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Progressive Loss of Renal Function Is an Age-Dependent Heritable Trait in Type 1 Autosomal Dominant Polycystic Kidney Disease

Andrew D. Paterson^*, Riccardo Magistroni^,, Ning He, Kairong Wang, Ann Johnson, Pamela R. Fain, Elizabeth Dicks^||, Patrick Parfrey^||, Peter St. George-Hyslop and York Pei

^* Program in Genetics and Genomic Biology, Hospital for Sick Children and Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada; Division of Nephrology, University of Modena and Reggio Emilia, Modena, Italy; Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Denver, Colorado; and ^|| Division of Nephrology, Memorial University, St. John’s, Newfoundland, Canada

Address correspondence to: Dr. York Pei, Division of Nephrology, University Health Network, 13 EN-228, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. Phone: 416-340-4257; Fax: 416-340-4999; E-mail: york.pei{at}uhn.on.ca

Significant intrafamilial phenotypic variability is well documented in autosomal dominant polycystic kidney disease (ADPKD) and suggests a modifier effect. In this study, variance components analysis was performed to estimate the contribution of genetic factors for within-family renal disease variability in 406 patients from 66 type 1 ADPKD families. Overall, 39% of the study patients had ESRD at their last follow-up, and their renal survival did not differ by gender (P = 0.35, log-rank test). Because their frequency plot of creatinine clearance (Ccr) assumed a bimodal distribution with a marked kurtosis that was not improved by transformations, the study cohort was decomposed into two separate groups (non-ESRD [n = 247] and ESRD [n = 159]) in which the Ccr plots were normally distributed. The heritability (h²) of Ccr and age at ESRD (age_ESRD) and the genetic correlations between these measures and their covariates were estimated. In patients without ESRD, a significant heritability was found for Ccr (h² = 0.42; P = 0.0015) after adjusting for age (P = 0.0001), systolic BP (P = 0.0006), and treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (P = 0.00001). Birth year, gender, BMI, diastolic and mean BP, and pack-years of cigarette smoking did not significantly influence the heritability of this trait. In patients with ESRD, age_ESRD provides a better measure than Ccr, which was very narrowly distributed. A significant heritability was found for age_ESRD (h² = 0.78; P = 0.00009) in these latter patients. None of the above covariates influenced the heritability of this trait. It is concluded that a significant modifier gene effect influences the progression of renal disease in type 1 ADPKD.

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