MAYO CLINIC
ADPKD is a common cause of end stage renal disease (ESRD) and, hence, is of significant medical importance and economic burden. A number of different potential therapies are now in Phase III trials with the prospects for an effective therapy in the next few years. At present, ADPKD is diagnosed by imaging methods (ultrasound, CT and MRI). While these are reliable in older individuals they are less certain in the younger, presymptomatic individuals that will be targeted for therapy. Molecular methods can also diagnose ADPKD by sequencing of PKD1 and PKD2, but this test is expensive and only generates definite results in two thirds of cases. A protein based test utilizing urine would be of particular utility if it had a high level of sensitivity and specificity. Our recent studies have shown that the ADPKD proteins polycystin-1 and -2, plus the ARPKD protein, fibrocystin are abundant in particular urinary vesicles from the multivesicular body pathway, PKD exosome-like vesicles (PKD-ELVs). We propose here to characterize the proteins in PKD-ELVs in an experimental system expressing or depleted for polycystin-1 or -2. Second, the PKD-ELV proteins of normal and presymptomatic PKD1 patients will be compared. Utilizing this data, we propose to develop a PKD-ELV based assay to allow early diagnostics of ADPKD patients. PUBLIC HEALTH RELEVANCE: Autosomal dominant polycystic kidney disease is a common hereditary renal disease affecting 1:400 to 1:800 individuals. This is a disease where many hundreds of tiny cysts develop in the kidney, slowly enlarging as the affect individual gets older. Eventually, at an average age of 54 yrs, for the commonest form of the disease PKD1, the kidney fails and the patient has to be dialyzed or undergo renal transplantation. At the moment, there are multiple therapies in clinical trials that show promise in slowing this disease. Ideally, therapy should be started before there is much renal damage. Unfortunately diagnosis depends on family history and direct imaging of the kidney for cysts by ultrasound or MRI scanning and then the diagnosis is confirmed by DNA sequencing of the genes involved PKD1 and PKD2. Neither of these are cheap or easy to interpret. We have recently shown that there is a population of small vesicular structures in human urine, called exosome-like vesicles, which are rich in the protein products of the genes involved in polycystic kidney disease, PC1 and PC2. We wish to investigate the protein composition of these in healthy individuals and individuals with PKD1. We think that we may be able to see significant differences in the exosome-like vesicles from PKD1 individuals and healthy age matched controls. These differences will be utilized in the development of a urine based test for autosomal dominant polycystic kidney disease. This would allow the very early diagnosis of the disease, without imaging or expensive DNA analysis, in the individuals most likely to benefit from treatment.