Kidney Failure In Participants Research Articles

NAT8 Variants, N-Acetylated Amino Acids, and Progression of CKD.

Genetic variants in NAT8, a liver- and kidney-specific acetyltransferase encoding gene, have been associated with eGFR and CKD in European populations. Higher circulating levels of two NAT8-associated metabolites, N-δ-acetylornithine and N-acetyl-1-methylhistidine, have been linked to lower eGFR and higher risk of incident CKD in the Black population. We aimed to expand upon prior studies to investigate associations between rs13538, a missense variant in NAT8, N-acetylated amino acids, and kidney failure in multiple, well-characterized cohorts. We conducted analyses among participants with genetic and/or serum metabolomic data in the African American Study of Kidney Disease and Hypertension (AASK; n=962), the Atherosclerosis Risk in Communities (ARIC) study (n=1050), and BioMe, an electronic health record-linked biorepository (n=680). Separately, we evaluated associations between rs13538, urinary N-acetylated amino acids, and kidney failure in participants in the German CKD (GCKD) study (n=1624). Of 31 N-acetylated amino acids evaluated, the circulating and urinary levels of 14 were associated with rs13538 (P<0.05/31). Higher circulating levels of five of these N-acetylated amino acids, namely, N-δ-acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure, after adjustment for confounders and combining results in meta-analysis (combined hazard ratios per two-fold higher amino acid levels: 1.48, 1.44, 1.21, 1.65, and 1.41, respectively; 95% confidence intervals: 1.21 to 1.81, 1.22 to 1.70, 1.08 to 1.37, 1.29 to 2.10, and 1.17 to 1.71, respectively; all P values <0.05/14). None of the urinary levels of these N-acetylated amino acids were associated with kidney failure in the GCKD study. We demonstrate significant associations between an NAT8 gene variant and 14 N-acetylated amino acids, five of which had circulation levels that were associated with kidney failure.

Effects of Canagliflozin in Patients with Baseline eGFR

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m2. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300-5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m2 at randomization. Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m2). From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, -1.30 versus -3.83 ml/min per 1.73 m2 per year; difference, -2.54 ml/min per 1.73 m2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.12). This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m2.

GSTM1 Copy Number Is Not Associated With Risk of Kidney Failure in a Large Cohort.

Deletion of glutathione S-transferase µ1 (GSTM1) is common in populations and has been asserted to associate with chronic kidney disease progression in some research studies. The association needs to be validated. We estimated GSTM1 copy number using whole exome sequencing data in the DiscovEHR cohort. Kidney failure was defined as requiring dialysis or receiving kidney transplant using data from the electronic health record and linkage to the United States Renal Data System, or the most recent eGFR < 15 ml/min/1.73 m2. In a cohort of 46,983 unrelated participants, 28.8% of blacks and 52.1% of whites had 0 copies of GSTM1. Over a mean of 9.2 years follow-up, 645 kidney failure events were observed in 46,187 white participants, and 28 in 796 black participants. No significant association was observed between GSTM1 copy number and kidney failure in Cox regression adjusting for age, sex, BMI, smoking status, genetic principal components, or comorbid conditions (hypertension, diabetes, heart failure, coronary artery disease, and stroke), whether using a genotypic, dominant, or recessive model. In sensitivity analyses, GSTM1 copy number was not associated with kidney failure in participants that were 45 years or older at baseline, had baseline eGFR < 60 ml/min/1.73 m2, or with baseline year between 1996 and 2002. In conclusion, we found no association between GSTM1 copy number and kidney failure in a large cohort study.

Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD

Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown. Prospective observational cohort study. 3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March2013. Baseline uric acid concentrations. Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality. During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs)≥ 45mL/min/1.73m2 (adjusted HR per 1-standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs<30mL/min/1.73m2. There was a nominally higher HR in participants with eGFRs of 30 to 44mL/min/1.73m2 (adjusted HR, 1.13; 95% CI, 0.99-1.29),butthis did not reach statistical significance.The relationship between uric acid concentrationand all-cause mortality was J-shaped (P=0.007). Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time. Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD.

Risk Factors for ESRD in Individuals With Preserved Estimated GFR With and Without Albuminuria: Results From the Kidney Early Evaluation Program (KEEP)

Given the increasing costs and poor outcomes of end-stage renal disease (ESRD), we sought to identify risk factors for ESRD in people with preserved estimated glomerular filtration rate (eGFR), with or without albuminuria, who were at high risk of ESRD. This cohort study included participants in the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) with eGFR ≥ 60 mL/min/1.73 m(2) at baseline stratified by the presence or absence of albuminuria. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate eGFR. Urine was tested for albuminuria by semiquantitative dipstick. The outcome was the development of treated chronic kidney failure, defined as initiation of maintenance dialysis therapy or kidney transplantation, determined by linkage to the US Renal Data System. We used a Cox model with the Fine-Gray method to assess risk factors for treated chronic kidney failure while accounting for the competing risk of death. During a median follow-up of 4.8 years, 126 of 13,923 participants with albuminuria (16/10,000 patient-years) and 56 of 109,135 participants without albuminuria (1.1/10,000 patient-years) developed treated chronic kidney failure. Diabetes was a strong risk factor for developing treated chronic kidney failure in participants with and without albuminuria (adjusted HRs of 9.3 [95% CI, 5.7-15.3] and 7.8 [95% CI, 4.1-14.8], respectively). Black race, lower eGFR, and higher systolic blood pressure also were associated with higher adjusted risks of developing treated chronic kidney failure. In a diverse high-risk cohort of KEEP participants with preserved eGFR, we showed that diabetes, higher systolic blood pressure, lower eGFR, and black race were risk factors for developing treated chronic kidney failure irrespective of albuminuria status, although the absolute risk of kidney failure in participants without albuminuria was very low. Our findings support testing for kidney disease in high-risk populations, which often have otherwise unrecognized kidney disease.