DOI: 10.1161/circ.148.suppl_1.18925 ISSN: 0009-7322

Abstract 18925: Hypertension Predicts Polycystic Kidney Disease 11 Years Ahead of Time in PKD1 and PKD2 Carriers, With a PPV of 71%

Natalie Telis, Lisa McEwen, Alexandre Bolze, Daniel Judge, Pamala Pawloski, Joseph Grzymski, Kelly Schiabor Barrett, Nicole Washington, Elizabeth Cirulli
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the leading hereditary form of kidney disease and is characterized by the formation of fluid-filled cysts that decrease kidney function and lead to complications including cardiovascular disease, kidney failure, and other organ failure. Although causal variants in the PKD1 and PKD2 genes have been identified, penetrance, morbidity, and outcome are known to vary widely in carriers. We propose to identify early markers of disease and to characterize disease presentation at the level of biomarkers, metabolites, and comorbidity incidence.

Methods: This study is based on exomes and medical information from the UK Biobank (n=470k) and 3 American cohorts (n>70k) sequenced with Helix: the Healthy Nevada Project, In Our DNA SC, and myGenetics. We identified individuals with rare LoF variants in either PKD1 or PKD2. We subsequently analyzed these individuals’ medical records, blood labs, and NMR-based metabolomics data (n~120k) to characterize the detailed clinical and biomarker-level disease presentation.

Results: We find that 0.05% of the general population has a relevant variant in PKD1 or PKD2 (1/2000 people). In this population-level sample, the prevalence of kidney disease in carriers with hypertension is 71% (74% for PKD1 and 66% for PKD2) compared to 12% for noncarriers with hypertension. For carriers without hypertension, the prevalence is 14% (2% for PKD1 and 30% for PKD2) vs. 1% for noncarriers without hypertension. Importantly, the hypertension diagnosis precedes the kidney disease diagnosis by a mean of 11 years in these carriers. We additionally identify a subset of carriers who are outliers for a set of metabolites that includes cystatin C, creatinine and urea. Assessed prospectively, these carriers have decreased eGFR and a number of other signs of early stage kidney disease a mean of 5 years prior to their KD diagnosis.

Conclusion: Identifying PKD1 and PKD2 carriers with hypertension would allow prediction of kidney disease a mean of 11 years in advance of the disease, with a PPV of 71%. Additionally, aberrant but subclinically significant biomarkers can provide an early warning of morbidity.

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