a protective effect of high BMI was observed in inflamed patients, this effect was mitigated in noninflamed patients.
EVALuna2:3810

Inflammation, vitamin D and dendritic cell precursors in chronic kidney disease - Paul, K.; Franke, S.; Nadal, J.; Schmid, M.; Yilmaz, A.; Kretzschmar, D.; Bärthlein, Barbara; Titze, S.; Koettgen, A.; Wolf, G.; Busch, M. (Clinical and Experimental Immunology, 2016)
Decreased blood dendritic cell precursors (DCP) count is linked with atherosclerotic disease, while reduction of circulating DCP is also seen in patients with chronic kidney disease (CKD). As poor vitamin D status could be linked to a compromised innate immune response, we hypothesized that vitamin D status might be involved in the decrease in circulating DCP in CKD. Moreover, the potential role of inflammation was considered. Circulating myeloid (mDCP), plasmacytoid (pDCP) and total DCP (tDCP) were analysed using flow cytometry in 287 patients with CKD stage 3. Serum 25(OH)D and 1,25(OH)2D levels were measured using enzyme-linked immunosorbent assays (ELISA), interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-? using cytometric bead array, C-reactive protein (CRP) using a high-sensitivity (hs) ELISA. Contrary to our hypothesis, there was no association between vitamin D levels and DCP, although their number was decreased significantly in CKD (P < 0·001). Instead, mDCP (r = -0·211) and tDCP (r = -0·188,) were associated slightly negatively with hsCRP but positively with the estimated glomerular filtration rate (eGFR, r = 0·314 for tDCP). According to multivariate linear regression, only higher hsCRP concentration and the presence of diabetes mellitus had a significant negative influence on DCP count (P < 0·03, respectively) but not vitamin D, age and eGFR. A significant impact of vitamin D on the reduction of circulating DCP in CKD 3 patients can be neglected. Instead, inflammation as a common phenomenon in CKD and diabetes mellitus had the main influence on the decrease in DCP. Thus, a potential role for DCP as a sensitive marker of inflammation and cardiovascular risk should be elucidated in future studies.
EVALuna2:158

Influence of Age on Upper Arm Cuff Blood Pressure Measurement - Picone, Dean S.; Schultz, Martin G.; Otahal, Petr; Black, J. Andrew; Bos, Willem J.; Chen, Chen Huan; Cheng, Hao Min; Cremer, Antoine; Dwyer, Nathan; Fonseca, Ricardo; Hughes, Alun D.; Kim, Hack Lyoung; et al. (Hypertension, 2020)
Blood pressure (BP) is a leading global risk factor. Increasing age is related to changes in cardiovascular physiology that could influence cuff BP measurement, but this has never been examined systematically and was the aim of this study. Cuff BP was compared with invasive aortic BP across decades of age (from 40 to 89 years) using individual-level data from 31 studies (1674 patients undergoing coronary angiography) and 22 different cuff BP devices (19 oscillometric, 1 automated auscultation, 2 mercury sphygmomanometry) from the Invasive Blood Pressure Consortium. Subjects were aged 64±11 years, and 32% female. Cuff systolic BP overestimated invasive aortic systolic BP in those aged 40 to 49 years, but with each older decade of age, there was a progressive shift toward increasing underestimation of aortic systolic BP (P<0.0001). Conversely, cuff diastolic BP overestimated invasive aortic diastolic BP, and this progressively increased with increasing age (P<0.0001). Thus, there was a progressive increase in cuff pulse pressure underestimation of invasive aortic PP with increasing decades of age (P<0.0001). These age-related trends were observed across all categories of BP control. We conclude that cuff BP as an estimate of aortic BP was substantially influenced by increasing age, thus potentially exposing older people to greater chance for misdiagnosis of the true risk related to BP.
CRIS-Team Scopus Importer:2020-03-17
Keywords: aging; cardiovascular disease; coronary angiography; risk factor; sphygmomanometers

Influence of blood flow on arteriolar wall-to-lumen ratio in the human retinal circulation in vivo - Ritt, Martin; Harazny, Joanna M.; Ott, Christian; Raff, Ulrike; Lehmann, Marina; Michelson, Georg; Schmieder, Roland (Microvascular Research, 2012)
We hypothesized that blood flow impacts on arteriolar wall-to-lumen ratio and that vasodilatory capacity is negatively related to arteriolar wall-to-lumen ratio in the human retinal vascular bed.The study cohort comprised 141 non-diabetic untreated male patients with (n=52) or without (n=89) arterial hypertension but without evidence for cardiovascular disease. Retinal capillary blood flow (RCF) before and after exposure to flicker light and to infusion of nitric oxide (NO) synthase inhibitor N-monomethyl-l-arginine (L-NMMA), and parameters of retinal arteriolar morphology, e.g. wall-to-lumen ratio, were assessed non-invasively and in vivo by scanning laser Doppler flowmetry.The study cohort was grouped according to the median RCF into two groups. Patients with RCF above the median revealed lower wall-to-lumen ratio (0.30±0.1 vs 0.34±0.1 (-), P adjusted=0.023) compared to patients with RCF equal or below the median. In addition, RCF was negatively related to wall-to-lumen ratio independently of cardiovascular risk factors (ß=-0.224, P=0.026). In parallel, the decrease of RCF to L-NMMA infusion was greater in patients with RCF above the median compared to the counter group (-8.95±11 vs. 0.35±15 (%), P adjusted <0.001). The increase in RCF to flicker light exposure was negatively related to wall-to-lumen ratio in hypertensive but not in normotensive or all patients (r=-0.292, P=0.047, r=-0.035, P=0.746 and r=-0.126, P=0.144, respectively).In the retinal circulation blood flow impacts on arteriolar wall-to-lumen ratio. Basal NO activity might modulate blood flow and arteriolar morphological changes. In hypertensive, but not in normotensive patients, the vasodilatory capacity is negatively related to arteriolar wall-to-lumen ratio in the human retinal vascular bed.
EVALuna2:3527

Influence of Gender on Blood Pressure Reduction After Renal Denervation in GSR DEFINE - Weil, Joachim; Mahfoud, Felix; Schmieder, Roland; Narkiewicz, Krzysztof; Williams, Bryan; Fahy, Martin; Mancia, Giuseppe (JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Influence of Low Protein Diet-Induced Fetal Growth Restriction on the Neuroplacental Corticosterone Axis in the Rat - Schmidt, Marius; Rauh, Manfred; Schmid, Matthias C.; Hübner, Hanna; Rübner, Matthias; Wachtveitl, Rainer; Cordasic, Nada; Rascher, Wolfgang; Menendez-Castro, Carlos; Hartner, Andrea; Fahlbusch, Fabian B. (Frontiers in Endocrinology, 2019)
Objectives: Placental steroid metabolism is linked to the fetal hypothalamus-pituitary-adrenal axis. Intrauterine growth restriction (IUGR) might alter this cross-talk and lead to maternal stress, in turn contributing to the pathogenesis of anxiety-related disorders of the offspring, which might be mediated by fetal overexposure to, or a reduced local enzymatic protection against maternal glucocorticoids. So far, direct evidence of altered levels of circulating/local glucocorticoids is scarce. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) allows quantitative endocrine assessment of blood and tissue. Using a rat model of maternal protein restriction (low protein [LP] vs. normal protein [NP]) to induce IUGR, we analyzed fetal and maternal steroid levels via LC-MS/MS along with the local expression of 11beta-hydroxysteroid- dehydrogenase (Hsd11b).
CRIS-Team WoS Importer:2019-03-20

Influence of officially ordered restrictions during the first wave of COVID-19 pandemic on physical activity and quality of life in patients after kidney transplantation in a telemedicine based aftercare program—a KTx360° sub study - Hanke, Alexander A.; Sundermeier, Thorben; Boeck, Hedwig T.; Schieffer, Elisabeth; Boyen, Johanna; Braun, Ana Céline; Rolff, Simone; Stein, Lothar; Kück, Momme; Schiffer, Mario; Pape, Lars; de Zwaan, Martina; et al. (International Journal of Environmental Research and Public Health, 2020)
Guidelines recommend a healthy lifestyle and regularly physical activity (PA) after kidney transplantation (KTx). The KTx360° program is a multicenter, multisectoral, multimodal, telemedicine-based follow-up care program. Effects of the first COVID-19 wave restrictions on health-related quality of life and PA of supervised KTx360° patients were evaluated using an online questionnaire. Six hundred and fifty-two KTx360° patients were contacted via email and were asked to complete the Freiburg questionnaire of physical activity and the Short form 12 Health Survey (SF12) online. Pre-pandemic and lockdown data were compared in 248 data sets. While sporting activity decreased during the COVID-19 pandemic, basic and leisure activity increased, resulting in increased overall activity. The physical component scale of the SF-12 was in the low normal range before as well as during the pandemic, with a small but significant increase during the pandemic. The mental component scale showed normal values before and during pandemic with a small but statistically significant decrease. Our study supports the effectiveness of a telemedicine based program for KTx patient care in maintaining PA and quality of life during the first peak of the COVID-19 pandemic. However, further research and observation during the ongoing pandemic are required.
CRIS-Team Scopus Importer:2020-12-25
Keywords: COVID-19; Kidney transplantation; Physical activity; QoL; Quality of life; Restrictions

Information Needs of kidney transplant Patients regarding immunosuppressive Medication: Prevalence and Correlates - Klewitz, Felix; Noehre, Mariel; Bauer-Hohmann, Maximilian; Tegtbur, Uwe; Schiffer, Lena; Pape, Lars; Schiffer, Mario; De Zwaan, Martina (ZEITSCHRIFT FUR PSYCHOSOMATISCHE MEDIZIN UND PSYCHOTHERAPIE, 2019)
CRIS-Team WoS Importer:2020-03-17

Information Needs of Patients About Immunosuppressive Medication in a German Kidney Transplant Sample: Prevalence and Correlates - Klewitz, Felix; Noehre, Mariel; Bauer-Hohmann, Maximilian; Tegtbur, Uwe; Schiffer, Lena; Pape, Lars; Schiffer, Mario; De Zwaan, Martina (Frontiers in Psychiatry, 2019)
Background: Worldwide clinical guidelines for the care of kidney transplant (KT) recipients recognize the importance of health care providers imparting appropriate immunosuppressive medication (ISM) information for the facilitation of safe medication self-management. The extent of medication information made available is, however, not necessarily what patients require to know about their prescribed medicines. A useful indicator for determining the quality of prescription practice is to what degree the provided information meets the personal needs of patients. No previous studies have focused on the ISM information needs of KT patients. This study aims to investigate how satisfied KT patients are with the provided ISM information and to examine the association between satisfaction levels and socio-demographic, psychosocial, and transplant-related variables.
CRIS-Team WoS Importer:2019-07-16

INFORMATION NEEDS OF PATIENTS IN A GERMAN KIDNEY TRANSPLANT SAMPLE: PREVALENCE AND CORRELATES - Klewitz, F.; Noehre, M.; Bauer-Hohmann, M.; Tegtbur, U.; Schiffer, L.; Pape, L.; Schiffer, Mario; De Zwaan, M. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Inhibition of oxygen-sensing prolyl hydroxylases increases lipid accumulation in human primary tubular epithelial cells without inducing ER stress - Schley, Gunnar; Grampp, Steffen; Goppelt-Strübe, Margarete (Cell and Tissue Research, 2020)
The role of the hypoxia-inducible transcription factor (HIF) pathway in renal lipid metabolism is largely unknown. As HIF stabilizing prolyl hydroxylase (PHD) inhibitors are currently investigated in clinical trials for the treatment of renal anemia, we studied the effects of genetic deletion and pharmacological inhibition of PHDs on renal lipid metabolism in transgenic mice and human primary tubular epithelial cells (hPTEC). Tubular cell-specific deletion of HIF prolyl hydroxylase 2 (Phd2) increased the size of Oil Red-stained lipid droplets in mice. In hPTEC, the PHD inhibitors (PHDi) DMOG and ICA augmented lipid accumulation, which was visualized by Oil Red staining and assessed by microscopy and an infrared imaging system. PHDi-induced lipid accumulation required the exogenous availability of fatty acids and was observed in both proximal and distal hPTEC. PHDi treatment was not associated with structural features of cytotoxicity in contrast to treatment with the immunosuppressant cyclosporine A (CsA). PHDi and CsA differentially upregulated the expression of the lipid droplet-associated genes PLIN2, PLIN4 and HILPDA. Both PHDi and CsA activated AMP-activated protein kinase (AMPK) indicating the initiation of a metabolic stress response. However, only CsA triggered endoplasmic reticulum (ER) stress as determined by the increased mRNA expression of multiple ER stress markers but CsA-induced ER stress was not linked to lipid accumulation. Our data raise the possibility that PHD inhibition may protect tubular cells from toxic free fatty acids by trapping them as triacylglycerides in lipid droplets. This mechanism might contribute to the renoprotective effects of PHDi in experimental kidney diseases.
CRIS-Team WoS Importer:2020-04-03

Inhibition of Rho kinases increases directional motility of microvascular endothelial cells - Breyer, Johannes; Samarin, Jana; Rehm, Margot; Lautscham, Lena; Fabry, Ben; Goppelt-Strübe, Margarete (Biochemical Pharmacology, 2012)

INHIBITION OF SGLT-2 CANNOT RESCUE NEPHRIN EXPRESSION IN DIABETIC NEPHROPATHY - Kotb, Ahmed; Klanke, Bernd; Kroll, Jens; Schiffer, Mario (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice - Fuchs, Michaela A.A.; Broeker, Katharina A.E.; Schrankl, Julia; Burzlaff, Nicolai; Willam, Carsten; Wagner, Charlotte; Kurtz, Armin (Kidney International, 2021)
Kidney fibrosis is characterized by the development of myofibroblasts originating from resident kidney and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various cytokines. Among these, transforming growth factor β1 (TGFβ1) is considered a central trigger for kidney fibrosis. We found a highly upregulated expression of TGFβ1 and TGFβ receptor 2 (TGFβ-R2) mRNAs in kidney interstitial cells in experimental fibrosis. Here, we investigated the contribution of TGFβ1 signaling in resident kidney interstitial cells to organ fibrosis using the models of adenine induced nephropathy and unilateral ureteral occlusion in mice. For this purpose TGFβ1 signaling was interrupted by inducible deletion of the TGFβ-R2 gene in interstitial cells expressing the fibroblast marker platelet derived growth factor receptor-β. Expression of profibrotic genes was attenuated up to 50% in kidneys lacking TGFβ-R2 in cells positive for platelet derived growth factor receptor-β. Additionally, deletion of TGFβ-R2 prevented the decline of erythropoietin production in ureter ligated kidneys. Notably, fibrosis associated expression of α-smooth muscle actin as a myofibroblast marker and deposits of extracellular collagens were not altered in mice with targeted deletion of TGFβ-R2. Thus, our findings suggest an enhancing effect of TGFβ1 signaling in resident interstitial cells that contributes to profibrotic gene expression and the downregulation of erythropoietin production, but not to the development of myofibroblasts during kidney fibrosis.
CRIS-Team Scopus Importer:2021-05-07
Keywords: erythropoietin; experimental kidney fibrosis; PDGFR-β; renal interstitial cells; TGFβ

Inhibitors of oxygen sensing prolyl hydroxylases regulate nuclear localization of the transcription factors Smad2 and YAP/TAZ involved in CTGF synthesis - Preisser, Felix; Giehl, Klaudia; Rehm, Margot; Goppelt-Strübe, Margarete (BBA - Biochimica et Biophysica Acta, 2016)
Pharmacological inhibition of oxygen sensing prolyl hydroxylase domain enzymes (PHDs) has been shown to preserve renal structure and function in various models of kidney disease. Since transforming growth factor ?-1 (TGF?-1) is one of the major mediators of kidney injury, we investigated if inhibition of PHDs with subsequent stabilization of hypoxia inducible transcription factors (HIF) might interfere with TGF?-1 signaling with special emphasis on its target gene connective tissue growth factor (CTGF). Overnight incubation of human renal tubular cells, primary cells and cell lines, with the PDH inhibitor DMOG increased Smad3 expression, but barely affected Smad2. Both Smads were translocated into the nucleus upon activation of the cells with TGF?-1. Interestingly, Smad3 nuclear localization was enhanced upon pretreatment of the cells with DMOG for several hours, whereas nuclear Smad2 was reduced. This differential localization was independent of Smad2/3 phosphorylation. Reduced nuclear Smad2 correlated with impaired CTGF secretion in DMOG-treated cells and transient downregulation of Smad2 interfered with TGF?-1-induced CTGF synthesis. Furthermore, YAP was confirmed as indispensable transcription factor involved in CTGF synthesis. Nuclear localization of YAP and TAZ was reduced in DMOG-treated cells. Our data thus provide evidence for DMOG-mediated reduction of CTGF expression by regulating the nuclear localization of the transcription factors Smad2, YAP and TAZ. Prolonged inhibition of PHDs was necessary to achieve alterations in cellular localization suggesting an indirect HIF-mediated effect. This mechanism might be extended to other transcription factors and target genes, and may thus represent a novel mechanism of negative regulation of gene expression by PHD inhibition.
EVALuna2:3862

In Liddle Syndrome, Epithelial Sodium Channel Is Hyperactive Mainly in the Early Part of the Aldosterone-Sensitive Distal Nephron - Nesterov, Viatcheslav; Krüger, Bettina; Bertog, Marko; Dahlmann, Anke; Palmisano, Ralf; Korbmacher, Christoph (Hypertension, 2016)
The epithelial sodium channel (ENaC) is rate limiting for Na(+) absorption in the aldosterone-sensitive distal nephron comprising the late distal convoluted tubule (DCT2), the connecting tubule (CNT), and the entire collecting duct. Liddle syndrome (pseudohyperaldosteronism), a severe form of salt-sensitive hypertension, is caused by gain-of-function mutations of ENaC, but the precise tubular site of increased ENaC function is unknown. In the cortical collecting duct (CCD), ENaC is known to be regulated by aldosterone. In contrast, we recently reported aldosterone-independent ENaC regulation in the early part of the aldosterone-sensitive distal nephron. Here, we investigated ENaC function in the transition zone of DCT2/CNT or CNT/CCD microdissected from mice homozygous for Liddle syndrome mutation or from wild-type control mice. Whole-cell patch-clamp recordings were used to measure amiloride-sensitive ENaC currents in nephron fragments from mice maintained on different sodium diets to vary plasma aldosterone levels. Our data indicate that in mice with Liddle syndrome, the primary site of increased Na(+) reabsorption is the DCT2/CNT. In addition, increased aldosterone responsiveness of ENaC in CNT/CCD may contribute to salt-sensitive hypertension in Liddle syndrome. Single channel properties of ENaC were similar in Liddle syndrome mutation and wild-type mice, but ENaC expression at the apical membrane was increased in Liddle syndrome mutation when compared with wild-type mice, in particular, in animals maintained on a high salt diet. Our findings highlight the importance of ENaC function and regulation in the early part of the aldosterone-sensitive distal nephron for the maintenance of sodium balance and blood pressure control.
EVALuna2:4523

In-situ analysis of mast cells and dendritic cells in coronary atherosclerosis in chronic kidney disease (CKD) - Wachter, David; Neureiter, D.; Campean, Valentina; Hilgers, Karl Friedrich; Buettner-Herold, M.; Daniel, Christoph; Benz, Kerstin; Amann, Kerstin Ute (Histology and Histopathology, 2018)
AIMS: Mast cells (MC) and dendritic cells (DC) have immune modulatory function and can influence T-cell activity. Both cell types have been found in atherosclerotic plaques and are thought to play an important role for plaque stability. Compared to matched segments of the non-renal population, patients with chronic kidney disease (CKD) show a more pronounced and more aggressive course of atherosclerosis with higher plaque calcification and significantly higher complications rates. It was the aim of this study to analyze the number and localization of MCs and DCs, macrophages, T- and B-cells as well as the expression of markers of inflammation such as CRP and NFκB in calcified and non-calcified atherosclerotic plaques of patients with CKD and control patients. METHODS: Fifty coronary atherosclerotic plaques from patients with endstage CKD (CKD, n=25) and control (n=25) patients were categorized according to the Stary classification and investigated using immunohistochemistry (markers for MC, DC, T, B, macrophage and NFκB). Expression was analyzed separately for the complete plaque area as well as for the different plaque subregions and correlations were analyzed. RESULTS: We found only very few DCs and MCs per lesion area with slightly increased numbers in calcified plaques. MCs per plaque area were significantly more frequent in CKD than in control patients and this was independent of plaque calcification. MCs were most frequently found in the shoulder and basis of the plaque. DCs per plaque area were significantly less in calcified plaques of CKD compared to control patients. In control, but not in CKD patients, DCs were significantly more frequent in calcified than in non-calcified plaques. Within the plaques DCs were similarly distributed between all 4 subregions. CONCLUSIONS: Coronary atherosclerotic plaques of CKD patients showed a significantly higher number of MCs whereas DCs were less frequent compared to control patients particularly if plaques were calcified. These findings might indicate a potential proinflammatory role of MCs, but not of DCs in atherosclerotic lesions of CKD patients, adding another characteristic of advanced atherosclerosis in these patients.
EVALuna2:34422

Intense immunostaining of heat shock protein 70 within renal interstitium associates with long-term renal survival in an ANCA-associated vasculitis cohort - Petrakis, Ioannis; Androvitsanea, Ariadni; Stratakis, Stavros; Daphnis, Eugene; Stylianou, Kostas (Cell Stress & Chaperones, 2020)
In anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) genetic predisposition, ANCA autoantibodies, neutrophil extracellular traps (NETs), complement activation, and toll-like receptor signaling are implicated in AAV pathogenesis. Heat shock proteins (HSPs), a highly conserved group of small-sized molecular chaperones, take part in protein folding during cellular stress. Although HSPs were initially observed intracellularly, it has been shown that they can be secreted in the extracellular space and modulate the immune response in various autoimmune diseases including AAV. The scope of the present study is to investigate the role of heat shock protein 60 (HSP60) and 70 (HSP70) in the long renal effects in an ANCA vasculitis cohort. In this cohort of ANCA-associated vasculitis, 29 patients were followed up over 20 years. At diagnosis, immunohistochemistry was performed for HSP60 and HSP70 within the various nephron compartments. Higher renal HSP60 expression was associated with increased interstitial inflammatory infiltrates at diagnosis, while HSP70 expression was associated with a greater extent of interstitial fibrosis at diagnosis. Notably, intense tissue expression of HSP70 at the time of biopsy was associated with a worsened kidney survival. Renal HSP70 expression was associated with poor renal outcomes during long-term follow-up. This finding may indicate a role of HSPs in renal disease progression in ANCA vasculitis. Further validating studies are needed to verify a causative association between HSP70 expression and renal outcomes in ANCA-associated vasculitis.
CRIS-Team Scopus Importer:2020-09-11
Keywords: ANCA-vasculitis; Heat shock protein; Interstitial fibrosis; Interstitial inflammation; Pauci-immune glomerulonephritis

Intensified pharmaceutical care is improving immunosuppressive medication adherence in kidney transplant recipients during the first post-transplant year: a quasi-experimental study - Joost, Robert; Dörje, Frank; Schwitulla, Judith; Eckardt, Kai-Uwe; Hugo, Christian (Nephrology Dialysis Transplantation, 2014)
Medication adherence is critical for transplant patients because the consequences of non-adherence can result in allograft loss and may be life threatening.A prospective study with 74 renal transplant recipients using a sequential control group design was performed to investigate the impact of a pharmaceutical intensified care programme led by a clinical pharmacist on daily drug adherence during the first year after renal transplantation. Thirty-nine patients of the control group received the already established standardized drug and transplant training, while 35 patients of the intensified care group (ICG) received additional inpatient and outpatient pharmaceutical care and counselling by a dedicated clinical pharmacist. Applied interventions were clustered and classified using the behaviour change technique taxonomy according to Michie. Adherence to immunosuppressive drug therapy was monitored up to 1 year using a medication event monitoring system, pill count (PC), drug holiday (DH) occurrence, Morisky questionnaire and self-report.Sixty-seven patients (35 of the standard care and 32 of the ICG) were analysed. Implementation of DA was significantly (P = 0.014) improved in patients of the ICG (91%) compared with SCG (75%) during the first year after transplantion. Daily adherence measures were already improved within 30-40 days after start of intensified patient care and continued throughout the study period. Intensified care patients also showed significantly better results for taking adherence (P = 0.006), PC (P = 0.008) and DHs (P = 0.001).The additional, intensified pharmaceutical care improved patients' medication adherence remarkably, suggesting that the applied additional care programme has the potential to improve outcomes after organ transplantation.
EVALuna2:3715

Interdisciplinary German clinical practice guidelines on the management of type B aortic dissection Interdisziplinäre deutsche Leitlinien für die klinische Praxis zur Behandlung der Aortendissektion Typ B - Oberhuber, A.; Raddatz, A.; Betge, S.; Ploenes, C.; Ito, W.; Janosi, R. A.; Ott, Christian; Langheim, E.; Czerny, M.; Puls, R.; Maßmann, A.; Zeyer, K.; et al. (Gefässchirurgie, 2023)
CRIS-Team Scopus Importer:2023-05-05

Interim analysis of the COSA (COVID-19 patients treated with the Seraph(R) 100 Microbind(R) Affinity filter) registry - Schmidt, Julius J.; Borchina, Dan Nicolae; Van'T Klooster, Mariet; Bulhan-Soki, Khalida; Okioma, Reuben; Herbst, Larissa; Rodriguez, Diego Sandoval; Premuzic, Vedran; Buettner, Stefan; Bader, Birgit; Serednicki, Wojciech; Zasada, Ewa; et al. (Nephrology Dialysis Transplantation, 2021)
Background The Seraph(R) 100 Microbind(R) Affinity Blood Filter is a haemoperfusion device that is licensed for the reduction of pathogens, including several viruses, in the blood. It received Emergency Use Authorization for the treatment of severe coronavirus disease 2019 (COVID-19) by the Food and Drug Administration (FDA). Several studies have shown that the blood viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlates with adverse outcomes and removal of the nucleocapsid of the SARS-CoV-2 virus by the Seraph(R) 100 has been recently demonstrated. The aim of this registry was to evaluate the safety and efficacy of Seraph(R) 100 treatment for COVID-19 patients. Methods Twelve hospitals from six countries representing two continents documented patient and treatment characteristics as well as outcome parameters without reimbursement. Additionally, mortality and safety results of the device were reported. A total of 102 treatment sessions in 82 patients were documented in the registry. Four patients were excluded from mortality analysis due to incomplete outcome data, which were available in the other 78 patients. Results Overall, a 30-day mortality rate of 46.2% in the 78 patients with complete follow-up was reported. The median treatment time was 5.00 h (4.00-13.42) and 43.1% of the treatments were performed as haemoperfusion only. Adverse events of the Seraph(R) 100 treatment were reported in 8.8% of the 102 treatments and represented the premature end of treatment due to circuit failure. Patients who died were treated later in their intensive care unit (ICU) stay and onset of COVID symptoms. They also had higher ferritin levels. Multivariate Cox regression revealed that delayed Seraph(R) 100 treatment after ICU admission (>60 h), as well as bacterial superinfection, were associated with mortality. While average predicted mortality rate according to Sequential Organ Failure Assessment (SOFA) score in ICU patients was 56.7%, the observed mortality was 50.7%. In non-ICU patients, Coronavirus Clinical Characterisation Consortium (4C) score average predicted a mortality rate of 38.0%, while the observed mortality rate was 11.1%. Conclusions The treatment of COVID-19 patients with Seraph(R) 100 is well tolerated and the circuit failure rate was lower than previously reported for kidney replacement therapy (KRT) in COVID-19 patients. Mortality correlated with late initiation of Seraph treatment after ICU admission and bacterial superinfection. Compared with predicted mortality according to 4C and SOFA scores, mortality of Seraph(R) 100-treated patients reported in the registry was lower.
CRIS-Team WoS Importer:2022-03-18

Interleukin-1 beta activates essential checkpoints in the formation of lung-resident memory T cell - Lapuente, D.; Fuchs, J.; Maier, Carolin; Bonsmann, M. Storcksdieck Genannt; Maaske, A.; Stab, V.; Heinecke, V.; Liedtke, K.; Hess, R.; Westendorf, A.; Bayer, W.; Ehrhardt, C.; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

International consensus definitions of clinical trial outcomes for kidney failure: 2020 - Levin, Adeera; Agarwal, Rajiv; Herrington, William G.; Heerspink, Hiddo L.; Mann, Johannes; Shahinfar, Shahnaz; Tuttle, Katherine R.; Donner, Jo Ann; Jha, Vivekanand; Nangaku, Masaomi; de Zeeuw, Dick; Jardine, Meg J.; et al. (Kidney International, 2020)
Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multi-stakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The consensus of the meeting participants was that clinical trial kidney failure outcomes should be comprised of a composite that includes receipt of a kidney transplant, initiation of maintenance dialysis, and death from kidney failure; it may also include outcomes based solely on laboratory measurements of glomerular filtration rate: a sustained low glomerular filtration rate and a sustained percent decline in glomerular filtration rate. Discussion included important considerations, such as (i) recognition of existing nomenclature for kidney failure; (ii) applicability across resource settings; (iii) ease of understanding for all stakeholders; and (iv) avoidance of inappropriate complexity so that the definitions can be used across ranges of populations and trial methodologies. The final definitions reflect the consensus for use in clinical trials.
CRIS-Team Scopus Importer:2020-10-09
Keywords: continuous kidney replacement therapy; kidney failure; maintenance dialysis; transplantation

International Network of Chronic Kidney Disease cohort studies (iNET-CKD): a global network of chronic kidney disease cohorts - Dienemann, Thomas; Fujii, Naohiko; Orlandi, Paula; Nessel, Lisa; Furth, Susan L.; Hoy, Wendy E.; Matsuo, Seiichi; Mayer, Gert; Methven, Shona; Schaefer, Franz; Schaeffner, Elke S.; Sola, Laura; et al. (BMC Nephrology, 2016)
Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within public health agendas in many countries. Studies focusing on the natural history of CKD are challenging to design and conduct, because of the long time-course of disease progression, a wide variation in etiologies, and a large amount of clinical variability among individuals with CKD. With the difference in health-related behaviors, healthcare delivery, genetics, and environmental exposures, this variability is greater across countries than within one locale and may not be captured effectively in a single study.Studies were invited to join the network. Prerequisites for membership included: 1) observational designs with a priori hypotheses and defined study objectives, patient-level information, prospective data acquisition and collection of bio-samples, all focused on predialysis CKD patients; 2) target sample sizes of 1,000 patients for adult cohorts and 300 for pediatric cohorts; and 3) minimum follow-up of three years. Participating studies were surveyed regarding design, data, and biosample resources.Twelve prospective cohort studies and two registries covering 21 countries were included. Participants age ranges from >2 to >70 years at inclusion, CKD severity ranges from stage 2 to stage 5. Patient data and biosamples (not available in the registry studies) are measured yearly or biennially. Many studies included multiple ethnicities; cohort size ranges from 400 to more than 13,000 participants. Studies' areas of emphasis all include but are not limited to renal outcomes, such as progression to ESRD and death.iNET-CKD (International Network of CKD cohort studies) was established, to promote collaborative research, foster exchange of expertise, and create opportunities for research training. Participating studies have many commonalities that will facilitate comparative research; however, we also observed substantial differences. The diversity we observed across studies within this network will be able to be leveraged to identify genetic, behavioral, and health services factors associated with the course of CKD. With an emerging infrastructure to facilitate interactions among the investigators of iNET-CKD and a broadly defined research agenda, we are confident that there will be great opportunity for productive collaborative investigations involving cohorts of individuals with CKD.
EVALuna2:3912

Interpretation of noninvasive retinal microvascular studies: the individual source of the automatic full field imaging analysis program has to be taken into account - Harazny, Joanna M.; Schmieder, Roland (Journal of Hypertension, 2018)
EVALuna2:35228

INTERSTITIAL HSP70 EXPRESSION AT DIAGNOSIS ASSOCIATES WITH LONG TERM RENAL SURVIVAL IN AN ANCA VASCULITIS COHORT. - Petrakis, Ioannis; Androvitsanea, Ariadni; Stratakis, Stavros; Daphnis, Eugene; Stylianou, Kostas (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2020)
CRIS-Team WoS Importer:2020-09-18

Inter-study reproducibility of arterial spin labelling magnetic resonance imaging for measurement of renal perfusion in healthy volunteers at 3 Tesla - Gillis, Keith A.; Mccomb, Christie; Foster, John E.; Taylor, Alison H. M.; Patel, Rajan K.; Morris, Scott T. W.; Jardine, Alan G.; Schneider, Markus P.; Roditi, Giles H.; Delles, Christian; Mark, Patrick B. (BMC Nephrology, 2014)
Measurement of renal perfusion is a crucial part of measuring kidney function. Arterial spin labelling magnetic resonance imaging (ASL MRI) is a non-invasive method of measuring renal perfusion using magnetised blood as endogenous contrast. We studied the reproducibility of ASL MRI in normal volunteers.ASL MRI was performed in healthy volunteers on 2 occasions using a 3.0 Tesla MRI scanner with flow-sensitive alternating inversion recovery (FAIR) perfusion preparation with a steady state free precession (True-FISP) pulse sequence. Kidney volume was measured from the scanned images. Routine serum and urine biochemistry were measured prior to MRI scanning.12 volunteers were recruited yielding 24 kidneys, with a mean participant age of 44.1 ± 14.6 years, blood pressure of 136/82 mmHg and chronic kidney disease epidemiology formula estimated glomerular filtration rate (CKD EPI eGFR) of 98.3 ± 15.1 ml/min/1.73 m2. Mean kidney volumes measured using the ellipsoid formula and voxel count method were 123.5 ± 25.5 cm3, and 156.7 ± 28.9 cm3 respectively. Mean kidney perfusion was 229 ± 41 ml/min/100 g and mean cortical perfusion was 327 ± 63 ml/min/100 g, with no significant differences between ASL MRIs. Mean absolute kidney perfusion calculated from kidney volume measured during the scan was 373 ± 71 ml/min. Bland Altman plots were constructed of the cortical and whole kidney perfusion measurements made at ASL MRIs 1 and 2. These showed good agreement between measurements, with a random distribution of means plotted against differences observed. The intra class correlation for cortical perfusion was 0.85, whilst the within subject coefficient of variance was 9.2%. The intra class correlation for whole kidney perfusion was 0.86, whilst the within subject coefficient of variance was 7.1%.ASL MRI at 3.0 Tesla provides a repeatable method of measuring renal perfusion in healthy subjects without the need for administration of exogenous compounds. We have established normal values for renal perfusion using ASL MRI in a cohort of healthy volunteers.
EVALuna2:3713

Intraprocedural reduction of the veno-arterial norepinephrine gradient correlates with blood pressure response after renal denervation - Tiroch, Klaus; Sause, Armin; Szymanski, Jacek; Nover, Ina; Leischik, Roman; Mann, Johannes; Vorpahl, Marc; Seyfarth, Melchior (EuroIntervention, 2015)
No intraprocedural assessment is currently available to evaluate the extent of nerve ablation by renal denervation (RDN). We prospectively evaluated the association of intraprocedural reduction of renal veno-arterial norepinephrine gradient with blood pressure (BP) response after RDN.In 46 consecutive RDN patients, the periprocedural norepinephrine veno-arterial difference was defined as veno-arterial norepinephrine gradient. We observed a reduction of the office systolic BP from 176±19 mmHg to 165±24 mmHg (p=0.02) at three months and 163±22 mmHg (p=0.02) at six months. The mean and maximum systolic ABP decreased by 5 mmHg (p=0.03) and 9 mmHg (p=0.02), respectively. There was a decrease of the norepinephrine RV-RA difference from pre- to post-procedural levels (median 186 pg/ml [54;466] vs. 81 pg/ml [0;182], p=0.02). OBP responders (office systolic BP reduction >=10 mmHg) showed a greater reduction of the norepinephrine gradient compared to non-responders (-290±450 pg/ml vs. -4±106 pg/ml, p=0.01). Patients with a reduction of norepinephrine gradient in both kidneys showed the most pronounced decrease of the systolic OBP (-24±14 mmHg) compared to patients with a reduction of norepinephrine gradient in only one kidney (-7±15 mmHg) or patients without a norepinephrine reduction (-3±19 mmHg, p=0.03 vs. bilateral reduction).Measuring renal norepinephrine gradient during RDN may be a method to gauge the extent of renal nerve ablation.
EVALuna2:3874

INTRARENAL HIGH SALT ADMINISTRATION CAUSES TONIC INHIBITION OF RENAL SYMPATHETIC NERVE ACTIVITY (RSNA) - Hindermann, Martin; Rodionova, Kristina; Dietz, Amelie; Ditting, Tilmann; Ott, Christian; Schmieder, Roland; Amann, Kerstin Ute; Veelken, Roland (2018)
EVALuna2:204842

„Intravasal trocken – Gewebe voll“: interstitielles Ödem und Volumenmanagement in der Intensivmedizin - Schley, Gunnar; Willam, Carsten (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2021)
In the second phase of shock therapy, we regularly find fluid overload with edema in our patients, which not only involves the skin and interstitial tissue but can also impair kidney, liver and pulmonary function. Revision of the Starling principle and new insights into physiology of the endothelial glycocalyx have important implications for fluid therapy in intensive care medicine. Determination of fluid overload and an appropriate therapy with either diuretics or ultrafiltration are the focus of “late goal-directed fluid removal” management.
CRIS-Team Scopus Importer:2021-10-15
Keywords: Critical care; Endothelial cells; Fluid therapy; Sepsis; Shock

Intravenous fluid therapy and acute kidney injury - What's new? - Willam, Carsten; Schley, Gunnar (Deutsche Medizinische Wochenschrift, 2021)
Was ist neu?
CRIS-Team WoS Importer:2021-08-13

Invasive treatment of resistant hypertension: present and future - Ott, Christian; Schmieder, Roland (Current Hypertension Reports, 2014)
The underlying pathophysiologic concept of diverse invasive devices to treat resistant hypertension (e.g., sympathetic denervation, carotid sinus nerve stimulation) is known for a long time. Since the pioneering work in the 1940s in humans, innovative techniques have been developed resulting in less invasive treatment procedures and, hence, overcoming serious side effects, which in turn improved safety and lead to more widespread use. Recently, new experimental technologies have been or are under evaluation in experiments and first-in-man studies have been conducted. Data with interventional techniques are rapidly expanding and have to be interpreted with caution. Additional data from randomized potentially sham-controlled studies are urgently needed. This article focuses on the increasing work of different invasive approaches for the treatment of resistant hypertension.
EVALuna2:3692

Investigation of a nonsense mutation located in the complex KIV-2 copy number variation region of apolipoprotein(a) in 10,910 individuals - Di Maio, Silvia; Grüneis, Rebecca; Streiter, Gertraud; Lamina, Claudia; Maglione, Manuel; Schoenherr, Sebastian; Öfner, Dietmar; Thorand, Barbara; Peters, Annette; Eckardt, Kai-Uwe; Köttgen, Anna; Kronenberg, Florian; et al. (Genome Medicine, 2020)
BACKGROUND: The concentrations of the highly atherogenic lipoprotein(a) [Lp(a)] are mainly genetically determined by the LPA gene locus. However, up to 70% of the coding sequence is located in the complex so-called kringle IV type 2 (KIV-2) copy number variation, a region hardly accessible by common genotyping and sequencing technologies. Despite its size, little is known about genetic variants in this complex region. The R21X variant is a functional variant located in this region, but it has never been analyzed in large cohorts. METHODS: We typed R21X in 10,910 individuals from three European populations using a newly developed high-throughput allele-specific qPCR assay. R21X allelic location was determined by separating the LPA alleles using pulsed-field gel electrophoresis (PFGE) and typing them separately. Using GWAS data, we identified a proxy SNP located outside of the KIV-2. Linkage disequilibrium was determined both statistically and by long-range haplotyping using PFGE. Worldwide frequencies were determined by reanalyzing the sequencing data of the 1000 Genomes Project with a dedicated pipeline. RESULTS: R21X carriers (frequency 0.016-0.021) showed significantly lower mean Lp(a) concentrations (- 11.7 mg/dL [- 15.5; - 7.82], p = 3.39e-32). The variant is located mostly on medium-sized LPA alleles. In the 1000 Genome data, R21X mostly occurs in Europeans and South Asians, is absent in Africans, and shows varying frequencies in South American populations (0 to 0.022). Of note, the best proxy SNP was another LPA null mutation (rs41272114, D' = 0.958, R2 = 0.281). D' was very high in all 1000G populations (0.986-0.996), although rs41272114 frequency varies considerably (0-0.182). Co-localization of both null mutations on the same allele was confirmed by PFGE-based long-range haplotyping. CONCLUSIONS: We performed the largest epidemiological study on an LPA KIV-2 variant so far, showing that it is possible to assess LPA KIV-2 mutations on a large scale. Surprisingly, in all analyzed populations, R21X was located on the same haplotype as the splice mutation rs41272114, creating "double-null" LPA alleles. Despite being a nonsense variant, the R21X status does not provide additional information beyond the rs41272114 genotype. This has important implications for studies using LPA loss-of-function mutations as genetic instruments and emphasizes the complexity of LPA genetics.
CRIS-Team Scopus Importer:2020-09-04

In vitro cyst puncture and injury-induced tubule formation using renal epithelial cells - Kraus, Andre; Lüdke, Andrea; Teschemacher, Barbara; Skoczynski, Kathrin; Buchholz, Björn (STAR Protocols, 2023)
Collecting-duct-derived renal epithelial cells switch from tubule to cyst formation; however, the cysts still form tubules after injury of the cyst-lining epithelium. Here, we provide a protocol that describes in vitro cyst growth with focus on glass-capillary-induced cyst wall injury to induce tubule formation. We detail steps for the establishment of the in vitro cyst assay, followed by puncture of the cysts in the collagen matrix. We further describe live imaging and steps to analyze the tubule growth. For complete details on the use and execution of this protocol, please refer to Scholz et al. (2022).1
CRIS-Team Scopus Importer:2023-02-03
Keywords: Cell Biology; Cell culture; Cell-based Assays; Microscopy

IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome - Trautmann, Agnes; Vivarelli, Marina; Samuel, Susan; Gipson, Debbie; Sinha, Aditi; Schaefer, Franz; Hui, Ng Kar; Boyer, Olivia; Saleem, Moin A.; Feltran, Luciana; Müller-Deile, Janina; Becker, Jan Ulrich; et al. (Pediatric Nephrology, 2020)
Idiopathic nephrotic syndrome newly affects 1–3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4–6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10–30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.
CRIS-Team Scopus Importer:2020-05-15
Keywords: Children; Chronic kidney disease; Genetics; Immunosuppressive treatment; Outcome; Pediatrics; Steroid-resistant nephrotic syndrome

Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference - Macdougall, Iain C.; Bircher, Andreas J.; Eckardt, Kai-Uwe; Obrador, Gregorio T.; Pollock, Carol A.; Stenvinkel, Peter; Swinkels, Dorine W.; Wanner, Christoph; Weiss, Guenter; Chertow, Glenn M. (Kidney International, 2016)
Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.
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Is Azilsartan More Effective in Younger Than in Older Patients? An Explorative Analysis of the Prospective EARLY Registry - Schmieder, Roland; Bramlage, Peter (Journal of Clinical Hypertension, 2016)
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IS BASAL NITRIC OXIDE ACTIVITY OF THE RENAL VASCULATURE ALTERED? ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL COMPARING TWO COMBINATION THERAPIES - Kannenkeril, Dennis; Ott, Christian; Bosch, Agnes; Striepe, Kristina; Pietschner, Robert; Schiffer, Mario; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2022)
CRIS-Team WoS Importer:2023-02-17

IS BASAL NITRIC OXIDE ACTIVITY OF THE RENAL VASCULATURE ALTERED? ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL COMPARING TWO COMBINATION THERAPIES - Kannenkeril, Dennis; Ott, Christian; Bosch, Agnes; Striepe, Kristina; Pietschner, Robert; Schiffer, Mario; Schmieder, Roland (Journal of Hypertension, 2022)
OBJECTIVE: Recently we demonstrated that a combination therapy with empagliflozin and linagliptin in patients with type 2 diabetes mellitus (T2DM) induce changes in renal hemodynamics. The purpose of this study was to analyze the influence of basal nitric oxide (NO) activity of the renal vasculature on the described changes of the renal hemodynamic profile. DESIGN AND METHOD: In this study patients with T2DM were nalysing to receive either empagliflozin and linagliptin (E+L group, n = 50) or metformin and insulin glargine (M+I group, n = 46), for 3 months. Renal hemodynamics were assessed with constant-infusion input-clearance technique with p-aminohippuric acid for renal plasma flow (RPF) and inulin for glomerular filtration rate (GFR) at baseline and after treatment. Due to withdrawal of inulin from the market during the study, GFR and filtration fraction (FF) were measured only in a sub-group of patients (E+L: n = 34; M+I: n = 31). Intraglomerular hemodynamics were calculated according the model established by Gomez. The basal NO activity in the renal circulation has been assessed by nalysing change in RPF in response to intravenously administrated NG-monomethyl-l-arginine (NO inhibitor). RESULTS: After 3 months of treatment, we did not observe any change in basal NO activity compared to baseline in either of the groups. In the E+L group, we found a correlation between basal NO activity of the renal vasculature after 3 months of treatment and change in RPF (r = -0.535, p < 0.001), renal blood flow (r = -0.468, p = 0.001) and renal vascular resistance (r = 0.377, p = 0.007) induced by treatment. Similar correlations with change in FF (r = 0.639, p < 0.001), preglomerular (r = 0.350, p = 0.046) and postglomerular resistance (r = 0.588, p < 0.001) have been found. No such relationships were found in the M+I group after 3 months and with basal NO activity at baseline in both treatment groups. CONCLUSIONS: Basal NO emerged as a determinant of the renal hemodynamic response in the combination therapy of empagliflozin and linagliptin, but not in the combination therapy of insulin and metformin.
CRIS-Team Scopus Importer:2022-09-09

Is COVID-19-associated pulmonary aspergillosis (CAPA) a myth? Frequency of Aspergillus detection from respiratory samples in intensive care unit patients with and without COVID-19 - Kuemmig, T.; Esse, Jan; Herbst, Larissa; Castellanos, I.; Strauss, Richard; Geißdörfer, Walter; Mihai, Sidonia; Rakova, Natalia; Cipa, Franziska; Pflaum, D.; Werblow, M.; Lang, Anne-Katharina; et al. (MYCOSES, 2021)
CRIS-Team WoS Importer:2021-10-08

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome? - Bobka, Steffen; Ebert, Nadja; Koertvely, Eloed; Jacobi, Johannes; Wiesener, Michael; Büttner-Herold, Maike; Amann, Kerstin Ute; Daniel, Christoph (Kidney & Blood Pressure Research, 2018)
BACKGROUND/AIMS: Complement activation is important in post-transplantation renal injury, but data on its role as predictor of transplant outcome/complications when assessed in donor kidneys are lacking. METHODS: In human renal transplant biopsies with delayed graft function (DGF, n=12), antibody mediated rejection (ABMR, n=8), T-cell mediated rejection (TCMR, n=11), 1 year protocol biopsies (control, n=10) and corresponding zero-biopsies we performed immunohistochemical analyses of 6 complement factors using FFPE sections and correlated the findings with kidney function, as assessed by serum creatinine, and morphological changes including interstitial fibrosis and tubular atrophy (IF/TA). RESULTS: In DGF, TCMR and ABMR significant complement deposition was observed, which was less pronounced in corresponding zero-biopsies. Zero-biopsies with subsequent ABMR showed glomerular complement factor D and C3c expression. Moreover, glomerular C3c and C9 and tubular MASP-2 and Collectin-11 expression in zero-biopsies significantly correlated with serum creatinine at diagnosis of DGF, TCMR or ABMR. Glomerular C1q was significantly increased in ABMR, but not in DGF and TCMR. In contrast, peritubular C1q was significantly enhanced in DGF and TCMR compared to zero-biopsies. Using C3d as a surrogate marker for complement activity we could confirm that stained complement factors are frequently associated with complement activity. CONCLUSION: Complement deposition strongly correlated with histopathological changes observed in renal transplants. All 3 complement pathways were operational in biopsies with DGF, TCMR and ABMR albeit with differential abundance and localization. Since complement deposition in zero-biopsies correlated with graft function and morphological changes, early specific complement inhibition in renal transplantation may be a new therapeutic option to prevent graft loss.
EVALuna2:35394

ISOLATED THROMBOTIC MICROANGIOPATHY OF THE SMALL INTESTINE IN A PATIENT WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME - A CASE REPORT - Nunius, Christoph; Büttner-Herold, Maike; Bertz, Simone; Schiffer, Mario; Buchholz, B. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Isolated thrombotic microangiopathy of the small intestine in a patient with atypical hemolytic uremic syndrome - a case report - Nunius, Christoph; Büttner-Herold, Maike; Bertz, Simone; Schiffer, Mario; Buchholz, Björn (BMC Nephrology, 2020)
Background: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy (TMA) reflected by hemolysis, anemia, thrombocytopenia and systemic organ injury. The optimal management of aHUS-patients when undergoing kidney transplantation to prevent recurrence in the allograft is eculizumab, an approved recombinant antibody targeting human complement component C5. Case presentation: A 39 year-old woman presented with severe abdominal pain, diarrhea and emesis for 3 days. In her past medical history she had experienced an episode of aHUS leading to end stage renal disease (ESRD) in 2007 and a genetic workup revealed a heterozygous mutation in the membrane cofactor protein gene. In 2014 she underwent cadaveric kidney transplantation. Four years later she had to go back on hemodialysis due to allograft failure following a severe systemic cytomegalovirus infection resulting in transplant failure. At presentation she still received calcineurin-inhibitor therapy and reported subfebrile temperatures and pain projecting over the transplant prior to the current symptoms. A contrast enhanced CT-scan of the abdomen revealed inflammatory wall thickening of the small intestine. Diagnostic endoscopy discovered fresh blood in the small intestine without a clear source of bleeding. Histopathology of the small intestine biopsies showed severe thrombotic microangiopathy. Of note, the patient persistently had no signs of systemic hemolysis. Since the TMA of the small intestine was most likely due to aHUS, eculizumab treatment was initiated which abolished the symptoms. Conclusion: Here we report a patient with thrombotic microangiopathy with predominant manifestation in a single organ, the small intestine, due to aHUS with absence of systemic signs and symptoms. aHUS patients usually require a secondary trigger for the disease to manifest. In this case, the trigger may be attributed to the dysfunctional renal transplant, which was subsequently explanted. Histology of the explanted kidney showed severe inflammation due to purulent nephritis and signs of cellular rejection. After nephrectomy, we continued eculizumab therapy until the patient completely recovered. No signs of TMA recurred after discontinuation of eculizumab, further supporting the concept of the renal transplant as the main trigger of TMA of the small intestine in our patient.
CRIS-Team Scopus Importer:2020-03-31
Keywords: Atypical hemolytic uremic syndrome; Case report; Renal transplant; Small intestine; Thrombotic microangiopathy

Is vascular remodelling in patients with chronic heart failure exaggerated? - Pietschner, Robert; Bosch, Agnes; Kannenkeril, Dennis; Striepe, Kristina; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland; Kolwelter, Julie (ESC Heart Failure, 2022)
Background Vascular remodelling of large arteries increases afterload of the left ventricle. The aim of this study was to analyse whether vascular remodelling and function under laboratory and 24-hour ambulatory conditions is impaired in patients with chronic heart failure (CHF) independently of cardiovascular risk factors.
CRIS-Team WoS Importer:2022-10-21

Kidney Autotransplantation in a 78-Year-Old Man with Proximal Ureteral Urothelial Carcinoma after Living Donor Nephrectomy - Wacker, Caroline; Schiffer, Mario; Richterstetter, Mario; Opgenoorth, Mirian; Apel, Hendrik (Urologia Internationalis, 2020)
Six years after living donor nephrectomy to his daughter, the 78-year-old donor presented to the emergency room with anuria for approximately 12 h. Only arterial hypertension, mildly reduced kidney function (eGFR 54 mL/min), and benign prostatic hyperplasia were known as preexisting medical conditions. In sonography, hydronephrosis III° was visible in the right single kidney. Ureterorenoscopy revealed an occlusive tumor in the right proximal ureter, which was treated via double J stent. Biopsy showed focal invasive papillary urothelial carcinoma of G2 high grade. Preoperative staging did not show any signs of lymph node or distant metastases. For therapeutic options, nephroureterectomy with consecutive need for dialysis was discussed versus partial ureteral resection with in situ ureteral reconstruction versus nephroureterectomy with partial ureteral resection and kidney autotransplantation. Eventually, laparoscopic right nephroureterectomy was performed with back-table preparation and tumor resection, followed by ipsilateral autotransplantation. The patient developed postsurgical acute kidney failure due to ischemia/reperfusion with a maximum serum Cr of 5.66 mg/dL (eGFR 10 mL/min), which quickly resolved. The papillary invasive urothelial carcinoma was graded pT1 pTis G2 high grade R0. Regular follow-ups showed no sign for cancer recurrence in computer tomography or cystoscopy; serum Cr was at 1.87 mg/dL (eGFR 53) 12 months after surgery.
CRIS-Team Scopus Importer:2020-11-12
Keywords: Kidney autotransplantation; Living donor nephrectomy; Upper urinary tract; Urothelial carcinoma

KidneyGPS: a user-friendly web application to help prioritize kidney function genes and variants based on evidence from genome-wide association studies - Stanzick, Kira J.; Stark, Klaus J.; Gorski, Mathias; Schödel, Johannes; Krüger, René; Kronenberg, Florian; Warth, Richard; Heid, Iris M.; Winkler, Thomas W. (BMC Bioinformatics, 2023)
Background: Genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with kidney function. By combining these findings with post-GWAS information (e.g., statistical fine-mapping to identify independent association signals and to narrow down signals to causal variants; or different sources of annotation data), new hypotheses regarding physiology and disease aetiology can be obtained. These hypotheses need to be tested in laboratory experiments, for example, to identify new therapeutic targets. For this purpose, the evidence obtained from GWAS and post-GWAS analyses must be processed and presented in a way that they are easily accessible to kidney researchers without specific GWAS expertise. Main: Here we present KidneyGPS, a user-friendly web-application that combines genetic variant association for estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics consortium with annotation of (i) genetic variants with functional or regulatory effects (“SNP-to-gene” mapping), (ii) genes with kidney phenotypes in mice or human (“gene-to-phenotype”), and (iii) drugability of genes (to support re-purposing). KidneyGPS adopts a comprehensive approach summarizing evidence for all 5906 genes in the 424 GWAS loci for eGFR identified previously and the 35,885 variants in the 99% credible sets of 594 independent signals. KidneyGPS enables user-friendly access to the abundance of information by search functions for genes, variants, and regions. KidneyGPS also provides a function (“GPS tab”) to generate lists of genes with specific characteristics thus enabling customizable Gene Prioritisation (GPS). These specific characteristics can be as broad as any gene in the 424 loci with a known kidney phenotype in mice or human; or they can be highly focussed on genes mapping to genetic variants or signals with particularly with high statistical support. KidneyGPS is implemented with RShiny in a modularized fashion to facilitate update of input data (https://kidneygps.ur.de/gps/). Conclusion: With the focus on kidney function related evidence, KidneyGPS fills a gap between large general platforms for accessing GWAS and post-GWAS results and the specific needs of the kidney research community. This makes KidneyGPS an important platform for kidney researchers to help translate in silico research results into in vitro or in vivo research.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Gene prioritization; GWAS; Kidney function; KidneyGPS; Web application

Kidney injury is independent of endothelial HIF-1? - Kalucka, Joanna; Schley, Gunnar; Georgescu, Adela; Klanke, Bernd; Roessler, Susanne; Baumgartl, Jasmin; Velden, Joachim; Amann, Kerstin Ute; Willam, Carsten; Johnson, Randall S.; Eckardt, Kai-Uwe; Weidemann, Alexander (Journal of Molecular Medicine, 2015)
Hypoxia-inducible transcription factors (HIFs) control cellular adaptation to low oxygen. In the kidney, activation of HIF is beneficial during injury; however, the specific contribution of HIF-1? in renal endothelial cells (EC) remains elusive. Since EC display tissue-specific heterogeneity, we investigated how HIF-1? affects key functions of glomerular EC in vitro and its contribution to renal development and pathophysiological adaptation to acute or chronic renal injury in vivo. Loss of HIF-1? in glomerular EC induces hypoxic cell death and reduces hypoxic adhesion of macrophages in vitro. In vivo, HIF-1? expression in EC in mouse kidneys is detectable but limited. Accordingly, EC-specific ablation of HIF-1? does not lead to developmental or phenotypical abnormalities in the kidney. Renal function and expression of adhesion molecules during acute ischemic kidney injury is independent of HIF-1? in EC. Likewise, inflammation and development of fibrosis after unilateral ureteric obstruction is not influenced by endothelial HIF-1?. Taken together, although HIF-1? exerts effects on glomerular EC in vitro, endothelial HIF-1? does not influence renal development and pathophysiological adaptation to kidney injury in vivo. This implies a profound difference of the hypoxic response of the renal vascular bed compared to other organs, such as the heart. This has implications for the development of pharmacological strategies targeting the endothelial hypoxic response pathways.HIF-1? controls hypoxic survival and adhesion on endothelial cells (EC) in vitro. In vivo, HIF-1? expression in renal EC is low. Deletion of HIF-1? in EC does not affect kidney development and function in mice. Renal function after acute and chronic kidney injury is independent of HIF-1? in EC. Data suggest organ-specific regulation of HIF-1? function in EC.
EVALuna2:3772

Kidney Transplantation After Rescue Allocation-the Eurotransplant Experience: A Retrospective Multicenter Outcome Analysis. - Assfalg, Volker; Miller, Gregor; Stocker, Felix; Van Meel, Marieke; Groenevelt, Tiny; Tieken, Ineke; Ankerst, Donna; Renders, Lutz; Novotny, Alexander; Hartmann, Daniel; Jell, Alissa; Rahmel, Axel; et al. (Transplantation, 2022)
BACKGROUND: At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P < 0.001), whereas other outcomes (mortality, death with functioning graft (DwFG)) were not significantly different. None of the 3 outcomes were significantly different when comparing RA with SA within the ESP program. CONCLUSIONS: Facing increased waiting times and mortality on dialysis due to donor shortage, this study reveals encouragingly positive DDRT outcomes following RA. This supports the extension of RA to more patients and as an alternative tool to enable transplantation in patients in countries with prohibitively long waiting times or at risk of deterioration.
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Kidney-transplant patients receiving living- or dead-donor organs have similar psychological outcomes (findings from the PI-KT study) - Müller, Helge H.O.; Lücke, Caroline; Englbrecht, Matthias; Wiesener, Michael S.; Siller, Teresa; Eckardt, Kai-Uwe; Kornhuber, Johannes; Maler, Juan Manuel (Mental Illness, 2020)
Purpose: Kidney transplantation (KT) is the treatment of choice for end-stage chronic kidney disease (CKD) and is well known to improve the clinical outcome of patients. However, the impact of KT on comorbid psychological symptoms, particularly depression and anxiety, is less clear, and recipients of living-donor (LD) organs may have a different psychological outcome from recipients of dead-donor (DD) organs. Design/methodology/approach: In total, 152 patients were included and analyzed using a cross-sectional design. Of these patients, 25 were pre-KT, 13 were post-KT with a LD transplant and 114 were post-KT with a DD transplant. The patients were tested for a variety of psychometric outcomes using the Hospital Anxiety and Depression Scale, the 12-Item Short Form Health Survey (assessing physical and mental health-related quality of life), the Resilience Scale, the Coping Self-Questionnaire and the Social Support Questionnaire. Findings: The mean age of the patients was 51.25 years and 40 per cent of the patients were female. As expected, the post-KT patients had significantly better scores on the physical component of the Short Form Health Survey than the pre-KT patients, and there were no significant differences between the two post-KT groups. There were no significant differences among the groups in any of the other psychometric outcome parameters tested, including anxiety, depression and the mental component of health-related quality of life. Research limitations/implications: KT and the origin of the donor organ do not appear to have a significant impact on the psychological well-being of transplant patients with CKD. Although the diagnosis and early treatment of psychological symptoms, such as depression and anxiety, remain important for these patients, decisions regarding KT, including the mode of transplantation, should not be fundamentally influenced by concerns about psychological impairments at the population level. Originality/value: CKD is a serious condition involving profound impairment of the physical and psychological well-being of patients. KT is considered the treatment of choice for most of these patients. KT has notable advantages over dialysis with regard to the long-term physical functioning of the renal and cardiovascular system and increases the life expectancy of patients. However, the data on the improvement of psychological impairments after KT are less conclusive.
CRIS-Team Scopus Importer:2020-06-16
Keywords: Coping; Kidney transplantation

Kif3a Guides Microtubular Dynamics, Migration and Lumen Formation of MDCK Cells - Boehlke, Christopher; Kotsis, Fruzsina; Buchholz, Björn; Powelske, Christian; Eckardt, Kai-Uwe; Walz, Gerd; Nitschke, Roland; Kuehn, E. Wolfgang (PLoS ONE, 2013)
The microtubular motor Kinesin-2 and its subunit Kif3a are essential for the formation of primary cilia, an organelle implicated in a wide spectrum of developmental abnormalities. Outside cilia, Kinesin-2 mediated transport has been implicated in vesicle and N-cadherin transport, but it is unknown if and how extraciliary Kif3a affects basic cellular functions such as migration or the formation of multicellular structures. Here we show that tetracycline inducible depletion of Kif3a in MDCK cells slows epithelial cell migration. Microtubules at the leading edge of Kif3a depleted cells failed to grow perpendicularly into the leading edge and microtubular dynamics were dampened in Kif3a depleted cells. Loss of Kif3a retarded lateral membrane specification and completely prevented the formation of three-dimensional spheres in collagen. These data uncover that Kif3a regulates the microtubular cytoskeleton in the cell periphery and imply that extra-ciliary Kif3a has an unexpected function in morphogenesis.

KLKB1 and CLSTN2 are associated with HDL-mediated cholesterol efflux capacity in a genome-wide association study - Schachtl-Riess, Johanna F.; Schönherr, Sebastian; Lamina, Claudia; Forer, Lukas; Coassin, Stefan; Streiter, Gertraud; Kheirkhah, Azin; Li, Yong; Meiselbach, Heike; Di Maio, Silvia; Eckardt, Kai-Uwe; Köttgen, Anna; et al. (Atherosclerosis, 2023)
Background and aims: HDL-mediated cholesterol efflux capacity (CEC) may protect from cardiovascular disease. Thus, we aimed to identify its genetic and non-genetic determinants. Methods: We measured CEC to 2% apolipoprotein B-depleted serum using BODIPY-cholesterol and cAMP-stimulated J774A.1 macrophages using serum samples from 4,981 participants in the German Chronic Kidney Disease (GCKD) study. Variance of CEC explained by clinical and biochemical parameters in a multivariable linear regression model was calculated by proportional marginal variance decomposition. A genome-wide association study with 7,746,917 variants was performed based on an additive genetic model. The main model was adjusted for age, sex and principal components 1-10. Further models were selected for sensitivity analysis and to reduce residual variance by known CEC pathways. Results: Variables that explained 1% and more of the variance of CEC were concentrations of triglycerides (12.9%), HDL-cholesterol (11.8%), LDL-cholesterol (3.0%), apolipoprotein A-IV (2.8%), PCSK9 (1.0%), and eGFR (1.0%). The KLKB1 (chr4) and APOE/C1 (chr19) loci were genome-wide significantly (p < 5x10−8) associated with CEC in our main model (p = 8.8x10−10 and p = 3.3x10−10, respectively). KLKB1 remained significantly associated after additional adjustment for either kidney parameters, HDL-cholesterol, triglycerides or apolipoprotein A-IV concentrations, while the APOE/C1 locus was not significantly associated anymore after adjustment for triglycerides. Adjustment for triglycerides also revealed an association with the CLSTN2 locus (chr3; p = 6.0x10−9). Conclusions: We identified HDL-cholesterol and triglycerides as the main determinants of CEC. Furthermore, we newly found a significant association of CEC with the KLKB1 and the CLSTN2 locus and confirmed the association with the APOE/C1 locus, likely mediated by triglycerides.
CRIS-Team Scopus Importer:2023-03-10
Keywords: Cholesterol efflux; Genome-wide association study; GWAS; HDL functionality

Knowledge about immunosuppressant medication and its correlates in a german kidney transplant population – results of a ktx360° substudy - de Boer, Sophie; Klewitz, Felix; Bauer-Hohmann, Maximilian; Schiffer, Lena; Tegtbur, Uwe; Pape, Lars; Schiffer, Mario; de Zwaan, Martina; Nöhre, Mariel (Patient Preference and Adherence, 2020)
Purpose: After organ transplantation, adherence to immunosuppressive medication (ISM) is crucial to prevent organ rejection. To enable adherence, patients need to be well informed about the different aspects associated with their ISM. However, literature suggests that knowledge regarding ISM is often inadequate. Patients and Methods: In a cross-sectional study, 702 patients after kidney transplantation participating in a structured multimodal follow-up program (KTx360°) were evaluated. We utilized a self-developed questionnaire which has been successfully used before to measure patients’ knowledge about the ISM. Above that we aimed to evaluate potential associations between sociodemographic, medical, donation-specific, and psychosocial variables including adherence, levels of depression and anxiety, perceived social support, and cognitive functioning with the knowledge level. Results: The mean age of the patients was 52.4 years, 58.1% were men, and 66.6% were living in a partnership. The mean time since transplantation was 65.1 months. On average, patients answered 70.9% of the questions correctly. The percentage of correct answers per question differed considerably (54%–92%). In univariate analyses, knowledge levels were positively associated with female gender, current partnership, German as first language and better cognitive functioning. However, the effect sizes were small. Conclusion: Taking into account that the patients after KTx can be expected to answer all questions correctly as they aim at basic knowledge, an average result of 70.9% corresponds to a moderate knowledge level. Consequently, the current educational approaches do not seem to be sufficient to inform all patients adequately. Further research is necessary on how to improve health knowledge in the long term.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Adherence; Health literacy; Immunosuppressive medication; Kidney transplantation; Renal transplantation

Laying the foundation for an ICF core set for community dwelling older adults in primary care: an expert survey Entwicklung eines ICF-Core-Sets für ältere Patienten in der Hausarztpraxis: eine Expertenumfrage - Gotthardt, Susann; Tomandl, Johanna; Höfle, Anina; Kühlein, Thomas; Book, Stephanie; Graessel, Elmar; Talaska, Michael; Sieber, Cornel; Freiberger, Ellen (Zeitschrift für Gerontologie und Geriatrie, 2021)
Background: A holistic biopsychosocial model focused on functioning in individual contexts (environment, task) is better suited to meet the needs of older patients than disease only based models. The International Classification of Functioning, Disability and Health (ICF) is the official standard for describing functional health. As the ICF is too detailed to be used in practice, brief core sets have been developed. Objective: This study aimed to identify relevant aspects of functioning for older primary care patients from the perspective of healthcare professionals in Germany. Material and methods: An internet-based cross-sectional expert survey was conducted in preparation for the development of an ICF core set for community-dwelling patients aged 75 years and older. Open-ended questions to identify the most important aspects of functioning and disability in old age were used. Responses were analyzed based on a content analysis approach to identify relevant concepts in the care of the target population. These concepts were then linked to ICF categories according to established linking rules. Results: A total of 63 experts participated in this survey. Across all responses, 2240 meaningful concepts were identified. A total of 75 ICF categories (4 first level categories, 67 second level categories, 4 code combinations) were identified by at least 5% of respondents and will thus be considered as candidate categories for the final ICF core set. Most of concepts were associated with the environmental factors component. The most frequently identified categories were immediate family and family relationships. Conclusion: This survey provides a list of relevant ICF categories from the experts’ perspective and together with other preparatory studies will be used for developing an ICF core set for community-dwelling older adults in primary care.
CRIS-Team Scopus Importer:2021-03-26
Keywords: Community-dwelling older patients; Expert survey; Functioning; ICF core set; Primary care

Laying the foundation for a primary care core set of the international classification of functioning, disability and health (icf) for community-dwelling older adults: A qualitative study - Tomandl, Johanna; Book, Stephanie; Höfle, Anina; Grässel, Elmar; Sieber, Cornel; Freiberger, Ellen; Kühlein, Thomas; Hueber, Susann; Gotthardt, Susann (Journal of Rehabilitation Medicine, 2021)
Objective: To explore relevant areas of functioning from the perspective of community-dwelling adults aged 75 years and over, in order to develop a Core Set of the International Classification of Functioning, Disability and Health (ICF) for community-dwelling older adults for use in primary care. Design: Qualitative study using semi-structured interviews and focus groups. Participants: A total of 27 community-dwelling older adults participated in the interviews and 24 of them in the focus groups. Methods: Following the proposed methodology of the ICF Research Branch, this is 1 of 4 preparatory studies in the Core Set development process. Within the transcripts, concepts of functioning were identified, based on Mayring s qualitative content analysis using deductive category assignment with the ICF being the category system. Results: Overall 6,667 concepts were identified. Most were linked to the Activities and Participation component. The most frequently identified categories were "recreation and leisure" and "family relationships". Conclusion: Categories from all ICF chapters were identified, demonstrating the complexity and multidimensionality of the ageing process, with a special emphasis on the component Activities and Participation. This qualitative study provides a list of relevant categories from the perspective of community-dwelling elderly people, which will be used to develop a Core Set for older primary care patients.
CRIS-Team Scopus Importer:2021-03-26
Keywords: aged; cross-sectional study; Disability and Health; focus group; general practice/methods.; geriatric assessment/ methods; independent living; International Classification of Functioning; interviews as topic

LCP-tacrolimus in long-term kidney graft recipients: Dosing and adherence - Schill, Yvonne; Schiffer, Mario; Pape, Lars (Transplantation Reports, 2023)
Introduction: The new LCP-formulation of tacrolimus (Tac) has shown pharmacokinetic advantages in patients after liver transplantation that are associated with better adherence. The influence of prolonged release Tac on adherence, trough levels and dosing of Tac remains unclear. Methods: A prospective study was performed in 62 patients from two centers, who were switched to LCP-Tac after kidney transplantation, to assess adherence as defined by the Tac trough level coefficient of variation (CoV) (primary endpoint) and BAASIS© Score, as well as kidney function, Tac trough level and tacrolimus dose. Results: BAASIS© Score and Tac trough level CoV demonstrated good adherence over the study period, with no difference between the study timepoints (0.26 ± 0.16 at study start and 0.26 ± 0.11 at study end, p = 0.976, paired t-test). Graft function and Tac trough levels remained stable, and Tac dose could be reduced. Conclusions: A switch to LCP-Tac is feasible and leads to stable adherence, graft function and Tac trough levels, in combination with lower Tac doses.
CRIS-Team Scopus Importer:2023-06-02
Keywords: Adherence; Coefficient of variation; Kidney transplantation; LCP; Tacrolimus; Trough level

LEADER 2: baseline calcitonin in 9340 people with type 2 diabetes enrolled in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial: preliminary observations - Daniels, G. H.; Hegedus, L.; Marso, S. P.; Nauck, M. A.; Zinman, Bernard; Bergenstal, R. M.; Mann, Johannes; Karsbol, J. Derving; Moses, A. C.; Buse, J. B.; Tuttle, M. (Diabetes Obesity & Metabolism, 2015)
To report preliminary data on baseline serum calcitonin concentrations and associated clinical characteristics in a global population with type 2 diabetes before liraglutide or placebo randomization.The ongoing LEADER trial has enrolled 9340 people with type 2 diabetes and at high risk of cardiovascular disease at 410 centres worldwide. People with baseline serum calcitonin <= 50 ng/l were randomized to liraglutide once daily or placebo and will be followed for up to 5 years. Serum calcitonin was measured at baseline and will be measured annually thereafter. An independent committee of thyroid experts will oversee calcitonin monitoring throughout the trial and will review all calcitonin concentrations >= 20 ng/l.The mean age of participants was 64.3 ± 7.2 years, 64.3% were men, and mean the body mass index was 32.5 ± 6.3 kg/m(2). The median (interquartile range) baseline serum calcitonin values were 3.9 (1.0 to >7.6) ng/l in men and 1.0 (1.0 to >1) ng/l in women. Serum calcitonin was >10 ng/l in 14.6% of men and in 0.96% of women. In sex-specific multivariable linear analysis of covariance models, a reduced glomerular filtration rate (GFR) was associated with higher serum calcitonin concentrations that were statistically significant. A 20 ml/min/1.73 m(2) decrease in estimated GFR (eGFR) was associated with a 14% increase in serum calcitonin in women and an 11% increase in men.In the LEADER population, the prevalence of elevated serum calcitonin concentrations at baseline was high, and there was an inverse association between eGFR and serum calcitonin concentrations.
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LEADER-4: blood pressure control in patients with type 2 diabetes and high cardiovascular risk: baseline data from the LEADER randomized trial - Petrie, John R.; Marso, Steven P.; Bain, Stephen C.; Franek, Edward; Jacob, Stephan; Masmiquel, Luis; Leiter, Lawrence A.; Haluzik, Martin; Satman, Ilhan; Omar, Mohamed; Shestakova, Marina; Van Gaal, Luc; et al. (Journal of Hypertension, 2016)
As glucagon-like peptide-1 receptor agonists lower blood pressure (BP) in type 2 diabetes mellitus (T2DM), we examined BP control in relation to targets set by international bodies prior to randomization in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial.We analyzed baseline data from LEADER (NCT01179048), an ongoing phase 3B, randomized, double-blind, placebo-controlled cardiovascular outcomes trial examining the cardiovascular safety of the glucagon-like peptide-1 receptor agonist liraglutide in 9340 people with T2DM from 32 countries [age (all mean ± SD) 64 ± 7.2 years, BMI 32.5 ± 6.3 kg/m, duration of diabetes 12.7 ± 8.0 years], all of whom were at high risk for cardiovascular disease (CVD).A total of 81% (n = 7592) of participants had prior CVD and 90% (n = 8408) had a prior history of hypertension. Despite prescription of multiple antihypertensive agents at baseline, only 51% were treated to a target BP of less than 140/85 mmHg and only 26% to the recommended baseline BP target of less than 130/80 mmHg. In univariate analyses, those with prior CVD were prescribed more agents (P < 0.001) and had lower BP than those without (137 ± 18.8/78 ± 10.6 mmHg versus 140 ± 17.7/80 ± 9.9 mmHg; P < 0.001). In logistic regression analyses, residency in North America (64% treated to <140/85 mmHg; 38% treated to <130/80 mmHg) was the strongest predictor of BP control.These contemporary data confirm that BP remains insufficiently controlled in a large proportion of individuals with T2DM at high cardiovascular risk, particularly outside North America. Longitudinal data from the LEADER trial may provide further insights into BP control in relation to cardiovascular outcomes in this condition.
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Left Ventricular Structure in Patients With Mild-to-Moderate CKD-a Magnetic Resonance Imaging Study - Schneider, Markus; Scheppach, Johannes B.; Raff, Ulrike; Toncar, Sebastian; Ritter, Christian; Klink, Thorsten; Stoerk, Stefan; Wanner, Christoph; Schlieper, Georg; Saritas, Turgay; Reinartz, Sebastian D.; Floege, Juergen; et al. (Kidney International Reports, 2019)
Introduction: The high burden of left ventricular (LV) abnormalities in patients with advanced chronic kidney disease (CKD) is well established. However, less is known about the prevalence, patterns, and determinants of LV abnormalities in patients with early CKD.
CRIS-Team WoS Importer:2019-02-21

Letter regarding “diagnosis and treatment of arterial hypertension 2021” - Ix, Joachim H.; Tomson, Charles R.V.; Cheung, Alfred K.; Mann, Johannes; Cushman, William C.; Cheung, Michael; Chang, Tara I. (Kidney International, 2022)
CRIS-Team Scopus Importer:2022-04-01

Lipid Peroxidation Drives Renal Cyst Growth In Vitro through Activation of TMEM16A - Schreiber, Rainer; Buchholz, Björn; Kraus, Andre; Schley, Gunnar; Scholz, Julia; Ousingsawat, Jiraporn; Kunzelmann, Karl (Journal of the American Society of Nephrology, 2019)
Background Transepithelial chloride2 secretion, through the chloride channels cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1), drives cyst enlargement in polycystic kidney disease (PKD). Polycystic kidneys are hypoxic, and oxidative stress activates TMEM16A. However, mechanisms for channel activation in PKD remain obscure.Methods Using tissue samples from patients with autosomal dominant PKD, embryonic kidney cultures, and anMDCK in vitro cyst model, we assessed peroxidation of plasmamembrane phospholipids in human and mouse polycystic kidneys. We also used electrophysiologic Ussing chamber and patch clamp experiments to analyze activation of TMEM16A and growth of renal cysts.Results Peroxidation of phospholipids in human and mouse kidneys as well as MDCK cysts in vitro is probably due to enhanced levels of reactive oxygen species. Lipid peroxidation correlated with increased cyst volume as shown in renal cultures and MDCK cysts in three-dimensional cultures. Reactive oxygen species and lipid peroxidation strongly activated TMEM16A, leading to depletion of calciumion stores and store-operated calcium influx. Activation of TMEM16A-and CFTR-dependent chloride secretion strongly augmented cyst growth. Exposure to scavengers of reactive oxygen species, such as glutathione, coenzyme Q10, or idebenone (a synthetic coenzyme Q10 homolog), as well as inhibition of oxidative lipid damage by ferrostatin-1 largely reduced activation of TMEM16A. Inhibition of TMEM16A reduced proliferation and fluid secretion in vitro.Conclusions These findings indicate that activation of TMEM16A by lipid peroxidation drives growth of renal cysts. We propose direct inhibition of TMEM16A or inhibition of lipid peroxidation as potentially powerful therapeutic approaches to delay cyst development in PKD.
CRIS-Team WoS Importer:2019-02-27
Keywords: ADPKD; TMEM16A; reactive oxygen species; lipid peroxidation; ferroptosis; anoctamin 1

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes - Marso, Steven P.; Daniels, Gilbert H.; Brown-Frandsen, Kirstine; Kristensen, Peter; Mann, Johannes; Nauck, Michael A.; Nissen, Steven E.; Pocock, Stuart; Poulter, Neil R.; Ravn, Lasse S.; Steinberg, William M.; Stockner, Mette; et al. (New England Journal of Medicine, 2016)
BACKGROUND: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).
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Local application of tropicamide 0.5% reduces retinal capillary blood flow - Harazny, Joanna M.; Schmieder, Roland; Welzenbach, Juergen; Michelson, Georg (Blood Pressure, 2013)
Abstract Introduction. Scanning laser Doppler flowmetry (SLDF) plays an important role in the study of arterial hypertension, diabetes and stroke. The technology enables non-invasive measurement of the retinal capillary perfusion (RCF), retinal haemodynamics and arteriolar morphology in human. The values can be measured in mydriasis or in non-mydriatic eyes. It is not clear whether the using of vasoactive mydriatica for pupil dilation affects the measured parameters in retina. Acetylcholine, a vasoactive neurotransmitter in human retina, affects the contractility of pericytes using muscarinic receptors and stimulates endothelial synthesis of nitric oxide (NO). We examined whether blockade of the retinal cholinergic receptors by tropicamide affects the RCF. Methods. We measured RCF in both eyes of 13 healthy subjects before and 30 min after the local application of one drop of 0.5% tropicamide to the right eye. The mean age of the group was 44 ± 14 years. The left eye was used as control. RCF was measured by Heidelberg retina flowmetry. Results. Thirty minutes after local application of one drop of 0.5% tropicamide to the right eye RCF decreased significantly (p = 0.001) by 31.9 ± 13% but did not change in the control eye. The maximal decrease was observed 20 min after application of the tropicamide. Conclusion. Locally administered tropicamide profoundly affects the RCF. Thus pupil dilatation impairs any assessment of retinal microcirculation.
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Local cancer therapy with magnetic nanoparticles - Tietze, Rainer; Lyer, Stefan; chreiber, Eveline; Mann, Johannes; Dürr, Stephan; Alexiou, Christoph (S. Karger AG, 2011)
The application of nanotechnology for treatment, diagnosis, and monitoring of diseases is summarized under the term nanomedicine. A particularly promising application is attributed to nanoparticular drug delivery systems. The goal of these carrier systems is the selective enrichment of active substances into diseased tissue structures, an increase in bioavailability, a decrease in active substance degradation, and above all the reduction and/or avoidance of unwanted side effects. Apart from numerous nanosystems acting as carriers, the use of iron oxide nanoparticles has to be particularly emphasized. On the one hand those particles are the carriers of the active substance and on the other hand they are also visualizable with conventional imaging techniques (X-ray and magnetic resonance tomography) and can therefore be used for 'theranostic' purposes. Beyond that, they can be employed for hyperthermia, a further important supporting pillar of nanomedicine. Both procedures should lead to personalized and specific therapy, which has medical and socioeconomic relevance in view of the worldwide increasing number of cancer patients.
CRIS-Team Scopus Importer:2022-06-27

Long-term efficacy and safety of renal denervation: an update from registries and randomised trials - Dimitriadis, Kyriakos; Schmieder, Roland; Iliakis, Panagiotis; Nickel, Laura; Tsioufis, Konstantinos; Weil, Joachim (Blood Pressure, 2023)
CRIS-Team Scopus Importer:2023-10-20

Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial - Mahfoud, Felix; Kandzari, David E.; Kario, Kazuomi; Townsend, Raymond R.; Weber, Michael A.; Schmieder, Roland; Tsioufis, Konstantinos; Pocock, Stuart; Dimitriadis, Kyriakos; Choi, James W.; East, Cara; D'Souza, Richard; et al. (Lancet, 2022)
Background: Renal denervation has been shown to lower blood pressure in the presence of antihypertensive medications; however, long-term safety and efficacy data from randomised trials of renal denervation are lacking. In this pre-specified analysis of the SPYRAL HTN-ON MED study, we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group. Methods: This randomised, single-blind, sham-controlled trial enrolled patients from 25 clinical centres in the USA, Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office systolic blood pressure between 150 mm Hg and 180 mm Hg and diastolic blood pressure of 90 mm Hg or higher. Eligible patients had to have 24-h ambulatory systolic blood pressure between 140 mm Hg and less than 170 mm Hg, while taking one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency renal denervation or a sham control procedure. Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross over after 12-month follow-up completion. The primary endpoint was the treatment difference in mean 24-h systolic blood pressure at 6 months between the renal denervation group and the sham control group. Statistical analyses were done on the intention-to-treat population. Long-term efficacy was assessed using ambulatory and office blood pressure measurements up to 36 months. Drug surveillance was used to assess medication use. Safety events were assessed up to 36 months. This trial is registered with ClinicalTrials.gov, NCT02439775; prospectively, an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial. Findings: Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n=38) or a sham control procedure (n=42). Mean ambulatory systolic and diastolic blood pressure were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of antihypertensive drugs. The medication burden at 36 months was 2·13 medications (SD 1·15) in the renal denervation group and 2·55 medications (2·19) in the sham control group (p=0·26). 24 (77%) of 31 patients in the renal denervation group and 25 (93%) of 27 patients in the sham control group adhered to medication at 36 months. At 36 months, the ambulatory systolic blood pressure reduction was −18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and −8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference −10·0 mm Hg, 95% CI −16·6 to −3·3; p=0·0039). Treatment differences between the renal denervation group and sham control group at 36 months were −5·9 mm Hg (95% CI −10·1 to −1·8; p=0·0055) for mean ambulatory diastolic blood pressure, −11·0 mm Hg (−19·8 to −2·1; p=0·016) for morning systolic blood pressure, and −11·8 mm Hg (−19·0 to −4·7; p=0·0017) for night-time systolic blood pressure. There were no short-term or long-term safety issues associated with renal denervation. Interpretation: Radiofrequency renal denervation compared with sham control produced a clinically meaningful and lasting blood pressure reduction up to 36 months of follow-up, independent of concomitant antihypertensive medications and without major safety events. Renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension. Funding: Medtronic.
CRIS-Team Scopus Importer:2022-04-15

LONG-TERM REDUCTION IN MORNING AND NIGHTTIME BLOOD PRESSURE AFTER RENAL DENERVATION: 36-MONTH RESULTS FROM SPYRAL HTN-ON MED PILOT TRIAL - Kario, Kazuomi; Mahfoud, Felix; Kandzari, David E.; Townsend, Raymond R.; Weber, Michael A.; Schmieder, Roland; Tsioufis, Konstantinos; Pocock, Stuart; Fahy, Martin; Boehm, Michael (JOURNAL OF HYPERTENSION, 2023)
CRIS-Team WoS Importer:2023-03-17

Long-term reduction in morning and nighttime blood pressure after renal denervation: 36-month results from SPYRAL HTN-ON MED trial - Kario, Kazuomi; Mahfoud, Felix; Kandzari, David E.; Townsend, Raymond R.; Weber, Michael A.; Schmieder, Roland; Tsioufis, Konstantinos; Pocock, Stuart; Brar, Sandeep; Hettrick, Douglas A.; Fahy, Martin; Boehm, Michael (Hypertension Research, 2022)
Elevated morning and nighttime blood pressures (BP) are associated with increased risk of cardiovascular events such as stroke and myocardial infarction. We compared the long-term changes in morning and nighttime BP in patients with uncontrolled hypertension (office systolic BP between 150 and <180 mmHg/diastolic BP ≥ 90 mmHg; mean ambulatory systolic BP (SBP) between 140 and <170 mmHg; 1–3 prescribed antihypertensive medications). Eighty patients were randomized to RDN or sham control. In patients taking at least 3 antihypertensive medications at 36 months (N = 23 RDN group; N = 23 sham group), the 24 h ambulatory SBP as well as morning (7:00–9:00AM) and nighttime (1:00–6:00AM) ambulatory SBP were significantly lower for the RDN group compared to sham control (24 h SBP: −20.2 vs. −10.2, p = 0.0087; morning SBP: −23.9 vs. −8.0 mmHg, p = 0.029; nighttime SBP: −20.8 vs. −7.2 mmHg, p = 0.0011). At 36 months, 24 h SBP was controlled to <130 mmHg in 40% of RDN patients in the morning compared to 6% for the sham group; P = 0.021 and in 80% of the RDN patients at night compared to 39% in the sham group; P = 0.019. Major adverse events through 36 months were rare in both groups, and there were no renal artery re-interventions or vascular complications. Morning and nighttime SBP were significantly lower in patients prescribed at least 3 antihypertensive medications at 36 months in the SPYRAL HTN-ON MED trial for RDN compared with sham control. The results suggest RDN has significant benefit when the risk of cardiovascular events is highest.
CRIS-Team Scopus Importer:2022-10-28
Keywords: Cardiovascular prognosis; Randomized controlled trial; Renal denervation; Resistant hypertension

LONG-TERM RESULTS FROM THE SPYRAL HTN-ON MED TRIAL: RENAL DENERVATION INCREASES TIME IN BLOOD PRESSURE TARGET RANGE OVER 36 MONTHS - Tsioufis, Konstantinos; Kandzari, David; Kario, Kazuomi; Townsend, Raymond; Mahfoud, Felix; Weber, Michael; Schmieder, Roland; Pocock, Stuart; Fahy, Martin; Bohm, Michael (JOURNAL OF HYPERTENSION, 2022)
CRIS-Team WoS Importer:2023-02-17

LONG-TERM RESULTS FROM THE SPYRAL HTN-ON MED TRIAL: RENAL DENERVATION INCREASES TIME IN BLOOD PRESSURE TARGET RANGE OVER 36 MONTHS - Tsioufis, Konstantinos; Kandzari, David; Kario, Kazuomi; Townsend, Raymond; Mahfoud, Felix; Weber, Michael; Schmieder, Roland; Pocock, Stuart; Fahy, Martin; Bohm, Michael (Journal of Hypertension, 2022)
OBJECTIVE: Six-month results from the SPYRAL HTN-ON MED pilot trial showed that patients with antihypertensive medications that underwent renal denervation (RDN) had a significantly greater reduction in 24-hr ambulatory and office systolic blood pressure (BP) from baseline compared to sham control. However, the effect of RDN on BP burden over time has not been established. Time in target range (TTR) analysis estimates the percent of time since procedure spent in a preferred systolic BP range as an indicator of BP control. An increase in TTR is associated with significantly lower risk of major cardiovascular events. In this analysis, we evaluate the long-term safety and efficacy of RDN in the SPYRAL HTN-ON MED pilot trial. DESIGN AND METHOD: Eligible patients were enrolled in SPYRAL HTN-ON MED with an office systolic BP (OSBP) of 150 to < 180 mmHg, office diastolic BP > = 90 mm Hg, and a 24-hr mean ambulatory systolic BP (ASBP) of 140 to < 170 mmHg. Successive follow-up BP measures over 36 months were linearly interpolated to estimate TTR over time. BP target range was defined as 24-hr ASBP < = 140 mmHg and OSBP < = 140 mmHg. TTR was calculated for each patient as the proportion of time spent in the target BP range since the procedure, including the baseline BP measurement. At 24 months (RDN, n = 34; control, n = 17) there were fewer patients with follow-up measures in the control group due to protocol requirements and the option for patients to crossover. For sham control patients who later crossed over to RDN before their 36-month follow-up (n = 13), the last measure prior to RDN was imputed at 36 months. RESULTS: Long-term, 36-month safety and efficacy outcomes of the first 80 patients andomised 1:1 into the RDN (n = 38) and sham control arms (n = 42) will be presented at ESH 2022, in addition to a time in blood pressure target range analysis. CONCLUSIONS: Thirty-six month results evaluating the long-term efficacy and durability of RDN compared to a sham control in SPYRAL HTN-ON MED for patients with uncontrolled hypertension will be presented at ESH 2022.
CRIS-Team Scopus Importer:2022-09-16

Long-Term Results up to 12 Months After Catheter-Based Alcohol-Mediated Renal Denervation for Treatment of Resistant Hypertension - Mahfoud, Felix; Sievert, Horst; Bertog, Stefan; Lauder, Lucas; Ewen, Sebastian; Lengele, Jean-Philippe; Wojakowski, Wojciech; Schmieder, Roland; Van Der Giet, Markus; Weber, Michael A.; Kandzari, David E.; Parise, Helen; et al. (Circulation: Cardiovascular Interventions, 2021)
BACKGROUND: Primary results of this prospective, open-label, multicenter trial suggested that alcohol-mediated renal denervation with perivascular injection of dehydrated alcohol using the Peregrine System Infusion Catheter safely reduces blood pressure (BP) in patients with resistant hypertension. To date, maintenance of the BP-lowering effect beyond 6 months using this novel technology has not been reported. This article describes the final, 12-month follow-up data on the safety and efficacy of alcohol-mediated renal denervation in these patients.
CRIS-Team WoS Importer:2021-10-01

Loss of Polycystin-1 causes cAMP-dependent switch from tubule to cyst formation. - Scholz, Julia; Kraus, Andre; Lueder, Dominik; Skoczynski, Kathrin; Schiffer, Mario; Grampp, Steffen; Schödel, Johannes; Buchholz, Björn (iScience, 2022)
Autosomal dominant polycystic kidney disease is the most common monogenic disease that causes end-stage renal failure. It primarily results from mutations in the PKD1 gene that encodes for Polycystin-1. How loss of Polycystin-1 translates into bilateral renal cyst development is mostly unknown. cAMP is significantly involved in cyst enlargement but its role in cyst initiation has remained elusive. Deletion of Polycystin-1 in collecting duct cells resulted in a switch from tubule to cyst formation and was accompanied by an increase in cAMP. Pharmacological elevation of cAMP in Polycystin-1-competent cells caused cyst formation, impaired plasticity, nondirectional migration, and mis-orientation, and thus strongly resembled the phenotype of Polycystin-1-deficient cells. Mis-orientation of developing tubule cells in metanephric kidneys upon loss of Polycystin-1 was phenocopied by pharmacological increase of cAMP in wildtype kidneys. In vitro, cAMP impaired tubule formation after capillary-induced injury which was further impaired by loss Polycystin-1.
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Loss of the collagen IV modifier prolyl 3-hydroxylase 2 causes thin basement membrane nephropathy - Aypek, Hande; Krisp, Christoph; Lu, Shun; Liu, Shuya; Kylies, Dominik; Kretz, Oliver; Wu, Guochao; Moritz, Manuela; Amann, Kerstin Ute; Benz, Kerstin; Tong, Ping; Hu, Zheng Mao; et al. (Journal of Clinical Investigation, 2022)
The glomerular filtration barrier (GFB) produces primary urine and is composed of a fenestrated endothelium, a glomerular basement membrane (GBM), podocytes, and a slit diaphragm. Impairment of the GFB leads to albuminuria and microhematuria. The GBM is generated via secreted proteins from both endothelial cells and podocytes and is supposed to majorly contribute to filtration selectivity. While genetic mutations or variations of GBM components have been recently proposed to be a common cause of glomerular diseases, pathways modifying and stabilizing the GBM remain incompletely understood. Here, we identified prolyl 3-hydroxylase 2 (P3H2) as a regulator of the GBM in an a cohort of patients with albuminuria. P3H2 hydroxylates the 3′ of prolines in collagen IV subchains in the endoplasmic reticulum. Characterization of a P3h2ΔPod mouse line revealed that the absence of P3H2 protein in podocytes induced a thin basement membrane nephropathy (TBMN) phenotype with a thinner GBM than that in WT mice and the development of microhematuria and microalbuminuria over time. Mechanistically, differential quantitative proteomics of the GBM identified a significant decrease in the abundance of collagen IV subchains and their interaction partners in P3h2ΔPod mice. To our knowledge, P3H2 protein is the first identified GBM modifier, and loss or mutation of P3H2 causes TBMN and focal segmental glomerulosclerosis in mice and humans.
CRIS-Team Scopus Importer:2022-05-20

Low adherence to CKD-specific dietary recommendations associates with impaired kidney function, dyslipidemia, and inflammation - Kaesler, Nadine; Baid-Agrawal, Seema; Grams, Sabine; Nadal, Jennifer; Schmid, Matthias; Schneider, Markus; Eckardt, Kai-Uwe; Floege, Jürgen; Bergmann, Manuela M.; Schlieper, Georg; Saritas, Turgay (European Journal of Clinical Nutrition, 2021)
Background/Objectives: A diet following chronic kidney disease (CKD)-specific recommendations is considered essential for optimal management of patients with CKD. However, data on the adherence to these recommendations and its implications for health-relevant biomarkers are lacking. The objectives were to estimate adherence to CKD-specific dietary recommendations, to identify characteristics and lifestyle variables associated with poor adherence, and to investigate the relationship of adherence with biomarkers. Methods: In this cross-sectional analysis, average dietary intake was estimated in 3193 participants with moderately severe CKD enrolled into the observational multicenter German CKD study using a food frequency questionnaire. A CKD diet score was developed to assess adherence to CKD-specific dietary recommendations based on intake of sodium, potassium, fiber, protein, sugar, and cholesterol. The associations of dietary adherence with characteristics, lifestyle variables, and biomarker levels were determined. Results: Logistic regression analysis revealed younger age, higher body mass index, male gender, lower educational attainment, various lifestyle variables (cigarette smoking, infrequent alcohol consumption, low physical activity), and lower estimated glomerular filtrate rate associated with lower adherence to dietary recommendations. Low adherence to dietary recommendations was further associated with dyslipidemia, higher uric acid, and C-reactive protein levels. Associations between low dietary adherence and biomarkers were mostly driven by low intake of fiber and potassium, and high intake of sugar and cholesterol. Conclusions: This study revealed differential characteristics and biomarkers associated with lower adherence to CKD-specific dietary recommendations. Promotion of CKD-specific dietary recommendations may help to mitigate the adverse prognosis in CKD patients.
CRIS-Team Scopus Importer:2021-02-12

Low-dose eplerenone decreases left ventricular mass in treatment-resistant hypertension - Schneider, Andreas; Schwab, Johannes; Karg, Margarete; Kalizki, Tatjana; Reinold, Annemarie; Schneider, Markus; Schmieder, Roland; Schmidt, Bernhard M. W. (Journal of Hypertension, 2017)
Mineralocorticoid receptor antagonists are increasingly used in patients with treatment-resistant hypertension (TRH). There is experimental evidence for blood pressure (BP) independent effects of mineralocorticoid receptor blockade on cardiovascular target organ damage. We hypothesized that low-dose eplerenone (50 mg) will reduce left ventricular mass (LVM) beyond its BP-lowering effects.We performed a randomized, double-blind, placebo-controlled, parallel group study in 51 patients with TRH. Patients were allocated to receive either eplerenone 50 mg or placebo for 6 months, while other antihypertensive agents could be added in both groups to achieve a BP target of less than 140/90 mmHg. LVM was assessed by MRI before and after treatment.Baseline office BP was similar in the eplerenone and the placebo group (166 ± 21/91 ± 15 versus 159 ± 19/94 ± 8 mmHg, n.s.). BP was similarly reduced in the eplerenone versus the placebo group (-35 ± 20/-15 ± 11 versus -30 ± 19/-13 ± 7 mmHg, n.s.). However, LVM was reduced only in the eplerenone group (from 155 ± 33 to 136 ± 33 g, P < 0.001), but not in the placebo group (152 ± 32 versus 148 ± 38 g, P = 0.45).Despite similar BP-lowering, only patients with TRH who were allocated to eplerenone experienced a reduction of LVM. Thus, our data suggest that in patients with TRH, mineralocorticoid receptor antagonists should be used preferentially in order to achieve an effective reduction of LVM along with the improvement of BP control.
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LOW DOSE-EPLERENONE TREATMENT DECREASES AORTIC STIFFNESS IN PATIENTS WITH METABOLIC SYNDROME - Kannenkeril, Dennis; Bosch, Agnes; Kolwelter, Julie; Striepe, Kristina; Ott, Christian; Schiffer, Mario; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Low dose-eplerenone treatment decreases aortic stiffness in patients with resistant hypertension - Kalizki, Tatjana; Schmidt, Bernhard Magnus Wilhelm; Raff, Ulrike; Reinold, Annemarie; Schwarz, Thomas K.; Schneider, Markus P.; Schmieder, Roland; Schneider, Andreas (Journal of Clinical Hypertension, 2017)
Vascular damage is aggravated in animal models of hypertension with mineralocorticoid (MR) excess and in hypertensive patients with primary hyperaldosteronism. MR antagonism has shown to provide effective blood pressure (BP)-control in patients with treatment resistant hypertension (TRH), but the concurrent effects on the vasculature have not been examined. In a randomized, double-blinded, placebo-controlled parallel-group study, 51 patients with TRH received either eplerenone 50 mg or placebo for 6 months together with additional antihypertensives titrated to achieve a BP target of <140/90 mm Hg. Pulse wave velocity (PWV), augmentation index (AIx), augmentation pressure (AP), AP normalized to a heart rate of 75/min (AP@HR75), renal resistive index (RRI), intima-media thickness (IMT) and urinary albumin excretion rate (UAER) were assessed before and after treatment. PWV was reduced only with eplerenone (from 11.3±3.6 to 9.8±2.6 m/s, P?.001), but not with placebo (10.3±2.0 to 10.1±1.8 m/s, P=.60), despite similar reductions in BP (-35±20/-15±11 mm Hg vs -30±19/-13±7 mm Hg, n.s.). Further, reductions in AP and AP@HR75 were greater with eplerenone, while changes in AIx, RRI, IMT and UAER were similar. Our data show that eplerenone beneficially affects markers of arterial stiffness and wave reflection in patients with TRH, independently of BP lowering. These data add to the evidence that MR antagonism should be the preferred treatment option in TRH.
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Low resting heart rates are associated with new-onset atrial fibrillation in patients with vascular disease: results of the ONTARGET/TRANSCEND studies - Boehm, M.; Schumacher, H.; Linz, D.; Reil, J. -C.; Ukena, C.; Lonn, E.; Teo, K.; Sliwa, K.; Schmieder, Roland; Sleight, P.; Yusuf, S. (Journal of Internal Medicine, 2015)
Elevated systolic blood pressure (SBP) and high resting heart rate (HR) are associated with cardiovascular end-points. Although the association between atrial fibrillation (AF) and SBP is well established, the relation between AF and HR remains unclear.In patients from the ONTARGET and TRANSCEND studies with high cardiovascular disease risk (n = 27 064), new-onset AF was evaluated in relation to mean SBP, visit-to-visit variation in SBP (SBP-CV; i.e. SD/mean × 100%), mean HR and visit-to-visit variation in HR (HR-CV).Low mean HR (P < 0.0001) and high SBP (P = 0.0021) were associated with incident AF. High SBP-CV (P = 0.031) and HR-CV (P < 0.0001) were also associated with incident AF. After adjustment for confounders, SBP and SBP-CV were no longer significantly associated with AF. The detrimental effect of low HR was particularly evident in subjects who were not receiving treatment with beta-blockers (P = 0.014 for interaction between beta-blocker use and mean HR). In addition to low HR, high HR-CV and high SBP had additive effects on incident AF.Low mean HR (<60 beats min(-1) ) is independently associated with incident AF, and low HR-CV and high SBP further increase the incidence of new-onset AF in patients at high risk of cardiovascular disease.
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Low-Salt Diet Attenuates B-Cell- and Myeloid-Cell-Driven Experimental Arthritides by Affecting Innate as Well as Adaptive Immune Mechanisms - Sehnert, Bettina; Pohle, Sandy; Heuberger, Cornelia; Rzepka, Rita; Seidl, Maximilian; Nimmerjahn, Falk; Chevalier, Nina; Titze, Jens; Voll, Reinhard E. (Frontiers in Immunology, 2021)
A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4+ T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis.
CRIS-Team Scopus Importer:2021-12-31
Keywords: collagen-induced arthritis; cytokines; diet; serum transfer-induced arthritis; sodium chloride

Lumen narrowing and increased wall to lumen ratio of retinal microcirculation are valuable biomarkers of hypertension-mediated cardiac damage - Dąbrowska, Edyta; Harazny, Joanna M.; Miszkowska-Nagórna, Eliza; Stefański, Adrian; Graff, Beata; Kunicka, Katarzyna; Świerblewska, Ewa; Rojek, Agnieszka; Szyndler, Anna; Wolf, Jacek; Gruchała, Marcin; Schmieder, Roland; et al. (Blood Pressure, 2019)
Purpose: In the course of hypertension, left ventricular hypertrophy and diastolic dysfunction develop very often and may progress toward heart failure. The aim of the study was to analyze the relationship between abnormalities of retinal microcirculation and cardiac damage defined as left ventricular hypertrophy and/or diastolic dysfunction. Materials and methods: The study comprised 88 patients with essential hypertension. The group was divided into two subgroups: hypertensives without cardiac damage (n = 55) and with cardiac damage (n = 33). Control group comprised 32 normotensive subjects. Scanning laser Doppler flowmetry was used to evaluate retinal microcirculation. Echocardiography was used to assess cardiac damage. Results: Lumen diameter of retinal arterioles was significantly smaller in patients with cardiac damage vs. controls (77 vs. 84 µm, p = 0.02). Additionally, there was an evident trend with respect to lumen diameter (LD) across all three studied subgroups; i.e.: the smallest dimeters were present in cardiac damage patients, moderate size in hypertensives’ without cardiac damage, and the largest diameters in healthy controls (pfor trend < 0.01). Lumen diameter was inversely correlated with cardiac intraventricular septum diameter (R = –0.25, p = 0.02), left ventricular mass (R = –0.24, p = 0.02), and left atrial volume (R = –0.22, p = 0.04). Wall to lumen ratio was associated with intraventricular septum diameter (R = 0.21, p = 0.044) and left atrial volume (R = 0.21, p = 0.045). In multivariable regression analysis, lumen diameter was independently associated with intraventricular septum diameter (β = –0.05, p = 0.03), left ventricular mass (β = –1.15, p = 0.04), and left atrial volume (β = –0.42, p = 0.047); wall to lumen ratio was independently associated with intraventricular septum diameter (β = 3.67, p = 0.02) and left atrial volume (β = 30.0, p = 0.04). Conclusions: In conclusion, retinal arterioles lumen diameter and wall to lumen ratio were independent biomarkers of cardiac damage. Retinal examination performed by means of scanning laser Doppler flowmetry might be a valuable tool to improve cardiovascular risk stratification of hypertensive patients.
CRIS-Team Scopus Importer:2019-09-17
Keywords: cardiac damage; diastolic dysfunction; left ventricular hypertrophy; Microcirculation

LUMEN NARROWING OF RETINAL ARTERIOLES IS A VALUABLE BIOMARKER OF CARDIAC DAMAGE - Dabrowska, E.; Harazny, J. M.; Miszkowska-Nagorna, E.; Stefanski, A.; Graff, B.; Szyndler, A.; Kunicka, K.; Swierblewska, E.; Rojek, A.; Schmieder, Roland; Laurent, S.; Narkiewicz, K. (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Lungen- und Nierenversagen - Pathogenese, Wechselwirkungen und Therapie - John, Stefan; Willam, Carsten (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2015)
The lungs and kidneys represent the most often affected organs (acute respiratory distress syndrome, ARDS or kidney failure) in multiple organ failure (MOF) due to shock, trauma, or sepsis with a still unacceptable high mortality for both organ failures.Although the exact pathophysiological mechanisms of MOF are not completely elucidated, it appears that the lungs and kidneys share several pathophysiologic pathways and have the potential to further harm each other (kidney-lung crosstalk). Inflammatory signals in both directions and volume overload with consecutive edema formation in both organs may play a key role in this crosstalk.The organ replacement therapies used in both organ failures have the potential to further injure the other organ (ventilator trauma, dialyte trauma). On the other hand, renal replacement therapy can have positive effects on lung injury by restoring volume and acid-base homeostasis. The new development of "low-flow" extracorporeal CO2 removal on renal replacement therapy platforms may further help to decrease ventilator trauma in the future.
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Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation - Saleh, Mohamed A.; Mcmaster, William G.; Wu, Jing; Norlander, Allison E.; Funt, Samuel A.; Thabet, Salim R.; Kirabo, Annet; Xiao, Liang; Chen, Wei; Itani, Hana A.; Michell, Danielle; Huan, Tianxiao; et al. (Journal of Clinical Investigation, 2015)
The lymphocyte adaptor protein LNK (also known as SH2B3) is primarily expressed in hematopoietic and endothelial cells, where it functions as a negative regulator of cytokine signaling and cell proliferation. Single-nucleotide polymorphisms in the gene encoding LNK are associated with autoimmune and cardiovascular disorders; however, it is not known how LNK contributes to hypertension. Here, we determined that loss of LNK exacerbates angiotensin II-induced (Ang II-induced) hypertension and the associated renal and vascular dysfunction. At baseline, kidneys from Lnk-/- mice exhibited greater levels of inflammation, oxidative stress, and glomerular injury compared with WT animals, and these parameters were further exacerbated by Ang II infusion. Aortas from Lnk-/- mice exhibited enhanced inflammation, reduced nitric oxide levels, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies demonstrated that loss of LNK in hematopoietic cells is primarily responsible for the observed renal and vascular inflammation and predisposition to hypertension. Ang II infusion increased IFN-?-producing CD8+ T cells in the spleen and kidneys of Lnk-/- mice compared with WT mice. Moreover, IFN-? deficiency resulted in blunted hypertension in response to Ang II infusion. Together, these results suggest that LNK is a potential therapeutic target for hypertension and its associated renal and vascular sequela.
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Macrophage migration inhibitory factor is regulated by HIF-1α and cAMP and promotes renal cyst cell proliferation in a macrophage-independent manner - Safi, Wajima; Kraus, Andre; Grampp, Steffen; Schödel, Johannes; Buchholz, Björn (Journal of Molecular Medicine, 2020)
Abstract: Progressive cyst growth leads to decline of renal function in polycystic kidney disease. Macrophage migration inhibitory factor (MIF) was found to be upregulated in cyst-lining cells in a mouse model of polycystic kidney disease and to promote cyst growth. In addition, MIF can be secreted by tubular cells and may contribute to cyst growth in an autocrine manner. However, the underlying mechanisms leading to induction of MIF in cyst-lining cells remained elusive. Here, we demonstrate that hypoxia-inducible transcription factor (HIF) 1α upregulates MIF in cyst-lining cells in a tubule-specific PKD1 knockout mouse. Pharmacological stabilization of HIF-1α resulted in significant increase of MIF in cyst epithelial cells whereas tubule-specific knockout of HIF-1α prevented MIF upregulation. Identical regulation could be found for ABCA1, which has been shown to act as a transport protein for MIF. Furthermore, we show that MIF and ABCA1 are direct target genes of HIF-1α in human primary tubular cells. Next to HIF-1α and hypoxia, we found MIF being additionally regulated by cAMP which is a strong promotor of cyst growth. In line with these findings, HIF-1α- and cAMP-dependent in vitro cyst growth could be decreased by the MIF-inhibitor ISO-1 which resulted in reduced cyst cell proliferation. In conclusion, HIF-1α and cAMP regulate MIF in primary tubular cells and cyst-lining epithelial cells, and MIF promotes cyst growth in the absence of macrophages. In line with these findings, the MIF inhibitor ISO-1 attenuates HIF-1α- and cAMP-dependent in vitro cyst enlargement. Key messages: • MIF is upregulated in cyst-lining cells in a polycystic kidney disease mouse model. • MIF upregulation is mediated by hypoxia-inducible transcription factor (HIF) 1α. • ABCA1, transport protein for MIF, is also regulated by HIF-1α in vitro and in vivo. • MIF is additionally regulated by cAMP, a strong promotor of cyst growth. • MIF-inhibitor ISO-1 reduces HIF-1α- and cAMP-dependent cyst growth.
CRIS-Team Scopus Importer:2020-09-11
Keywords: cAMP; Hypoxia-inducible factor 1α; Macrophage migration inhibitory factor; Polycystic kidney disease

Macrophages in homeostatic immune function - Jantsch, Jonathan; Binger, Katrina J.; Mueller, Dominik N.; Titze, Jens (Frontiers in Physiology, 2014)
Macrophages are not only involved in inflammatory and anti-infective processes, but also play an important role in maintaining tissue homeostasis. In this review, we summarize recent evidence investigating the role of macrophages in controlling angiogenesis, metabolism as well as salt and water balance. Particularly, we summarize the importance of macrophage tonicity enhancer binding protein (TonEBP, also termed nuclear factor of activated T-cells 5 [NFAT5]) expression in the regulation of salt and water homeostasis. Further understanding of homeostatic macrophage function may lead to new therapeutic approaches to treat ischemia, hypertension and metabolic disorders.
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Magnetic resonance-determined sodium removal from tissue stores in hemodialysis patients - Dahlmann, Anke; Dörfelt, Kathrin; Eicher, Florian; Linz, Peter; Kopp, Christoph; Mössinger, Irina; Horn, Stephan; Bueschges-Seraphin, Beatrix; Wabel, Peter; Hammon, Matthias; Eckardt, Kai-Uwe; Kotanko, Peter; et al. (Kidney International, 2015)
We have previously reported that sodium is stored in skin and muscle. The amounts stored in hemodialysis (HD) patients are unknown. We determined whether (23)Na magnetic resonance imaging (sodium-MRI) allows assessment of tissue sodium and its removal in 24 HD patients and 27 age-matched healthy controls. We also studied 20 HD patients before and shortly after HD with a batch dialysis system with direct measurement of sodium in dialysate and ultrafiltrate. Age was associated with higher tissue sodium content in controls. This increase was paralleled by an age-dependent decrease of circulating levels of vascular endothelial growth factor-C (VEGF-C). Older (>60 years) HD patients showed increased sodium and water in skin and muscle and lower VEGF-C levels compared with age-matched controls. After HD, patients with low VEGF-C levels had significantly higher skin sodium content compared with patients with high VEGF-C levels (low VEGF-C: 2.3 ng/ml and skin sodium: 24.3 mmol/l; high VEGF-C: 4.1 ng/ml and skin sodium: 18.2 mmol/l). Thus, sodium-MRI quantitatively detects sodium stored in skin and muscle in humans and allows studying sodium storage reduction in ESRD patients. Age and VEGF-C-related local tissue-specific clearance mechanisms may determine the efficacy of tissue sodium removal with HD. Prospective trials on the relationship between tissue sodium content and hard end points could provide new insights into sodium homeostasis, and clarify whether increased sodium storage is a cardiovascular risk factor.
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Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study - Mark, Patrick B.; Carrero, Juan J.; Matsushita, Kunihiro; Sang, Yingying; Ballew, Shoshana H.; Grams, Morgan E.; Coresh, Josef; Surapaneni, Aditya; Brunskill, Nigel J.; Chalmers, John; Chan, Lili; Chang, Alex R.; et al. (European Heart Journal, 2023)
Aims Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). Methods and results The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m(2), 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. Conclusion Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.
CRIS-Team WoS Importer:2023-02-24

Managing Treatment-Resistant Patients - Schmieder, Roland (High Blood Pressure and Cardiovascular Prevention, 2015)
Treatment-resistant hypertension (TRH) has a prevalence of approximately 10-20 %, and up to 5 % of patients with TRH experience a major cardiovascular or cerebrovascular event each year. Effective management of real TRH is important but can present a significant clinical challenge. Utilisation of treatment options that maximise treatment compliance is recommended, particularly combinations that have supporting data from clinical studies. Renal denervation can be considered for a subset of truly resistant patients.
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Massive intoxication with rivaroxaban, phenprocoumon, and diclofenac: A case report - Pfeiffer, Hella; Herbst, Larissa; Schwarze, Bernd; Eckstein, Reinhold; Weisbach, Volker Günter (Medicine, 2016)
RATIONALE: Oral anticoagulants and painkillers, some with an additional effect on the coagulation system, are widely used and are therefore prone to abuse and (intentional) overdose. We report the case of a patient with a massive mixed anticoagulant intoxication. PATIENT CONCERNS: The patient had ingested 1960 mg rivaroxaban, 31.5 mg phenprocoumon, 1425 mg diclofenac, and 21,000 mg metamizole in suicidal intention. DIAGNOSES: Massive mixed anticoagulant overdose. INTERVENTIONS: The patient was closely monitored. The phenprocoumon overdose was treated by the administration of vitamin K and PCC. OUTCOMES: Despite the massive inhibition of the coagulation system, the patient did not experience bleeding apart from a slight gross hematuria. LESSONS: Despite the ingestion of a massive amount of rivaroxaban, the plasma levels were not as high as feared, due to the ceiling effect of rivaroxaban absorption. Elimination occurred according to the half-life of rivaroxaban and was not unduly prolonged by the ingested quantity.
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Maßnahmen und Empfehlungen für die Sicherstellung adäquater stationärer Versorgungskapazitäten für das Pandemiemanagement innerhalb einer Region – Ergebnisse eines hybriden Delphi-Verfahrens - Panchyrz, Ivonne; Hoffmann, Julia; Harst, Lorenz; Pohl, Solveig; Bauer, Michael; Blaschke, Sabine; Bodenstein, Marc; Engelhart, Steffen; Gärtner, Barbara; Graf, Jürgen; Hanses, Frank; Held, Hanns Christoph; et al. (Gesundheitswesen, 2023)
Introduction Since the beginning of the pandemic in spring 2020, inpatient healthcare has been under enormous burden, which is reflected especially in overworked staff, imprecise bed planning and/or data transfer. According to the recommendation of the Science Council, university clinics should play a controlling role in regional healthcare and act in conjunction with surrounding hospitals and practices. Methods In September 2021, 31 representatives from 18 university hospitals were invited to a hybrid Delphi study with a total of 4 survey rounds to discuss criteria for effective inpatient care in a pandemic situation, which were extracted from previous expert interviews. Criteria that were classified as very important/relevant by ≥ 75 % of the participants in the first round of the survey (consensus definition) were then further summarized in 4 different small groups. In a third Delphi round, all participants came together again to discuss the results of the small group discussions. Subsequently, these were prioritized as Optional (can), Desirable (should) or Necessary (must) recommendations. Results Of the invited clinical experts, 21 (67.7 %) participated in at least one Delphi round. In an online survey (1st Delphi round), 233 criteria were agreed upon and reduced to 84 criteria for future pandemic management in four thematic small group discussions (2nd Delphi round) and divided into the small groups as follows: Crisis Management and Crisis Plans (n = 20), Human Resources Management and Internal Communication (n = 16), Regional Integration and External Communication (n = 24) and Capacity Management and Case & Care (n = 24). In the following group discussion (3rd Delphi round), the criteria were further modified and agreed upon by the experts, so that in the end result, there were 23 essential requirements and recommendations for effective inpatient care in a pandemic situation. Conclusion The results draw attention to key demands of clinical representatives, for example, comprehensive digitization, standardization of processes and better (supra) regional networking in order to be able to guarantee needs-based care even under pandemic conditions. The present consensus recommendations can serve as guidelines for future pandemic management in the inpatient care sector.
CRIS-Team Scopus Importer:2023-09-15
Keywords: COVID-19; Delphi study; expert recommendations; inpatient pandemic management; pandemic preparedness

Measurement of kidney perfusion by magnetic resonance imaging: Comparison of MRI with arterial spin labeling to para-aminohippuric acid plasma clearance in male subjects with metabolic syndrome - Ritt, Martin; Janka, Rolf Matthias; Schneider, Markus P.; Martirosian, Petros; Hornegger, Joachim; Bautz, Werner; Uder, Michael; Schmieder, Roland (Nephrology Dialysis Transplantation, 2010)
Background. Magnetic resonance imaging with arterial spin labeling (MRI-ASL) is a non-invasive approach to measure organ perfusion. We aimed to examine whether MRI-ASL kidney perfusion measurements are related to measurements of renal plasma flow (RPF) by para-aminohippuric acid (PAH) plasma clearance and whether changes of kidney perfusion in response to treatment with telmisartan can be detected by MRI-ASL.Methods. Twenty-four patients with metabolic syndrome and an estimated creatinine clearance according to Cockroft and Gault of ≥60ml/min were included in the study. Kidney perfusion was assessed by MRI-ASL measurements of a single coronal kidney slice (with flow-sensitive alternating inversion recovery and true fast imaging with steady-state processing sequence) and by measurements of RPF using PAH plasma clearance before and after 2 weeks of treatment with the angiotensin receptor blocker telmisartan. All MRI-ASL examinations were performed on a 1.5 T scanner.Results. Two weeks of therapy with telmisartan led to a significant increase of RPF (from 313 ± 47 to 348 ± 69ml/min/m, P = 0.007) and MRI-ASL kidney perfusion measurements (from 253 ± 20 to 268 ± 25ml/min/100g, P = 0.020). RPF measurements were related with MRI-ASL kidney perfusion measurements (r = 0.575, P < 0.001). Changes of RPF measurements and changes of MRI-ASL kidney perfusion measurements in response to treatment with telmisartan revealed a close relationship when expressed in absolute terms (r = 0.548, P = 0.015) and in percentage changes (r = 0.514, P = 0.025).Conclusions. Perfusion measurement of a single coronal kidney slice by MRI-ASL is able to approximate kidney perfusion and to approximate changes in kidney perfusion due to pharmacological intervention. © 2009 The Author.