Abstract
BackgroundADPKD affects approximately 1:1000 of the worldwide population. It is caused by mutations in two genes, PKD1 and PKD2. Although allelic variation has some influence on disease severity, genic effects are strong, with PKD2 mutations predicting later onset of ESRF by up to 20 years. We therefore screened a cohort of ADPKD patients attending a nephrology out-patient clinic for PKD2 mutations, to identify factors that can be used to offer targeted gene testing and to provide patients with improved prognostic information.Methods142 consecutive individuals presenting to a hospital nephrology out-patient service with a diagnosis of ADPKD and CKD stage 4 or less were screened for mutations in PKD2, following clinical evaluation and provision of a detailed family history (FH).ResultsPKD2 mutations were identified in one fifth of cases. 12% of non-PKD2 patients progressed to ESRF during this study whilst none with a PKD2 mutation did (median 38.5 months of follow-up, range 16–88 months, p < 0.03). A significant difference was found in age at ESRF of affected family members (non-PKD2 vs. PKD2, 54 yrs vs. 65 yrs; p < 0.0001). No PKD2 mutations were identified in patients with a FH of ESRF occurring before age 50 yrs, whereas a PKD2 mutation was predicted by a positive FH without ESRF.ConclusionsPKD2 testing has a clinically significant detection rate in the pre-ESRF population. It did not accurately distinguish those individuals with milder renal disease defined by stage of CKD but did identify a group less likely to progress to ESRF. When used with detailed FH, it offers useful prognostic information for individuals and their families. It can therefore be offered to all but those whose relatives have developed ESRF before age 50.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) affects approximately 1:1000 of the worldwide population
Twenty-five different pathogenic or likely pathogenic PKD2 mutations were identified in 27 cases, with an additional one being indeterminate according to the PKD Mutation Database
We demonstrated that a fifth of an unselected ADPKD patient cohort from a single clinic that sees patients only with Estimated glomerular filtration rate (eGFR) > 15 mL/min/1.73 m2 had a likely pathogenic PKD2 mutation
Summary
ADPKD affects approximately 1:1000 of the worldwide population It is caused by mutations in two genes, PKD1 and PKD2. ADPKD is an important monogenic cause of renal disease worldwide, affecting more than 1:1000 of the population. Several recent studies have suggested that PKD2 mutations may be present in up 36% of cases depending on the population screened (Table 1) These studies have suggested that in many individuals, PKD2-linked disease is mild and they either do not present or come late to medical attention [2,6]. This is supported by studies reporting that patients with PKD2 mutations develop ESRF some 15–20 years later than those with a PKD1 mutation (69 yrs vs 53 yrs respectively) [7,8]. Clinical indicators of disease severity such as magnetic resonance-measured renal volume have been proposed as important, both in monitoring early progression and in providing more accurate long term predictions of outcomes such as ESRF before a decline in GFR is evident, but are currently confined to research use [10,11]
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