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, and treatment efficacy in these carriers lags compared to patients with other forms of chronic kidney disease (CKD). To develop a population screening strategy with high sensitivity to individuals likely to develop disease, we characterize the presentation and progression of ADPKD in variant carriers, identified in a multi-center all-comers cohort, as well as the UK Biobank. We show that the positive predictive value of hypertension for future diagnosis of kidney disease 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. Using pre-disease timepoint measurements of kidney function prior to their ADPKD diagnosis, we find that PKD1 and PKD2 variant carriers show significantly decreased kidney function (eGFR) an average of 5 years before their clinical diagnosis. Unlike other CKD patients, 54% of variant carriers with hypertension meet the diagnostic threshold for CKD years prior to their disease diagnosis, and their eGFR are statistically indistinguishable from variant carriers who have already been diagnosed. Together, these findings suggest that a population screening strategy using a combination of targeted sequencing and routine monitoring could identify cases of ADPKD with high sensitivity, and support initiating treatment years prior to the current standard of care.
