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Journal of the American Society of Nephrology: JASN

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https://www.readbyqxmd.com/read/27909047/exercise-in-patients-on-dialysis-a-multicenter-randomized-clinical-trial
#1
Fabio Manfredini, Francesca Mallamaci, Graziella D'Arrigo, Rossella Baggetta, Davide Bolignano, Claudia Torino, Nicola Lamberti, Silvio Bertoli, Daniele Ciurlino, Lisa Rocca-Rey, Antonio Barillà, Yuri Battaglia, Renato Mario Rapanà, Alessandro Zuccalà, Graziella Bonanno, Pasquale Fatuzzo, Francesco Rapisarda, Stefania Rastelli, Fabrizio Fabrizi, Piergiorgio Messa, Luciano De Paola, Luigi Lombardi, Adamasco Cupisti, Giorgio Fuiano, Gaetano Lucisano, Chiara Summaria, Michele Felisatti, Enrico Pozzato, Anna Maria Malagoni, Pietro Castellino, Filippo Aucella, Samar Abd ElHafeez, Pasquale Fabio Provenzano, Giovanni Tripepi, Luigi Catizone, Carmine Zoccali
Previous studies have suggested the benefits of physical exercise for patients on dialysis. We conducted the Exercise Introduction to Enhance Performance in Dialysis trial, a 6-month randomized, multicenter trial to test whether a simple, personalized walking exercise program at home, managed by dialysis staff, improves functional status in adult patients on dialysis. The main study outcomes included change in physical performance at 6 months, assessed by the 6-minute walking test and the five times sit-to-stand test, and in quality of life, assessed by the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire...
December 1, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27895157/beneficial-effects-of-myo-inositol-oxygenase-deficiency-in-cisplatin-induced-aki
#2
Rajesh K Dutta, Vinay K Kondeti, Isha Sharma, Navdeep S Chandel, Susan E Quaggin, Yashpal S Kanwar
Overexpression of the proximal tubular enzyme myo-inositol oxygenase (MIOX) induces oxidant stress in vitro However, the relevance of MIOX to tubular pathobiology remains enigmatic. To investigate the role of MIOX in cisplatin-induced tubular AKI, we generated conditional MIOX-overexpressing transgenic (MIOX-TG) mice and MIOX-knockout (MIOX(-/-)) mice with tubule-specific MIOX overexpression or knockout, respectively. Compared with cisplatin-treated wild-type (WT) mice, cisplatin-treated MIOX-TG mice had even greater increases in urea, creatinine, and KIM-1 levels and more tubular injury and apoptosis, but these effects were attenuated in cisplatin-treated MIOX(-/-) mice...
November 28, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27895156/sildenafil-prevents-podocyte-injury-via-ppar-%C3%AE-mediated-trpc6-inhibition
#3
Ramon Sonneveld, Joost G Hoenderop, Andrea M Isidori, Carole Henique, Henry B Dijkman, Jo H Berden, Pierre-Louis Tharaux, Johan van der Vlag, Tom Nijenhuis
Transient receptor potential channel C6 (TRPC6) gain-of-function mutations and increased TRPC6 expression in podocytes induce glomerular injury and proteinuria. Sildenafil reduces TRPC6 expression and activity in nonrenal cell types, although the mechanism is unknown. Peroxisome proliferator-activated receptor γ (PPAR-γ) is a downstream target of sildenafil in the cyclic guanosine monophosphate (cGMP)-activated protein kinase G (PKG) axis. PPAR-γ agonists, like pioglitazone, appear antiproteinuric. We hypothesized that sildenafil inhibits TRPC6 expression in podocytes through PPAR-γ-dependent mechanisms, thereby counteracting podocyte injury and proteinuria...
November 28, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27895155/investigations-of-glucocorticoid-action-in-gn
#4
Christoph Kuppe, Claudia van Roeyen, Katja Leuchtle, Nazanin Kabgani, Michael Vogt, Marc Van Zandvoort, Bart Smeets, Jürgen Floege, Hermann-Josef Gröne, Marcus J Moeller
For several decades, glucocorticoids have been used empirically to treat rapid progressive GN. It is commonly assumed that glucocorticoids act primarily by dampening the immune response, but the mechanisms remain incompletely understood. In this study, we inactivated the glucocorticoid receptor (GR) specifically in kidney epithelial cells using Pax8-Cre/GR(fl/fl) mice. Pax8-Cre/GR(fl/fl) mice did not exhibit an overt spontaneous phenotype. In mice treated with nephrotoxic serum to induce crescentic nephritis (rapidly progressive GN), this genetic inactivation of the GR in kidney epithelial cells exerted renal benefits, including inhibition of albuminuria and cellular crescent formation, similar to the renal benefits observed with high-dose prednisolone in control mice...
November 28, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27895154/kidney-tubular-ablation-of-ocrl-inpp5b-phenocopies-lowe-syndrome-tubulopathy
#5
Kazunori Inoue, Daniel M Balkin, Lijuan Liu, Ramiro Nandez, Yumei Wu, Xuefei Tian, Tong Wang, Robert Nussbaum, Pietro De Camilli, Shuta Ishibe
Lowe syndrome and Dent disease are two conditions that result from mutations of the inositol 5-phosphatase oculocerebrorenal syndrome of Lowe (OCRL) and share the feature of impaired kidney proximal tubule function. Genetic ablation of Ocrl in mice failed to recapitulate the human phenotypes, possibly because of the redundant functions of OCRL and its paralog type 2 inositol polyphosphate-5-phosphatase (INPP5B). Germline knockout of both paralogs in mice results in early embryonic lethality. We report that kidney tubule-specific inactivation of Inpp5b on a global Ocrl-knockout mouse background resulted in low molecular weight proteinuria, phosphaturia, and acidemia...
November 28, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27881608/genetics-of-diabetic-kidney-disease-from-the-worst-of-nightmares-to-the-light-of-dawn
#6
EDITORIAL
Ronald C W Ma, Mark E Cooper
No abstract text is available yet for this article.
November 23, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27881607/bicarbonate-balance-and-prescription-in-esrd
#7
Matthew K Abramowitz
The optimal approach to managing acid-base balance is less well defined for patients receiving hemodialysis than for those receiving peritoneal dialysis. Interventional studies in hemodialysis have been limited and inconsistent in their findings, whereas more compelling data are available from interventional studies in peritoneal dialysis. Both high and low serum bicarbonate levels associate with an increased risk of mortality in patients receiving hemodialysis, but high values are a marker for poor nutrition and comorbidity and are often highly variable from month to month...
November 23, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27881606/mitochondria-protection-after-acute-ischemia-prevents-prolonged-upregulation-of-il-1%C3%AE-and-il-18-and-arrests-ckd
#8
Hazel H Szeto, Shaoyi Liu, Yi Soong, Surya V Seshan, Leona Cohen-Gould, Viacheslav Manichev, Leonard C Feldman, Torgny Gustafsson
The innate immune system has been implicated in both AKI and CKD. Damaged mitochondria release danger molecules, such as reactive oxygen species, DNA, and cardiolipin, which can cause NLRP3 inflammasome activation and upregulation of IL-18 and IL-1β It is not known if mitochondrial damage persists long after ischemia to sustain chronic inflammasome activation. We conducted a 9-month study in Sprague-Dawley rats after 45 minutes of bilateral renal ischemia. We detected glomerular and peritubular capillary rarefaction, macrophage infiltration, and fibrosis at 1 month...
November 23, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27864431/apol1-mediated-cell-injury-involves-disruption-of-conserved-trafficking-processes
#9
Etty Kruzel-Davila, Revital Shemer, Ayala Ofir, Ira Bavli-Kertselli, Ilona Darlyuk-Saadon, Pazit Oren-Giladi, Walter G Wasser, Daniella Magen, Eid Zaknoun, Maya Schuldiner, Adi Salzberg, Daniel Kornitzer, Zvonimir Marelja, Matias Simons, Karl Skorecki
APOL1 harbors C-terminal sequence variants (G1 and G2), which account for much of the increased risk for kidney disease in sub-Saharan African ancestry populations. Expression of the risk variants has also been shown to cause injury to podocytes and other cell types, but the underlying mechanisms are not understood. We used Drosophila melanogaster and Saccharomyces cerevisiae to help clarify these mechanisms. Ubiquitous expression of the human APOL1 G1 and G2 disease risk alleles caused near-complete lethality in D...
November 18, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27864430/apol1-g1-in-nephrocytes-induces-hypertrophy-and-accelerates-cell-death
#10
Yulong Fu, Jun-Yi Zhu, Adam Richman, Yi Zhang, Xuefang Xie, Jharna R Das, Jinliang Li, Patricio E Ray, Zhe Han
People of African ancestry carrying certain APOL1 mutant alleles are at elevated risk of developing renal diseases. However, the mechanisms underlying APOL1-associated renal diseases are unknown. Because the APOL1 gene is unique to humans and some primates, new animal models are needed to understand the function of APOL1 in vivo We generated transgenic Drosophila fly lines expressing the human APOL1 wild type allele (G0) or the predominant APOL1 risk allele (G1) in different tissues. Ubiquitous expression of APOL1 G0 or G1 in Drosophila induced lethal phenotypes, and G1 was more toxic than was G0...
November 18, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27856633/effects-of-vitamin-d-receptor-activation-and-dietary-sodium-restriction-on-residual-albuminuria-in-ckd-the-virtue-ckd-trial
#11
Charlotte A Keyzer, G Fenna van Breda, Marc G Vervloet, Maarten A de Jong, Gozewijn D Laverman, Marc H Hemmelder, Wilbert M T Janssen, Hiddo J Lambers Heerspink, Arjan J Kwakernaak, Stephan J L Bakker, Gerjan Navis, Martin H de Borst
Reduction of residual albuminuria during single-agent renin-angiotensin-aldosterone blockade is accompanied by improved cardiorenal outcomes in CKD. We studied the individual and combined effects of the vitamin D receptor activator paricalcitol (PARI) and dietary sodium restriction on residual albuminuria in CKD. In a multicenter, randomized, placebo (PLAC)-controlled, crossover trial, 45 patients with nondiabetic CKD stages 1-3 and albuminuria >300 mg/24 h despite ramipril at 10 mg/d and BP<140/90 mmHg were treated for four 8-week periods with PARI (2 μg/d) or PLAC, each combined with a low-sodium (LS) or regular sodium (RS) diet...
November 17, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27852637/mhc-class-ii-risk-alleles-and-amino-acid-residues-in-idiopathic-membranous-nephropathy
#12
Zhao Cui, Li-Jun Xie, Fang-Jin Chen, Zhi-Yong Pei, Li-Jie Zhang, Zhen Qu, Jing Huang, Qiu-Hua Gu, Yi-Miao Zhang, Xin Wang, Fang Wang, Li-Qiang Meng, Gang Liu, Xu-Jie Zhou, Li Zhu, Ji-Cheng Lv, Fan Liu, Hong Zhang, Yun-Hua Liao, Lu-Hua Lai, Pierre Ronco, Ming-Hui Zhao
Epitopes of phospholipase A2 receptor (PLA2R), the target antigen in idiopathic membranous nephropathy (iMN), must be presented by the HLA-encoded MHC class II molecules to stimulate autoantibody production. A genome-wide association study identified risk alleles at HLA and PLA2R loci, with the top variant rs2187668 within HLA-DQA1 showing a risk effect greater than that of the top variant rs4664308 within PLA2R1. How the HLA risk alleles affect epitope presentation by MHC class II molecules in iMN is unknown...
November 16, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27837150/il-6-trans-signaling-links-inflammation-with-angiogenesis-in-the-peritoneal-membrane
#13
Rusan Catar, Janusz Witowski, Nan Zhu, Christian Lücht, Alicia Derrac Soria, Javier Uceda Fernandez, Lei Chen, Simon A Jones, Ceri A Fielding, Andras Rudolf, Nicholas Topley, Duska Dragun, Achim Jörres
Vascular endothelial growth factor (VEGF) is implicated in the peritoneal membrane remodeling that limits ultrafiltration in patients on peritoneal dialysis (PD). Although the exact mechanism of VEGF induction in PD is unclear, VEGF concentrations in drained dialysate correlate with IL-6 levels, suggesting a link between these cytokines. Human peritoneal mesothelial cells (HPMCs), the main source of IL-6 and VEGF in the peritoneum, do not bear the cognate IL-6 receptor and are thus unable to respond to classic IL-6 receptor signaling...
November 11, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27837149/chronic-hyperphosphatemia-and-vascular-calcification-are-reduced-by-stable-delivery-of-soluble-klotho
#14
Julia M Hum, Linda M O'Bryan, Arun K Tatiparthi, Taryn A Cass, Erica L Clinkenbeard, Martin S Cramer, Manoj Bhaskaran, Robert L Johnson, Jonathan M Wilson, Rosamund C Smith, Kenneth E White
αKlotho (αKL) regulates mineral metabolism, and diseases associated with αKL deficiency are characterized by hyperphosphatemia and vascular calcification (VC). αKL is expressed as a membrane-bound protein (mKL) and recognized as the coreceptor for fibroblast growth factor-23 (FGF23) and a circulating soluble form (cKL) created by endoproteolytic cleavage of mKL. The functions of cKL with regard to phosphate metabolism are unclear. We tested the ability of cKL to regulate pathways and phenotypes associated with hyperphosphatemia in a mouse model of CKD-mineral bone disorder and αKL-null mice...
November 11, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27821631/apol1-renal-risk-variants-induce-mitochondrial-dysfunction
#15
Lijun Ma, Jeff W Chou, James A Snipes, Manish S Bharadwaj, Ann L Craddock, Dongmei Cheng, Allison Weckerle, Snezana Petrovic, Pamela J Hicks, Ashok K Hemal, Gregory A Hawkins, Lance D Miller, Anthony J A Molina, Carl D Langefeld, Mariana Murea, John S Parks, Barry I Freedman
APOL1 G1 and G2 variants facilitate kidney disease in blacks. To elucidate the pathways whereby these variants contribute to disease pathogenesis, we established HEK293 cell lines stably expressing doxycycline-inducible (Tet-on) reference APOL1 G0 or the G1 and G2 renal-risk variants, and used Illumina human HT-12 v4 arrays and Affymetrix HTA 2.0 arrays to generate global gene expression data with doxycycline induction. Significantly altered pathways identified through bioinformatics analyses involved mitochondrial function; results from immunoblotting, immunofluorescence, and functional assays validated these findings...
November 7, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27821630/mitochondrial-nadp-dependent-isocitrate-dehydrogenase-deficiency-exacerbates-mitochondrial-and-cell-damage-after-kidney-ischemia-reperfusion-injury
#16
Sang Jun Han, Hee-Seong Jang, Mi Ra Noh, Jinu Kim, Min Jung Kong, Jee In Kim, Jeen-Woo Park, Kwon Moo Park
Mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, synthesizing NADPH, which is essential for mitochondrial redox balance. Ischemia-reperfusion (I/R) is one of most common causes of AKI. I/R disrupts the mitochondrial redox balance, resulting in oxidative damage to mitochondria and cells. Here, we investigated the role of IDH2 in I/R-induced AKI. I/R injury in mice led to the inactivation of IDH2 in kidney tubule cells. Idh2 gene deletion exacerbated the I/R-induced increase in plasma creatinine and BUN levels and the histologic evidence of tubule injury, and augmented the reduction of NADPH levels and the increase in oxidative stress observed in the kidney after I/R...
November 7, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27821629/polyomavirus-reactivation-and-immune-responses-to-kidney-specific-self-antigens-in-transplantation
#17
Michael E Seifert, Muthukumar Gunasekaran, Timothy A Horwedel, Reem Daloul, Gregory A Storch, Thalachallour Mohanakumar, Daniel C Brennan
Humoral immune responses against donor antigens are important determinants of long-term transplant outcomes. Reactivation of the polyomavirus BK has been associated with de novo antibodies against mismatched donor HLA antigens in kidney transplantation. The effect of polyomavirus reactivation (BK viremia or JC viruria) on antibodies to kidney-specific self-antigens is unknown. We previously reported excellent 5-year outcomes after minimization of immunosuppression for BK viremia and after no intervention for JC viruria...
November 7, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27821628/gene-specific-dna-methylation-changes-predict-remission-in-patients-with-anca-associated-vasculitis
#18
Britta E Jones, Jiajin Yang, Akhil Muthigi, Susan L Hogan, Yichun Hu, Joshua Starmer, Candace D Henderson, Caroline J Poulton, Elizabeth J Brant, William F Pendergraft, J Charles Jennette, Ronald J Falk, Dominic J Ciavatta
ANCA-associated vasculitis is an autoimmune condition characterized by vascular inflammation and organ damage. Pharmacologically induced remission of this condition is complicated by relapses. Potential triggers of relapse are immunologic challenges and environmental insults, both of which associate with changes in epigenetic silencing modifications. Altered histone modifications implicated in gene silencing associate with aberrant autoantigen expression. To establish a link between DNA methylation, a model epigenetic gene silencing modification, and autoantigen gene expression and disease status in ANCA-associated vasculitis, we measured gene-specific DNA methylation of the autoantigen genes myeloperoxidase (MPO) and proteinase 3 (PRTN3) in leukocytes of patients with ANCA-associated vasculitis observed longitudinally (n=82) and of healthy controls (n=32)...
November 7, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27821627/a-randomized-controlled-trial-of-rituximab-in-iga-nephropathy-with-proteinuria-and-renal-dysfunction
#19
Richard A Lafayette, Pietro A Canetta, Brad H Rovin, Gerald B Appel, Jan Novak, Karl A Nath, Sanjeev Sethi, James A Tumlin, Kshama Mehta, Marie Hogan, Stephen Erickson, Bruce A Julian, Nelson Leung, Felicity T Enders, Rhubell Brown, Barbora Knoppova, Stacy Hall, Fernando C Fervenza
IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody-producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy-proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1...
November 7, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27811066/transmembrane-tnf-%C3%AE-facilitates-hiv-1-infection-of-podocytes-cultured-from-children-with-hiv-associated-nephropathy
#20
Jinliang Li, Jharna R Das, Pingtao Tang, Zhe Han, Jyoti K Jaiswal, Patricio E Ray
Studies have shown that podocytes and renal tubular epithelial cells from patients with HIV-associated nephropathy (HIVAN) express HIV-1 transcripts, suggesting that productive infection of renal epithelial cells precipitates development of HIVAN. However, podocytes and renal tubular epithelial cells do not express CD4 receptors, and it is unclear how these cells become productively infected in vivo We investigated the mechanisms underlying the infection by HIV-1 of podocytes cultured from the urine of children with HIVAN...
November 3, 2016: Journal of the American Society of Nephrology: JASN
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