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