Journal of the American Society of Nephrology

BackgroundMitochondria-driven oxidative/redox stress and inflammation play a major role in chronic kidney disease (CKD) pathophysiology. Compounds targeting mitochondrial metabolism may improve mitochondrial function, inflammation, and redox stress; however, there is limited evidence of their efficacy in CKD. MethodsWe conducted a randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/day of coenzyme Q10 (CoQ10) or 1000 mg/day of nicotinamide riboside (NR)...

Arteriolar hyalinosis in kidneys is an independent predictor of cardiovascular disease, the main cause of mortality in chronic kidney disease (CKD). The underlying molecular mechanisms of protein accumulation in the subendothelial space are not well understood. Using single cell transcriptomic data and whole slide images from kidney biopsies of patients with CKD and acute kidney injury in the Kidney Precision Medicine Project, the molecular signals associated with arteriolar hyalinosis were eval...

BackgroundChronic kidney disease (CKD) is a genetically complex disease determined by an interplay of monogenic, polygenic, and environmental risks. Most forms of monogenic kidney diseases have incomplete penetrance and variable expressivity. It is presently unknown if some of the variability in penetrance can be attributed to polygenic factors. MethodsUsing the UK Biobank (N=469,835 participants) and the All of Us (N=98,622 participants) datasets, we examined two most common forms of monogenic...

Urinary plasminogen/plasmin, or plasmin(ogen)uria, has been demonstrated in proteinuric patients and exposure of cultured podocytes to plasminogen results in injury via oxidative stress pathways. A causative role for plasmin(ogen) as a "second hit" in kidney disease progression has yet to be demonstrated in vivo, and the association between plasmin(ogen)uria and kidney function in glomerular diseases remains unclear. We performed comparative studies in a puromycin aminonucleoside (PAN) nephropat...

BackgroundChronic kidney disease (CKD) affects over 10% of the global population. A genetic diagnosis can be identified in about 30% of pediatric and 10-30% of adults, informing treatment, prognosis, and family-based risk assessment. However, access to renal genetics services remains limited across many healthcare systems. ObjectivesTo characterize the clinical and genetic landscape of CKD in patients referred for genetic evaluation within a Canadian single-centre nephrology-genetics program, a...

BackgroundThe extent to which achieving multiple metabolic treatment targets confers sustained cardiorenal protection across all stages of cardiovascular - kidney - metabolic (CKM) syndrome remains uncertain. MethodsThis multicenter retrospective cohort study used data from the China Renal Data System (CRDS). Participants were classified into CKM stages 1-4. Metabolic target achievement was defined as simultaneous control of blood pressure (BP<130/80 mmHg), fasting blood glucose (FBG<5.6 mmol/L...

Individuals with chronic kidney disease (CKD) have higher rates of hip fracture and post-fracture mortality. Although they may develop age-related osteoporosis similar to those without CKD, they may also exhibit CKD-related metabolic bone disease (MBD), characterized by low, high, or mixed turnover at similar levels of bone mineral density (BMD). Because BMD does not provide information about turnover status, clinical decision-making is challenging. This study evaluated the associations between ...

BackgroundSolute carrier family 13 member 5 (SLC13A5) is a Na -coupled citrate co-transporter that mediates the entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a therapeutic target for reducing progression of kidney disease via its effects on citrate metabolism. However, evidence of its efficacy in humans is limited. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans,...

The burden of advanced chronic kidney disease (CKD) falls disproportionately on minorities including African Americans (AAs) and Hispanic Americans (HAs) with admixed ancestry. Even though APOL1 high-risk genotypes increase risk of kidney disease, their penetrance is incomplete, indicating that the modification of APOL1 high risk may be polygenic. For this study, we used three multi-ethnic cohorts with APOL1 high risk genotypes and calculated a multi-ethnic PRS using publicly available summary s...

BackgroundProgression into more severe stages of chronic kidney disease (CKD) based on estimated glomerular filtration rate (eGFR) and albuminuria are associated with increased risk of end-stage renal failure, cardiovascular diseases, and mortality. Vesicles in the urine are cell-derived particles containing constituents of the cells of origin. Little is known about the prognostic capacity of urinary vesicles for CKD progression. PurposeTo evaluate the association between components of urinary ...

BackgroundATP-citrate lyase (ACLY) inhibition is a promising therapeutic target for dyslipidemia, atherosclerotic cardiovascular disease, non-alcoholic steatohepatitis, and metabolic syndrome. Genetic analysis of its role in chronic kidney disease (CKD) has not been performed. MethodsWe constructed a genetic instrument by selecting variants associated with ACLY expression level in the expression quantitative trait loci genetics consortium (eQTLGen) that includes blood samples from 31,684 partic...

IntroductionThere remains considerable debate as to the cause of the epidemic of Mesoamerican Nephropathy (MeN). We have previously reported early loss of estimated glomerular filtration rate (eGFR) as a surrogate for disease onset in a population-representative cohort study of young-adults at risk of disease from Northwest Nicaragua. Using a nested case-control approach we analysed urine and serum proteins surrounding this timepoint with the aim of gaining insight into the primary disease aetio...

BackgroundVascular and kidney dysfunction commonly co-exist. There is an unmet need for biomarkers of vascular health. Circulating microRNAs (miRs) are disease biomarkers; miR-126 is endothelial cell-enriched. We measured circulating miR-126 in rats with nephrotoxic nephritis (NTN) and humans with acute endothelial and renal injury (vasculitis associated with autoantibodies to neutrophil cytoplasm antigens (ANCA)). We then compared these findings to those from patients with chronic kidney diseas...

BackgroundChronic kidney disease (CKD) represents a leading non-communicable disease, significantly contributing to global morbidity and mortality. Mendelian randomization studies (MR) have been integral in providing robust evidence that increased body mass index (BMI) has a causal impact on CKD. However, dissecting which specific mechanisms are primarily responsible for disease development remains challenging. ObjectiveTo explore whether the effects of BMI to kidney function are driven primari...

BackgroundThe Kidney Precision Medicine Project (KPMP) consortium aims to redefine chronic kidney disease (CKD) by integrating clinical, pathological, and molecular tissue data from kidney biopsies. Here, we demonstrate how biopsy data in CKD can clarify disease etiology and contribute to understandings of disease pathophysiology and clinical prognosis. MethodsThe KPMP is obtaining research kidney biopsies from individuals with CKD (defined as an estimated glomerular filtration rate [eGFR] < 60...

Background and AimsChronic kidney disease (CKD) significantly contributes to global morbidity and mortality. Early, targeted intervention offers an ideal strategy for mitigating this burden. Peptidomic changes inform on CKD onset and progression and hold insights for treatment strategies. We investigated the molecular effects of six different therapeutic interventions in silico in all possible combinations on the urine peptidome, aiming to identify the most beneficial treatment for individual pa...

BackgroundUnexplained kidney failure (uKF) affects 15% of individuals requiring kidney replacement therapy. Absence of a diagnosis creates uncertainty around recurrence after transplantation, familial risk, and participation in therapeutic trials. Whole genome sequencing (WGS) was used to identify genetic variants contributing to uKF. Methods218 patients who presented with uKF < 50 years old were recruited to the UKs 100,000 Genomes Project. Candidate variants in 183 genes were reviewed for pat...

BackgroundC3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN) are rare disorders that frequently result in kidney failure over the long-term. At present, there are no disease-specific treatments approved for these disorders, although there is much interest in the therapeutic potential of complement inhibition. However, the limited duration and necessarily small size of controlled trials means there is a need to quantify how well short-term changes in eGF...

Most data on Alport Syndrome (AS) due to COL4A3 are limited to families with autosomal recessive AS or severe manifestations such as focal segmental glomerulosclerosis (FSGS). Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants (0.2%) who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases ...

COVID-19 morbidity and mortality is increased in patients with diabetes and kidney disease via unknown mechanisms. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Since ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease (DKD) and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of healthy living donor (LD) and DKD kidney biopsies revealed ACE2 expression primarily in proximal tubular epithel...