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Earlier HAART Suggested for African-Americans At-Risk for Kidney Disease
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Nature Clinical Practice Nephrology (2008) 4, 467
doi:10.1038/ncpneph0874
"The incidence of CKD declined in sequential calendar periods as HIV treatments improved, and ACE-I/ARB was significantly associated with a lower risk of progression to ESRD.....
....Lucas et al. report in this issue, these data may suggest a role for earlier initiation of ART in high-risk patients, prior to the establishment of kidney disease. This recommendation goes beyond the recently updated treatment guidelines, which now recommend the initiation of ART in patients with HIVAN, regardless of CD4 cell count [14], and is even more sweeping than the Infectious Diseases Society of America's recommendations to consider ART in all patients with HIV and CKD....While awaiting the results of this large international randomized trial (START), HIV providers should focus on the identification of early CKD in patients at high risk for progression, including African Americans and patients with a family history of ESRD. The results presented by Lucas et al. also provide further support for the use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers in these patients [12], in addition to individualized consideration of ART."
Faster CKD progression explains higher ESRD incidence among African Americans with HIV
Original article, Lucas GM et al. (2008) Chronic kidney disease incidence, and progression to end-stage renal disease, in HIV-infected individuals: a tale of two races. J Infect Dis 197: 1548-1557 Article
The risk of developing end-stage renal disease (ESRD) is 50 times greater for HIV-infected African Americans than for HIV-infected whites, although little is known about the effect of race on the incidence of chronic kidney disease (CKD) and its progression to ESRD.
Lucas et al. performed a cohort study in 3,332 HIV-infected African Americans and 927 HIV-infected whites who had received primary care at the Johns Hopkins Medical Center in Baltimore, MD, USA, since 1990. After a mean follow-up period of 4.5 years, 210 of the 4,185 patients who had no evidence of CKD at enrollment developed the disease. Of the 284 patients who either had pre-existing CKD or developed new-onset CKD, 100 progressed to ESRD; 99 were African Americans and one was white. African Americans were only 1.9 (95% CI 1.2-2.8) times more likely than whites to develop CKD, but had a 17.7 (95% CI 2.5-127) times greater risk of developing ESRD than their white counterparts. These data indicate that the higher incidence of ESRD in HIV-infected African Americans than in HIV-infected whites reflects accelerated disease progression more than a greater incidence of CKD.
Given that the incidence of CKD was 40% lower after 2001 than before 1996, probably as a result of improvements in antiretroviral treatment, and that use of an angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker was associated with a 50% reduction in the risk of developing ESRD, HIV-infected African Americans should be considered for routine CKD screening and for early initiation of highly active antiretroviral therapy.
The Journal of Infectious Diseases June 2008;197:1490-1492
EDITORIAL COMMENTARY
HIV and the Kidney: A Spotlight on Racial Disparities
Christina M. Wyatt
Division of Nephrology, Mount Sinai School of Medicine, New York, New York
In 1984, physicians at a New York City hospital described an aggressive form of kidney disease affecting 12% of their patients with AIDS [1]. Progression to end-stage renal disease (ESRD) was nearly universal, and all affected patients were African American or Haitian immigrants. Subsequent studies have consistently demonstrated a strong association between black race and this unique form of kidney disease, now recognized as HIV-associated nephropathy (HIVAN) [2-4]. In the United States, African Americans account for nearly 90% of the incident ESRD attributed to HIVAN [5], a racial predisposition rivaling that associated with sickle-cell nephropathy [6]. Because these data are based primarily on clinical diagnoses, it is likely that many cases of ESRD that are attributed to HIVAN actually reflect a broader spectrum of HIV-related and comorbid kidney diseases [4, 7]. Until recently, the impact of race on these other forms of HIV-related kidney disease has not been well understood.
Several recent publications have highlighted the significant influence of race on the epidemiology of chronic kidney disease (CKD) in HIV-infected patients, regardless of the underlying pathology [8-11]. Although decreased kidney function was identified in <5% of the largely white EuroSIDA cohort [8], cross-sectional data from a New York City HIV clinic demonstrated a high prevalence of kidney disease in minority patients, including ESRD in 4% and pre-end-stage CKD in >11% of patients [9]. In addition to this striking disparity in prevalence, investigators from the US Veterans Affairs Medical System have recently described racial differences in the incidence and progression of HIV-related kidney disease [10]. Although the baseline prevalence of decreased kidney function was similar in HIV-infected veterans regardless of their race, the incidence of ESRD was nearly 6-fold higher in HIV-infected African Americans. HIVAN was the most common presumed diagnosis, but more than half of the cases of ESRD were attributed to another etiology [10]. In a smaller cohort of veterans who had preexisting kidney disease the rate of progression in HIV-infected African Americans was similar to that observed in patients with diabetes [11].
In this issue of the Journal, Lucas et al. describe the impact of race on the epidemiology of CKD in the Johns Hopkins HIV Clinical Cohort [12]. The findings of their study are consistent with those arising from the study of the Veterans Affairs cohort [10] and suggest that the disproportionate burden of ESRD in HIV-infected African Americans is primarily attributable to more-rapid progression of kidney disease. Although the incidence of CKD was only slightly increased in African American participants compared with white participants, the risk of progression to ESRD was 18-fold higher. In a subgroup of patients, for whom kidney-biopsy data were available, African Americans were significantly more likely to progress to ESRD, regardless of the etiology of kidney disease, suggesting that the observed racial disparity is not unique to HIVAN.
The incidence of ESRD in whites in the Johns Hopkins cohort was actually so low that Lucas et al. were unable to adjust for other demographic and clinical characteristics that could confound the relationship between race and the progression of kidney disease; however, it is reassuring that similar results were observed in the larger Veterans Affairs cohort after adjustment for age, sex, baseline kidney function, comorbid conditions, and socioeconomic status. Notably, fewer than one-tenth of HIV-infected veterans were women, compared with nearly one-third of the participants in the Johns Hopkins cohort. The impact of sex on the risk for progression of kidney disease should be the subject of further study in other patient cohorts, particularly because Lucas et al. have identified female sex as a risk factor for incident kidney disease but not for ESRD [12, 13].
Although the inclusion of data from a single institution or hospital network may limit the generalizability of these recent studies, single- and multicenter cohorts are increasingly important resources for the study of HIV-related kidney disease. Previous studies of HIV-related ESRD often relied on data from the US Renal Data System, a federally funded database that collects demographic and clinical information on all patients who start chronic dialysis or receive a kidney transplant [5]. The database continues to collect information on patients with a primary diagnosis of "AIDS nephropathy" but, because of state confidentiality laws, no longer collects data on the prevalence of comorbid HIV/AIDS. As a result, nationally representative estimates are available only for patients with ESRD attributed to HIVAN, and the true prevalence of HIV-related ESRD is unknown.
Lucas et al. recently demonstrated the continued utility of this national database to identify or confirm ESRD events in established HIV cohorts [13]. Combining data from the Johns Hopkins HIV cohort and from HIV-positive participants in the AIDS Link to the IntraVenous Experience (ALIVE) cohort, Lucas et al. demonstrated a 31-fold increase in the risk of ESRD in African-Americans, compared with that in whites. Consistent with the findings reported by Lucas et al. in this issue, the incidence of HIV-related ESRD was similar in the periods before and after the introduction of combination antiretroviral therapy (ART), regardless of the regimen used and despite a decline in the incidence of earlier stages of CKD [13]. As Lucas et al. report in this issue, these data may suggest a role for earlier initiation of ART in high-risk patients, prior to the establishment of kidney disease. This recommendation goes beyond the recently updated treatment guidelines, which now recommend the initiation of ART in patients with HIVAN, regardless of CD4 cell count [14], and is even more sweeping than the Infectious Diseases Society of America's recommendations to consider ART in all patients with HIV and CKD [15].
The current guidelines are based on expert opinion and strong observational data, in the absence of rigorous prospective trials, and the impact that ART has on other forms of HIV-related kidney disease is less clear [4]. The National Institutes of Health-funded Strategic Timing of AntiRetroviral Treatment (START) Study is expected to begin enrollment later this year and will investigate the impact of early initiation of ART (at CD4 counts >500 cells/mm3, compared with deferral of ART to a CD4 count of 350 cells/mm3), on AIDS and non-AIDS events, including kidney disease. While awaiting the results of this large international randomized trial, HIV providers should focus on the identification of early CKD in patients at high risk for progression, including African Americans and patients with a family history of ESRD. The results presented by Lucas et al. also provide further support for the use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers in these patients [12], in addition to individualized consideration of ART.
Beyond the implications for individual patient care, the observed racial disparities in HIV-related ESRD have significant implications for global public health. In the United States, the prevalence of ESRD attributed to HIVAN continues to increase, the result of improved survival in the ART era and continued growth of the population at risk [5]. The potential implications for sub-Saharan Africa are even more staggering, particularly in light of the limited infrastructure for identification and management of kidney disease and ESRD. Emerging data suggest that the prevalence of HIV-related kidney disease in African populations is similar to that observed in African Americans. In a South African study, 7% of HIV-positive patients without overt kidney disease were found to have proteinuria on screening [16], whereas dipstick proteinuria was identified in 21% of ART-naive patients in Uganda [17]. More than 40% of patients in the Ugandan study had an estimated creatinine clearance <50 mL/min [17], and similar findings were reported in a small study from Nigeria, where the median creatinine clearance was <60 mL/min [18]. In a larger Nigerian study, 38% of HIV-infected patients had some evidence of kidney disease, defined by the presence of proteinuria and/or elevated levels of serum creatinine [19].
Interpretation of these findings is complicated by the lack of validated estimates of glomerular filtration in these populations. The 2 most commonly used estimation equations provided remarkably different estimates of the prevalence of decreased kidney function in ART-naive ambulatory patients in Kenya (11.5% vs. 4.8%), despite reasonable overall correlation between the equations [20]. Accurate and reliable identification of patients with decreased kidney function is essential to guide selection of ART dosing and regimen, particularly in resource-limited settings where close monitoring of toxicity is not feasible. In light of the potential for an epidemic of HIV-related kidney disease and ESRD in disadvantaged minority populations and in Africa, the international medical community should work to develop simple, inexpensive, and reliable methods to detect and manage early kidney disease in these vulnerable populations.
Chronic Kidney Disease Incidence, and Progression to End-Stage Renal Disease, in HIV-Infected Individuals: A Tale of Two Races
Gregory M. Lucas,1 Bryan Lau,2,4 Mohamed G. Atta,3 Derek M. Fine,3 Jeanne Keruly,1 and Richard D. Moore2,4
Divisions of 1Infectious Diseases, 2General Internal Medicine, and 3Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, and 4Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
ABSTRACT
Background. Little is known about the racial differences in the incidence and progression of HIV-related chronic kidney disease (CKD) that underlie African American-white disparities in HIV-related end-stage renal disease (ESRD).
Methods. In a cohort in Baltimore, Maryland, we measured CKD incidence, glomerular filtration rate (GFR) slope, and progression to ESRD in 3332 African American and 927 white HIV-infected subjects.
Results. A total of 284 subjects developed CKD, 100 (35%) of whom subsequently developed ESRD. African American subjects were at slightly increased risk for incident CKD, compared with white subjects (hazard ratio [HR], 1.9 [95% confidence interval {CI}, 1.2-2.8]). However, once CKD had commenced, the African American subjects developed ESRD markedly faster than did the white subjects (HR, 17.7 [95% CI, 2.5-127.0]), and, correspondingly, their GFR decline after diagnosis of CKD was 6-fold more rapid (p<.001). In the subset of African American subjects for whom kidney-biopsy data were available, progression to ESRD was significantly faster than that in white subjects with CKD, irrespective of the presence of HIV-associated nephropathy.
Conclusions. The results of this study suggest that African American-white disparities in HIV-related ESRD are explained predominantly by a more aggressive natural disease history in African Americans and less by racial differences in CKD incidence.
Discussion
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In HIV-infected individuals, the risk of ESRD is 50-fold higher in African Americans than in whites [2]. However, the racial differences in the natural history of CKD that underlie this discrepancy have not been well characterized. We assessed the incidence of CKD, subsequent GFR slope, and progression to ESRD in a large, long-running HIV cohort, composed mostly of African American and white subjects. In unadjusted analysis, African Americans were found to be 1.9-fold more likely to develop CKD than were white subjects; however, when adjusted for sex, age, AIDS status, injection drug use, and calendar time, the HR decreased to 1.65 and was of borderline statistical significance. In contrast, the unadjusted risk for progression to ESRD in subjects with CKD was nearly 20-fold higher in African Americans than in whites, although a caveat worth noting is that the 95% CIs for this point estimate are wide. These data suggest that, although the risk of CKD is slightly higher in HIV-infected African Americans than in whites, the preponderance of the markedly increased risk of ESRD in the former group is explained by a more rapid progression of CKD, once commenced. This view was corroborated both by the higher prevalence of aggressive disease features in African Americans with CKD than in whites with CKD (e.g., 45% vs. 4%, respectively, had high-grade proteinuria) and by the difference in GFR decline, which was >6-fold more rapid in African Americans than in whites.
The pathology of HIV-associated CKD is heterogeneous, with a wide range of pathologic lesions being identified in autopsy [12] and biopsy series [11, 14, 15]. However, a collapsing variant of focal segmental glomerulosclerosis, termed "HIVAN," occurs nearly exclusively in individuals of African descent [11-13] and has been associated with an aggressive course and rapid progression to ESRD [16, 17]. The present study found that, in the subset of African American subjects with CKD who had kidney biopsy data, the risk of progression to ESRD was 3-fold-higher in those with HIVAN than in those with other histopathologic lesions. It is clear that the racial predilection of HIVAN accounts for a portion of the excess risk of CKD progression that we observed in African American versus white subjects. However, we also found that, in subjects with CKD, the risk of progression to ESRD was significantly higher in African American subjects with non-HIVAN histopathology than in white subjects. These results suggest that a substantial racial difference in CKD progression exists independent of HIVAN. It should be noted that kidney biopsies were performed at the discretion of consulting nephrologists and that the biopsied group may be a biased subset (e.g., more-rapidly progressive disease, greater medical adherence, etc.) of those with CKD.
The present study's finding that African American race was a substantially stronger risk factor for progression of CKD to ESRD than for development of CKD accords with epidemiological findings for the general US population [18, 19]; for example, Hsu et al., using data from the third National Health and Nutrition Examination Survey and the United States Renal Data System, found that, although the prevalence of CKD was similar in African American subjects and white subjects, the risk of progression from CKD to ESRD was 5-fold higher in the former group [18]. Genetic susceptibility to kidney failure has been hypothesized on the basis of familial clustering of ESRD, in several settings [20-22].
In the present study, increasing age was associated with a significantly higher risk of CKD but with a significantly lower risk of progression to ESRD once CKD had developed. However, the association between age and progression to ESRD may have been confounded by the fact that, at the time of diagnosis of CKD, the African American subjects were younger than the white subjects; when adjusted for race, the association between age and ESRD was no longer statistically significant (data not shown). AIDS status was the strongest risk factor for incident CKD. Immunologic deterioration, as indicated by prior opportunistic condition or a CD4 count <200 cells/mm3, may potentiate the onset of CKD. Finally, we found that the incidence of CKD declined in successive calendar periods but that the risk of progression to ESRD was similar during the pre-HAART and HAART eras and was not associated with the type of antiretroviral therapy being used at the onset of the disease (table 3). Others have reported that HAART is associated with slowed progression to ESRD in patients with HIVAN but not in those with non-HIVAN histopathology [11, 23].
Although the present study has notable strengths, it also has limitations that should be noted. First, it was conducted in a single urban center, and therefore its results may not necessarily be generalizable to other settings. However, the study's well-characterized cohort, which includes nearly 19,000 person-years of follow-up in African American and white HIV-infected individuals, offers an exceptional opportunity to evaluate racial differences in the epidemiology of CKD.
Second, although the cohort included 1000 white subjects, only 1 progressed to ESRD; thus, the CIs for the relative race-specific HRs of progression to ESRD were wide, and adjustment for other covariates was not possible. This finding is consistent with the low rates of CKD and, particularly, ESRD that have been observed in predominantly white-European HIV cohorts [24, 25]. Future research of racial differences in HIV-related CKD in a multicohort consortium would be of interest.
Third, our diagnosis of CKD (stage 3 or higher) was based on GFR estimated, on the basis of serum creatinine concentrations, by the Modification of Diet in Renal Disease equation, which has not been validated with a gold-standard measure of GFR in HIV-infected individuals. However, this equation was derived from a large sample of African American and white subjects with CKD [26] and both the National Kidney Foundation practice guidelines [8] and the HIV Medicine Association of the Infectious Diseases Society of America [27] recommend it as the preferred method of GFR estimation in clinical practice. To add specificity to our diagnosis of CKD, we required (1) that at least 2 GFR measurements be <60 mL/min/1.73 m2 and separated by >3 months and (2) that >50% of all GFR measurements (which followed the index <60 measurement) also be <60 mL/min/1.73 m2; this was done to avoid classification of subjects as having CKD who may have had 2 episodes of acute renal failure but normal renal function otherwise.
The present study has several implications. First, it serves to highlight the importance of CKD and ESRD in HIV-infected African Americans, who are disproportionately affected by the HIV epidemic. In 2005, African Americas constituted just 12% of the general population but accounted for 49% of newly diagnosed HIV infections [28]. Moreover, little is known about the burden of HIV-related CKD in sub-Saharan Africa, where >60% of the world's HIV-infected individuals reside. As patients live longer because of HAART, it will be important to monitor HIV-related CKD in developed and developing areas of the world.
Second, the high prevalence and incidence of CKD that we observed strongly support the incorporation of screening into routine HIV care, as has been recommended in recently published guidelines [27]. The results of the present study imply that ACE-I/ARB substantially reduces the risk of progression to ESRD in patients with HIV-related CKD. Identification of CKD at an early stage is likely to maximize the benefits of therapy. Because serum creatinine-based GFR estimates are insensitive markers of early kidney disease [29], annual urinalysis or quantitation of the urine protein:creatinine ratio [27] should be viewed as a quality-of-care indicator in HIV treatment centers.
Third, the present study found that the incidence of CKD decreased in sequential calendar periods, coincident with temporal improvements in antiretroviral therapy [30]. These findings suggest that initiation of HAART be considered earlier during HIV disease than is suggested by current treatment guidelines [31]. This point may be particularly applicable to HIV-infected African Americans, who, compared with whites, tend to start therapy later during the course of the disease [32, 33] and are at substantially higher risk of progressing to ESRD. Results from the SMART study, in which CD4 cell-guided treatment interruptions were compared with continuous HAART, indicate (1) that fatal and nonfatal renal-disease outcomes are significantly more common in the treatment-interruption arm than in the continuous-therapy arm [34], and (2) that the risk that study outcomes are associated with treatment interruptions is larger in African Americans than in whites [35].
In summary, the present study found that racial differences in the incidence of CKD in HIV-infected subjects were relatively small, with AIDS status being the strongest risk factor identified as being associated with new onset of CKD; in contrast, once CKD had commenced, its progression was much more rapid in African Americans than in whites, as demonstrated by both a significantly faster decline in GFR and an 18-fold-higher risk of progression to ESRD. The incidence of CKD declined in sequential calendar periods as HIV treatments improved, and ACE-I/ARB was significantly associated with a lower risk of progression to ESRD.
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