Hypertension increases PPV for polycystic kidney disease in PKD1 and PKD2 variant carriers

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic form of kidney disease. Although rare causal variants in the PKD1 and PKD2 genes have been identified, their penetrance and the disease progression and outcome are known to vary widely in carriers, and treatment efficacy in these carriers lags compared to patients with chronic kidney disease (CKD). We characterize the presentation and progression of ADPKD by identifying variant carriers in a novel exome sequencing cohort as well as in the UK Biobank. We show that the positive predictive value of hypertension for future diagnosis of kidney disease in variant carriers is extremely high: 74% and 66% for PKD1 and PKD2 respectively. It is also highly preemptive, with hypertension occurring an average of 11 years before a kidney disease diagnosis. We estimate measures of kidney function for individuals at timepoints prior to their diagnoses and find that PKD1 and PKD2 variant carriers show significantly decreased eGFR an average of 5 years before their eventual diagnosis of kidney disease. In fact, at a standard assessment performed a mean of 5 years prior to kidney disease diagnosis, 54% of PKD1 and PKD2 variant carriers with hypertension already meet the diagnostic threshold for kidney disease, and their eGFR levels are statistically indistinguishable from carriers who have already been diagnosed. Together, these findings suggest that ADPKD could be anticipated and treated significantly earlier using a combination of targeted sequencing and routine monitoring. ### Competing Interest Statement Authors affiliated with Helix are employees of Helix. ### Funding Statement Funding was provided to the Desert Research Institute by the Renown Institute for Health Innovation and the Renown Health Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Helix cohorts were reviewed by Salus IRB (Reliance on Salus for all sites) and approved (approval number 21143), the WIRB CG IRB (Western Institutional Review Board, WIRB-Copernicus Group) and approved (approval number 20224919), the MUSC Institutional Review Board for Human Research and approved (approval number Pro00129083), and the University of Nevada, Reno Institutional Review Board and approved (approval number 7701703417). The UK Biobank study was approved by the North West Multicenter Research Ethics Committee, United Kingdom. All participants gave their informed, written consent before participation. All data used for research were de-identified. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Summary data produced in the present work are contained in the manuscript.