Dietary potassium and gene-environment interactions in apolipoprotein L1 nephropathy

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Boston Medical Center Corporation $888,383 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate dietary potassium and gene-environment interactions in apolipoprotein L1 nephropathy.

The research examines how dietary potassium intake modulates kidney disease progression and hypertension in individuals carrying APOL1 high-risk genotypes, which occur in 13 percent of African Americans and drive disproportionate chronic kidney disease burden in this population. The study builds on prior findings showing that Black individuals with high-risk genotypes consuming high dietary potassium were 67 percent less likely to experience progressive chronic kidney disease than those with low potassium intake. The project will determine the impact of dietary potassium on the renin-angiotensin-aldosterone system, inflammation, and blood pressure across APOL1 genotypes using stored human samples with three-year follow-up data from the investigator's prior K23 study, combined with translational research in APOL1 transgenic mice. The central hypothesis posits that low potassium intake in high-risk genotype carriers stimulates angiotensin II production, increasing interferon-gamma and APOL1 gene expression, leading to podocytopathy, chronic kidney disease progression, and endothelial dysfunction.

Work is performed in Roxbury, Massachusetts. The period of performance runs from September 1, 2026, through May 31, 2030.

Abstract

Individuals of african ancestry are disproportionately affected by chronic kidney disease (CKD) and high blood pressure (BP), in part due to the apolipoprotein L1 (APOL1) high-risk genotypes, which are present in 13% in african americans. Identifying gene by environment interactions in APOL1 kidney disease and hypertension is crucial to better understand, treat, and manage CKD in this significant US population. Low dietary potassium (k) is also a known risk factor for CKD and hypertension. The PI of this study builds upon a previously discovered novel relationship between dietary k (measured by urinary k excretion) and APOL1: black individuals with high-risk genotypes with high k intake were 67% less likely to have progressive CKD than those with low k intake. However, the mechanisms underlying the divergent effects of k, especially the involvement of renin angiotensin aldosterone system (raas) modulation across APOL1 genotypes, remain to be elucidated. Thus, our specific aims are to: 1) determine the impact of dietary k on raas and inflammation leading to podocytopathy and CKD progression across APOL1-genotypes, and 2) determine the impact of k on raas, endotheliopathy, and BP across APOL1 genotypes. Our central hypothesis is that in APOL1 high- risk genotypes, low k intake stimulates angiotensin II (ANG II), resulting in increased production of interferon gamma (IFN-γ), inducing APOL1 gene expression, leading to podocytopathy, and CKD progression, endotheliopathy, and elevated BP. Using stored human samples, adding 3-year follow-up to the PI's K23 diet, CKD, and APOL1 (DCA) study and APOL1 transgenic mice, our team of clinical and translational scientists propose synergistic human and animal studies. Our overall approach will utilize the gold-standard of dietary k measurement-24H urine k excretion, biomarker measurements (IFN-γ and endothelin-1) and CKD and BP outcomes in a unique, prospective cohort of individuals in sub-saharan africa. Synergistic animal studies will use the bacterial artificial chromosome (BAC)/APOL1 transgenic mice to examine the impact of low, normal and high-k diet on APOL1 gene expression, investigate raas-related mechanistic pathways, and examine histopathology. The successful completion of these aims will not only establish the significance of dietary k and raas modulation for APOL1-mediated CKD and hypertension but also provide vital mechanistic data to support future randomized controlled trials and other studies investigating k supplementation in individuals who are carriers of the high-risk APOL1 genotypes. This study will employ an innovative novel methodological approach using the DCA study population and identify and explain novel gene-diet interaction in CKD and hypertension. IT would also develop a scientific basis for a precision medicine approach to dietary interventions in individuals of african ancestry. The proposed work will generate insights that fundamentally shape scientific and clinical landscape of APOL1 kidney disease, with implications for patient care in the u.s and worldwide.