Characterization of inter- and intrafamilial variability in autosomal dominant polycystic kidney disease

Henry Gaspard Published in the journal : November 2018 Category : Mémoires de Recherche Clinique

Summary :

Autosomal dominant polycystic disease (ADPKD) is the most common inherited renal disease, accounting for 5 to 10% of patients requiring renal replacement therapy. ADPKD is characterized by the development of multiple cysts in both kidneys, leading to end-stage renal disease (ESRD) before the age of 60 years in approximately half of patients. This multisystem disorder can potentially affect the liver, pancreas, heart, and intracerebral arteries. ADPKD is a genetically heterogeneous disease caused by mutations in the PKD1 and PKD2 genes.

Previous studies have described the interfamilial variability of the renal phenotype and its determinants. We sought to confirm these determinants of interfamilial variability (i.e., PKD1 vs. PKD2 gene locus, PKD1 allele truncating vs. non-truncating mutations, and gender) and their impact on age at ESRD onset, renal function, and total kidney volume in non ESRD patients from the ADPKD cohort of the Cliniques universitaires Saint-Luc (CUSL). We also studied the intrafamilial variability of the age at ESRD onset and its determinants.

The CUSL cohort was composed of 825 patients, of whom 45 pediatric and non ADPKD patients were excluded; 173 affected family members with available age at ESRD onset were added, resulting in a study population of 953 patients. The mean age of the study cohort was 55 ± 16 years; 51% of patients had reached ESRD, 28% were genotyped (for clinical or research purposes), and 52% had a known personal or familial genotype.

We confirmed that the gene locus (PKD1 vs. PKD2) was significantly associated with the renal phenotype in the subpopulation of 493 patients belonging to genotyped families. We did not, however, find an effect of the gene allele (PKD1 truncating vs. non-truncating mutations) on the renal phenotype, unlike previous studies. Mean ages at ERSD onset were 50, 52, and 63 years for PKD1 truncating mutation, PKD1 non-truncating mutation, and PKD2 patients, respectively. Our hypothesis is that the absence of gene allele effect on the renal phenotype is due to the different population studied in our cohort. Concerning the gender effect, female patients had smaller kidneys and higher eGFR, but reached ESRD somewhat earlier than male patients.

We showed that intrafamilial variability was lower than interfamilial variability in terms of age at ESRD onset, eGFR, and htTKV, after adjustment for the genotype. When comparing intrafamilial variability in terms of age at ESRD onset between PKD1 truncating and non-truncating families, mean intrafamilial difference was 12 vs. 10 years in PKD1 truncating vs. PKD1 nontruncating families. Moreover, we showed an increased, albeit not significant, intrafamilial variability in the PKD1 truncating group.

Better characterization of intrafamalial variability and identification of its determinants remain important challenges for further studies.