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.

Analysis of Nationwide Data to Determine the Incidence and Diagnosed Prevalence of Autosomal Dominant Polycystic Kidney Disease in the USA: 2013–2015

“…Although several epidemiologic studies of ADPKD have recently been published in Europe [15-19], contemporary estimates of the incidence and prevalence in the USA are lacking. This study examines minimum or diagnosed prevalence, defined as the prevalence of diagnosed ADPKD cases divided by the population at a single point in time.…”

Estimation of minimal disease prevalence from population genomic data: Application to primary familial brain calcification

“…Observing a different distribution of these variants in the EGFr domains of NOTCH3 in ExAC compared to Dutch patients with CADASIL, the authors hypothesized that variants located in certain EGFr domains could have a milder effect leading to incomplete penetrance (Rutten et al, ). Conversely, PKD2 ‐Related Autosomal Dominant Polycystic Kidney Disease prevalence estimates was 0.63 (95%CI, 0.54–0.72) per 10,000 in the population of Brittany based on patients included in a cohort and 2.31 (95%CI, 1.10–3.51) per 10,000 in ExAC (Cornec‐Le Gall et al, ), revealing a much lower difference between the two estimations than for CADASIL.…”

“…Given the fact that (i) a significant proportion of PFBC patients do not exhibit neuropsychiatric symptoms; (ii) most of the symptomatic patients have a disease onset during adulthood; (iii) the few patients with symptomatic PFBC starting during childhood rarely present severe symptoms; and (iv) the disease penetrance is full when considering abnormal brain calcification as the major diagnostic criterion, it is reasonable to estimate a minimal prevalence from genomic data. The power of genome and exome sequencing in large populations gathered by ExAC makes this strategy now applicable through access to publicly available data (Appadurai et al, ; Cornec‐Le Gall et al, ; Minikel et al, ; Rutten et al, ; Sleat, Gedvilaite, Zhang, Lobel, & Xing, ).…”

Prediction of Renal Prognosis in Patients with Autosomal Dominant Polycystic Kidney Disease Using PKD1/PKD2 Mutations

“…Several studies have reported differences in renal prognosis by genotype [8][9][10][11][12][13]19]. The kidney survival rate depends on the causal genes (PKD1, PKD2) and differences between truncating or non-truncating mutations.…”

“…The kidney survival rate depends on the causal genes (PKD1, PKD2) and differences between truncating or non-truncating mutations. Patients with PKD1 mutations, particularly those with truncating mutations, show poor prognosis [8][9][10][11][12][13]19]. However, the relationship between differences in disease progression and mutation types, such as nonsense, frameshift, splicing mutation, and large deletions as truncating mutations, substitution, and in-frame deletion as non-truncating mutations, is unknown.…”