HIV-specific risk factors associated with higher ACR were lower CD4 lymphocyte count (P = 0.009 for 200–400 versus < 200 cells/ml, and P = 0.005 for > 400 versus < 200 cells/ml), current HIV RNA level (P = 0.05), and current use of NNRTI (P = 0.01). Current use of NNRTI was the only ARV selected into the model (entrance criterion P < 0.05) among candidate predictors that included duration or use of each individual ARV, class of ARV, and use of HAART regimens. Co-infection with hepatitis C virus (P = 0.58) was not significantly associated with higher ACR.
This analysis demonstrated that HIV infection is a strong risk factor for the presence of microalbuminuria, independent of other risk factors for the presence of renal disease. Among HIV-infected individuals, risk factors for microalbuminuria included traditional HIV specific markers such as CD4 lymphocyte count and HIV RNA level. The association of HIV infection with albuminuria and proteinuria was reported in an earlier era of the HIV epidemic in the USA with a prevalence of between 19 and 34% [5–7]. One of these prior studies demonstrated associations between the presence of microalbuminuria and ‘stage’ of HIV-infection . A more recent study also found that HIV RNA level, CD4 lymphocyte count, and African–American race were important determinants of overt proteinuria . In the study described in this report, decreased CD4 cell count, increased viral load, and African–American race were all associated with higher ACR.
However, higher albumin excretion rate in this study was also strongly associated with several traditional renal and cardiovascular risk factors such as higher systolic blood pressure, insulin resistance, and glycosuria [32,33]. The importance of these renal and cardiovascular risk factors as determinants of albumin excretion rate in HIV-infected individuals may mark a shift in the significance of microalbuminuria in the current era of HIV in the USA. Rather than a marker of the severity of HIV infection and HIV-related renal disease, the increased prevalence of microalbuminuria among HIV infected patients may signal an increase in their cardiovascular risk.
Our findings indicate that within the HIV-infected population, non-HIV factors may be more important predictors of microalbuminuria than HIV severity in the current era of HIV in the USA. In particular, the cardiovascular risk factors of increased systolic blood pressure, insulin resistance, and older age (risk factors previously noted in the general population) were strongly associated with microalbuminuria in our HIV-infected cohort. These results suggest that microalbuminuria may be a sign of current endothelial dysfunction and microvascular disease rather than of advanced HIV infection in this cohort, and may thus portend substantial risk of future cardiovascular disease events. Possible contributing factors include early kidney disease such as HIV-associated nephropathy, a marker of end organ damage related to comorbidities of diabetes mellitus or hypertension, or more diffuse endothelial cells dysfunction. Nevertheless, after adjustment for non-HIV factors, HIV itself is a major risk factor.
A relationship between microalbuminuria and current use of NNRTI was noted but was not as strong as the association of microalbuminuria with other measures, such as HOMA and CD4 lymphocyte count. While the potential for an indication bias related to the prescription of a class of antiretroviral medications such as NNRTI is not intuitive, it does remain a possibility. However, clearly, the limited strength of the relationship in the setting of multiple hypothesis-testing with dozens of individual and classes of medications should be reflected in its interpretation. While certain antiretroviral medications have been associated with acute renal failure and nephrolithiasis [34–37], glomerular damage has not previously been reported with those medications and they were not apparently associated with microalbuminuria in this study. Tenofovir use was very low at the time of study; indinavir use was not associated with microalbuminuria.
Given the recent findings that even a very low ACR is a predictor of cardiovascular disease and death , a similar correlation of these findings with outcomes in HIV-infected persons as well as assessments of therapeutic interventions will be essential. Given the analogous clinical scenario of a decrement in microalbuminuria with agents that disrupt the renin–angiotensin axis among patients with diabetes mellitus , a similar therapeutic use among HIV-infected persons with microalbuminuria is plausible.
While the strengths of this study include recruitment of subjects from 16 geographically diverse centers, with subject demographics similar to those of HIV infected subjects in the USA , this study does have important limitations. With respect to study design, it is important to note that cross-sectional studies such as this may be affected by a survival bias. Additionally, causation and whether treatment of predictors such as systolic blood pressure and insulin resistance would decrease albuminuria in HIV cannot be determined from these data.
In summary, the presence of HIV infection was independently associated with a fivefold risk of microalbuminuria as compared with an age-matched cohort without HIV infection. Cardiovascular risk factors appeared to be stronger predictors of microalbuminuria than markers of HIV severity. Persons with HIV infection and microalbuminuria therefore appear to potentially bear the burden of two separate pathologic processes: microvascular end organ damage related to known vascular risk factors, and HIV specific processes such as the direct viral infection of kidney cells . The high prevalence of microalbuminuria among the HIV infected could be a harbinger of future increased risks of both kidney and cardiovascular disease. Further study defining the prognostic significance of microalbuminuria among HIV-infected persons will be essential.
FRAM is supported by grants from the National Institutes of Health (R01-DK-57508, R01-HL-74814, and R01-HL-53359). NIH support for this project is also provided through grants to General Clinical Research Centers (M01-RR00036, M01-RR00051, M01-RR00052, M01-RR00054, M01-RR00083, M01-RR00636, and M01-RR00865). Dr. Szczech's work is supported by grant DK02724-01A1 from the National Institutes of Health. Drs. van der Horst and Wohl are supported by the UNC Center for AIDS Research (P30-AI50410), the UNC AIDS Clinical Trials Unit (AI25868). Dr. Shlipak is supported by R01 HL073208-01, R01 DK066488-01, the American Federation for Aging Research and National Institute on Aging (Paul Beeson Scholars Program) and the Robert Wood Johnson Foundation (Generalist Faculty Scholars Program).
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