PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis

Abstract

Background: PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort.

Study design: Case series, January 2010 to March 2016.

Settings & participants: Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history. Publicly available whole-exome sequencing data from the ExAC database were used to provide an estimate of the genetic prevalence of the disease.

Outcomes: Molecular analysis of PKD1 and PKD2 genes. Renal survival, age- and sex-adjusted estimated glomerular filtration rate.

Results: The Genkyst cohort included 293 patients with PKD2 mutations (203 pedigrees). PKD2 patients with a nephrology follow-up corresponded to 0.63 (95% CI, 0.54-0.72)/10,000 in Brittany, while PKD2 genetic prevalence was calculated at 1.64 (95% CI, 1.10-3.51)/10,000 inhabitants in the European population. Median age at diagnosis was 42 years. Flank pain was reported in 38.9%; macroscopic hematuria, in 31.1%; and cyst infections, in 15.3% of patients. At age 60 years, the cumulative probability of end-stage renal disease (ESRD) was 9.8% (95% CI, 5.2%-14.4%), whereas the probability of hypertension was 75.2% (95% CI, 68.5%-81.9%). Although there was no sex influence on renal survival, men had lower kidney function than women. Nontruncating mutations (n=36) were associated with higher age-adjusted estimated glomerular filtration rates. Among the 18 patients with more severe outcomes (ESRD before age 60), 44% had associated conditions or nephropathies likely to account for the early progression to ESRD.

Limitations: Younger patients and patients presenting with milder forms of PKD2-related disease may not be diagnosed or referred to nephrology centers.

Conclusions: Patients with PKD2-related ADPKD typically present with mild disease. In case of accelerated degradation of kidney function, a concomitant nephropathy should be ruled out.

Keywords: Autosomal dominant polycystic kidney disease (ADPKD); PKD2; case series; disease progression; disease severity; end-stage renal disease (ESRD); genetic prevalence; genetics; kidney function; mutation detection; mutation spectrum; prognosis; renal survival; sequencing.

Figure 1

Distribution of mutations identified along the PKD2 gene. The 83 distinct PKD2 pathogenic mutations identified in the 203 pedigrees were plotted against their respective positions within the PKD2 coding sequence and the primary protein sequence. Note that in the figure, large rearrangements, a subclass of truncating mutations, are illustrated as an independent type of pathogenic mutation (represented as arrows if deletion boundaries are defined or lines in the opposite case), and truncating and nontruncating mutations (represented as diamonds) refer to conventional types of mutation such as point mutations, small deletions, small insertions, or small indels. Abbreviations: CC, coil-coiled domain; EF, EF hand domain; TM, transmembrane domain.

Figure 2

Context of diagnosis in PKD2 patients.

Figure 3

Hypertension-free survival, renal survival, and kidney function in PKD2 patients. (A) Kaplan survival curves represent hypertension-free survival in PKD2 patients, showing that age at diagnosis of hypertension is not influenced by sex and that most PKD2 patients develop hypertension. (B) Kaplan survival curves show that renal survival does not differ in male (M) and female (F) patients. (C) Age-adjusted estimated glomerular filtration rates (eGFRs) in male and female patients show that male PKD2 patients tend to have lower eGFRs than female PKD2 patients (nonlinear scale due to the square-root transformation of eGFR values). (D) Age-adjusted eGFRs in patients with nontruncating versus truncating mutations of PKD2 show that patients with nontruncating variants tend to have higher eGFRs (nonlinear scale due to square-root transformation of eGFR values). Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; ESRD, end-stage renal disease.

Figure 4

Distribution of inclusion estimated glomerular filtration rate > 30 mL/min/1.73 m² according to sex and age. The given percentage is for men and women of the given age range. Number of patients in each subcategory is indicated in the bottom of each column.