Background Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder leading to end-stage renal disease, (ESRD) in the majority of cases. There is significant interindividual variability in clinical severity, attributed to randomly acquired somatic mutations or “second hits” affecting renal cystogenesis. Disease severity has been traditionally based on age of onset of ESRD. Decline in glomerular filtration rate (GFR) is late, after renal enlargement and increased mean renal volume (MRV) occurs. Preliminary reports from CRISP study suggest that MRV seems to be an earlier marker of disease severity. The respective influence of genetic and environmental factors in causing the severity of the disease is unknown.
Methods We determined heritability estimate (h2) of MRV and GFR in ADPKD by analyzing available sib-pairs from the COHORT study. 256 ADPKD individuals (age: 43.6 10.7 range: 15-73 years) not yet on dialysis (GFR: 67.9 34.3 mL/min/1.73 m2 range: 6.7-170.6 mL/min/1.73 m2) were studied in a prospective fashion as part of the COHORT study funded by the Polycystic Kidney Disease Foundation. WE studied 55 adult sibs (age: 36.8 ± 8.7, range: 18, 53 years, GFR: 86.4 ± 33.6, range: 18.3, 154.4 mL/min/1.73 m2, MRV: 652.5 ± 408.9 mL, range: 190.6, 1756.2 mL). There were 27 single sibs, 24 with 2 members, and 2 with 3 members. During the baseline visit, all subjects underwent iothalamate GFR, magnetic resonance determination of MRV and determination of clinical variables including age, weight, height, blood pressure, and serum creatinine level. Sib-pairs were defined as sibs within a single generation in each family. Relevant covariates including age and gender were included in the heritability estimates of MRV; age was included in the heritability estimates of height; and age, gender and log MRV were included in the heritability estimates of GFR. H2 was defined as 2 times the interclass correlation coefficient (ICC).
Results ICC for height, log MRV and GFR was 0.27, 0.41 and 0.38, and H2 was 0.55, 0.82 and 0.77 respectively. These results indicate that genetic and environmental factors respectively explain 82% and 18% of clinical variability of the MRV and 77% and 23 % of the variability of GFR.
Conclusion In our population of adults with ADPKD, heritability estimates (h2) for MRV and GFR indicate that genetic contributions, when compared to environmental factors, play a predominant role in variability of disease severity as assessed by MRV and GFR.