Mulenga L, Kruse G, Lakhi S, et al. Baseline renal insufficiency and risk of death among HIV-infected adults on antiretroviral therapy in Lusaka, Zambia. AIDS 2008;22:1821-7.
To examine the association between baseline renal insufficiency and mortality among adults initiating antiretroviral therapy (ART) in an urban African setting
A cohort study of HIV-infected, ART-naïve adults initiating treatment
18 primary care facilities within the Lusaka, Zambia public health sector
A total of 25,779 patients of 36,289 initiating ART were included in the cohort if they were older than 15 years of age, were treatment naïve, had a baseline creatinine test result, and had initiated ART between May 1, 2004 and September 31, 2007.
Patients with documented HIV-positive serostatus underwent medical history and physical examination and had blood collected for CD4 cell counts. Those with CD4+ cell counts of <200 cells/µL, WHO stage 4, or WHO stage 3 and CD4 cell counts of <350 cells/µL were eligible for ART. Before initiating ART, screening tests for hematologic, renal, and hepatic function were performed. If serum creatinine levels were ≥120 umol/L, creatinine clearance was calculated via the Cockcroft-Gault equation. Dosages of ART drugs were adjusted accordingly.
The researchers used published clinical guidelines from the U.S. National Kidney Foundation's Kidney Disease Outcome Quality Initiative (K/DOQI) to categorize renal insufficiency.(1) Creatinine clearance of >90 mL/min was considered normal; creatinine clearance of 60-89 mL/min (K/DOQI stage 2) was categorized as mild renal insufficiency; 30-59 mL/min as moderate insufficiency (K/DOQI stage 3); and <30 mL/min as severe insufficiency (K/DOQI stage 4 and 5).
The researchers performed two secondary analyses using two other measures of renal function: serum creatinine levels and glomerular filtration rate (GFR) calculated by the Modification of Diet in Renal Disease (MDRD) equation.(2) A creatinine value was considered normal if it was ≤120 umol/L. Renal insufficiency was considered mild if creatinine values were 121-150 umol/L; moderate if 151-200 umol/L; and severe if >200 umol/L. The aforementioned K/DOQI-based categories for renal insufficiency were used for MDRD estimates of GFR.
The primary outcome was mortality. Mortality was estimated separately for the first 90 days after ART initiation and for the period greater than 90 days.
97.9% of the 25,779 individuals had complete individual data for calculation of creatinine clearance with the Cockcroft-Gault formula. 8456 patients (33.5%, confidence interval [CI]: 32.9%-34.1%) had renal insufficiency. Of these, 6216 (73.5%) had mild, 1976 (23.4%) had moderate, and 264 (3.1%) had severe insufficiency. In multivariate analysis, predictors of renal disease included female sex (adjusted risk ratio [ARR] =1.2; 95% CI: 1.1-1.2), increasing age (ARR=1.5 per 10 years; 95% CI: 1.4-1.5), hemoglobin levels of <8 g/dL (ARR=1.5; 95% CI: 1.4-1.6), body mass index (BMI) of <16 kg/m2 (ARR=1.7; 95% CI: 1.6-1.8), and WHO stage 3 (ARR=1.2; 95% CI: 1.2, 1.3) or stage 4 (ARR=1.3; 95% CI: 1.2, 1.4). Risk for renal insufficiency increased slightly as CD4+ cell counts decreased.
Using Cox proportional hazards modeling, risk for mortality at <90 days was elevated for patients with mildly (adjusted hazard ration [AHR] = 1.7; 95%CI: 1.5-1.9), moderately (AHR=2.3; 95% CI: 2.0-2.7), and severely (AHR=4.3; 95% CI: 3.1-5.5) reduced creatinine clearance. Mild (AHR=1.4; 95% CI: 1.2-1.6), moderate (AHR=1.9; 95% CI: 1.5-2.3), and severe (AHR=3.6; 95% CI: 2.4-5.5) insufficiency also were associated with increased mortality after 90 days, when compared with people who had normal renal function. Trends were similar when renal function was estimated with MDRD or serum creatinine levels.
The authors conclude that renal insufficiency at the time of ART initiation was prevalent and was associated with increased risk of mortality among adults in this population. The results are particularly relevant in settings such as Zambia, where tenofovir (a drug with known nephrotoxicity) has been adopted as part of first-line therapy. The authors emphasize the need for resource-appropriate screening algorithms for renal disease as part of ART eligibility and pretreatment assessment.
Based on the Newcastle-Ottawa quality rating for observational cohort studies, this study is of good quality. One of the limitations of the analysis was that nearly 30% of individuals initiating ART had missing baseline serum creatinine results that could have biased the representativeness of the cohort. Another limitation was the lack of detailed information regarding causes of renal insufficiency and causes of death. In addition, the study was unable to causally link renal insufficiency with mortality, thus making it difficult to conclude that increased mortality was due to initial renal insufficiency.
Two large cohorts in the United States, the HIV Epidemiology Research Study and the Women's Interagency HIV Study, demonstrated a 2-fold to 2.5-fold risk of death among HIV-infected women with serum creatinine levels of ≥1.4 mg/dL.(3,4) Similar findings have been observed in hospital settings in industrialized and developing settings.(5,6)
Although the results from this study do not establish a causal relation between renal insufficiency and mortality, they do indicate the need for further evaluation of ART eligibility and screening, specifically for renal function. In resource-limited settings, screening for renal function may be reasonable as part of ART delivery programs, especially programs that offer antiretroviral drugs, such as tenofovir or indinavir, or antimicrobial drugs, such as aminogylcosides or trimethoprim-sulfamethoxazole, that have known nephrotoxicities.
- National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-S266. Abstract not available.
- Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70.
- Szczech LA, Hoover DR, Feldman JG, et al. Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy. Clin Infect Dis 2004;39:1199-206.
- Gardner LI, Holmberg SD, Williamson JM, et al. Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women. J Acquir Immune Defic Syndr 2003;32:203-9.
- Wyatt CM, Arons RR, Klotman PE, Klotman ME. Acute renal failure in hospitalized patients with HIV: risk factors and impact on in-hospital mortality. AIDS 2006;20:561-5.
- Ole-Nguyaine S, Crump JA, Kibiki GS, et al. HIV-associated morbidity, mortality and diagnostic testing opportunities among inpatients at a referral hospital in northern Tanzania. Ann Trop Med Parasitol 2004;98:171-9.