Family history of renal disease severity predicts the mutated gene in ADPKD

Abstract

Mutations of PKD1 and PKD2 account for 85 and 15% of cases of autosomal dominant polycystic kidney disease (ADPKD), respectively. Clinically, PKD1 is more severe than PKD2, with a median age at ESRD of 53.4 versus 72.7 yr. In this study, we explored whether a family history of renal disease severity predicts the mutated gene in ADPKD. We examined the renal function (estimated GFR and age at ESRD) of 484 affected members from 90 families who had ADPKD and whose underlying genotype was known. We found that the presence of at least one affected family member who developed ESRD at age < or =55 was highly predictive of a PKD1 mutation (positive predictive value 100%; sensitivity 72%). In contrast, the presence of at least one affected family member who continued to have sufficient renal function or developed ESRD at age >70 was highly predictive of a PKD2 mutation (positive predictive value 100%; sensitivity 74%). These data suggest that close attention to the family history of renal disease severity in ADPKD may provide a simple means of predicting the mutated gene, which has prognostic implications.

Figure 1.

Age at last follow-up for all of the affected study participants grouped by family. Each dot within a vertical line represents an affected member from the same family.

Figure 2.

Age plot for affected study participants who developed ESRD, grouped by family. Each dot within a vertical line represents the age at which an affected member of the same family developed ESRD. Significant intrafamilial variability is noted with the gray zone denoting the age range at which both patients with PKD1 and PKD2 overlap, presumably as a result of a modifier effect from genetic and environmental factors; however, having at least one family member who developed ESRD at or before the age of 58 is highly predictive of PKD1. Conversely, having at least one family member who developed ESRD at or after the age of 68 is highly predictive of PKD2,

Figure 3.

Age plot of affected study participants who remained renal sufficient at the last follow-up. A significant number of patients with PKD2 but none with PKD1 remained renal sufficient despite their old age (>68 yr as denoted by the gray line). Having at least one family member who maintained renal sufficiency at or after the age of 68 is highly predictive of PKD2.