Characterisation of inter and intrafamilial variability in Autosomal dominant polycystic kidney disease

Details

Supervisors

Devuyst, Olivier ; Demoulin, Nathalie

Faculty

Faculté de médecine et médecine dentaire

Degree label

Master [180] en médecine

Abstract

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 characterised by the development of multiple cysts in both kidneys, leading to end-stage renal disease (ESRD) in about half of patients by the age of 60 years. It is a multisystemic disorder, po- tentially affecting the liver, pancreas, heart and intracerebral arteries. ADPKD is genetically heterogeneous and caused by mutations of PKD1 and PKD2. Previous studies have described interfamilial variability of renal phenotyope and its deter- minants. We sought to confirm these determinants of interfamilial variability (i.e. gene locus PKD 1 vs PKD2, gene allele PKD1 truncating vs non-truncating mutations, gender effect) on age of ESRD, renal function and total kidney volume for non ESRD patients in the Cliniques universitaires St-Luc (CUSL) ADPKD cohort. We also studied intrafamilial variability of age of ESRD and its determinants. Using the CUSL cohort made of 825 patients, 45 pediatric and non PKRAD patients were excluded and 173 affected family members in whom available age at onset of ESRD were added, resulting in a study population of 953. The mean age of the cohort is 55 ± 16 years old, 51% had reached ESRD, 28% of patients are genotyped (for clinical or research purposes) and 52% have a personal or familial genotype. We confirmed that gene locus (PKD1 vs PKD2) was significantly associated with renal phenotype in the subpopulation of 493 patients belonging to genotyped families. We did not however show a gene allele effect (PKD1 truncating vs non-truncating) on renal phenotype, unlike previous studies. Mean age at ERSD was 50, 52 and 63 years respectively for PKD1 truncating , PKD1 non-truncating and PKD2 patients. Our hypothesis to explain the absence of gene allele effect on renal phenotype in our cohort is the difference in population studied. Concerning the gender effect, female patients had smaller kidneys and higher eGFR but reached ESRD a little earlier than male patients. We showed that intrafamilial variability is lower than interfamilial variability in terms of age at ESRD, eGFR and htTKV, after adjustment for genotype. When we compared the in- trafamilial variability in terms of age of ESRD between PKD1 truncating and non-truncating families, mean intrafamililal difference of age at ESRD was 12 vs 10 years in PKD1 truncating vs PKD1 non-truncating families. Moreover we showed a more important, albeit not significant, intrafamilial variability in the PKD1 truncating group. Better characterisation of intrafamalial variability and identification of its determinants re- main an important challenge for further studies.

Citations

• APA

Henry, G. (2018). Characterisation of inter and intrafamilial variability in Autosomal dominant polycystic kidney disease.