Use of ADT Associated with Risk of AKI

Patients with advanced prostate cancer are often treated with androgen deprivation therapy (ADT), a therapy that is also increasingly being used in patients with less severe disease. Studies have demonstrated that ADT provides beneficial effects on the progression of prostate cancer; however, treatment can result in serious adverse effects.

ADT reduces testosterone levels, which, in turn, leads to a hypogonadal condition manifested by metabolic changes that include dyslipidemia, hyperglycemia, and an increase in fat mass. Hyperglycemia and dyslipidemia can affect the renal system by disrupting glomerular function, expanding and thickening the interstitial tubular membrane. With these and other effects on the renal system, the use of ADT may increase the risk of acute kidney injury (AKI).

Given the increasing use of ADT in patients with less severe prostate cancer, researchers recently conducted a study to determine whether the use of ADT is associated with an increased risk of AKI in patients. Study results were reported in JAMA [2013:310(3):289-296].

Using the United Kingdom Clinical Practice Research Datalink combined with the Hospital Episode Statistics database, the researchers assembled a cohort of patients newly diagnosed with prostate cancer between January 1, 1998, and December 31, 2008, with follow-up until December 31, 2009. Inclusion criteria were at least 1 year of up-to-standard medical history at the time of the diagnosis (cohort entry) and at least 40 years of age. Exclusion criteria were metastatic disease recorded at any time before cohort entry up until the first 3 months after cohort entry and a history of any other cancers, history of AKI, chronic kidney failure, dialysis-related procedures, hepatitis, systemic connection tissue diseases, rheumatoid arthritis, crush injury, HIV infection, and any drug abuse.

The primary outcomes and measures were the odds ratios (ORs) with 95% confidence intervals (CIs) of AKI associated with the use of ADT. ADT was categorized into 1 of 6 mutually exclusive groups: (1) gonadotropin-releasing hormone agonists, (2) oral anti-androgens, (3) combined androgen blockade, (4) bilateral orchiectomy, (5) estrogens, and (6) combination of the above.

There were 10,250 patients who met study criteria. Among those, during a mean follow-up of 4.1 years (42,070 person-years), 232 cases of a first-ever AKI admission were identified and matched with 2721 controls. All cases were matched with at least 1 control, 135 with at least 10 controls, and 187 with at least 4 controls.

Overall, current use of ADT was associated with an increased risk of AKI when compared with never use (OR, 2.48; 95% CI, 1.61-3.82), generating a rate difference of 4.43/1000 persons-per-year (95% CI, 1.54-7.33). This association was driven primarily by a combined androgen blockade consisting of gonadotropin-releasing hormone agonists with oral anti-androgens (OR, 4.05; 95% CI, 2.61-7.78), estrogens (OR, 4.00; 95% CI, 1.06-15.03), other combination therapies (OR, 4.04; 95% CI, 1.88-8.69), and gonadotropin-releasing hormone agonists (OR, 1.93; 95% CI, 1.20-3.10).

Study limitations cited by the researchers included not conducting a formal validation of AKI cases and possible concerns regarding residual confounding due to unmeasured variables such as the grade and state of prostate cancer at diagnosis as well as cancer progression during follow-up.

In summary, the researchers said, “In this study of patients newly diagnosed with nonmetastatic prostate cancer, the use of ADT was associated with a significantly increased risk of AKI. These findings require replication in other carefully designed studies as well as further investigation of their clinical importance.”