Mechanisms of hypoxia signalling: new implications for nephrology - Schödel, Johannes; Ratcliffe, Peter J. (Nature Reviews Nephrology, 2019)
Studies of the regulation of erythropoietin (EPO) production by the liver and kidneys, one of the classical physiological responses to hypoxia, led to the discovery of human oxygen-sensing mechanisms, which are now being targeted therapeutically. The oxygen-sensitive signal is generated by 2-oxoglutarate-dependent dioxygenases that deploy molecular oxygen as a co-substrate to catalyse the post-translational hydroxylation of specific prolyl and asparaginyl residues in hypoxia-inducible factor (HIF), a key transcription factor that regulates transcriptional responses to hypoxia. Hydroxylation of HIF at different sites promotes both its degradation and inactivation. Under hypoxic conditions, these processes are suppressed, enabling HIF to escape destruction and form active transcriptional complexes at thousands of loci across the human genome. Accordingly, HIF prolyl hydroxylase inhibitors stabilize HIF and stimulate expression of HIF target genes, including the EPO gene. These molecules activate endogenous EPO gene expression in diseased kidneys and are being developed, or are already in clinical use, for the treatment of renal anaemia. In this Review, we summarize information on the molecular circuitry of hypoxia signalling pathways underlying these new treatments and highlight some of the outstanding questions relevant to their clinical use.
CRIS-Team Scopus Importer:2019-09-27

Medication adherence in hypertension - Poulter, Neil R.; Borghi, Claudio; Parati, Gianfranco; Pathak, Atul; Toli, Diana; Williams, Bryan; Schmieder, Roland (Journal of Hypertension, 2020)
: Suboptimal adherence to antihypertensive medication is a major contributor to poor blood pressure control. Several methods, direct or indirect, are available for measuring adherence, including the recently developed biochemical screening, although there is no gold-standard method routinely used in clinical practice to accurately assess the different facets of adherence. Adherence to treatment is a complex phenomenon and several of the barriers to adherence will need to be addressed at the healthcare system level; however, when looking at adherence from a more practical side and from the practitioner's perspective, the patient-practitioner relationship is a key element both in detecting adherence and in attempting to choose interventions tailored to the patient's profile. The use of single-pill combinations enabling simplification of treatment regimen, the implementation of a collaborative team-based approach and the development of electronic health tools also hold promise for improving adherence, and thus impacting cardiovascular outcomes and healthcare costs.
CRIS-Team Scopus Importer:2020-03-17

Meta-analyses identify DNA methylation associated with kidney function and damage - Schlosser, Pascal; Tin, Adrienne; Matias-Garcia, Pamela R.; Thio, Chris H. L.; Joehanes, Roby; Liu, Hongbo; Weihs, Antoine; Yu, Zhi; Hoppmann, Anselm; Grundner-Culemann, Franziska; Min, Josine L.; Adeyemo, Adebowale A.; et al. (Nature Communications, 2021)
Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
CRIS-Team WoS Importer:2021-12-17

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline - Gorski, Mathias; Jung, Bettina; Li, Yong; Matias-Garcia, Pamela R.; Wuttke, Matthias; Coassin, Stefan; Thio, Chris H.L.; Kleber, Marcus E.; Winkler, Thomas W.; Wanner, Veronika; Chai, Jin Fang; Chu, Audrey Y.; et al. (Kidney International, 2021)
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more (“Rapid3”; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline (“CKDi25”; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
CRIS-Team Scopus Importer:2021-03-05
Keywords: acute kidney injury; end-stage kidney disease; genome-wide association study; rapid eGFRcrea decline

Metabolic effects and cardiovascular safety of an oral triple therapy of type 2 diabetes: The metformin, empagliflozin, linagliptin example - Gallwitz, Baptist; Schmieder, Roland (Diabetologie und Stoffwechsel, 2020)
Based on new evidence and guidelines we discuss the triple therapy of type 2 diabetes using the example of a combination of metformin, empagliflozin and linagliptin. The SGLT-2 inhibitor empagliflozin improves the combined endpoint of cardiovascular death, non-fatal myocardial infarction and stroke (MACE-3) compared to placebo and reduces the incident probability of hospitalization due to heart failure as well as overall mortality. A newly occurring or deteriorating nephropathy is also observed less frequently. The DPP-4 inhibitor linagliptin lowers blood glucose and HbA 1c and has no effects on the cardiovascular endpoint MACE-3, but reduces the progression of albuminuria as compared to placebo. In comparison to the sulfonylurea glimepiride cardiovascular outcomes are similar, but hypoglycemia is much less frequent. The combination of the insulinotropic linagliptin and the insulin-independent, glucosuric empagliflozin improves the metabolic function as compared to placebo in patients who are insufficiently treated with metformin. In such patients the fixed combination of empagliflozin and linagliptin is the first for which three long-term outcome studies have demonstrated metabolic, cardiovascular and renal effects.
CRIS-Team Scopus Importer:2020-09-11
Keywords: cardiovascular outcome study; empagliflozin; hypoglycemia; linagliptin; metformin; renal function

Metabolic management and nutrition in critically ill patients with renal dysfunction : Recommendations from the renal section of the DGIIN, ÖGIAIN, and DIVI - Druml, W.; Joannidis, M.; John, S.; Joerres, A.; Schmitz, M.; Kielstein, J.; Kindgen-Milles, D.; Oppert, M.; Schwenger, V.; Willam, Carsten; Zarbock, A. (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2018)
BACKGROUND: Intensive care patients with renal failure or insufficiency comprise a heterogeneous group of subjects with widely differing metabolic patterns and nutritional requirements. They include subjects with various stages of acute kidney injury (AKI), acute-on-chronic renal failure (A-CKD), without/with renal replacement therapy (RRT), chronic kidney disease (CKD), and subjects on regular hemodialysis or peritoneal dialysis therapy (HD/PD). GOALS: Development of recommendations by the renal section of DGIIN (Deutsche Gesellschaft für Internistische Intensivmedizin und Notfallmedizin), ÖGIAIN (Österreichische Gesellschaft für Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin) for the metabolic management and the planning, indication, implementation, and monitoring of nutrition therapy in this heterogeneous group of patients. MATERIALS AND METHODS: The recommendations are based on recent evidence and current recommendations of DGEM (Deutsche Gesellschaft für Ernährungsmedizin), ASPEN (American Society for Parenteral and Enteral Nutrition) and ESPEN (European Society for Clinical Nutrition and Metabolism) and also the KDGIO (Kidney Disease: Improving Global Outcomes) clinical practice guidelines for AKI and the expert knowledge and clinical experience of the authors. RESULTS: Nutrition support in these patient groups is not fundamentally different from that in other disease states but must consider the multiple variations in metabolism and nutrient requirements. Nutrition therapy must be adapted to the stage of disease and especially, in those patients on RRT. Nutritional needs can differ widely between patients but also in the same patient during the course of the disease. CONCLUSIONS: Thus, the patient with renal failure requires an individualized approach in nutrition support and because of the altered metabolism of many nutrients and intolerances for electrolytes and fluids, the nutrition support in patients with renal insufficiency requires close clinical and laboratory monitoring.
EVALuna2:34518

Meta-GWAS on PCSK9 concentrations reveals associations of novel loci outside the PCSK9 locus in White populations - Kheirkhah, Azin; Schachtl-Riess, Johanna Franziska; Lamina, Claudia; Di Maio, Silvia; Koller, Adriana; Schönherr, Sebastian; Coassin, Stefan; Forer, Lukas; Sekula, Peggy; Gieger, Christian; Peters, Annette; Köttgen, Anna; et al. (Atherosclerosis, 2023)
Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. A few earlier genome-wide association studies (GWAS) investigated genetic variants associated with circulating PCSK9 concentrations. However, uncertainty remains about some of the genetic loci discovered beyond the PCSK9 locus. By conducting the largest PCSK9 meta-analysis of GWAS (meta-GWAS) so far, we aimed to identify novel loci and validate the previously reported loci that regulate PCSK9 concentrations. Methods: We performed GWAS for PCSK9 concentrations in two large cohorts (GCKD (n = 4,963) and KORA F3 (n = 2,895)). These were meta-analyzed with previously published data encompassing together 20,579 individuals. We further conducted a second meta-analysis in statin-naïve individuals (n = 15,390). A genetic risk score (GRS) was constructed on PCSK9-increasing SNPs and assessed its impact on the risk for coronary artery disease (CAD) in 394,943 statin-naïve participants (17,077 with events) of the UK Biobank by performing CAD-free survival analysis. Results: Nine loci were genome-wide significantly associated with PCSK9 concentrations. These included the previously described PCSK9, APOB, KCNA1/KCNA5, and TM6SF2/SUGP1 loci. All imputed SNPs in the PCSK9 locus account for ∼15% of variance of PCSK9 concentrations. We further identified FADS2 as a novel locus that was also found in statin-naïve participants. All imputed SNPs within the FADS2 locus explain ∼1.2% of variance of PCSK9 concentrations. Additionally, four further loci (a region on chromosome 5, SDK1, SPATA16 and HPR) were genome-wide significant in either the main model or the statin-naïve subset. The linear increase in a PCSK9 genetic risk score was associated with 1.41-fold (95%CI 1.16–1.72, p < 0.001) higher risk for incident CAD. Conclusions: We identified five novel loci (FADS2, SPATA16, SDK1, HPR and a region on chromosome 5) for PCSK9 concentrations that would require further research. Additionally, we confirm the genome-wide significant loci that were previously detected.
CRIS-Team Scopus Importer:2023-12-01
Keywords: Cardiovascular disease; FADS2; Meta-GWAS; PCSK9

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin - Joseph, Christina B.; Mariniello, Marta; Yoshifuji, Ayumi; Schiano, Guglielmo; Lake, Jennifer; Marten, Jonathan; Richmond, Anne; Huffman, Jennifer E.; Campbell, Archie; Harris, Sarah E.; Troyanov, Stephan; Cocca, Massimiliano; et al. (Journal of the American Society of Nephrology, 2022)
BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.
CRIS-Team Scopus Importer:2022-03-11
Keywords: cytokeratin; KRT40; loop of Henle; Tamm-Horsfall protein; thick ascending limb; WDR72

Microvascular changes at different stages of chronic kidney disease - Kannenkeril, Dennis; Frost, Shaun; Nolde, Janis M.; Kiuchi, Márcio Galindo; Carnagarin, Revathy; Lugo-Gavidia, Leslie Marisol; Chan, Justine; Joyson, Anu; Matthews, Vance B.; Herat, Lakshini Y.; Azzam, Omar; Mehdizadeh, Maryam; et al. (Journal of Clinical Hypertension, 2020)
Patients with progressing chronic kidney disease (CKD) are more likely to experience cardio- and cerebrovascular events than progressing to end-stage renal disease. The authors explored whether retinal microvascular calibers differed with the degree of renal impairment and between the standard and extended optic disk and may serve as a simple additional tool for risk stratification in this highly vulnerable patient cohort. The authors analyzed central retinal arteriolar and venular equivalent calibers (CRAE, CRVE) at different retinal zones (zone B&C) using digital retinal imaging in hypertensive patients with stage 2 (n = 66) or stage 3 CKD (n = 30). Results were adjusted for age, sex, HbA1c, and 24-hour diastolic blood pressure. Mean eGFR was 77.7 ± 8.9 and 48.8 ± 7.9 ml/min/1.73 m2 for stage 2 and 3 CKD, respectively. CRAE and CRVE in zones B and C were significantly lower in patients with stage 3 CKD compared to patients with stage 2 CKD (CRAE-B:141.1 ± 21.4 vs. 130.5 ± 18.9 µm, p =.030; CRAE-C:137.4 ± 19.4 vs 129.2 ± 18.2 µm, p =.049; CRVE-B:220.8 ± 33.0 vs. 206.0 ± 28.4 µm, p =.004; and CRVE-C:215.9 ± 33.0 vs. 201.2 ± 25.1µm, p =.003). In patients with stage 2 CKD, CRAE-B was higher than CRAE-C (141.1 ± 21.4 vs. 137.4 ± 19.4µm, p <.001). In contrast, such a difference was not found in patients with stage 3 CKD. CRAE of both retinal zones correlated with eGFR for the entire cohort. In patients with stage 3 CKD, retinal narrowing is more pronounced compared to patients with stage 2 CKD. Whether the novel observation of difference in arteriolar caliber between zones B and C in stage 2 CKD could serve as an early marker of CKD progression warrants further investigation.
CRIS-Team Scopus Importer:2020-12-25
Keywords: chronic kidney disease; glomerular filtration rate; microvascular change; retinal vessel caliber hypertension sympathetic nervous system

Midkine is a tumor cell survival factor that displays metastatic and therapeutic resistance functions in uveal melanoma - Karg, Margarete; John, Lukas; Refaian, Narin; Büttner, Christian; Rottmar, Tanja; Sommer, Jonas; Bock, Barbara; Resheq, Yazid; Ksander, Bruce; Heindl, Ludwig M.; Mackensen, Andreas; Bosch, Jacobus (INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2020)
CRIS-Team WoS Importer:2020-09-11

Midkine Promotes Metastasis and Therapeutic Resistance via mTOR/RPS6 in Uveal Melanoma. - Karg, Margarete; John, Lukas; Refaian, Nasrin; Büttner, Christian; Rottmar, Tanja; Sommer, Jonas; Bock, Barbara; Resheq, Yazid; Ksander, Bruce R.; Heindl, Ludwig M.; Mackensen, Andreas; Bosch, Jacobus J. (Molecular Cancer Research, 2022)
Uveal melanoma is a rare form of melanoma that originates in the eye, exerts widespread therapeutic resistance, and displays an inherent propensity for hepatic metastases. Because metastatic disease is characterized by poor survival, there is an unmet clinical need to identify new therapeutic targets in uveal melanoma. Here, we show that the pleiotropic cytokine midkine is expressed in uveal melanoma. Midkine expression in primary uveal melanoma significantly correlates with poor survival and is elevated in patients that develop metastatic disease. Monosomy 3 and histopathologic staging parameters are associated with midkine expression. In addition, we demonstrate that midkine promotes survival, migration across a barrier of hepatic sinusoid endothelial cells and resistance to AKT/mTOR inhibition. Furthermore, midkine is secreted and mediates mTOR activation by maintaining phosphorylation of the mTOR target RPS6 in uveal melanoma cells. Therefore, midkine is identified as a uveal melanoma cell survival factor that drives metastasis and therapeutic resistance, and could be exploited as a biomarker as well as a new therapeutic target. IMPLICATIONS: Midkine is identified as a survival factor that drives liver metastasis and therapeutic resistance in melanoma of the eye.
EVALuna2:503899

Mid-Term Vascular Safety of Renal Denervation Assessed by Follow-up MR Imaging. - Schmid, Axel; Schmieder, Raphael; Lell, Michael; Janka, Rolf Matthias; Veelken, Roland; Schmieder, Roland; Uder, Michael; Ott, Christian (Cardiovascular and Interventional Radiology, 2016)
Renal denervation (RDN) emerged as a treatment option for reducing blood pressure (BP) in patients with treatment-resistant hypertension (TRH). However, concerns have been raised regarding the incidence of late renal artery stenosis or thromboembolism after RDN. The goal of the current study was, therefore, to conduct a prospective clinical trial on the mid-term vascular integrity of the renal arteries and the perfusion of the renal parenchyma assessed by magnetic resonance imaging (MRI) in the follow-up after catheter-based RDN.In our single-centre investigator initiated study, 51 patients with true TRH underwent catheter-based RDN using the Symplicity Flex(TM) catheter (Medtronic Inc., Palo Alto, CA). Follow-up MRI was performed at a median of 11 months (interquartile range 6-18 months) after RDN on a 1.5T MR unit. High-resolution MR angiography (MRA) and MRI results were compared to the baseline digital angiography of renal arteries obtained at time of RDN. In case of uncertainties (N = 2) catheter angiography was repeated.Both office and 24-h ambulatory BP were significantly reduced 6 and 12 months after RDN. Renal function remained unchanged 6 and 12 months after RDN. In all patients, MRA excluded new or progression of pre-existing low grade renal artery stenosis as well as focal aneurysms at the sites of radiofrequency ablation. In none of the patients new segmental perfusion deficits in either kidney were detected on MRI.No vascular or parenchymal complications after radiofrequency-based RDN were detected in 51 patients followed up by MRI.
EVALuna2:3794

Mild Salt-Sensitive Hypertension in Genetically Determined Low Nephron Number is Associated with Chloride but Not Sodium Retention - Benz, Kerstin; Schlote, Julia; Daniel, Christoph; Kopp, Christoph; Dahlmann, Anke; Schröder, Agnes; Cordasic, Nada; Klanke, Bernd; Hilgers, Karl Friedrich; Titze, Jens; Amann, Kerstin Ute (Kidney & Blood Pressure Research, 2018)
BACKGROUND/AIMS: One potential pathomechanism how low nephron number leads to hypertension in later life is altered salt handling. We therefore evaluated changes in electrolyte and water content in wildtype (wt) and GDNF+/- mice with a 30% reduction of nephron number. METHODS: 32 GDNF+/- and 36 wt mice were fed with low salt (LSD, 0.03%, normal drinking water) or high salt (HSD, 4%, 0.9% drinking water) diet for 4 weeks. Blood pressure was continuously measured by telemetry in a subgroup. At the end of the experiment and after standardized ashing processes electrolyte- and water contents of the skin and the total body were determined. RESULTS: We found higher blood pressure in high salt treated GDNF+/-compared to wt mice. Of interest, we could not confirm an increase in total-body sodium as predicted by prevailing explanations, but found increased total body and skin chloride that interestingly correlated with relative kidney weight. CONCLUSION: We hereby firstly report significant total body and skin chloride retention in salt sensitive hypertension of GDNF+/-mice with genetically determined lower nephron number. Thus, in contrast to the prevailing opinion our data argue for the involvement of non-volume related mechanisms.
EVALuna2:34423

Mineralocorticoid receptor antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease - Ortiz, Alberto; Ferro, Charles J.; Balafa, Olga; Burnier, Michel; Ekart, Robert; Halimi, Jean-Michel; Kreutz, Reinhold; Mark, Patrick B.; Persu, Alexandre; Rossignol, Patrick; Ruilope, Luis M.; Schmieder, Roland; et al. (Nephrology Dialysis Transplantation, 2021)
Diabetic kidney disease (DKD) develops in similar to 40% of patients with diabetes and is the most common cause of chronic kidney disease (CKD) worldwide. Patients with CKD, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular (CV) death. The use of renin-angiotensin system (RAS) blockers to reduce the incidence of kidney failure in patients with DKD dates back to studies that are now >= 20 years old. During the last few years, sodium-glucose co-transporter-2 inhibitors (SGLT2is) have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with RAS blockers and SGLT2is, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of CV death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists (MRAs) reduce albuminuria and surrogate markers of CV disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In the FInerenone in reducing kiDnEy faiLure and dIsease prOgression in DKD (FIDELIO-DKD) study comparing the actions of the non-steroidal MRA finerenone with placebo, finerenone reduced the progression of DKD and the incidence of CV events, with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of MRAs, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic CKD.
CRIS-Team WoS Importer:2022-03-18

Minimal change disease and focal segmental glomerulosclerosis - Mueller-Deile, J.; Schenk, H.; Schiffer, Mario (Internist, 2019)
Minimal change disease (MCD) or minimal change glomerulonephritis and focal segmental glomerulosclerosis (FSGS) are the two major causes of nephrotic syndrome in children and young adults. Both disease entities resemble each other and can sometimes only be discriminated on the basis of their clinical courses. MCD and FSGS display two classical examples that share a common pathophysiology in which the glomerular podocyte and the cytoskeleton of its foot processes play important roles. Therefore, the term "podocytopathy" was introduced for both diseases. In this article, we compare their differences and similarities, and summarized new data on pathophysiology and treatment. In adults, only a renal biopsy including electron microscopy allows for the discrimination of MCD and FSGS and other differential diagnoses. The identification of a primary or secondary form of the disease is based on the clinical course. Data from studies on the treatment are sparse; hence, treatment is still based on high-dose steroids followed by additional immunosuppressive agents. In secondary forms, treatment of the underlying disease is elementary.
CRIS-Team WoS Importer:2019-05-17

Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease - Fazzini, Federica; Lamina, Claudia; Fendt, Liane; Schultheiss, Ulla T.; Kotsis, Fruzsina; Hicks, Andrew A.; Meiselbach, Heike; Weissensteiner, Hansi; Forer, Lukas; Krane, Vera; Eckardt, Kai-Uwe; Köttgen, Anna; et al. (Kidney International, 2019)
Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD.
CRIS-Team Scopus Importer:2019-07-02
Keywords: chronic kidney disease; infections; mitochondrial DNA copy number; mortality

Mitoxantrone-loaded superparamagnetic iron oxide nanoparticles as drug carriers for cancer therapy: Uptake and toxicity in primary human tubular epithelial cells - Cicha, Iwona; Scheffler, Laura; Ebenau, Astrid; Lyer, Stefan; Alexiou, Christoph; Goppelt-Strübe, Margarete (Nanotoxicology, 2016)
Superparamagnetic iron oxide nanoparticles (SPIONs) are in use for many clinical diagnostic and experimental therapeutic applications, for example, for targeted drug delivery. To analyze the cellular responses to mitoxantrone-carrying SPIONs (SPION-MTO), and to the drug released from SPIONs, we used an in vitro system that allows comparison of primary human cells with different endocytotic capacities, namely, epithelial cells from proximal and distal parts of the nephron. SPIONs were selectively and rapidly internalized by proximal tubular cells with high endocytotic potential, but not by distal tubular cells. Uptake did not affect cell viability or morphology. In both cell types, free MTO (10-100 nM) induced double-strand DNA breaks and senescence, cell hypertrophy and reduced cell proliferation. However, cadherin-mediated cell-cell adhesion, cytoskeletal structures or polarity of the cells were not affected. Interestingly, a comparable response was also observed upon treatment with SPION-MTO and was independent of uptake of the particles. The effect of SPION-MTO on cells which did not internalize particles was primarily related to the release of MTO from drug-coated particles upon incubation in serum-containing cell growth medium. In conclusion, we show that whereas the uptake of SPIONs does not affect cellular functions or viability, the toxicity of drug-loaded SPIONs depends essentially on the type of drug bound to nanoparticles. Due to the relatively low systemic toxicity of MTO, the effects of MTO-SPIONs on human tubular cells were moderate, but they may become clinically relevant when more nephrotoxic drugs are bound to SPIONs.
EVALuna2:3835

Mobile Technology Affinity in Renal Transplant Recipients - Reber, Sandra Therese; Scheel, J.; Stößel, Lisa; Schieber, Katharina; Jank, S.; Luker, C.; Vitinius, F.; Grundmann, F.; Eckardt, Kai-Uwe; Prokosch, Hans-Ulrich; Erim, Yesim (Transplantation Proceedings, 2018)
Medication nonadherence is a common problem in renal transplant recipients (RTRs). Mobile health approaches to improve medication adherence are a current trend, and several medication adherence apps are available. However, it is unknown whether RTRs use these technologies and to what extent. In the present study, the mobile technology affinity of RTRs was analyzed. We hypothesized significant age differences in mobile technology affinity and that mobile technology affinity is associated with better cognitive functioning as well as higher educational level.A total of 109 RTRs (63% male) participated in the cross-sectional study, with an overall mean age of 51.8 ± 14.2 years. The study included the Technology Experience Questionnaire (TEQ) for the assessment of mobile technology affinity, a cognitive test battery, and sociodemographic data.Overall, 57.4% of the patients used a smartphone or tablet and almost 45% used apps. The TEQ sum score was 20.9 in a possible range from 6 (no affinity to technology) to 30 (very high affinity). Younger patients had significantly higher scores in mobile technology affinity. The only significant gender difference was found in having fun with using electronic devices: Men enjoyed technology more than women did. Mobile technology affinity was positively associated with cognitive functioning and educational level.Young adult patients might profit most from mobile health approaches. Furthermore, high educational level and normal cognitive functioning promote mobile technology affinity. This should be kept in mind when designing mobile technology health (mHealth) interventions for RTRs. For beneficial mHealth interventions, further research on potential barriers and desired technologic features is necessary to adapt apps to patients' needs.
EVALuna:35443

Mobile Workflow in Computed Tomography of the Chest - Wetzl, Matthias; Weller, Melanie; Heiß, Rafael; Schrüfer, Eleni; Wüst, Wolfgang; Thierfelder, Carsten; Lerch, Daniel; Amarteifio, Patrick; Uder, Michael; May, Matthias; Cavallaro, Alexander Josef (Journal of Medical Systems, 2018)
A CT system with a tablet as mobile user interface and a wireless remote control for positioning and radiation release has recently been presented. Our aim was to evaluate the effects of a mobile CT examination workflow on the radiographers' performance compared to conventional examinations. A prototype of a radiation protection cabin was installed besides the gantry of a CT system. The CT system was equipped with a simplified user interface on a portable tablet and a mobile remote control. 98 patients with an indication for CT of the chest were randomly assigned to examination using the mobile devices (study group, n = 47) or using the conventional stationary workflow on the console (reference group, n = 51). Three ceiling mounted fisheye cameras were used for motion tracking of the radiographers, two in the examination room and one in the control room. Relative density of detection heat-maps and area counts were assessed using a dedicated software tool to quantify radiographers' movements. Duration of each task of the examination was manually recorded using a stopwatch. In the reference group 25% of the area counts were located inside of the examination room, while it was 48% in the study group. The time spent in the same room with the patient increased from 3:06 min (29%) to 6:01 min (57%) using the mobile workflow (p < 0.05), thereof 0:59 min (9%) were spent in moderate separation with maintained voice and visual contact in the radiation protection cabin. Heat-maps showed an increase of the radiographer's working area, indicating a higher freedom of movement. Total duration of the examination was slightly less in the study group without statistical significance (median time: study 10:36, reference 10:50 min; p = 0.29). A mobile CT examination transfers the radiographers' interaction with the scanner from the control room into the examination room. There, radiographers' freedom of movement is higher, without any tradeoffs regarding the examination duration.
EVALuna2:36096

Modifiable lifestyle and social factors affect chronic kidney disease in high-risk individuals with type 2 diabetes mellitus - Dunkler, Daniela; Kohl, Maria; Heinze, Georg; Teo, Koon K.; Rosengren, Annika; Pogue, Janice; Gao, Peggy; Gerstein, Hertzel; Yusuf, Salim; Oberbauer, Rainer; Mann, Johannes (Kidney International, 2015)
This observational study examined the association between modifiable lifestyle and social factors on the incidence and progression of early chronic kidney disease (CKD) among those with type 2 diabetes. All 6972 people from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) with diabetes but without macroalbuminuria were studied. CKD progression was defined as decline in GFR of more than 5% per year, progression to end-stage renal disease, microalbuminuria, or macroalbuminuria at 5.5 years. Lifestyle/social factors included tobacco and alcohol use, physical activity, stress, financial worries, the size of the social network and education. Adjustments were made for known risks such as age, diabetes duration, GFR, albuminuria, gender, body mass index, blood pressure, fasting plasma glucose, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers use. Competing risk of death was considered. At study end, 31% developed CKD and 15% had died. The social network score (SNS) was a significant independent risk factor of CKD and death, reducing the risk by 11 and 22% when comparing the third to the first tertile of the SNS (odds ratios of CKD 0.89 and death 0.78). Education showed a significant association with CKD but stress and financial worries did not. Those with moderate alcohol consumption had a significantly decreased CKD risk compared with nonusers. Regular physical activity significantly decreased the risk of CKD. Thus, lifestyle is a determinant of kidney health in people at high cardiovascular risk with diabetes.
EVALuna2:3881

Molecular diagnosis of kidney transplant failure based on urine - Wiesener, Antje; Knaup, Karl; Büttner-Herold, Maike; Dieterle, Anne; Stoeckert, Johanna; Riedl, Bernhard; Morath, Christian; Wald, Alexandra; Vondran, Florian; Braun, Felix; Schoedel, Johannes; Schüler, Markus; et al. (American Journal of Transplantation, 2020)
In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor's disease of oral-facial-digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient ' s urine more than 10 years after transplantation. Next-generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long-term outcome was enabled for 5 recipients.
CRIS-Team WoS Importer:2020-01-31

MOLECULAR DIAGNOSIS OF KIDNEY TRANSPLANT FAILURE BY THE URINE - Knaup, Karl; Wiesener, A.; Buettner-Herold, M.; Dieterle, A.; Morath, C.; Vondran, F. W. R.; Wald, A.; Braun, F.; Schüler, Markus; Schoedel, J.; Schiffer, Mario; Reis, André; et al. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Monitoring complement biomarkers in C3 glomerulopathy patients with factor H or FHR gene mutations before and after treatment with eculizumab or ravulizumab - Vanderliek, Kim; Afonso, Sara; Loeschmann, Ina; Krebs, Christian; Wiech, Thorsten; Skerka, Christine; Zipfel, Peter; Wiesener, Michael (MOLECULAR IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2022-04-29

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders - Wehling, C.; Amon, O.; Bommer, M.; Hoppe, B.; Kentouche, K.; Schalk, G.; Weimer, R.; Wiesener, M.; Hohenstein, B.; Toenshoff, B.; Buescher, R.; Fehrenbach, H.; et al. (Clinical and Experimental Immunology, 2017)
Various complement-mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n = 12), C3 glomerulopathies (C3G, n = 9) and acute antibody-mediated renal graft rejection (AMR, n = 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analysing the haemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3 and the activation products C3d, C5a and sC5b-9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific enzyme-linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082 ?g/ml point to drug accumulation, especially in paediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56 ?g/ml correlated with proteinuria. In aHUS patients, effective complement inhibition was demonstrated by significant reductions of CH50, APH50, C3d and sC5b-9 levels, whereas C5a levels were only reduced significantly after 6 months' treatment. C3G patients presented increased C3d and consistently low C3 levels, reflecting ongoing complement activation and consumption at the C3 level, despite eculizumab treatment. A comprehensive complement analysis together with drug monitoring is required to distinguish mode of complement activation and efficacy of eculizumab treatment in distinct renal disorders. Accumulation of the anti-C5 antibody points to the need for a patient-orientated tailored therapy.
EVALuna2:3934

Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis - Schley, Gunnar; Klanke, Bernd; Kalucka, Joanna; Schatz, Valentin; Daniel, Christoph; Mayer, Marleen; Goppelt-Strübe, Margarete; Herrmann, Martin; Thorsteinsdottir, Margret; Palsson, Runolfur; Beneke, Angelika; Katschinski, Dörthe M.; et al. (Kidney International, 2019)
Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis. After three weeks, renal dysfunction and tubulointerstitial damage, including proximal and distal tubular injury, tubular dilation and renal crystal deposition were significantly attenuated in PHDI-treated (the isoquinoline derivative ICA and Roxadustat) compared to vehicle-treated mice with adenine-induced nephropathy. Crystal-induced renal fibrosis was only partially diminished by treatment with ICA. Renoprotective effects of ICA treatment could not be attributed to changes in adenine metabolism or urinary excretion of the metabolite 2,8-dihydroxyadenine. ICA treatment reduced inflammatory infiltrates of F4/80+ mononuclear phagocytes in the kidneys and supported a regulatory, anti-inflammatory immune response. Furthermore, interstitial deposition of complement C1q was decreased in ICA-treated mice fed an adenine-enriched diet. Tubular cell-specific HIF-1α and myeloid cell-specific HIF-1α and HIF-2α expression were not required for the renoprotective effects of ICA. In contrast, depletion of mononuclear phagocytes with clodronate largely abolished the nephroprotective effects of PHD inhibition. Thus, our findings indicate novel and potent systemic anti-inflammatory properties of PHDIs that confer preservation of kidney function and structure in chronic tubulointerstitial inflammation and might counteract kidney disease progression.
CRIS-Team Scopus Importer:2019-06-04
Keywords: adenine; chronic inflammation; chronic kidney disease; hypoxia-inducible factor; mononuclear phagocyte; PHD inhibitor

Mortality and morbidity in relation to changes in albuminuria, glucose status and systolic blood pressure: an analysis of the ONTARGET and TRANSCEND studies - Schmieder, Roland; Schutte, Rudolph; Schumacher, Helmut; Boehm, Michael; Mancia, Giuseppe; Weber, Michael A.; Mcqueen, Matthew; Teo, Koon; Yusuf, Salim (Diabetologia, 2014)
Urinary albumin excretion is a strong predictor of cardiovascular disease. It is uncertain whether improvement from microalbuminuria or deterioration from normoalbuminuria over time in patients with differing changes in glucose and BP change their cardiovascular risk.Data on mortality, cardiovascular and renal outcomes were analysed in 22,984 patients from two large parallel randomised clinical trials followed for 56 months. A central laboratory analysed first morning spot urine samples at baseline and after 24 months, and events were recorded over the subsequent 32 months. Patients were stratified by changes in albuminuria, glucose status and mean systolic BP over 2 years.There was a strong association between albuminuria status and all-cause and cardiovascular mortality and combined cardiovascular and renal endpoints (all p < 0.0001). Changes in systolic BP control had no effect on mortality, whereas glucose status was significantly associated with all outcomes. Irrespective of BP control or glucose status, patients showing an improvement from microalbuminuria to normoalbuminuria after 2 years were at a lower risk of all outcome measures than patients showing deterioration from normoalbuminuria to microalbuminuria (HR for all-cause mortality 0.65 [0.52-0.83], p = 0.0004).Patients who showed improvement to normoalbuminuria over 2 years were at lower risk of all-cause and cardiovascular mortality and of cardiovascular and renal events than those who deteriorated to microalbuminuria over time. Albuminuria over time was significantly better than glucose status and BP control in predicting mortality and both cardiovascular and renal outcomes in patients at a high cardiovascular risk.
EVALuna2:3720

Moving beyond GWAS and eQTL Analysis to Validated Hits in Chronic Kidney Disease - Müller-Deile, Janina; Jobst-Schwan, Tilman; Schiffer, Mario (Cell Metabolism, 2019)
Genome-wide association studies (GWAS) have identified multiple chronic kidney disease (CKD)-associated single-nucleotide polymorphisms (SNPs) mainly localized to non-coding genomic regions. To understand which genes and which cell types are affected by these genetic variants, compartment-specific transcriptome, genome, and epigenome data were analyzed in an integrative manner in a recent study by Qiu et al. (Qiu et al., 2018).
EVALuna2:118628

Mri of finger pulleys at 7t—direct characterization of pulley ruptures in an ex vivo model - Heiß, Rafael; Librimir, Alexander; Lutter, Christoph; Janka, Rolf Matthias; Kuerten, Stefanie; Roemer, Frank; Nagel, Armin Michael; Uder, Michael; Bayer, Thomas (Diagnostics, 2021)
The aim of this study was to evaluate 7 Tesla (7T) magnetic resonance imaging (MRI) for direct visualization and specific characterization of the finger flexor pulleys A2, A3, and A4 before and after ex vivo pulley rupture. Thirty fingers of human cadavers were examined before and after pulley disruption with a 26 min clinical 7T pulse sequence protocol. Images were assessed by two experienced radiologists for the presence of pulley rupture. Injury characterization included definition of rupture location, morphology, and complications. Image quality was evaluated according to a 4-point Likert-type scale from “not evaluable” to “excellent”. Macroscopic preparations were used as the reference standard. Direct characterization of intact A2, A3, and A4 pulleys and the corresponding pulley lesions was possible in all cases. The rupture location was distributed equally at the radial, ulnar, and central parts of the pulleys. A dislocation and intercalation of the pulley stump between the flexor tendon and finger phalanges was observed as a complication in 62.5% of cases. The average Likert score for direct visualization of pulleys was 2.67 before rupture and 2.79 after rupture creation, demonstrating adequate image quality for routine application. 7T MRI enables a direct characterization of A2, A3, and A4 pulleys before and after artificial disruption, including the definition of rupture morphology and location as well as the detection of rupture complications. This promises a precise presurgical evaluation of pulley injuries and complicated pulley stump dislocations.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Climbing; Finger flexor pulleys; Imaging; Injury classification; Ultra-high-field MRI

Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation - Mahajan, Anubha; Spracklen, Cassandra N.; Zhang, Weihua; Ng, Maggie C. Y.; Petty, Lauren E.; Kitajima, Hidetoshi; Yu, Grace Z.; Rueger, Sina; Speidel, Leo; Kim, Young Jin; Horikoshi, Momoko; Mercader, Josep M.; et al. (Nature Genetics, 2022)
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
CRIS-Team WoS Importer:2022-06-03

Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis - Tangri, Navdeep; Grams, Morgan E.; Levey, Andrew S.; Coresh, Josef; Appel, Lawrence J.; Astor, Brad C.; Chodick, Gabriel; Collins, Allan J.; Djurdjev, Ognjenka; Elley, Raina; Evans, Marie; Garg, Amit X.; et al. (Journal of the American Medical Association, 2016)
Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed.To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis.Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014.Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease.Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed.Kidney failure (treatment by dialysis or kidney transplant).During a median follow-up of 4 years of 721,357 participants with CKD, 23,829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90; 95% CI, 0.89-0.92 at 2 years; C statistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 and P = .02).Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary.
EVALuna2:3846

Multiparametric magnetic resonance imaging of experimental chronic kidney disease: A quantitative correlation study with histology - Schley, Gunnar; Jordan, Jutta; Ellmann, Stephan; Rosen, Seymour; Eckardt, Kai-Uwe; Uder, Michael; Willam, Carsten; Bäuerle, Tobias (PLoS ONE, 2018)
OBJECTIVES: In human chronic kidney disease (CKD) the extent of renal tubulointerstitial fibrosis correlates with progressive loss of renal function. However, fibrosis can so far only be assessed by histology of kidney biopsies. Magnetic resonance imaging (MRI) can provide information about tissue architecture, but its potential to assess fibrosis and inflammation in diseased kidneys remains poorly defined. MATERIALS AND METHODS: We evaluated excised kidneys in a murine adenine-induced nephropathy model for CKD by MRI and correlated quantitative MRI parameters (T1, T2, and T2* relaxation times, apparent diffusion coefficient and fractional anisotropy) with histological hallmarks of progressive CKD, including renal fibrosis, inflammation, and microvascular rarefaction. Furthermore, we analyzed the effects of paraformaldehyde fixation on MRI parameters by comparing kidney samples before and after fixation with paraformaldehyde. RESULTS: In diseased kidneys T2 and T2* relaxation times, apparent diffusion coefficient and fractional anisotropy in the renal cortex and/or outer medulla were significantly different from those in control kidneys. In particular, T2 relaxation time was the best parameter to distinguish control and CKD groups and correlated very well with the extent of fibrosis, inflammatory infiltrates, tubular dilation, crystal deposition, and loss of peritubular capillaries and normal tubules in the renal cortex and outer medulla. Fixation with paraformaldehyde had no impact on T2 relaxation time and fractional anisotropy, whereas T1 times significantly decreased and T2* times and apparent diffusion coefficients increased in fixed kidney tissue. CONCLUSIONS: MRI parameters provide a promising approach to quantitatively assess renal fibrosis and inflammation in CKD. Especially T2 relaxation time correlates well with histological features of CKD and is not influenced by paraformaldehyde fixation of kidney samples. Thus, T2 relaxation time might be a candidate parameter for non-invasive assessment of renal fibrosis in human patients.
EVALuna2:34510

Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway - Grampp, Steffen; Schmid, Virginia; Salama, Rafik; Lauer, Victoria; Kranz, Franziska; Platt, James L.; Smythies, James; Choudhry, Hani; Goppelt-Strübe, Margarete; Ratcliffe, Peter J.; Mole, David R.; Schödel, Johannes (PLoS Genetics, 2017)
Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12.1. This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF-binding site that mediates HIF-1? isoform specific upregulation of its target BHLHE41. The alignment of multiple sites in the HIF cis-acting apparatus with RCC-susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development.
EVALuna2:3965

Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway - Grampp, Steffen; Schmid, Virginia; Salama, Rafik; Lauer, Victoria; Kranz, Franziska; Platt, James L.; Smythies, James; Choudhry, Hani; Goppelt-Strübe, Margarete; Ratcliffe, Peter J.; Mole, David R.; Schoedel, Johannes (PLoS Genetics, 2017)
Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12.1. This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF-binding site that mediates HIF-1? isoform specific upregulation of its target BHLHE41. The alignment of multiple sites in the HIF cis-acting apparatus with RCC-susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development.

Multiplex gene analysis reveals T-cell and antibody-mediated rejection-specific upregulation of complement in renal transplants - Vonbrunn, Eva; Ries, Tajana; Söllner, Stefan; Müller-Deile, Janina; Büttner, Maike; Amann, Kerstin Ute; Daniel, Christoph (Scientific Reports, 2021)
In renal transplantation, complement is involved in ischemia reperfusion injury, graft rejection and dysfunction. However, it is still unclear how induction of complement and its activation are initiated. Using allograft biopsies of a well-characterized cohort of 28 renal transplant patients with no rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection (ABMR) we analyzed differences in complement reaction. For that mRNA was isolated from FFPE sections, quantified with a multiplex gene expression panel and correlated with transplant conditions and follow-up of patients. Additionally, inflammatory cells were quantified by multiplex immunohistochemistry. In allograft biopsies with TCMR and ABMR gene expression of C1QB was 2-4 fold elevated compared to Ctrl. In TCMR biopsies, mRNA counts of several complement-related genes including C1S, C3, CFB and complement regulators CFH, CR1 and SERPING1 were significantly increased compared to Ctrl. Interestingly, expression levels of about 75% of the analyzed complement related genes correlated with cold ischemia time (CIT) and markers of inflammation. In conclusion, this study suggest an important role of complement in transplant pathology which seems to be at least in part triggered by CIT. Multiplex mRNA analysis might be a useful method to refine diagnosis and explore new pathways involved in rejection.
CRIS-Team Scopus Importer:2021-08-13

Mutation of microphthalmia-associated transcription factor (mitf) in zebrafish sensitizes for glomerulopathy - Müller-Deile, Janina; Schenk, Heiko; Niggemann, Philipp; Bolanõs-Palmieri, Patricia; Teng, Beina; Higgs, Alysha; Staggs, Lynne; Haller, Hermann; Schroder, Patricia; Schiffer, Mario (Biology Open, 2019)
Different glomerular diseases that affect podocyte homeostasis can clinically present as nephrotic syndrome with massive proteinuria, hypoalbuminemia, hyperlipidemia and edema. Up to now, no drugs that specifically target the actin cytoskeleton of podocytes are on the market and model systems for library screenings to develop anti-proteinuric drugs are of high interest. We developed a standardized proteinuria model in zebrafish using puromycin aminonucleoside (PAN) via treatment in the fish water to allow for further drug testing to develop anti-proteinuric drugs for the treatment of glomerular diseases. We noticed that fish that carry the nacre-mutation show a significantly higher susceptibility for the disruption of the glomerular filtration barrier following PAN treatment, which results in a more pronounced proteinuria phenotype. Nacre zebrafish inherit a mutation yielding a truncated version of microphthalmia-associated transcription factor/melanogenesis associated transcription factor (mitf). We hypothesized that the nacre mutation may lead to reduced formin expression and defects in cytoskeletal rearrangement. Based on the observations in zebrafish, we carried out a PAN treatment on cultured human podocytes after knockdown with MITF siRNA causing a rearrangement of the actin cytoskeleton.
CRIS-Team Scopus Importer:2019-05-09
Keywords: Glomerulopathy; MITF; PAN; Podocyte; Zebrafish

Mutations in mitochondrial DNA causing tubulointerstitial kidney disease - Connor, Thomas M.; Hoer, Simon; Mallett, Andrew; Gale, Daniel P.; Gomez-Duran, Aurora; Posse, Viktor; Antrobus, Robin; Moreno, Pablo; Sciacovelli, Marco; Frezza, Christian; Duff, Jennifer; Sheerin, Neil S.; et al. (PLoS Genetics, 2017)
Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A>T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNAPhe, tRNALeu1 and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNAPhe (m.616T>C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNAPhe.
EVALuna2:3945

Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction - Tiosano, Dov; Baris, Hagit N.; Chen, Anlu; Hitzert, Marrit M.; Schüler, Markus; Gulluni, Federico; Wiesener, Antje; Bergua, Antonio; Mory, Adi; Copeland, Brett; Gleeson, Joseph G.; Rump, Patrick; et al. (PLoS Genetics, 2019)
PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.
CRIS-Team Scopus Importer:2019-05-28

Myeloid Cell-Derived HIF-1? Promotes Control of Leishmania major - Schatz, Valentin; Strussmann, Yannic; Mahnke, Alexander; Schley, Gunnar; Waldner, Maximilian; Ritter, Uwe; Wild, Jens; Willam, Carsten; Dehne, Nathalie; Brune, Bernhard; Mcniff, Jennifer M.; Colegio, Oscar R.; et al. (Journal of Immunology, 2016)
Hypoxia-inducible factor-1? (HIF-1?), which accumulates in mammalian host organisms during infection, supports the defense against microbial pathogens. However, whether and to what extent HIF-1? expressed by myeloid cells contributes to the innate immune response against Leishmania major parasites is unknown. We observed that Leishmania-infected humans and L. major-infected C57BL/6 mice exhibited substantial amounts of HIF-1? in acute cutaneous lesions. In vitro, HIF-1? was required for leishmanicidal activity and high-level NO production by IFN-?/LPS-activated macrophages. Mice deficient for HIF-1? in their myeloid cell compartment had a more severe clinical course of infection and increased parasite burden in the skin lesions compared with wild-type controls. These findings were paralleled by reduced expression of type 2 NO synthase by lesional CD11b(+) cells. Together, these data illustrate that HIF-1? is required for optimal innate leishmanicidal immune responses and, thereby, contributes to the cure of cutaneous leishmaniasis.
EVALuna2:2181

Myocardial infarction with a preserved ejection fraction—the impaired function of the cardio-renal baroreflex - Pickny, Lisa; Hindermann, Martin; Ditting, Tilmann; Hilgers, Karl Friedrich; Linz, Peter; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Rodionova, Kristina (Frontiers in Physiology, 2023)
Introduction: In experimental myocardial infarction with reduced ejection fraction causing overt congestive heart failure, the control of renal sympathetic nerve activity (RSNA) by the cardio-renal baroreflex was impaired. The afferent vagal nerve activity under these experimental conditions had a lower frequency at saturation than that in controls. Hence, by investigating respective first neurons in the nodose ganglion (NG), we wanted to test the hypothesis that after myocardial infarction with still-preserved ejection fraction, the cardiac afferent nerve pathway is also already impaired. Material and methods: A myocardial infarction was induced by coronary artery ligature. After 21 days, nodose ganglion neurons with cardiac afferents from rats with myocardial infarction were cultured. A current clamp was used to characterize neurons as “tonic,” i.e., sustained action potential (AP) firing, or “phasic,” i.e., <5 APs upon current injection. Cardiac ejection fraction was measured using echocardiography; RSNA was recorded to evaluate the sensitivity of the cardiopulmonary baroreflex. Renal and cardiac histology was studied for inflammation and fibrosis markers. Results: A total of 192 neurons were investigated. In rats, after myocardial infarction, the number of neurons with a tonic response pattern increased compared to that in the controls (infarction vs. control: 78.6% vs. 48.5%; z-test, *p < 0.05), with augmented production of APs (23.7 ± 2.86 vs. 15.5 ± 1.86 APs/600 ms; mean ± SEM, t-test, *p < 0.05). The baseline activity of RSNA was subtly increased, and its control by the cardiopulmonary baroreflex was impaired following myocardial infarction: the fibrosis marker collagen I augmented in the renal interstitium. Discussion: After myocardial infarction with still-preserved ejection fraction, a complex impairment of the afferent limb of the cardio-renal baroreflex caused dysregulation of renal sympathetic nerve activity with signs of renal fibrosis.
CRIS-Team Scopus Importer:2023-05-05
Keywords: cardiac afferent neurons after myocardial infarction cardiac afferent innervation; congestive heart failure; myocardial infarction; neuronal cell culture; preserved ejection fraction; renal innervation

Na+ deposition in the fibrotic skin of systemic sclerosis patients detected by 23Na-magnetic resonance imaging - Kopp, Christoph; Beyer, Christian; Linz, Peter; Dahlmann, Anke; Hammon, Matthias; Jantsch, Jonathan; Neubert, Patrick; Rosenhauer, Daniela; Mueller, Dominik N.; Eckardt, Kai-Uwe; Schett, Georg; Luft, Friedrich C.; et al. (Rheumatology, 2017)
Skin fibrosis is the predominant feature of SSc and arises from excessive extracellular matrix deposition. Glycosaminoglycans are macromolecules of the extracellular matrix, which facilitate Na(+) accumulation in the skin. We used (23)Na-MRI to quantify Na(+) in skin. We hypothesized that skin Na(+) might accumulate in SSc and might be a biomarker for skin fibrosis.In this observational case-control study, skin Na(+) was determined by (23)Na-MRI using a Na(+) volume coil in 12 patients with diffuse cutaneous SSc and in 21 control subjects. We assessed skin fibrosis by the modified Rodnan skin score prior to (23)Na-MRI and on follow-up 12 months later.(23)Na-MRI demonstrated increased Na(+) in the fibrotic skin of SSc patients compared with skin from controls [mean (sd): 27.2 (5.6) vs 21.4 (5.3) mmol/l, P < 0.01]. Na(+) content was higher in fibrotic than in non-fibrotic SSc skin [26.2 (4.8) vs 19.2 (3.4) mmol/l, P < 0.01]. Furthermore, skin Na(+) amount was correlated with changes in follow-up modified Rodnan skin score (R(2) = 0.68).(23)Na-MRI detected increased Na(+) in the fibrotic SSc skin; high Na(+) content was associated with progressive skin disease. Our findings provide the first evidence that (23)Na-MRI might be a promising tool to assess skin Na(+) and thereby predict progression of skin fibrosis in SSc.
EVALuna:33997

Native cardiac T1 Mapping: Standardized inline analysis of long and short axis at three identical 1.5 Tesla MRI scanners - Heiß, Rafael; Wiesmüller, Marco; Uder, Michael; May, Matthias; Wüst, Wolfgang (European Journal of Radiology, 2018)
BACKGROUND: Interpretation of native T1 time values remains difficult due to limited hard- and software comparability and the lack of measurement recommendations for the number of slices and their orientation. To provide a standardized comparison of native T1 time values in short and long axis and to investigate the interscanner reproducibility. METHODS: 78 cardiac MRIs in 26 healthy volunteers were performed with three structurally identical 1.5 T MRI scanners. A commercially available software package for T1 mapping with automatic in-line motion correction was used for analysis. On T1 mapping images regions of interest were manually placed in each of the 16 myocardial segments according to the AHA model in three short and three long axis. RESULTS: A total of 2652 ROIs were drawn and 102 segments per volunteer were analysed. Interscanner reproducibility was high and the mean myocardial T1 time value for all evaluated segments was 996 ± 34 ms. Significant variations of T1 time values were found between heart segments in the same axis. Mean T1 time values were comparable between long and short axis but differed in 33% of corresponding short and long axis segments. CONCLUSIONS: Native T1 time values in short and long axis are highly reproducible but can vary significantly between heart segments in the same axis. Comparability between corresponding short and long axis segments is limited. To get representative results native T1 time values should be obtained in more than one heart segment and for follow-up studies identical segments should be used to avoid a systematic bias.
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Negative Impact of the UEFA European Soccer Championship on Central Hemodynamics and Arterial Stiffness: A Multicenter Study - Franzen, Klaas F.; Mortensen, Kai; Ott, Christian; Herber, Katrin; Busse, Marlene; Soling, Charlotte; Schneppe, Daniel; Lassig, Saskia; Dorr, Marcus; Tilz, Roland; Dromann, Daniel; Schunkert, Heribert; et al. (Life, 2022)
(1) Background: watching sporting events may trigger cardiovascular events by elevating emotional stress levels. The underlying reasons and specific populations at risk are not well defined. (2) Methods: we conducted a multicenter prospective trial at three German sites during the UEFA Soccer EC 2012 and 2021 comprising 52 healthy participants (noCVD) and 18 patients hospitalized with cardiovascular disease (CVD). Subjects were studied during matches of the German national team (GP) as well as corresponding matches without German participation (noGP). Peripheral and central blood pressure (BP) and parameters of arterial stiffness were measured (Mobil-O-Graph™, I.E.M., Stolberg, Germany) before, during, and after the matches. (3) Results: in terms of CVD, peripheral as well as central BP and heart rate increased significantly during GP as well as noGP matches and remained elevated beyond the end of the matches. Likewise, arterial stiffness parameters and vascular resistance were higher during the matches and remained elevated after the matches. No consistent significant differences were found between GP and noGP matches. (4) Conclusions: this is the first study on real-life changes in hemodynamics during sport-associated emotional stress, with comparison between noCVD and CVD. We found that alterations were profound in CVD and remained elevated even after the matches.
CRIS-Team Scopus Importer:2022-11-25
Keywords: arterial stiffness; cardiovascular disease; central hemodynamics; emotional stress; European soccer championship

Neonatal nephron loss during active nephrogenesis - detrimental impact with long-term renal consequences - Menendez-Castro, Carlos; Nitz, Doerte; Cordasic, Nada; Jordan, Jutta; Bäuerle, Tobias; Fahlbusch, Fabian B.; Rascher, Wolfgang; Hilgers, Karl Friedrich; Hartner, Andrea (Scientific Reports, 2018)
Neonatal nephron loss may follow hypoxic-ischemic events or nephrotoxic medications. Its long-term effects on the kidney are still unclear. Unlike term infants, preterm neonates less than 36 weeks gestational age show ongoing nephrogenesis. We hypothesized that nephron loss during nephrogenesis leads to more severe renal sequelae than nephron loss shortly after the completion of nephrogenesis. Rats show nephrogenesis until day 10 of life resembling the situation of preterm infants. Animals were uninephrectomized at day 1 (UNX d1) resulting in nephron reduction during nephrogenesis and at day 14 of life (UNX d14) inducing nephron loss after the completion of nephrogenesis. 28 days after uninephrectomy the compensatory renal growth was higher in UNX d1 compared to UNX d14. Nephrin was reduced and collagen deposition increased in UNX d1. At 1 year of age, glomerulosclerosis and markers of tubulointerstitial damage were most prevalent in UNX d1. Moreover, the number of desmin-positive podocytes was higher and nephrin was reduced in UNX d1 indicating podocyte damage. Infiltration of inflammatory cells was heightened after UNX d1. Uninephrectomized animals showed no arterial hypertension. We conclude that neonatal nephron loss during active nephrogenesis leads to more severe glomerular and tubulointerstitial damage, which is not a consequence of compensatory arterial hypertension.
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Neonatal nephron loss during active nephrogenesis results in altered expression of renal developmental genes and markers of kidney injury - Raming, Roman; Cordasic, Nada; Kirchner, Philipp; Ekici, Arif Bülent; Fahlbusch, Fabian; Wölfle, Joachim; Hilgers, Karl Friedrich; Hartner, Andrea; Menendez-Castro, Carlos (Physiological Genomics, 2021)
Preterm neonates are at a high risk for nephron loss under adverse clinical conditions. Renal damage potentially collides with postnatal nephrogenesis. Recent animal studies suggest that nephron loss within this vulnerable phase leads to renal damage later in life. Nephrogenic pathways are commonly reactivated after kidney injury supporting renal regeneration. We hypothesized that nephron loss during nephrogenesis affects renal development, which, in turn, impairs tissue repair after secondary injury. Neonates prior to 36 wk of gestation show an active nephrogenesis. In rats, nephrogenesis is ongoing until day 10 after birth. Mimicking the situation of severe nephron loss during nephrogenesis, male pups were uninephrectomized at day 1 of life (UNXd1). A second group of males was uninephrectomized at postnatal day 14 (UNXd14), after terminated nephrogenesis. Agematched controls were sham operated. Three days after uninephrectomy transcriptional changes in the right kidney were analyzed by RNA-sequencing, followed by functional pathway analysis. In UNXd1, 1,182 genes were differentially regulated, but only 143 genes showed a regulation both in UNXd1 and UNXd14. The functional groups “renal development” and “kidney injury” were among the most differentially regulated groups and revealed distinctive alterations. Reduced expression of candidate genes concerning renal development (Bmp7, Gdnf, Pdgf-B, Wt1) and injury (nephrin, podocin, Tgf-b 1) were detected. The downregulation of Bmp7 and Gdnf persisted until day 28. In UNXd14, Six2 was upregulated and Pax2 was downregulated. We conclude that nephron loss during nephrogenesis affects renal development and induces a specific regulation of genes that might hinder tissue repair after secondary kidney injury.
CRIS-Team Scopus Importer:2021-12-17
Keywords: Neonatal nephron loss; Neonatal uninephrectomy; Nephrogenesis; Renal regeneration; RNA-sequencing

Nephron-specific knockout of TMEM16A leads to reduced number of glomeruli and albuminuria - Schenk, Laura K.; Buchholz, Björn; Henke, Sebastian F.; Michgehl, Ulf; Daniel, Christoph; Amann, Kerstin Ute; Kunzelmann, Karl; Pavenstaedt, Hermann (American Journal of Physiology-Renal Physiology, 2018)
TMEM16A is a transmembrane protein from a conserved family of calcium activated proteins, which is highly expressed in the kidney. TMEM16A confers calcium-activated chloride channel activity which is of importance for various cellular functions in secretory epithelia and involved in secretion-dependent renal cyst growth. However, its specific function in renal physiology has remained elusive so far. Therefore we generated conditional nephron specific TMEM16A knockout mice and found that these animals suffered from albuminuria. Kidney histology demonstrated an intact corticomedullary differentiation and absence of cysts. Electron microscopy showed a normal slit diaphragm. However, the total number of glomeruli and total nephron count was decreased in TMEM16A knockout animals. At the same time, glomerular diameter was increased, presumably as a result of the hyperfiltration in the remaining glomeruli. TUNEL and PCNA stainings showed increased cell death and increased proliferation. Proximal tubular cilia were intact in young animals but the number of properly ciliated cells was decreased in older, albuminuric animals. Taken together, our data suggests that TMEM16A may be involved in ureteric bud branching and proper nephron endowment. Loss of TMEM16A resulted in reduced nephron number and, subsequently, albuminuria and tubular damage.
EVALuna2:35395
Keywords: albuminuria; Ano1; kidney; nephron number; TMEM16A

Neurogenic substance P-influences on action potential production in afferent neurons of the kidney? - Rodionova, Kristina; Hilgers, Karl Friedrich; Linz, Peter; Schaetzl, Johannes; Raschke, Giulia; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Ditting, Tilmann (Pflügers Archiv: European Journal of Physiology, 2021)
We recently showed that a substance P (SP)-dependent sympatho-inhibitory mechanism via afferent renal nerves is impaired in mesangioproliferative nephritis. Therefore, we tested the hypothesis that SP released from renal afferents inhibits the action potential (AP) production in their dorsal root ganglion (DRG) neurons. Cultured DRG neurons (Th11-L2) were investigated in current clamp mode to assess AP generation during both TRPV1 stimulation by protons (pH 6) and current injections with and without exposure to SP (0.5 mu mol) or CGRP (0.5 mu mol). Neurons were classified as tonic (sustained AP generation) or phasic (<= 4 APs) upon current injection; voltage clamp experiments were performed for the investigation of TRPV1-mediated inward currents due to proton stimulation. Superfusion of renal neurons with protons and SP increased the number of action potentials in tonic neurons (9.6 +/- 5 APs/10 s vs. 16.9 +/- 6.1 APs/10 s, P < 0.05, mean +/- SD, n = 7), while current injections with SP decreased it (15.2 +/- 6 APs/600 ms vs. 10.2 +/- 8 APs/600 ms, P < 0.05, mean +/- SD, n = 29). Addition of SP significantly reduced acid-induced TRPV1-mediated currents in renal tonic neurons (- 518 +/- 743 pA due to pH 6 superfusion vs. - 82 +/- 50 pA due to pH 6 with SP superfusion). In conclusion, SP increased action potential production via a TRPV1-dependent mechanism in acid-sensitive renal neurons. On the other hand, current injection in the presence of SP led to decreased action potential production. Thus, the peptide SP modulates signaling pathways in renal neurons in an unexpected manner leading to both stimulation and inhibition of renal neuronal activity in different (e.g., acidic) environmental contexts.
CRIS-Team WoS Importer:2021-04-16

Neurogenic tachykinin mechanisms in experimental nephritis of rats - Rodionova, Kristina; Hilgers, Karl Friedrich; Paulus, Eva-Maria; Tiegs, Gisa; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Ditting, Tilmann (Pflügers Archiv: European Journal of Physiology, 2020)
We demonstrated earlier that renal afferent pathways combine very likely "classical" neural signal transduction to the central nervous system and a substance P (SP)-dependent mechanism to control sympathetic activity. SP content of afferent sensory neurons is known to mediate neurogenic inflammation upon release. We tested the hypothesis that alterations in SP-dependent mechanisms of renal innervation contribute to experimental nephritis. Nephritis was induced by OX-7 antibodies in rats, 6 days later instrumented for recording of blood pressure (BP), heart rate (HR), drug administration, and intrarenal administration (IRA) of the TRPV1 agonist capsaicin to stimulate afferent renal nerve pathways containing SP and electrodes for renal sympathetic nerve activity (RSNA). The presence of the SP receptor NK-1 on renal immune cells was assessed by FACS. IRA capsaicin decreased RSNA from 62.4 +/- 5.1 to 21.6 +/- 1.5 mV s (*p < 0.05) in controls, a response impaired in nephritis. Suppressed RSNA transiently but completely recovered after systemic administration of a neurokinin 1 (NK1-R) blocker. NK-1 receptors occurred mainly on CD11(+)dendritic cells (DCs). An enhanced frequency of CD11c(+)NK1R(+)cell, NK-1 receptor(+)macrophages, and DCs was assessed in nephritis. Administration of the NK-1R antagonist aprepitant during nephritis reduced CD11c(+)NK1R(+)cells, macrophage infiltration, renal expression of chemokines, and markers of sclerosis. Hence, SP promoted renal inflammation by weakening sympathoinhibitory mechanisms, while at the same time, substance SP released intrarenally from afferent nerve fibers aggravated immunological processes i.e. by the recruitment of DCs.
CRIS-Team WoS Importer:2020-11-06

Neurometabolic Dysfunction in SPG11 Hereditary Spastic Paraplegia. - Winner, Beate; Marterstock, Dominique; Kopp, Christoph; Dörfler, Arnd; Regensburger, Martin; Krumm, Laura; Schmidt, Manuel; Schmid, Andreas; Spatz, Imke; Marterstock, Dominique; Kopp, Christoph; Kohl, Zacharias; et al. (Nutrients, 2022)
Body composition, adipokine levels, and hypothalamic volume are altered in SPG11. Our data indicate a link between obesity and hypothalamic neurodegeneration in SPG11 and imply that specific metabolic interventions may prevent obesity despite severely impaired mobility in SPG11. Pathogenic variants in SPG11 cause the most common autosomal recessive complicated hereditary spastic paraplegia. Besides the prototypical combination of spastic paraplegia with a thin corpus callosum, obesity has increasingly been reported in this multisystem neurodegenerative disease. However, a detailed analysis of the metabolic state is lacking. In order to characterize metabolic alterations, a cross-sectional analysis was performed comparing SPG11 patients (n = 16) and matched healthy controls (n = 16). We quantified anthropometric parameters, body composition as determined by bioimpedance spectroscopy, and serum metabolic biomarkers, and we measured hypothalamic volume by high-field MRI. Compared to healthy controls, SPG11 patients exhibited profound changes in body composition, characterized by increased fat tissue index, decreased lean tissue index, and decreased muscle mass. The presence of lymphedema correlated with increased extracellular fluid. The serum levels of the adipokines leptin, resistin, and progranulin were significantly altered in SPG11 while adiponectin and C1q/TNF-related protein 3 (CTRP-3) were unchanged. MRI volumetry revealed a decreased hypothalamic volume in SPG11 patients. CONCLUSIONS BACKGROUND METHODS RESULTS
Keywords: SPG11; adipokines; bioimpedance spectroscopy; hypothalamus; leptin; obesity

Neurovascular compression in arterial hypertension: Correlation of clinical data to 3d-visualizations of mri-findings - Manava, Panagiota; Hastreiter, Peter; Schmieder, Roland; Jung, Susanne; Fahlbusch, Rudolf; Dörfler, Arnd; Lell, Michael; Buchfelder, Michael; Naraghi, Ramin (Open Neuroimaging Journal, 2021)
Aims: In this study, we attempted to identify clinical parameters predicting the absence or presence of Neurovascular Compression (NVC) at the Ventrolateral Medulla (VLM) in arterial hypertension (HTN) in MRI findings. Background: Cardiovascular and pulmonary afferences are transmitted through the left vagus and glossopharyngeal nerve to the brain stem and vasoactive centers. Evidence supports the association between HTN and NVC at the left VLM. Several independent studies indicate a reduction of HTN after Microvascular Decompression (MVD) of the left. Several independent studies indicate a reduction of HTN after Microvascular Decompression (MVD) of the left VLM. Image processing of MRI provides comprehensible detection of NVC. HTN affects hemodynamic parameters and organs. Objective: This study analyzes and correlates clinical data and MRI findings in patients with and without NVC at the VLM in treatment resistant HTN to obtain possible selection criteria for neurogenic hypertension. Methods: In 44 patients with treatment resistant HTN, we compared MRI findings of neurovascular imaging to demographic, clinical and lifestyle data, office and 24-hour ambulatory Blood Pressure (BP), and cardiovascular imaging and parameters. Results: Twenty-nine (66%) patients had evidence of NVC at the VLM in MRI. Sixteen patients (36%) had unilateral NVC on the left side, 7 (16%) unilateral right and 6 (14%) bilateral NVC. Fifteen (34%) had no evidence of NVC at the VLM. Patients with left sided NVC were significantly younger, than those without NVC (p=0.034). They showed a statistically significant variance in daytime (p=0.020) and nighttime diastolic BP (p<0.001) as the mean arterial pressure (p=0.020). Other measured parameters did not show significant differences between the two groups. Conclusion: We suggest to examine young adults with treatment resistant HTN for the presence of NVC at VLM, before signs of permanent organ damage appear. Clinical and hemodynamic parameters did not emerge as selection criteria to predict NVC. MVD as a surgical treatment of NVC in HTN is not routine yet as a surgical treatment of NVC in HTN is not routine yet. Detection of NVC by imaging and image processing remains the only criteria to suggest MVD, which should be indicated on an individual decision.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Hypertension; Image fusion; MRI; Neuroimaging; Neurovascular compression; Ventrolateral medulla

New approaches in the treatment of hypertension - Oparil, Suzanne; Schmieder, Roland (Circulation Research, 2015)
Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of the hypertensive population has uncontrolled blood pressure. The unmet need of controlling blood pressure in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. In this Compendium Review, we discuss new drugs and interventional treatments that are undergoing preclinical or clinical testing for hypertension treatment. New drug classes, eg, inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine ?-hydroxylase, and the intestinal Na(+)/H(+) exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1-7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or preclinical development. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment resistant hypertension in some countries. Renal denervation is also being evaluated for treatment of various comorbidities, eg, chronic heart failure, cardiac arrhythmias and chronic renal failure. Novel interventional approaches in early development include carotid body ablation and arteriovenous fistula placement. Importantly, none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.
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New data, new studies, new hopes for renal denervation in patients with uncontrolled hypertension - Papademetriou, Vasilios; Stavropoulos, Konstantinos; Imprialos, Kostas; Doumas, Michael; Schmieder, Roland; Pathak, Atul; Tsioufis, Costas (International Journal of Cardiology: Hypertension, 2019)
Background: following the publication of SYMPLICITY HTN-3 the field of renal of denervation was put on hold. Although SYMPLICITY HTN-3 was well-designed and sham-controlled trial it failed to show any meaningful reduction in office or 24 h ambulatory blood pressure. The procedure was however safe and allowed research to continue. Although several pitfalls of the study have been pointed out, incomplete renal denervation was also implicated. Since then, a great deal of basic and clinical research took place and will be briefly commented on in this article. Methods and results: Before and after SYMPLICITY-HTN-3, numerous uncontrolled, single or unblinded studies have shown substantial office BP reduction ranging from −7.7 to −32 mmHg and ambulatory BP ranging from −2.2 to 10.2 mmHg. Average weighted office systolic BP reduction was −20.8 mmHg and weighted average 24 h ambulatory BPM reduction was −7.8 mmHg. National and international registries have shown similar BP reductions, but results remained unconvincing due to lack of reliable sham controls. In recent years, 5 well-designed sham – controlled studies (beyond, SYMPLICITY-HTN-3) have been published. Of those studies two were single center and three were multicenter international studies. Four studies used single tip or multi-electrode, radiofrequency catheters and one used focused ultrasound. The three multicenter studies reported positive-placebo subtracted results and established BP reductions measured both in the office and by ambulatory monitoring. No serious adverse events were reported. Conclusions: It can therefore be concluded that the latest sham controlled studies established efficacy and safety of renal denervation.
CRIS-Team Scopus Importer:2019-12-27
Keywords: Denervation; Hypertension; Renal artery; Sympathetic nervous system

New software analyses increase the reliability of measurements of retinal arterioles morphology by scanning laser Doppler flowmetry in humans - Harazny, Joanna M.; Raff, Ulrike; Welzenbach, Juergen; Ott, Christian; Ritt, Martin; Lehmann, Maria; Michelson, Georg; Schmieder, Roland; Lehmann, Maria (Journal of Hypertension, 2011)
The investigation of the retinal arterioles offers the unique opportunity to analyze in vivo arteriolar remodeling in arterial hypertension in humans. We analyzed the reliability of assessing retinal arteriolar morphology with our new version of the software analyses for scanning laser Doppler flowmetry.In the test-retest reliability study, 10 eyes of 10 healthy persons were measured during 5 days under routine laboratory conditions with the Heidelberg Retinal Flowmetry. In a second study, interobserver and intraobserver reliability was analyzed from retinal images of 18 patients with three types of arterial hypertension by three readers and the most experienced reader analyzed all images twice on two different days. Images were analyzed by the old and the newly developed software versions. To characterize the reliability, the coefficients of variation were calculated.The test-retest study analyzed with the new program showed that the variation coefficients of vessel and lumen diameter, wall thickness, wall/lumen ratio and new calculated parameter: lumen/vessel diameter ratio of retinal arterioles were significantly less than 10%, with the exception of the wall cross-sectional area (12.5%). The interobserver and intraobserver reliability showed in nearly all circumstances coefficients of variations of less than 10% and did not differ across various readers and patient groups.The new software 'SLDF version 4.0' clearly improved the reliability of assessing the structural parameters of the retinal arterioles. The application delivers reliable measurements of the retinal arteriolar structure in vivo in human
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New strategies to improve clinical outcomes for diabetic kidney disease - Forst, Thomas; Mathieu, Chantal; Giorgino, Francesco; Wheeler, David C.; Papanas, Nikolaos; Schmieder, Roland; Halabi, Atef; Schnell, Oliver; Streckbein, Marina; Tuttle, Katherine R. (BMC Medicine, 2022)
Background: Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. Main body: This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. Conclusion: With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes.
CRIS-Team Scopus Importer:2022-10-21
Keywords: Diabetic kidney disease; Kidney protective agents; Type 2 diabetes

No benefit of HIF prolyl hydroxylase inhibition for hypertensive renal damage in renovascular hypertensive rats - Hartner, Andrea; Dambietz, Thomas; Cordasic, Nada; Willam, Carsten; Burzlaff, Nicolai; Brötsch, Martin; Daniel, Christoph; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Schley, Gunnar; Hilgers, Karl Friedrich (Frontiers in Physiology, 2023)
Introduction: We previously reported that malignant hypertension is associated with impaired capillary density of target organs. Here, we tested the hypothesis that stabilization of hypoxia-inducible factor (HIF) in a modified “preconditioning” approach prevents the development of malignant hypertension. To stabilize HIF, we employed pharmacological inhibition of HIF prolyl hydroxylases (PHD), that profoundly affect HIF metabolism. Methods: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats; controls were sham operated. 2K1C rats received either intermittent injections of the PHD inhibitor ICA (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate) or placebo. Thirty-five days after clipping, the frequency of malignant hypertension was assessed (based on weight loss and the occurrence of characteristic vascular lesions). In addition, kidney injury was compared between all ICA treated versus all placebo treated 2K1C, regardless of the occurrence of malignant hypertension. HIF stabilization was evaluated by immunohistochemistry, and HIF target gene expression by RT-PCR. Results: Blood pressure was elevated to the same degree in ICA- and placebo-treated 2K1C compared to control rats. ICA treatment did not affect the frequency of malignant hypertension or the extent of kidney tissue fibrosis, inflammation, or capillary density. There was a trend towards higher mortality and worse kidney function in ICA-treated 2K1C rats. ICA increased the number of HIF-1α-positive renal tubular cell nuclei and induced several HIF-1 target genes. In contrast, expression of HIF-2α protein as well as HIF-2 target genes were markedly enhanced by 2K1C hypertension, irrespective of ICA treatment. Discussion: We conclude that intermittent PHD inhibition did not ameliorate severe renovascular hypertension in rats. We speculate that the unexpected strong renal accumulation of HIF-2α in renovascular hypertension, which could not be further augmented by ICA, may contribute to the lack of a benefit from PHD inhibition.
CRIS-Team Scopus Importer:2023-07-21
Keywords: capillarization; HIF stabilization; malignant hypertension; renovascular; vascular lesions

No evidence of the unfolded protein response in the placenta of two rodent models of preeclampsia and intrauterine growth restriction - Denkl, Barbara; Cordasic, Nada; Hübner, Hanna; Menendez-Castro, Carlos; Schmidt, Marius; Mocker, Alexander; Wölfle, Joachim; Hartner, Andrea; Fahlbusch, Fabian (Biology of Reproduction, 2021)
In humans, intrauterine growth restriction (IUGR) and preeclampsia (PE) are associated with induction of the unfolded protein response (UPR) and increased placental endoplasmic reticulum (ER) stress. Especially in PE, oxidative stress occurs relative to the severity of maternal vascular underperfusion (MVU) of the placental bed. On the premise that understanding the mechanisms of placental dysfunction could lead to targeted therapeutic options for human IUGR and PE, we investigated the roles of the placental UPR and oxidative stress in two rodent models of these human gestational pathologies. We employed a rat IUGR model of gestational maternal protein restriction, as well as an endothelial nitric oxide synthase knockout mouse model (eNOS-/-) of PE/IUGR. Placental expression of UPR members was analyzed via qRT-PCR (Grp78, Calnexin, Perk, Chop, Atf6, and Ern1), immunohistochemistry, and Western blotting (Calnexin, ATF6, GRP78, CHOP, phospho-eIF2α, and phospho-IRE1). Oxidative stress was determined via Western blotting (3-nitrotyrosine and 4-hydroxy-2-nonenal). Both animal models showed a significant reduction of fetal and placental weight. These effects did not induce placental UPR. In contrast to human data, results from our rodent models suggest retention of placental plasticity in the setting of ER stress under an adverse gestational environment. Oxidative stress was significantly increased only in female IUGR rat placentas, suggesting a sexually dimorphic response to maternal malnutrition. Our study advances understanding of the involvement of the placental UPR in IUGR and PE. Moreover, it emphasizes the appropriate choice of animal models researching various aspects of these pregnancy complications.
CRIS-Team Scopus Importer:2021-08-27
Keywords: eNOS; ER stress; IUGR; oxidative stress; placenta; preeclampsia

Non-invasive cardiovascular imaging for evaluating subclinical target organ damage in hypertensive patients: A consensus paper from the European Association of Cardiovascular Imaging (EACVI), the European Society of Cardiology Council on Hypertension, and - Perrone-Filardi, Pasquale; Coca, Antonio; Galderisi, Maurizio; Paolillo, Stefania; Alpendurada, Francisco; De Simone, Giovanni; Donal, Erwan; Kahan, Thomas; Mancia, Giuseppe; Redon, Josep; Schmieder, Roland; Williams, Bryan; et al. (European Heart Journal - Cardiovascular Imaging, 2017)
Arterial hypertension (HTN) accounts for the largest amount of attributable cardiovascular (CV) mortality worldwide, and risk stratification in hypertensive patients is of crucial importance to manage treatment and prevent adverse events. Asymptomatic involvement of different organs in patients affected by HTN represents an independent determinant of CV risk and the identification of target organ damage (TOD) is recommended to further reclassify patients' risk. Non-invasive CV imaging is progressively being used and continues to provide new technological opportunities to TOD evaluation at early stage. The aim of this article is to provide the community of cardiology with an update on appropriate and justified use of non-invasive imaging tests in the growing population of hypertensive patients.
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Noninvasive Diagnosis of Acute Rejection in Renal Transplant Patients Using Mass Spectrometric Analysis of Urine Samples: A Multicenter Diagnostic Phase III Trial - Gwinner, Wilfried; Karch, Annika; Braesen, Jan H.; Khalifa, Abedalrazag A.; Metzger, Jochen; Naesens, Maarten; Van Loon, Elisabet; Anglicheau, Dany; Marquet, Pierre; Budde, Klemens; Matz, Mareen; Arns, Wolfgang; et al. (Transplantation Direct, 2022)
Background. Timely recognition and treatment of acute kidney graft rejection is important to prevent premature graft failure. A predefined urinary marker set for acute T cell-mediated rejection (TCMR) containing 14 peptides was tested for this purpose in a multicenter in-place validation study. Methods. Three hundred twenty-nine prospectively collected and 306 archived urine samples from 11 transplant centers in Germany, France, and Belgium were examined. Samples were taken immediately before a biopsy, performed for graft dysfunction within the first transplant year. Primary outcomes were sensitivity and specificity of the marker set for the diagnosis of biopsy-proven acute TCMR, with prespecified thresholds of 83% for sensitivity and 70% for specificity. Results. Eighty-two patients (13%) had acute TCMR grade I-III. In relation to the biopsy diagnosis of TCMR, the sensitivity of the urine test was 0.66 (95% confidence interval, 0.56-0.76) and the specificity 0.47 (95% confidence interval, 0.43-0.51), with an area under the curve (AUC) of 0.60. The different TCMR grades I-III were not reflected by the marker set, and borderline TCMR was not specifically detected. Secondary independent masked assessment of biopsies consented by 2 pathologists revealed an interobserver kappa value of 0.49 for diagnosing TCMR, compared with the local center's diagnosis. Using this consensus diagnosis, the AUC of the urine test was 0.63 (sensitivity 0.73, specificity 0.45). Post hoc optimization of the marker set improved the diagnostic performance in the study cohort (AUC 0.67) and in an independent patient cohort (AUC 0.69). Conclusions. This study illustrates the difficulty of proteomics-based diagnosis of TCMR and highlights the need for rigorous independent in-place validation and optimization of diagnostic biomarkers.
CRIS-Team WoS Importer:2022-04-29

Non-invasive Renal Denervation: Update on External Ultrasound Approaches - Schmieder, Roland; Ott, Christian; Bramlage, Peter (Current Hypertension Reports, 2016)
In the last decade, intravenous renal denervation (RDN) has emerged as an alternative to pharmacological treatment in patients with resistant hypertension, but currently involves an invasive and technically challenging procedure. The Surround Sound(TM) system utilises externally delivered ultrasound to achieve RDN using a completely non-invasive, automated real-time tracking system coupled with a therapeutic delivery module thereby addressing these limitations. A brief history, technical overview and summary of preclinical and clinical studies of the KonaMedical Surround Sound(TM) system are presented. A literature search using the terms "renal denervation", "resistant hypertension" and "external ultrasound" was performed using PubMed, and references retrieved were selected based on relevancy and year of publication (date range 1991-2015). The Surround Sound(TM) system appears to be a promising approach to RDN which eliminates several of the factors currently limiting the intravenous approach. So far, it has demonstrated efficacy for reducing blood pressure in resistant hypertension patients with minimal adverse effects. Several double-blind, sham-controlled clinical trials are currently underway to confirm the validity of these findings.
EVALuna2:3851

Non-professional phagocytosis: a general feature of normal tissue cells - Seeberg, Jacob; Loibl, Monika; Moser, Fabian; Schwegler, Manuela; Büttner-Herold, Maike; Daniel, Christoph; Engel, Felix; Hartmann, Arndt; Schlötzer-Schrehardt, Ursula; Goppelt-Strübe, Margarete; Schellerer, Vera; Naschberger, Elisabeth; et al. (Scientific Reports, 2019)
Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.
CRIS-Team Scopus Importer:2019-08-27

Non-rigid motion-corrected free-breathing 3D myocardial Dixon LGE imaging in a clinical setting - Zeilinger, Martin; Kunze, Karl Philipp; Munoz, Camila; Neji, Radhouene; Schmidt, Michaela; Croisille, Pierre; Heiß, Rafael; Wuest, Wolfgang; Uder, Michael; Botnar, René Michael; Treutlein, Christoph; Prieto, Claudia (European Radiology, 2022)
Objectives: To investigate the efficacy of an in-line non-rigid motion-compensated reconstruction (NRC) in an image-navigated high-resolution three-dimensional late gadolinium enhancement (LGE) sequence with Dixon water–fat separation, in a clinical setting. Methods: Forty-seven consecutive patients were enrolled prospectively and examined with 1.5 T MRI. NRC reconstructions were compared to translational motion-compensated reconstructions (TC) of the same datasets in overall and different sub-category image quality scores, diagnostic confidence, contrast ratios, LGE pattern, and semiautomatic LGE quantification. Results: NRC outperformed TC in all image quality scores (p < 0.001 to 0.016; e.g., overall image quality 5/5 points vs. 4/5). Overall image quality was downgraded in only 23% of NRC datasets vs. 53% of TC datasets due to residual respiratory motion. In both reconstructions, LGE was rated as ischemic in 11 patients and non-ischemic in 10 patients, while it was absent in 26 patients. NRC delivered significantly higher LGE-to-myocardium and blood-to-myocardium contrast ratios (median 6.33 vs. 5.96, p < 0.001 and 4.88 vs. 4.66, p < 0.001, respectively). Automatically detected LGE mass was significantly lower in the NRC reconstruction (p < 0.001). Diagnostic confidence was identical in all cases, with high confidence in 89% and probable in 11% datasets for both reconstructions. No case was rated as inconclusive. Conclusions: The in-line implementation of a non-rigid motion-compensated reconstruction framework improved image quality in image-navigated free-breathing, isotropic high-resolution 3D LGE imaging with undersampled spiral-like Cartesian sampling and Dixon water–fat separation compared to translational motion correction of the same datasets. The sharper depictions of LGE may lead to more accurate measures of LGE mass. Key Points: • 3D LGE imaging provides high-resolution detection of myocardial scarring. • Non-rigid motion correction provides better image quality in cardiac MRI. • Non-rigid motion correction may lead to more accurate measures of LGE mass.
CRIS-Team Scopus Importer:2022-02-25
Keywords: Heart; Magnetic resonance imaging; Myocardium; Three-dimensional imaging

Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease - Bramlage, Peter; Swift, Stephanie L.; Thoenes, Martin; Minguet, Joan; Ferrero, Carmen; Schmieder, Roland (European Journal of Heart Failure, 2016)
Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a next-generation non-steroidal dihydropyridine-based MR antagonist designed to minimize off-target effects while maintaining potent efficacy. In this review, the outcomes of finerenone therapy in several diseases associated with MR activity are explored. The (pre-) clinical efficacy of finerenone is compared with that of traditional steroid-based MR antagonists. Finally, recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy are discussed. Taken together, pre-clinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared with traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease.
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Novel approaches to management of hypertension - Bosch, Agnes; Schmieder, Roland (Current Opinion in Nephrology and Hypertension, 2021)
Purpose of review Of the roughly 1.4 billion people with hypertension worldwide, only about one in seven has their blood pressure (BP) successfully treated and adequately controlled. This review will focus on new therapeutic approaches of hypertension. Recent findings Several recent clinical studies and guidelines have favoured the assessment of target organ damage and cardiovascular risk scores for the diagnosis and treatment approach of hypertension. Paradigm shifts recommended in the guidelines are the initiation of antihypertensive treatment with combination (not mono) therapy and the recommendation of single-pill combinations (SPC), which improve adherence and result in rapid and effective BP control. In clinical trials with optimized design and renal denervation (RDN) technology, the biological proof of concept has been established. Consistent, durable ambulatory and office BP reductions without procedure associated serious adverse events have been documented. The challenges are now to identify patients who respond best to interventional treatment. Major key points in the treatment strategy for hypertension are: individualization of the therapy according to total cardiovascular risk, combination therapy as initial step, recommendation of SPC and RDN as promising interventional therapy.
CRIS-Team WoS Importer:2021-01-15

Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis - Müller-Deile, Janina; Sarau, George; Kotb, Ahmed M.; Jaremenko, Christian; Rolle-Kampczyk, Ulrike E.; Daniel, Christoph; Kalkhof, Stefan; Christiansen, Silke H.; Schiffer, Mario (Scientific Reports, 2021)
Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead to early recurrence of FSGS and kidney failure after kidney transplantation. In the past three decades, many research endeavors were undertaken to identify these unknown factors. Even though some potential candidates have been recently discussed in the literature, “the” actual factor remains elusive. Therefore, there is an increased demand in FSGS research for the use of novel technologies that allow us to study FSGS from a yet unexplored angle. Here, we report the successful treatment of recurrent FSGS in a patient after living-related kidney transplantation by removal of circulating factors with CytoSorb apheresis. Interestingly, the classical published circulating factors were all in normal range in this patient but early disease recurrence in the transplant kidney and immediate response to CytoSorb apheresis were still suggestive for pathogenic circulating factors. To proof the functional effects of the patient’s serum on podocytes and the glomerular filtration barrier we used a podocyte cell culture model and a proteinuria model in zebrafish to detect pathogenic effects on the podocytes actin cytoskeleton inducing a functional phenotype and podocyte effacement. We then performed Raman spectroscopy in the < 50 kDa serum fraction, on cultured podocytes treated with the FSGS serum and in kidney biopsies of the same patient at the time of transplantation and at the time of disease recurrence. The analysis revealed changes in podocyte metabolome induced by the FSGS serum as well as in focal glomerular and parietal epithelial cell regions in the FSGS biopsy. Several altered Raman spectra were identified in the fractionated serum and metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, which were supported by disturbances in the Raman spectra. Our novel innovative analysis reveals changed lipid metabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.
CRIS-Team Scopus Importer:2021-03-19

NOVEL DIAGNOSTIC AND THERAPEUTIC TECHNIQUES REVEAL CHANGED METABOLOMIC PROFILE IN RECURRENT FOCAL SEGMENTAL GLOMERULOSCLEROSIS - Müller-Deile, Janina; Sarau, George; Kotb, Ahmed; Daniel, Christoph; Kalkhof, Stefan; Christiansen, Silke; Schiffer, Mario (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03
Keywords: Transplantation; Urology & Nephrology

Novel parietal epithelial cell subpopulations contribute to focal segmental glomerulosclerosis and glomerular tip lesions - Kuppe, Christoph; Leuchtle, Katja; Wagner, Anton; Kabgani, Nazanin; Saritas, Turgay; Puelles, Victor G.; Smeets, Bart; Hakroush, Samy; van der Vlag, Johan; Boor, Peter; Schiffer, Mario; Gröne, Hermann Josef; et al. (Kidney International, 2019)
Beside the classical flat parietal epithelial cells (PECs), we investigated proximal tubular epithelial-like cells, a neglected subgroup of PECs. These cells, termed cuboidal PECs, make up the most proximal part of the proximal tubule and may also line parts of Bowman's capsule. Additionally, a third intermediate PEC subgroup was identified at the junction between the flat and cuboidal PEC subgroups at the tubular orifice. The transgenic mouse line PEC-rtTA labeled all three PEC subgroups. Here we show that the inducible Pax8-rtTA mouse line specifically labeled only cuboidal and intermediate PECs, but not flat PECs. In aging Pax8-rtTA mice, cell fate mapping showed no evidence for significant transdifferentiation from flat PECs to cuboidal or intermediate PECs or vice versa. In murine glomerular disease models of crescentic glomerulonephritis, and focal segmental glomerulosclerosis (FSGS), intermediate PECs became more numerous. These intermediate PECs preferentially expressed activation markers CD44 and Ki-67, suggesting that this subgroup of PECs was activated more easily than the classical flat PECs. In mice with FSGS, cuboidal and intermediate PECs formed sclerotic lesions. In patients with FSGS, cells forming the tip lesions expressed markers of intermediate PECs. These novel PEC subgroups form sclerotic lesions and were more prone to cellular activation compared to the classical flat PECs in disease. Thus, colonization of Bowman's capsule by cuboidal PECs may predispose to lesion formation and chronic kidney disease. We propose that tip lesions originate from this novel subgroup of PECs in patients with FSGS.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Columbia classification; FSGS; glomerular disease; parietal epithelial cells; tip lesions

Now a Nobel gas: oxygen - Fandrey, Joachim; Schödel, Johannes; Eckardt, Kai-Uwe; Katschinski, Dörthe M.; Wenger, Roland H. (Pflügers Archiv: European Journal of Physiology, 2019)
The recent bestowal of the Nobel Prize 2019 in Physiology or Medicine to Gregg L. Semenza, Sir Peter J. Ratcliffe, and William G. Kaelin Jr. celebrates a series of remarkable discoveries that span from the physiological research question on how oxygen deficiency (hypoxia) induces the red blood cell forming hormone erythropoietin (Epo) to the first clinical application of a novel family of Epo-inducing drugs to treat patients suffering from renal anemia. This review looks back at the most important findings made by the three Nobel laureates, highlights current research trends, and sheds an eye on future perspectives of hypoxia research, including emerging and potential clinical applications.
CRIS-Team Scopus Importer:2019-12-03
Keywords: Erythropoietin; High altitude; Hypoxia; Oxygen sensing; Protein hydroxylation; von Hippel-Lindau

NT-proBNP and stem cell factor plasma concentrations are independently associated with cardiovascular outcomes in end-stage renal disease hemodialysis patients. - Rossignol, P.; Duarte, K.; Bresso, E.; Åsberg, A.; Devignes, M. D.; Eriksson, N.; Girerd, N.; Glerup, R.; Jardine, A. G.; Holdaas, H.; Lamiral, Z.; Leroy, C.; et al. (European Heart Journal Open, 2022)
AIMS: End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine. METHODS AND RESULTS: The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths. CONCLUSIONS: Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.
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Nuclear and mitochondrial genetic variants associated with mitochondrial DNA copy number - Koller, Adriana; Filosi, Michele; Weissensteiner, Hansi; Fazzini, Federica; Gorski, Mathias; Pattaro, Cristian; Schönherr, Sebastian; Forer, Lukas; Herold, Janina M.; Stark, Klaus J.; Döttelmayer, Patricia; Hicks, Andrew A.; et al. (Scientific Reports, 2024)
Mitochondrial DNA copy number (mtDNA-CN) is a biomarker for mitochondrial dysfunction associated with several diseases. Previous genome-wide association studies (GWAS) have been performed to unravel underlying mechanisms of mtDNA-CN regulation. However, the identified gene regions explain only a small fraction of mtDNA-CN variability. Most of this data has been estimated from microarrays based on various pipelines. In the present study we aimed to (1) identify genetic loci for qPCR-measured mtDNA-CN from three studies (16,130 participants) using GWAS, (2) identify potential systematic differences between our qPCR derived mtDNA-CN measurements compared to the published microarray intensity-based estimates, and (3) disentangle the nuclear from mitochondrial regulation of the mtDNA-CN phenotype. We identified two genome-wide significant autosomal loci associated with qPCR-measured mtDNA-CN: at HBS1L (rs4895440, p = 3.39 × 10–13) and GSDMA (rs56030650, p = 4.85 × 10–08) genes. Moreover, 113/115 of the previously published SNPs identified by microarray-based analyses were significantly equivalent with our findings. In our study, the mitochondrial genome itself contributed only marginally to mtDNA-CN regulation as we only detected a single rare mitochondrial variant associated with mtDNA-CN. Furthermore, we incorporated mitochondrial haplogroups into our analyses to explore their potential impact on mtDNA-CN. However, our findings indicate that they do not exert any significant influence on our results.
CRIS-Team Scopus Importer:2024-02-02

Obesity After Kidney Transplantation-Results of a KTx360 degrees Substudy - Noehre, Mariel; Schieffer, Elisabeth; Hanke, Alexander; Pape, Lars; Schiffer, Lena; Schiffer, Mario; De Zwaan, Martina (Frontiers in Psychiatry, 2020)
Objective
CRIS-Team WoS Importer:2020-06-16

Olmesartan improves pulse wave velocity and lowers central systolic blood pressure and ambulatory blood pressure in patients with metabolic syndrome - Raff, Ulrike; Walker, Stefanie Elke; Ott, Christian; Schneider, Markus P.; Schmieder, Roland (Journal of Clinical Hypertension, 2015)
Ambulatory blood pressure (BP) and central systolic BP (cSBP) are superior to brachial office BP measurements in predicting cardiovascular end organ damage. The authors aimed to analyze the effect of olmesartan 80 mg (OLM 80) vs 20 mg (OLM 20) vs amlodipine 5 mg (AML 5) on central hemodymamics and ambulatory BP in patients with metabolic syndrome (MetS).In a double-blind, three-phase crossover study comprising 69 untreated patients with MetS defined by the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults guidelines, the effects of OLM 80 on central hemodynamics (cSBP), central pulse pressure), pulse wave velocity (PWV), and 24-hour ambulatory BP were compared with OLM 20 and AML 5, given for 6 weeks each. In 69 patients (47 men, 22 women) (51.5±9.75 years), reduction in cSBP was the highest with OLM 80 and significantly greater than the reduction with AML 5 (-14.1 mm Hg vs -9.7 mm Hg, P=.0117). All three substances significantly reduced 24-hour ambulatory systolic (OLM 80 and OLM 20 P<.0001; AML 5 P=.0105). BP and 24-hour diastolic BP (OLM 80 and OLM 20 P<.0001; AML 5 P=.0126). PWV was significantly reduced by OLM 80 (-0.58 m/s, P=.0088) and by OLM 20 (-0.48 m/s, P=.0362) but not by AML 5 (-0.28 m/s, P=.2065). For PWV, no significant differences were detected between the three groups. OLM significantly improves arterial stiffness as demonstrated by the reduction in PWV and in cSBP. In addition, 24-hour ambulatory BP was reduced to a greater extent with OLM 80 than with AML 5.
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One case - two unequally spectacular and life-threatening critical conditions - Scurt, Florian G.; Büstgens, Felix; Katsounas, Antonios; Chatzikyrkou, Christos (Clinical Nephrology, 2023)
CRIS-Team Scopus Importer:2023-11-24

Optimal translational termination requires C4 lysyl hydroxylation of eRF1 - Feng, Tianshu; Yamamoto, Atsushi; Wilkins, Sarah E.; Sokolova, Elizaveta; Yates, Luke A.; Muenzel, Martin; Singh, Pooja; Hopkinson, Richard J.; Fischer, Roman; Cockman, Matthew E.; Shelley, Jake; Trudgian, David C.; et al. (Molecular Cell, 2014)
Efficient stop codon recognition and peptidyl-tRNA hydrolysis are essential in order to terminate translational elongation and maintain protein sequence fidelity. Eukaryotic translational termination is mediated by a release factor complex that includes eukaryotic release factor 1 (eRF1) and eRF3. The N terminus of eRF1 contains highly conserved sequence motifs that couple stop codon recognition at the ribosomal A site to peptidyl-tRNA hydrolysis. We reveal that Jumonji domain-containing 4 (Jmjd4), a 2-oxoglutarate- and Fe(II)-dependent oxygenase, catalyzes carbon 4 (C4) lysyl hydroxylation of eRF1. This posttranslational modification takes place at an invariant lysine within the eRF1 NIKS motif and is required for optimal translational termination efficiency. These findings further highlight the role of 2-oxoglutarate/Fe(II) oxygenases in fundamental cellular processes and provide additional evidence that ensuring fidelity of protein translation is a major role of hydroxylation.
EVALuna2:3712

Optimization of electronically monitored non-adherence in highly adherent renal transplant recipients by reducing the dosing frequency – a prospective single-center observational study - Lieb, Marietta; Schiffer, Mario; Erim, Yesim (Patient Preference and Adherence, 2020)
Background: Non-adherence (NA) after renal transplantation poses a major risk for allo-graft rejection, graft loss, and patient mortality. Yet, there is still ambiguity about its etiology and its possible relationships with patient-related factors. In order to prevent poor outcomes after transplantation, it is crucial to gain a more refined understanding of potential determi-nants, to identify patients at risk, and to intervene accordingly. The objective of this study was to assess potential risk factors of NA by prospectively applying electronic monitoring. Materials and Methods: This was a single-center prospective observational study. Prior to study initiation, sociodemographic, biomedical, and psychosocial variables (depression, health-related quality of life, self-efficacy, social support, attachment, experiences and attitudes towards immunosuppressive medication, emotional responses after organ transplantation, satisfaction with information about immunosuppressive medication, and perceptions and beliefs about medications) were assessed. Thereafter, immunosuppressive adherence behavior was measured prospectively via electronic monitoring (EM, VAICA©) during a 3-month period to receive the percentage frequency of Taking and Timing Adherence (±2h, ±30min) for each patient. Focus of this study was the phase of medication implementation. Results: A total of 78 patients participated in our study (mean age 55.28, 56% male). We found rates of 99.39% for Taking Adherence, 98.34% for Timing Adherence ±2h, and 93.34% for Timing Adherence ±30min, respectively. Multiple regression analyses revealed that the type of medication could significantly predict Taking Adherence. Patients receiving Advagraf© (once daily) depicted better Taking Adherence than patients receiving Prograf© (twice daily) (p=0.04). No associations were found for Timing Adherence (±2h, ±30min). Sociodemographic, biomedical, or psychosocial variables were not found to be associated with adherence behavior. Discussion: In highly adherent populations, only a few factors can be altered to improve adherence. Changing the immunosuppressive regimen from twice-daily to once-daily could be an option for optimizing adherence. However, risk factors for NA could be different in a less adherent population.
CRIS-Team Scopus Importer:2020-08-14
Keywords: Adherence; Electronic monitoring; Immunosuppressive medication; Patient-related factors; Psychosocial variables

Oral health of patients suffering from end-stage solid organ insufficiency prior to solid organ re-transplantation: a retrospective case series study - Möst, Tobias; Lutz, Rainer; Jahn, Arne Eric; Heller, Katharina M.; Schiffer, Mario; Adler, Werner; Deschner, James; Weber, Manuel; Kesting, Marco Rainer (BMC Oral Health, 2021)
Background: The oral health of organ transplanted patients before organ re-transplantation is largely unknown. This retrospective clinical study evaluates the necessity for intraoral surgical intervention and/or conservative treatment in candidates awaiting organ re-transplantation, both for graft failure and for reasons of another upcoming solid organ transplantation (renal or non-renal). Methods: From January 2015 to March 2020 n = 19 transplant recipients in evaluation on the waiting list for solid organ re-transplantation could be included in the retrospective case series study. Using clinical and radiological examinations, necessity for oral surgical or conservative dental treatment was evaluated. On the basis of anamnesis data, current kidney function, renal replacement treatment (RRT), and medication, a risk profile for several patient subgroups was created. Results: The clinical and radiological examinations showed a conservative and/or surgical treatment need in n = 13 cases (68.42%). In n = 7 cases (36.84%) surgical intervention was recommended due to residual root remnants (n = 5), unclear mucosal changes (n = 1), and periimplantitis (n = 1). In n = 16 recipients (84.2%) RRT (n = 15 hemodialysis; n = 1 peritoneal dialysis) had been performed. N = 14 recipients (73.68%) received immunosuppressants. In n = 1 patient (5.3%) displayed intraoral and n = 4 patients (21.1%) extraoral neoplasms due to drug-induced immunosuppression. Conclusions: Solid organ transplant recipients with renal failure present a complex treatment profile due to a double burden of uremia plus immunosuppressants. In cases of surgical treatment need a hospitalized setting is recommended, where potentially necessary follow-up care and close cooperation with disciplines of internal medicine is possible in order to avoid surgical and/or internal complications.
CRIS-Team Scopus Importer:2021-11-05
Keywords: Immunosuppression; Oral health; Organ transplantation

Organ integration in kidney transplant patients – Results of a KTx360° substudy - Hennemann, Khira; Bauer-Hohmann, Maximilian; Klewitz, Felix; Tegtbur, Uwe; Pape, Lars; Schiffer, Lena; Schiffer, Mario; de Zwaan, Martina; Nöhre, Mariel (Journal of psychosomatic research, 2021)
Objective: Organ transplantation is the treatment of choice for patients with end-stage organ disease. From early on, the psychological perspective on integrating the organ has been of interest. As quantitative studies on organ integration are scarce, we aimed at evaluating this aspect in a large sample of kidney transplant (KTx) recipients. Methods: For this cross-sectional study, 684 patients after KTx were recruited within the structured post-transplant care program KTx360°. To measure organ integration and donor relationship, a previously developed and published questionnaire (FOSP), generated explicitly for this purpose, was used. Associations with sociodemographic, medical, donation-specific, and psychological variables were investigated. Results: Overall, more than 90% of the patients perceived the transplant as part of themselves; however, a small minority reported perceiving it as a foreign object. Frequent thoughts about the donor and the belief of having adopted some of the donor's traits were common (52% and 14%, respectively), specifically in living donor recipients. Higher anxiety and depression scores and reduced kidney functioning were associated with less ideal organ integration, while a more extended period since KTx and more perceived social support correlated with better organ integration. No association between organ integration and adherence, as well as organ integration and cognitive functioning, could be found. Conclusion: Organ integration and donor relationship were unproblematic in most KTx patients. However, offering psychosocial support to those struggling with organ integration and donor relationship is crucial from a clinical perspective.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Coping; Kidney transplantation; Organ integration; Renal transplantation

Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation - Marton, Adriana; Kaneko, Tatsuroh; Kovalik, Jean Paul; Yasui, Atsutaka; Nishiyama, Akira; Kitada, Kento; Titze, Jens (Nature Reviews Nephrology, 2020)
Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation — an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics.
CRIS-Team Scopus Importer:2020-10-09

OS 12-03 SGLT-2-INHIBITION WITH DAPAGLIFLOZIN REDUCES TISSUE SODIUM CONTENT - Schmieder, Roland; Ott, Christian; Linz, Peter; Jumar, Agnes; Friedrich, Stefanie; Titze, Jens; Hammon, Matthias; Uder, Michael; Kistner, Iris (Journal of Hypertension, 2016)
Sodium tissue content by Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and, in parallel, of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes leads to decreased tissue sodium content due to its pharmacological action.In a prospective, double blind, placebo controlled, cross-over trial 59 patients (61 ± 7.6 years) with type 2 diabetes were randomized to dapagliflozin 10 mg o.d. and placebo for 6 weeks each. In addition to metabolic parameters and ambulatory blood pressure (BP) we analyzed the sodium content in the skin and muscles of the lower leg by the Na-MRI at baseline, after the first and second treatment phase of 6 weeks.Compared to baseline 6 weeks treatment with the SGLT-2 inhibitor dapagliflozin decreased fasting (132 ± 28 vs. 114 ± 19 mg/dl, p < 0.001), postprandial blood glucose (178 ± 66 mg/dl vs. 153 ± 46 mg/dl, p < 0.001), body weight (87.6 vs. 86.6 kg, p < 0.001) and systolic (129 ± 12 vs. 126 ± 11, p = 0.010) and diastolic (77.4 ± 9 vs. 75.6 ± 8 mmHg, p = 0.024) 24-hour ambulatory BP. Tissue sodium content in the skin was reduced after 6 weeks treatment with dapagliflozin compared to baseline (24.1 ± 6.6 vs.22.7 ± 6.4 mmol/L; p = 0.013). No significant reduction of tissue sodium content was observed in the muscle (M. triceps surae: 20.5 ± 3.5 vs. 20.4 ± 3.7 mmol/L, p = 0.801). No clear significant difference in tissue water content of muscle and skin was observed after 6 weeks of treatment with dapagliflozin, compared to baseline.SGLT-2 inhibition with dapagliflozin resulted in a significant decrease in sodium tissue content of the skin after 6 weeks. This observation point to a decrease of total sodium content in patients with type 2 diabetes known to be salt sensitive and prone to cardiovascular complications, that might be mitigated by SGLT-2 inhibition.
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OS 28-03 SECRETORY CAPACITY OF PANCREATIC BETA CELLS IS ENHANCED 6 MONTHS AFTER RENAL DENERVATION IN TREATMENT RESISTANT HYPERTENSIVE PATIENTS - Ott, Christian; Kistner, Iris; Schmid, Axel; Friedrich, Stefanie; Ditting, Tilmann; Veelken, Roland; Mahfoud, Felix; Boehm, Michael; Uder, Michael; Schmieder, Roland (Journal of Hypertension, 2016)
Renal denervation (RDN) lowers blood pressure (BP) by interruption of sympathetic nerve activity. A high sympathetic tone increases not only BP but also decreases pancreatic beta cell insulin secretion. Hence, the objective of the study was to analyze whether RDN improves secretory capacity of beta cells.In 40 patients (7 diabetics, 19 prediabetics, 14 non diabetics) with treatment resistant hypertension (defined by office BP >= 140/90 mmHg and diagnosis confirmed with 24-h ambulatory BP >= 130/80 mmHg), insulin secretion was measured before and 6 months after RDN (Simplicity flex catheter, Medtronic) by glucagon test. At each time point blood was sampled prior to glucagon administration and 6 minutes after intravenous injection of 1 ml glucagon for measurement of C-peptide, insulin and proinsulin (by ELISA).In these 40 patients (mean age 58 ± 12 years, mean office BP 154 ± 22 mmHg / 89 ± 14 mmHg while on 5.2 ± 1.4 antihypertensive drugs) office systolic and diastolic BP was significantly reduced 6 months after RDN (both p < 0.01). Fasting plasma glucose and HbA1c level was significantly reduced 6 month after RDN (both p < 0.01). Six months after RDN, the increase of C-peptide concentration and insulin concentration after glucagon injection was significantly higher compared to before RDN (both p < 0.05).Thus, our data indicate an improved pancreatic beta cell function after RDN in patients with treatment resistant hypertension.
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OSTEOPONTIN AND ITS ASSOCIATION WITH ADVERSE EVENTS IN THE GERMAN CHRONIC KIDNEY DISEASE STUDY - Steinbrenner, Inga; Cheng, Yurong; Nadal, Jennifer; Schmid, Matthias; Kotsis, Fruzsina Kinga; Meiselbach, Heike; Schneider, Markus; Krane, Vera; Nauck, Matthias; Eckardt, Kai-Uwe; Koettgen, Anna; Sekula, Peggy; et al. (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling - Rodionov, Roman N.; Jarzebska, Natalia; Burdin, Dmitrii; Todorov, Vladimir; Martens-Lobenhoffer, Jens; Hofmann, Anja; Kolouschek, Anne; Cordasic, Nada; Jacobi, Johannes; Rubets, Elena; Morawietz, Henning; O'Sullivan, John; et al. (Scientific Reports, 2022)
Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.
CRIS-Team WoS Importer:2022-07-01

Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice - Mulay, Shrikant R.; Eberhard, Jonathan N.; Pfann, Victoria; Marschner, Julian A.; Darisipudi, Murthy N.; Daniel, Christoph; Romoli, Simone; Desai, Jyaysi; Grigorescu, Melissa; Kumar, Santhosh V.; Rathkolb, Birgit; Wolf, Eckhard; et al. (American Journal of Physiology-Renal Physiology, 2016)
Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis, with the extent of tissue involvement depending on the duration of oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings established to reflect inflammation and fibrosis parallel the histological changes. Within 3 wk, the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 activation, hyperphosphatemia, and hyperparathyroidism. In addition, the model is characterized by profound arterial hypertension as well as cardiac fibrosis that persist following the switch to a control diet. Together, this new model of inducible CKD overcomes a number of previous experimental limitations and should serve useful in research related to CKD and its complications.
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Oxalate, inflammasome, and progression of kidney disease - Ermer, Theresa; Eckardt, Kai-Uwe; Aronson, Peter S.; Knauf, Felix (Current Opinion in Nephrology and Hypertension, 2016)
Oxalate is an end product of metabolism excreted via the kidney. Excess urinary oxalate, whether from primary or enteric hyperoxaluria, can lead to oxalate deposition in the kidney. Oxalate crystals are associated with renal inflammation, fibrosis, and progressive renal failure. It has long been known that as the glomerular filtration rate becomes reduced in chronic kidney disease (CKD), there is striking elevation of plasma oxalate. Taken together, these findings raise the possibility that elevation of plasma oxalate in CKD may promote renal inflammation and more rapid progression of CKD independent of primary cause.The inflammasome has recently been identified to play a critical role in oxalate-induced renal inflammation. Oxalate crystals have been shown to activate the NOD-like receptor family, pyrin domain containing 3 inflammasome (also known as NALP3, NLRP3, or cryopyrin), resulting in release of IL-1? and macrophage infiltration. Deletion of inflammasome proteins in mice protects from oxalate-induced renal inflammation and progressive renal failure.The findings reviewed in this article expand our understanding of the relevance of elevated plasma oxalate levels leading to inflammasome activation. We propose that inhibiting oxalate-induced inflammasome activation, or lowering plasma oxalate, may prevent or mitigate progressive renal damage in CKD, and warrants clinical trials.
EVALuna2:3859

Oxidized LDL, statin use, morbidity, and mortality in patients receiving maintenance hemodialysis - Wagner, Sandra; Apetrii, Mugurel; Massy, Ziad A.; Kleber, Marcus E.; Delgado, Graciela E.; Scharnagel, Hubert; Maerz, Winfried; Metzger, Marie; Rossignol, Patrick; Jardine, Alan; Holdaas, Hallvard; Fellstroem, Bengt; et al. (Free Radical Research, 2017)
Statin treatment reduces the risk of cardiovascular mortality in the general population, but it has little or no benefit in hemodialyzed (HD) patients. This may reflect different underlying pathophysiology of cardiovascular disease (CVD) in patients treated with HD, maybe involving the oxidative stress. Our aim was to assess the association of oxidized low-density lipoprotein (oxLDL), determined by Mercodia oxLDL enzyme-linked immunosorbent assay (ELISA) kit, with major adverse cardiac events (MACE) and all-cause mortality in HD patients based on the AURORA trial (rosuvastatin vs placebo), and patients not on HD from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We also assessed whether its decrease due to statin use improves these outcomes using Cox proportional hazard models. Baseline oxLDL level was 34.2 ± 13.8 U/L in AURORA and did not differ between treatment groups, and 74.6 ± 28.1 U/L in LURIC. Lower baseline oxLDL levels were associated with higher hazard ratios (HRs) for outcomes, but not anymore after adjusting for apolipoprotein B level in AURORA and was not related to mortality in LURIC. OxLDL levels decreased by 30.9% between baseline and 3 months in the statin-treated group and increased by 10.5% between 3 and 12 months. Nevertheless, oxLDL reduction was not significantly associated with adjusted HRs for MACE and for all-cause mortality. These results showed no association between oxLDL and MACE after adjustment on apolipoprotein B, which may relate to the properties of the method used for oxLDL. Our results also showed no benefit for oxLDL reduction by rosuvastatin on outcomes. Future clinical trials are needed to define the relative CVD risks and benefits of other modalities of oxidative stress modification in this population.
EVALuna2:4040

P2X7 Receptor Stimulation Is Not Required for Oxalate Crystal-nduced Kidney Injury - Luz, Hannah L.; Reichel, Martin; Unwin, Robert J.; Mutig, Kerim; Najenson, Ana C.; Tonner, Louise M.; Eckardt, Kai-Uwe; Tam, Frederick W. K.; Knauf, Felix (Scientific Reports, 2019)
Oxalate crystal-induced renal inflammation is associated with progressive kidney failure due to activation of the NLRP3/CASP-1 inflammasome. It has been suggested previously that purinergic P2X7 receptor signaling is critical for crystal-induced inflammasome activation and renal injury. Therefore, we investigated the role of the P2X7 receptor in response to crystal-induced cytokine release, inflammation, and kidney failure using in vitro and in vivo models. Dendritic cells and macrophages derived from murine bone marrow and human peripheral blood mononucleated cells stimulated with calcium-oxalate crystals, monosodium urate crystals, or ATP lead to the robust release of interleukin-1beta (IL-1 beta). Treatment with the P2X7 inhibitor A740003 or the depletion of ATP by apyrase selectively abrogated ATP-induced, but not oxalate and urate crystal-induced IL-1 beta release. In line with this finding, dendritic cells derived from bone marrow (BMDCs) from P2X7(-/-) mice released reduced amounts of IL-1 beta following stimulation with ATP, while oxalate and urate crystal-induced IL-1 beta release was unaffected. In sharp contrast, BMDCs from Casp1(-/-) mice exhibited reduced IL-1 beta release following either of the three stimulants. In addition, P2X7(-/-) mice demonstrated similar degrees of crystal deposition, tubular damage and inflammation when compared with WT mice. In line with these findings, increases in plasma creatinine were no different between WT and P2X7(-/-) mice. In contrast to previous reports, our results indicate that P2X7 receptor is not required for crystal-induced CKD and it is unlikely to be a suitable therapeutic target for crystal-induced progressive kidney disease.
CRIS-Team WoS Importer:2020-02-07

P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells - Kraus, Andre; Grampp, Steffen; Goppelt-Strübe, Margarete; Schreiber, Rainer; Kunzelmann, Karl; Peters, Dorien J. M.; Leipziger, Jens; Schley, Gunnar; Schoedel, Johannes; Eckardt, Kai-Uwe; Buchholz, Björn (Purinergic Signalling, 2016)
Polycystic kidney diseases are characterized by numerous renal cysts that continuously enlarge resulting in compression of intact nephrons and tissue hypoxia. Recently, we have shown that hypoxia-inducible factor (HIF)-1 alpha promotes secretion-dependent cyst expansion, presumably by transcriptional regulation of proteins that are involved in calcium-activated chloride secretion. Here, we report that HIF-1 alpha directly activates expression of the purinergic receptor P2Y2R in human primary renal tubular cells. In addition, we found that P2Y2R is highly expressed in cyst-lining cells of human ADPKD kidneys as well as PKD1 orthologous mouse kidneys. Knockdown of P2Y2R in renal collecting duct cells inhibited calcium-dependent chloride secretion in Ussing chamber analyses. In line with these findings, knockdown of P2Y2R retarded cyst expansion in vitro and prevented ATP- and HIF-1 alpha-dependent cyst growth. In conclusion, P2Y2R mediates ATP-dependent cyst growth and is transcriptionally regulated by HIF-1 alpha. These findings provide further mechanistic evidence on how hypoxia promotes cyst growth.
EVALuna2:3913
Keywords: Polycystic kidney disease; Cyst growth; Chloride secretion; ATP; P2Y2R; Hypoxia; HIF-1 alpha

Partner, Neighbor, Housekeeper and Dimension: 3D versus 2D Glomerular Co-Cultures Reveal Drawbacks of Currently Used Cell Culture Models - Rederer, Anna; Rose, Victoria; Krüger, René; Schmittutz, Linda; Swierzy, Izabela; Fischer, Lena; Thievessen, Ingo; Bauer, Julian; Friedrich, Oliver; Schiffer, Mario; Müller-Deile, Janina (International Journal of Molecular Sciences, 2023)
Signaling-pathway analyses and the investigation of gene responses to different stimuli are usually performed in 2D monocultures. However, within the glomerulus, cells grow in 3D and are involved in direct and paracrine interactions with different glomerular cell types. Thus, the results from 2D monoculture experiments must be taken with caution. We cultured glomerular endothelial cells, podocytes and mesangial cells in 2D/3D monocultures and 2D/3D co-cultures and analyzed cell survival, self-assembly, gene expression, cell–cell interaction, and gene pathways using live/dead assay, time-lapse analysis, bulk-RNA sequencing, qPCR, and immunofluorescence staining. Without any need for scaffolds, 3D glomerular co-cultures self-organized into spheroids. Podocyte- and glomerular endothelial cell-specific markers and the extracellular matrix were increased in 3D co-cultures compared to 2D co-cultures. Housekeeping genes must be chosen wisely, as many genes used for the normalization of gene expression were themselves affected in 3D culture conditions. The transport of podocyte-derived VEGFA to glomerular endothelial cells confirmed intercellular crosstalk in the 3D co-culture models. The enhanced expression of genes important for glomerular function in 3D, compared to 2D, questions the reliability of currently used 2D monocultures. Hence, glomerular 3D co-cultures might be more suitable in the study of intercellular communication, disease modelling and drug screening ex vivo.
Created from Fastlane, Scopus look-up
Keywords: 3D co-culture; bulk-RNA sequencing; cell culture model; cell matrix; cell–cell communication; glomerular spheroids

Pathogenic Relationships in Cystic Fibrosis and Renal Diseases: CFTR, SLC26A9 and Anoctamins - Kunzelmann, Karl; Ousingsawat, Jiraporn; Kraus, Andre; Park, Julien H.; Marquardt, Thorsten; Schreiber, Rainer; Buchholz, Björn (International Journal of Molecular Sciences, 2023)
The Cl−-transporting proteins CFTR, SLC26A9, and anoctamin (ANO1; ANO6) appear to have more in common than initially suspected, as they all participate in the pathogenic process and clinical outcomes of airway and renal diseases. In the present review, we will therefore concentrate on recent findings concerning electrolyte transport in the airways and kidneys, and the role of CFTR, SLC26A9, and the anoctamins ANO1 and ANO6. Special emphasis will be placed on cystic fibrosis and asthma, as well as renal alkalosis and polycystic kidney disease. In essence, we will summarize recent evidence indicating that CFTR is the only relevant secretory Cl− channel in airways under basal (nonstimulated) conditions and after stimulation by secretagogues. Information is provided on the expressions of ANO1 and ANO6, which are important for the correct expression and function of CFTR. In addition, there is evidence that the Cl− transporter SLC26A9 expressed in the airways may have a reabsorptive rather than a Cl−-secretory function. In the renal collecting ducts, bicarbonate secretion occurs through a synergistic action of CFTR and the Cl−/HCO3− transporter SLC26A4 (pendrin), which is probably supported by ANO1. Finally, in autosomal dominant polycystic kidney disease (ADPKD), the secretory function of CFTR in renal cyst formation may have been overestimated, whereas ANO1 and ANO6 have now been shown to be crucial in ADPKD and therefore represent new pharmacological targets for the treatment of polycystic kidney disease.
CRIS-Team Scopus Importer:2023-09-15
Keywords: anoctamin; CFTR; pendrin; SLC26A9; TMEM16A; TMEM16F

Patient-Level Pooled Analysis of Endovascular Ultrasound Renal Denervation or a Sham Procedure 6 Months After Medication Escalation: The RADIANCE Clinical Trial Program - Azizi, Michel; Sharp, Andrew S.P.; Fisher, Naomi D.L.; Weber, Michael A.; Lobo, Melvin D.; Daemen, Joost; Lurz, Philipp; Mahfoud, Felix; Schmieder, Roland; Basile, Jan; Bloch, Michael J.; Saxena, Manish; et al. (Circulation, 2024)
BACKGROUND: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials. METHODS: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. RESULTS: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT (P=0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients (P=0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mm Hg (95% CI, -5.7, -0.2; P=0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mm Hg (.6.8, -4.0; P<0.001) and -5.2 mm Hg (.7.1, -3.3; P<0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. CONCLUSIONS: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs.
CRIS-Team Scopus Importer:2024-03-15
Keywords: ablation; catheter; antihypertensive drugs; blood pressure; denervation; hypertension; hypertension; renal

Patient preference for therapies in hypertension: a cross-sectional survey of German patients - Schmieder, Roland; Högerl, Karin; Jung, Susan; Bramlage, Peter; Veelken, Roland; Ott, Christian (Clinical Research in Cardiology, 2019)
BACKGROUND: Hypertension is poorly controlled in numerous patients despite effective medication being available. Catheter-based renal denervation (RDN) has emerged as an alternative treatment option. We aimed to assess how likely patients with elevated blood pressure (BP) are to accept RDN as treatment option. METHODS: A questionnaire-based cross-sectional survey was performed in patients with elevated BP in Germany. Data on patient demographics, clinical characteristics and treatment preferences were collected, anonymized and analyzed. RESULTS: One thousand and eleven patients completed the survey. Mean age was 66 years (55% male). If not already on medication (n = 172), 38.2% of patients would prefer RDN. Of those already on drug therapy (n = 839), 28.2% would opt for RDN. Patients who were pro-RDN were younger (p < 0.0001) and more often male (p < 0.0001). Nineteen percent would choose RDN if it lowered systolic BP by at least 20 mmHg, more than 40% if they did not have to take any more pills thereafter, and 30% if it would lower BP by at least 10 mmHg. Experiences of side effects and drug adherence were identified as determinants of patient preference. Physicians were the main source of information regarding medical problems (95.5%) and influence patients' decision regarding therapies (98%). CONCLUSIONS: This survey found that a significant proportion of patients would choose catheter-based RDN over lifelong pharmacotherapy. These patients were younger and more likely to be male but their expectation of the extent of BP decrease with RDN was high. Physicians are key mediators for treatment selection. They need to incorporate patient preferences into shared decision making.
EVALuna2:118640

Patient-reported non-adherence and immunosuppressant trough levels are associated with rejection after renal transplantation - Scheel, Jennifer; Reber, Sandra Therese; Stößel, Lisa; Waldmann, Elisabeth; Jank, Sabine; Eckardt, Kai-Uwe; Grundmann, Franziska; Vitinius, Frank; De Zwaan, Martina; Bertram, Anna; Erim, Yesim (BMC Nephrology, 2017)
EVALuna2:3948

Patient's Experience with Living Donation: A Questionnaire-Based Survey of 144 Living Kidney Donors - Schieber, Katharina; Gaag, Sonja; Heller, Katharina; Erim, Yesim (Psychotherapie Psychosomatik Medizinische Psychologie, 2018)
Keywords: evaluation; consequences; psychosocial consequences; living donation; living kidney donation

Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin-Converting Enzyme Inhibitors: The Prospective EARLY Registry - Schmieder, Roland; Potthoff, Sebastian A; Bramlage, Peter; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ouarrak, Taoufik; Ehmen, Martina; Senges, Jochen; Gitt, Anselm K; EARLY Registry Group, (Journal of Clinical Hypertension, 2015)
For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first-line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors.
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Patients With Resistant Hypertension in the Global SYMPLICITY Registry: Antihypertensive Medication Burden and Changes in Blood Pressure out to 3 Years - Schlaich, Markus; Boehm, Michael; Mancia, Giuseppe; Schmieder, Roland; Narkiewicz, Krzysztof; Ruilope, Luis; Williams, Bryan; Shen, Cheryl; Mahfoud, Felix (JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2020)
CRIS-Team WoS Importer:2020-12-25

Patterns of medication use and the burden of polypharmacy in patients with chronic kidney disease: The German Chronic Kidney Disease study - Schmidt, Insa M.; Hübner, Silvia; Nadal, Jennifer; Titze, Stephanie; Schmid, Matthias; Bärthlein, Barbara; Schlieper, Georg; Dienemann, Thomas; Schultheiss, Ulla T.; Meiselbach, Heike; Köttgen, Anna; Flöge, Jürgen; et al. (Clinical Kidney Journal, 2019)
Background: Patients with chronic kidney disease (CKD) bear a substantial burden of comorbidities leading to the prescription of multiple drugs and a risk of polypharmacy. However, data on medication use in this population are scarce. Methods: A total of 5217 adults with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2 or an eGFR ≥60 mL/min/1.73m2 and overt proteinuria (>500 mg/day) were studied. Self-reported data on current medication use were assessed at baseline (2010-12) and after 4 years of follow-up (FU). Prevalence and risk factors associated with polypharmacy (defined as the regular use of five or more drugs per day) as well as initiation or termination of polypharmacy were evaluated using multivariable logistic regression. Results: The prevalence of polypharmacy at baseline and FU was almost 80%, ranging from 62% in patients with CKD Stage G1 to 86% in those with CKD Stage G3b. The median number of different medications taken per day was eight (range 0-27). β-blockers, angiotensin-converting enzyme inhibitors and statins were most frequently used. Increasing CKD G stage, age and body mass index, diabetes mellitus, cardiovascular disease and a history of smoking were significantly associated with both the prevalence of polypharmacy and its maintenance during FU. Diabetes mellitus was also significantly associated with the initiation of polypharmacy [odds ratio (OR) 2.46, (95% confidence interval 1.36-4.45); P = 0.003]. Conclusion: Medication burden in CKD patients is high. Further research appears warranted to address the implications of polypharmacy, risks of drug interactions and strategies for risk reduction in this vulnerable patient population.
CRIS-Team Scopus Importer:2019-10-22
Keywords: Chronic kidney disease; GCKD study; Medication use; Polypharmacy; Prescription patterns

PCSK9 and Cardiovascular Disease in Individuals with Moderately Decreased Kidney Function - Kheirkhah, Azin; Lamina, Claudia; Kollerits, Barbara; Schachtl-Riess, Johanna F.; Schultheiss, Ulla T.; Forer, Lukas; Sekula, Peggy; Kotsis, Fruzsina; Eckardt, Kai-Uwe; Kronenberg, Florian (Clinical Journal of the American Society of Nephrology, 2022)
Background and objectives Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. Studies investigating the association between PCSK9 and cardiovascular disease in large cohorts of patients with CKD are limited.& nbsp;Design, setting, participants, & measurements The association of PCSK9 concentrations with prevalent and incident cardiovascular disease was investigated in 5138 White participants of the German Chronic Kidney Disease study with a median follow-up of 6.5 years. Inclusion criteria were eGFR of 30-60 or > 60 ml/min per 1.73 m2 in the presence of overt proteinuria (urine albumin-creatinine ratio > 300 mg/g or equivalent). Prevalent cardiovascular disease was defined as a history of nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, carotid arteries interventions, and stroke. Incident major adverse cardiovascular disease events included death from cardiovascular causes, acute nonfatal myocardial infarction, and nonfatal stroke.& nbsp;Results Median PCSK9 concentration in the cohort was 285 ng/ml (interquartile range, 231-346 ng/ml). There was no association between PCSK9 concentrations and baseline eGFR and albuminuria. With each 100-ng/ml increment of PCSK9, the odds for prevalent cardiovascular disease (n=1284) were 1.22-fold (95% confidence interval, 1.12 to 1.34; P < 0.001) higher in a model with extended adjustment for major confounders. This association was stronger in nonstatin than statin users (P value for interaction =0.009). During follow-up, 474 individuals experienced a major adverse cardiovascular disease event, and participants in PCSK9 quartiles 2-4 had a 32%-47% higher risk compared with those in quartile 1 (P < 0.05). Subgroup analysis revealed that this association was restricted to those participants who already had cardiovascular disease at baseline (all hazard ratios > 1.75; P=0.01). In addition, PCSK9 showed a valuable gain in classification accuracy for both prevalent cardiovascular disease (net reclassification index =0.27; 95% confidence interval, 0.20 to 0.33) and incident major adverse cardiovascular disease events during follow-up (net reclassification index =0.10; 95% confidence interval, 0.01 to 0.21) when added to an extended adjustment model.& nbsp;Conclusions Our findings reveal no relation of PCSK9 with baseline eGFR and albuminuria but a significant association between higher PCSK9 concentrations and risk of cardiovascular disease independent of traditional risk factors, including LDL cholesterol levels.
CRIS-Team WoS Importer:2022-06-03

PCSK-9-inhibitor therapy improves endothelial function in high-risk patients with cardiovascular disease - Kannenkeril, Dennis; Bosch, Agnes; Kolwelter, Julie; Striepe, Kristina; Pietschner, Robert; Ott, Christian; Schiffer, Mario; Achenbach, Susanne; Schmieder, Roland (EUROPEAN HEART JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

Peculiarities in the panoramic radiograph of patients with secondary hyperparathyroidism due to terminal renal disease: a radiologic controlled comparative study - Möst, Tobias; Jahn, Arne Eric; Heller, Katharina M.; Schiffer, Mario; Adler, Werner; Rohde, Maximilian; Weber, Manuel; Kesting, Marco Rainer; Lutz, Rainer (Oral Radiology, 2022)
Objectives The present radiological observational controlled study aims to evaluate the impact of secondary hyperparathyroidism (SHPT) due to chronic kidney disease (CKD) as well as the duration of dialysis on the mineralization of the mandible by standardized qualitative evaluation of digital panoramic radiographs. Methods Panoramic radiographs of CKD patients with SHPT and healthy controls were used for the qualitative analysis of the mandibular cortical index (MCI), the trabecular bone pattern (TBP), and calcification and resorption foci. Radiomorphometric indices were correlated to biochemical parameters and the duration of dialysis using the Spearman Rho test. Group comparisons were conducted using the Mann-Whitney U test and Fisher's exact test at a significance level of alpha <= 0.05. Interrater reliability of two physicians was estimated using Cohen's kappa. Results Inclusion and exclusion criteria were fulfilled by N = 41 patients. Statistically significant differences in the MCI (p < 0.001) as well as the TBP (p = 0.002) could be detected for the experimental group in comparison to the healthy control group. Focusing on calcification and resorption foci, no statistically significant difference could be detected between the groups (p = 0.244). The level of the detected parathyroid hormone (PTH) significantly correlated with TBP (Rho = 0.338; p = 0.031), while no significant relationship between TBP and the duration of the dialysis could be found. Conclusions Patients with SHPT due to CKD show statistically significant bone changes in the panoramic radiograph, whereby the grade of trabecular bone change correlates to PTH values.
CRIS-Team WoS Importer:2022-05-20

Percutaneous Creation of a Central Iliac Arteriovenous Anastomosis for the Treatment of Arterial Hypertension - Bertog, S. C.; Sobotka, Nathan A.; Sobotka, P. A.; Lobo, M. D.; Sievert, K.; Vaskelyte, L.; Sievert, H.; Schmieder, Roland (Current Hypertension Reports, 2018)
PURPOSE OF REVIEW: Provision of a summary on the physiologic effects of arteriovenous fistula creation and description of previously published human data on the efficacy of a percutaneously implanted device creating an arteriovenous fistula. Though antihypertensive therapy is effective, some patient's blood pressure remains poorly controlled despite adherence to optimal medical therapy. Moreover, some patients are not compliant with recommended medical therapy due to side effects or personal decision. This has prompted exploration of alternative, device-based antihypertensive therapies including, among others, the percutaneous creation of an arteriovenous fistula. An arteriovenous fistula is accompanied by a number of favorable physiologic changes that may lower blood pressure. These physiologic changes, conduction of the procedure, and previously published human experience are summarized in this review article. RECENT FINDINGS: The results of a recently published trial comparing arteriovenous fistula creation and standard antihypertensive therapy versus standard antihypertensive therapy alone are summarized. Creation of an arteriovenous fistula is accompanied by a significant blood pressure reduction likely related to a reduction in total arterial resistance, perhaps blood volume reduction, inhibition of the baroreceptor reflex, and release of natriuretic peptides. These findings foster further interest in studying the impact of an arteriovenous fistula and arterial blood pressure. The design of a large randomized trial comparing arteriovenous fistula creation to sham control is outlined.
EVALuna2:34238

PERICARDECTOMY AFTER PERICARDITIS CONSTRICTIVA LED TO ONSET OF TRANSPLANT KIDNEY FUNCTION AFTER 13 WEEKS OF ANURIC KIDNEY GRAFT - A CASE REPORT - Wacker, Caroline; Visconti, V.; Schiffer, Mario; Opgenoorth, M. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Pericardectomy after pericarditis constrictiva led to onset of transplant kidney function after 98 days of anuric kidney graft: a case report - Wacker, Caroline; Weyand, Michael; Schiffer, Mario; Opgenoorth, Mirian (BMC Nephrology, 2020)
BACKGROUND: Constrictive pericarditis is easily overlooked and can lead to severe problems in hemodynamics and end-organ perfusion, in our patient leading to 98 days of anuria after living kidney transplantation. This was completely reversible after pericardectomy. CASE PRESENTATION: A 43-year-old female caucasian patient received a living kidney donation from her mother. She had developed end-stage renal disease 2 years prior due to nephrotic syndrome linked to graft-versus-host disease after allogenic stem-cell transplantation for aplastic anemia. The graft showed insufficient function already in the early postoperative phase. Dialysis was paused after surgery, but the patient developed hypervolemia with ascites and edema in the lower extremities. Doppler ultrasonography showed scarce perfusion, with intrarenal arterial waveforms without end-diastolic flow. The venous perfusion profiles showed pulsatile retrograde flow. There was no identifiable reason for a primary vascular perfusion problem on ultrasonography or transplant kidney angiography. Kidney transplant biopsy revealed no rejection but extensive acute tubular necrosis. Three weeks after transplantation, the patient developed an acute anuric graft failure caused by severe cardiac decompensation. Echocardiography revealed a previously unnoticed constrictive pericarditis, which could be confirmed in a cardio computed tomography scan. The constrictive pericarditis had not been apparent on previous x-rays, computed tomography scans, or echocardiographies, including those for transplantation evaluation. Conservative management of the constrictive pericarditis was not successful and the graft remained anuric. Eventually, the patient underwent pericardectomy 16 weeks after kidney transplantation. Shortly after surgery, the graft started urine production again, which significantly increased within a few days. The clearance improved and 2 weeks later, the patient was free from dialysis. CONCLUSIONS: This case illustrates that special attention should be given to the pericardium during transplant evaluation, especially for patients who previously underwent stem-cell transplantations, chemotherapy or radiation.
CRIS-Team Scopus Importer:2020-07-17
Keywords: Case report; Constrictive pericarditis; Delayed graft function; Kidney transplant; Pericardectomy

Persistence and cardiovascular outcomes with ramipril, atorvastatin, ASA as a single pill compared to the multi pill combination. A subanalysis of the START study, a claims data analysis - Predel, H. G.; Weisser, B.; Wassmann, S.; Schmieder, Roland; Blettenberg, J.; Gillessen, A.; Fournier,; Noetel, A.; Randerath, O.; Boehm, M. (EUROPEAN HEART JOURNAL, 2020)
CRIS-Team WoS Importer:2021-02-12

Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling - Bernkopf, Dominic; Jalal, Kowcee; Brückner, Martina; Knaup, Karl; Gentzel, Marc; Schambony, Alexandra; Behrens, Jürgen (The Journal of Cell Biology, 2018)
Mitochondrial abundance is dynamically regulated and was previously shown to be increased by Wnt/β-catenin signaling. Pgam5 is a mitochondrial phosphatase which is cleaved by the rhomboid protease presenilin-associated rhomboid-like protein (PARL) and released from membranes after mitochondrial stress. In this study, we show that Pgam5 interacts with the Wnt pathway component axin in the cytosol, blocks axin-mediated β-catenin degradation, and increases β-catenin levels and β-catenin-dependent transcription. Pgam5 stabilized β-catenin by inducing its dephosphorylation in an axin-dependent manner. Mitochondrial stress triggered by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment led to cytosolic release of endogenous Pgam5 and subsequent dephosphorylation of β-catenin, which was strongly diminished in Pgam5 and PARL knockout cells. Similarly, hypoxic stress generated cytosolic Pgam5 and led to stabilization of β-catenin, which was abolished by Pgam5 knockout. Cells stably expressing cytosolic Pgam5 exhibit elevated β-catenin levels and increased mitochondrial numbers. Our study reveals a novel mechanism by which damaged mitochondria might induce replenishment of the mitochondrial pool by cell-intrinsic activation of Wnt signaling via the Pgam5-β-catenin axis.
EVALuna2:34942

Phase II randomized sham-controlled study of renal denervation for individuals with uncontrolled hypertension - WAVE IV - Schmieder, Roland; Ott, Christian; Toennes, Stefan W.; Bramlage, Peter; Gertner, Michael; Dawood, Omar; Baumgart, Peter; O'Brien, Benjamin; Dasgupta, Indranil; Nickenig, Georg; Ormiston, John; Saxena, Manish; et al. (Journal of Hypertension, 2017)
The aim of this double-blind, randomized, sham-controlled study was to verify the blood pressure (BP)-lowering efficacy of externally delivered focused ultrasound for renal denervation (RDN).Nonrandomized, first proof-of-concept study and experimental evidence suggested that noninvasive techniques of RDN emerged as an alternative approach of RDN to invasive technologies.WAVE IV, an international, randomized (1 : 1) sham-controlled, double-blind prospective clinical study, was prematurely stopped. Patients were enrolled if office BP was at least 160 mmHg and 24-h ambulatory BP was at least 135 mmHg, while taking three or more antihypertensive medications. The treatment consisted of bilateral RDN using therapeutic levels of ultrasound energy and the sham consisted of bilateral application of diagnostic levels of ultrasound energy.In the 81 treated patients neither changes in office BP at 12 and 24 weeks, nor changes in 24-h ambulatory BP at 24-week follow-up visit differed between the two groups significantly. Of note, no safety signal was observed. Adherence analysis disclosed full adherence in 77% at baseline and 82% at 6 months' follow-up visit. Post hoc analysis revealed that stricter criteria for stabilization of BP at baseline were associated with a numerically greater change in 24-h ambulatory BP in the RDN group than in the sham group.Our data did not prove that antihypertensive efficacy of the externally delivered focused ultrasound for RDN was greater than the sham effect. Stabilization of BP at baseline was identified as an important determinant of BP changes.
EVALuna2:4028

Photoactivation of olfactory sensory neurons does not affect action potential conduction in individual trigeminal sensory axons innervating the rodent nasal cavity - Maurer, Margot; Papotto, Nunzia; Sertel-Nakajima, Julika; Schüler, Markus; De Col, Roberto; Möhrlen, Frank; Meßlinger, Karl; Frings, Stephan; Carr, Richard W. (PLoS ONE, 2019)
Olfactory and trigeminal chemosensory systems reside in parallel within the mammalian nose. Psychophysical studies in people indicate that these two systems interact at a perceptual level. Trigeminal sensations of pungency mask odour perception, while olfactory stimuli can influence trigeminal signal processing tasks such as odour localization. While imaging studies indicate overlap in limbic and cortical somatosensory areas activated by nasal trigeminal and olfactory stimuli, there is also potential cross-talk at the level of the olfactory epithelium, the olfactory bulb and trigeminal brainstem. Here we explored the influence of olfactory and trigeminal signaling in the nasal cavity. A forced choice water consumption paradigm was used to ascertain whether trigeminal and olfactory stimuli could influence behaviour in mice. Mice avoided water sources surrounded by both volatile TRPV1 (cyclohexanone) and TRPA1 (allyl isothiocyanate) irritants and the aversion to cyclohexanone was mitigated when combined with a pure odorant (rose fragrance, phenylethyl alcohol, PEA). To determine whether olfactory-trigeminal interactions within the nose could potentially account for this behavioural effect we recorded from single trigeminal sensory axons innervating the nasal respiratory and olfactory epithelium using an isolated in vitro preparation. To circumvent non-specific effects of chemical stimuli, optical stimulation was used to excite olfactory sensory neurons in mice expressing channel-rhodopsin (ChR2) under the olfactory marker protein (OMP) promoter. Photoactivation of olfactory sensory neurons produced no modulation of axonal action potential conduction in individual trigeminal axons. Similarly, no evidence was found for collateral branching of trigeminal axon that might serve as a conduit for cross-talk between the olfactory and respiratory epithelium and olfactory dura mater. Using direct assessment of action potential activity in trigeminal axons we observed neither paracrine nor axon reflex mediated cross-talk between olfactory and trigeminal sensory systems in the rodent nasal cavity. Our current results suggest that olfactory sensory neurons exert minimal influence on trigeminal signals within the nasal cavity.
CRIS-Team Scopus Importer:2019-08-23

Physician Preferences for Recommending Renal Denervation to Hypertensive Patients Is Influenced by Patients' Antihypertensive Medication Nonadherence Due to Medication Side Effects - Wang, Tzung-Dau; Schmieder, Roland; Kandzari, David E.; Lee, Ying-Hsiang; Haro, Carlos F.; Pathak, Atul (JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2022)
CRIS-Team WoS Importer:2022-05-13

PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation - Gulluni, Federico; Prever, Lorenzo; Li, Huayi; Krafcikova, Petra; Corrado, Ilaria; Lo, Wen-Ting; Margaria, Jean Piero; Chen, Anlu; De Santis, Maria Chiara; Cnudde, Sophie J.; Fogerty, Joseph; Yuan, Alex; et al. (Science, 2021)
Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)–dependent control of membrane remodeling at the midbody, a subcellular organelle that defines the cleavage site. Alteration of ESCRT function can lead to cataract, but the underlying mechanism and its relation to cytokinesis are unclear. We found a lens-specific cytokinetic process that required PI3K-C2a (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2a), its lipid product PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate), and the PI(3,4)P2–binding ESCRT-II subunit VPS36 (vacuolar protein-sorting-associated protein 36). Loss of each of these components led to impaired cytokinesis, triggering premature senescence in the lens of fish, mice, and humans. Thus, an evolutionarily conserved pathway underlies the cell type–specific control of cytokinesis that helps to prevent early onset cataract by protecting from senescence.
CRIS-Team Scopus Importer:2021-12-24

Plasma histamine and tumour necrosis factor-alpha levels in Crohn's disease and ulcerative colitis at various stages of disease - Hagel, Alexander; De Rossi, T.; Konturek, Peter; Albrecht, H.; Walker, Stefanie Elke; Hahn, Eckhart Georg; Raithel, M. (Journal of Physiology and Pharmacology, 2015)
Mast cells secrete numerous mediators and this study investigated plasma levels of histamine, and tumor necrosis factor alpha (TNF-?) in chronic inflammatory bowel disease (IBD). Plasma levels of histamine were determined in 68 patients with Crohn's disease (CD), 22 with ulcerative colitis (UC) and 13 controls. TNF-? levels were assessed in 29 CD patients, 11 UC patients, and in 11 controls. Plasma histamine levels in the control group were 0.25 ng (0.14 - 0.33) and showed no difference to CD (0.19 ng, 0.09 - 0.35) or UC (0.23 ng, 0.11 - 0.60). Significantly lower histamine levels were only found in CD patients on 5-aminosalicylic acid treatment (P <= 0.04). Plasma TNF-? levels in the control group were significantly lower 0.44 ml/m(2) (0 - 1.15) than in CD patients (4.62 ml/m(2), 1.82 - 9.22, P = 0.005) or UC (3.14 ml/m(2); 0.08 - 11.34, P = 0.01). In CD disease activity, fistula, and extraintestinal manifestations (EM) were associated with significantly higher plasma TNF-? values, but not the type of treatment. We concluded that in contrast to TNF-?, histamine levels were normal in CD and UC. There is no correlation with histamine and thus the proportion of TNF-? secreted from mast cells in the plasma in patients with IBD is less important.
EVALuna2:2032

Plasma renin and aldosterone concentrations related to endovascular ultrasound renal denervation in the RADIANCE-HTN SOLO trial - Fisher, Naomi D.L.; Kirtane, Ajay J.; Daemen, Joost; Rader, Florian; Lobo, Melvin D.; Saxena, Manish; Abraham, Josephine; Schmieder, Roland; Sharp, Andrew S.P.; Gosse, Philippe; Claude, Lisa; Song, Yang; et al. (Journal of Hypertension, 2022)
Objective: The RADIANCE-HTN SOLO trial demonstrated a greater reduction in daytime ambulatory SBP at 2 months by endovascular ultrasound renal denervation than sham procedure. We hypothesized that plasma renin and aldosterone concentrations would be associated with the SBP response to renal denervation. Methods: Hypertensive patients were randomized to renal denervation (n=74) or sham (n=72) after a 4-week washout of antihypertensive medications. In a 53-patient subset, 2-month and 6-month plasma renin and aldosterone concentration were measured. Dietary sodium was not controlled. Results: Mean age of the 29 treatment and 24 sham patients was 54years; 62% were men; 17% black. Daytime ambulatory SBP fell in the denervation but not the sham group at 2 months (-7.8=10.7 vs. -0.1=10.1mmHg; P=0.048). Baseline plasma renin and aldosterone concentrations were in the low-normal range, did not change significantly at 2 months in either group and did not predict response to renal denervation. At 6 months, after the addition of antihypertensive medications, there was a significant rise in renin in the sham but not the denervation group. Conclusion: Although renal denervation but not sham resulted in a decrease in daytime ambulatory SBP at 2 months, renin and aldosterone concentrations did neither predict the BP response to renal denervation; nor did they fall after denervation. A rise in renin at 6 months in the sham group likely represents confounding from antihypertensive medications. Whether the BP-lowering effect of renal denervation depends on reducing local intrarenal renin release requires further study.
CRIS-Team Scopus Importer:2022-02-04
Keywords: Aldosterone; Hypertension; Renal denervation; Renin

Platelet CD40 contributes to enhanced monocyte chemoattractant protein 1 levels in patients with resistant hypertension - Stumpf, Christian; Raaz, Dorette; Klinghammer, Lutz; Schneider, Markus; Schmieder, Roland; Garlichs, Christoph D.; Achenbach, Stephan (European Journal of Clinical Investigation, 2016)
Growing evidence shows that inflammation plays a pivotal role in the pathophysiology of essential hypertension (EH). Although it is acknowledged that target organ damage involves an inflammatory response, most work has focused on the role of macrophages. However, recently, platelets were identified as inducing inflammation partly by releasing cytokines. The goal of our study was to evaluate the role of platelets as inflammatory cells in the pathogenesis of EH.Thirty-nine patients with EH and 30 healthy normotensive controls have been examined. Expression of platelet CD40 was measured by flow cytometry. Serum levels of monocyte chemoattractant protein 1 (MCP-1) and sCD40L were measured via a multiplexing assay. In in vitro experiments, activated platelets were cocultured with human umbilical vein endothelial cells (HUVEC) in the presence and absence of anti-CD154 antibodies. MCP-1 in the supernatants was measured by EIA.Essential hypertension patients showed significantly enhanced MCP-1 levels with highest levels in EH patients with microalbuminuria. EH patients showed increased expression of platelet CD40. In the cell coculture model, activated platelets were able to significantly induce MCP-1 release from HUVEC in a CD40L-dependent manner. EH patients showed elevated sCD40L levels with a positive correlation with MCP-1 levels.Platelets can contribute to enhanced MCP-1 levels in EH. MCP-1 is markedly elevated in serum of EH patients with highest levels in patients with microalbuminuria, one early sign of renal target organ damage. Further studies are required to test whether MCP-1 blocking or antiplatelet strategies may represent new therapeutic options in preventing hypertensive target organ damage.
EVALuna2:3852

Pleiotropic effects under combined therapy with empagliflozin and linagliptin compared to metformin and insulin glargine in patients with type 2 diabetes - Jung, Susan; Ott, Christian; Kannenkeril, D.; Bosch, Agnes; Karg, M.; Striepe, Kristina; Bramlage, P.; Schmieder, Roland (DIABETOLOGIA, 2019)
CRIS-Team WoS Importer:2019-10-11

PODOCYTE AND GLOMERULAR ENDOTHELIAL CELL DERIVED MICRORNAS REGULATE PODOCYTE NEPHRONECTIN IN MEMBRANOUS GLOMERULONEPHRITIS - Müller-Deile, Janina; Sopel, Nina; Ohs, Alexandra; Kotb, Ahmed; Gröner, Marwin; Daniel, Christoph; Amann, Kerstin Ute; Schiffer, Mario (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Podocyte density and albuminuria in aging diabetic ins2± mice with or without adenosine a1 receptor signaling - Faulhaber-Walter, Robert; Jiang, Lanping; Mizel, Diane; Zerfas, Patricia M.; Kopp, Jeffrey B.; Schnermann, Jurgen B.; Chen, Limeng; Schiffer, Mario (International Journal of Nephrology and Renovascular Disease, 2020)
Aim of Study: To investigate podocyte density in aging diabetic Ins2± and Ins2±, A1AR-/-mouse models in C57Bl/6 background. Methods: Ins2± mice and especially Ins2±, adenosine A1 receptor knockout mice (Ins2±, A1AR-/-) are mouse models with a phenotype of diabetic nephropathy. Aged mice (at 40 weeks) were assessed for glomerular filtration barrier function by measuring albuminuria, glomerular filtration, glomerular damage by electron microscopy, and podocyte numbers by Wilms Tumor protein (WT-1) staining. Results: Compared to healthy wild-type mice, both diabetic mouse models developed diabetic nephropathy, including hyperfiltration (p<0.01) and albuminuria (p<0.05). Typical diabetic structural glomerular and podocyte damage was visualized by electron microscopy. Podocyte count per glomerular area (podocyte density) was significantly decreased in both diabetic mouse models (p<0.01). In contrast, no significant correlation was detected between albuminuria and absolute podocyte count per glomerulus. Conclusion: The amount of albuminuria as marker of diabetic nephropathy does not correlate with the podocytes density; however, a relative podocyte deficiency became evident with an increase in glomerular area in the diabetic animals, suggesting a relative podocytopenia.
CRIS-Team Scopus Importer:2020-03-06
Keywords: Diabetes nephropathy podocyte mouse Akita WT-1

PODOCYTE NEPHRONECTIN IS REGULATED BY TRANSFORMING GROWTH FACTOR BETA VIA THE CANONICAL AND NON-CANONICAL PATHWAYS - Sopel, Nina; Ohs, Alexandra; Schiffer, Mario; Müller-Deile, Janina (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Podocyte-specific loss of sialylation in mice results in renal defects resembling human focal segmental glomerulosclerosis - Niculovic, Kristina; Blume, Linda; Wedekind, Henri; Groos, Stephanie; Melk, Anette; Schiffer, Mario; Weinhold, Birgit; Munster-Kuehnel, Anja (GLYCOBIOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-04

Podocyte-Specific Sialylation-Deficient Mice Serve as a Model for Human FSGS - Niculovic, Kristina M.; Blume, Linda; Wedekind, Henri; Kats, Elina; Albers, Iris; Groos, Stephanie; Abeln, Markus; Schmitz, Jessica; Beuke, Esther; Bräsen, Jan H.; Melk, Anette; Schiffer, Mario; et al. (Journal of the American Society of Nephrology, 2019)
BACKGROUND: The etiology of steroid-resistant nephrotic syndrome, which manifests as FSGS, is not completely understood. Aberrant glycosylation is an often underestimated factor for pathologic processes, and structural changes in the glomerular endothelial glycocalyx have been correlated with models of nephrotic syndrome. Glycans are frequently capped by sialic acid (Sia), and sialylation's crucial role for kidney function is well known. Human podocytes are highly sialylated; however, sialylation's role in podocyte homeostasis remains unclear. METHODS: We generated a podocyte-specific sialylation-deficient mouse model (PCmas-/- ) by targeting CMP-Sia synthetase, and used histologic and ultrastructural analysis to decipher the phenotype. We applied CRISPR/Cas9 technology to generate immortalized sialylation-deficient podocytes (asialo-podocytes) for functional studies. RESULTS: Progressive loss of sialylation in PCmas-/- mice resulted in onset of proteinuria around postnatal day 28, accompanied by foot process effacement and loss of slit diaphragms. Podocyte injury led to severe glomerular defects, including expanded capillary lumen, mesangial hypercellularity, synechiae formation, and podocyte loss. In vivo, loss of sialylation resulted in mislocalization of slit diaphragm components, whereas podocalyxin localization was preserved. In vitro, asialo-podocytes were viable, able to proliferate and differentiate, but showed impaired adhesion to collagen IV. CONCLUSIONS: Loss of cell-surface sialylation in mice resulted in disturbance of podocyte homeostasis and FSGS development. Impaired podocyte adhesion to the glomerular basement membrane most likely contributed to disease development. Our data support the notion that loss of sialylation might be part of the complex process causing FSGS. Sialylation, such as through a Sia supplementation therapy, might provide a new therapeutic strategy to cure or delay FSGS and potentially other glomerulopathies.
EVALuna2:118631

Population-Attributable Fractions of Modifiable Lifestyle Factors for CKD and Mortality in Individuals With Type 2 Diabetes: A Cohort Study - Dunkler, Daniela; Kohl, Martin; Teo, Koon K.; Heinze, Georg; Dehghan, Mahshid; Clase, Catherine M.; Gao, Peggy; Yusuf, Salim; Mann, Johannes; Oberbauer, Rainer (American Journal of Kidney Diseases, 2016)
BACKGROUND: We quantified the impact of lifestyle and dietary modifications on chronic kidney disease (CKD) by estimating population-attributable fractions (PAFs). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Middle-aged adults with type 2 diabetes but without severe albuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET; n=6,916). FACTORS: Modifiable lifestyle/dietary risk factors, such as physical activity, size of social network, alcohol intake, tobacco use, diet, and intake of various food items. OUTCOMES: The primary outcome was CKD, ascertained as moderate to severe albuminuria or ≥5% annual decline in estimated glomerular filtration rate (eGFR) after 5.5 years. The competing risk for death was considered. PAF was defined as the proportional reduction in CKD or mortality (within 5.5 years) that would occur if exposure to a risk factor was changed to an optimal level. RESULTS: At baseline, median urinary albumin-creatinine ratio and eGFR were 6.6 (IQR, 2.9-25.0) mg/mmol and 71.5 (IQR, 58.1-85.9) mL/min/1.73m(2), respectively. After 5.5 years, 704 (32.5%) participants developed albuminuria, 1,194 (55.2%) had a ≥5% annual eGFR decline, 267 (12.3%) had both, and 1,022 (14.8%) had died. Being physically active every day has PAFs of 5.1% (95% CI, 0.5%-9.6%) for CKD and 12.3% (95% CI, 4.9%-19.1%) for death. Among food items, increasing vegetable intake would have the largest impact on population health. Considering diet, weight, physical activity, tobacco use, and size of social network, exposure to less than optimum levels gives PAFs of 13.3% (95% CI, 5.5%-20.9%) for CKD and 37.5% (95% CI, 27.8%-46.7%) for death. For the 17.8 million middle-aged Americans with diabetes, improving 1 of these lifestyle behaviors to the optimal range could reduce the incidence or progression of CKD after 5.5 years by 274,000 and the number of deaths within 5.5 years by 405,000. LIMITATIONS: Ascertainment of changes in kidney measures does not precisely match the definitions for incidence or progression of CKD. CONCLUSIONS: Healthy lifestyle and diet are associated with less CKD and mortality and may have a substantial impact on population kidney health.
EVALuna2:33866

Posttranscriptional Regulation of LOXL1 Expression Via Alternative Splicing and Nonsense-Mediated mRNA Decay as an Adaptive Stress Response - Berner, Daniel; Zenkel, Matthias; Pasutto, Francesca; Hoja, Ursula; Liravi, Panah; Gusek-Schneider, Gabriele C.; Kruse, Friedrich; Schödel, Johannes; Reis, André; Schlötzer-Schrehardt, Ursula (Investigative Ophthalmology & Visual Science, 2017)
Alternative mRNA splicing coupled to nonsense-mediated decay (NMD) is a common mRNA surveillance pathway also known to dynamically modulate gene expression in response to cellular stress. Here, we investigated the involvement of this pathway in the regulation of lysyl oxidase-like 1 (LOXL1) expression in response to pseudoexfoliation (PEX)-associated pathophysiologic factors.Transcript levels of LOXL1 isoforms were determined in ocular tissues obtained from donor eyes without and with PEX syndrome. Pseudoexfoliation-relevant cell types, including human Tenon's capsule fibroblasts (hTCF) and trabecular meshwork cells (hTMC), were exposed to puromycin, caffeine, TGF-?1, homocysteine, IL-6, retinoic acid, UV-B radiation, oxidative stress, and mechanical stress for up to 48 hours. Western blot analysis was carried out using antibodies against LOXL1, (phosphorylated-) eukaryotic initiation factor 2-? (eIF2-?), and regulator of nonsense transcripts 2 (UPF2). RNA interference was used to knockdown UPF1-3 and Serine/threonine-protein kinase (SMG1).Constitutive expression of wild-type LOXL1 and alternatively spliced LOXL1-a transcripts was detected in all ocular tissues showing highest levels in trabecular meshwork and differential expression between PEX and control specimens. LOXL1-a transcripts were upregulated in hTCF and hTMC by NMD inhibitors puromycin and caffeine (>=6-fold; P < 0.01) or after knockdown of NMD core factors (>=2-fold; P < 0.05), whereas mRNA and protein levels of LOXL1 were reduced (<=0.8 fold; P < 0.05). Exposure of cells to various PEX-associated (stress) factors, including TGF-?1, UV-B light, oxidative stress, mechanical stress, and retinoic acid enhanced LOXL1-a transcript levels (>=1.5-fold; P < 0.05), while partially downregulating LOXL1 levels (<=0.7-fold; P < 0.05). Stress-induced inhibition of NMD was dependent on phosphorylation of eIF2?.These findings provide evidence for a functional role of alternative splicing coupled to NMD in the posttranscriptional regulation of LOXL1 gene expression and suggest this mechanism to represent a dynamic mode of adapting LOXL1 expression to PEX-associated environmental and nutritional cues.
EVALuna2:9393

Potential kidney protection with liraglutide and semaglutide: Exploratory mediation analysis - Mann, Johannes; Buse, John B.; Idorn, Thomas; Leiter, Lawrence A.; Pratley, Richard E.; Rasmussen, Soren; Vilsboll, Tina; Wolthers, Benjamin; Perkovic, Vlado (Diabetes Obesity & Metabolism, 2021)
Aims: To investigate whether effects on chronic kidney disease risk factors could explain the apparent reduction in kidney outcomes (composite of macroalbuminuria, doubling of serum creatinine, renal replacement therapy, or renal death), primarily driven by changes in albuminuria, after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide in patients with type 2 diabetes in the LEADER and SUSTAIN 6 trials.
CRIS-Team WoS Importer:2021-06-11

Potential life-years gained over a 5-year period by correcting DOPPS-identified modifiable practices in haemodialysis: results from the European MONITOR-CKD5 study - Combe, Christian; Mann, Johannes; Goldsmith, David; Dellanna, Frank; Zaoui, Philippe; London, Gerard; Denhaerynck, Kris; Krendyukov, Andriy; Abraham, Ivo; Macdonald, Karen (BMC Nephrology, 2019)
BackgroundDOPPS reported that thousands of life-years could be gained in the US and Europe over 5years by correcting six modifiable haemodialysis practices. We estimated potential life-years gained across 10 European countries using MONITOR-CKD5 study data.MethodsThe DOPPS-based target ranges were used, except for haemoglobin due to label changes, as well as DOPPS-derived relative mortality risks. Percentages of MONITOR-CKD5 patients outside targets were calculated. Consistent with the DOPPS-based analyses, we extrapolated life-years gained for the MONITOR-CKD5 population over 5years if all patients were within targets.ResultsBringing the 10 MONITOR-CKD5 countries' dialysis populations into compliance on the six practices results in a 5-year gain of 97,428 patient-years. In descending order, survival impact was the highest for albumin levels, followed by phosphate levels, vascular access, haemoglobin, dialysis adequacy, and interdialytic weight gain.ConclusionsOptimal management of the six modifiable haemodialysis practices may achieve 6.2% increase in 5-year survival.Trial RegistrationNCT01121237. Clinicaltrials.gov registration May 12, 2010 (retrospectively registered).
CRIS-Team WoS Importer:2019-03-20

Pre- and post-conditional inhibition of prolyl-4-hydroxylase domain enzymes protects the heart from an ischemic insult - Vogler, Melanie; Zieseniss, Anke; Hesse, Amke R.; Levent, Elif; Tiburcy, Malte; Heinze, Eva; Burzlaff, Nicolai; Schley, Gunnar; Eckardt, Kai-Uwe; Willam, Carsten; Katschinski, Doerthe M. (Pflügers Archiv: European Journal of Physiology, 2015)
Several genetically modified mouse models implicated that prolyl-4-hydroxylase domain (PHD) enzymes are critical mediators for protecting tissues from an ischemic insult including myocardial infarction by affecting the stability and activation of hypoxia-inducible factor (HIF)-1 and HIF-2. Thus, the current efforts to develop small-molecule PHD inhibitors open a new therapeutic option for myocardial tissue protection during ischemia. Therefore, we aimed to investigate the applicability and efficacy of pharmacological HIF? stabilization by a small-molecule PHD inhibitor in the heart. We tested for protective effects in the acute phase of myocardial infarction after pre- or post-conditional application of the inhibitor. Application of the specific PHD inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) resulted in HIF-1? and HIF-2? accumulation in heart muscle cells in vitro and in vivo. The rapid and robust responsiveness of cardiac tissue towards ICA was further confirmed by induction of the known HIF target genes heme oxygenase-1 and PHD3. Pre- and post-conditional treatment of mice undergoing myocardial infarction resulted in a significantly smaller infarct size. Tissue protection from ischemia after pre- or post-conditional ICA treatment demonstrates that there is a therapeutic time window for the application of the PHD inhibitor (PHI) post-myocardial infarction, which might be exploited for acute medical interventions.
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Predictors of blood pressure response after renal denervation beyond pretreatment blood pressure - Schmieder, Roland; Delles, C.; Lauder, L.; Ott, Christian; Boehm, M.; Mahfoud, F. (EUROPEAN HEART JOURNAL, 2021)
CRIS-Team WoS Importer:2021-12-10

Predictors of blood pressure response to ultrasound renal denervation in the RADIANCE-HTN SOLO study - Saxena, Manish; Schmieder, Roland; Kirtane, Ajay J.; Mahfoud, Felix; Daemen, Joost; Basile, Jan; Lurz, Philipp; Gosse, Philippe; Sanghvi, Kintur; Fisher, Naomi D. L.; Rump, Lars C.; Pathak, Atul; et al. (Journal of Human Hypertension, 2021)
The blood pressure (BP) lowering response to renal denervation (RDN) remains variable with about one-third of patients not responding to ultrasound or radiofrequency RDN. Identification of predictors of the BP response to RDN is needed to optimize patient selection for this therapy. This is a post-hoc analysis of the RADIANCE-HTN SOLO study. BP response to RDN was measured by the change in daytime ambulatory systolic blood pressure (dASBP) at 2 months post procedure. Univariate regression was used initially to assess potential predictors of outcome followed by multivariate regression analysis. In the univariate analysis, predictors of response to RDN were higher baseline daytime ambulatory diastolic blood pressure (dADBP), the use of antihypertensive medications at screening, and presence of orthostatic hypertension (OHTN) whilst the presence of untreated accessory arteries was a negative predictor of response. Multivariate analysis determined that dADBP and use of antihypertensive medications were predictors of response to RDN with a trend for OHTN to predict response. Obese females also appeared to be better responders to RDN in an interaction model. RDN is more effective in patients with elevated baseline dADBP and those with OHTN, suggesting increased peripheral vascular resistance secondary to heightened sympathetic tone. These assessments are easy to perform in clinical setting and may help in phenotyping patients who will respond better to RDN.
CRIS-Team Scopus Importer:2021-06-04

Predictors of congestive heart failure after treatment with an endothelin receptor antagonist - Hoekman, Jamo; Heerspink, Hiddo J. Lambers; Viberti, Giancarlo; Green, Damien; Mann, Johannes; De Zeeuw, Dick (Clinical Journal of the American Society of Nephrology, 2014)
The Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death (ASCEND) trial tested the renoprotective effect of the endothelin receptor antagonist avosentan in patients with diabetes and nephropathy, but the study was terminated due to an excess of congestive heart failure (CHF) events in the avosentan arms, likely due to fluid retention. The aim of this study was to identify risk markers of CHF after treatment with avosentan.In a post hoc analysis of the ASCEND trial (N=1392 participants), we assessed which baseline characteristics predicted CHF risk during avosentan treatment. Furthermore, postrandomization changes between baseline and the first available measurement of body weight and hemoglobin were examined as potential clinical indicators of fluid retention for their relationship with CHF development.Relative to placebo, avosentan increased CHF risk (hazard ratio, 2.76; 95% confidence interval, 1.68 to 4.54). The avosentan-related CHF risk was higher with lower baseline cholesterol levels (P interaction=0.003) and concomitant statin use (P interaction=0.06), whereas it was lower with a lower estimated GFR (P interaction=0.04). Patients allocated to avosentan had a median body weight increase of 0.6 kg (interquartile range, 0.0 to 2.0 kg) and a median hemoglobin decrease of 1.4 g/dl (interquartile range, -2.1 to -0.7 g/dl) at the first postrandomization measurement. The body weight increase induced by avosentan was associated with CHF development (P interaction=0.04), whereas hemoglobin decrease was not (P interaction=0.64). The increase in body weight was particularly pronounced in patients with a cardiovascular disease history and in patients using statins.In avosentan-treated patients, body weight increase, but not hemoglobin decrease, was associated with CHF development, indicating that close body weight monitoring could provide an early signal of CHF development in future trials with endothelin receptor antagonists.
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Prenatal diagnosis of HNF1B-associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome? - Vasileiou, Georgia; Hoyer, Juliane; Thiel, Christian; Schaefer, Jan Thomas; Zapke, Maren; Krumbiegel, Mandy; Kraus, Cornelia; Zweier, Markus; Uebe, Steffen; Ekici, Arif Bülent; Schneider, Michael; Wiesener, Michael; et al. (Prenatal Diagnosis, 2019)
Objective 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. Methods Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. Results In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum. Conclusions We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.
CRIS-Team WoS Importer:2019-11-08

Prevalence and correlates of cognitive impairment in kidney transplant patients using the demtect—results of a ktx360 substudy - Nöhre, Mariel; Bauer-Hohmann, Maximilian; Klewitz, Felix; Tun, Eva Marie Kyaw Tha; Tegtbur, Uwe; Pape, Lars; Schiffer, Lena; de Zwaan, Martina; Schiffer, Mario (Frontiers in Psychiatry, 2019)
Cognitive impairment in kidney transplantation (KTx) patients is associated with allograft survival and mortality. However, the prevalence of cognitive impairment after KTx is still understudied. Thus, we aimed to assess the prevalence of cognitive impairment in KTx patients and to identify sociodemographic, medical, donation-specific, and psychological variables associated with cognitive impairment. In this cross-sectional two-center study, 583 KTx patients participated in a structured post-transplant care program. The DemTect was used to assess cognition, and cognitive impairment was defined as a score of < 13. Mean age was 52.11 years, 59% were male, 27.4% had ≥12 years of school attendance, and 85.9% had hypertension. The prevalence of cognitive impairment was 15.6%. Cognitive impairment was significantly associated with higher age, male sex, lower educational level, subjective perception of cognitive decline, higher rates of hypertension, lower kidney functioning, and obesity (BMI > 30 kg/m2). Using logistic regression analysis, all variables except age remained significant. Our results suggest that cognitive impairment affects a significant number of patients after KTx. Transplant centers may consider screening for cognitive impairment using objective tests, especially in patients with a high-risk profile. Furthermore, studies with longitudinal designs are required in order to assess moderators and mediators for cognitive trajectories.
CRIS-Team Scopus Importer:2019-11-26
Keywords: cognitive functioning; Cognitive impairment; DemTect; Kidney transplantation; Renal transplantation

Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German Chronic Kidney Disease (GCKD) study - Jing, Jiaojiao; Kielstein, Jan T.; Schultheiss, Ulla T.; Sitter, Thomas; Titze, Stephanie I.; Schaeffner, Elke S.; Mcadams-Demarco, Mara; Kronenberg, Florian; Eckardt, Kai-Uwe; Köttgen, Anna (Nephrology Dialysis Transplantation, 2015)
Reduced kidney function is a risk factor for hyperuricaemia and gout, but limited information on the burden of gout is available from studies of patients with chronic kidney disease (CKD). We therefore examined the prevalence and correlates of gout in the large prospective observational German Chronic Kidney Disease (GCKD) study.Data from 5085 CKD patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) of 30-<60 mL/min/1.73 m(2) or eGFR >=60 and overt proteinuria at recruitment and non-missing values for self-reported gout, medications and urate measurements from a central laboratory were evaluated.The overall prevalence of gout was 24.3%, and increased from 16.0% in those with eGFR >=60 mL/min/1.73 m(2) to 35.6% in those with eGFR <30. Of those with self-reported gout, 30.7% of individuals were not currently taking any gout medication and among gout patients on urate lowering therapy, 47.2% still showed hyperuricaemia. Factors associated with gout were serum urate, lower eGFR, advanced age, male sex, higher body mass index and waist-to-hip ratio, higher triglyceride and C-reactive protein (CRP) concentrations, alcohol intake and diuretics use. While lower eGFR categories showed significant associations with gout in multivariable-adjusted models (prevalence ratio 1.46 for eGFR <30 compared with eGFR >=60, 95% confidence interval 1.21-1.77), associations between gout and higher urinary albumin-to-creatinine ratio in this CKD population were not significant.Self-reported gout is common among patients with CKD and lower GFR is strongly associated with gout. Pharmacological management of gout in patients with CKD is suboptimal. Prospective follow-up will show whether gout and hyperuricaemia increase the risk of CKD progression and cardiovascular events in the GCKD study.
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Prevalence and Modifiable Determinants of Non-Adherence in Adult Kidney Transplant Recipients in a German Sample - Reber, Sandra Therese; Morawa, Eva; Stößel, Lisa; Jank, Sabine; Vitinius, Frank; Eckardt, Kai-Uwe; Erim, Yesim (Zeitschrift für Psychosomatische Medizin und Psychotherapie, 2016)
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Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study - Popp, Bernt; Ekici, Arif Bülent; Knaup, Karl; Schneider, Karen; Uebe, Steffen; Park, Jonghun; Bafna, Vineet; Meiselbach, Heike; Eckardt, Kai-Uwe; Schiffer, Mario; Wiesmann da Silva Reis, André; Kraus, Cornelia; et al. (European Journal of Human Genetics, 2022)
Hereditary chronic kidney disease (CKD) appears to be more frequent than the clinical perception. Exome sequencing (ES) studies in CKD cohorts could identify pathogenic variants in similar to 10% of individuals. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose. We used a targeted panel (29 genes) and MUC1-SNaPshot to sequence 271 DNAs, selected in defined disease entities and age cutoffs from 5217 individuals in the German Chronic Kidney Disease cohort. We identified 33 pathogenic variants. Of these 27 (81.8%) were in COL4A3/4/5, the largest group being 15 COL4A5 variants with nine unrelated individuals carrying c.1871G>A, p.(Gly624Asp). We found three cysteine variants in UMOD, a novel missense and a novel splice variant in HNF1B and the homoplastic MTTF variant m.616T>C. Copy-number analysis identified a heterozygous COL4A5 deletion, and a HNF1B duplication/deletion, respectively. Overall, pathogenic variants were present in 12.5% (34/271) and variants of unknown significance in 9.6% (26/271) of selected individuals. Bioinformatic predictions paired with gold standard diagnostics for MUC1 (SNaPshot) could not identify the typical cytosine duplication ("c.428dupC") in any individual, implying that ADTKD-MUC1 is rare. Our study shows that >10% of selected individuals carry disease-causing variants in genes partly associated with tubulointerstitial kidney diseases. COL4A3/4/5 genes constitute the largest fraction, implying they are regularly overlooked using clinical Alport syndrome criteria and displaying the existence of phenocopies. We identified variants easily missed by some ES pipelines. The clinical filtering criteria applied enriched for an underlying genetic disorder.
CRIS-Team WoS Importer:2022-09-23

Prevalence of mental disorders in a German kidney transplant population - results of a KTx360 degrees-substudy - Noehre, Mariel; Birkefeld, Katrin; Bauer-Hohmann, Maximilian; Tun, Eva-Marie Kyaw Tha; Tegtbur, Uwe; Pape, Lars; Schiffer, Lena; Schiffer, Mario; De Zwaan, Martina (JOURNAL OF PSYCHOSOMATIC RESEARCH, 2021)
CRIS-Team WoS Importer:2021-06-04

Prevalence of mental Illness in Patients after Kidney Transplantation - Results of an NTx360 degrees Sub-study - Noehre, Mariel; Birkefeld, Katrin; Klewitz, Felix; Bauer-Hohmann, Maximilian; Tun, Kyaw Tha Eva-Marie; Tegtbur, Uwe; Pape, Lars; Schiffer, Lena; Schiffer, Mario; De Zwaan, Martina (ZEITSCHRIFT FUR PSYCHOSOMATISCHE MEDIZIN UND PSYCHOTHERAPIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Prevalence of MRI-Detected Ankle Injuries in Athletes in the Rio de Janeiro 2016 Summer Olympics. - Heiß, Rafael; Guermazi, Ali; Jarraya, Mohamed; Engebretsen, Lars; Hotfiel, Thilo; Parva, Pedram; Roemer, Frank (Academic Radiology, 2019)
OBJECTIVE: To describe the prevalence, severity, and location of ankle injuries as assessed on magnetic resonance imaging (MRI) in athletes participating in the Rio de Janeiro 2016 Summer Olympic Games. METHODS: We analyzed all ankle MRIs that were acquired for suspected injury as reported by the National Olympic Committee medical teams and the Organizing Committee medical staff during the Rio 2016 Summer Olympics. Diagnostic imaging was performed through the Olympic Village Polyclinic. Images were interpreted retrospectively according to standardized criteria. RESULTS: A total of 11,274 athletes participated in the Games, of which 89 (8.8%) were referred for an ankle MRI. Eighty-eight of the 89 (99%) had at least 1 abnormal finding, and some had as many as 27, for an average of 6.2 abnormalities per examination. Around one-fifth of all abnormal findings were considered pre-existing (21%) and 79% were assumed to be the result of an acute or subacute injury. The highest proportion of acute/subacute injuries per athlete occurred in ball sports (7.0 injuries per examination) and in the age group >30. Most pre-existing findings per athlete were identified in the group of others (no track and field or ball sports athletes) with 2.5 findings per examination and respectively in the age group >30 (1.7). CONCLUSION: Our study demonstrated a high prevalence of acute and subacute, but also pre-existing injuries in Olympic athletes undergoing ankle MRI. Tendon injuries were the most common acute injuries, found mainly in ball sports athletes. Most pre-existing ankle injuries were identified at the ligaments.
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Prevalence of undiagnosed stage 3 chronic kidney disease in France, Germany, Italy, Japan and the USA: results from the multinational observational REVEAL-CKD study - Tangri, Navdeep; Moriyama, Toshiki; Schneider, Markus; Virgitti, Jean Blaise; De Nicola, Luca; Arnold, Matthew; Barone, Salvatore; Peach, Emily; Wittbrodt, Eric; Chen, Hungta; Järbrink, Krister; Kushner, Pamela (BMJ Open, 2023)
OBJECTIVES: REVEAL-CKD aims to estimate the prevalence of, and factors associated with, undiagnosed stage 3 chronic kidney disease (CKD). DESIGN: Multinational, observational study. SETTING: Data from six country-specific electronic medical records and/or insurance claims databases from five countries (France, Germany, Italy, Japan and the USA [two databases]). PARTICIPANTS: Eligible participants (≥18 years old) had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements (calculated from serum creatinine values, sex and age) taken from 2015 onwards that were indicative of stage 3 CKD (≥30 and <60 mL/min/1.73 m2). Undiagnosed cases lacked an International Classification of Diseases 9/10 diagnosis code for CKD (any stage) any time before, and up to 6 months after, the second qualifying eGFR measurement (study index). MAIN OUTCOME MEASURES: The primary outcome was point prevalence of undiagnosed stage 3 CKD. Time to diagnosis was assessed using the Kaplan-Meier approach. Factors associated with lacking a CKD diagnosis and risk of diagnostic delay were assessed using logistic regression adjusted for baseline covariates. RESULTS: The prevalence of undiagnosed stage 3 CKD was 95.5% (19 120/20 012 patients) in France, 84.3% (22 557/26 767) in Germany, 77.0% (50 547/65 676) in Italy, 92.1% (83 693/90 902) in Japan, 61.6% (13 845/22 470) in the US Explorys Linked Claims and Electronic Medical Records Data database and 64.3% (161 254/250 879) in the US TriNetX database. The prevalence of undiagnosed CKD increased with age. Factors associated with undiagnosed CKD were female sex (vs male, range of odds ratios across countries: 1.29-1.77), stage 3a CKD (vs 3b, 1.81-3.66), no medical history (vs a history) of diabetes (1.26-2.77) or hypertension (1.35-1.78). CONCLUSIONS: There are substantial opportunities to improve stage 3 CKD diagnosis, particularly in female patients and older patients. The low diagnosis rates in patients with comorbidities that put them at risk of disease progression and complications require attention. TRIAL REGISTRATION: NCT04847531.
CRIS-Team Scopus Importer:2023-06-02
Keywords: Adult nephrology; Chronic renal failure; EPIDEMIOLOGY; NEPHROLOGY

Prevalence, phenotypic characteristics and prognostic role of apparent treatment resistant hypertension in the German Chronic Kidney Disease (GCKD) study - Mielke, Johanna; Trucks-Jansen, Holger; Schurmann, Claudia; Kotsis, Fruzsina; Koettgen, Anna; Schneider, Markus; Eckardt, Kai-Uwe; Freitag, Daniel F.; Eitner, Frank; Becker, Michael S. (Journal of Human Hypertension, 2022)
Treatment resistant hypertension (TRH) appears of particular relevance in patients with chronic kidney disease (CKD). However, causes and consequences of TRH in CKD patients remain incompletely understood. Therefore, we analyzed the prevalence of apparent TRH (aTRH), and phenotypic characteristics and prognosis associated with aTRH among participants of the German Chronic Kidney Disease (GCKD) study. As insufficient medication adherence has been shown to be a frequent cause of pseudoresistance, we also assessed treatment adherence. Study participants were classified as having aTRH, controlled hypertension and uncontrolled hypertension based on study visit blood pressure and self-reported medication intake. Drug adherence was assessed by comparing self-reported antihypertensive medication with detectable urinary drug metabolites measured by mass spectroscopy. Out of 4901 individuals included in this study, 38% were classified as having aTRH. Male sex, older age, lower estimated glomerular filtration rate (eGFR), higher body mass index (BMI), higher urine albumin-to-creatinine ratio (UACR) and presence of diabetes mellitus were independently associated with higher prevalence of aTRH in a multivariable adjusted regression model. Patients classified as aTRH had higher risk for major adverse cardiovascular events and worsening of kidney disease compared to patients with no aTRH after multivariate adjustment for potential confounders. There was a high agreement between self-reported medication and detectable urinary drug metabolites. In conclusion, in a cohort of Caucasian patients with moderately severe CKD, aTRH was highly prevalent and, in most cases, likely not caused by low medication adherence. Furthermore, aTRH was linked to cardio-renal endpoints, emphasizing the need for improved management.
CRIS-Team WoS Importer:2022-05-20

Prevention of acute kidney injury in critically ill patients : Recommendations from the renal section of the DGIIN, ÖGIAIN and DIVI - Joannidis, M.; Klein, S. J.; John, S.; Schmitz, M.; Czock, D.; Druml, W.; Joerres, A.; Kindgen-Milles, D.; Kielstein, J. T.; Oppert, M.; Schwenger, V.; Willam, Carsten; et al. (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2018)
BACKGROUND: Acute kidney injury (AKI) has both high mortality and morbidity. OBJECTIVES: To prevent the occurrence of AKI, current recommendations from the renal section of the DGIIN (Deutschen Gesellschaft für Internistische Intensivmedizin und Notfallmedizin), ÖGIAIN (Österreichischen Gesellschaft für Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin) are stated. MATERIALS AND METHODS: The recommendations stated in this paper are based on the current Kidney Disease Improving Global Outcomes (KDIGO) guidelines, the published statements of the "Working Group on Prevention, AKI section of the European Society of Intensive Care Medicine" and the expert knowledge and clinical experience of the authors. RESULTS: Currently there are no approved clinically effective drugs for the prevention of AKI. Therefore the mainstay of prevention is the optimization of renal perfusion by improving the mean arterial pressure (>65 mm Hg, higher target may be considered in hypertensive patients). This can be done by vasopressors, preferably norepinephrine and achieving or maintaining euvolemia. Hyperhydration that can lead to AKI itself should be avoided. In patients with maintained diuresis this can be done by diuretics that are per se no preventive drug for AKI. Radiocontrast enhanced imaging should not be withheld from patients at risk for AKI; if indicated, however, the contrast media should be limited to the smallest possible volume.
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Prevention of electrocardiographic left ventricular remodeling by the angiotensin receptor blocker olmesartan in patients with type 2 diabetes - Raff, Ulrike; Ott, Christian; Ruilope, Luis M.; Menne, Jan; Haller, Hermann; Schmieder, Roland (Journal of Hypertension, 2014)
To assess the ability of olmesartan (OLM) to prevent or delay left ventricular remodeling and hypertrophy in patients with type 2 diabetes.This prespecified ECG substudy of Randomised OlmesArtan and Diabetes MicroAlbuminuria Prevention (ROADMAP), which compared OLM with placebo, assessed the signs of left ventricular remodeling in patients with a 12-lead ECG at baseline and after at least 2 years. Cornell voltage QRS duration product (primary objective), Cornell voltage index and Sokolow-Lyon index were assessed.In total, 9418 ECG recordings and 1513 patients from ROADMAP were analyzed (placebo, n = 736; OLM, n = 777). Quartiles defined by baseline Cornell voltage QRS duration product were assessed and the proportion of patients in the highest quartile (>=200 mVms) increased from 24.0 to 26.5% in the placebo group and decreased from 25.5 to 22.3% in the OLM group [odds ratio (OR) 0.598 (95% confidence interval [CI] 0.440-0.813); P = 0.0011]. The OR did not change after adjustment for baseline parameters. By the end of study, 38.7% of patients in the placebo group and 34.7% in the OLM group shifted from a lower to a higher quartile or remained in the highest quartile of Cornell voltage QRS duration product [OR 0.797 (95% CI 0.637-0.996); P = 0.0465]. This translated into a 20.3% risk reduction with OLM and suggested OLM attenuated the progression of left ventricular remodeling versus placebo.OLM substantially delayed the development of left ventricular remodeling in type 2 diabetes. This effect was not explained by the differences in blood pressure control. Thus, OLM delayed the onset of microalbuminuria, as well as the ECG signs of cardiac structural adaptation in type 2 diabetes.
EVALuna2:3738

Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future - Mahfoud, Felix; Schmieder, Roland; Azizi, Michel; Pathak, Atul; Sievert, Horst; Tsioufis, Costas; Zeller, Thomas; Bertog, Stefan; Blankestijn, Peter J.; Boehm, Michael; Burnier, Michel; Chatellier, Gilles; et al. (European Heart Journal, 2017)
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Proceedings from the 3rd European Clinical Consensus Conference for clinical trials in device-based hypertension therapies - Mahfoud, Felix; Azizi, Michel; Ewen, Sebastian; Pathak, Atul; Ukena, Christian; Blankestijn, Peter J.; Böhm, Michael; Burnier, Michel; Chatellier, Gilles; Durand Zaleski, Isabelle; Grassi, Guido; Joner, Michael; et al. (European Heart Journal, 2020)
CRIS-Team Scopus Importer:2020-05-15

Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design - Mahfoud, Felix; Boehm, Michael; Azizi, Michel; Pathak, Atul; Zaleski, Isabelle Durand; Ewen, Sebastian; Tsioufis, Kostantinos; Andersson, Bert; Blankestijn, Peter J.; Burnier, Michel; Chatellier, Gilles; Gafoor, Sameer; et al. (European Heart Journal, 2015)
EVALuna2:3763

PROGNOSTIC IMPACT OF NECK CIRCUMFERENCE ON CARDIVASCULAR OUTCOMES AND MORTALITY IN PATIENTS WITH MODERATE CHRONIC KIDNEY DISEASE: AN ANALYSIS FROM THE GERMAN CHRONIC KIDNEY DISEASE (GCKD) STUDY - Cejka, Vladimir; Stoerk, Stefan; Nadal, Jennifer; Schultheiss, Ulla T.; Koettgen, Anna; Sommerer, Claudia; Sitter, Thomas; Meiselbach, Heike; Busch, Martin; Schneider, Markus; Saritas, Turgay; Kotsis, Fruzsina Kinga; et al. (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2020)
CRIS-Team WoS Importer:2020-09-18

Prolyl-4-hydroxylases 2 and 3 control erythropoietin production in renin-expressing cells of mouse kidneys - Broeker, Katharina A. E.; Fuchs, Michaela A. A.; Schrankl, Julia; Lehrmann, Claudia; Schley, Gunnar; Todorov, Vladimir T.; Hugo, Christian; Wagner, Charlotte; Kurtz, Armin (The Journal of Physiology, 2021)
Activation of the hypoxia-signalling pathway induced by deletion of the ubiquitin-ligase von Hippel-Lindau protein causes an endocrine shift of renin-producing cells to erythropoietin (EPO)-expressing cells. However, the underlying mechanisms have not yet been investigated. Since oxygen-regulated stability of hypoxia-inducible transcription factors relevant for EPO expression is dependent on the activity of prolyl-4-hydroxylases (PHD) 2 and 3, this study aimed to determine the relevance of different PHD isoforms for the EPO expression in renin-producing cells in vivo. For this purpose, mice with inducible renin cell-specific deletions of different PHD isoforms were analysed. Our study shows that there are two subgroups of renal renin-expressing cells, juxtaglomerular renin(+) cells and platelet-derived growth factor receptor-beta(+) interstitial renin(+) cells. These interstitial renin(+) cells belong to the cell pool of native EPO-producing cells and are able to express EPO and renin in parallel. In contrast, co-deletion of PHD2 and PHD3, but not PHD2 deletion alone, induces EPO expression in juxtaglomerular and hyperplastic renin(+) cells and downregulates renin expression. A strong basal PHD3 expression in juxtaglomerular renin(+) cells seems to prevent the hypoxia-inducible transcription factor-2-dependent phenotype shift into EPO cells. In summary, PHDs seem important for the stabilization of the juxtaglomerular renin cell phenotype. Moreover, these findings reveal tubulointerstitial cells as a novel site of renal renin expression and suggest a high endocrine plasticity of these cells. Our data concerning the distinct expression patterns and functions of PHD2 and PHD3 provide new insights into the regulation of renin-producing cells and highlight the need for selective PHD inhibitors. Key points Renal renin-expressing cells can be clearly distinguished into two subgroups, the typical juxtaglomerular renin-producing cells and interstitial renin(+) cells. Interstitial renin(+) cells belong to the cell pool of native erythropoietin (EPO)-producing cells, show a fast EPO response to acute hypoxia-inducible factor-2 (HIF-2) stabilization and are able to express EPO and renin in parallel. Only co-deletion of the prolyl-4-hydroxylases (PHD) 2 and 3, but not PHD2 deletion alone, induces EPO expression in juxtaglomerular renin(+) cells. Chronic HIF-2 stabilization in juxtaglomerular renin-expressing cells leads to their phenotypic shift into EPO-producing cells. A strong basal PHD3 expression in juxtaglomerular renin(+) cells seems to prevent a HIF-2-dependent phenotype shift into EPO cells suggesting PHD3 fulfils a stabilizer function for the juxtaglomerular renin cell phenotype.
CRIS-Team WoS Importer:2022-01-07

Prolyl-hydroxylase inhibitor activating hypoxia-inducible transcription factors reduce levels of transplant arteriosclerosis in a murine aortic allograft model - Heim, Christian; Bernhardt, Wanja; Jalilova, Sabina; Wang, Zhendi; Motsch, Benjamin; Ramsperger-Gleixner, Martina; Burzlaff, Nicolai; Weyand, Michael; Eckardt, Kai-Uwe; Ensminger, Stephan M. (Interactive Cardiovascular and Thoracic Surgery, 2016)
The development of transplant arteriosclerosis, the hallmark feature of heart transplant rejection, is associated with a chronic immune response and also influenced by an initial injury to the graft through ischaemia and reperfusion. Hypoxia-inducible transcription factor (HIF)-1 pathway signalling has a protective effect against ischaemia-reperfusion injury and has already been demonstrated to ameliorate allograft nephropathy in previous animal studies. Therefore, the aim of this study was to investigate the effect of stabilization of hypoxia-inducible transcription factors with a prolyl-hydroxylase domain (PHD) inhibitor on transplant arteriosclerosis in an experimental aortic allograft model.MHC-class I mismatched C.B10-H2(b)/LilMcdJ donor thoracic aortas were heterotopically transplanted into the abdominal aorta of BALB/c mice. Donor animals received a single dose of the PHD inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) (40 mg/kg) or vehicle i.p. 4 h before transplantation. Intragraft HIF accumulation after ICA treatment was detected by immunohistochemistry before and after cold ischaemia (n = 5). Grafts were harvested 30 days after transplantation and analysed by histology (n = 7) and immunofluorescence (n = 7). In addition, intragraft mRNA expression for cytokines, adhesion molecules and growth factors was determined on Day 14 (n = 7).Donor preconditioning with ICA resulted in HIF accumulation in the aorta and induction of the HIF target genes vascular endothelial growth factor and transforming growth factor-beta. Vascular lesions were present in both experimental groups. However, there was significantly reduced intimal proliferation in preconditioned grafts when compared with vehicle controls [intimal proliferation 31.3 ± 8% (ICA) vs 55.3 ± 20% (control), P < 0.01]. In addition, experimental groups revealed a down-regulation of E-selectin (-57%) and MCP1 (-33%) expression after ICA pretreatment compared with controls, going along with decreased T-cell [1.4% CD4+ T-cell infiltration vs 8.4% (control) and 4.9% CD8+ T-cell infiltration vs 10.7% (control)], dendritic cell (0.6% dendritic cells infiltration vs 1.9% infiltration(control)] and macrophage infiltration [4.8% macrophages (ICA) vs 10.9% (control)] within vascular grafts.These data of an animal transplant model show that the pharmaceutical activation of HIF with endogenous up-regulation of protective target genes leads to adaptation of the graft to low oxygen-saturation and hereby attenuates the development of transplant arteriosclerosis and allograft injury. Pharmaceutical inhibition of PHDs appears to be a very attractive strategy for organ preservation that deserves further clinical evaluation.
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Prolyl hydroxylase inhibitors-new kids in the blood - Grampp, Steffen; Schödel, Johannes (Die Nephrologie, 2023)
CRIS-Team WoS Importer:2023-03-17

Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1 - Pasutto, Francesca; Zenkel, Matthias; Hoja, Ursula; Berner, Daniel; Uebe, Steffen; Ferrazzi, Fulvia; Schoedel, Johannes; Liravi, Panah; Ozaki, Mineo; Paoli, Daniela; Frezzotti, Paolo; Mizoguchi, Takanori; et al. (Nature Communications, 2017)
Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXR? (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression.
EVALuna2:9367

Psychological processing of a kidney transplantation, perceived quality of life, and immunosuppressant medication adherence - Scheel, Jennifer Felicia; Schieber, Katharina; Reber, Sandra Therese; Jank, Sabine; Eckardt, Kai-Uwe; Grundmann, Franziska; Vitinius, Frank; De Zwaan, Martina; Bertram, Anna; Erim, Yesim (Patient Preference and Adherence, 2019)
Introduction: Though psychosocial well-being and quality of life generally improve after transplantation, a relevant proportion of patients suffers from psychosocial problems. Further analysis of the psychological coping after kidney transplantation is needed to identify patients at risk. The aim of this study was to examine the psychological response after kidney transplantation and its associations with health-related quality of life and immunosuppressant medication adherence.
CRIS-Team WoS Importer:2019-06-04

Psychosocial Variables Associated with Immunosuppressive Medication Non-Adherence after Renal Transplantation. - Scheel, Jennifer Felicia; Schieber, Katharina; Reber, Sandra; Stoessel, Lisa; Waldmann, Elisabeth; Jank, Sabine; Eckardt, Kai-Uwe; Grundmann, Franziska; Vitinius, Frank; de Zwaan, Martina; Bertram, Anna; Erim, Yesim (Frontiers in Psychiatry, 2018)

Qualitätsverbessernde Maßnahmen in der Versorgung von kritisch kranken Intensivpatienten mit Nierenersatztherapie bei akuter Nierenschädigung - Kindgen-Milles, Detlef; Heering, Peter; Meersch-Dini, Melanie; Schmitz, Michael; Oppert, Michael; John, Stefan; Joerres, Achim; Zarbock, Alexander; Willam, Carsten (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2020)
Renal replacement therapy is after mechanical ventilation one of the most important and frequently used organ replacement therapies in daily routine intensive care practice. In contrast to mechanical ventilation, quality standards for renal replacement therapy are less well known and defined. In this position paper of the German Interdisciplinary Association for Intensive Care and Emergency Medicine, we describe quality standards of renal replacement procedures in order to improve therapy of patients with severe acute kidney injury.
CRIS-Team Scopus Importer:2020-10-16
Keywords: Acute renal failure; Dialysis; Hemofiltration; Quality standards; Renal replacement therapy

Quality Of Life And Emotional Impact Of A Fixed Dose Combination Of Antihypertensive Drugs In Patients With Uncontrolled Hypertension - Schmieder, Roland; Fronk, Eva-Maria; Alexandre, A. F.; Bramlage, Peter (Value in Health, 2015)
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Quality of life and emotional impact of a fixed-dose combination of antihypertensive drugs in patients with uncontrolled hypertension - Schmieder, Roland; Jumar, Agnes; Fronk, Eva-Maria; Alexandre, Ana-Filipa; Bramlage, Peter (Journal of Clinical Hypertension, 2017)
Often considered to be a symptomless condition, hypertension can be associated with a significant emotional burden. To analyze changes of health-related quality of life as well as the emotional burden questions regarding the impact of hypertension were incorporated into the noninterventional SeviTarget study. Comparisons were made between baseline and follow-up findings, and between patients with treatment target achievement and those without. A total of 5831 patients were recruited. At baseline, only 33.3% of patients described their current state of health as good or excellent, while at follow-up this value had risen to 75.8%. Responses regarding symptoms and limitations in activities and mental factors such as anxiety associated with treatment all improved during antihypertensive treatment. Changes to more optimistic responses were more likely for patients who achieved a target BP of <140/90 mm Hg. The study demonstrates that improvements in quality of life and the perceived emotional burden related to hypertension can be achieved with effective management of hypertension.
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Quantitative Assessment of Intraoperative Laser Fluorescence Angiography With Indocyanine Green Predicts Early Graft Function After Kidney Transplantation - Gerken, Andreas L. H.; Nowak, Kai; Meyer, Alexander; Weiss, Christel; Krueger, Bernd; Nawroth, Nina; Karampinis, Ioannis; Heller, Katharina M.; Apel, Hendrik; Reissfelder, Christoph; Schwenke, Kay; Keese, Michael; et al. (Annals of Surgery, 2022)
Objective: This study was designed to demonstrate the predictive ability of quantitative indocyanine green (ICG) fluorescence angiography for the short-term postoperative outcome, the occurrence of delayed graft function (DGF), and long-term graft survival. Summary Background Data: DGF is a relevant problem after kidney transplantation; sufficient microperfusion of the allograft is crucial for postoperative organ function. Fluorescence angiography with ICG can serve as an intraoperative quality control of microperfusion. Methods: This prospective diagnostic study, conducted in 2 German transplantation centers from November 2015 to October 2018, included 128 consecutive kidney transplantations. Intraoperative assessment of the allograft microperfusion was performed by near-infrared fluorescence angiography with ICG; a software was used for quantitative analysis. The associations between perfusion parameters (eg, ICG Ingress) and donor, recipient, peri-procedural, and postoperative characteristics were evaluated. Results: DGF occurred in 23 (24%) kidney recipients from deceased donors. ICG Ingress (P = 0.0027), donor age (P = 0.0452), recipient age (P = 0.0139), and recipient body mass index (P = 0.0017) were associated with DGF. ICG Ingress correlated significantly with recipient age (r = -0.27662, P = 0.0016), cold and warm ischemia time (r = -0.25204, P = 0.0082; r = -0.19778, P = 0.0283), operating time (r = -0.32208, P = 0.0002), eGFR on postoperative days 1 (r =+0.22674, P = 0.0104) and 7 (r = +0.33189, P = 0.0001). The cutoff value for ICG Ingress was 106.23 AU with sensitivity of 78.3% and specificity of 80.8% (P < 0.0001) for the prediction of DGF. Conclusion: Fluorescence angiography with ICG allows intraoperative quantitative assessment of microperfusion during kidney transplantation. The parameter ICG Ingress reflects recipient and procedure characteristics and is able to predict the incidence of DGF.
CRIS-Team WoS Importer:2022-07-22

Quantitative assessment of microperfusion by indocyanine green angiography in kidney transplantation resembles chronic morphological changes in kidney specimens - Rother, Ulrich; Amann, Kerstin Ute; Adler, Werner; Nawroth, Nina; Karampinis, Ioannis; Keese, Michael; Manap, Serhat; Regus, Susanne; Meyer, Alexander; Porubsky, Stefan; Hilgers, Karl Friedrich; Krämer, Bernhard K.; et al. (Microcirculation, 2019)
OBJECTIVE: Indocyanine green fluorescence angiography enables a quantitative real-time perfusion assessment in kidney transplantation. The results of intraoperative microperfusion of the kidney allograft were compared to the renal chronicity score in pre-transplantation kidney biopsy specimens. The intrarenal resistance index was calculated by duplex sonography as a method of reference. METHODS: Seventy-seven patients with end stage renal disease undergoing kidney transplantation were prospectively included in two centers. Correlation analysis of chronic changes in kidney biopsy specimens and the ingress of ICG fluorescence signal were investigated. RESULTS: The results yielded a significantly negative correlation for the renal chronicity (r= -0.294, p=0.017) as well as the intestinal fibrosis and tubular atrophy score (r=-0.328, p=0.007). There was a significant inverse relationship between the ingress and the mean RI values of the upper pole of the kidney allograft. CONCLUSION: In summary, fluorescence angiography reflects preexisting morphological changes of the renal cortex. ICG angiography may serve as an alternative method for the assessment of microperfusion of the kidney allograft. This article is protected by copyright. All rights reserved.
EVALuna2:35427

Quantitative assessment of muscle injury by (23)Na magnetic resonance imaging - Dahlmann, Anke; Kopp, Christoph; Linz, Peter; Seuß, Hannes; Eckardt, Kai-Uwe; Luft, Friedrich C.; Titze, Jens; Uder, Michael; Hammon, Matthias; Cavallaro, Alexander Josef (SpringerPlus, 2016)
(23)Na magnetic resonance imaging ((23)Na-MRI) is able to measure Na(+) in vivo in humans and allows quantification of tissue sodium distribution. We now tested the utility of (23)Na-MRI technique in detecting and assessing sports-related acute muscular injury.We assessed tissue Na(+) of both lower legs with a 3T MRI scanner using a customized (23)Na knee coil. The affected left calf muscle in an injured volleyball player showed a hyperintense Na(+) signal. Follow-up measurements revealed persistently increased muscle Na(+) content despite complete clinical recovery.Our findings suggest that (23)Na-MRI could have utility in detecting subtle muscular injury and might indicate when complete healing has occurred. Furthermore, (23)Na-MRI suggests the presence of substantial injury-related muscle electrolyte shifts that warrant more detailed investigation.
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Race and ethnicity influences on cardiovascular and renal events in patients with diabetes mellitus - Lewis, Eldrin F.; Claggett, Brian; Parfrey, Patrick S.; Burdmann, Emmanuel A.; Mcmurray, John J. V.; Solomon, Scott D.; Levey, Andrew S.; Ivanovich, Peter; Eckardt, Kai-Uwe; Kewalramani, Reshma; Toto, Robert; Pfeffer, Marc A. (American Heart Journal, 2015)
The incidence of end-stage renal disease (ESRD) has been consistently shown to be higher among blacks and Hispanics compared to whites with unmeasured risk factors and access to care as suggested explanations. In a high-risk cohort with frequent protocol-directed follow-up, we evaluated the influence of race on cardiovascular (CV) outcomes and incidence of ESRD.TREAT was a randomized, double-blind, placebo-controlled study. This secondary analysis focused on role of race on outcomes. TREAT enrolled 4,038 patients with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate 20-60 mL/min per 1.73 m(2)), and anemia (hemoglobin level <=11 g/dL) treated with either darbepoetin alfa or placebo. We compared self-described black and Hispanic patients to white patients with regard to baseline characteristics and outcomes, including mortality, CV outcomes (myocardial infarction, stroke, heart failure, resuscitated sudden death, and coronary revascularization), and incident ESRD. Multivariate adjusted Cox models were developed for these outcomes.Black and Hispanic patients were younger, more likely women, had less prior CV disease, and higher blood pressure. During a mean follow-up of 2.4 years with comparable access to care, blacks and Hispanics had a greater risk of ESRD but a significant lower risk of myocardial infarction and coronary revascularization than whites. After adjusting for confounders, blacks remained at significantly greater risk of ESRD than whites (hazard ratio 1.53, 95% CI 1.26-1.85, P < .001), whereas this ESRD risk did not persist among Hispanics.Despite similar access to care and lower CV event rates, the risk of ESRD was higher among blacks and Hispanics than whites. For blacks, but not Hispanics, this increase was independent of known attributable risk factors.
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RADIANCE-HTN SOLO: A MULTICENTER, RANDOMIZED, SHAM-CONTROLLED STUDY OF RENAL DENERVATION IN PATIENTS WITH UNCONTROLLED HYPERTENSION IN THE ABSENCE OF ANTIHYPERTENSIVE MEDICATIONS - Azizi, M.; Schmieder, Roland; Mahfoud, F.; Weber, M.; Daemen, J.; Davies, J.; Basile, J.; Kirtane, A.; Wang, Y.; Mauri, L. (2018)
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Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism - Cheng, Yurong; Schlosser, Pascal; Hertel, Johannes; Sekula, Peggy; Oefner, Peter J.; Spiekerkoetter, Ute; Mielke, Johanna; Freitag, Daniel F.; Schmidts, Miriam; Oefner, Peter J.; Kronenberg, Florian; Eckardt, Kai-Uwe; et al. (Nature Communications, 2021)
Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e−7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.
CRIS-Team Scopus Importer:2021-02-26

Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design - Böhm, Michael; Townsend, Raymond R.; Kario, Kazuomi; Kandzari, David; Mahfoud, Felix; Weber, Michael A.; Schmieder, Roland; Tsioufis, Konstantinos; Hickey, Graeme L.; Fahy, Martin; DeBruin, Vanessa; Brar, Sandeep; et al. (Clinical Research in Cardiology, 2020)
Background: The SPYRAL HTN clinical trial program was initiated with two 80-patient pilot studies, SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, which provided biological proof of principle that renal denervation has a blood pressure-lowering effect versus sham controls for subjects with uncontrolled hypertension in the absence or presence of antihypertensive medications, respectively. Trial design: Two multicenter, prospective, randomized, sham-controlled trials have been designed to evaluate the safety and efficacy of catheter-based renal denervation for the reduction of blood pressure in subjects with hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) or presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications. The primary efficacy endpoint is baseline-adjusted change from baseline in 24-h ambulatory systolic blood pressure. The primary safety endpoint is incidence of major adverse events at 1 month after randomization (or 6 months in cases of new renal artery stenosis). Both trials utilize a Bayesian design to allow for prespecified interim analyses to take place, and thus, the final sample sizes are dependent on whether enrollment is stopped at the first or second interim analysis. SPYRAL HTN-OFF MED Pivotal will enroll up to 300 subjects and SPYRAL HTN-ON MED Expansion will enroll up to 221 subjects. A novel Bayesian power prior approach will leverage historical information from the pilot studies, with a degree of discounting determined by the level of agreement with data from the prospectively powered studies. Conclusions: The Bayesian paradigm represents a novel and promising approach in device-based hypertension trials. Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02439749 (SPYRAL HTN-OFF MED Pivotal) and NCT02439775 (SPYRAL HTN-ON MED Expansion).
CRIS-Team Scopus Importer:2020-02-18
Keywords: Blood pressure; Device-based statistics; Renal sympathetic nervous system; Sham; Trial design

Rationale, design, and baseline characteristics of ARTS-DN: a randomized study to assess the safety and efficacy of finerenone in patients with type 2 diabetes mellitus and a clinical diagnosis of diabetic nephropathy - Ruilope, Luis M.; Agarwal, Rajiv; Chan, Juliana C.; Cooper, Mark E.; Gansevoort, Ron T.; Haller, Hermann; Remuzzi, Giuseppe; Rossing, Peter; Schmieder, Roland; Nowack, Christina; Ferreira, Anna C.; Pieper, Alexander; et al. (American Journal of Nephrology, 2014)
Finerenone decreases albuminuria in patients having heart failure with reduced ejection fraction and mild-to-moderate (stage 2-3) chronic kidney disease. The MinerAlocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN; NCT01874431) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b study. ARTS-DN investigated whether the mineralocorticoid receptor antagonist finerenone reduces albuminuria without causing major alterations in serum potassium levels in patients with type 2 diabetes mellitus and a clinical diagnosis of DN who were receiving a renin-angiotensin-system (RAS) inhibitor.Patients were randomized to oral finerenone 1.25-20 mg or placebo once daily. The primary objectives were to assess the ratio of the urinary albumin-to-creatinine ratio at day 90 to that at baseline in patients receiving finerenone, and to compare it with that in the placebo group. Additional exploratory analyses included evaluating changes from baseline in serum potassium levels, efficacy and safety biomarkers, and health-related quality of life.Of 1,501 patients screened, 821 (the sample population) received at least one dose of finerenone/placebo. Baseline characteristics included: male, 77.8%; white, 84.2%; very high albuminuria (formerly macroalbuminuria), 38.4%; high albuminuria (formerly microalbuminuria), 60.3%; median (range) estimated glomerular filtration rate, 66.3 (24.5-130.7) ml/min/1.73 m(2); and systolic blood pressure (mean ± standard deviation), 138.1 ± 14.4 mm Hg. There was a history of cardiovascular disease in 39.6%, diabetic neuropathy in 20.0%, and diabetic retinopathy in 19.9% of patients.ARTS-DN is the first phase 2b trial of finerenone in combination with a RAS inhibitor in patients with type 2 diabetes mellitus and a clinical diagnosis of DN.
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Real-time cell analysis of human cancer cell lines after chemotherapy with functionalized magnetic nanoparticles - Dürr, Stephan; Lyer, Stefan; Mann, Johannes; Janko, Christina; Tietze, Rainer; Schreiber, Eveline; Herrmann, Martin; Alexiou, Christoph (Anticancer Research, 2012)
Background: Magnetic drug targeting is a new and innovative approach in cancer treatment. In order to avoid the adverse effects of chemotherapy, the therapeutic agent is linked to superparamagnetic nanoparticles which are injected into a tumour-supporting artery and is focused by an external magnetic field to the tumour region in order to provoke maximum local impact. Analysis of nanoparticles and chemotherapeutic substances in human cancer cell culture is necessary to provide respective information for in vivo applications. Materials and Methods: The effect of pure mitoxantrone and mitoxantrone bound to nanoparticles was tested on human cancer cell lines using real-time cell analysis (RTCA) and lactate dehydrogenase (LDH) assays. RTCA was performed by impedance measuring. The impedance is expressed as the cell index (CI), which is a parameter of cell viability. Results: RTCA showed that mitoxantrone when bound to nanoparticles was more toxic than the drug alone. The CI clearly decreased faster after adding the chemotherapeutic bound to nanoparticles than when adding the pure drug alone. However, in the first experiments, the particles themselves showed no toxicity at therapeutically relevant concentrations. These results were confirmed by LDH assays. Conclusion: The toxic effects of chemotherapeutic agents (e.g. mitoxantrone) on human cancer cell lines (e.g. MCF-7) can be enhanced if these drugs are bound to magnetic nanoparticles. These preliminary data show a dependency on the different application modes of RTCA. The results presented here are a first step for a better understanding of the effectiveness of magnetic drug targeting as a new and innovative cancer treatment.
CRIS-Team Scopus Importer:2022-06-27
Keywords: Cell culture; Magnetic drug targeting MCF-7 breast cancer cells; Magnetic nanoparticles; Real-time cell analysis

Reasons for antihypertensive medication nonadherence influence physician preferences for hypertension management - Schmieder, Roland; Kandzari, D. E.; Wang, T. -D.; Lee, Y. -H.; Haro, C.; Pathak, A. (EUROPEAN HEART JOURNAL, 2021)
CRIS-Team WoS Importer:2021-12-10

Recent development of hypertension and acute renal failure in a 59-year-old woman - Uebner, M.; Jacobi, Johannes; Schmidt, D.; Büttner-Herold, M.; Mackensen, Andreas; Spriewald, B. M. (Internist, 2017)
We report on a 59-year-old woman who presented with nausea, fatigue, arterial hypertension, and acute renal failure. Clinical examination, laboratory findings of blood and urine and abdominal sonography were inconclusive. Renal biopsy revealed infiltration by a diffuse large B-cell lymphoma. In fluorodeoxyglucose positron emission tomography/computed tomography tracer enrichment was demonstrated in both kidneys, skeletal system and retroperitoneal lymph nodes. Renal function improved already after the first cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). After chemotherapy, a complete remission, normalization of blood pressure and renal function were achieved.
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Receptor-independent modulation of TGF-β-induced pro-fibrotic pathways by relaxin-2 in human primary tubular epithelial cells - Grampp, Steffen; Goppelt-Strübe, Margarete (Cell and Tissue Research, 2018)
Renal tubular epithelial cells actively contribute to the development of renal fibrosis and may be targeted by anti-fibrotic drugs. Relaxin-2 (RLX2) applied as recombinant protein is suggested to be renoprotective. Therefore, we investigated whether human primary tubular epithelial cells (hPTEC) obtained from various donors were target cells for the anti-fibrotic actions of RLX2. Treatment of hPTEC with RLX2 reduced the TGF-β1-induced secretion of the pro-fibrotic factor CTGF (connective tissue growth factor) and inhibited fibronectin synthesis and secretion. Furthermore, metalloproteinase MMP2 secretion was increased, with no effect on MMP9. Considerable differences were observed between hPTEC obtained from different donors. Therefore, expression of the relaxin family peptide receptor RXFP1, the major mediator of renal RLX2 effects, was analyzed. A validated antibody detected a double band of 80–90 kDa in cellular homogenates by Western blotting. Expression of the detected protein was not altered by incubation with TGF-β1 and RLX2-induced modulation of CTGF expression did not correlate with the putative receptor expression. Therefore, relaxin family receptors RXFP1–4 were assessed by RNA-seq analysis. No evidence was found for mRNA expression of any of these receptors in several hPTEC preparations. Lack of RXFP1 mRNA was confirmed by qPCR using mRNA obtained from THP-1 cells as positive control. Our data thus provide evidence for primary renal human tubular epithelial cells as targets for the anti-fibrotic actions of RLX2. However, anti-fibrotic effects were observed at micromolar concentrations of RLX2 and shown to be independent of RXFP1 expression.
Created from Fastlane, Scopus look-up
Keywords: CTGF; Fibronectin; Human primary renal epithelial cells; MMP; Relaxin-2; RXFP1; Transforming growth factor beta

Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice - Gansevoort, Ron T.; Arici, Mustafa; Benzing, Thomas; Birn, Henrik; Capasso, Giovambattista; Covic, Adrian; Devuyst, Olivier; Drechsler, Christiane; Eckardt, Kai-Uwe; Emma, Francesco; Knebelmann, Bertrand; Le Meur, Yannick; et al. (Nephrology Dialysis Transplantation, 2016)
Recently, the European Medicines Agency approved the use of the vasopressin V2 receptor antagonist tolvaptan to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adult patients with chronic kidney disease stages 1-3 at initiation of treatment with evidence of rapidly progressing disease. In this paper, on behalf of the ERA-EDTA Working Groups of Inherited Kidney Disorders and European Renal Best Practice, we aim to provide guidance for making the decision as to which ADPKD patients to treat with tolvaptan. The present position statement includes a series of recommendations resulting in a hierarchical decision algorithm that encompasses a sequence of risk-factor assessments in a descending order of reliability. By examining the best-validated markers first, we aim to identify ADPKD patients who have documented rapid disease progression or are likely to have rapid disease progression. We believe that this procedure offers the best opportunity to select patients who are most likely to benefit from tolvaptan, thus improving the benefit-to-risk ratio and cost-effectiveness of this treatment. It is important to emphasize that the decision to initiate treatment requires the consideration of many factors besides eligibility, such as contraindications, potential adverse events, as well as patient motivation and lifestyle factors, and requires shared decision-making with the patient.
EVALuna2:3848

Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension - Ewen, Sebastian; Ukena, Christian; Linz, Dominik; Kindermann, Ingrid; Cremers, Bodo; Laufs, Ulrich; Wagenpfeil, Stefan; Schmieder, Roland; Boehm, Michael; Mahfoud, Felix (Hypertension, 2015)
Renal denervation can reduce blood pressure in certain patients with resistant hypertension. The effect in patients with isolated systolic hypertension (ISH, >=140/<90 mm Hg) is unknown. This study investigated the effects of renal denervation in 126 patients divided into 63 patients with ISH and 63 patients with combined hypertension (CH, >=140/>=90 mm Hg) defined as baseline office systolic blood pressure (SBP) >=140 mm Hg despite treatment with >=3 antihypertensive agents. Renal denervation significantly reduced office SBP and diastolic blood pressure (DBP) at 3, 6, and 12 months by 17/18/17 and 5/4/4 mm Hg in ISH and by 28/27/30 and 13/16/18 mm Hg in CH, respectively. The reduction in SBP and DBP in ISH was lower compared with patients with CH at all observed time points (P<0.05 for SBP/DBP intergroup comparison). The nonresponder rate (change in office SBP <10 mm Hg) after 6 months was 37% in ISH and 21% in CH (P<0.001). Mean 24-hour ambulatory SBP and DBP after 3, 6, and 12 months were significantly reduced by 10/13/15 and 6/6/9 mm Hg in CH, respectively. In patients with ISH the reduction in systolic ambulatory blood pressure was 4/8/7 mm Hg (P=0.032/P<0.001/P=0.009) and 3/4/2 mm Hg (P=0.08/P<0.001/P=0.130) in diastolic ambulatory blood pressure after 3, 6, and 12 months, respectively. The ambulatory blood pressure reduction was significantly lower after 3 and 12 months in SBP and after 12 months in ambulatory DBP, respectively. In conclusion, renal denervation reduces office and ambulatory blood pressure in patients with ISH. However, this reduction is less pronounced compared with patients with CH.
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Reduced tissue sodium content is related to improvement of vascular function in patients with chronic heart failure treated with the SGLT2 inhibitor empagliflozin - Kolwelter, Julie; Kannenkeril, Dennis; Linz, Peter; Jung, Susanne; Nagel, Armin Michael; Bosch, Agnes; Ott, Christian; Bramlage, P.; Uder, Michael; Achenbach, Stephan; Schmieder, Roland (EUROPEAN HEART JOURNAL, 2021)
CRIS-Team WoS Importer:2021-12-10

Reduction in blood pressure following renal denervation for patients with differing baseline cardiovascular risk - Mahfoud, F.; Mancia, G.; Schmieder, Roland; Narkiewicz, K.; Ruilope, L.; Schlaich, M.; Williams, B.; Fahy, M.; Bohm, M. (EUROPEAN HEART JOURNAL, 2019)
CRIS-Team WoS Importer:2020-02-04

Reduction of Clinical Events in High-Risk Hypertension Patients Treated With Renal Denervation: A Modeled Estimate From 36-Month Global SYMPLICTY Registry Data - Schlaich, Markus; Pietzsch, Jan Benjamin; Mahfoud, Felix; Wiliams, Bryan; Mancia, Giuseppe; Narkiewicz, Krzystzof; Ruilope, Luis; Hettrick, Doug; Bohm, Michael; Schmieder, Roland (JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2022)
CRIS-Team WoS Importer:2022-05-13

Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model - Heim, Christian; Motsch, Benjamin; Jalilova, Sabina; Bernhardt, Wanja M.; Ramsperger-Gleixner, Martina; Burzlaff, Nicolai; Weyand, Michael; Eckardt, Kai-Uwe; Ensminger, Stephan (Transplant Immunology, 2016)
Obliterative bronchiolitis (OB) is the major limiting factor for long-term survival after lung transplantation. As previously shown, donor treatment with a PHD-inhibitor activating hypoxia-inducible transcription factors (HIFs) prevents graft injury both in an allogenic kidney and aortic allograft transplant model. The aim of this study was to investigate the effect of HIF activation with a PHD-inhibitor on the development of OB.Fully MHC-mismatched C57BL/6 (H-2(b)) donor tracheas were orthotopically transplanted into CBA/J (H-2(k)) recipients. Donor animals received a single dose of PHD-inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) (40mg/kg i.p.) or vehicle control 4h before transplantation. Transplanted tracheas were harvested 14 or 30days after transplantation and were analyzed by histology, by immunofluorescence and by rtPCR for mRNA expression.Donor pre-conditioning with ICA resulted in HIF accumulation and induction of HIF target genes: HO-1, VEGF, MIF, TGF?, and EpoR, which persisted during different times of ischemia. Grafts of vehicle treated controls showed substantially more luminal obliteration on postoperative day 30 in contrast to groups pre-treated with ICA [luminal obliteration 29.2±5% (ICA) vs. 36.7±8% (control), p<0.01]. We found significantly lower expression of TNF?, PDGFß, MCP-1, E-selectin, and ICAM-1 14days after ICA premedication. In addition ICA pre-treated groups revealed decreased T-cell and macrophage infiltration in tracheal grafts on days 30 after transplantation (p<0.05).Pre-treatment with ICA effectively reduced obliterative bronchiolitis. Our data suggest that activation of hypoxia-inducible transcription factors (HIFs) and thereby adaptation to low oxygen prevents the development of OB and allograft injury. Pharmaceutical inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves further clinical evaluation.
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Reduction of Tissue Na+ Accumulation After Renal Transplantation - Dahlmann, Anke; Linz, Peter; Zucker, Isabelle; Haag, Viktor; Jantsch, Jonathan; Dienemann, Thomas; Nagel, Armin Michael; Neubert, Patrick; Rosenhauer, Daniela; Rauh, Manfred; Horn, Stephan; Müller, Dominik N.; et al. (Kidney International Reports, 2021)
Introduction: Chronic kidney disease (CKD) engenders salt-sensitive hypertension. Whether or not tissue Nathorn accumulation is increased in CKD patients remains uncertain. How tissue Nathorn is affected after renal transplantation has not been assessed.
CRIS-Team WoS Importer:2021-10-01

Reduction of tissue sodium content by SGLT-2-inhibition with dapagliflozin - Karg, M. V.; Ott, Christian; Linz, Peter; Jumar, A.; Kannenkeril, D.; Titze, J.; Hammon, Matthias; Uder, Michael; Schmieder, Roland (2017)
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Reference values of retinal microcirculation parameters derived from a population random sample - Cífková, Renata; Harazny, Joanna M.; Bruthans, Jan; Wohlfahrt, Peter; Krajčoviechová, Alena; Lánská, Věra; Gelžinský, Július; Mateřánková, Markéta; Mareš, Štěpán; Filipovský, Jan; Mayer, Otto; Schmieder, Roland (Microvascular Research, 2021)
Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Our objective has been to establish reference values for major functional and structural parameters of retinal microcirculation in a randomly selected urban population sample. A total of 398 randomly selected individuals from an urban population aged 25 to 65 years, resident in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry (SLDF), with data evaluable in 343 patients. Of this number, complete data were available for 256 individuals free from manifest cardiovascular disease, diabetes and drug treatment for hypertension and/or dyslipidemia, constituting the reference value population. Juxtapapillary retinal capillary blood flow has increased significantly with age whereas vessel and luminal diameters have decreased. No sex differences in retinal microcirculation parameters have been found. Therefore, reference values for retinal microcirculation parameters have been established by age groups. Unattended automated office systolic BP, after adjusting for age, correlated significantly with wall-to-lumen ratio (WLR) and wall thickness (WT). Moreover, after adjusting for age and mean BP, a positive relationship has been found between carotid femoral pulse wave velocity and WT, WLR and wall cross-sectional area, indicating the interaction between micro- and macro-vasculature. In conclusion, our study is the first to provide reference values of retinal microcirculation parameters in a random Caucasian population sample. Our results have shown that, at the population level, the first structural changes in retinal microcirculation are those in lumen diameters. Of note, a close relationship between BP and vascular remodeling of retinal arterioles and between aortic stiffness and WLR of retinal arterioles suggests an interaction between micro- and macro-vasculature.
CRIS-Team Scopus Importer:2020-12-11
Keywords: Czech post-MONICA study; Juxtapapillary retinal capillary blood flow; Luminal diameter; Retinal vascular resistance; Scanning laser Doppler flowmetry; Vessel diameter; Wall cross-sectional area; Wall thickness; Wall-to-lumen ratio

REFERENCE VALUES OF RETINAL MICROCIRCULATION PARAMETERS IN A WHITE POPULATION RANDOM SAMPLE. CZECH POST-MONICA STUDY - Cifkova, R.; Harazny, J. M.; Bruthans, J.; Wohlfahrt, P.; Krajcoviechova, A.; Lanska, V.; Gelzinsky, J.; Materankova, M.; Mares, S.; Filipovsky, J.; Mayer, O.; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Regional citrate anticoagulation in renal replacement therapy in the intensive care station : Recommendations from the renal section of the DGIIN, ÖGIAIN and DIVI - Schmitz, M.; Joannidis, M.; Czock, D.; John, S.; Joerres, A.; Klein, S. J.; Oppert, M.; Schwenger, V.; Kielstein, J.; Zarbock, A.; Kindgen-Milles, D.; Willam, Carsten (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2018)
BACKGROUND: Regional citrate anticoagulation (RCA) in continuous renal replacement therapy can effectively anticoagulate dialysis circuits without having adverse effects on systemic heparin application. In particular, in continuous renal replacement therapy RCA is well established and represents a safe procedure with longer filter lifetimes and fewer bleeding complications. OBJECTIVES: To provide guidance on the indications, advantages and disadvantages, and use of RCA, current recommendations from the renal section of the DGIIN (Deutschen Gesellschaft für Internistische Intensivmedizin und Notfallmedizin), ÖGIAIN (Österreichischen Gesellschaft für Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin) are stated. MATERIALS AND METHODS: The recommendations in this paper are based on the current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, other published guidelines and protocols as well as the expert knowledge and clinical experience of the authors. RESULTS: The use of commercially available machines with coupled pumps and integrated safety features, effective personal training and standardized protocols for clinical usage (SOP) is particularly important for the safe clinical use of RCA in renal replacement therapy. Contrary to previous recommendations, even liver failure or shock with lactic acidosis may no longer be an absolute contra-indication for RCA. However, these particular patients have to be carefully monitored for signs of citrate accumulation.
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RELATION BETWEEN NOISE ANNOYANCE, STRESS HORMONES AND THE RENAL HEMODYNAMIC - Bosch, Agnes; Kannenkeril, Dennis; Rauh, Manfred; Ott, Christian; Striepe, Kristina; Jung, Susanne; Kolwelter, Julie; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Relationship Between Ubiquitin-Specific Peptidase 18 and Hypertension in Polish Adult Male Subjects: A Cross-Sectional Pilot Study - Dziamałek-Macioszczyk, Paulina; Harazny, Joanna M.; Kwella, Norbert; Wojtacha, Paweł; Jung, Susanne; Dienemann, Thomas; Schmieder, Roland; Stompór, Tomasz (Medical Science Monitor, 2020)
BACKGROUND Arterial hypertension (HT) is a leading cause of cardiac hypertrophy and heart failure. Ubiquitin-specific peptidase 18 (USP18) has been recently described as a factor that prevents myocardial dysfunction. The present study measured serum USP18 levels in normotensive (n=29), isolated diastolic hypertensive (n=20), and systolic-diastolic hypertensive (n=30) male participants and correlated these results with biochemical parameters that are included in routine assessments of patients with hypertension. MATERIAL AND METHODS Seventy-nine men, aged 24 to 82 years (mean=50.8±11.4 years), were included in the study. None of the participants had ever been treated for HT. Blood and urine parameters were assessed using routine techniques. Serum USP18 levels were measured by enzyme-linked immunosorbent assay. RESULTS The means and 95% confidence intervals (CIs) of USP18 levels in the HT(-), iDHT(+), and HT(+) groups were 69.3 (22.1-116.5) pg/ml, 90.1 (29.0-151.3) pg/ml, and 426.7 (163.1-690.3) pg/ml, respectively. In the HT(+) group, the mean serum USP18 level was 6.2-times higher than in the HT(-) group (p=0.014) and 4.7-times higher than in the iDHT(+) group (p=0.19). The partial correlation analysis that was adjusted for risk factors of arteriosclerosis indicated that USP18 levels were correlated with systolic blood pressure, pulse pressure, and heart rate. CONCLUSIONS This preliminary study found that serum USP18 levels were significantly higher in drug-naive male participants with arterial hypertension compared with normotensive controls. USP18 exerts cardiovascular-protective effects. Elevations of USP18 levels may indicate a counterregulatory process that is engaged during increases in pressure in the left ventricle.
CRIS-Team Scopus Importer:2020-06-23

Relative and Combined Prognostic Importance of On-Treatment Mean and Visit-to-Visit Blood Pressure Variability in ONTARGET and TRANSCEND Patients - Mancia, Giuseppe; Schumacher, Helmut; Boehm, Michael; Redon, Josep; Schmieder, Roland; Verdecchia, Paolo; Sleight, Peter; Teo, Koon; Yusuf, Salim (Hypertension, 2017)
In 28 790 patients recruited for the ONTARGET (Ongoing Treatment Alone and in Combination With Ramipril Global End Point Trials) and TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease) trials, we investigated the prognostic value for cardiovascular events (primary outcome) of (1)on-treatment visit-to-visit systolic blood pressure (SBP) variability versus mean SBP and (2) the 2 measures together. SBP variability was measured by the coefficient of variation (CV) of mean SBP to which it was unrelated. Confounders such as variable time and number of visits from which to calculate SBP-CV were avoided by using the same number of visits at identical times in all patients. The covariate-adjusted risk of the primary outcome (Cox models) increased as SBP-CV or mean on-treatment quintile SBP increased, but only for mean on-treatment SBP, the relationship achieved statistical significance: global test for trend, P=0.12 versus P<0.0001. SBP-CV showed a relationship with fatal events, but it was unrelated to the risk of myocardial infarction and stroke, which were predicted by on-treatment mean SBP. Prediction of the primary outcome improved by the combined use of both measures: global test for trend, P<0.0001; hazard ratio for combined fifth versus first quintile, 1.42 (1.20-1.68) compared with 1.13 (1.01-1.27) for SBP-CV and 1.24 (1.11-1.40) for mean SBP. Thus, in the present study, on-treatment mean SBP provided an overall better prediction of cardiovascular risk than visit-to-visit SBP-CV. Prediction improved by their combined use, which may thus offer a more precise estimate of the protective effect of treatment.URL: http//www.clinicaltrial.gov. Unique identifier: NCT153.101.
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Renal and intraglomerular haemodynamics in chronic heart failure with preserved and reduced ejection fraction - Jung, Susanne; Bosch, Agnes; Kolwelter, Julie; Striepe, Kristina; Kannenkeril, Dennis; Schuster, Tizia; Ott, Christian; Achenbach, Stephan; Schmieder, Roland (ESC Heart Failure, 2021)
Aims: Congestive heart failure (CHF) and impaired renal function are two often co-existing medical conditions and associated with adverse cardiovascular outcome. The aim of the current study was to assess renal and intraglomerular haemodynamics by constant infusion input clearance technique in subjects with CHF. Methods and results: The group of subjects with CHF consisted of 27 individuals with HFpEF and 27 individuals with HFrEF and were compared with 31 healthy controls. Subjects underwent renal clearance examination to measure glomerular filtration rate (GFR) and renal blood and plasma flow (RBF and RPF) and to calculate intraglomerular haemodynamics such as resistances of the afferent (RA) and efferent arterioles (RE) as well as intraglomerular pressure (Pglom). Measured GFR was lower in CHF subjects (68.1 ± 10.1 mL/min/1.73 m2) compared with controls (83.6 ± 13.4 mL/min/1.73 m2, Padj < 0.001) as was Pglom (Padj < 0.001). Total renal vascular resistance (RVR) was higher in CHF subjects (87.3 ± 20.1 vs. 73.8 ± 17.1 dyn × s/cm5, Padj < 0.001) mediated by an increased resistance at the afferent site (3201 ± 1084 vs. 2181 ± 796 dyn × s/cm5, Padj < 0.001). Comparing HFpEF and HFrEF subjects, RA was higher in HFrEF subjects. The severity of CHF assessed by NT-proBNP revealed an inverse association with renal perfusion (RPF r = −0.421, P = 0.002, RBF r = −0.414, P = 0.002) and a positive relation with RVR (r = 0.346, P = 0.012) at the post-glomerular site (RE: r = 0.318, P = 0.022). Conclusions: Renal function assessed by measured GFR is reduced and renal vascular resistance at the preglomerular, afferent site is increased in HFpEF and, to greater extent, in HFrEF. Our data indicate a close cardiorenal interaction in CHF.
CRIS-Team Scopus Importer:2021-02-26
Keywords: Cardiorenal interaction; Heart failure; Preserved ejection fraction; Reduced ejection fraction; Renal haemodynamics

Renal artery denervation for treatment of patients with self-reported obstructive sleep apnea and resistant hypertension: results from the Global SYMPLICITY Registry - Linz, Dominik; Mancia, Giuseppe; Mahfoud, Felix; Narkiewicz, Krzysztof; Ruilope, Luis; Schlaich, Markus; Kindermann, Ingrid; Schmieder, Roland; Ewen, Sebastian; Williams, Bryan; Boehm, Michael (Journal of Hypertension, 2017)
Sleep-disordered breathing, predominantly obstructive sleep apnea (OSA), is highly prevalent in patients with hypertension. OSA may underlie the progression to resistant hypertension, partly due to increased activation of the sympathetic nervous system. This analysis of patients with and without OSA evaluated the blood pressure (BP)-lowering effect of sympathetic modulation by renal denervation (RDN) in a real-world setting.The Global SYMPLICITY Registry (NCT01534299) is a prospective, open-label, multicenter registry conducted worldwide to evaluate the safety and effectiveness of RDN in patients with uncontrolled hypertension. Office and 24-h ambulatory BP were reported for all patients, based on the presence of OSA.Among 1868 patients, self-reported OSA occurred in 205 patients, who were more likely to be men (76 vs 57%, P < 0.001), have a higher BMI (34 ± 6 vs 30 ± 5 kg/m, P < 0.001), chronic kidney disease (30 vs 21%, P = 0.003), left ventricular hypertrophy (25 vs 15%, P < 0.001), and type 2 diabetes (50 vs 36%, P < 0.001). Among OSA patients, the baseline office SBP (166 ± 26 mmHg) was reduced by 14.0 ± 25.3 mmHg at 6 months (P < 0.001). Ambulatory 24-h SBP was reduced by 4.9 ± 18.0 mmHg (n = 115, P = 0.005) from 155 ± 19 mmHg at baseline. The 6-month change in SBP from baseline was not statistically different between OSA and non-OSA patients. BP reduction after RDN was also similar in OSA patients already treated with and not treated with continuous positive airway pressure.RDN resulted in significant BP reductions at 6 months in hypertensive patients with and without OSA, and regardless of continuous positive airway pressure usage in OSA patients.
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Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis - Mocker, Alexander; Hilgers, Karl Friedrich; Cordasic, Nada; Wachtveitl, Rainer; Menendez-Castro, Carlos; Wölfle, Joachim; Hartner, Andrea; Fahlbusch, Fabian (International Journal of Molecular Sciences, 2019)
Chemerin and its receptor, chemokine-like receptor 1 (CmklR1), are associated with chemotaxis, inflammation, and endothelial function, especially in metabolic syndrome, coronary heart disease, and hypertension. In humans, circulating chemerin levels and renal function show an inverse relation. So far, little is known about the potential role of chemerin in hypertensive nephropathy and renal inflammation. Therefore, we determined systemic and renal chemerin levels in 2-kidney-1-clip (2k1c) hypertensive and Thy1.1 nephritic rats, respectively, to explore the correlation between chemerin and markers of renal inflammation and fibrosis. Immunohistochemistry revealed a model-specific induction of chemerin expression at the corresponding site of renal damage (tubular vs. glomerular). In both models, renal expression of chemerin (RT-PCR, Western blot) was increased and correlated positively with markers of inflammation and fibrosis. In contrast, circulating chemerin levels remained unchanged. Taken together, these findings demonstrate that renal chemerin expression is associated with processes of inflammation and fibrosis-related to renal damage. However, its use as circulating biomarker of renal inflammation seems to be limited in our rat models.
CRIS-Team Scopus Importer:2019-12-24
Keywords: 2-kidney-1-clip; 2k1c; chemerin; CmklR1; renal fibrosis; renal inflammation; renal injury; renovascular hypertension; Thy1.1 nephritis

Renal Denervation: A Practical Guide for Health Professionals Managing Hypertension - Schmieder, Roland; Burnier, Michel; East, Cara; Tsioufis, Konstantinos; Delaney, Sean (Interventional Cardiology (London), 2023)
Growing evidence demonstrates the suitability of renal denervation in a broad population of patients; however, questions remain over its suitability and practical implementation. Given the rapidity of emerging data, this has been a challenging field for potential adopters to navigate. The purpose of this article is twofold: to provide navigation through emerging clinical data and evolving guidance; and to provide physicians with practical, evidence-based advice for identifying eligible patients and providing appropriate management in the pre- and postintervention settings. Although many of these recommendations are based on existing published guidance documents, we reflect equally on our own experiences of using this technology.
CRIS-Team Scopus Importer:2023-04-07
Keywords: antihypertensive; blood pressure control; cardiovascular risk; Hypertension; recommendations; renal denervation

Renal denervation-a valid treatment option despite SYMPLICITY HTN-3 - Schmieder, Roland (Nature Reviews Cardiology, 2014)
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Renal Denervation for Resistant Hypertension: Past, Present, and Future - Ott, Christian; Schmieder, Roland (Current Hypertension Reports, 2015)
Renal denervation (RDN) for treatment of resistant hypertension was introduced only 5 years ago. A clear pathophysiological role of renal sympathetic activity for the initiation and maintenance of hypertension and promising data showing a substantial and sustained blood pressure (BP) reduction after RDN has promoted the widespread use of the method at least in Europe. However, in a pivotal trial that included a sham-control group, no significant BP lowering effects was observed. Afterwards, it became clear that methodological issues and poor performance and execution of the intervention have hampered the results of Symplicity HTN-3 study, thereby limiting its validity profoundly. Now, in 2015, the renaissance of RDN has begun and new randomized prospective clinical trials have or will be started soon. In the meantime, it may be wise not to ignore all previous findings, as a rescue therapy for treatment resistant hypertension. A new science era emerged, with changes of the interventional approach and selection of patients potentially profiting most from RDN.
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Renal Denervation for Treating Hypertension: Current Scientific and Clinical Evidence - Weber, Michael A.; Mahfoud, Felix; Schmieder, Roland; Kandzari, David E.; Tsioufis, Konstantinos P.; Townsend, Raymond R.; Kario, Kazuomi; Böhm, Michael; Sharp, Andrew S.P.; Davies, Justin E.; Osborn, John W.; Fink, Greg D.; et al. (Jacc-Cardiovascular Interventions, 2019)
Initial studies of catheter-based renal denervation (RDN) for uncontrolled HTN using radiofrequency ablation in the main renal arteries showed that RDN was effective in lowering office blood pressure (BP). However, the first randomized sham-controlled trial, SYMPLICITY-HTN-3, did not show significantly lower office or 24-h ambulatory systolic BP compared with sham treatment. Subsequent studies in both animals and humans demonstrated the potential importance of more distal and branch renal artery radiofrequency ablation, and a second-generation multielectrode system became available. Two recent randomized sham-controlled trials in patients not taking antihypertensive drugs (SPYRAL HTN-OFF MED) or continuing to take drugs (SPYRAL HTN-ON MED) performed RDN with the second-generation radiofrequency ablation system using an ablation protocol that included treatment of the distal renal artery as well as the branch renal arteries. These studies showed that RDN significantly reduced office and 24-h ambulatory BP compared with sham treatment. Another recent randomized sham-controlled trial in patients not receiving medications showed that RDN with catheter-based ultrasound (RADIANCE-HTN SOLO) applied in just the main renal arteries significantly lowered daytime ambulatory and office BP compared with sham treatment. These trials have renewed clinical and scientific interest in defining the appropriate role of RDN in hypertension treatment. In addition, other important issues will need to be addressed in the future such as the development of tests to determine the extent of RDN at the time of the procedure and the potential of renal nerve fibers to regain their patency at some later stage following the ablation procedure.
CRIS-Team Scopus Importer:2019-06-21
Keywords: ambulatory blood pressure; hypertension; radiofrequency; renal denervation; ultrasound

Renal denervation-implications for chronic kidney disease - Veelken, Roland; Schmieder, Roland (Nature Reviews Nephrology, 2014)
Catheter-based renal denervation to treat patients with resistant hypertension and chronic kidney disease (CKD) has generated considerable interest. Data from the majority of, but not all, observational studies and randomized controlled trials suggest that the procedure does not impair renal function and can effectively reduce office and ambulatory blood pressure in patients with primary hypertension. The putative beneficial effects of renal denervation seem to result from the interruption of renal efferent and afferent nerves. In patients with resistant hypertension and CKD, interruption of afferent reflexes might lead to a reduction in global sympathetic tone. The subsequent sustained reduction in blood pressure is expected to slow the progression of renal disease. However, renal denervation might also improve glucose metabolism, increase insulin sensitivity and reduce renal inflammation, with renoprotective effects in patients with CKD. Additional large randomized controlled trials of renal denervation in hypertensive and normotensive patients with CKD are required to precisely define the clinical value of the procedure in this population.
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Renal denervation improves 24-hour central and peripheral blood pressures, arterial stiffness, and peripheral resistance - Ott, Christian; Franzen, Klaas F.; Graf, Tobias; Weil, Joachim; Schmieder, Roland; Reppel, Michael; Mortensen, Kai (Journal of Clinical Hypertension, 2018)
Ambulatory blood pressure (BP) and central BP are better predictors for overall cardiovascular risk and mortality than brachial BP. Renal denervation (RDN) has been shown to reduce office brachial and central BP as well as brachial ambulatory BP, but data on central ambulatory BP are limited. Patients (N = 94) with treatment resistant hypertension (TRH) who underwent RDN were included. Ambulatory BP, including central pressures, hemodynamics, and arterial stiffness were measured at baseline and 3, 6, 12 months after RDN by an oscillometric device (MobiloGraph™). At 3, 6, and 12-month follow-ups, brachial ambulatory BP was reduced (P for all < .001). Consistently, central ambulatory BP was reduced (P for all < .001). Ambulatory assessed averaged daytime pulse wave velocity improved after RDN (P < .05). Total vascular resistance decreased (P for all < .01). In patients with TRH, RDN improves brachial and central ambulatory BP, arterial stiffness, and total vascular resistance, indicating an improvement of cardiovascular outcome.
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Renal Denervation in High-Risk Patients With Hypertension - Mahfoud, Felix; Mancia, Giuseppe; Schmieder, Roland; Narkiewicz, Krzysztof; Ruilope, Luis; Schlaich, Markus; Whitbourn, Robert; Zirlik, Andreas; Zeller, Thomas; Stawowy, Philipp; Cohen, Sidney A.; Fahy, Martin; et al. (Journal of the American College of Cardiology, 2020)
Background: Renal denervation (RDN) is under investigation for treatment of uncontrolled hypertension and might represent an attractive treatment for patients with high cardiovascular (CV) risk. It is important to determine whether baseline CV risk affects the efficacy of RDN. Objectives: The purpose of this study was to assess blood pressure (BP) reduction and event rates after RDN in patients with various comorbidities, testing the hypothesis that RDN is effective and durable in these high-risk populations. Methods: BP reduction and adverse events over 3 years were evaluated for several high-risk subgroups in the GSR (Global proSpective registrY for syMPathetic renaL denervatIon in seleCted IndicatIons Through 3 Years Registry), an international registry of RDN in patients with uncontrolled hypertension (n = 2,652). Comparisons were made for patients age ≥65 years versus age <65 years, with versus without isolated systolic hypertension, with versus without atrial fibrillation, and with versus without diabetes mellitus. Baseline cardiovascular risk was estimated using the American Heart Association (AHA)/American College of Cardiology (ACC) atherosclerosis cardiovascular disease (ASCVD) risk score. Results: Reduction in 24-h systolic BP at 3 years was −8.9 ± 20.1 mm Hg for the overall cohort, and for high-risk subgroups, BP reduction was −10.4 ± 21.0 mm Hg for resistant hypertension, −8.7 ± 17.4 mm Hg in patients age ≥65 years, −10.2 ± 17.9 mm Hg in patients with diabetes, −8.6 ± 18.7 mm Hg in isolated systolic hypertension, −10.1 ± 20.3 mm Hg in chronic kidney disease, and −10.0 ± 19.1 mm Hg in atrial fibrillation (p < 0.0001 compared with baseline for all). BP reduction in patients with measurements at 6, 12, 24, and 36 months showed similar reductions in office and 24-h BP for patients with varying baseline ASCVD risk scores, which was sustained to 3 years. Adverse event rates at 3 years were higher for patients with higher baseline CV risk. Conclusions: BP reduction after RDN was similar for patients with varying high-risk comorbidities and across the range of ASCVD risk scores. The impact of baseline risk on clinical event reduction by RDN-induced BP changes could be evaluated in further studies. (Global proSpective registrY for syMPathetic renaL denervatIon in seleCted IndicatIons Through 3 Years Registry; NCT01534299)
CRIS-Team Scopus Importer:2020-06-09
Keywords: blood pressure; cardiovascular risk; device-based hypertension therapy; hypertension; renal denervation

Renal denervation in hypertensive patients not on blood pressure lowering drugs - De Jager, Rosa L.; Sanders, Margreet F.; Bots, Michiel L.; Lobo, Melvin D.; Ewen, Sebastian; Beeftink, Martine M. A.; Boehm, Michael; Daemen, Joost; Doerr, Oliver; Hering, Dagmara; Mahfoud, Felix; Nef, Holger; et al. (Clinical Research in Cardiology, 2016)
Studies on the blood pressure lowering effect of renal denervation (RDN) in resistant hypertensive patients have produced conflicting results. Change in medication usage during the studies may be responsible for this inconsistency. To eliminate the effect of medication usage on blood pressure we focused on unmedicated hypertensive patients who underwent RDN.Our study reports on a cohort of patients, who were not on blood pressure lowering drugs at baseline and during follow-up, from eight tertiary centers. Data of patients were used when they were treated with RDN and had a baseline office systolic blood pressure (SBP) >=140 mmHg and/or 24-h ambulatory SBP >=130 mmHg. Our primary outcome was defined as change in office and 24-h SBP at 12 months after RDN, compared to baseline. Fifty-three patients were included. There were three different reasons for not using blood pressure lowering drugs: (1) documented intolerance or allergic reaction (57 %); (2) temporary cessation of medication for study purposes (28 %); and (3) reluctance to take antihypertensive drugs (15 %). Mean change in 24-h SBP was -5.7 mmHg [95 % confidence interval (CI) -11.0 to -0.4; p = 0.04]. Mean change in office SBP was -13.1 mmHg (95 % CI -20.4 to -5.7; p = 0.001). No changes were observed in other variables, such as eGFR, body-mass-index and urinary sodium excretion.This explorative study in hypertensive patients, who are not on blood pressure lowering drugs, suggests that at least in some patients RDN lowers blood pressure.
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Renal denervation in moderate treatment-resistant hypertension - Ott, Christian; Mahfoud, Felix; Schmid, Axel; Ditting, Tilmann; Sobotka, Paul A.; Veelken, Roland; Spies, Aline; Ukena, Christian; Laufs, Ulrich; Uder, Michael; Boehm, Michael; Schmieder, Roland (Journal of the American College of Cardiology, 2013)
Objectives This study sought to investigate the effect of renal denervation (RDN) in patients with treatment-resistant hypertension according to the established definition (Joint National Committee VII and European Society of Hypertension/European Society of Cardiology guidelines), that is, office blood pressure (BP) ≥140/90 mm Hg (with at least three antihypertensive drugs, including a diuretic, in adequate doses) and confirmed by 24-h ambulatory BP monitoring (ABPM). Background RDN emerged as an innovative interventional antihypertensive therapy. However, so far, only patients with severe hypertension (systolic BP ≥160 mm Hg or ≥150 mm Hg for patients with type 2 diabetes) have been investigated. Methods In this study, there were 54 patients with moderate treatment-resistant hypertension (office BP ≥140/90 mm Hg and <160/100 mm Hg and diagnosis confirmed by 24-h ABPM of ≥130/80 mm Hg) who underwent catheter-based RDN using the Symplicity catheter (Medtronic Inc., Mountain View, California). Results Patients were treated with 5.1 ± 1.4 antihypertensive drugs on average. Office BP was significantly reduced by 13/7 mm Hg 6 months after RDN (systolic: 151 ± 6 mm Hg vs. 138 ± 21 mm Hg, p < 0.001; diastolic: 83 ± 11 mm Hg vs. 75 ± 11 mm Hg, p < 0.001). In patients (n = 36) who underwent ABPM 6 months after treatment, there was a reduction in average 24-h ABPM by 14/7 mm Hg (systolic: 150 ± 16 mm Hg vs. 136 ± 16 mm Hg, p < 0.001; diastolic: 83 ± 10 mm Hg vs. 76 ± 10 mm Hg, p < 0.001). In 51% of patients, office BP was controlled below 140/90 mm Hg after RDN. In addition, heart rate decreased from 67 ± 11 to 63 ± 10 beats/min (p = 0.006). Conclusions Our data indicate that RDN may reduce office and 24-h ambulatory BP substantially in patients with moderate treatment-resistant hypertension. (Renal Denervation in Treatment Resistant Hypertension; NCT01687725). © 2013 by the American College of Cardiology Foundation.
CRIS-Team Scopus Importer:2023-03-08
Keywords: 24-h ambulatory blood pressure; renal denervation; treatment-resistant hypertension

Renal denervation in patients with chronic kidney disease: current evidence and future perspectives - Schmieder, Roland (Nephrology Dialysis Transplantation, 2022)
Supported by several high-quality randomized controlled trials and registry analyses, catheter-based renal denervation is becoming an important adjunctive treatment modality for the safe and efficacious treatment of hypertension besides lifestyle modifications and antihypertensive medication. Renal denervation is of particular interest to nephrologists as the intervention may provide additional benefits to hypertensive people with chronic kidney disease (CKD), a condition typically characterized by sympathetic hyperactivity. A growing body of clinical evidence supports the safety and efficacy of renal denervation in this difficult-to-control population. In addition, preclinical and clinical research works indicate potential nephroprotective effects in CKD patients. The current review examines recent research on renal denervation with a focus on renal disease and assesses the latest findings and their implications from a nephrologist's perspective.
CRIS-Team WoS Importer:2022-07-29

Renal denervation in patients with versus without chronic kidney disease: results from the Global SYMPLICITY Registry with follow-up data of 3 years - Ott, Christian; Mahfoud, Felix; Mancia, Giuseppe; Narkiewicz, Krzysztof; Ruilope, Luis M.; Fahy, Martin; Schlaich, Markus P.; Böhm, Michael; Schmieder, Roland (Nephrology Dialysis Transplantation, 2022)
BACKGROUND: Activity of the sympathetic nervous system is increased in patients with hypertension and chronic kidney disease (CKD). Here we compare short- and long-term blood pressure (BP)-lowering effects of renal denervation (RDN) between hypertensive patients with or without CKD in the Global SYMPLICITY Registry. METHODS: Office and 24-h ambulatory BP (ABP) were assessed at prespecified time points after RDN. The presence of CKD was defined according to the estimated glomerular filtration rate (eGFR) and enrolled patients were stratified based on the presence (n = 475, eGFR <60 mL/min/1.73 m2) or absence (n = 1505, eGFR ≥60mL/min/1.73 m2) of CKD. RESULTS: Patients with CKD were older (P < 0.001) and were prescribed more antihypertensive medications (P < 0.001). eGFR decline per year was not significantly different between groups after the first year. Office and 24-h ABP were significantly reduced from baseline at all time points after RDN in both groups (all P < 0.001). After adjusting for baseline data, patients without CKD had a greater reduction in office systolic BP (-17.3 ± 28.3 versus -11.7 ± 29.9 mmHg; P = 0.009) but not diastolic BP at 36 months compared with those with CKD. Similar BP and eGFR results were found when the analysis was limited to patients with both baseline and 36-month BP data available. There was no difference in the safety profile of the RDN procedure between groups. CONCLUSIONS: After adjusting for baseline data, 24-h systolic and diastolic ABP reduction were similar in patients with and without CKD after RDN, whereas office systolic but not diastolic BP was reduced less in patients with CKD. We conclude that RDN is an effective antihypertensive treatment option in CKD patients.
CRIS-Team Scopus Importer:2022-02-11
Keywords: blood pressure; hypertension; renal function

Renal denervation in refractory hypertension: joint statement of the German hypertension league DHL eV and the German societies of cardiology, angiology, nephrology and radiology - Vonend, Oliver; Boehm, Michael; Eckert, Siegfried; Hausberg, Martin; Rittger, Harald; Rump, Lars-Christian; Schmieder, Roland; Schulte, Karl-Ludwig; Schunkert, Heribert; Uder, Michael; Veelken, Roland; Vorwerk, Dierk; et al. (Deutsche Medizinische Wochenschrift, 2015)
Arterial hypertension is a major risk factor for cardiovascular mortality and remains insufficiently controlled in Germany. The sham controlled Symplicity HTN-3 trial did meet its primary safety endpoint but failed to meet its primary efficacy endpoint. Renal denervation can not replace established, well-proven therapies. It can only be used in selected truly resistant hypertensive patients as an additive approach and should be performed by specialized centers only. Randomized controlled trials are needed to further evaluate renal denervation.
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Renal denervation in the management of hypertension in adults. A clinical consensus statement of the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). - Barbato, Emanuele; Azizi, Michel; Schmieder, Roland; Lauder, Lucas; Böhm, Michael; Brouwers, Sofie; Bruno, Rosa Maria; Dudek, Dariusz; Kahan, Thomas; Kandzari, David E.; Lüscher, Thomas F.; Parati, Gianfranco; et al. (EuroIntervention, 2023)
Since the publication of the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines for the Management of Arterial Hypertension, several high-quality studies, including randomised, sham-controlled trials on catheter-based renal denervation (RDN) were published, confirming both the blood pressure (BP)-lowering efficacy and safety of radiofrequency and ultrasound RDN in a broad range of patients with hypertension, including resistant hypertension. A clinical consensus document by the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on RDN in the management of hypertension was considered necessary to inform clinical practice. This expert group proposes that RDN is an adjunct treatment option in uncontrolled resistant hypertension, confirmed by ambulatory BP measurements, despite best efforts at lifestyle and pharmacological interventions. RDN may also be used in patients who are unable to tolerate antihypertensive medications in the long term. A shared decision-making process is a key feature and preferably includes a patient who is well informed on the benefits and limitations of the procedure. The decision-making process should take (i) the patient's global cardiovascular (CV) risk and/or (ii) the presence of hypertension-mediated organ damage or CV complications into account. Multidisciplinary hypertension teams involving hypertension experts and interventionalists evaluate the indication and facilitate the RDN procedure. Interventionalists require expertise in renal interventions and specific training in RDN procedures. Centres performing these procedures require the skills and resources to deal with potential complications. Future research is needed to address open questions and investigate the impact of BP-lowering with RDN on clinical outcomes and potential clinical indications beyond hypertension.
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Renal denervation in the management of hypertension in adults. A clinical consensus statement of the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). - Barbato, Emanuele; Azizi, Michel; Schmieder, Roland; Lauder, Lucas; Boehm, Michael; Brouwers, Sofie; Bruno, Rosa Maria; Dudek, Dariusz; Kahan, Thomas; Kandzari, David E.; Luscher, Thomas F.; Parati, Gianfranco; et al. (European Heart Journal, 2023)
Since the publication of the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines for the Management of Arterial Hypertension, several high-quality studies, including randomised, sham-controlled trials on catheter-based renal denervation (RDN) were published, confirming both the blood pressure (BP)-lowering efficacy and safety of radiofrequency and ultrasound RDN in a broad range of patients with hypertension, including resistant hypertension. A clinical consensus document by the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on RDN in the management of hypertension was considered necessary to inform clinical practice. This expert group proposes that RDN is an adjunct treatment option in uncontrolled resistant hypertension, confirmed by ambulatory BP measurements, despite best efforts at lifestyle and pharmacological interventions. RDN may also be used in patients who are unable to tolerate antihypertensive medications in the long term. A shared decision-making process is a key feature and preferably includes a patient who is well informed on the benefits and limitations of the procedure. The decision-making process should take (i) the patient's global cardiovascular (CV) risk and/or (ii) the presence of hypertension-mediated organ damage or CV complications into account. Multidisciplinary hypertension teams involving hypertension experts and interventionalists evaluate the indication and facilitate the RDN procedure. Interventionalists require expertise in renal interventions and specific training in RDN procedures. Centres performing these procedures require the skills and resources to deal with potential complications. Future research is needed to address open questions and investigate the impact of BP-lowering with RDN on clinical outcomes and potential clinical indications beyond hypertension.
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Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension - Ott, Christian; Mahfoud, Felix; Schmid, Axel; Toennes, Stefan W.; Ewen, Sebastian; Ditting, Tilmann; Veelken, Roland; Ukena, Christian; Uder, Michael; Boehm, Michael; Schmieder, Roland (Journal of Hypertension, 2015)
Arterial hypertension and increased sympathetic activity are underlying pathogenetic mechanisms of the progressive loss of renal function in patients with chronic kidney disease (CKD). Meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor. We hypothesized that renal denervation (RDN) decreases the decline of renal function in patients with CKD stages 3 and 4 and treatment-resistant hypertension.We performed an observational study of 27 patients with CKD stages 3 and 4, office blood pressure (BP) >= 140/90 mmHg, while on at least three antihypertensive drug classes including diuretic, and diagnosis confirmed by 24-h ambulatory BP measurement >= 130/80 mmHg. All patients underwent catheter-based RDN using the Symplicity Flex RDN System (Medtronic Inc., Santa Rosa, California, USA). Renal function was evaluated for up to 3 years prior and 1 year after RDN. The change in estimated glomerular filtration rate (eGFR) was calculated by regression slope individually for each patient before and after RDN. The study was registered at http://www.clinicaltrials.gov (ID: NCT01442883).Mean baseline BP was 156 ± 12/82 ± 13 mmHg, despite treatment with 6.2 ± 1.1 antihypertensive drugs. One year after RDN, office BP was reduced by 20 ± 20 (P < 0.001)/8 ± 14 mmHg (P = 0.005) and average 24-h ambulatory BP by 9 ± 14 (P = 0.009)/4 ± 7 mmHg (P = 0.019). Before RDN, eGFR declined by -4.8 ± 3.8 ml/min per 1.73 m per year, and after RDN eGFR improved by +1.5 ± 10 ml/min per 1.73 m at 12 months (P = 0.009).Our observational pilot study in patients with CKD stages 3 and 4 indicates that treatment of hypertension with RDN decreases BP and slows or even halts the decline of renal function.
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Renal denervation Really an alternative to reducing blood pressure? - Striepe, Kristina; Schiffer, Mario; Schmieder, Roland (Internist, 2022)
Since the current guidelines were published in 2018, a total of 5 sham-controlled high-quality studies evaluating renal denervation have been conducted and the results were published. These five studies clearly confirmed the efficacy and safety of renal denervation, which correspond to the knowledge of the Clinical Consensus Conference. Thus, an update of the guidelines for the treatment of arterial hypertension regarding the clinical significance of renal denervation is urgently necessary. For this reason, the position paper of the working group of the European Society of Hypertension on the current state of renal denervation was reviewed. An approval of this procedure can soon be expected. In Germany there is a diagnosis-related group (DRG) for the reimbursement of renal denervation, which was suspended due to the erroneous Symplicity 3 study. This DRG should be revived in practice by a structured process of the implementation of renal denervation. It will then be a joint task of treating physicians and specialists in certified centers to identify eligible patients. In the future, antihypertensive treatment will consist of three pillars: lifestyle measures, pharmacotherapy and interventional treatment. These three treatment options should not be regarded as competitive (which is better) but alternative (patient preference) and additive (the aim is blood pressure control). It is the task of the treating physician to provide the patient with the ideal treatment concept. Clearly, renal denervation will not replace antihypertensive pharmacotherapy; however, it can lead to a reduction of the drug burden and increase of patient adherence to medication. It represents an option of modern antihypertensive treatment and will also become increasingly more important in special patient groups.
CRIS-Team WoS Importer:2022-01-21

Renal Denervation Update From the International Sympathetic Nervous System Summit: JACC State-of-the-Art Review - Kiuchi, Márcio G.; Esler, Murray D.; Fink, Gregory D.; Osborn, John W.; Banek, Christopher T.; Böhm, Michael; Denton, Kate M.; DiBona, Gerald F.; Everett, Thomas H.; Grassi, Guido; Katholi, Richard E.; Knuepfer, Mark M.; et al. (Journal of the American College of Cardiology, 2019)
Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications.
CRIS-Team Scopus Importer:2019-06-18
Keywords: blood pressure; cardiovascular disease; hypertension; renal denervation; sympathetic nervous system

Renal denervation: where do we stand and what is the relevance to the nephrologist? - Schmieder, Roland (Nephrology Dialysis Transplantation, 2022)
Catheter-based renal denervation to reduce high blood pressure (BP) has received well-deserved attention after a recent series of sham-controlled trials reported significant antihypertensive efficacy and very favourable tolerability and safety of the intervention. This emerging treatment option is of high relevance to nephrologists. Patients with chronic kidney disease (CKD) are at elevated risk of cardiovascular adverse events and often present with hypertension, which is very difficult to control with medication. Renal denervation promises a new tool to reduce BP and to prevent loss of renal function in this population. The current review considers the role of the kidney and neurohormonal activation in the development of hypertension and the rationale for renal denervation. The current state of the evidence for the effectiveness and tolerability of the procedure is considered from the nephrologists' perspective, with a focus on the potential future role of renal denervation in the management of CKD patients with hypertension.
CRIS-Team WoS Importer:2022-04-08

Renal fibrosis is the common feature of autosomal dominant tubulointerstitial kidney diseases caused by mutations in mucin 1 or uromodulin - Ekici, Arif Bülent; Hackenbeck, Thomas; Moriniere, Vincent; Panness, Andrea; Büttner, Maike; Uebe, Steffen; Janka, Rolf Matthias; Wiesener, Antje; Hermann, Ingo; Grupp, Sina; Hornberger, Martin; Huber, Tobias B.; et al. (Kidney International, 2014)
For decades, ill-defined autosomal dominant renal diseases have been reported, which originate from tubular cells and lead to tubular atrophy and interstitial fibrosis. These diseases are clinically indistinguishable, but caused by mutations in at least four different genes: UMOD, HNF1B, REN, and, as recently described, MUC1. Affected family members show renal fibrosis in the biopsy and gradually declining renal function, with renal failure usually occurring between the third and sixth decade of life. Here we describe 10 families and define eligibility criteria to consider this type of inherited disease, as well as propose a practicable approach for diagnosis. In contrast to what the frequently used term 'Medullary Cystic Kidney Disease' implies, development of (medullary) cysts is neither an early nor a typical feature, as determined by MRI. In addition to Sanger and gene panel sequencing of the four genes, we established SNaPshot minisequencing for the predescribed cytosine duplication within a distinct repeat region of MUC1 causing a frameshift. A mutation was found in 7 of 9 families (3 in UMOD and 4 in MUC1), with one indeterminate (UMOD p.T62P). On the basis of clinical and pathological characteristics we propose the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' as an improved terminology. This should enhance recognition and correct diagnosis of affected individuals, facilitate genetic counseling, and stimulate research into the underlying pathophysiology.
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Renal Function and Patient-Reported Outcomes in Stable Kidney Transplant Patients Following Conversion From Twice-Daily Immediate-Release Tacrolimus to Once-Daily Prolonged-Release Tacrolimus: A 12-Month Observational Study in Routine Clinical Practice in Germany (ADAGIO) - Hugo, Christian; Weihprecht, Horst; Banas, Bernhard; Schröppel, Bernd; Jank, Sabine; Arns, Wolfgang; Schenker, Peter; Rath, Thomas; Hergesell, Olaf; Feldkamp, Thorsten; Hermann, Birgit; Schiffer, Mario (Transplantation Proceedings, 2021)
Introduction: This 12-month, noninterventional study on routine clinical practice in Germany evaluated renal function in stable kidney transplant recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). Methods: Renal function was assessed in 183 patients by estimated glomerular filtration rate using the modification of diet in renal disease-4 formula. Self-reported gastrointestinal health-related quality of life, adherence, satisfaction with PR-T, suspected rejection episodes, and safety were also assessed at conversion and at 3, 6, and 12 months. Results: Conversion from IR-T to PR-T resulted in stable kidney function over 12 months, with a difference in estimated glomerular filtration rate between the first and final visits of 0.1 mL/min/1.73 m2 (95% confidence interval, −1.6, 1.8). Eight patients experienced an acute rejection episode (4.4%). At each assessment, gastrointestinal health-related quality of life was low and adherence was high. Most patients reported that they were very satisfied (69.8%) or satisfied (28.1%) with PR-T at the final visit. Among patients reporting a preference, 78.4% preferred PR-T, 2.2% preferred IR-T, and 19.4% reported no preference. The safety profile of PR-T was consistent with that previously described. Conclusion: Conversion of stable kidney transplant recipients from IR-T to PR-T provided stable kidney and graft function over 12 months (Verband Forschender Arzneimittelhersteller–registered study: NIS ADV-02).
CRIS-Team Scopus Importer:2021-03-05

Renal Function, Blood Pressure, and Histologic Changes in Living Kidney Transplant Recipients from Hypertensive Donors - Dienemann, T.; Schellenberg, J.; Amann, Kerstin Ute; Heller, K.; Weidemann, Alexander (2018)
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Renal function in patients with non-dialysis chronic kidney disease receiving intravenous ferric carboxymaltose: an analysis of the randomized FIND-CKD trial - Macdougall, Iain C.; Bock, Andreas H.; Carrera, Fernando; Eckardt, Kai-Uwe; Gaillard, Carlo; Van Wyck, David; Meier, Yvonne; Larroque, Sylvain; Roger, Simon D. (BMC Nephrology, 2017)
Preclinical studies demonstrate renal proximal tubular injury after administration of some intravenous iron preparations but clinical data on renal effects of intravenous iron are sparse.FIND-CKD was a 56-week, randomized, open-label, multicenter study in which patients with non-dialysis dependent chronic kidney disease (ND-CKD), anemia and iron deficiency without erythropoiesis-stimulating agent therapy received intravenous ferric carboxymaltose (FCM), targeting either higher (400-600 ?g/L) or lower (100-200 ?g/L) ferritin values, or oral iron.Mean (SD) eGFR at baseline was 34.9 (11.3), 32.8 (10.8) and 34.2 (12.3) mL/min/1.73 m(2) in the high ferritin FCM (n = 97), low ferritin FCM (n = 89) and oral iron (n = 167) groups, respectively. Corresponding values at month 12 were 35.6 (13.8), 32.1 (12.7) and 33.4 (14.5) mL/min/1.73 m(2). The pre-specified endpoint of mean (SE) change in eGFR from baseline to month 12 was +0.7 (0.9) mL/min/1.73 m(2) with high ferritin FCM (p = 0.15 versus oral iron), -0.9 (0.9) mL/min/1.73 m(2) with low ferritin FCM (p = 0.99 versus oral iron) and -0.9 (0.7) mL/min/1.73 m(2) with oral iron. No significant association was detected between quartiles of FCM dose, change in ferritin or change in TSAT versus change in eGFR. Dialysis initiation was similar between groups. Renal adverse events were rare, with no indication of between-group differences.Intravenous FCM at doses that maintained ferritin levels of 100-200 ?g/L or 400-600 ?g/L did not negatively impact renal function (eGFR) in patients with ND-CKD over 12 months versus oral iron, and eGFR remained stable. These findings show no evidence of renal toxicity following intravenous FCM over a 1-year period.ClinicalTrials.gov NCT00994318 (first registration 12 October 2009).
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RENAL HEMODYNAMIC CHANGES AFTER RENAL DENERVATION - Schmieder, R. S.; Schmid, Axel; Janka, Rolf Matthias; Ditting, T.; Veelken, Roland; Uder, Michael; Schmieder, Roland; Ott, Christian (2016)
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