*Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC; †Department of Epidemiology, The Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD; ‡State University of New York Downstate Medical Center, Brooklyn, NY; §Department of Medicine Georgetown University Medical Center, Washington, DC; ∥Department of Medicine University of California, San Francisco, San Francisco, CA, ¶Quintiles, Inc. Research Triangle Park, NC; #Departments of Medicine and Epidemiology and Population Health, Montefiore Medical Center, Bronx, NY
To the Editor:
Human immunodeficiency virus (HIV) infection is an independent risk factor for microalbuminuria.1 Microalbuminuria has not yet been linked to poorer renal outcomes among persons with HIV infection as it has among persons with hypertension or diabetes mellitus,2 but overt proteinuria is associated with an increased risk of new AIDS-defining illness (ADI) and mortality.3 Because highly active antiretroviral therapy (HAART) has been demonstrated to improve patient and renal survival,4 this study was undertaken to investigate the association of HAART initiation with changes in urinary albumin excretion.
This study utilized stored urine samples from the Women's Interagency HIV cohort study.5 Women initiating HAART before October 1998 were matched to HIV-positive women not initiating HAART during the same time period using propensity scores. Two visits between 6 and 12 months apart were selected for albuminuria testing, corresponding to the last visit before HAART initiation (baseline visit) and the visit after HAART initiation when it was documented (follow-up visit), among the HAART initiators. Visits for noninitiators of HAART were selected to correspond to these visits in calendar time. Urine albumin and creatinine were measured for selected specimens in batch from stored urine samples. Albumin-to-creatinine ratio (ACR) was calculated and was race adjusted for women who self-identified themselves as black by multiplying the urine creatinine measurement by 0.88.6 The main outcome of interest was ACR at the follow-up visit; and the main exposure of interest was antiretroviral therapy. Therapy reported at the later visit was classified as no antiretroviral therapy, monotherapy or combination therapy, or HAART.7 Linear regression models were constructed to estimate the effect of HAART therapy on ACR over time.
Women who began HAART therapy were similar in urinary excretion of albumin as compared with those who did not begin HAART when both ratios adjusted and not adjusted for race were compared (P = 0.56 and 0.69, respectively). There were no differences between HAART initiators and noninitiators at the baseline visit in age; systolic or diastolic blood pressures; hematocrit; albumin; serum creatinine; glomenular filtration rate (GFR); race; and history of diabetes, hypertension, or prior ADI. The HAART initiators had significantly higher CD4+ lymphocyte counts (336 vs 193 cells/mL, P = 0.002), lower HIV RNA levels (19,000 vs 26,000 copies/mL, P = 0.02), higher body mass index (26.4 vs 23.6 kg/m2, P = 0.01), and a trend toward a lower likelihood of hepatitis C (33.3% vs 47.4%, P = 0.07).
At baseline, higher ACR was associated with older age (P = 0.03), black race (as compared with white or other, P = 0.01), lower CD4+ lymphocyte count (P = 0.02), greater HIV RNA level (P = 0.001), lower hematocrit (P < 0.0001), the presence of diabetes mellitus (P = 0.006) or hypertension (P = 0.05), greater systolic and diastolic blood pressures (P = 0.04 and 0.05, respectively), and prior ADI (P = 0.0009).
In this study, 49.4% of women had an increase in the ACR, 10.5% had no change in their ACR, and 40.1% had a decrease. Women not initiating HAART had a significantly larger increase in ACR between first and second measurements (Table 1) (P = 0.01). This difference in change in ACR by treatment group was greatest among subgroups of women with CD4+ lymphocyte counts ≤200 cells/mL (P = 0.006) and HIV RNA levels greater than the median for the cohort at baseline (P = 0.02). It was also more pronounced among women without hepatitis C coinfection (P = 0.05) and in women without diabetes mellitus (P = 0.01) or without hypertension (P = 0.005).
In a multivariable linear regression model examining predictors of greater ACR at follow-up, the use of HAART was associated with a lower ACR as compared with no therapy (P = 0.04). Variables associated with an increased ACR at follow-up include a greater baseline ACR (P < 0.0001) and baseline HIV RNA level (P = 0.008) and black race (P = 0.04).
This study examines the association of the initiation of HAART with subsequent urinary albumin excretion in a cohort of women with HIV infection. In the absence of HAART, greater albumin excretion was associated with black race; lower CD4+ lymphocyte count and hematocrit; greater age, HIV RNA level, and systolic and diastolic blood pressures; the presence of diabetes mellitus or hypertension; and history of an ADI. Women who did not begin HAART therapy had a significantly larger increase in ACR over time. The associative benefit of HAART on ACR was greatest in women with lower CD4+ lymphocyte counts, higher HIV RNA levels, coinfection with hepatitis C, and without diabetes or hypertension.
Although the mechanism of albuminuria is not clear, possible HIV-related pathways such as endothelial cell dysfunction may be hypothesized. Hypotheses such as these are supported by a relative improvement in ACR with the administration of HAART and associations between baseline ACR and parameters that reflect a more advanced stage of HIV infection such as lower CD4+ lymphocyte count, higher HIV RNA level, and history of prior ADI. Endothelial cell dysfunction is a precursor to vascular damage and is common in cardiovascular-related diseases and chronic kidney disease. Endothelial cell dysfunction has been demonstrated in multiple studies as a risk factor for cardiovascular events and death among patients with coronary artery disease, hypertension, peripheral artery disease, stroke, and diabetes.8,9
It is estimated that more than one third of persons with HIV infection have either microalbuminuria or proteinuria.1,10 Proteinuria has been associated with increased risk of new ADI and death.3 Although to date the association between microalbuminuria and poorer outcomes has not been established, the association of microalbuminuria with overt proteinuria and the parallel between diabetic nephropathy and kidney abnormalities in the HIV-infected community suggest that a relationship might exist. Pending investigation of these associations in the HIV-infected community, specifically, the clinical significance of microalbuminuria and the therapeutic benefit of lowering albumin excretion when present even at low levels in the general population need to be underscored.11,12 This study demonstrates a beneficial association of initiation of HAART therapy, with a lesser increase in microalbuminuria over time. An understanding of whether the beneficial associations demonstrated here are related to nonspecific suppression of viral replication or to specific antiretrovirals or regimens will be essential toward implementing treatment strategies to have maximum impact on hard clinical outcomes.
Lynda Szczech MD, MSCE*
Elizabeth T. Golub PhD†
Gayle Springer MS†
Michael Augenbraun MD‡
Mary Young MD§
Monica Gandhi MD∥
Barbara S Gillepsie MD¶
Kathryn Anastos MD#
*Division of Nephrology, Department of Medicine Duke University Medical Center, Durham, NC
†Department of Epidemiology The Johns Hopkins University, Bloomberg School of Public Health Baltimore, MD
‡Department of Medicine State University of New York Downstate Medical Center Brooklyn, NY
§Department of Medicine Georgetown University Medical Center Washington, DC
∥Department of Medicine University of California, San Francisco San Francisco, CA
¶Quintiles, Inc Research Triangle Park, NC
#Departments of Medicine and Epidemiology and Population Health Montefiore Medical Center Bronx, NY
1. Szczech LA, Grunfeld C, Scherzer R, et al. Microalbuminuria in HIV infection. AIDS
2. Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA
3. Szczech LA, Hoover D, Cai X, et al. The association between renal disease and outcomes among HIV-infected women taking and not taking antiretroviral therapy. Clin Infect Dis
4. Szczech LA, Edwards LJ, Sanders LL, et al. Protease inhibitors are associated with a slowed progression of HIV-associated renal diseases. Clin Nephrol
5. Barkan SE, Melnick SL, Preston-Martin S, et al, for the WIHS Collaborative Study Group. The Women's Interagency HIV Study. Epidemiology
6. Jacobs DR, Murtaugh MA, Steffes M, et al. Gender- and race-specific determination of albumin excretion rate using albumin-to-creatinine ratio in single, untimed urine specimens. Am J Epidemiol
8. Vita JA. Endothelial function and clinical outcome. Heart
9. Meigs JB, Hu FB, Rifai N, et al. Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA
10. Szczech LA, Gange SJ, van der Horst C, et al. Predictors of proteinuria and renal failure among women with HIV infection. Kidney Int
11. Asselbergs FW, Diercks GFH, Hillege HL, et al, for the PREVEND IT Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation
12. Klaus K, Borch-Johnsen K, Feldt-Rasmussen B, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation