Factors associated with RRT in HIV-infected African-Americans are shown in Table 3. In univariate analysis, increasing age, AIDS, and follow-up in the HAART era were statistically significantly associated with higher RRT incidence. Women had a slightly lower risk of RRT than men (P = 0.09). Cohort (JHHC or ALIVE), history of injection drug use, hepatitis C antibody status, and attained education were not associated with RRT. In multivariate analysis, only AIDS status remained statistically significantly associated with RRT (IRR 2.7; 95% CI, 1.9–4.0). No statistically significant interactions were detected.
Among HIV-infected African-American participants, characteristics were compared for those who received RRT in the pre-HAART (36) and HAART (140) eras. The proportions of women and injection drug users were similar in subjects who received RRT in the two treatment eras (data not shown). However, participants who initiated RRT in the pre-HAART era were significantly younger than those in the HAART era: median age 36 years [interquartile range (IQR), 33–41) and 42 years (IQR 37–48), respectively (P < 0.001). Compared with subjects who received RRT in the pre-HAART era, those who received RRT in the HAART era had lower current CD4 cell counts [median 303 cells/μl (IQR, 64–460) versus 162 cells/μl (IQR, 50–311); P = 0.03], lower nadir CD4 cell counts [median 212 cells/μl (IQR, 64–335) versus 99 cells/μl (IQR, 19–193); P = 0.002], and were more likely to be defined as having AIDS (47% versus 77%; P = 0.001).
Because the primary enrollment for the ALIVE study was in 1988–1989, this cohort's participants accounted for a larger percentage of those who received RRT in the pre-HAART era (47%) than in the HAART era (14%) (P < 0.001). As shown in Table 1, ALIVE participants were younger and had less-advanced HIV disease than JHHC participants at enrollment. However, the observations that RRT recipients in the pre-HAART era were younger and had less-advanced HIV disease than those in the HAART era were not affected when analyses were stratified by cohort. For example, among participants who initiated RRT in ALIVE, the median ages were 38 and 42 years in the pre-HAART and HAART eras, respectively (P = 0.007). Similarly, among participants who initiated RRT in JHHC, the median ages were 35 and 42 years in the pre-HAART and HAART eras, respectively (P = 0.003). Similar trends were observed in cohort-stratified analyses of current CD4 cell count, nadir CD4 cell count, and AIDS status (data not shown).
To explore the association between CKD epidemiology and RRT incidence in the two HIV treatment eras, additional analyses were conducted in the subset of HIV-infected African-American participants followed in the JHHC (3735) for whom longitudinal serum creatinine data were available (Table 4). Adjusting for age and AIDS status, the period prevalence CKD was 37% higher in the HAART era than in the pre-HAART era (P = 0.021). In contrast, the adjusted incidence of CKD was 36% lower (P = 0.002) in the HAART era than the pre-HAART era. The incidence CKD-death prior to RRT was 46% lower in the HAART era than in the pre-HAART era (P = 0.006). Consistent with data from the composite cohort, the adjusted incidence of RRT was 46% higher in the HAART era than the pre-HAART era in the JHHC subgroup (not statistically significant). The risk of the composite outcome, RRT or CKD-death prior to RRT, was similar in the pre-HAART and HAART eras (P = 0.56).
In this 15-year cohort study, the incidence of RRT in HIV-infected African-Americans approached 1% per year, a risk approximately 10-fold higher than in age-matched African-Americans in the general population. Among HIV-infected participants, the risk of RRT was approximately 30-fold higher in African-Americans than in whites, as has been reported previously . Our study is the first to provide data on the relative risk of RRT in the HAART era compared with the pre-HAART era in a well-characterized cohort. We found that the incidence of RRT in HIV-infected African-Americans has not changed significantly with the introduction and widespread implementation of HAART. The continued high risk of ESRD in this group during the HAART era is of particular public health relevance because African-Americans are disproportionately affected by the HIV epidemic. In 2005, African-Americans, who constitute approximately 12% of the general population, accounted for 49% of newly diagnosed HIV infections .
Our supplementary analyses of CKD in the JHHC shed light on the dynamic epidemiology underlying the stable incidence of RRT that we observed during follow-up. First, we found that age- and AIDS-adjusted incidence of CKD was approximately 40% lower in the HAART era compared with the pre-HAART era. This suggests that the availability of HAART, or potentially other temporal factors, have reduced the risk of CKD. Conversely, the period prevalence of CKD was approximately 40% higher in the later era. As prevalence is determined by both incidence and duration of disease, it is likely that longer survival among individuals with CKD in the HAART era accounts for this finding. Second, we found that the incidence of the composite outcome, RRT or CKD-death prior to RRT, which make up the competing endpoints of CKD, was similar in the pre-HAART and HAART eras, at approximately 1.5% per year. The individual components of this composite had opposing trends, with RRT incidence increasing and CKD-death prior to RRT decreasing between the pre-HAART and HAART eras.
We found substantial differences in age and HIV disease severity among participants who initiated RRT in the two HIV treatment eras. Subjects who initiated RRT in the pre-HAART era were younger, had higher current CD4 cell counts, higher nadir CD4 cell counts, and were less likely to be defined with AIDS than subjects who initiated RRT in the HAART era. Three phenomena may account for these differences. First, individuals with CKD may have been more likely to survive until RRT was required in the HAART era than in the pre-HAART era because HIV-related competing risks were lower. Second, nephrologists may have been more willing to initiate RRT in HIV-infected patients with poor prognostic factors in the HAART era than in the pre-HAART era. A third possibility is that the age and HIV disease severity differences in RRT recipients in the two treatment eras reflect temporal changes in the underlying pathophysiology of renal disease in this population.
Prior studies have documented a high prevalence and incidence of renal abnormalities in HIV-infected subjects, including proteinuria and hypercreatinemia [24–28]. In longitudinal studies, renal abnormalities have been found to be independent predictors of opportunistic conditions  and all-cause mortality [29,30] in HIV-infected individuals. In an analysis of data from the US Renal Data System, Eggers and Kimmel  found that the number of new HIV-associated cases entering the RRT registry annually remained stable between 1995 and 2000, a period corresponding to the early HAART era. However, the prevalence of HIV in the ESRD program increased 2.6-fold over this same time period because 1-year survival among HIV-infected individuals receiving RRT increased by approximately 40%. Schwartz and colleagues modeled data from the US Renal Data System and predicted continuing rise in the prevalence of HIV-associated ESRD.
Renal diseases associated with hepatitis C infection are well described . Injection drug use, which is a major risk factor for hepatitis C, has also been linked to kidney damage [18,32]. We were unable to assess the association between injection drug use and RRT in HIV-seronegative individuals, because all HIV-seronegative participants in our analysis were from the ALIVE study, in which injection drug use was an enrollment criterion. We did find that hepatitis C-seropositive status was associated with an increased risk of RRT in HIV-seronegative African-Americans (borderline statistical significance); although this analysis was limited by the small number of participants seronegative for both HIV and hepatitis C. The HIV-seronegative group had a risk of RRT that was 2.3-fold higher than expected from age-matched rates in the general African-American population. It is possible that hepatitis C, injection drug use, or other associated factors accounted for the higher than expected incidence of RRT in these participants. Interestingly, we found no association between either hepatitis C antibody status or history of injection drug use and RRT incidence among HIV-infected African-Americans, despite adequate numbers of subjects for comparison.
Our study has limitations. First, while conducted in two well-characterized cohorts, the study population resided in a single metropolitan area and the results may not generalize to HIV-infected populations in other areas, particularly those where the racial makeup is different from ours. Our findings should not be extrapolated to HIV-infected African-Americans in the United States as a whole. Future studies should combine cohorts from geographically distinct areas. Second, cohort studies are potentially susceptible to selection or follow-up biases, where either inclusion in the cohort or loss-to-follow-up is not independent of the outcome of interest. The JHHC is a treatment cohort and may have been susceptible to enrolling participants at higher risk of RRT; however, individuals would be unlikely to drop out or become lost to follow-up as they became ill. In contrast, the community-based recruitment design of ALIVE would be unlikely to enroll individuals at higher risk of RRT, although drop-out or loss to follow-up might be more likely as individuals became ill. Reassuringly, we observed a similar trend for higher RRT risk in the later calendar period compared with the earlier period in both the JHHC and the ALIVE study (data not shown), arguing against cohort design as a source of bias.
This study has important implications for resource planning and future research. Although HIV-infected individuals currently account for only 1–2% of the prevalent ESRD population in the United States [6,33], the disproportionately high rates of HIV infection among African-Americans and the increased longevity and comorbidity of those living with HIV infection suggest that substantial increases will be needed for CKD and RRT resources for this population in the future . Prospective, longitudinal studies are needed to characterize the precursors, natural history, and underlying etiologies of CKD in HIV-infected African-Americans. While clinical practice guidelines have been formulated for screening and management of CKD in HIV-infected individuals , clinical trials that assess specific screening strategies and early interventions are needed.
In conclusion, we found that the incidence of ESRD requiring RRT in HIV-infected African-Americans approaches 1% annually, approximately 10-fold higher than age-comparable rates among African-Americans in the general population. The incidence of RRT has increased nonsignificantly in the HAART era compared with the pre-HAART era. An increased risk of RRT was strongly associated with advanced HIV disease. Hepatitis C seropositivity was associated with a higher rate of RRT in HIV-seronegative participants. Hepatitis C seropositivity and injection drug use, however, were not risk factors for RRT in HIV-infected subjects. In subgroup analysis, we found that CKD incidence decreased significantly, while CKD period prevalence increased significantly in the HAART era compared with the pre-HAART era, suggesting that the increased prevalence of CKD and the stable incidence of RRT are largely a consequence of longer survival with CKD in the HAART era.
Sponsorship: This study was supported by the National Institutes of Health (R01DA11602, R21AA15032, R01DA012568, R01DA04334, K23DA15616, and K24DA00432).
Data reported here have been supplied by the US Renal Data Service. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government.
We appreciate the assistance of Peter O'Driscoll.
1. US Renal Data System. USRDS 2005 Annual Data Report: Atlas of End-stage Renal Disease in the United States
. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive Diseases and Kidney Diseases; 2005. http://www.usrds.org
. Accessed August 2006.
2. Coresh J, Jaar B. Further trends in the etiology of end-stage renal disease in African-Americans. Curr Opin Nephrol Hypertens 1997; 6:243–249.
4. Szczech LA, Gupta SK, Habash R, Guasch A, Kalayjian R, Appel R, et al
. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int 2004; 66:1145–1152.
5. Atta MG, Choi MJ, Longenecker JC, Haymart M, Wu J, Nagajothi N, et al
. Nephrotic range proteinuria and CD4 count as noninvasive indicators of HIV-associated nephropathy. Am J Med 2005; 118:1288.
6. Eggers PW, Kimmel PL. Is there an epidemic of HIV Infection in the US ESRD program? J Am Soc Nephrol 2004; 15:2477–2485.
7. Moore RD, Chaisson RE. Natural history of HIV infection in the era of combination antiretroviral therapy. AIDS 1999; 13:1933–1942.
8. Vlahov D, Galai N, Safaeian M, Galea S, Kirk GD, Lucas GM, et al
. Effectiveness of highly active antiretroviral therapy among injection drug users with late-stage human immunodeficiency virus infection. Am J Epidemiol 2005; 161:999–1012.
9. Wali RK, Drachenberg CI, Papadimitriou JC, Keay S, Ramos E. HIV-associated nephropathy and response to highly-active antiretroviral therapy. Lancet 1998; 352:783–784.
10. Szczech LA, Edwards LJ, Sanders LL, van der Horst C, Bartlett JA, Heald AE, et al
. Protease inhibitors are associated with a slowed progression of HIV-related renal diseases. Clin Nephrol 2002; 57:336–341.
11. Atta MG, Gallant JE, Rahman MH, Nagajothi N, Racusen LC, Scheel PJ, et al
. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant 2006; 21:2809–2813.
12. Lucas GM, Eustace JA, Sozio S, Mentari EK, Appiah KA, Moore RD. Highly active antiretroviral therapy and the incidence of HIV-associated nephropathy: a 12-year cohort study. AIDS 2004; 18:541–546.
13. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kidney Dis 2005; 45:804–817.
14. Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, et al
. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 2005; 165:1179–1184.
15. Seaberg EC, Munoz A, Lu M, Detels R, Margolick JB, Riddler SA, et al
. Association between highly active antiretroviral therapy and hypertension in a large cohort of men followed from 1984 to 2003. AIDS 2005; 19:953–960.
16. Cheng JT, Anderson HL Jr, Markowitz GS, Appel GB, Pogue VA, D'Agati VD. Hepatitis C virus-associated glomerular disease in patients with human immunodeficiency virus coinfection. J Am Soc Nephrol 1999; 10:1566–1574.
17. Dettmeyer R, Wessling B, Madea B. Heroin associated nephropathy: a postmortem study. Forensic Sci Int 1998; 20:109–116.
18. Norris KC, Thornhill-Joynes M, Robinson C, Strickland T, Alperson BL, Witana SC, et al
. Cocaine use, hypertension, and end-stage renal disease. Am J Kidney Dis 2001; 38:523–528.
19. Moore RD. Understanding the clinical and economic outcomes of HIV therapy: The Johns Hopkins HIV Clinical Practice Cohort. J Acquir Immune Defic Syndr 1998; 17(suppl. 1):S38–S41.
20. Vlahov D, Anthony JC, Munoz A, Margolick J, Nelson KE, Celentano DD, et al
. The ALIVE study, a longitudinal study of HIV infection in intravenous drug users: description of methods and characteristics of participants. NIDA Res Monogr 1991; 109:75–100.
21. United States Renal Data System. Researcher's Guide to the USRDS Database
. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2006. http://www.usrds.org
. Accessed August 2006.
22. Centers for Disease Control and Prevention. 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults. MMWR
23. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al
. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003; 139:137–147.
24. Szczech LA, Gange SJ, van der Horst C, Bartlett JA, Young M, Cohen MH, et al
. Predictors of proteinuria and renal failure among women with HIV infection. Kidney Int 2002; 61:195–202.
25. Gupta SK, Mamlin BW, Johnson CS, Dollins MD, Topf JM, Dube MP. Prevalence of proteinuria and the development of chronic kidney disease in HIV-infected patients. Clin Nephrol 2004; 61:1–6.
26. Han TM, Naicker S, Ramdial PK, Assounga AG. A cross-sectional study of HIV-seropositive patients with varying degrees of proteinuria in South Africa. Kidney Int 2006; 69:2243–2250.
27. Agaba EI, Agaba PA, Sirisena ND, Anteyi EA, Idoko JA. Renal disease in the acquired immunodeficiency syndrome in north central Nigeria. Niger J Med 2003; 12:120–125.
28. Kimmel PL, Umana WO, Bosch JP. Abnormal urinary protein excretion in HIV-infected patients. Clin Nephrol 1993; 39:17–21.
29. Szczech LA, Hoover DR, Feldman JG, Cohen MH, Gange SJ, Gooze L, et al
. Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy. Clin Infect Dis 2004; 39:1199–1206.
30. Gardner LI, Holmberg SD, Williamson JM, Szczech LA, Carpenter CC, Rompalo AM, et al
. Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women. J Acquir Immune Defic Syndr 2003; 32:203–209.
31. Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman PE. Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am Soc Nephrol 2005; 16:2412–2420.
32. Dettmeyer RB, Preuss J, Wollersen H, Madea B. Heroin-associated nephropathy. Expert Opin Drug Saf 2005; 4:19–28.
33. Tokars JI, Frank M, Alter MJ, Arduino MJ. National surveillance of dialysis-associated diseases in the United States, 2000. Semin Dial 2002; 15:162–171.
34. Gupta SK, Eustace JA, Winston JA, Boydstun II, Ahuja TS, Rodriguez RA, et al
. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2005; 40:1559–1585.
Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; chronic kidney disease; cohort study; end-stage renal disease; HIV infection; renal replacement therapy