Zebrafish Model to Study Podocyte Function Within the Glomerular Filtration Barrier - Sopel, Nina; Müller-Deile, Janina (Methods in Molecular Biology, 2023)
The zebrafish model has been used in many different fields of research because of its high homology to the human genome, its easy genetic manipulation, its high fecundity, and its rapid development. For glomerular diseases, zebrafish larvae have proven to be a versatile tool to study the contribution of different genes, because the zebrafish pronephros is very comparable to the human kidney in function and ultrastructure. Here we describe the principle and use of a simple screening assay based on the measurement of the fluorescence in the retinal vessel plexus of the Tg(l-fabp:DBP:eGFP) zebrafish line ("eye assay") to indirectly determine proteinuria as a hallmark of podocyte dysfunction. Furthermore, we illustrate how to analyze the obtained data and outline methods to attribute the findings to podocyte impairment.
CRIS-Team Scopus Importer:2023-07-21
Keywords: Fluorescence-based assay; Glomerular disease; Kidney; Podocyte; Proteinuria; Zebrafish; “Eye assay”

ZERO-BIOPSY AND KIDNEY TRANSPLANT FUNCTION OF DONOR KIDNEYS FROM ACCELERATED ORGAN ALLOCATION PROCEDURE (AOAP): REAL, RESCUE, CENTER OFFER COMPARED TO STANDARD EUROTRANSPLANT KIDNEY ALLOCATION SYSTEM (ETKAS) - SINGLE CENTER ANALYSIS 12/2013-12/2017 - Heller, Katharina M.; Hendrik, Apel; Wach, Sven (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-11-08

β-(1→3)-D-glucan- and mannan-guided early termination of antifungal therapy in ICU patients: a randomized controlled study - Erb, Timothy; Mihai, Sidonia; Strauss, Richard; Herbst, Larissa; Castellanos, Ixchel; Diesch, Katharina; Cipa, Franziska; Bihlmaier, Karl; Lang, Anne-Katharina; Ganslmayer, Marion; Willam, Carsten; Bremer, Frank Felix; et al. (Antimicrobial Agents and Chemotherapy, 2023)
Candida spp. are frequently encountered in specimens from ICUs. However, most of these detections represent colonization. Nevertheless, clinical practice shows that a considerable proportion of these patients will receive antifungal therapy (AT). β-(1→3)-D-glucan (BDG) and mannan are fungal biomarkers with high negative predictive values. We aimed to examine whether biomarker-guided discontinuation of AT can reduce the antifungal consumption. Therefore, we conducted a prospective, randomized intervention study between 1 April 2019 and 31 March 2020. All adult ICU patients with a newly started systemic AT but without fungal infection were eligible for inclusion. Enrolled patients were randomized into an intervention and a control group. In both groups, serum BDG and mannan were determined on days 1 and 2 of AT. If all measurements were negative, AT was discontinued in the intervention group. The primary endpoint was antifungal use. The study was terminated after 12 months. Until this time-point, 41 patients had been included. In the intervention group (n = 19), AT was stopped in only two patients because all others showed either positive BDG and∕or mannan levels. One of these two patients developed candidemia and AT had to be restarted. There was no significant difference in the primary and secondary endpoints. In summary, the strategy of using two negative BDG and mannan levels to stop AT failed to reduce antifungal consumption in our cohort. Indeed, there will inevitably be patients with invasive candidiasis in whom necessary AT is discontinued. The optimal patient population, biomarker set, and termination criteria are critical to the success of biomarker-based termination strategies.
CRIS-Team Scopus Importer:2023-12-15
Keywords: antibiotic stewardship; antifungal therapy; biomarker; Candida infection; candidemia; candidosis; discontinuation; fungal infection

Клинические практические рекомендации IPNA по диагностике и лечению детей со стероид-резистентным нефротическим синдромом - Trautmann, Agnes; Vivarelli, Marina; Samuel, Susan; Gipson, Debbie; Sinha, Aditi; Schaefer, Franz; Hui, Ng Kar; Boyer, Olivia; Saleem, Moin A.; Feltran, Luciana; Müller-Deile, Janina; Becker, Jan Ulrich; et al. (Нефрология и диализ, 2021)
Idiopathic nephrotic syndrome newly affects 1-3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4-6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10-30% of steroid resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Children; Chronic kidney disease; Genetics; Immunosuppressive treatment; Outcome; Pediatrics; Steroid-resistant nephrotic syndrome

CXCL13 as a new biomarker of systemic lupus erythematosus and lupus nephritis - from bench to bedside? - Schiffer, L.; Worthmann, K.; Haller, H.; Schiffer, Mario (Clinical and Experimental Immunology, 2015)
Different studies over the last decade have linked the B cell-attracting chemokine CXC ligand 13 (CXCL13) to the autoimmune disease systemic lupus erythematosus (SLE). A pathogenetic role of this chemokine for disease manifestation in SLE was described initially in mouse models for SLE. Mechanisms of CXCL13 actions were also identified in SLE patients. Moreover, various clinical studies have identified CXCL13 serum levels as a useful biomarker in patients with SLE of different ethnicities for disease activity. In addition, CXCL13 seems to be a promising marker for the diagnosis of lupus nephritis, one of the most severe complications of SLE. However, its exact place within the mechanisms that lead to SLE remains to be defined. Further research is needed to resolve more details of the pathomechanism and the signalling pathway of CXCL13 in SLE. Blocking CXCL13 or the signal pathways of CXCL13 is seen as a promising therapeutic approach for SLE and will be addressed in the near future. This review summarizes all papers that linked CXCL13 to SLE and highlights its importance in the pathogenesis and diagnosis of SLE.
EVALuna:34567

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors - Horton, Sarah J.; Giotopoulos, George; Yun, Haiyang; Vohra, Shabana; Sheppard, Olivia; Bashford-Rogers, Rachael; Rashid, Mamunur; Clipson, Alexandra; Chan, Wai-In; Sasca, Daniel; Yiangou, Loukia; Osaki, Hikari; et al. (Nature Cell Biology, 2017)
Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.
EVALuna2:34722

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition - Sciacovelli, Marco; Goncalves, Emanuel; Johnson, Timothy Isaac; Zecchini, Vincent Roberto; Da Costa, Ana Sofia Henriques; Gaude, Edoardo; Drubbel, Alizee Vercauteren; Theobald, Sebastian Julian; Abbo, Sandra Riekje; Tran, Maxine Gia Binh; Rajeeve, Vinothini; Cardaci, Simone; et al. (Nature, 2016)
Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster mir-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.
EVALuna2:34725

Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition - Gallipoli, Paolo; Giotopoulos, George; Tzelepis, Konstantinos; Costa, Ana S. H.; Vohra, Shabana; Medina-Perez, Paula; Basheer, Faisal; Marando, Ludovica; Di Lisio, Lorena; Dias, Joao M. L.; Yun, Haiyang; Sasca, Daniel; et al. (Blood, 2018)
FLT3 internal tandem duplication (FLT3ITD) mutations are common in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new-generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3ITD AML patients remains poor and demands the identification of novel, specific, and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3ITD AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3ITD and other TK activating mutation-driven leukemias.
EVALuna2:34721

Glutathione peroxidase 8 is transcriptionally regulated by HIF? and modulates growth factor signaling in HeLa cells - Bosello-Travain, Valentina; Forman, Henry J.; Roveri, Antonella; Toppo, Stefano; Ursini, Fulvio; Venerando, Rina; Warnecke, Christina; Zaccarin, Mattia; Maiorino, Matilde (Free Radical Biology and Medicine, 2015)
GPx8 is a mammalian Cys-glutathione peroxidase of the endoplasmic reticulum membrane, involved in protein folding. Its regulation is mostly unknown. We addressed both the functionality of two hypoxia-response elements (HREs) within the promoter, GPx8 HRE1 and GPx8 HRE2, and the GPx8 physiological role. In HeLa cells, treatment with HIF? stabilizers, such as diethyl succinate (DES) or 2-2'-bipyridyl (BP), induces GPx8 expression at both mRNA and protein level. Luciferase activity of pGL3(GPx8wt), containing a fragment of the GPx8 promoter including the two HREs, is also induced by DES/BP or by overexpressing either individual HIF? subunit. Mutating GPx8 HRE1 within pGL3(GPx8wt) resulted in a significantly higher inhibition of luciferase activity than mutating GPx8 HRE2. Electrophoretic mobility-shift assay showed that both HREs exhibit enhanced binding to a nuclear extract from DES/BP-treated cells, with stronger binding by GPx8 HRE1. In DES-treated cells transfected with pGL3(GPx8wt) or mutants thereof, silencing of HIF2?, but not HIF1?, abolishes luciferase activity. Thus GPx8 is a novel HIF target preferentially responding to HIF2? binding at its two novel functional GPx8 HREs, with GPx8 HRE1 playing the major role. Fibroblast growth factor (FGF) treatment increases GPx8 mRNA expression, and reporter gene experiments indicate that induction occurs via HIF. Comparing the effects of depleting GPx8 on the downstream effectors of FGF or insulin signaling revealed that absence of GPx8 results in a 16- or 12-fold increase in phosphorylated ERK1/2 by FGF or insulin treatment, respectively. Furthermore, in GPx8-depleted cells, phosphorylation of AKT by insulin treatment increases 2.5-fold. We suggest that induction of GPx8 expression by HIF slows down proliferative signaling during hypoxia and/or growth stimulation through receptor tyrosine kinases.
EVALuna2:3889

Heterogenous bone response to biologic DMARD therapies in rheumatoid arthritis patients and their relationship to functional indices - Brunet, S. C.; Tse, J. J.; Kuczynski, M. T.; Engelke, Klaus; Boyd, S. K.; Barnabe, C.; Manske, S. L. (Scandinavian Journal of Rheumatology, 2021)
Objectives: Previous studies of high-resolution peripheral quantitative computed tomography (HR-pQCT) imaging of hand joints in patients with rheumatoid arthritis (RA) have suggested that erosion healing may occur. Our objective was to examine changes in erosion volume, joint space width (JSW), bone mineral density (BMD), and bone remodelling, and their association with clinical outcomes and measures of patient hand function. Method: We examined 48 patients who achieved a good response to a newly initiated biologic therapy. HR-pQCT images of the dominant hands’ second and third metacarpophalangeal joints were obtained 3 and 12 months after therapy initiation. Bone erosion volume, JSW, BMD, and bone remodelling were quantified from HR-pQCT images, with improvement, no change (unchanged), or progression in these measures determined by least significant change. Disease activity and hand function measures were collected. Results: There were no significant group changes in HR-pQCT outcomes over the 9 month period. Twenty-two patients had total erosion volumes that remained unchanged, nine showed improvement, and two progressed. The majority of JSW and BMD measures remained unchanged. There was a significant association between the baseline Health Assessment Questionnaire score and the change in minimum JSW, but no other significant associations between HR-pQCT outcomes and function were observed. Conclusions: The vast majority of patients maintained unchanged JSW and BMD over the course of follow-up. Significant improvements in total erosion volume occurred in 27% of patients, suggesting that biologic therapies may lead to erosion healing in some patients, although this did not have an impact on self-reported and demonstrated hand function.
CRIS-Team Scopus Importer:2021-04-09

Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis - Idowu, Temitayo O.; Etzrodt, Valerie; Seeliger, Benjamin; Bolanos-Palmieri, Patricia; Thamm, Kristina; Haller, Hermann; David, Sascha (eLife, 2020)
Endothelial Tie2 signaling plays a pivotal role in vascular barrier maintenance at baseline and after injury. We previously demonstrated that a sharp drop in Tie2 expression observed across various murine models of critical illnesses is associated with increased vascular permeability and mortality. Matrix metalloprotease (MMP)-14-mediated Tie2 ectodomain shedding has recently been recognized as a possible mechanism for Tie2 downregulation in sepsis. Here, we identified the exact MMP14-mediated Tie2 ectodomain cleavage sites and could show that pharmacological MMP14 blockade in experimental murine sepsis exerts barrier protective and anti-inflammatory effects predominantly through the attenuation of Tie2 cleavage to improve survival both in a pre-treatment and rescue approach. Overall, we show that protecting Tie2 shedding might offer a new therapeutic opportunity for the treatment of septic vascular leakage.
CRIS-Team Scopus Importer:2020-09-04
Keywords: endothelial cells; immunology; inflammation; medicine; MMP14; mouse; permeability; Sepsis; Tie2; vascular barrier function

Impact of C-reactive protein on osteo-/chondrogenic transdifferentiation and calcification of vascular smooth muscle cells - Henze, Laura A.; Luong, Trang T.D.; Boehme, Beate; Masyout, Jaber; Schneider, Markus; Brachs, Sebastian; Lang, Florian; Pieske, Burkert; Pasch, Andreas; Eckardt, Kai-Uwe; Voelkl, Jakob; Alesutan, Ioana (Aging-Us, 2019)
Medial vascular calcification occurs during the aging process and is strongly accelerated by chronic kidney disease (CKD). Elevated C-reactive protein (CRP) levels are associated with vascular calcification, cardiovascular events and mortality in CKD patients. CRP is an important promoter of vascular inflammation. Inflammatory processes are critically involved in initiation and progression of vascular calcification. Thus, the present study explored a possible impact of CRP on vascular calcification. We found that CRP promoted osteo-/chondrogenic transdifferentiation and aggravated phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of primary human aortic smooth muscle cells (HAoSMCs). These effects were paralleled by increased cellular oxidative stress and corresponding pro-calcific downstream-signaling. Antioxidants or p38 MAPK inhibition suppressed CRP-induced osteo-/chondrogenic signaling and mineralization. Furthermore, silencing of Fc fragment of IgG receptor IIa (FCGR2A) blunted the pro-calcific effects of CRP. Vascular CRP expression was increased in the klotho-hypomorphic mouse model of aging as well as in HAoSMCs during calcifying conditions. In conclusion, CRP augments osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells through mechanisms involving FCGR2A-dependent induction of oxidative stress. Thus, systemic inflammation may actively contribute to the progression of vascular calcification.
CRIS-Team Scopus Importer:2019-08-30
Keywords: CKD; CRP; Osteo-/chondrogenic signaling; Oxidative stress; Vascular calcification; Vascular smooth muscle cells

Long-term patient survival and kidney allograft survival in post-transplant diabetes mellitus: a single-center retrospective study - Dienemann, Thomas; Fujii, Naohiko; Li, Yimei; Govani, Shivali; Kosaraju, Nikitha; Bloom, Roy D.; Feldman, Harold I. (Transplant International, 2016)
A decade ago, observations suggested that post-transplant diabetes mellitus (PTDM) was linked to allograft loss and shorter patient survival. Increasing awareness, improvements in care, and changes in the immunosuppressive regimen may have modified this association. Single-center analysis of 1990 (age>18; transplantation date 1996-2012) primary kidney recipients (KTR). Patients with <12 months follow-up were excluded. Diabetes was diagnosed according to ADA criteria and characterized as follows: No diabetes, PTDM in the first post-transplant year not treated with glucose-lowering medications (GLM) at 12 months, PTDM in the first post-transplant year treated with GLM at 12 months, and pretransplant diabetes. Cox proportional hazards models were used to examine the relationship of PTDM with allograft and patient survival. Mean follow-up time was 6.8 years for allograft survival and 7.4 years for patient survival. PTDM treated with medication at year one was not associated with allograft survival (HR 1.28, 95% CI 0.97-1.69), but was significantly associated with overall mortality and death with functioning graft (DWFG) (HR overall: 1.81, 95% CI 1.36-2.39; HR DWFG: 1.59 95% CI 1.05-2.38). In this cohort, KTR with PTDM being treated with glucose-lowering medication at 12 months experienced significantly shorter overall survival and survival with functioning graft.
EVALuna2:3897

Novel Biomarkers in Patients with Chronic Kidney Disease: An Analysis of Patients Enrolled in the GCKD-Study - Mirna, Moritz; Topf, Albert; Wernly, Bernhard; Rezar, Richard; Paar, Vera; Jung, Christian; Salmhofer, Hermann; Kopp, Kristen; Hoppe, Uta C.; Schulze, P. Christian; Kretzschmar, Daniel; Schneider, Markus; et al. (Journal of Clinical Medicine, 2020)
Background: Chronic kidney disease (CKD) and cardiovascular diseases (CVD) often occur concomitantly, and CKD is a major risk factor for cardiovascular mortality. Since some of the most commonly used biomarkers in CVD are permanently elevated in patients with CKD, novel biomarkers are warranted for clinical practice. Methods: Plasma concentrations of five cardiovascular biomarkers (soluble suppression of tumorigenicity (sST2), growth differentiation factor 15 (GDF-15), heart-type fatty acid-binding protein (H-FABP), insulin-like growth factor-binding protein 2 (IGF-BP2), and soluble urokinase plasminogen activator receptor) were analyzed by means of enzyme-linked immunosorbent assay (ELISA) in 219 patients with CKD enrolled in the German Chronic Kidney Disease (GCKD) study. Results: Except for sST2, all of the investigated biomarkers were significantly elevated in patients with CKD (2.0- to 4.4-fold increase in advanced CKD (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m(2) body surface area (BSA)) and showed a significant inverse correlation with eGFR. Moreover, all but H-FABP and sST2 were additionally elevated in patients with micro- and macro-albuminuria. Conclusions: Based on our findings, sST2 appears to be the biomarker whose diagnostic performance is least affected by decreased renal function, thus suggesting potential viability in the management of patients with CVD and concomitant CKD. The predictive potential of sST2 remains to be proven in endpoint studies.
CRIS-Team WoS Importer:2020-05-08

Risikoscores für chronisch nierenkranke Menschen - Schneider, Markus; Eckardt, Kai-Uwe (Deutsche Medizinische Wochenschrift, 2019)
Assessing the risk of adverse outcomes associated with chronic kidney disease (CKD) is important for physicians and affected patients alike. Categorizing CKD according to the cause-GFR category-albuminuria category (CGA)-classification system proposed by KDIGO already provides a semi-quantitative assessment of risks. The more recent development of the Tangri-formula provides a means to quantify the risk of progression for patients with CKD stage G3a-G5 (eGFR 10-59ml/min/1.73m 2) to kidney failure requiring kidney replacement therapy. To use this formula, the variables age, sex, eGFR and albuminuria are required (4-variable equation). An extended formula with the additional parameters calcium, phosphate, bicarbonate and albumin (8-variable equation) allows an even more precise estimation of progression risk. In patients with advanced CKD, stage G4 or higher (GFR category ≥4, i.e. eGFR <30ml/min/1.73m 2), models recently developed by the CKD-prognosis consortium can not only be used to predict the risk of kidney failure but also the risk of cardiovascular disease events and death. The risk estimators can be accessed through websites (http://kidneyfailurerisk.com, http://www.ckdpcrisk.org/lowgfrevents/) and via downloading of the respective apps. These novel tools may prove useful for health care decisions and as a basis for discussions with CKD patients.
CRIS-Team Scopus Importer:2019-06-18
Keywords: cardiovascular diseases; kidney; kidney disease; prognosis; risk

Risk Factors for Prognosis in Patients With Severely Decreased GFR - Evans, Marie; Grams, Morgan E.; Sang, Yingying; Astor, Brad C.; Blankestijn, Peter J.; Brunskill, Nigel J.; Collins, John F.; Kalra, Philip A.; Kovesdy, Csaba P.; Levin, Adeera; Mark, Patrick B.; Moranne, Olivier; et al. (Kidney International Reports, 2018)
Introduction: Patients with chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) <30 ml/min per 1.73 m2 (corresponding to CKD stage G4+) comprise a minority of the overall CKD population but have the highest risk for adverse outcomes. Many CKD G4+ patients are older with multiple comorbidities, which may distort associations between risk factors and clinical outcomes. Methods: We undertook a meta-analysis of risk factors for kidney failure treated with kidney replacement therapy (KRT), cardiovascular disease (CVD) events, and death in participants with CKD G4+ from 28 cohorts (n = 185,024) across the world who were part of the CKD Prognosis Consortium. Results: In the fully adjusted meta-analysis, risk factors associated with KRT were time-varying CVD, male sex, black race, diabetes, lower eGFR, and higher albuminuria and systolic blood pressure. Age was associated with a lower risk of KRT (adjusted hazard ratio: 0.74; 95% confidence interval: 0.69-0.80) overall, and also in the subgroup of individuals younger than 65 years. The risk factors for CVD events included male sex, history of CVD, diabetes, lower eGFR, higher albuminuria, and the onset of KRT. Systolic blood pressure showed a U-shaped association with CVD events. Risk factors for mortality were similar to those for CVD events but also included smoking. Most risk factors had qualitatively consistent associations across cohorts. Conclusion: Traditional CVD risk factors are of prognostic value in individuals with an eGFR <30 ml/min per 1.73 m2, although the risk estimates vary for kidney and CVD outcomes. These results should encourage interventional studies on correcting risk factors in this high-risk population.
EVALuna2:215686

Short- and long-term effects of the use of RAAS blockers immediately after renal transplantation - Chatzikyrkou, Christos; Eichler, Jenny; Karch, Annika; Clajus, Christian; Scurt, Florian Gunnar; Ramackers, Wolf; Lehner, Frank; Menne, Jan; Haller, Hermann; Mertens, Peter R.; Schiffer, Mario (Blood Pressure, 2017)
BACKGROUND: The efficacy and safety of renin angiotensin aldosterone system blockers (RAASB's) if introduced immediately after renal transplantation have not been extensively investigated. METHODS: The medical charts of 142 kidney transplant recipients who received a RAASB in the early postoperative period and of 114 matched controls were analyzed. The RAASB was given primarily for blood pressure control. RESULTS: 117 patients continued to receive and 50 controls remained continuously free of the RAASB in the first year. The RAASB was added on average at postoperative day 8 and the mean duration of follow-up was 5.4 years. Systolic, blood pressure at treatment initiation was increased in the RAASB group (150 ± 17 vs. 141 ± 16, p < 0.001). At discharge from hospital and during follow-up blood pressure was similar in both groups, without differences in GFR, potassium and proteinuria. The endpoints "graft failure" and "graft failure or death from any cause" were significantly better in patients treated with RAASB's (p = 0.03 and p = 0.04, respectively). The treatment effects in the RAASB group persisted even after adjustment for demographic parameters, immunological risk factors, peritransplant risk factors, duration of dialysis prior to transplantation and medical comorbidities. CONCLUSIONS: Thus, RAASB's can be used effectively and safely to treat hypertension in the early postoperative period after kidney transplantation and are renoprotective in the long term.
EVALuna2:34553

Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves - Klein, Amanda H.; Vyshnevska, Alina; Hartke, Timothy V.; De Col, Roberto; Mankowski, Joseph L.; Turnquist, Brian; Bosmans, Frank; Reeh, Peter; Schmelz, Martin; Carr, Richard W.; Ringkamp, Matthias (The Journal of Neuroscience, 2017)
Voltage-gated sodium (NaV) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaVchannel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (NaV1.1-NaV1.4, NaV1.6-NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaVchannel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys (Macaca nemestrina). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and NaV1.9-/-mice. In nerves from NaV1.8-/-mice, TTX-r C-CAPs could not be detected. These data indicate that NaV1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of NaV1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of NaV1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.SIGNIFICANCE STATEMENTIt is unclear whether individual sodium channel isoforms exert differential roles in action potential conduction along the axonal membrane of nociceptive, unmyelinated peripheral nerve fibers, but clarifying the role of sodium channel subtypes in different axonal segments may be useful for the development of novel analgesic strategies. Here, we provide evidence from mice and nonhuman primates that a substantial portion of the C-fiber compound action potential in distal peripheral nerves, but not proximal nerves or dorsal roots, is resistant to tetrodotoxin and that, in mice, this effect is mediated solely by voltage-gated sodium channel 1.8 (NaV1.8). The functional prominence of NaV1.8 within the axonal compartment immediately proximal to its termination may affect strategies targeting pain of peripheral origin.
EVALuna2:33345

Sulfatases, in Particular Sulf1, Are Important for the Integrity of the Glomerular Filtration Barrier in Zebrafish - Schenk, Heiko; Masseli, Anna; Schroder, Patricia; Bolanos-Palmieri, Patricia; Beese, Michaela; Hegermann, Jan; Braesen, Jan Hinrich; Haller, Hermann (BioMed Research International, 2019)
The 6-O-endosulfatases (sulfs) are important enzymatic components involved in the regulation of heparan sulfate by altering the sulfatation pattern. Specifically in the kidney, sulfs have been implicated in the glomerular podocyte-endothelial cell crosstalk and in the preservation of the glomerular filtration barrier (GFB) in different mouse models. Since it has been shown that in zebrafish larvae, Sulf1, Sulf2a, and Sulf2b are expressed in the pronephric kidney we set out to establish if a reduction in sulf expression leads to GFB dysfunction. Here, we show that a reduced sulf expression following morpholino (MO) induced knockdown in zebrafish larvae promotes damage to the GFB leading to renal plasma protein loss from the circulation. Moreover, a combined knockdown of Sulf1, Sulf2a, and Sulf2b is associated with severe morphologic changes including narrowing of the fenestration between glomerular endothelial cells as well as thickening of the glomerular basement membrane and podocyte foot process effacement, suggesting that glomerular damage is an underlying cause of the circulatory protein loss observed after MO injection. Additionally, we show that a decrease in sulf expression reduces the bioavailability of VegfA in the glomerulus of the pronephros, which may contribute to the structural changes observed in the glomeruli of morphant fish. Furthermore, consistent with previous results, knockdown of the sulfs is associated with arteriovenous malformations in particular in the tail region of the larvae. Overall, taken together our results suggest that 6-O-endosulfatases are important in the preservation of GFB integrity and a reduction in their expression levels induces phenotypic changes that are indicative of renal protein loss.
CRIS-Team WoS Importer:2019-08-16

Tear fluid collection methods: Review of current techniques - Pieczyński, Janusz; Szulc, Urszula; Harazna, Joanna; Szulc, Aleksandra; Kiewisz, Jolanta (European Journal of Ophthalmology, 2021)
Tear fluid, composed of lipid, aqueous, and mucin layers, contains electrolytes, water, proteins, peptides, and glycoproteins. Its components may serve as diagnostic indicators of local and systemic diseases. The aim of the study was to conduct literature review in order to identify the current methods of tear collection. The most commonly used method which was relatively easy to perform and allowed to obtain sufficient tear volume for further chemical and physical analysis was selected through PubMed database search for the following keywords: tear sampling, human tears, chemical analysis of tears, physical tear analysis, animal tear sampling. Final criteria of articles selection were: human tears, tear sample collection, chemical and physical analysis of tears. Time of publication of the articles not older than 1995. The analysis of 70 articles revealed that the most common tear fluid collection methods are Schirmer tear strips and capillary tubes. Thus, we recommend the use of Schirmer strips and microcapillary tubes as the cheapest and easiest methods for sampling of tear fluid for further chemical analysis.
CRIS-Team Scopus Importer:2021-03-19
Keywords: animal tear sampling; chemical analysis of tears; human tears; physical analysis of tears; Tear sample collection

Ten key messages of the guidelines for family-centered care in intensive care medicine - Petros, S.; John, Stefan (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2019)
The family plays an important role in the care of the critically ill patient. There is asubstantial psychological burden to family members during the intensive care management of the patient. The family has to bear the pitiable state of the patient with the feeling of helplessness. The critically ill patient is frequently unable to actively decide on the processes of intensive care. Therefore, the family has to take over the responsibility of representing the values and wishes of the patient and become involved in decision making, for which most family members are not prepared. Aconsiderable proportion of family members suffers from stress, anxiety and depression. This psychological burden also continues after the conclusion of the intensive care management. Therefore, structured approaches are needed to support family members of critically ill patients during the intensive care management. In this short review, we present the ten key messages of the recent guidelines for family-centered care in the intensive care unit by the Society of Critical Care Medicine.
CRIS-Team WoS Importer:2019-02-21

The eye — a window to cardiovascular diseases - Dąbrowska, Edyta; Harazny, Joanna; Wolf, Jacek; Szulc, Urszula; Narkiewicz, Krzysztof (Arterial Hypertension, 2020)
Microvascular alterations can parallel and even precede development of cardiovascular disease. Ocular bulb, due to transparent anatomical elements provides a unique opportunity to examine microcirculation non-invasively and in vivo by means of scanning laser Doppler flowmetry. This device enables to obtain both structural and functional parameters of retinal microvasculature. Alterations observed in retinal arterioles, i.e. lumen narrowing, increased wall-to-lumen ratio, rarefaction or reduced retinal capillary flow, have been independently associated with cardiometabolic diseases: hypertension, heart failure, coronary artery disease, stroke, chronic kidney disease and diabetes. Therefore, examination of easily accessible retinal microcirculation may provide novel insights into the mechanisms underlying various diseases, serve as a marker of target organ damage and add valuable information to cardiovascular risk stratification.
CRIS-Team Scopus Importer:2020-10-16
Keywords: Microcirculation; Remodeling; Retinal arterioles

Transplant Surgeon Meets Nephrologist: Important Nephrological Aspects Before and After Kidney or Liver Transplantation - Vondran, F. W. R.; Wintterle, S.; Braesen, J. H.; Haller, H.; Klempnauer, J.; Richter, N.; Lehner, F.; Schiffer, M. (Zentralblatt für Chirurgie, 2017)
In cases of chronic renal insufficiency, successful kidney transplantation is the method of choice to restore patients' health, well-being and physical fitness. The interdisciplinary collaboration of nephrologists and transplant surgeons has always been a prerequisite for the successful pre-, peri- and post-transplant care of renal transplant patients. The same holds true for liver transplant patients. Here the nephrologist is often involved in cases requiring pre- or post-transplant dialysis as well as in decision making for combined liver-kidney transplantation. This review focuses on nephrological aspects in patient care before and after kidney and liver transplantation.
EVALuna2:34552

UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs - Gozdecka, Malgorzata; Meduri, Eshwar; Mazan, Milena; Tzelepis, Konstantinos; Dudek, Monika; Knights, Andrew J.; Pardo, Mercedes; Yu, Lu; Choudhary, Jyoti S.; Metzakopian, Emmanouil; Iyer, Vivek; Yun, Haiyang; et al. (Nature Genetics, 2018)
The histone H3 Lys27-specific demethylase UTX (or KDM6A) is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (or KDM6C). In keeping with this, we demonstrate concomitant loss/mutation of KDM6A (UTX) and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27me3 but significant and bidirectional alterations in H3K27ac and chromatin accessibility; a predominant loss of H3K4me1 modifications; alterations in ETS and GATA-factor binding; and altered gene expression after Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex and enhanced pioneering activity of ETS factors during evolution to AML. Collectively, our findings identify a dual role for UTX in suppressing acute myeloid leukemia via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs.
EVALuna2:34720