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.)

/pdf/tolvaptan-in-patients-with-autosomal-dominant-polycystic-2bpl115tjo.pdf

Tolvaptan in patients with autosomal dominant polycystic kidney disease

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)60601-1.pdf

Autosomal dominant polycystic kidney disease

A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.

http://science.sciencemag.org/content/sci/272/5266/1339.full.pdf

PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein

Characterization of the polycystic kidney disease 1 (PKD1) gene has been complicated by genomic rearrangements on chromosome 16. We have used an exon linking strategy, taking RNA from a cell line containing PKD1 but not the duplicate loci, to clone a cDNA contig of the entire transcript. The transcript consists of 14,148 bp (including a correction to the previously described C terminus), distributed among 46 exons spanning 52 kb. The predicted PKD1 protein, polycystin, is a glycoprotein with multiple transmembrane domains and a cytoplasmic C-tail. The N–terminal extracellular region of over 2,500 aa contains leucine–rich repeats, a C–type lectin, 16 immunoglobulin–like repeats and four type III fibronectin–related domains. Our results indicate that polycystin is an integral membrane protein involved in cell–cell/matrix interactions.

The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains

https://repub.eur.nl/pub/55815/REPUB_55815_OA.pdf

The polycystic kidney-disease-1 gene encodes a 14-kb transcript and lies within a duplicated region on chromosome-16

Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1

Treatable complications in undiagnosed cases of autosomal dominant polycystic kidney disease

Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease.

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Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1

Treatable complications in undiagnosed cases of autosomal dominant polycystic kidney disease

Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease.