Variation in age at ESRD in autosomal dominant polycystic kidney disease

Abstract

Background: Heterogeneity manifest as more severe disease in successive generations has been attributed to genetic anticipation in patients with autosomal dominant polycystic kidney disease (ADPKD). We evaluated variation in age at end-stage renal disease (ESRD) in ADPKD families for evidence of anticipation.

Study design: Retrospective.

Setting & participants: 413 families with ADPKD seen at our single center between 1985 and 2004 (including 95 families with documented polycystic disease type 1 [PKD1] and 213 ADPKD families with parents born before 1930).

Predictor: Generational status.

Outcome: Age at ESRD onset.

Measurements: Time to ESRD was evaluated by using survival analysis, Cox regression, and descriptive statistics. Unstable trinucleotide repeat expansion was evaluated by means of genotyping in 6 PKD1 families.

Results: We analyzed 413 ADPKD families (1,391 parent-offspring pairs) with known age at ESRD or last known age without ESRD (informative pairs). There was no difference in age at ESRD between parents and offspring by means of Cox regression after adjusting for correlations among family members and sex (hazard ratio, 1.019; 95% confidence interval, 0.919 to 1.13; P = 0.7). Similar analysis of PKD1 informative pairs and those with parents born before 1930 showed no differences in age at ESRD. Male ADPKD patients were 42% more likely to reach ESRD (P < 0.001), and male patients with documented PKD1 were 41% more likely to reach ESRD (P = 0.01) than female patients.

Limitations: Hypertension treatment unknown.

Conclusions: We found no evidence for anticipation of ESRD in patients with ADPKD; thus, the observed variation in age at ESRD may result from other genetic, sex, or environmental causes.

Figure 1

Selection criteria for families with parent-offspring pairs for study. The polycystic kidney disease (PKD) database at University of Colorado Health Sciences Center containing 1,228 PKD families with 4,618 individuals was queried, and 413 families (2,409 affected) with 1,807 parent-offspring pairs for potential analysis were identified. Detailed distribution of the 1,391 parent-offspring pairs informative for age at end-stage renal disease (ESRD) or last known age without ESRD identified is listed in Table 2. Abbreviation: ADPKD, autosomal dominant PKD.

Figure 2

Survival until end-stage renal disease (ESRD) in all polycystic kidney disease parents and offspring. Survival functions from the Cox regression are plotted against age (years) for parents and offspring from 1,391 parent-offspring pairs informative for age at ESRD onset or survival age without ESRD. Male and female affected parents and children are plotted separately. A Cox proportional hazards method showed a significant effect of male sex (hazard ratio, 1.424; 95% confidence interval, 1.180 to 1.719; P < 0.001) on survival until ESRD. The lines for female parent and female child overlay each other and are indicated by an arrow on the right of the figure. An arrow to the left indicates the position of the lines for male parent and male child that are similarly overlaid.

Figure 3

Survival until end-stage renal disease (ESRD) in all polycystic kidney disease (PKD) parents and offspring with parental birth dates before 1930. Survival functions from the Cox regression are plotted against age (years) for parents and offspring from 725 parent-offspring pairs with parental birth dates before 1930 (or if the parent’s year of birth was unknown, the offspring was born before 1945) that were informative for age at ESRD onset or survival age without ESRD. Male and female affected parents and children are plotted separately. Cox proportional hazards method showed a significant effect of male sex (hazard ratio, 1.431; 95% confidence interval, 1.149 to 1.781; P < 0.01) on survival until ESRD.

Figure 4

Survival until end-stage renal disease (ESRD) in all informative polycystic kidney disease type 1 (PKD1) parents and offspring. Survival functions from the Cox regression are plotted against age (years) for parents and offspring from 585 PKD1 parent-offspring pairs informative for age at ESRD onset or survival age without ESRD. Male and female affected parents and children are plotted separately. A Cox proportional hazards method showed a significant effect of male sex (hazard ratio, 1.412; 95% confidence interval, 1.084 to 1.839; P = 0.01) on survival until ESRD.

Figure 5

Survival until end-stage renal disease (ESRD) in all polycystic kidney disease type 1 (PKD1) parents and offspring with parental birth dates before 1930. Survival functions from Cox regression are plotted against age (years) for parents and offspring from 725 PKD1 parent-offspring pairs with parental birth dates before 1930 (or if the parent’s year of birth was unknown, the offspring was born before 1945) that were informative for age at ESRD onset or survival age without ESRD. Male and female affected parents and children are plotted separately. There were no significant differences in survival time until ESRD between parents and children. A Cox proportional hazards method showed a significant effect of male sex (hazard ratio, 1.380; 95% confidence interval, 1.027 to 1.855; P = 0.03) on survival until ESRD.