Journal of the American Society of Nephrology: JASN | Page 2

Sequence and copy number variations in the human CFHR-Factor H gene cluster comprising the complement genes CFHR1 , CFHR2 , CFHR3 , CFHR4 , CFHR5 , and Factor H are linked to the human kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alterations, deletions, or duplications generate hybrid or mutant CFHR genes, as well as hybrid CFHR-Factor H genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging: CFHR1 , CFHR3 , and Factor H gene alterations combined with intact CFHR2 , CFHR4 , and CFHR5 genes are reported in atypical hemolytic uremic syndrome...

BACKGROUND: Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear. METHODS: Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number...

BACKGROUND: Despite efforts to increase arteriovenous fistula and graft use, 80% of patients in the United States start hemodialysis on a central venous catheter (CVC). METHODS: To better understand in incident hemodialysis patients how sex and race/ethnicity are associated with time on a central venous catheter and transition to an arteriovenous fistula and graft, our observational cohort study analyzed US Renal Data System data for patients with incident ESKD aged ≥66 years who started hemodialysis on a CVC in July 2010 through 2013...

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BACKGROUND: Mononuclear phagocytes (MPs), including macrophages, monocytes, and dendritic cells (DCs), are phagocytic cells with important roles in immunity. The developmental origin of kidney DCs has been highly debated because of the large phenotypic overlap between macrophages and DCs in this tissue. METHODS: We used fate mapping, RNA sequencing, flow cytometry, confocal microscopy, and histo-cytometry to assess the origin and phenotypic and functional properties of renal DCs in healthy kidney and of DCs after cisplatin and ischemia reperfusion-induced kidney injury...

BACKGROUND: Inhibition of angiotensin II (AngII) signaling, a therapeutic mainstay of glomerular kidney diseases, is thought to act primarily through regulating glomerular blood flow and reducing filtration pressure. Although extravascular actions of AngII have been suggested, a direct effect of AngII on podocytes has not been demonstrated in vivo . METHODS: To study the effects of AngII on podocyte calcium levels in vivo , we used intravital microscopy of the kidney in mice expressing the calcium indicator protein GCaMP3...

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BACKGROUND: Mutations in the gene encoding inverted formin-2 (INF2), a member of the formin family of actin regulatory proteins, are among the most common causes of autosomal dominant FSGS. INF2 is regulated by interaction between its N-terminal diaphanous inhibitory domain (DID) and its C-terminal diaphanous autoregulatory domain (DAD). INF2 also modulates activity of other formins, such as the mDIA subfamily, and promotes stable microtubule assembly. Why the disease-causing mutations are restricted to the N terminus and how they cause human disease has been unclear...

BACKGROUND: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. METHODS: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study...

BACKGROUND: Several genetic susceptibility loci associated with diabetic nephropathy have been documented, but no causative variants implying novel pathogenetic mechanisms have been elucidated. METHODS: We carried out whole-genome sequencing of a discovery cohort of Finnish siblings with type 1 diabetes who were discordant for the presence (case) or absence (control) of diabetic nephropathy. Controls had diabetes without complications for 15-37 years. We analyzed and annotated variants at genome, gene, and single-nucleotide variant levels...

BACKGROUND: Cardiorenal syndrome is a well known concept, bolstered by extensive investigations of CKD as a risk factor of cardiovascular disease. However, data on whether cardiovascular disease increases long-term risk of ESKD are sparse. METHODS: We assessed the association of incident hospitalization with major cardiovascular diseases (heart failure, atrial fibrillation, coronary heart disease, and stroke) with subsequent risk of ESKD among individuals enrolled in the Atherosclerosis Risk in Communities study; the analysis included 9047 individuals without prevalent cardiovascular disease at their fourth study visit...

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BACKGROUND: Although most American patients with ESKD become eligible for Medicare by their fourth month of dialysis, some never do. Information about where patients with limited health insurance receive maintenance dialysis has been lacking. METHODS: We identified patients initiating maintenance dialysis (2008-2015) from the US Renal Data System, defining patients as "safety-net reliant" if they were uninsured or had only Medicaid coverage at dialysis onset and had not qualified for Medicare by the fourth dialysis month...

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BACKGROUND: The progression rate of CKD varies substantially among patients. The genetic and epigenetic contributions that modify how individual patients respond to kidney injury are largely unknown. Emerging evidence has suggested that histone H3 K79 methyltransferase Dot1l has an antifibrotic effect by repressing Edn1 , which encodes endothelin 1 in the connecting tubule/collecting duct. METHODS: To determine if deletion of the Dot1l gene is a genetic and epigenetic risk factor through regulating Edn1, we studied four groups of mice: wild-type mice, connecting tubule/collecting duct-specific Dot1l conditional knockout mice ( Dot1lAC ), Dot1l and Edn1 double-knockout mice ( DEAC ), and Edn1 connecting tubule/collecting duct-specific conditional knockout mice ( Edn1AC ), under three experimental conditions (streptozotocin-induced diabetes, during normal aging, and after unilateral ureteral obstruction)...

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BACKGROUND: Sickle cell trait and sickle cell disease are thought to be independent risk factors for CKD, but the trajectory and predictors of kidney function decline in patients with these phenotypes are not well understood. METHODS: Our multicenter, observational study used registry data (collected January 2005 through June 2018) and included adult black patients with sickle cell trait or disease (exposures) or normal hemoglobin phenotype (reference) status (ascertained by electrophoresis) and at least 1 year of follow-up and three eGFR values...

BACKGROUND: Renal autoregulation maintains stable renal function despite BP fluctuations and protects glomerular capillaries from hypertensive injury. However, real-time dynamics of renal autoregulation in conscious animals have not been characterized. METHODS: To develop novel analytic methods for assessing renal autoregulation, we recorded concurrent BP and renal blood flow in conscious rats, comparing animals with renal autoregulation that was intact versus impaired (from 3/4 nephrectomy), before and after additional impairment (from the calcium channel blocker amlodipine)...