Background:  The use of conventional formulation amphotericin B (AMB) in the treatment of cryptococcal meningitis, is limited by potentially severe adverse reactions, especially nephrotoxicity and infusion-related events. We wanted to determine the prevalence of AMB-induced nephrotoxicity and the clinical, as well as the demographic, factors associated with it, in HIV-infected patients with cryptococcal meningitis in a resource-poor setting.

Methods:  This was a prospective, controlled study with the sample size and power calculations based on a goal of being able to detect a reasonable risk ratio for AMB or other risk factors for nephrotoxicity. We enrolled 116 confirmed HIV⁺ patients with a diagnosis of cryptococcal meningitis into the CCM arm of the study, followed them for a maximum of 14 days, and compared with 69 HIV⁺ patients without cryptococcal meningitis. Patients were evaluated for nephrotoxicity defined as at least 50% increase in serum creatinine from the baseline or a creatinine value >1.6 mg/dL.

Results:  Overall, nephrotoxicity occurred in 59.1% of the CCM patients compared to 15.9% in the control group (p = 0.0001). The attributable incidence of AMB-induced nephrotoxicity was 47cases/1000 person-days (rate ratio = 2.88). Nephrotoxicity occurred as early as by the third dose of AMB. Electrolyte abnormalities occurred early with hypokalemia being the commonest derangement, which was observed at frequencies of 26%, 39.5%, and 62.7% by the third, seventh, and 14th days, respectively. Total AMB dose >600 mg  and a baseline creatinine value >1.5 mg/dL were the only independent predictors of nephrotoxicity using the Cox proportional hazards regression model (HR 1.69, 95%CI 0.308 to 0.986; p = 0.045,  and HR 2.1, 95%CI 1.1 to 4.0, respectively).

The mortality rate in this study was 40% in the CCM group and 26.1% in the control group (OR 1.9, 95%CI 0.98 to 3.63; p = 0.058). Patients without nephrotoxicity were more likely to have died by the end of the study than patients with nephrotoxicity (p = 0.001).

Conclusions:  AMB-induced nephrotoxicity is very common and is observed early, in a dose- and time-dependent fashion. The first week of treatment is the most critical period.