NEJM：托伐坦用于多囊肾病效果佳
2012-12-25 NEJM CMT 银子 编译
Vicente E. Torres博士等人12月20日发表在《新英格兰医学杂志》上的一项最新研究表明，托伐坦（Tolvaptan）用于常染色体显性多囊肾病，可以明显延缓肾功能衰退。 随着常染色体显性多囊肾病（ADPKD）的病情进展，患者常并发疼痛、高血压和肾功能衰竭。临床前试验表明，垂体后叶素V2受体拮抗剂可抑制肾囊肿的生长，延缓肾功能的下降。
Vicente E. Torres博士等人12月20日发表在《新英格兰医学杂志》上的一项最新研究表明，托伐坦（Tolvaptan）用于常染色体显性多囊肾病，可以明显延缓肾功能衰退。
随着常染色体显性多囊肾病（ADPKD）的病情进展，患者常并发疼痛、高血压和肾功能衰竭。临床前试验表明，垂体后叶素V2受体拮抗剂可抑制肾囊肿的生长，延缓肾功能的下降。
在这个三项，多中心，双盲，安慰剂对照，3年的试验中，研究人员将1445例18～50岁的ADPKD（总肾脏体积不小于750ml，估计肌酐清除率不小于60ml/min）患者随机分配。以2：1的比例分别接受V2受体拮抗剂托伐坦和安慰剂的治疗。在病人可耐受的情况下，三组最高的给药剂量是每日两次。观察指标是每年肾脏总体积的变化率。二次序贯终点为综合的临床进展期（即：肾功能恶化、肾区疼痛、高血压、蛋白尿）和肾功能衰退率。
经过了3年的研究，托伐坦组的肾脏总体积增长速度是每年2.8% [95％可信区间（CI）=2.5~3.1）]，安慰剂组肾脏总体积的增长速度是每年5.5%（95%CI=2.1～6.1；P<0.001）。每100人年随访，托伐坦组与安慰剂组相比，复合终结点为分别出现44和50个事件， P = 0.01；肾功能恶化率较低，为分别出现2和5个不良事件，P <0.001；肾区疼痛发生分别为5和7个事件，P = 0.007。肾功能下降率（倒数血清肌酐水平）分别为-2.61mg/ml*年和-3.81mg/ml*年，P <0.001。托伐坦与肾功能下降缓慢密切相关。托伐坦组ADPKD相关的不良事件较少，而与ADPKD无关的利水剂（游离的电解质排泄）不良事件和肝不良事件增多，这导致停药率增高到 23％，而安慰剂组停药率仅为14％。
研究表明：托伐坦可以延缓肾脏总体积的增加，可在3年内延缓了ADPKD患者的肾功能下降。但由于不良反应，停药率增高。
Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
BACKGROUND
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.
METHODS
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.
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 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]−1per 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.)
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#多囊肾#
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