HIV-associated nephropathy (HIVAN) is the third leading cause of end-stage renal disease (ESRD) among blacks aged 20–64 years . As the widespread use of potent antiretroviral therapy continues to increase, the prevalence of persons living with HIV at risk for developing renal disease and ESRD will also become greater . The 1-year mortality rate for HIV-infected persons with ESRD was approximately 50% in the pre-highly active antiretroviral therapy (HAART) era [3,4], and is approximately 30% in the HAART era . Survival for HIV-positive persons with renal disease differs little between males and females. Survival among those with HIVAN has been shown to improve with increasing CD4+ cell count, decreasing serum creatinine and proteinuria levels, increasing hemoglobin level, and the receipt of corticosteroid therapy . Survival among HIV-positive patients undergoing hemodialysis has been shown to improve with increasing CD4+ cell count and decreasing blood pressure (systolic, diastolic and mean arterial) .
Among HIV-infected persons, 60 to 67% of renal disease diagnoses are HIVAN, a glomerulopathy whose histological features include collapsing focal segmental glomerulosclerosis [1,7–11]. The remaining 33 to 40% of renal diseases are of other histologies including membranoproliferative glomerulonephritis, minimal change disease, membranous glomerulopathy, amyloidosis, acute immune-complex glomerulonephritis, cryoglobulinemia, and IgA nephropathy [8,10–12]. Risk factors for HIVAN include black race, male gender, a history of injection drug use, hepatitis C antibody, decreased CD4+ cell count, and concurrent AIDS-defining condition [10,13]. Little risk factor information exists for other renal disease histologies probably due to the relatively low incidence for each type of disease among HIV-positive persons.
Despite the understanding that HIV can infect cells within the kidney and establish renal viral reservoirs thus leading to HIVAN and other renal diseases [14–16], few studies have assessed the relationship of HIV RNA level (viral load) and the presence or progression of renal disease. Furthermore, little information exists regarding risk factors for renal diseases other than HIVAN. Therefore, the current nested case–control study was conducted to ascertain whether an advanced stage of HIV disease, determined by viral load and CD4+ cell count, is associated with subsequent development of HIVAN and other chronic renal diseases.
The HIV Outpatient Study (HOPS; see Appendix) is an ongoing Centers for Disease Control and Prevention prospective observational follow-up study with continuous dynamic recruitment [17,18]. Study participants were HIV-1-infected persons receiving care at 11 HIV clinics in 10 cities: Atlanta, Georgia; Portland, Oregon; Stony Brook, New York; Philadelphia, Pennsylvania; Washington, DC; Tampa, Florida; Chicago Illinois; Denver Colorado; Oakland California; and San Leandro California. Since 1992, information has been collected for 6361 HIV-infected persons yielding over 155 000 irregularly occurring outpatient clinic visits.
Data from each outpatient visit is abstracted from the patient medical record and entered electronically by trained data abstractors. The data are then compiled centrally, reviewed, and if necessary are corrected before inclusion in the HOPS database. Since patient primary care is provided by study physicians, all symptoms, diagnoses and treatments since the previous visit are charted, including treatment changes. Categories of abstracted information include: demographic characteristics, risk factors for HIV-infection, HIV-related symptoms and general symptoms, diagnosed diseases, treatment dosage and duration, and laboratory measures including CD4+ cell counts and viral load quantification. Federal (Centers for Disease Control and Prevention), contractor (Cerner Corporation, Vienna, Virginia, USA), and local (participating HIV outpatient clinic) institutional review boards annually review and approve the ethical conduct of this study.
To allow for temporal assessment of exposures and disease, the current analysis was restricted to 5241 (82.4%) participants who (1) contributed at least 6 months of follow-up; or (2) were still under observation as of September 2002, the last date of clinical observations included in the current analysis. Cases were those subjects diagnosed with chronic renal disease while under observation. Study personnel confirmed all diagnoses by medical record review, and verified elevated serum creatinine and urine proteinuria levels. Biopsy reports were available for a limited number of cases (n = 4; 5% of cases). Only the initial diagnosis was considered for subjects with multiple renal disease diagnoses (n = 6; 7.5% of cases).
To avoid any type I errors and biases, subjects diagnosed with renal conditions other than those in our case definition were excluded as eligible controls. One hundred and five (2.0%) participants were excluded for having one or more elevated serum creatinine levels (n = 73; 1.4%) or an acute or solid-mass renal condition (n = 32; 0.6%). Controls were selected using incidence density sampling with replacement, and were matched 4 : 1 on age (± 2.5 years), race (white/non-Hispanic, black/non-Hispanic, Hispanic, other), and gender (male, female).
Nadir (lowest ever) CD4+ cell count and highest quantified viral load measurements formed the primary exposure measures. Only measurements occurring prior to the cases initial renal diagnosis date were considered for cases. Relevant measures for controls were those occurring before the initial renal diagnosis date of the matched case. CD4+ cell count was categorized as < 200 × 106 cells/l and 200 to 349 × 106 cells/l. No participants had nadir CD4+ cell counts ≥ 350 × 106 cells/l. Viral load was categorized as ≥ 100 000 copies/ml, 10 000 to 99 999 copies/ml, and < 10 000 copies/ml including undetectable measures.
In our analyses, we considered a history of illicit drug use (ever, unknown, never), documented diabetes mellitus (yes, no), and documented hepatitis C antibody (positive, negative) as potential confounders. Among adherent patients with drug-susceptible virus, HAART is regarded as clinically effective by 8 weeks duration . So, in order to assess the clinical benefits of HAART and avoid misclassifying short-term HAART use, participants ever receiving HAART for 56 days or more were compared with those who were HAART-naive or ever received HAART for less than 56 days. Documented history of hypertension and antihypertensive therapy use were combined to indicate hypertensives using angiotensin-converting enzyme (ACE) inhibitors, hypertensives using non-ACE antihypertensive therapy, hypertensives receiving no therapy, and non-hypertensives receiving no antihypertensive therapy. Ten participants (three cases, seven controls) were receiving antihypertensive therapy for conditions other than hypertension and were excluded from these analyses.
Baseline population characteristics, matched variables, and exposure variables were compared between cases and controls using χ2 and t-tests for categorical and continuous variables, respectively. To account for incidence sampling and to efficiently adjust for matched variables, odds ratios (OR) and 95% confidence intervals (95% CI) were obtained using multivariate conditional logistic regression (SAS Institute, Inc., Cary, North Carolina, USA). Effect modification was assessed using stratified analyses. Interaction terms combining primary exposure and confounding measures were evaluated using α = 0.05 to determine statistically significant interactions. Backwards elimination procedures were used to determine the most parsimonious models.
One hundred and eight cases of chronic renal disease were identified up to September 2002. Among these, 28 (25.9%) participants were excluded because the date of renal diagnosis preceded enrollment into HOPS (n = 18) or they contributed less than 6 months of follow-up (n = 10). Renal diagnoses of included cases (n = 80) were: glomerulonephritis (n = 3), HIVAN (n = 15), renal insufficiency (n = 54), ESRD (n = 3), interstitial nephritis (n = 1), membranous nephropathy (n = 1), IgG nephropathy (n = 1), and nephrotic syndrome (n = 2). Among those with multiple chronic renal diagnoses, three (3.8%) had progressed from their initial condition to ESRD, two (2.5%) received new diagnoses, and one (1.3%) received the same diagnosis.
Three hundred and fourteen matched controls were selected for inclusion in these analyses. Four risk sets included only one eligible matched control, and two risk sets included only two matched controls. Mean follow-up time from enrollment in the study differed among cases and controls (4.0 versus 5.1 years respectively, P = 0.005) (Table 1). As expected, cases and controls were similar with regards to the matched characteristics of race/ethnicity, gender and age. Cases were more likely to be deceased compared with controls (frequency of deceased cases versus controls: 35 versus 7%, P < 0.001). Nadir CD4+ cell count significantly differed between cases and controls (P < 0.001). Among participants with quantified highest viral load, a higher proportion of cases expressed levels ≥ 100 000 copies/ml (n = 33; 41.3%), whereas viral load among controls was evenly distributed across categories (P = 0.031). Among potential explanatory and confounding variables, only hypertension and antihypertensive therapy use significantly differed among cases and controls (P = 0.004).
Cases were 4.3 times more likely (95% CI, 2.1–8.7) to have nadir CD4+ cell counts < 200 × 106 cells/l (Table 2). Participants with a history of hypertension, regardless of antihypertensive therapy use, were also more likely to develop chronic renal disease (using ACE inhibitors: OR = 4.6; 95% CI, 1.8–11.6; using non-ACE: OR = 2.5; 95% CI, 1.0–6.2; no antihypertensive therapy: OR = 4.2; 95% CI, 0.8–21.6). Participants ever using HAART for 56 days or more were 50% less likely (95% CI, 0.3–1.0) to develop chronic renal disease. Highest quantified viral load was not independently associated with an increased risk except among those with an unknown measure (OR = 3.1; 95% CI, 1.0–9.5). No significant interactions were detected. In all conditional logistic regression analyses, diabetes, illicit drug use, and hepatitis C were not confounders or significant explanatory variables.
When stratified by ever HAART use, the observed associations for nadir CD4+ cell count and a history of hypertension and antihypertensive therapy differed considerably. Among participants ever receiving HAART for 56 days or more, those with nadir CD4+ cell counts < 200 × 106 cells/l were 4.1 (95% CI, 1.2–14.7) times more likely to be diagnosed with chronic renal disease (Table 3), whereas those with nadir CD4+ cell counts < 200 × 106 cells/l but not receiving HAART for 56 days or more were 13.3 (95% CI, 2.4–75.0) times more likely to be diagnosed with chronic renal disease. In comparison with persons who had no history of hypertension, hypertensives treated with ACE inhibitors who ever received HAART for 56 days or more were 3.8 (95% CI, 1.1–12.4) times more likely to develop chronic renal disease, whereas those with no history of HAART use for 56 days or more were 29.1 (95% CI, 1.2–732.6) times more likely to develop chronic renal disease. Participants with untreated hypertension were at increased risk regardless of HAART use, although the small number of subjects limited accurate assessment of effect modification.
The current nested case–control study examined several factors and their role in the development of chronic renal disease among HIV-infected persons. Among the factors evaluated, persons with chronic renal disease were more likely to have nadir CD4+ cell count < 200 × 106 cells/l, to have not received HAART for 56 days or more, and to have a history of treated and untreated hypertension. Previous studies have implicated low CD4+ cell count as a risk factor for developing chronic renal disease [11,13,20–22], but have generally identified patients retrospectively through either hospital admission or biopsy and autopsy results. These studies are therefore limited by the potential for selection bias. Previous studies were also unable to determine if lower CD4+ cell count increases the risk of developing chronic renal disease, results in a more aggressive form of prevalent disease, or both. Other cohort-based studies have reported increased risk of renal failure  and mortality  among women with absolute CD4+ cell counts < 200 × 106 cells/l.
Few studies have assessed viral load as a risk factor for chronic renal disease despite evidence for a direct pathogenic role of HIV [14–16,24–28]. Studies assessing viral load have reported, among women, an association with reduced creatinine clearance  and renal failure . Although univariate analyses of highest ever viral load were statistically significant in the current study, significance was not achieved in multivariate analyses. Prior to 1995, widespread availability of technology to quantify viral load was limited . Therefore, viral load measures were unavailable for 16% of subjects included in these analyses. A variable indicating unknown highest viral load measure was included and achieved statistical significance in most of these analyses. Further inspection of these data revealed that among 18 cases with missing highest ever viral load measures, 11 (61.1%) had baseline CD4+ cell counts < 200 × 106 cells/l and 13 (72.2%) had nadir CD4+ cell counts < 200 × 106 cells/l. Given the established relationship between CD4+ cell count and viral load [30,31], we can conjecture that these subjects likely had high viral loads. If these measures had been available, statistical significance may have also been obtained in multivariate analyses. Although this is certainly a possibility, there also exists the potential that viral load may not be a sensitive indicator for risk of serious renal disease when patients are fairly advanced in their HIV and have initiated HAART. This was shown to be true in a recent study in which viral load was associated with declining creatinine clearance only during early study visits where few had received antiretroviral treatment .
Several studies have reported the beneficial prognostic effects of HAART and renal disease, including non-HIVAN histologies [32–36]. Results from the current study indicate potential beneficial effects of HAART in also reducing chronic renal disease pathogenesis. When modeled assuming uniformity, HAART use decreased the risk of developing chronic renal disease by 50%. However, HAART use was a strong effect modifier of the association between nadir CD4+ cell count < 200 × 106 cells/l and chronic renal disease in which those not receiving HAART were 13 times more likely to develop chronic renal disease compared with a four-fold increased risk among those receiving HAART for 56 days or more. These latter results and the prior observation that renal abnormalities appeared in 77% of participants prior to CD4+ cell counts < 200 × 106 cells/l  suggest the importance of initiating HAART before CD4+ cell counts of 200 × 106 cells/l. The current analysis did not attempt to evaluate the individual benefits conferred by specific antiretroviral agents. Additional research is needed to determine specific antiretroviral benefits, and if differences exist by renal disease histology and risk group.
In the current study, only 18.8% of cases were HIVAN, a proportion far less than previously reported [8,10–12]. Black race has consistently been identified as a risk factor for HIVAN [8,11,12,37–40] potentially due to underlying host genetic factors . One estimate identifies 98% of HIVAN cases occurring among blacks (Lynda Szczech, personal communication). Among HIVAN cases in the current study, 60% were black (n = 9), 26.7% were white (n = 4), while Hispanic (n = 1) and other race (n = 1) each accounted for 6.7%. Additionally, other histologies such as glomerulonephritis, interstitial nephritis, membranous nephropathy, and IgG nephropathy that are not mutually exclusive from HIVAN were more likely to occur among whites (n = 5) than blacks (n = 2). The lower proportion of HIVAN cases among blacks may account for the reduced overall proportion of HIVAN in this cohort. Although chance alone is another possible explanation for decreased incidence of HIVAN, it is unlikely given the use of population-based sampling and the size of this cohort. A more likely explanation is that few cases were biopsy-confirmed (n = 4). As a result, many cases of renal insufficiency may be unrecognized cases of HIVAN.
Given the increased risk observed among hypertensives in the current study, one would expect treatment of hypertension to reduce the likelihood of developing chronic renal disease. When modeled assuming uniform effects and compared to untreated hypertensives, treatment with ACE inhibitors did not reduce risk. Treatment with non-ACE inhibitors reduced risk nearly two-fold. These results were modified by ever HAART use. Although hypertensives treated with ACE inhibitors were still at increased risk of renal disease, risk was 25-fold less among those ever using HAART for 56 days or more. A similar effect was obtained among hypertensives using non-ACE inhibitors, although the magnitude was not as dramatic. Although small numbers and the fact that adequate control of hypertension was not ascertained in the current analysis limits our conclusions, these results do suggest further potential benefits from HAART. A large, prospective, population-based sample is needed to accurately assess the effects of HAART and antihypertensives, as well as the optimal treatment regimen for preventing HIV-associated chronic renal disease among hypertensives. Specifically, a cohort with increased frequency of hypertension, antihypertensive therapy, ascertainment of effective control of hypertension, and HAART use is needed.
Several limitations should be noted. Although disease status was ascertained from medical records, biopsy reports were only available for four (5%) cases. Additionally, small numbers limited some analyses, particularly stratified analyses of HAART use. The current analysis did not distinguish between nephrotoxic antiretroviral drug-related and HIV-related toxicities. Drug effects were unlikely to contribute substantially given the duration of abnormal serologic and urine results and that most of the renal diagnoses predated widespread use of nephrotoxic drugs such as tenofovir. Finally, unknown biases may have occurred as a result of non-fixed visit intervals and unknown mechanisms of dropout. Despite these limitations, our results are strengthened by the minimal potential for selection bias as a result of our clinic-based study design and sampling of controls from those clinics that produced cases. The current analysis also included participants with a broad age range, males and females, and a variety of racial backgrounds. Additionally, all cases and all exposure measures were obtained from patient medical records, therefore reducing the potential for misclassification of exposure or disease. Finally, by analyzing longitudinal data, the temporal assessment of exposure and disease was possible.
Results from the current study provide further evidence that serious renal disease is a late manifestation of HIV infection, indicates the importance of preserving immune function, and initiating HAART before an AIDS-defining CD4+ cell count. These results also indicate the increased importance of diagnosing and treating hypertension, as well as broadening our attention to histologies other than HIVAN.
The authors would like to thank Julie Simmons, Haydee Martinez, Aleksandr Lazaryan, and Paul MacLennan of the University of Alabama at Birmingham, School of Public Health, Department of Epidemiology for their assistance in formulating this research and review of research methods.
Sponsorship: This research was funded by the Centers for Disease Control and Prevention contract 200-2001-00133.
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The HOPS Investigators include the following investigators and sites: Anne C. Moorman, Tony Tong, and Scott D. Holmberg, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention (NCHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, Georgia; Kathleen C. Wood and Rose K. Baker, Cerner Corporation., Vienna, Virginia; Frank J. Palella, Joan S. Chmiel, Maria Deloria Knoll, Barbara Gillespie, and Erin Nekervis, Northwestern University Medical School, Chicago, Illinois; Kenneth A. Lichtenstein, Kenneth S. Greenberg, Benjamin Young, Barbara Widick, Cheryl Stewart, and Peggy Zellner, Rose Medical Center, Denver, Colorado; Bienvenido G. Yangco, Kalliope Halkias, and Cheryl Lapierre, Infectious Disease Research Institute, Tampa, Florida; Douglas J. Ward and Charles A. Owen, Dupont Circle Physicians Group, Washington, DC; Jack Fuhrer, Linda Ording-Bauer, Rita Kelly, and Jane Esteves, State University of New York (SUNY), Stony Brook, New York; Ellen M. Tedaldi and Linda Walker-Kornegay, Temple University Hospital, Philadelphia, Pennsylvania; Joseph B. Marzouk, Roger T. Phelps, and Mark Rachel, Adult Immunology Clinic, Oakland, California; Robert E. McCabe and Mark Rachel, Fairmont Hospital, San Leandro, California; Richard M. Novak, Jonathan P. Uy and Andrea Wendrow, University of Illinois at Chicago, Chicago, Illinois.