Increasing Lipid Droplet Formation to Divert Harmful APOL1 Risk Variant Polypeptides
Variants G1 and G2 of the gene encoding apolipoprotein L1 (APOL1) are associated with increased risk of kidney disease in certain populations. In previous work, the authors demonstrated that recruitment of these variants from the endoplasmic reticulum to lipid droplets is associated with reduced APOL1 risk variant–mediated cytotoxicity in human podocytes. In this study, they developed isogenic human kidney organoids expressing wild-type APOL1 or risk variant APOL1. After IFN-γ treatment, risk variant organoids had greater increases in APOL1 expression compared with wild-type organoids, and they downregulated genes involved in lipogenesis and lipid droplet formation. Unstimulated risk variant organoids also had fewer lipid droplets. In addition, the authors showed that inhibition of diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride biosynthesis, upregulates genes involved in lipid droplet formation and diverts APOL1 risk variant polypeptides to the lipid droplets, with associated reduction in cytotoxicity. DGAT2 inhibitors may thus represent a potential therapeutic approach to reduce the cytotoxic effects of APOL1 risk variants that contribute to APOL1 nephropathy. See Chun et al., pages 889–907.
Clonal Hematopoiesis of Indeterminate Potential in Advanced Chronic Kidney Disease
Clonal hematopoiesis of indeterminate potential (CHIP), a premalignant expansion of clonal leukocytes caused by acquired somatic mutations in myeloid stem/progenitor cells, occurs in 10%–15% of the general population aged 65 years or older. This proinflammatory condition appears causally associated with cardiovascular disease and death, but its role in chronic kidney disease (CKD) is unknown. The authors performed targeted sequencing to detect CHIP mutations in two independent cohorts of adults with advanced CKD, finding that that 43 of 172 individuals (25%) had CHIP. Those with CHIP had a 2.2-fold greater risk of kidney failure over 5 years of follow-up and were more likely to have anemia and other complications of CKD compared with those without CHIP. More research, including studies in animal models, is needed to understand the relationship between CHIP and CKD. CHIP-related inflammation might offer a novel therapeutic target for those with CHIP and CKD. See Vlasschaert et al., pages 985–995. Also see related editorial by Niroula and Belizaire, pages 878–879.
TNFR1 and TNFR2 as Biomarkers of Kidney Outcomes
Recent research suggests that biomarkers of the tumor necrosis factor pathway, the soluble TNF receptors 1 and 2 (TNFR1 and TNFR2), are associated with worse kidney outcomes. Most of these studies, however, evaluated baseline levels of these biomarkers of inflammation rather than longitudinal changes. To investigate such changes, Chen et al. studied two cohorts, the African American Study of Kidney Disease and Hypertension (AASK), which enrolled African American persons with CKD attributed to hypertension, and the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, which enrolled veterans with albuminuric CKD and type 2 diabetes. In the AASK cohort, greater longitudinal increases in serum or plasma TNFR1 and TNFR2 over a median of 7.0 years were associated with higher risks of ESKD. In the VA NEPHRON-D cohort, greater increases of TNFR1 and TNFR2 over a median of 1.5 years were associated with subsequent kidney function decline. These associations were independent of baseline biomarker level and kidney function. Longitudinal trajectories in TNFR1 and TNFR2 may ultimately allow improved risk assessment for kidney failure in persons with CKD. See Chen et al., pages 996–1010.
