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HCV Coinfection Increases Risk for HIV-Related Kidney Disease
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From Jules: these data suggest a good reason to consider earlier HCV therapy for patients at risk for kidney disease and for evaluation of all patients for kidney disease.
"Hepatitis C coinfection is associated with a significant increase in the risk of HIV-related kidney disease.....The pooled relative risk of chronic kidney disease in patients with HIV-HCV coinfection compared with those without HCV coinfection was 1.49.....The pooled relative risk of proteinuria in patients with HIV-HCV coinfection compared with those without HCV coinfection was 1.15 (95% CI 1.02-1.30).....After adjusting for age, race, antiretroviral use, and CD4 cell count, HCV coinfection remained associated with a modest increase in the odds of proteinuria in that study (adjusted odds ratio 1.27, 95% CI 1.16-1.35).....None of the three studies demonstrated an association between HCV coinfection and increased risk for tenofovir nephrotoxicity (Table 2), although pooled analysis was not possible.....The pooled relative risk of acute renal failure in patients with HIV-HCV coinfection compared with those without HCV coinfection was 1.64 (95% CI 1.21-2.23; Q = 0.37, P = 0.54, I2 = 0%). In both studies, the association between HCV coinfection and acute renal failure remained significant in multivariate analysis (Table 2)."
The impact of hepatitis C virus coinfection on HIV-related kidney disease: a systematic review and meta-analysis
[CLINICAL SCIENCE]
AIDS:Volume 22(14)12 September 2008p 1799-1807
Wyatt, Christina Ma; Malvestutto, Carlosb; Coca, Steven Gc; Klotman, Paul Eb; Parikh, Chirag Rc
aDepartment of Medicine, Division of Nephrology, Mount Sinai School of Medicine, USA
bDepartment of Medicine, Mount Sinai School of Medicine, New York, New York, USA
cDepartment of Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
Abstract
Background: In the era of antiretroviral therapy, non-AIDS complications such as kidney disease are important contributors to morbidity and mortality.
Objective: To estimate the impact of hepatitis C coinfection on the risk of kidney disease in HIV patients.
Design and methods: Two investigators identified English-language citations in MEDLINE and Web of Science from 1989 through 1 July 2007. References of selected articles were reviewed. Observational studies and clinical trials of HIV-related kidney disease and antiretroviral nephrotoxicity were eligible if they included at least 50 subjects and reported hepatitis C status. Data on study characteristics, population, and kidney disease outcomes were abstracted by two independent reviewers.
Results: After screening 2516 articles, 27 studies were eligible and 24 authors confirmed or provided data. Separate meta-analyses were performed for chronic kidney disease outcomes (n = 10), proteinuria (n = 4), acute renal failure (n = 2), and indinavir toxicity (n = 5). The pooled incidence of chronic kidney disease was higher in patients with hepatitis C coinfection [6.2 versus 4.0%; relative risk 1.49, 95% confidence interval (CI) 1.08-2.06]. In meta-regression, prevalence of black race and the proportion of patients with documented hepatitis C status were independently associated with the risk of chronic kidney disease. The relative risk associated with hepatitis C coinfection was significantly increased for proteinuria (1.15; 95% CI 1.02-1.30) and acute renal failure (1.64; 95% CI 1.21-2.23), with no significant statistical heterogeneity. The relative risk of indinavir toxicity was 1.59 (95% CI 0.99-2.54) with hepatitis C coinfection.
Conclusion: Hepatitis C coinfection is associated with a significant increase in the risk of HIV-related kidney disease.
Introduction
Infection with HIV affects more than 30 million people worldwide [1]. In the era of effective antiretroviral therapy, progression to AIDS is less common, and non-AIDS complications such as kidney disease have become significant contributors to morbidity and mortality [2,3]. From 1999 to 2003, there were more than 4000 new cases of end-stage renal disease attributed to HIV in the United States [4], primarily in African-Americans [5,6]. With improvements in the survival of HIV-infected dialysis patients [7] and increasing prevalence of HIV infection among African-Americans, the prevalence of HIV-related end-stage renal disease continues to rise [8]. The increased recognition of kidney disease as an important non-AIDS complication is evident in the recent publication of consensus guidelines for the detection and management of chronic kidney disease in patients with HIV [9].
Hepatitis C virus (HCV) coinfection is another increasingly important cause of morbidity and mortality in patients with HIV [2,10] and affects approximately 30% of HIV-infected individuals [11]. Studies [12] have demonstrated that coinfection with HIV and HCV translates into higher morbidity and mortality related to end-stage liver disease. Definitive studies of the impact of HIV-HCV coinfection on kidney disease are lacking, although expert guidelines [9] include HCV coinfection as a possible risk factor for kidney disease. In the general population, studies of the impact of HCV infection on the risk for kidney disease have produced inconsistent results. Data from the United States Veterans Affairs Medical System support an association between HCV infection and risk for end-stage renal disease [13]. In contrast, nationally representative data from the National Health and Nutrition Examination Survey (NHANES) suggest a negative association between HCV infection and early declines in kidney function and only a weak association between HCV infection and increased risk for proteinuria [14]. Although some smaller cohorts have demonstrated an increased risk of kidney disease outcomes associated with HIV-HCV coinfection [15,16], others have failed to find a significant association [17,18] or have even suggested a decreased risk in coinfected patients [19,20].
Both HIV and HCV have been implicated in the pathogenesis of specific glomerular diseases [21], and both viruses have been associated with immune dysregulation [22] and diabetes mellitus [23-25], which may contribute to the development of comorbid kidney disease. In addition, complex antiviral regimens for HIV and HCV often include medications with nephrotoxic potential [9,26,27]. With the disproportionate burden of HIV-HCV coinfection in minority populations at increased risk of kidney disease [11], identification of HCV coinfection as a risk factor for kidney disease would have significant implications for public health and for clinical care. We conducted a systematic review of the literature to identify studies of kidney disease in HIV-infected patients with known HCV status and performed a meta-analysis of available data to estimate the impact of HCV coinfection on the risk of kidney disease in patients with HIV.
Results
We identified 3219 citations meeting our MEDLINE search criteria. After excluding review articles, 2513 abstracts were evaluated and 121 articles were selected for further review (Fig. 1). Twenty-seven articles met our criteria for inclusion in the summary table, including 22 articles with adequate data for inclusion in our meta-analysis [15,17-20,33-54]. Two of the eligible papers reported outcomes from the same cohort [40,41]; therefore, a total of 21 studies were included in the pooled analyses (Tables 1 and 2). Only 18 studies provided a clear definition of HCV coinfection and only one study required HCV RNA testing for diagnosis [53]. Thirteen of 20 longitudinal studies did not include any information on patient attrition and only one described the characteristics of patients lost to follow-up. Fifteen studies reported data on age, race, antiretroviral use, and CD4 cell count, although only five studies accounted for all four important potential confounders in their analyses.
Study and patient characteristics from the selected articles are summarized in Table 1. The majority of studies were performed in the United States or Western Europe. Several different study designs are represented, most commonly prospective (n = 14) and retrospective cohort studies (n = 6). Sixteen studies were performed after the widespread introduction of effective combination antiretroviral therapy in 1996 and 11 studies spanned the years before and after 1996. Among the 19 studies that provided complete data on race, the prevalence of black race ranged from 1 to 89%. The prevalence of documented HCV coinfection ranged from 3 to 58.1% across studies.
The most frequently measured kidney disease outcomes (Table 2) included longitudinal measures of progression (time to end-stage renal disease, doubling of serum creatinine, decline in creatinine clearance) and cross-sectional measures of laboratory abnormalities (microalbuminuria, proteinuria, or elevated serum creatinine). Other studies analyzed the incidence of treatment-associated renal adverse events, the prevalence of documented acute or chronic kidney disease, and the incidence or prevalence of specific kidney diseases (HIV-associated nephropathy and hemolytic uremic syndrome). One study evaluated the frequency of hospitalization for kidney disease. Several studies contributed data on more than one kidney disease outcome [15,40,41,48], but each cohort was only represented once in any meta-analysis. The authors of 24 studies provided additional information and/or confirmed abstracted data, including age of the study population, the proportion with documented HCV status, the method used to determine HCV status, the prevalence of black race, and the distribution of kidney disease endpoints among subjects with and without HCV coinfection.
Chronic kidney disease
Twelve studies [15,17-20,40,43,44,46,50-52] provided data on the prevalence, incidence, or progression of chronic kidney disease in patients with HCV coinfection, including HIV-associated nephropathy. Ten studies with adequate data were included in the meta-analysis, representing more than 14 000 individuals with HIV infection (Fig. 2). The definition of chronic kidney disease varied among studies, but was most commonly based on an elevation in serum creatinine or a decrease in creatinine clearance (n = 4). One additional study described a combined endpoint of elevated serum creatinine or proteinuria and four studies described the prevalence or incidence of a documented renal diagnosis. A single study of incident HIV-associated nephropathy was also included in this group. The absolute incidence of chronic kidney disease in patients without HCV coinfection ranged from less than 1 to 16.9% (pooled incidence 4.0%) and in patients with HCV coinfection ranged from 1.7 to 25.1% (pooled incidence 6.2%). The pooled relative risk of chronic kidney disease in patients with HIV-HCV coinfection compared with those without HCV coinfection was 1.49 [95% confidence interval (CI) 1.08-2.06], with some evidence of statistical heterogeneity (Q = 24.0, P = 0.004, I2 = 62.5%).
Only three studies provided adjusted estimates of the chronic kidney disease outcomes in patients with HCV coinfection (Table 2). One study reported age-adjusted estimates [18], whereas two studies adjusted for age, race, antiretroviral use, and severity of HIV disease [46,52]. The association between HCV coinfection and progression of chronic kidney disease remained highly significant in one study (adjusted hazard ratio 2.6; 95% CI 1.26-5.37) [52], which was not included in meta-analysis because of unavailable data. In the other two cohorts, there was a strong trend toward an association between HCV coinfection and chronic kidney disease in adjusted analyses.
The pooled relative risk of acute renal failure in patients with HIV-HCV coinfection compared with those without HCV coinfection was 1.64 (95% CI 1.21-2.23; Q = 0.37, P = 0.54, I2 = 0%). In both studies, the association between HCV coinfection and acute renal failure remained significant in multivariate analysis (Table 2).
Proteinuria
Four studies reported the prevalence of proteinuria in patients with HIV-HCV coinfection, totaling 3588 individuals with HIV infection. Two studies defined proteinuria by standard dipstick urinalysis, one study described the prevalence of microalbuminuria, and one study defined significant proteinuria as a 24-h urine protein excretion of at least 1.5 g. The pooled prevalence of proteinuria in patients without HCV coinfection was 19.3%, compared with 28% in patients with HCV coinfection (Fig. 2). The pooled relative risk of proteinuria in patients with HIV-HCV coinfection compared with those without HCV coinfection was 1.15 (95% CI 1.02-1.30). There was no evidence of substantial statistical heterogeneity (Q = 1.9, P = 0.59, I2 = 0%). Only one study reported an adjusted odds ratio for HCV coinfection. After adjusting for age, race, antiretroviral use, and CD4 cell count, HCV coinfection remained associated with a modest increase in the odds of proteinuria in that study (adjusted odds ratio 1.27, 95% CI 1.16-1.35) [15].
Antiretroviral nephrotoxicity
Eight studies addressed nephrotoxic or urologic complications of antiretroviral agents, primarily tenofovir (n = 3) [39,49,54] and indinavir (n = 4) [35-37,47,48]. One study evaluated the incidence of adverse drug events in patients initiating therapy containing any protease inhibitor, and data on renal adverse events were provided by the authors [37]. Additional data were provided for two studies of tenofovir toxicity [39,49]; however, adequate data for meta-analysis were only available for one study [49]. None of the three studies demonstrated an association between HCV coinfection and increased risk for tenofovir nephrotoxicity (Table 2), although pooled analysis was not possible.
Data were available for meta-analysis for all five studies involving indinavir or other protease inhibitors (Fig. 2) [35,36,47,48]. The absolute incidence of renal or urologic complications in patients without HCV coinfection ranged from 2 to 21% (pooled incidence 9.8%) and in patients with HCV coinfection ranged from 4 to 46% (pooled incidence 15.7%). The pooled relative risk of indinavir toxicity in patients with HIV-HCV coinfection compared with those without HCV coinfection was 1.59 (95% CI 0.99-2.54). There was some evidence of statistical heterogeneity (Q = 8.2, P = 0.08, I2 = 51.3%).
Acute renal failure
Two studies focused on the incidence of acute renal failure in patients with HIV (Fig. 2). Both studies used criteria based on an acute rise in serum creatinine relative to baseline values. The absolute incidence of acute renal failure in patients without HCV coinfection was 8% in an ambulatory cohort [38] and 43% in critically ill patients [45] (pooled incidence 12.5%), and risk of acute renal failure in patients with HCV coinfection was 15 and 65%, respectively (pooled incidence 20.6%). The pooled relative risk of acute renal failure in patients with HIV-HCV coinfection compared with those without HCV coinfection was 1.64 (95% CI 1.21-2.23; Q = 0.37, P = 0.54, I2 = 0%). In both studies, the association between HCV coinfection and acute renal failure remained significant in multivariate analysis (Table 2).
Meta-regression and subgroup analyses
Meta-regression was used to identify study-level factors that may have contributed to the statistical heterogeneity observed in pooled analyses of chronic kidney disease and indinavir-related outcomes. For studies examining chronic kidney disease, two study-level factors were significantly associated with the relative risk of chronic kidney disease. These factors were the percentage of individuals with confirmed HCV status (P = 0.01) and the percentage of black patients in the cohort (P = 0.004). For studies examining indinavir-related toxicity, no study-level factor was associated with the demonstrated effect.
We performed two subgroup analyses based on the results of our meta-regression. Only three studies [15,18,43] exploring chronic kidney disease outcomes documented HCV status in 100% of subjects. The pooled relative risk in these three studies was 1.59 (95% CI 0.98-2.57), with less statistical heterogeneity compared with the pooled analysis of all 10 studies (Q = 3.68, P = 0.16, I2 = 46%). Pooled analysis of the studies without universal documentation of HCV status yielded a similar point estimate [pooled relative risk (RR) 1.37, 95% CI 0.8-2.37; Q = 16.32, P = 0.006]. For the second study-level factor, the regression line demonstrated that there was an increased relative risk of chronic kidney disease in studies with more than 25% black subjects. A separate meta-analysis including the seven studies with a higher prevalence of black race (>25%) demonstrated a pooled relative risk of 1.72 for chronic kidney disease in patients with HCV coinfection (95% CI 1.33-2.23; Q = 8.6, P = 0.2, I2 = 30%). In contrast, HCV coinfection was not associated with increased risk of chronic kidney disease in pooled analysis of the three studies with a lower prevalence of black race (pooled RR 0.75, 95% CI 0.53-1.07; Q = 0.51, P = 0.77).
Methods
The present work was performed in accordance with published guidelines for systematic review, analysis, and reporting for meta-analyses of observational studies [28].
Literature review and study selection
Two authors independently reviewed English-language citations from the MEDLINE database from 1989 through 1 July 2007, using the search terms 'HIV' or 'AIDS' and 'renal' or 'kidney' or 'nephropathy.' Data on HCV status were not available prior to 1989, when the first assay for HCV antibodies was described [29]. An additional search was conducted to identify studies of renal adverse events associated with antiretroviral therapy, using the search terms 'antiretroviral' or 'indinavir' or 'tenofovir' and 'renal' or 'kidney' or 'toxicity.' MEDLINE searches were limited to human studies. A second database search was performed via the Science Citation Index Expanded on the Web of Science, and the references of all selected articles were reviewed to identify any additional studies.
Observational studies of kidney disease in HIV-infected patients were selected for further review if the study included at least 50 subjects and collected data on HCV status. Clinical trials and observational studies of the antiretroviral agents indinavir and tenofovir were included if data on renal adverse events and HCV status were reported. Nephrology referral cohorts and biopsy series were excluded unless they described kidney disease prevalence in the source population or included data on kidney disease progression. Because of the low prevalence of HCV infection in children, pediatric studies were not included. Unpublished studies and abstracts were not considered for inclusion in this meta-analysis. Data on study design, study period, patient characteristics, HCV prevalence, and kidney disease outcomes were abstracted by two independent reviewers. All authors of selected articles were contacted to obtain missing data and to confirm published results. Authors were asked to confirm or provide data on the age of the study population, the proportion with documented HCV status and the method used to determine HCV status (HCV antibody or RNA testing), the prevalence of black race, and the distribution of kidney disease endpoints among subjects with and without HCV coinfection, including only those subjects with documented HCV status.
Manuscript quality was assessed using criteria adapted from Hayden et al. [30]. Eligible studies were included in the meta-analysis if adequate data on renal outcomes were available from published results or provided by the study author. Only data from subjects with known HCV status were included in the meta-analysis.
Statistical analysis
We assessed several kidney disease outcomes in patients with HIV-HCV coinfection compared with outcomes in patients with HIV alone in stratified 2 x 2 contingency tables. We pooled outcomes based on clinical and biological grounds; for example, doubling of serum creatinine in a longitudinal study was considered a 'chronic kidney disease' outcome. Overall results for each type of outcome were mathematically pooled using techniques that accounted for within and between study heterogeneity (random effects method of DerSimonian and Laird [31]). We formally assessed heterogeneity of treatment effects among studies with the Cochran Q and the I2 statistics [32]. To examine the association of study-level characteristics and treatment effect, we fitted random-effect meta-regression models to the natural logarithm of the relative risks by using the PROC GLM procedure in SAS statistical software, version 9.1 (SAS Institute, Cary, North Carolina, USA). We performed subgroup analyses of the factors that were significantly associated with the risk of renal outcomes in the meta-regression models. Publication bias was assessed by examination of funnel plots. All meta-analyses were performed using Comprehensive Meta Analysis 1.0.25 (Englewood, New Jersey, USA).
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