Phenotype PKD2 vs PKD1; results from the European concerted action.
ASN 30th Annual Meeting, San Antonio
J Am Soc Nephrol (Sep) 8:373A 1997
Background: We now know that the vast majority of autosomal dominant Polycystic Kidney Disease (ADPKD) is caused by a mutation in one of two genes. Mutation of PKD1 on Chromosome 16 accounts for 85-90% of cases and causes cyst formation via loss of function of the PKD1 gene product Polycystin1 (Pcys 1). Most of the remaining cases are believed to be due to mutation of a second gene, PKD2, which encodes a protein thought to function downstream of PKD1 in a common signalling pathway. Early studies involving small numbers of ADPKD2 families have suggested a milder clinical course as compared to affected individuals in ADPKD1 families (see Ravine et al. The Lancet 340: 1330, Nov 28, 1992).
Hateboer et al now report results from the first large multicenter study directly comparing clinical outcomes in 32 PKD2 families (with 306 affected members) vs. 17 PKD1 families (with 288 affected members). All families were Caucasian; spouses and non-affected siblings served as controls. Age at onset of dialysis was examined by survival analysis; prevalence of complications was assessed using logistic regression to correct for the influence of age and sex. Although PKD2 patients had reduced survival as compared to normal controls (median age at death 69.8 vs. 75 yrs), their clinical course was significantly milder than that observed in PKD1 patients. Specifically, PKD2 patients were older at initial clinical presentation (61 vs. 35 yrs), older at onset of dialysis (74 vs 60 yrs), and were considerably less likely to have hypertension, renal infection history, or subarachnoid hemorrhage.
Comment: This large study directly comparing PKD1 and PKD2 patients provides compelling new evidence for a substantially milder clinical course in PKD2 patients. Although genetic testing to differentiate the PKD genes involved is not currently routine, these observations strengthen the case for such testing in the future, since prognostic information provided to family members would necessarily differ. Because of the extremely large size of the PKD1 gene, many researchers studying ADPKD feel that therapeutic interventions are more likely to derive from modifying the process of cyst formation rather than from primary gene therapy to restore the missing protein. From this pathophysiologic perspective, it becomes important to discover why the functional deficit in PKD2 -- which causes disease so similar to PKD1 in overall renal pathology -- manifests later and with reduced severity. The answer may lead to new therapies for slowing progression of disease in PKD1 patients. Finally, previously published studies of ADPKD natural history must be reinterpreted in light of this inhomogeneity of the ADPKD population and future studies of both natural history and molecular pathogenesis of ADPKD must clearly differentiate PKD1 vs PKD2. (Susan P. Bagby, M.D., Oregon Health Sciences University and VA Portland Medical Center, Portland, OR)
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ASN 30th Annual Meeting, San Antonio
Cystic disease : Hereditary polycystic disease