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Background: Apolipoprotein L1 gene (APOL1) G1 and G2 kidney-risk variants (KRVs) cause CKD in African Americans, inducing mitochondrial dysfunction. Modifying factors are required, because a minority of individuals with APOL1 high-risk genotypes develop nephropathy. Given that APOL1 function is pH-sensitive and the pH of the kidney interstitium is <7, we hypothesized the acidic kidney interstitium may facilitate APOL1 KRV-induced mitochondrial dysfunction., Methods: Human embryonic kidney (HEK293) cells conditionally expressing empty vector (EV), APOL1-reference G0, and G1 or G2 KRVs were incubated in media pH 6.8 or 7.4 for 4, 6, or 8 h. Genotype-specific pH effects on mitochondrial length (µm) were assessed using confocal microscopy in live cells and Fiji derivative of ImageJ software with MiNA plug-in. Lower mitochondrial length indicated fragmentation and early dysfunction., Results: After 6 h doxycycline (Dox) induction in pH 6.8 media, G2-expressing cells had shorter mitochondria (6.54 ± 0.40) than cells expressing EV (7.65 ± 0.72, p = 0.02) or G0 (7.46 ± 0.31, p = 0.003). After 8 h Dox induction in pH 6.8 media, both G1- (6.21 ± 0.26) and G2-expressing cells had shorter mitochondria (6.46 ± 0.34) than cells expressing EV (7.13 ± 0.32, p = 0.002 and p = 0.008, respectively) or G0 (7.22 ± 0.45, p = 0.003 and p = 0.01, respectively). Mitochondrial length in cells incubated in pH 7.4 media were comparable after 8 h Dox induction regardless of genotype. APOL1 mRNA expression and cell viability were comparable regardless of pH or genotype after 8 h Dox induction., Conclusion: Acidic pH facilitates early mitochondrial dysfunction induced by APOL1 G1 and G2 KRVs in HEK293 cells. We propose that the acidic kidney interstitium may play a role in APOL1-mediated mitochondrial pathophysiology and nephropathy., (© 2020 S. Karger AG, Basel.)

Background: Arteriovenous accesses (AVA) in patients performing hemodialysis (HD) are labeled "permanent" for AV fistulas (AVF) or grafts (AVG) and "temporary" for tunneled central venous catheters (TCVC). Durability and outcomes of permanent vascular accesses based on the sequence in which they were placed or used receives little attention. This study analyzed longitudinal transitions between TCVC-based and AVA-based HD outcomes according to the order of placement., Methods: All 391 patients initiating chronic HD via a TCVC between 2012 and 2013 at 12 outpatient academic dialysis units were included in this study. Chronological distributions of HD vascular accesses were recorded over a mean (SD) of 2.8 (0.9) years and sequentially grouped into periods for TCVC-delivered and AVA-delivered (AVF or AVG) HD. Primary AVA failure and cumulative access survival were evaluated based on access placement sequence and type, adjusting for age., Results: In total, 92.3% (361/391) of patients underwent 497 AVA placement surgeries. Analyzing the initial 3 surgeries, primary AVF failure rates increased with each successive fistula placement (p = 0.008). Among the 82.9% (324/391) of TCVC patients successfully converted to an AVA, 30.9% returned to a TCVC, followed by a 58.0% conversion rate to another AVA. Annual per-patient vascular access transition rates were 2.02 (0.09) HD periods using a TCVC and 0.54 (0.03) HD periods using an AVA. Comparing the first AVA used with the second, cumulative access survivals were 701.0 (370.0) vs. 426.5 (275.0) days, respectively. Excluding those never converting to an AVF or AVG, 169 (52.2%) subsequently converted from a TCVC to a permanent access and received HD via AVA for ≥80% of treatments., Conclusions: HD vascular access outcomes differ based on the sequence of placement. In spite of frequent AVA placements, only half of patients effectively achieved a "permanent" vascular access and used an AVA for the majority of HD treatments., (© 2017 S. Karger AG, Basel.)

Background: The utility of glycated hemoglobin (HbA1c) and glycated albumin (GA) in diabetic dialysis patients remains unknown. GA was previously associated with all-cause hospitalization and patient survival. Relationships between GA, HbA1c, and casual plasma glucose (PG) with cause-specific cardiovascular (CV) disease, infectious disease (ID), and vascular access- (VA) related hospitalization rates and length of stay (LOS) were assessed., Methods: 444 prevalent diabetic dialysis patients had monthly PG, quarterly GA, and all HbA1c values recorded for 2.33 years; hospitalizations within 17 and 30 days of testing were evaluated. Best-fit, time-dependent Cox models were constructed in unadjusted, case-mix-adjusted (age, sex, race, BMI, diabetes duration, dialysis vintage), and case-mix- plus lab-adjusted (hemoglobin, albumin, phosphorus) models., Results: Mean ± SD diabetes duration was 18.5 ± 10.8 years and dialysis vintage 2.9 ± 2.6 years. In fully adjusted models, CV hospitalization rates were associated with increasing GA (HR 1.32; 95% CI 1.11-1.57; p = 0.002 at 17 days; HR 1.21; p = 0.02 at 30 days) and PG (HR 1.10; 95% CI 1.02-1.17; p = 0.01 at 17 days; HR 1.07; p = 0.03 at 30 days), not HbA1c (HR 1.24; 95% CI 0.89-1.73; p = 0.21 at 17 days; HR 1.26; p = 0.10 at 30 days). LOS for CV admissions was positively associated with GA (HR 1.18; 95% CI 1.01-1.39; p = 0.03), not PG (HR 1.04; 95% CI 0.99-1.10; p = 0.15) or HbA1c (HR 1.03; 95% CI 0.92-1.15; p = 0.21). Admissions due to ID and VA complications (and LOS) did not correlate with these assays., Conclusions: Improved glycemic control based on GA and PG predicted CV-related hospitalizations; GA also predicted CV hospitalization LOS. HbA1c did not predict cause-specific hospitalizations in dialysis populations., (Copyright © 2012 S. Karger AG, Basel.)

Background: African-Americans (AAs) with diabetes have high incidence rates of end-stage renal disease (ESRD) with associated high mortality. Genetic factors modulating the risk of mortality on dialysis are poorly understood., Methods: A genome-wide association study was performed in 610 AAs with type 2 diabetes (T2D) and ESRD on dialysis, using the Affymetrix 6.0 platform (868,155 SNPs). Time to death was assessed using Cox proportional hazards model adjusting for ancestry and other confounding variables. Cases were censored at kidney transplant or (if living) at study conclusion., Results: Mean follow-up was 5.4 ± 3.5 years; 434 deaths were recorded. Five SNPs were associated with time to death at p < 1.00 × 10(-6): rs2681019 (HR = 2.58, P(REC) = 8.00 × 10(-8)), rs815815 in CALM2 (HR = 1.51, P(ADD) = 6.50 × 10(-7)), rs926392 (HR = 2.37, P(REC) = 4.80 × 10(-7)), and rs926391 (HR = 2.30, P(REC) = 7.30 × 10(-7)) near DHX35, and rs11128347 in PDZRN3 (HR = 0.57, P(ADD) = 6.00 × 10(-7)). Other SNPs had nominal associations with time to death (p < 1.00 × 10(-5))., Conclusion: Genetic variation may modify the risk of death on dialysis. SNPs in proximity to genes regulating vascular extracellular matrix, cardiac ventricular repolarization, and smoking cessation are associated with dialysis survival in AAs with T2D. These results warrant replication in other cohorts and races., (Copyright © 2011 S. Karger AG, Basel.)

Background: African Americans (AA) disproportionately develop lupus nephritis (LN) relative to European Americans and familial clustering supports causative genes. Since MYH9 underlies approximately 40% of end-stage renal disease (ESRD) in AA, we tested for genetic association with LN., Methods: Seven MYH9 single nucleotide polymorphisms (SNPs) and the E1 risk haplotype were tested for association with LN in three cohorts of AA., Results: A preliminary analysis revealed that the MYH9 E1 risk haplotype was associated with ESRD in 25 cases with presumed systemic lupus erythematosus (SLE)-associated ESRD, compared to 735 non-SLE controls (odds ratio 3.1; p = 0.010 recessive). Replication analyses were performed in 583 AA with SLE in the PROFILE cohort (318 with LN; 265 with SLE but without nephropathy) and 60 AA from the NIH (39 with LN; 21 with SLE but without nephropathy). Analysis of the NIH and larger PROFILE cohorts, as well as a combined analysis, did not support this association., Conclusions: These results suggest that AA with ESRD and coincident SLE who were recruited from dialysis clinics more likely have kidney diseases in the MYH9-associated spectrum of focal segmental glomerulosclerosis. PROFILE and NIH participants, recruited from rheumatology practices, demonstrate that MYH9 does not contribute substantially to the development of LN in AA., (Copyright 2010 S. Karger AG, Basel.)

Podocytes play a key role in the maintenance of the glomerular filtration barrier. Depletion or dysregulative mechanisms of podocytes can lead to the development of glomerulosclerosis. Signaling pathways that control these processes in podocytes are not fully understood. Recent studies from our and other laboratories found that genes that belong to the Notch pathway are regulated in patients and in animal models of renal disease. Genetic studies performed on mice with conditional expression of active Notch1 protein showed massive albuminuria, glomerulosclerosis, and ultimately renal failure and death of the animals. gamma-Secretase inhibitors and genetic deletion of Notch transcriptional binding partner (Rbpj) protected animals from nephrotic syndrome. Further studies are needed to define whether the activation of Notch pathway in podocytes represents a common pathomechanism in glomerular injury, and its potential to be a therapeutic target for the treatment of chronic kidney disease., (2009 S. Karger AG, Basel.)