Trends in Nephropathy Among HIV-Infected Patients

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Trends in Nephropathy Among HIV-Infected Patients Susan E. Buskin, PhD; Mauro S. Torno, MD; Deborah F. Talkington, PhD; Ming Zhang, PhD; Jeffrey L. Jones, MD; Jay C. Butler, MD; A.D. McNaghten, PhD; Mark S. Dworkin, MD

Funding/Support: This work was funded in part by a cooperative agreement with the Centers for Disease Control and Prevention. Disclaimer: The findings and conclusions in this paper are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. Background: Nephropathy complicates the course and adversely impacts on the prognosis of HIV-infected patients. We examined trends and correlates of all-cause nephropathy (ACN). Methods: Correlates of and trends in ACN were examined in the entire Adult/Adolescent Spectrum of HIV Disease longitudinal observational cohort. Patients were enrolled and followed in the cohort for a median period of 3 years between January 1990 and December 2003 in 11 US metropolitan areas. Results: The incidence of ACN rose among HIV-infected individuals through the mid-1990s, then declined. The proportion of patients with ACN at the time of death increased over the study period. Black race, injection-drug use (IDU), indinavir, hypertension, diabetes, decreased CD4+ lymphocyte count, increased viral load, and increased age were all highly associated with ACN. Discussion: Nephropathy represents an important health disparity impacting HIV-infected blacks and IDU with implications for mortality. Keywords: HIV/AIDS n kidney J Natl Med Assoc. 2009;101:1205-1213 Author Affiliations: HIV/AIDS Program, Prevention Division, Public Health– Seattle and King County, Seattle, Washington (Dr Buskin); Department of Epidemiology, University of Washington, Seattle Washington (Dr Buskin); David Geffen School of Medicine at University of California Los Angeles, California and Harbor-UCLA Medical Center, Torrance, California (Dr Torno); Enteric Diseases Laboratory Branch, Division of Foodborne, Bacterial, and Mycotic Diseases, National Center for Zoonotic, Vector-Borne and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia (Dr Talkington); Respiratory Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases (Drs Talkington, Zhang, and Butler, formerly of), Nutritional Biomarkers Branch, Division of Laboratory Sciences, National Center for Environmental Health (Dr Zhang), Behavioral and Clinical Surveillance Branch, Division of HIV/

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AIDS Prevention (Drs Jones, McNaghten, and Dworkin), Centers for Disease Control and Prevention, Atlanta, Georgia; Alaska Division of Public Health, Anchorage; Alaska (Dr Butler); Illinois Department of Public Health, Division of Infectious Diseases (Dr Dworkin) and University of Illinois at Chicago School of Public Health, Chicago, Illinois (Dr Dworkin) Corresponding Author: Susan Buskin, PhD, MPH, Senior Epidemiologist, 400 Yesler Way, 3rd Floor, Seattle WA 98104 ([email protected]).

Introduction

I

nfection with HIV has been associated with a variety of nephropathies, including a distinct form of renal disease termed HIV-associated nephropathy (HIVAN). Although the incidence and prevalence of HIVAN are not well characterized, especially in the era of highly active antiretroviral therapy (HAART), the prevalence has been estimated to be between 3.5% and 10% of people living with HIV infection.1 The prevalence varies predominantly due to the proportion of people of African descent among the HIV-infected population, as HIVAN occurs predominantly in blacks.2-7 Few data on trends in nephropathy among HIV-infected patients are available, although the incidence of HIVAN requiring dialysis has been reported to have increased during the early 1990s.8 One large cohort demonstrated a decrease in HIVAN associated with HAART.7 An accurate accounting of HIVAN is limited by the infrequency of renal biopsy, while all-cause nephropathy is more easily measured. To help put these data into perspective, we examined trends in nephropathy due to all causes among HIVinfected patients in a large multisite national medical record review cohort project. Although HIVAN declined in the United States with the introduction of HAART around 1996, nephropathy remains an important problem in HIV-infected patients, and its development is influenced by multiple factors, including HIV itself, treatment for HIV or other medications, coexisting medical conditions, and age-related declines in kidney function.9

Methods

The national Adult/Adolescent Spectrum of HIV Disease (ASD) data set was used to examine correlates of and trends in nephropathy, which was defined as a provider diagnosis of HIV-associated nephropathy, other VOL. 101, NO. 12, DECEMBER 2009 1205

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nephropathies, renal disease, renal insufficiency, and/or renal failure. All-cause (rather than disease-specific cause) nephropathy was examined to explore the burden of renal disease in general. The methods of ASD have been previously described.10 In collaboration with 11 state and local health departments, this national surveillance project of the Centers for Disease Control (CDC) collected information from the medical records of HIVinfected patients at selected health care facilities (approximately 70% public and 30% private institutions).11 Initial

abstraction of data from these records included demographic characteristics, the mode of exposure to HIV, previous occurrences of conditions listed in the surveillance case definition of AIDS,12 and, for the 12 months prior to enrollment, other conditions, types of medications prescribed, viral load, and CD4+ cell counts per cubic millimeter were recorded. Each initial abstraction was followed by abstractions every 6 months until death, relocation to another health care provider or geographic region, or loss to follow-up (18 months with no contact).

Table 1. Characteristics of HIV-Infected People With Incident All-Cause Nephropathy vs Those Without All-Cause Nephropathy; Adult/Adolescent Spectrum of HIV Disease, United States, 1990-2003

Characteristic Sex Male Female Race/ethnicity White Black Hispanic/Latino Asian/Pacific Islander Native American/Alaska Native Other/unknown HIV exposure mode Men who had sex with men Injection drug user Men who had sex with men/IDU Otherd No identified risk Age group, y 13-19 20-29 30-39 40-49 50-59 ≥60 Hypertensiona Yes No Diabetesa Yes No Hepatitis Ca Yes No Hepatitis Ba Yes No Indinavira Yes No

% No. % No. With With Without Without Relative ACN ACN ACN Risk ACN

95% CI

cb P Value (cb for Trend P Value)

3982 1060

8.9 8.3

40 927 11724

91.1 91.7

1.0 1.07

(reference) 0.00-1.14

1299 2882 795 33 27 6

6.2 11.5 7.3 6.5 9.7 4.7

19 504 22 205 10093 476 250 123

93.8 88.5 92.7 93.5 90.3 95.3

1.0 1.84 1.17 1.04 1.56 N/A

(reference) 1.73-1.96 1.07-1.27 0.74-1.45 1.09-2.24

<.001 <.001 .83 .017

2124 1290 500 614 514

8.2 11.9 9.4 8.0 6.5

23 852 9558 4792 7068 7381

91.8 88.1 90.6 92.0 93.5

1.0 1.45 1.16 0.98 N/A

(reference) 1.36-1.55 1.05-1.27 0.90-1.07

<.001 .002 .6

44 949 2268 1302 386 93

4.7 6.9 8.7 10.1 11.6 12.3

891 12 752 23 769 11 648 2929 662

95.3 93.1 91.3 89.9 88.4 87.7

1.0 1.47 1.85 2.14 2.47 2.62

(reference) 1.10-1.98 1.38-2.48 1.59-2.86 1.83-3.35 1.85-3.70

(<.0001)

947 4095

12.7 8.2

6502 46 149

87.3 91.8

1.56 1.0

1.46-1.67 (reference)

<.001

353 4689

14.0 8.5

2160 50 491

86.0 91.5

1.65 1.0

1.49-1.83 (reference)

<.001

455 4587

8.9 8.7

4686 47 965

91.1 91.3

1.01 1.0

0.92-1.11 (reference)

.77

402 4640

9.7 8.7

3753 48 898

90.3 91.3

1.12 1.0

1.01-1.23 (reference)

.03

745 4297

9.9 8.6

6753 45 898

90.1 91.4

1.16 1.0

1.08-1.25 (reference)

<.001

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A diagnosis of nephropathy was sought during the initial 12 months prior to enrollment and, if found, was considered prevalent. To describe trends in nephropathy over time, prevalence was calculated as the number of persons diagnosed with nephropathy per 1000 people followed at their initial baseline interval. Nephropathy initially diagnosed during a follow-up interval was considered incident. Incidence trends were compared by calculating incident nephropathy diagnoses per 1000 persons observed for each year during follow-up and excluding the initial baseline observation period. Nephropathy at time of death was defined as a nephropathy diagnosis during the medical

chart abstraction period of up to 6 months prior to death. Data collection began in 1990 (Atlanta, Georgia; Dallas, Houston; San Antonio, Texas; Denver, Colorado; Detroit, Michigan; Los Angeles, California; New Orleans, Louisiana; Seattle, Washington), 1991 (New York, New York), and 1992 (Bayamón, Puerto Rico). The San Antonio site ceased data collection in 1999. More than 100 facilities participated, including hospitals, outpatient offices, and emergency rooms. Data may have been abstracted from multiple participating health care facilities for a given patient, but there were not adequate resources to follow patients at additional, nonparticipating facilities.

Table 1. Characteristics of HIV-Infected People With Incident All-Cause Nephropathy vs Those Without All-Cause Nephropathy; Adult/Adolescent Spectrum of HIV Disease, United States, 1990-2003 (contd)

Characteristic Ritonavira Yes No Viral loada Undetected to 9999 10 000-99 999 100 000-999 999 ≥1 000 000 or above limit of detection Missing CD4 categorya per mmc <100 100-199 200-499 ≥500 Missing MDRD glomerular filtration rate estimateb,c Stage I/normal Stage II Stage III Stage IV Kidney failure Unknown Serum creatinineb Mean Median Follow time, mo Mean Median Total

% No. % No. With With Without Without Relative ACN ACN ACN Risk ACN

95% CI

cb P Value (cb for Trend P Value)

539 4503

9.3 5234 8.7 47 417

90.7 91.3

1.08 1.0

0.99-1.17 (reference)

.09

342 482 866 153 3199

4.4 7395 5.3 8665 9.8 7937 9.6 1446 10.5 27 208

95.6 94.7 90.2 90.4 89.5

1.0 1.19 2.23 2.16 N/A

(reference) (<.001) 1.04-1.36 1.97-2.51 1.80-2.60

2896 759 858 191 338

12.3 20 656 9.4 7340 5.3 15 277 3.0 6206 9.6 3172

87.7 90.6 94.7 97.0 90.4

4.12 3.14 1.78 1.0 N/A

3.57-4.76 (<.001) 2.69-3.67 1.53-2.08 (reference)

102 268 600 580 640 2851

1.1 9552 2.9 8877 20.7 2300 100.0 0 100.0 0 8.2 31 922

98.9 97.1 79.3 0.0 0.0 91.8

4.8 2.7

1.1 1

41.9 30.1 5042

34.7 22.9 8.7 52651

91.3

Abbreviations: ACN, all-cause nephropathy; CI, confidence interval; IDU, injection-drug user; MDRD, Modification of Diet in Renal Disease; NA, not applicable. a

Prior to ACN for persons diagnosed with ACN and at any time during observation for persons not diagnosed with ACN.

b

Used to define the outcome of all-cause nephropathy thus relative risk and c2 statistics were not calculated.

c

See reference Levey et al for details on calculation of MDRD.a,c Note these data are limited to 1996-2003, as creatinine levels were added to the data collection form at that time.

d

 ther HIV risk includes a history of heterosexual sex with an individual known to be HIV-infected or in another HIV risk category, O hemophiliac, transfusion recipient, and documented occupational exposure to HIV.

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The July 2004 data set was used for the trends analysis, including patients enrolled and followed in ASD between January 1990 and December 2003. Trends in antiretroviral use and hepatitis are limited to 1996 through 2003, when selected antiretrovirals became available and hepatitis screening was more widely performed. In addition to diagnoses of nephropathy, highest serum creatinine values in mg/dL were collected in ASD for each observation period (12 month initial and 6-month followups) for observation periods starting approximately in 1996. Thus, trends in measures related to serum creatinine are given for 1996 through 2003. Moderately elevated creatinine levels were defined as 1.5 to 2.9 mg/dL for men and 1.3 to 2.9 mg/dL for women. Highly elevated creatinine levels were defined as greater than 2.9 mg/dL for both men and women. These cutoff levels roughly corresponded to tercile serum creatinine levels among subjects diagnosed with nephropathy. An estimate of the glomerular filtration rate (GFR) called the Modification of Diet in Renal Disease (MDRD) GFR was calculated based on highest serum creatinine, age, gender, and race/ethnicity (black vs other).13 MDRD GFR categories range from 1 (normal GFR >90) to 5 (stage V kidney disease/kidney failure, GFR <15).14 MDRD GFR indicating stage IV or V disease, serum creatinine levels greater than 4.9 mg/dL, and receipt of dialysis were also considered evidence of all-cause nephropathy. Mortality rates, or the percent of individuals who had died within the observation periods, were calculated by MDRD GFR level and also by highest serum creatinine levels.

Statistical Methods Relative risks of all-cause nephropathy and their 95% confidence intervals (CIs) were examined. Categorical data were compared by c2 and c2 for trend tests; continuous data, such as mean creatinine levels, were compared by Student t tests. For individuals under observation during the period of 1996-2003, a proportional hazards regression model was fit to look at the risk of all-cause nephropathy while adjusting for potentially confounding risk factors. The proportional hazards ratios are estimates of the relative risk for each factor, taking into account the amount of time to development of all-cause nephropathy. Each covariate was entered in the model as a bivariate term or group of terms (such as different levels of plasma viral load or decades of age). Software used for data analyses included SAS (Statistical Analysis Software version 8.2, SAS Institute, Cary, North Carolina) and Epi Info (Version 6.04; CDC, Atlanta, Georgia).

Results

From the inception of the ASD project in January 1990, a total of 59 705 patients with HIV infection were enrolled through December 2003. The median followtime was 23.7 months. There were 7054 (12%) patients diagnosed with nephropathy due to all causes. Of these, 2012 (29%) had nephropathy at their initial observation (prevalent nephropathy) and 5042 (71%) had incident nephropathy. Of all cases, prevalent and incident, 489 (7%) received dialysis at some point during their observa-

Figure 1. Incidence and Prevalence of All-Cause Nephropathy and Proportion With All-Cause Nephropathy at Time of Death, Adult/Adolescent Spectrum of HIV Disease Project, United States, 1990-2003

All-cause nephropathy (ACN) was defined as any provider diagnosis of nephropathy, including HIV-associated nephropathy, other nephropathies, renal disease, and/or renal failure. Prevalence of ACN was calculated as the number of persons diagnosed with ACN per 1,000 people followed at their initial/baseline interval in the Adult/Adolescent Spectrum of Disease project. Incidence of ACN was defined as the number of people with ACN diagnoses per 1,000 persons observed excluding baseline observation periods. ACN at time of death was defined as an ACN diagnosis during the medical chart abstraction period of up to six months prior to death.

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tion time. Patients diagnosed with incident all-cause nephropathy relative to those without all-cause nephropathy were older, had higher plasma HIV viral load and

lower CD4+ lymphocyte count (Table 1). All-cause nephropathy was significantly more prevalent among blacks, Native Americans/Alaskan Natives, Hispanics,

Figure 2. Trends in the Prevalence of Age 50 Years and Greater, Hypertension and Diabetes Prior to AllCause Nephropathy; Adult/Adolescent Spectrum of HIV Disease Project, United States, 1991-2003

Hypertension and diabetes were both based on provider diagnoses without specific laboratory findings or measurements required.

Figure 3. Trends in the Prevalence of Hepatitis B, Hepatitis C, Indinavir, and Ritonavir Prior to All-Cause Nephropathy; Adult/Adolescent Spectrum of HIV Disease Project, United States, 1996-2003

Hepatitis B and hepatitis C were based on laboratory findings of antigen (hepatitis B), antigen or antibody (hepatitis C), or provider diagnosis. Indinavir and ritonavir prevalence were based on provider prescriptions of these antiretrovirals.

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injection-drug users, people diagnosed with hypertension or diabetes, and those who were prescribed indinavir. The prevalence and incidence of nephropathy peaked in 1992 (prevalence) and 1995 (incidence), with spikes in 1998 (both) (Figure 1). Both prevalence and incidence declined significantly over the observation period and especially since 1998 (c2 for linear trend p <.001). The proportion of people who had a diagnosis of all-cause nephropathy at their time of death is also shown in Figure 1. All-cause nephropathy as a condition present at time of death increased, especially during the HAART era (c2 for linear trend p <.001) (Figure 1). The prevalence of patients with all-cause nephropathy with hypertension, diabetes, and age greater than 49 years rose during the study period (Figure 2). The prevalence of hepatitis C and prescription of indinavir and ritonavir substantially increased during the HAART era among patients with all-cause nephropathy (Figure 3). Among the 28 709 patients for which information on highest serum creatinine level was collected, the mean highest creatinine level was 1.5 mg/dL; and the median was 1.1 (95% CI, 1.5-1.6; 25th- and 75th-percentile interquartile range, 0.9-1.3). The mean highest serum creatinine levels for those with and without all-cause nephropathy were 4.8 mg/dL and 1.1 mg/dL, respectively. The mean creatinine level for blacks, regardless of nephropathy, was 1.8 mg/dL (median 1.1) compared to 1.2 mg/dL

(median 1.0) for whites (p value comparing means < .001). The mean highest creatinine levels for patients with injection-drug use as a mode of HIV transmission was 1.8 mg/dL (median 1.1) vs a mean of 1.5 mg/dL for men who had sex with men (median 1.1) (p < .001). Black injection-drug users had a mean highest creatinine of 2.2 mg/ dL (median 1.1) compared to 1.2 mg/dL (median 1.1) for white injection-drug users (p < .001). Moderately elevated creatinine levels increased over the observation period, but highly elevated creatinine levels remained fairly stable over time (Figure 4). Black injection drug users had nearly 3 times the risk of all-cause nephropathy relative to nonblacks without a history of injection-drug use (relative risk, 2.8; 95% CI, 2.7-3.0). Among nonblacks, the relative risk of all-cause nephropathy for injection-drug use relative to those with no history of injection-drug use was 1.4 (95% CI, 1.31.5). Among non–injection-drug users, the relative risk of having black race/ethnicity relative to other race/ethnicity was 1.9 (95% CI, 1.8-2.0). Relative risks, as estimated by proportional hazards ratios, were calculated for selected potential risk factors for individuals under observation during 1996-2003 (Table 2). Blacks had a relative risk of all-cause nephropathy of about 1.5, Hispanics had a relative risk of 1.2, and Native Americans/Alaska Natives had a relative risk of 1.8 relative to those of other race/ethnicity groups.

Figure 4. Trends in the Prevalence of Elevated Serum Creatinine Levels in mg/dL; Adult/Adolescent Spectrum of HIV Disease Project, United States, 1996-2003

Creatinine measurements graphed are in mg/dL and were the highest measurement available for each 6-month interval.

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Individuals with a history of injection-drug use who were aged 60 years or more with a history of hypertension or diabetes and/or who had been prescribed indinavir all had excess risks of all-cause nephropathy relative to those without each characteristic after adjusting for all the other factors listed in Table 2. Annual mortality rates increased significantly with declining kidney function as measured by MDRD GFR. Among those subjects for whom an MDRD GFR could be calculated (N = 22 920, 40%), 4% to 6% mortality was observed per year in those with normal through MDRD GFR stage II (mild decrease in kidney function). Stage III MDRD GFR (moderate decrease in kidney

function) was associated with a 20% annual mortality rate. MDRD GFR stages IV to V (severely decreased kidney function) were associated with 42% to 52% annual mortality (c2 for trend p < .001). A similar association was seen with highest creatinine level.

Discussion

These data demonstrate that the incidence and prevalence of all-cause nephropathy have declined among HIV-infected patients in the HAART era in the United States despite a concomitant rise in conditions associated with nephropathy (such as hypertension and diabetes mellitus) in this aging population. However, among

Table 2. Proportional Hazards Ratio Estimates of Adjusted Relative Risks, for Selected Potential Risk Factors for Incident All-Cause Nephropathy; Adult/Adolescent Spectrum of HIV Disease, United States, 1996-2003 Adjusted Characteristics Sex Female vs male Race/ethnicity Black Hispanic Asian/Pacific Islanders Native American/Alaska Native HIV exposure mode Men who had sex with men Injection-drug users Age group at baseline, y 30-39 40-49 50-59 ≥60 Comorbidity Hypertension Diabetes Hepatitis B Hepatitis C Antiretroviral therapy Indinavir Ritonavir Highly active antiretroviral therapy Viral loada Undetected to 9999 10 000-99 999 100 000-999 999 ≥1 000 000 or above limit of detection CD4 category per mm3 <100 100-199 200-499 ≥500 a

PHR Estimate of Relative Risk

95% CI

0.87

0.78–0.98

1.51 1.19 1.66 1.77

1.34-1.70 1.02-1.38 0.97-2.83 1.07-2.92

0.87 1.24

0.78-0.98 1.11-1.37

1.21 1.13 1.14 1.82

1.07-1.36 1.00-1.28 0.98-1.34 1.45-2.30

1.21 1.51 0.89 0.88

1.09-1.35 1.30-1.74 0.76-1.05 0.78-1.00

1.15 0.87 0.30

1.02-1.29 0.77-0.98 0.27-0.34

0.43 0.48 0.66 0.59

0.36-0.52 0.41-0.55 0.58-0.75 0.48-0.71

1.12 0.68 0.29 0.18

0.90-1.41 0.54-0.87 0.23-0.37 0.14-0.25

Abbreviations: CI, confidence interval; PHR, proportional hazards ratio. a

 rior to all-cause nephropathy for persons diagnosed with all-cause nephropathy and at any time during observation for persons not P diagnosed with all-cause nephropathy.

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those dying with HIV, nephropathy has become more common. In addition, the prevalence of a moderately high serum creatinine measurement has increased, which could be important in planning for the health needs of HIV-infected patients in populations where longevity is increasing due to HAART. The declining trend in the incidence and prevalence of all-cause nephropathy among HIV-infected patients in the United States starting in the early 1990s may have been disrupted in 1998-1999 in part by use of indinavir, a drug that may cause nephrolithiasis in 6% to 36% of patients,15,16 as well as other renal disease, including crystalluria and interstitial nephritis.17,18 The ASD project previously found an incidence of 38.9 episodes of nephrolithiasis per 1000 person-years when indinavir is prescribed.19 However, trend data demonstrate that indinavir prescription rose steadily during 1996 through 2000, while the prevalence of all-cause nephropathy was generally declining. What is more likely to explain the declining incidence and prevalence of all-cause nephropathy is the reversal of immune suppression and decrease in viremia that HAART has brought to those with access to treatment. Immune suppression brings with it an increased incidence of opportunistic diseases and bacterial infections that may cause sepsis or invade the kidneys and is also associated with increased use of potentially nephrotoxic medications (eg, foscarnet, aminoglycosides, and antifungals). The important role of declining CD4+ T-lymphocyte count on the incidence all-cause nephropathy is supported by our ASD analysis. Further, HAART-mediated viral suppression may also be an important explanatory factor in the decrease in all-cause nephropathy, in part due to the presumptive role of HIV itself as an etiologic factor for HIVassociated nephropathy.20-23 The ASD data also demonstrated that black HIVinfected patients were disproportionately diagnosed with nephropathy. This was true even after adjusting for numerous other potential cofactors. Blacks had a 50% higher mean serum creatinine than whites; blacks with a history of injection-drug use had an 80% higher mean creatinine than their white counterparts. This is especially significant because elevated creatinine was associated with higher mortality. One urban US study demonstrated that blacks had an increased risk of chronic kidney disease and, once chronic kidney disease was diagnosed, a much faster progression to end-stage renal disease relative to whites.24 Among patients with endstage renal disease, those with HIVAN have among the highest mortality rates,25 and HIVAN occurs disproportionately more often among blacks3,21 as does end-stage renal disease.26 Although survival of HIV-infected patients initiating dialysis has improved during the era of HAART, HIV-infected patients on dialysis still have decreased survival relative to HIV-infected patients after an AIDS-opportunistic illness.27 In addition to elevated creatinine, all-cause nephropathy, and HIVAN other fac1212 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

tors that may adversely effect survival such as hepatitis C virus coinfection, injection-drug use, diabetes, and hypertension are often present among HIV-infected blacks.26,28,29 Further, there has been recent evidence that genetic mutations responsible for focal segmental glomerulosclerosis, 1 type of nephropathy, are 2 to 10 times more common in blacks than Caucasians.30 Our data support the need for greater attention to nephropathy prevention to decrease racial disparities associated with HIV and nephropathy. Limitations of the ASD project include its retrospective observational and potentially nonrepresentative methodology. Sites participating in and patients followed by ASD were not selected using randomized sampling methods to ensure a representative cohort, although the large sample size may have helped increase the representativeness of the data. While the study collected diagnoses of nephropathy, ASD was not able to measure the exact onset of nephropathy, distinguish acute from chronic nephropathy, nor definitively ascertain the specific cause of nephropathy, including whether or not HIVAN was diagnosed. This limited our ability to generalize ASD findings to the subpopulations of patients with nephropathy, such as those with reversible etiologies. Also, we did not observe a sufficient number of prescriptions of tenofovir to evaluate its impact on the outcome of nephropathy. Data were further limited by only reviewing medical records at ASD sites, as patients may have sought care at facilities not included in ASD. Also, because collection of serum creatinine was not part of the methods of this study when it first began in the early 1990s, trends in creatinine measurement could not be examined reliably before 1996. Therefore, the incidence and prevalence data in ASD could underestimate the true burden of nephropathy. Incomplete data may have been more of a limitation in 2003 than in previous years, as ASD ended in 2004, making 2003 ASD trend data less reliable. A final limitation was that we were unable to determine causes of death, and could only look at all-cause-nephropathy as a condition present at the time of death. Thus, any associations seen with nephropathy present at the time of death may have been spurious and due to factors associated with both death and nephropathy. Other causes of nephropathy in the HIV-infected population include hypertension, chronic hepatitis virus infection, injection-drug use with heroin, acute tubular necrosis secondary to medications (such as pentamidine, aminoglycosides, trimethoprim-sulfamethoxazole, and nonsteroidal anti-inflammatory drugs), dehydration, and hypotension.18,20 Routine care for HIV-infected patients should include screening for kidney disease in addition to other preventive care, including monitoring of blood pressure and evaluation and treatment of hypertension, evaluation of hepatitis B immunity and vaccination against hepatitis B when indicated, and identifying injecVOL. 101, NO. 12, DECEMBER 2009

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tion-drug use, accompanied with counseling and treatment when indicated.18,31 Injection-drug users who choose not to discontinue their use should be educated regarding why it is important to use clean needles and avoid needle sharing. These recommendations are especially important for providers who care for blacks because of the higher incidence of conditions associated with nephropathy and nephropathy itself in this population.19,32

Acknowledgments

The authors greatly thank Scott McCombs (project management); Michael Adams, Márta Juhász, and Debra Hanson (data analyses); Leah Haseley (analytical and medical specialty advice); and especially the ASD study investigators: Melanie Thompson, Erica Sinclair, David Cohen, Arthur Davidson, Cornelius Rietmeijer, Wendy Garland, Amy Wohl, Anne Morse, Linda Wotring, Eve Mokotoff, Chris Murrill, Marie Antoinette Bernard, Alejandro Amill, Robert Hunter, Maria de los Angeles Gomez, Sandra Miranda, Elizabeth Barash, Sylvia Odem, Philip Keiser, and Adebowale Awosika-Olumo.

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