Elsevier

The Lancet

Volume 353, Issue 9147, 9 January 1999, Pages 103-107
The Lancet

Articles
Comparison of phenotypes of polycystic kidney disease types 1 and 2

https://doi.org/10.1016/S0140-6736(98)03495-3Get rights and content

Summary

Background

Although autosomal dominant polycystic kidney disease type 2 (PKD2) is known to have a milder clinical phenotype than PKD1, neither disorder has been compared with an unaffected control population in terms of survival. We report the findings of a multicentre survey that aimed to define more precisely the survival and clinical expression of PKD1 and PKD2.

Methods

Clinical data from 333 people with PKD1 (31 families) were compared with data from 291 people with PKD2 (31 families) and 398 geographically matched controls. Survival analysis was used to compare age-at event data. Differences in the prevalence of complications were assessed by logistic regression.

Findings

Median age at death or onset of end-stage renal disease was 53·0 years (95% CI 51·2–54·8) in individuals with PKD1, 69·1 years (66·9–71·3) in those with PKD2, and 78·0 years (73·8–82·2) in controls. Women with PKD2 had a significantly longer median survival than men (71·0 [67·4–74·8] vs 67·3 [64·9–69·7] years), but no sex influence was apparent in PKD1. Age at presentation with kidney failure was later in PKD2 than in PKD1 (median age 74·0 [67·2–80·8] vs 54·3 [52·7–55·9] years). PKD2 patients were less likely to have hypertension (odds ration 0·25 [95% CI 0·15–0·42]), a history of urinary-tract infection. (0·50 [0·31–0·83]), or haematuria (0·59 [0·35–0·98]).

Interpretation

Although PKD2 is clinically milder than PKD1, it has a deleterious impact on overall life expectancy and cannot be regarded as a benign disorder.

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common dominantly inherited conditions, with an estimated prevalence of 1 in 1000.1 ADPKD is an important cause of chronic renal failure; 77% of patients die or reach end-stage renal disease (ESRD) by the age of 70 years.2 ADPKD is a multisystem disease, with cysts and connective-tissue abnormalities, involving many organs.3 The more common complications include hypertension, macrohaematuria, urinary-tract infection, cardiac-valve abnormalities, herniae of the anterior abnormalities, herniae of the anterior abdominal wall, and cerebral berry aneurysms.

Mutations in at least three different genes can lead to ADPKD. The PKD1 gene covers about 52 kb of genomic DNA on chromosome 16 (16p13.3) and consists of 46 exons from which 14·1 Kb transcript is produced. The 4303-aminoacid product of PKD1, polycystin-1, is an integral membrane protein with a large extracellular region and many transmembrane domains.4, 5 The PKD2 gene, situated on chromosome 4 (4q21–23), has also been identified and characterised.6 PKD2 encodes a 5·4 kb transcript, from which a 968-aminoacid product is predicted to be an integral membrane protein similar to the α1 subunit of voltage-activated Ca2+ and Na+ channels, which suggests a related role for polycystin-2. The polycystins interact through their C-terminal cytoplasmic tails, which suggests that PKD1 and PKD2 may function through a common signalling pathway.7 At least one other gene containing mutations that lead to ADPKD is known to exist; its chromosomal location is not yet known.8

Among the European ADPKD population, PKD1 is the cause in about 85% of families and PKD2 the cause in about 15%.9 Compared with individuals affected by PKD2, those with PKD1 have more severe disease with a higher prevalence of hypertension, an increased risk of progression into renal failure, and shorter life expectancy.2, 10, 11, 12, 13, 14 Although these reports consistently show that the phenotype of PKD2 is milder than that of PKD1, the relative rarity of PKD2 disease has limited the sample size in each report, and no study has compared ADPKD patients with unaffected controls. To overcome these limitations, a study group within the European Concerted Action on PKD was established. The aim of the group was to collect standard data from large families with both types of ADPKD and to compare these data with those from unaffected controls to define the overall clinical impact of the two major ADPKD genotypes.

Section snippets

Families and clinical evaluation

Ethical approval was given by the various ethics committees of the centres in Leiden, Santander, Barcelona, Madrid, Cardiff, and London. Informed consent was obtained from all individuals involved. Seven European centres from the Netherlands, Spain, Bulgaria, and the UK contributed to the study. Large ADPKD families, selected only because of their suitability for study by genetic linkage, were tested for evidence of linkage to the PKD1 and PKD2 loci by means of polymorphisms flanking both loci.

Results

From 31 families with PKD2, 291 affected individuals were identified; 83 (29%) had died or had reached ESRD before the study. Among 31 PKD1 families from the same geographical regions, 333 affected individuals were included; 145 (44%) had reached the same endpoints. Of the 398 controls, 73 (18%) had died or had reached ESRD (table 1).

With age at onset of ESRD or death (whichever occurred first) as the failure time, the cumulative probability of survival was least for PKD1 (median age for PKD1

Discussion

PKD2 patients, compared with those who have PKD1, present with symptoms later in life, live longer, have a lower risk of progressing to renal failure, and have fewer complications. In this study, PKD2 was associated with a reduction of 10 years in median survival to death or onset of ESRD compared with the survival of those without ADPKD. This population of patients included some individuals who died of uraemia in the days before dialysis, as well as others who reached ESRD more recently and

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  • Cited by (0)

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