Tolvaptan in patients with autosomal dominant polycystic kidney disease.
Tolvaptan in patients with autosomal dominant polycystic kidney disease.
复制标题
DOI：
10.1056/nejmoa1205511
复制
发表时间：
2012-12-20
期刊：
影响因子：
--
通讯作者：
TEMPO 3:4 Trial Investigators
中科院分区：
文献类型：
--
作者：
Torres VE;Chapman AB;Devuyst O;Gansevoort RT;Grantham JJ;Higashihara E;Perrone RD;Krasa HB;Ouyang J;Czerwiec FS;TEMPO 3:4 Trial Investigators
常染色体显性遗传性多囊肾病（ADPKD）的病程通常与疼痛、高血压和肾衰竭有关。临床前研究表明，加压素V2受体拮抗剂抑制囊肿生长和减缓肾功能下降。在这项3期、多中心、双盲、安慰剂对照、为期3年的试验中，我们将1445例年龄在18至50岁之间、肾脏总体积≥ 750 ml、估计肌酐清除率≥ 60 ml/min的ADPKD患者以2：1的比例随机分配接受托伐普坦（一种V2受体拮抗剂）或安慰剂，托伐普坦的剂量为患者可耐受的3种每日两次剂量方案中的最高剂量。主要结果是肾脏总体积的年变化率。序贯次要终点包括临床进展时间（定义为肾功能恶化、肾痛、高血压和蛋白尿）和肾功能下降率的复合终点。在3年期间，托伐普坦组的总肾脏体积每年增加2.8%（95%置信区间[CI]，2.5至3.1），而安慰剂组每年增加5.5%（95% CI，5.1至6.0; P<0.001）。复合终点显示托伐普坦组优于安慰剂组（每100随访年发生44例与50例事件，P = 0.01），肾功能恶化（每100随访人年发生2例与5例事件，P<0.001）和肾痛（每100随访人年发生5例与7例事件，P = 0.007）的发生率较低。托伐普坦与肾功能下降较慢相关（血清肌酐水平的倒数，每年-2.61 [mg/ml]-1 vs.每年-3.81 [mg/ml]-1; P<0.001）。托伐普坦组中ADPKD相关不良事件较少，但与水排泄（排泄无电解质水）相关的事件和与ADPKD无关的肝脏不良事件较多，导致停药率较高（23%，安慰剂组为14%）。与安慰剂相比，托伐普坦在3年内减缓了ADPKD患者总肾脏体积的增加和肾功能的下降，但由于不良事件，与较高的停药率相关。（由Otsuka Pharmaceuticals和Otsuka Pharmaceutical Development and Commercialization资助;克里思3：4 ClinicalTrials.gov编号，NCT 00428948。）
The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V2-receptor antagonists inhibit cyst growth and slow the decline of kidney function. 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 V2-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. 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 follow-up, 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). 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.)