We performed secondary analysis using other estimates of renal insufficiency. Baseline serum creatinine was elevated in 979 of 25 779 individuals in our analysis population (3.8%; 95% CI: 3.7%, 4.0%). Of these, half had mild renal insufficiency (n = 503, 51.4%); the remainder had moderate (n = 242, 24.7%) or severe (n = 234, 23.9%) disease. When GFR was calculated by the MDRD equation, 3209 individuals (12.4%; 95% CI: 12.0%, 12.9%) had renal insufficiency: 2397 (74.7%) of them were mild, 642 (20.0%) were moderate, and 170 (5.3%) were severe. Regardless of measure of renal function in these secondary analyses, similar survival trends were observed according to renal insufficiency categories in Kaplan–Meier analysis (Fig. 2). When mortality risk was assessed using a Cox proportional hazards model, risk for mortality gradually increased as renal insufficiency worsened, before or at 90 days and after 90 days (Table 2).
In this programmatic cohort, we found a high baseline prevalence of renal insufficiency among individuals initiating ART. One-third demonstrated some degree of renal impairment when the Cockcroft–Gault method was used. This finding is concerning, as renal insufficiency – at all grades – was associated with increased risk for death. Even individuals with mild insufficiency had nearly a two-fold increase in early mortality when compared with those with no renal dysfunction. Like factors such as BMI and hemoglobin [13,27–29], baseline renal function appears to be an important independent predictor of survival among HIV-infected individuals initiating ART in Africa.
Although these observational data do not establish a direct causal relationship between renal insufficiency and mortality, they do indicate the need to further evaluate ART eligibility criteria. In the mean time, it would seem reasonable to consider renal function screening – by serum creatinine measurement – for all HIV-infected patients wherever feasible. Measurement with urine protein should also be considered, as it may help to differentiate HIV-associated nephropathy (HIVAN) from other causes. Early and ongoing assessment for renal insufficiency among individuals who do not immediately qualify for ART may also be an important strategy, given the rapid and severe clinical course associated with HIVAN . In cases wherever a diagnosis of HIVAN is made via biopsy – or highly suspected based on nonbiopsy algorithms  – a trial of empiric ART could preserve long-term renal function and improve clinical outcomes.
In settings in which renal insufficiency is diagnosed but the cause is unknown, provision of ART in itself has been shown to improve renal function . However, there may also be a role for adjunctive interventions. Small studies have demonstrated improved outcomes with the use of corticosteroids [32,33] and angiotensin-converting enzyme inhibitors [34,35] among patients with HIVAN. Empiric treatment with these interventions may be reasonable when a patient's initial response to ART is marginal or when clinical expertise and laboratory systems allow for the close patient monitoring. These measures could be particularly important in resource-limited settings like Zambia, where there is only one hemodialysis center available to support patients with either acute or chronic renal failure.
We observed a high prevalence of renal insufficiency among individuals initiating ART when the Cockcroft–Gault method was used. Our findings have particular relevance for HIV treatment locally, as the Zambian Ministry of Health recently introduced the nucleotide reverse transcriptase inhibitor tenofovir as part of first-line therapy. Although tenofovir has demonstrated efficacy, low pill burden, and a favorable safety profile , dose adjustments are needed to prevent chronic renal failure when creatinine clearance drops below 50 ml/min [37–39]. In our analysis, approximately 5% of patients would have required tenofovir dose adjustments if the drug had been used at the time of ART initiation. Nearly 30% would have benefited from serial creatinine monitoring following initiation of tenofovir-based ART due to mild-to-moderate baseline impairment (i.e. creatinine clearance of 50–89 ml/min). These considerations should probably be included in future cost–benefit analyses of tenofovir use in resource-limited settings. Although a strategy of routine screening will increase costs in resource-constrained settings, this must be balanced against the risk of iatrogenic renal failure. Similar concerns should be raised for other routinely used drugs with known renal toxicities, including antiretroviral (e.g. indinavir) or antimicrobial (e.g. aminoglycocides, trimethoprim–sulfamethoxazole) agents.
The prevalence of renal insufficiency varied significantly when measures other than Cockcroft–Gault-derived creatinine clearance were evaluated. Only 4% met criteria when serum creatinine was used alone; 12% met criteria when GFR was calculated by the MDRD formula. Both of these measures will likely require further validation in African settings, where malnutrition and lowered muscle mass might lead to lower measurements overall. Establishment of regionally appropriate screening cutoffs for renal insufficiency – particularly for serum creatinine  – could be useful in settings like Lusaka, where the majority of HIV care is provided by nonphysician clinicians [13,14].
One limitation of this analysis was the high proportion of individuals with missing serum creatinine results: nearly 30% of patients initiating ART did not have a recorded baseline value. The reasons for this are varied, but mostly relate to the rapid nature of service scale-up in already busy primary care clinics (e.g. patient refusals, insufficient samples, lost laboratory results, oversight by health provider). As the populations with and without serum creatinine appeared comparable according to important demographic characteristics and mortality risk factors, we believe the effect of ascertainment bias is likely small. Another limitation was the lack of detailed information regarding possible causes of renal insufficiency. Due to prohibitive cost and limited availability, access to histological diagnoses through renal biopsy is out of reach for most individuals seeking care in the Lusaka public sector. Routine urinalysis is not a standard practice at most sites; information regarding acute and chronic medical comorbidities is not routinely collected. Finally, information describing renal function over time could have provided greater insight into the relationship between baseline renal insufficiency and death; however, these data are not reliably collected in our setting. The impact of ART on long-term renal outcomes is another area requiring further study, particularly in settings in which screening modalities may be limited.
In summary, we observed higher risk for mortality among patients with renal insufficiency at time of ART initiation, even among individuals with mild renal disease. This finding was consistent across different measures of renal function and independent of other known predictors of mortality. Our results suggest that, wherever feasible, screening for renal function should be instituted as part of ART expansion programs, particularly when drugs with known nephrotoxicities have been incorporated into HIV treatment. Algorithms for more aggressive assessment and management of renal insufficiency should also be developed specifically for settings with limited diagnostic capabilities.
L.B.M., G.K. and B.H.C. developed the study concept, designed the analysis plan, interpreted the data, and wrote the manuscript. S.L., S.E.R., I.Z., E.M.S. and J.S.A.S. contributed to the study concept, interpreted the data, and provided critical revision of the manuscript for intellectual content. R.A.C. provided data management, conducted statistical analyses, and edited the manuscript. Z.K., A.M. and M.S.S. contributed to the data interpretation and provided critical revision of the manuscript for intellectual content. All authors approved the final version for submission.
The authors acknowledge the Zambian Ministry of Health for consistent and high-level support of operations research surrounding its national HIV care and treatment program. They thank Dr Sten Vermund for his thoughtful review of the manuscript. Investigator and trainee support was provided by the National Institutes of Health (K23 AI01411, K01 TW05708, K01 TW06670 D43-TW001035), the University of Alabama at Birmingham Center for AIDS Research (P30 AI27767-20), and the Doris Duke Clinical Scientist Development Award (2007061). The clinical program described in this manuscript was supported by a multicountry grant to the Elizabeth Glaser Pediatric AIDS Foundation from the US Centers for Disease Control and Prevention (U62/CCU12354). Data monitoring and quality improvement was supported in part by a Doris Duke Charitable Foundation grant for Operations Research for AIDS Care and Treatment in Africa (2005047).
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