Type of PKD1 mutation influences renal outcome in ADPKD

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is heterogeneous with regard to genic and allelic heterogeneity, as well as phenotypic variability. The genotype-phenotype relationship in ADPKD is not completely understood. Here, we studied 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort and confirmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations. The median age at onset of ESRD was 58 years for PKD1 carriers and 79 years for PKD2 carriers. Regarding the allelic effect on phenotype, in contrast to previous studies, we found that the type of PKD1 mutation, but not its position, correlated strongly with renal survival. The median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation. This observation allows the integration of genic and allelic effects into a single scheme, which may have prognostic value.

Figure 1.

PKD1 mutation type, but not its location, influences renal survival. Renal survival plots. (A) Significant differences in renal survival between PKD1 truncating mutation carriers, PKD1 nontruncating mutation carriers and PKD2 mutation carriers. (B) The absence of a position effect of PKD1 mutation on renal survival.

Figure 2.

Patients with milder phenotypes are more likely to harbor non-truncating mutations. Distribution of the patients according to the type and location of PKD1 mutations in the four quartiles of renal survival. Quartile 1, ESRD before 50.5 years; quartile 2, ESRD between 50.5 and 58.2 years; quartile 3, ESRD between 58.1 and 68.4 years; quartile 4, patients >68.4 years without ESRD or reaching ESRD after 68.4 years. The 258 PKD1 mutation carriers presented in these figures have reached ESRD or are older than 68.4 years, corresponding to the lower limit of the last quartile. (A) Proportion of truncating mutations in patients with milder renal phenotypes, represented by quartile 4, is significantly lower than that in patients with more severe diseases (quartile 1, 2, or 3). (B) Median positions of mutations does not differ in the four groups of renal survival.