Autosomal dominant polycystic kidney disease

About: Autosomal dominant polycystic kidney disease is a research topic. Over the lifetime, 4261 publications have been published within this topic receiving 120424 citations. The topic is also known as: Polycystic kidney disease, adult type (disorder) & Polycystic kidney, autosomal dominant.

Tolvaptan in patients with autosomal dominant polycystic kidney disease

Abstract: In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V 2 -receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline. RESULTS Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P = 0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of followup, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P = 0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, −2.61 [mg per milliliter] −1 per year vs. −3.81 [mg per milliliter] −1 per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group). CONCLUSIONS Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.)

Autosomal dominant polycystic kidney disease.

Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease occurring in 1 in 200 to 1 in 1,000 individuals. ADPKD is characterized by cystic lesions in the kidneys and often by structural abnormalities in the gastrointestinal tract and cardiovascular system. The pathogenesis of the disorder appears to involve both cellular proliferation and altered extracellular matrix synthesis. Diagnosis can be established most readily by the sonographic demonstration of renal cysts or by gene linkage analysis. Renal manifestations of ADPKD include hypertension, infection, nephrolithiasis and malignancy. The prominent extrarenal manifestations include hepatic cysts, mitral valve prolapse and intracranial aneurysms. Although only 2% of nephrons appear to be involved in cyst formation, the renal function often slowly deteriorates. Presently, there is a 52% probability of an ADPKD subject’s being alive without renal replacement therapy at age 73. ADPKD patients with endstage renal disease respond to renal replacement therapy as well as other patient groups.

Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents

Abstract: The human kidney is composed of roughly 1.2-million renal tubules that must maintain their tubular structure to function properly. In autosomal dominant polycystic kidney disease (ADPKD) cysts develop from renal tubules and enlarge independently, in a process that ultimately causes renal failure in 50% of affected individuals. Mutations in either PKD1 or PKD2 are associated with ADPKD but the function of these genes is unknown. PKD1 is thought to encode a membrane protein, polycystin-1, involved in cell-cell or cell-matrix interactions, whereas the PKD2 gene product, polycystin-2, is thought to be a channel protein. Here we show that polycystin-1 and -2 interact to produce new calcium-permeable non-selective cation currents. Neither polycystin-1 nor -2 alone is capable of producing currents. Moreover, disease-associated mutant forms of either polycystin protein that are incapable of heterodimerization do not result in new channel activity. We also show that polycystin-2 is localized in the cell in the absence of polycystin-1, but is translocated to the plasma membrane in its presence. Thus, polycystin-1 and -2 co-assemble at the plasma membrane to produce a new channel and to regulate renal tubular morphology and function.

Volume Progression in Polycystic Kidney Disease

Abstract: Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of cyst-filled kidneys. Methods In a three-year study, we measured the rates of change in total kidney volume, total cyst volume, and iothalamate clearance in patients with ADPKD. Of a total of 241 patients, in 232 patients without azotemia who were 15 to 46 years old at baseline we used magnetic-resonance imaging to correlate the total kidney volume and total cyst volume with iothalamate clearance. Statistical methods included analysis of variance, Pearson correlation, and multivariate regression analysis. Results Total kidney volume and total cyst volume increased exponentially, a result consistent with an expansion process dependent on growth. The mean (±SD) total kidney volume was 1060±642 ml at baseline and increased by a mean of 204±246 ml (5.27±3.92 percent per year, P<0.001) over a three-year period among 214 patients. Total cyst volume increased by 218±263 ml (P<0.001) during the same perio...