Saturday, July 20, 2013

In The News: Androgen deprivation therapy and AKI

Androgen deprivation therapy (ADT) is one of the mainstay treatments for prostate cancer. A recent study in JAMA2013, via a nested case control study show that these agents might be leading to or may be associated with acute kidney injury. Total of over 10,000 patients were looked at and comparing to matched controls, found these agents to be associated with AKI.

What are the different hormone therapies for prostate cancer?
Orchiectomy (surgical castration)

Luteinizing hormone-releasing hormone (LHRH) analogs
These drugs lower the amount of testosterone made by the testicles. Treatment with these drugs is sometimes called chemical castration because they lower androgen levels just as well as orchiectomy.
The LHRH analogs available in the United States include leuprolide (Lupron, Eligard), goserelin (Zoladex) to name a few.

Luteinizing hormone-releasing hormone (LHRH) antagonists
LHRH antagonists work like LHRH agonists, but they reduce testosterone levels more quickly and do not cause tumor flare like the LHRH agonists do. Degarelix (Firmagon) is an LHRH antagonist used to treat advanced prostate cancer.
Anti-androgens block(ADT) the body's ability to use any androgens. Even after orchiectomy or during treatment with LHRH analogs, the adrenal glands still make small amounts of androgens.Drugs of this type, such as flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron), are taken daily as pills.
Other androgen-suppressing drugs
Estrogens , Ketoconazole (Nizoral)
The report in JAMA focuses on ADT and its anti androgen effects. During follow-up, the investigators identified 232 cases with a first-ever AKI admission. These cases were compared with controls matched for age, one year since prostate cancer diagnosis, and duration of follow-up. Compared with never use, current use of ADT was significantly associated with a 2.5 times increased odds of AKI.
The association was mainly driven by a combined androgen blockade, estrogen only, and other combination therapies, which were associated with a 4.5 times, 4.0 times, and 4.0 times increased odds of AKI, respectively, in adjusted analyses. Oral antiandrogens only, gonadotropin-releasing hormone agonists only, and bilateral orchiectomy each was associated with about a twofold increased odds. There might be a combined effect as stated by the authors.
One case report of flutamide associated AKI does exists. The case had shown temporal association in a patient with metastatic prostate cancer. No biopsy was done.
Few questions remain?
1.       How come we don’t see this as frequently then? ( or perhaps we are missing it)
2.       What is the biopsy findings of these patients? Is it tubular damage, glomerular damage, - no mention of that anywhere. There might be protective benefits of androgens to the kidneys but there are basic science papers that have shown the opposite as well.
3.       Looking closely at cases vs cohorts in this manuscript, while no p values are provided, there were more percentages of cases with HTN, CAD, CHF, on NSAIDs, antibiotics, Given complex statistical analysis and more sensitive analysis, they were able to still show an association.

4.       Repeat study to confirm this association needs to be done. This is an observational data from outcomes type of research. This deserves a well designed trial to replicate this and see if this clinical holds true.

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