ABSTRACT/SUMMARY Autosomal dominant polycystic kidney (ADPKD) affects an estimated 600,000 individuals in the US and accounts for 5% of patients with end-stage kidney disease (ESKD). At the current time there is only one approved therapy available for patients diagnosed with rapidly progressing disease. This underlines the need for identification of additional measures to slow kidney disease progression in ADPKD patients. Kidney stone disease is highly prevalent, increasingly common, and associated with considerable comorbidity among patients affected with ADPKD. In this proposal, we build on our preliminary data which demonstrates that patients with ADPKD and kidney stone disease have a more rapid loss of kidney function compared to ADPKD patients without kidney stone disease. We will leverage an interdisciplinary team that is uniquely poised to define kidney stone disease in ADPKD by combining expertise in large data analytics and high-dimensional microbiome and metabolomic data. The overall goal of this application is to demonstrate that kidney stone disease in patients with ADPKD represents a significant risk factor for faster kidney disease progression and that antibiotic exposure increases stone risk in this population. A secondary goal is to determine how dysbiosis of the gut microbiome contributes to kidney stone disease. We hypothesize that kidney stone disease contributes to more rapid decline in kidney function in ADPKD through worsening inflammation and that antibiotics contribute to kidney stone disease by perturbing the gut-PKD axis through alterations of the gut microbiome. We test this hypothesis in 3 specific aims. In aim 1, we seek to describe the distribution and composition of kidney stones by sex and age and to determine the link between kidney stone disease and decline in kidney function independent of markers of inflammation and other known risk factors for kidney disease progression. In Aim 2 we investigate the link between antibiotic exposure and kidney stone disease while in Aim 3 we will define the link between oral antibiotic exposure and change in urinary kidney stone risk factors resultant from changes in the microbiome. We will leverage the Intermountain Healthcare System database with medical and pharmacy coverage, and clinical data including stone analysis and the longitudinal data and samples from the NIDDK sponsored HALT-PKD clinical trials. These resources will provide access to 1,823 patients with ADPKD including 296 with kidney stones. We will recruit 100 patients with ADPKD with or without antibiotic exposure to facilitate microbiome and stone risk analysis in aim 3. A barrier to developing new therapies for stone prevention is a lack of understanding of how perturbations of the gut microbiome and downstream metabolite changes in the intestinal and urinary tracts contributes to kidney stone disease. Understanding the gut-PKD axis from the proposed studies will introduce a new paradigm for kidney stone prevention in ADPKD and will provide key insights into novel therapeutic targets for kidney stone disease in ADPKD.

R01DK128842

2021-09-22

2026-06-30