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Journal of the American Society of Nephrology: JASN

Julia Hagenstein, Simon Melderis, Anna Nosko, Matthias T Warkotsch, Johannes V Richter, Torben Ramcke, Georg R Herrnstadt, Jürgen Scheller, Isabell Yan, Hans-Willi Mittrücker, Malte A Kluger, Oliver M Steinmetz
BACKGROUND: New therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown. METHODS: To learn more about the complex role of CD4+ T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell-specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations...
July 16, 2019: Journal of the American Society of Nephrology: JASN
Philip A Clayton, Stephen P McDonald, Graeme R Russ, Steven J Chadban
BACKGROUND: Declining rates of acute rejection (AR) and the high rate of 1-year graft survival among patients with AR have prompted re-examination of AR as an outcome in the clinic and in trials. Yet AR and its treatment may directly or indirectly affect longer-term outcomes for kidney transplant recipients. METHODS: To understand the long-term effect of AR on outcomes, we analyzed data from the Australia and New Zealand Dialysis and Transplant Registry, including 13,614 recipients of a primary kidney-only transplant between 1997 and 2017 with at least 6 months of graft function...
July 15, 2019: Journal of the American Society of Nephrology: JASN
Bernard M van den Berg, Gangqi Wang, Margien G S Boels, M Cristina Avramut, Erik Jansen, Wendy M P J Sol, Franck Lebrin, Anton Jan van Zonneveld, Eelco J P de Koning, Hans Vink, Hermann-Josef Gröne, Peter Carmeliet, Johan van der Vlag, Ton J Rabelink
BACKGROUND: A glycocalyx envelope consisting of proteoglycans and adhering proteins covers endothelial cells, both the luminal and abluminal surface. We previously demonstrated that short-term loss of integrity of the luminal glycocalyx layer resulted in perturbed glomerular filtration barrier function. METHODS: To explore the role of the glycocalyx layer of the endothelial extracellular matrix in renal function, we generated mice with an endothelium-specific and inducible deletion of hyaluronan synthase 2 (Has2), the enzyme that produces hyaluronan, the main structural component of the endothelial glycocalyx layer...
July 15, 2019: Journal of the American Society of Nephrology: JASN
Minxian Wang, Justin Chun, Giulio Genovese, Andrea U Knob, Ava Benjamin, Maris S Wilkins, David J Friedman, Gerald B Appel, Richard P Lifton, Shrikant Mane, Martin R Pollak
BACKGROUND: Over the past two decades, the importance of genetic factors in the development of FSGS has become increasingly clear. However, despite many known monogenic causes of FSGS, single gene defects explain only 30% of cases. METHODS: To investigate mutations underlying FSGS, we sequenced 662 whole exomes from individuals with sporadic or familial FSGS. After quality control, we analyzed the exome data from 363 unrelated family units with sporadic or familial FSGS and compared this to data from 363 ancestry-matched controls...
July 15, 2019: Journal of the American Society of Nephrology: JASN
Calum D Moulton, Thahesh Tharmaraja, Jonathan L Dumbrill, Christopher W P Hopkins
No abstract text is available yet for this article.
July 12, 2019: Journal of the American Society of Nephrology: JASN
Marta Vaquero, Sara Cuesta, Carlos Anerillas, Gisela Altés, Joan Ribera, M Albert Basson, Jonathan D Licht, Joaquim Egea, Mario Encinas
BACKGROUND: Studies in mice suggest that perturbations of the GDNF-Ret signaling pathway are a major genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT). Mutations in Sprouty1, an intracellular Ret inhibitor, results in supernumerary kidneys, megaureters, and hydronephrosis in mice. But the underlying molecular mechanisms involved and which structural domains are essential for Sprouty1 function are a matter of controversy, partly because studies have so far relied on ectopic overexpression of the gene in cell lines...
July 12, 2019: Journal of the American Society of Nephrology: JASN
Nadia M Chu, Alden L Gross, Ashton A Shaffer, Christine E Haugen, Silas P Norman, Qian-Li Xue, A Richey Sharrett, Michelle Carlson, Karen Bandeen-Roche, Dorry L Segev, Mara A McAdams-DeMarco
No abstract text is available yet for this article.
July 12, 2019: Journal of the American Society of Nephrology: JASN
Taishi Fang, Tai Yeon Koo, Jae-Ghi Lee, Joon Young Jang, Yixuan Xu, Ju Hee Hwang, Sunjoo Park, Ji-Jing Yan, Jung-Hwa Ryu, Yeon-Mi Ryu, Sang-Yeob Kim, Kyung-Suk Suh, Jaeseok Yang
BACKGROUND: Regulatory B cells are a newly discovered B cell subset that suppresses immune responses. Recent studies found that both anti-CD45RB and anti-Tim-1 treatments regulate immune responses by inducing regulatory B cells; however, the role of these cells in renal ischemia-reperfusion injury (IRI) is unknown. METHODS: Using mouse models, including T cell-deficient (RAG1 knockout and TCR α knockout) mice and B cell-deficient ( μ MT) mice, we investigated the effects of regulatory B cells and anti-CD45RB on IRI and the mechanisms underlying these effects...
July 11, 2019: Journal of the American Society of Nephrology: JASN
Shrikant Ramesh Mulay, Mohsen M Honarpisheh, Orestes Foresto-Neto, Chongxu Shi, Jyaysi Desai, Zhi Bo Zhao, Julian A Marschner, Bastian Popper, Ewa Miriam Buhl, Peter Boor, Andreas Linkermann, Helen Liapis, Rostyslav Bilyy, Martin Herrmann, Paola Romagnani, Ilya Belevich, Eija Jokitalo, Jan U Becker, Hans-Joachim Anders
BACKGROUND: Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycol poisoning and are a well known cause of AKI. Established contributors to oxalate crystal-induced renal necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein-dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function...
July 11, 2019: Journal of the American Society of Nephrology: JASN
Morgan E Grams, Yingying Sang, Shoshana H Ballew, Kunihiro Matsushita, Brad C Astor, Juan Jesus Carrero, Alex R Chang, Lesley A Inker, Timothy Kenealy, Csaba P Kovesdy, Brian J Lee, Adeera Levin, David Naimark, Michelle J Pena, Jesse D Schold, Varda Shalev, Jack F M Wetzels, Mark Woodward, Ron T Gansevoort, Andrew S Levey, Josef Coresh
BACKGROUND: Decline in eGFR is a biologically plausible surrogate end point for the progression of CKD in clinical trials. However, it must first be tested to ensure strong associations with clinical outcomes in diverse populations, including patients with higher eGFR. METHODS: To investigate the association between 1-, 2-, and 3-year changes in eGFR (slope) with clinical outcomes over the long term, we conducted a random effects meta-analysis of 3,758,551 participants with baseline eGFR≥60 ml/min per 1...
July 10, 2019: Journal of the American Society of Nephrology: JASN
Tom Greene, Jian Ying, Edward F Vonesh, Hocine Tighiouart, Andrew S Levey, Josef Coresh, Jennifer S Herrick, Enyu Imai, Tazeen H Jafar, Bart D Maes, Ronald D Perrone, Lucia Del Vecchio, Jack F M Wetzels, Hiddo J L Heerspink, Lesley A Inker
BACKGROUND: Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up. METHODS: We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure...
July 10, 2019: Journal of the American Society of Nephrology: JASN
Lesley A Inker, Hiddo J L Heerspink, Hocine Tighiouart, Andrew S Levey, Josef Coresh, Ron T Gansevoort, Andrew L Simon, Jian Ying, Gerald J Beck, Christoph Wanner, Jürgen Floege, Philip Kam-Tao Li, Vlado Perkovic, Edward F Vonesh, Tom Greene
BACKGROUND: Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits. METHODS: To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects...
July 10, 2019: Journal of the American Society of Nephrology: JASN
Ming-Zhi Zhang, Kensuke Sasaki, Yan Li, Zhilian Li, Yu Pan, Guan-Nan Jin, Yinqiu Wang, Aolei Niu, Suwan Wang, Xiaofeng Fan, Jian Chun Chen, Corina Borza, Haichun Yang, Ambra Pozzi, Agnes B Fogo, Raymond C Harris
BACKGROUND: Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. METHODS: To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines...
July 10, 2019: Journal of the American Society of Nephrology: JASN
Anne Blanchard, Marion Vallet, Laurence Dubourg, Marguerite Hureaux, Julien Allard, Jean-Philippe Haymann, Renaud de la Faille, Armelle Arnoux, Aurelie Dinut, Damien Bergerot, Pierre-Hadrien Becker, Pierre-Yves Courand, Stéphanie Baron, Pascal Houillier, Ivan Tack, Olivier Devuyst, Xavier Jeunemaitre, Michel Azizi, Rosa Vargas-Poussou
BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. Previous studies suggested an intermediate phenotype for heterozygous carriers. METHODS: To evaluate the phenotype of heterozygous carriers of pathogenic SLC12A3 mutations, we performed a cross-sectional study of patients with Gitelman syndrome, heterozygous carriers, and healthy noncarriers. Participants measured their BP at home for three consecutive days before hospital admission for blood and urine sampling and an oral glucose tolerance test...
July 8, 2019: Journal of the American Society of Nephrology: JASN
Sonia Zambrano, Katja Möller-Hackbarth, Xidan Li, Patricia Q Rodriguez, Emmanuelle Charrin, Angelina Schwarz, Jenny Nyström, Annika Östman Wernerson, Mark Lal, Jaakko Patrakka
BACKGROUND: Inflammatory processes play an important role in the pathogenesis of glomerulopathies. Finding novel ways to suppress glomerular inflammation may offer a new way to stop disease progression. However, the molecular mechanisms that initiate and drive inflammation in the glomerulus are still poorly understood. METHODS: We performed large-scale gene expression profiling of glomerulus-associated G protein-coupled receptors (GPCRs) to identify new potential therapeutic targets for glomerulopathies...
July 8, 2019: Journal of the American Society of Nephrology: JASN
Weijia Zhang, Zhengzi Yi, Karen L Keung, Huimin Shang, Chengguo Wei, Paolo Cravedi, Zeguo Sun, Caixia Xi, Christopher Woytovich, Samira Farouk, Weiqing Huang, Khadija Banu, Lorenzo Gallon, Ciara N Magee, Nader Najafian, Milagros Samaniego, Arjang Djamali, Stephen I Alexander, Ivy A Rosales, Rex Neal Smith, Jenny Xiang, Evelyne Lerut, Dirk Kuypers, Maarten Naesens, Philip J O'Connell, Robert Colvin, Madhav C Menon, Barbara Murphy
BACKGROUND: In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies. METHODS: We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant...
July 5, 2019: Journal of the American Society of Nephrology: JASN
Zhangzhe Peng, Renna Luo, Tingting Xie, Weiru Zhang, Hong Liu, Wei Wang, Lijian Tao, Rodney E Kellems, Yang Xia
BACKGROUND: Oxygen deprivation or hypoxia in the kidney drives CKD and contributes to end organ damage. The erythrocyte's role in delivery of oxygen (O2 ) is regulated by hypoxia, but the effects of CKD are unknown. METHODS: We screened all of the metabolites in the whole blood of mice infused with angiotensin II (Ang II) at 140 ng/kg per minute up to 14 days to simulate CKD and compared their metabolites with those from untreated mice. Mice lacking a receptor on their erythrocytes called ADORA2B, which increases O2 delivery, and patients with CKD were studied to assess the role of ADORA2B-mediated O2 delivery in CKD...
July 5, 2019: Journal of the American Society of Nephrology: JASN
Geoffrey A Block, Martha S Block, Gerard Smits, Rupal Mehta, Tamara Isakova, Myles Wolf, Glenn M Chertow
BACKGROUND: Researchers have yet to determine the optimal care of patients with advanced CKD. Evidence suggests that anemia and CKD-related disordered mineral metabolism (including abnormalities in phosphate and fibroblast growth factor 23 [FGF23]) contribute to adverse outcomes in this population. METHODS: To investigate whether fixed-dose ferric citrate coordination complex favorably affects multiple biochemical parameters in patients with advanced CKD, we randomly assigned 203 patients with eGFR≤20 ml/min per 1...
July 5, 2019: Journal of the American Society of Nephrology: JASN
Aleksandar Denic, Luisa Ricaurte, Camden L Lopez, Ramya Narasimhan, Lilach O Lerman, John C Lieske, R Houston Thompson, Walter K Kremers, Andrew D Rule
BACKGROUND: Age, CKD risk factors, and kidney function are associated with larger glomerular volume and a higher percentage of globally sclerotic glomeruli. Knowledge of how these associations may differ by cortical depth is limited. METHODS: To investigate glomerular volume and glomerulosclerosis across different depths of cortex, we studied wedge sections of the renal parenchyma from 812 patients who underwent a radical nephrectomy (for a tumor), separately characterizing glomeruli in the superficial (subcapsular), middle, and deep (juxtamedullary) regions...
July 5, 2019: Journal of the American Society of Nephrology: JASN
Maatje D A van Gastel, Marie E Edwards, Vicente E Torres, Bradley J Erickson, Ron T Gansevoort, Timothy L Kline
BACKGROUND: The formation and growth of cysts in kidneys, and often liver, in autosomal dominant polycystic kidney disease (ADPKD) cause progressive increases in total kidney volume (TKV) and liver volume (TLV). Laborious and time-consuming manual tracing of kidneys and liver is the current gold standard. We developed a fully automated segmentation method for TKV and TLV measurement that uses a deep learning network optimized to perform semantic segmentation of kidneys and liver. METHODS: We used 80% of a set of 440 abdominal magnetic resonance images (T2-weighted HASTE coronal sequences) from patients with ADPKD to train the network and the remaining 20% for validation...
July 3, 2019: Journal of the American Society of Nephrology: JASN
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