雄激素去势治疗与急性肾损害相关

根据7月17日《JAMA》上的一篇报告，在非转移性前列腺癌患者中，雄激素去势治疗与急性肾损害风险增高呈强相关性。

研究者称，这是首个研究雄激素去势治疗与急性肾损害关联的以人群为基础的研究。之所以开展这项研究是因为，尽管雄激素去势治疗在传统上多用于晚期疾病，但目前有越来越多地用于较早期前列腺癌患者的趋势。此外，急性肾损害相关的死亡率很高(约50%)，这也是激发研究者评估雄激素去势治疗与急性肾损害之间关联的另一原因。“尽管迄今仅有1篇关于氟他胺相关急性肾损害的病例报告发表，但雄激素去势治疗及其性功能减退效应具有广为人知的后果，与我们的结果一致。”

蒙特利尔市犹太全科医院临床流行病学中心的Lapi博士及其同事使用英国的两个大型数据库——临床实践研究数据链接和医院事件统计学数据库，确定了10,250例1998~2008年间新诊断为前列腺癌的患者，诊断时年龄≥40岁，平均随访4年，因此随访量为42,000患者年。

结果显示，共发生232例急性肾损害，总发生率为5.5/1,000患者年。将这些病例与2,721例未发生急性肾损害的对照受试者的年龄、诊断年和随访持续时间进行匹配。与对照受试者相比，接受雄激素去势治疗的患者发生急性肾损害的风险显著增高，危险比为2.48。当对潜在混淆因素(如已知损害肾功能的疾病、已知对肾脏有毒性的药物、基础前列腺癌的严重程度以及其他癌症治疗的强度)进行校正后，发现相关性未改变。

然后，研究者根据雄激素去势治疗的类型对数据进行了分析，将治疗方案分为6个相互排斥的分类：促性腺激素释放激素(GnRH)激动剂(亮丙瑞林、戈舍瑞林、曲普瑞林)；口服抗雄激素治疗(醋酸环丙孕酮、氟他胺、比卡鲁胺、尼鲁米特)；联合雄激素阻断治疗(GnRH激动剂加口服抗雄激素治疗)；双侧睾丸切除术；雌激素和以上的联合治疗。分析结果显示，联合雄激素阻断治疗的危险比最高，其他联合治疗的危险比也显著增高。仅单纯口服抗雄激素治疗和单纯睾丸切除术治疗的风险增高无统计学意义，但也均高于1.0。

研究者在进一步分析中评估了雄激素去势治疗持续时间的影响，发现急性肾损害风险在治疗早期最高，之后随治疗时间延长而略有降低，但仍保持显著增高。研究者还在一项敏感性分析中排除了基线时肌酐水平异常的54个病例和842个对照患者，得出了与主要分析一致的结果。

该研究由加拿大前列腺癌学会、加拿大卫生研究所和de recherche en San基金资助。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Androgen deprivation therapy was strongly associated with an increased risk of acute kidney injury among men with nonmetastatic prostate cancer, according to a report in the July 17 issue of JAMA.

This elevation in risk varied slightly among different types of androgen deprivation agents, and was strongest with therapies that combine gonadotropin-releasing hormone agonists with oral antiandrogens. That suggests "a possible additive effect ... on both receptor antagonism and reduction of testosterone excretion," said Francesco Lapi, Pharm.D., Ph.D., of the Centre for Clinical Epidemiology, Jewish General Hospital, Montreal, and his associates (JAMA 2013;310:289-96).

The researchers discovered the risk elevation in what they described as the first population-based study to investigate the association between androgen deprivation therapy and acute kidney injury. They performed the study because even though the treatment traditionally has been reserved for advanced disease, it is now used increasingly in patients with earlier stages of prostate cancer.

In addition, the investigators were prompted to examine a possible link because of the high mortality (approximately 50%) associated with acute kidney injury.

"Although only one case report of flutamide-related acute kidney injury has been published to date, androgen deprivation therapy and its hypogonadal effect have well-known consequences consistent with our findings," they noted.

Dr. Lapi and his colleagues used two large databases in the United Kingdom, the Clinical Practice Research Datalink and the Hospital Episodes Statistics database, to identify 10,250 men newly diagnosed as having prostate cancer in 1998-2008 who were 40 years of age or older at diagnosis and were followed for a mean of 4 years. This yielded more than 42,000 person-years of follow-up.

A total of 232 cases of acute kidney injury occurred, for an overall incidence of 5.5/1,000 person-years, said Dr. Lapi and his associates.

These cases were matched for age, year of diagnosis, and duration of follow-up with 2,721 control subjects who did not develop acute kidney injury.

Compared with control subjects, men who were using androgen deprivation therapy had a significantly increased risk of acute kidney injury, with an odds ratio of 2.48. That association did not change when the data were adjusted to account for possible confounders, such as comorbidities known to impair kidney function, medications known to have renal toxicity, the severity of the underlying prostate cancer, and the intensity of other cancer treatments.

The investigators then analyzed the data according to type of androgen deprivation therapy, dividing the regimens into six mutually exclusive categories: gonadotropin-releasing hormone (GnRH) agonists (leuprolide, goserelin, triptorelin); oral antiandrogens (cyproterone acetate, flutamide, bicalutamide, nilutamide); combined androgen blockade (GnRH agonists plus oral antiandrogens); bilateral orchiectomy; estrogens; and combinations of those.

The odds ratios were highest for combined androgen blockade and also were significantly elevated for other combination therapies. Only the odd ratios for oral antiandrogens alone and for orchiectomy alone failed to reach statistical significance, although both were above 1.0, the investigators said.

The duration of androgen deprivation therapy was examined in a further analysis of the data. The risk of acute kidney injury was highest early in the course of treatment and decreased slightly, but it remained significantly elevated with longer duration of use.

Finally, in a sensitivity analysis that excluded the 54 cases and 842 controls who had abnormal creatinine levels at baseline, the results were consistent with those of the primary analysis.

The mechanism by which androgen deprivation therapy exerts an adverse effect on the kidney is not known, but the treatment is known to raise the risks of the metabolic syndrome and cardiovascular disease. "A similar rationale can be postulated for the risk of acute kidney injury," Dr. Lapi and his associates said.

The dyslipidemia and hyperglycemia of the metabolic syndrome may promote tubular atrophy and interstitial fibrosis, and may impair glomerular function by expanding and thickening the membranes of the interstitial tubules. Both dyslipidemia and hyperglycemia also raise the risk of thrombosis and induce oxidative stress, which can impact renal function.

In addition, testosterone is thought to protect the kidneys by inducing vasodilation in the renal vessels and enhancing nitric oxide production. So, antagonizing testosterone could promote damage to the glomerulus. And the hypogonadism induced by androgen deprivation can also lead to estrogen deficiency, reducing estrogen’s protective effect against ischemic renal injury, the investigators said.

The study was supported by Prostate Cancer Canada, the Canadian Institutes of Health Research, and Fonds de recherche en Sant》