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

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney disease. Enlarging cysts within the kidneys are the clinical hallmark of the disease. Renal manifestations include varying degrees of kidney injury, urinary tract infections, kidney stones, and hematuria. Extrarenal manifestations can include pain, hypertension, left ventricular hypertrophy, hepatic cysts, intracranial aneurysm, diverticulosis, and abdominal and inguinal hernias. The progression of ADPKD cannot be reversed with current treatment modalities; therefore, therapies target the resulting clinical manifestations. Early detection and management of hypertension are important to delay the progression of renal dysfunction and development of cardiovascular complications. Pain management includes evaluation of concomitant illnesses, use of analgesics, and adjuvant therapy. Fluoroquinolones may be the most useful class of antibiotics for the treatment of urinary tract infections because of their lipophilic properties and bactericidal action against gram-negative pathogens. Nephrolithiasis is twice as common in persons with ADPKD compared with the general population and is suggested by flank pain with or without hematuria. Cystic hemorrhages usually resolve within one week, although microscopic hematuria may still be present. Because of the proliferative effect of estrogen on hepatic cysts, oral contraceptives containing estrogen and menopausal estrogen therapy should be administered at the lowest effective dose or avoided in patients with ADPKD. Intracranial aneurysms are at least twice as common in patients with ADPKD than in the general population. Renal ultrasonography is the diagnostic modality of choice to screen at-risk individuals for ADPKD.

Autosomal dominant polycystic kidney disease.

Background/Aims: In this retrospective study we aimed to compare the effect of tranexamic acid (TXA) vs etamsylate, two hemostatic agents, on hematuria duration i

/pdf/treatment-of-persistent-gross-hematuria-with-tranexamic-acid-2t8ob386xv.pdf

Treatment of Persistent Gross Hematuria with Tranexamic Acid in Autosomal Dominant Polycystic Kidney Disease

Individuals who are at risk for autosomal dominant polycystic kidney disease are often screened by ultrasound using diagnostic criteria derived from individuals with mutations in PKD1. Families with mutations in PKD2 typically have less severe disease, suggesting a potential need for different diagnostic criteria. In this study, 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, respectively, were assessed by renal ultrasound and molecular genotyping. Using sensitivity data derived from genetically affected individuals and specificity data derived from genetically unaffected individuals, various diagnostic criteria were compared. In addition, data sets were created to simulate the PKD1 and PKD2 case mix expected in practice to evaluate the performance of diagnostic criteria for families of unknown genotype. The diagnostic criteria currently in use performed suboptimally for individuals with mutations in PKD2 as a result of reduced test sensitivity. In families of unknown genotype, the presence of three or more (unilateral or bilateral) renal cysts is sufficient for establishing the diagnosis in individuals aged 15 to 39 y, two or more cysts in each kidney is sufficient for individuals aged 40 to 59 y, and four or more cysts in each kidney is required for individuals 60 yr. Conversely, fewer than two renal cysts in at-risk individuals aged 40 yr is sufficient to exclude the disease. These unified diagnostic criteria will be useful for testing individuals who are at risk for autosomal dominant polycystic kidney disease in the usual clinical setting in which molecular genotyping is seldom performed.

/pdf/unified-criteria-for-ultrasonographic-diagnosis-of-adpkd-3wlw9b02kv.pdf

Unified Criteria for Ultrasonographic Diagnosis of ADPKD

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

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