BACKGROUND Cytosine methylation is an epigenetic mark that dictates cell fate and response to stimuli. The timing and establishment of methylation logic during kidney development remains unknown. DNA methyltransferase 3a and 3b are the enzymes capable of establishing de novo methylation. METHODS We generated mice with genetic deletion of Dnmt3a and Dnmt3b in nephron progenitor cells (Six2 Cre Dnmt3a/3b)

BACKGROUND In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding α-galactosidase A lead to accumulation of globotriaosylceramide (GL3) in various cell types. In the glomerular podocytes, accumulation of GL3 progresses with age. Of concern, podocytes are relatively resistant to enzyme replacement therapy and are

BACKGROUND Physician burnout and emotional distress are associated with work dissatisfaction and provision of suboptimal patient care. Little is known about burnout among nephrology fellows. METHODS Validated items on burnout, depressive symptoms, and well being were included in the American Society of Nephrology annual survey emailed to US nephrology fellows in May to June 2018. Burnout was defined

BACKGROUND Although AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized

BACKGROUND Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown. METHODS Using animal models and patient kidney biopsies, we assessed the pathogenic

BACKGROUND Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis

BACKGROUND The analysis and reporting of glomerular features ascertained by electron microscopy are limited to few parameters with minimal predictive value, despite some contributions to disease diagnoses. METHODS We investigated the prognostic value of 12 electron microscopy histologic and ultrastructural changes (descriptors) from the Nephrotic Syndrome Study Network (NEPTUNE) Digital Pathology Scoring

BACKGROUND Because stroke prevention is a major goal in the management of ESKD hemodialysis patients with atrial fibrillation, investigating racial/ethnic disparities in stroke among such patients is important to those who could benefit from strategies to maximize preventive measures. METHODS We used the United States Renal Data System to identify ESKD patients who initiated hemodialysis from 2006

BACKGROUND Leveraging quality metrics can be a powerful approach to identify substantial performance gaps in kidney disease care that affect patient outcomes. However, metrics must be meaningful, evidence-based, attributable, and feasible to improve care delivery. As members of the American Society of Nephrology Quality Committee, we evaluated existing kidney quality metrics and provide a framework

BACKGROUND Aldosterone activates the intercalated cell mineralocorticoid receptor, which is enhanced with hypokalemia. Whether this receptor directly regulates the intercalated cell chloride/bicarbonate exchanger pendrin is unclear, as are potassium's role in this response and the receptor's effect on intercalated and principal cell function in the cortical collecting duct (CCD). METHODS We measured

BACKGROUND Understanding podocyte-specific responses to injury at a systems level is difficult because injury leads to podocyte loss or an increase of extracellular matrix, altering glomerular cellular composition. Finding a window into early podocyte injury might help identify molecular pathways involved in the podocyte stress response. METHODS We developed an approach to apply proteome analysis to

Anemia is a complication that affects a majority of individuals with advanced CKD. Although relative deficiency of erythropoietin production is the major driver of anemia in CKD, iron deficiency stands out among the mechanisms contributing to the impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency plays a significant role in anemia in CKD. This may be due to a true paucity

BACKGROUND The pathophysiology of the leading cause of pediatric acute nephritis, acute postinfectious GN, including mechanisms of the pathognomonic transient complement activation, remains uncertain. It shares clinicopathologic features with C3 glomerulopathy, a complement-mediated glomerulopathy that, unlike acute postinfectious GN, has a poor prognosis. METHODS This retrospective study investigated

BACKGROUND Regulation of sodium chloride transport in the aldosterone-sensitive distal nephron is essential for fluid homeostasis and BP control. The chloride-bicarbonate exchanger pendrin in β-intercalated cells, along with sodium chloride cotransporter (NCC) in distal convoluted tubules, complementarily regulate sodium chloride handling, which is controlled by the renin-angiotensin-aldosterone system

BACKGROUND Gdf15 encodes a TGF-β superfamily member that is rapidly activated in response to stress in multiple organ systems, including the kidney. However, there has been a lack of information about Gdf15 activity and effects in normal kidney and in AKI. METHODS We used genome editing to generate a Gdf15 nuGFP-CE mouse line, removing Gdf15 at the targeted allele, and enabling direct visualization

BACKGROUND The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for γ-adducin (ADD3), a cytoskeletal protein encoded by Add3. METHODS We investigated renal vascular function in vitro and in vivo and the susceptibility to CKD in rats with wild-type or mutated Add3 and in genetically modified rats with

BACKGROUND Urine albumin-to-creatinine ratio (ACR) and protein-to-creatinine ratio (PCR) are used to measure urine protein. Recent guidelines endorse ACR use, and equations have been developed incorporating ACR to predict risk of kidney failure. For situations in which PCR only is available, having a method to estimate ACR from PCR as accurately as possible would be useful. METHODS We used data from

BACKGROUND In 2011, inclusion of injectable medications into an expanded ESKD payment bundle prompted concerns that dialysis facilities facing higher costs might close, disrupting care delivery and access to care. Whether this policy change influenced dialysis facility closures is unknown. METHODS To examine whether facility closures increased after 2011 and whether factors influencing closures changed

BACKGROUND Treatment options to address the hyponatremia induced by the syndrome of inappropriate antidiuresis (SIAD) are inadequate. The sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion and therefore, might offer a novel treatment option for SIAD. METHODS In this double-blind, randomized trial, we recruited 88 hospitalized patients

BACKGROUND Distal diuretics are considered less effective than loop diuretics in CKD. However, data to support this perception are limited. METHODS To investigate whether distal diuretics are noninferior to dietary sodium restriction in reducing BP in patients with CKD stage G3 or G4 and hypertension, we conducted a 6-week, randomized, open-label crossover trial comparing amiloride/hydrochlorothiazide

BACKGROUND Prolyl-4-hydroxylase domain-containing proteins 1-3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor

BACKGROUND Prolyl hydroxylase domain (PHD) inhibitors, which stimulate erythropoietin production through the activation of hypoxia-inducible factor (HIF), are novel therapeutic agents used for treating renal anemia. Several PHD inhibitors, including enarodustat, are currently undergoing phase 2 or phase 3 clinical trials. Because HIF regulates a broad spectrum of genes, PHD inhibitors are expected

BACKGROUND In donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen presentation. After injury, however, resident renal macrophages coexpressing these surface markers acquire a proreparative phenotype, which is pivotal in

Retrospective analyses and single-center prospective studies identify chronic metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase acid excretion but lead to a decline in kidney

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

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

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

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

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

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

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

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

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

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

Patients with ESKD who would benefit from a kidney transplant face a critical and continuing shortage of kidneys from deceased human donors. As a result, such patients wait a median of 3.9 years to receive a donor kidney, by which time approximately 35% of transplant candidates have died while waiting or have been removed from the waiting list. Those of blood group B or O may experience a significantly

BACKGROUND Myeloperoxidase-specific ANCA (MPO-ANCA) are implicated in the pathogenesis of vasculitis and GN. Kinins play a major role during acute inflammation by regulating vasodilatation and vascular permeability and by modulating adhesion and migration of leukocytes. Kinin system activation occurs in patients with ANCA vasculitis. Previous studies in animal models of GN and sclerosing kidney diseases

BACKGROUND Ferroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation

BACKGROUND Mutations in about 50 genes have been identified as monogenic causes of nephrotic syndrome, a frequent cause of CKD. These genes delineated the pathogenetic pathways and rendered significant insight into podocyte biology. METHODS We used whole-exome sequencing to identify novel monogenic causes of steroid-resistant nephrotic syndrome (SRNS). We analyzed the functional significance of an

BACKGROUND The rarity of pediatric glomerular disease makes it difficult to identify sufficient numbers of participants for clinical trials. This leaves limited data to guide improvements in care for these patients. METHODS The authors developed and tested an electronic health record (EHR) algorithm to identify children with glomerular disease. We used EHR data from 231 patients with glomerular disorders

BACKGROUND Despite growth in value-based payment, attributes of nephrology care associated with payer-defined value remains unexplored. METHODS Using national health insurance claims data from private preferred provider organization plans, we ranked nephrology practices using total cost of care and a composite of common quality metrics. Blinded to practice rankings, we conducted site visits at four

BACKGROUND GSTM1 encodes glutathione S-transferase μ-1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent GSTM1 deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study. METHODS We generated a Gstm1 knockout mouse line

BACKGROUND Vitamin K antagonists (VKAs), although commonly used to reduce thromboembolic risk in atrial fibrillation, have been incriminated as probable cause of accelerated vascular calcification (VC) in patients on hemodialysis. Functional vitamin K deficiency may further contribute to their susceptibility for VC. We investigated the effect of vitamin K status on VC progression in 132 patients on

BACKGROUND Kidney transplant recipients must take immunosuppressant drugs to prevent rejection and maintain transplant function. Medicare coverage of immunosuppressant drugs for kidney transplant recipients ceases 36 months after transplantation, potentially increasing the risk of transplant failure. A contemporary economic analysis of extending Medicare coverage for the duration of transplant survival

BACKGROUND The matricellular protein periostin has been associated with CKD progression in animal models and human biopsy specimens. Periostin functions by interacting with extracellular matrix components to drive collagen fibrillogenesis and remodeling or by signaling through cell-surface integrin receptors to promote cell adhesion, migration, and proliferation. However, its role in AKI is unknown