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The impact of hepatitis C virus coinfection on HIV-related kidney disease: a systematic review and meta-analysis

Wyatt, Christina Ma; Malvestutto, Carlosb; Coca, Steven Gc; Klotman, Paul Eb; Parikh, Chirag Rc

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doi: 10.1097/QAD.0b013e32830e0152
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Abstract

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.

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 × 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).

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.

Fig. 1
Fig. 1:
Flow diagram of studies of HIV-related kidney disease considered for inclusion.
Table 1
Table 1:
Characteristics of studies of HIV-related kidney disease outcomes.
Table 2
Table 2:
Kidney disease outcomes in patients with HIV and HIV-hepatitis C coinfection.

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%).

Fig. 2
Fig. 2:
Pooled analysis of kidney disease outcomes.

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.

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).

Discussion

The results of the current meta-analysis suggest that HIV–HCV coinfection is associated with an increased risk of kidney disease compared with HIV infection alone. In pooled analyses of data from more than 18 000 HIV-infected patients, HCV coinfection was associated with an increased risk of chronic kidney disease by nearly 50%, proteinuria by 15%, and acute renal failure by 64%, and with an increased risk for urologic and nephrotoxic complications of the antiretroviral agent indinavir. These findings have important implications for clinical care and for global public health, and they may provide a new impetus for pathogenic studies of kidney disease in patients with HIV and HCV.

The demonstrated association between HCV coinfection and risk for acute and chronic kidney disease supports existing guidelines for the diagnosis and management of kidney disease in patients with HIV [9]. These consensus guidelines consider HCV coinfection a risk factor for kidney disease and recommend increased frequency of screening for proteinuria and decline in glomerular filtration rate. Timely recognition of kidney disease may allow targeted therapy to delay progression and is essential to guide selection and dosing of antiretroviral medications. The impact of HCV coinfection on the risk for antiretroviral nephrotoxicity has not been well described, in part, because data on HCV status have not been routinely reported in clinical trials of the relevant agents. Available data do not suggest an increased risk for tenofovir nephrotoxicity in patients with HCV coinfection, although future studies should be encouraged to collect and report data on HCV status [39,49,54]. The results of the current meta-analysis demonstrate a trend toward increased risk of nephrotoxic or urologic complications of indinavir in patients with HIV–HCV coinfection. Although indinavir has been largely replaced by newer protease inhibitors in the United States and Western Europe, it is still commonly used in Africa, Asia, and Eastern Europe, regions with increased HCV seroprevalence [55]. As the prevalence of HIV–HCV coinfection varies widely based on the primary mode of HIV transmission [11], the local prevalence of HCV coinfection may be an important consideration in the choice of appropriate antiretroviral regimens for use in resource-limited settings.

Although this is the first quantitative review to address this important clinical question, systematic reviews have a number of inherent limitations. Most importantly, this review is limited by heterogeneity in the design and quality of the available studies. The majority of longitudinal studies did not adequately describe study attrition, and the inclusion of cross-sectional studies limits the ability to establish temporal relationships. The prevalence and impact of important potential confounders were not reported in all studies; in particular, data on race were missing from six studies, primarily from studies conducted in Europe and Australia. The prevalence of black race is likely to be lower in these study populations, which may significantly decrease the background risk of kidney disease [5,6,20,56]. A sensitivity analysis excluding studies with a prevalence of black race below 25% yielded qualitatively similar results, with noticeably less statistical heterogeneity. In addition to the variability in race, there was also significant variability in the kidney disease outcomes measured in the individual studies, and it is possible that HCV coinfection has heterogeneous effects. For example, black race is strongly associated with HIV-related chronic kidney disease and end-stage renal disease [4–6], but does not appear to be a risk factor for acute renal failure in patients with HIV [16,57]. HCV coinfection may also have heterogeneous effects on different renal outcomes, including the diverse endpoints considered together as chronic kidney disease in the current analysis. Of interest, the effect size was similar for studies of chronic kidney disease and acute renal failure, although this conclusion is limited by the inclusion of only two studies of acute renal failure. Another important limitation of the current study involves the assessment of HCV status. The proportion of study subjects with documented HCV status ranged from 42 to 100% across studies, with universal documentation of HCV status in fewer than half of the studies. Although only data from subjects with known HCV status were included in the current meta-analysis, the lack of universal HCV screening may have biased our study population. Comparisons between subjects with and without documented HCV status were not possible based on study-level data.

Few of the studies included in the current meta-analysis provided adjusted estimates of the risk for kidney disease associated with HCV coinfection. The observed association between HCV coinfection and increased risk for kidney disease could reflect confounding by other factors, such as older age, black race, history of injection drug use, or exposure to nephrotoxic medications. Data on potential mediators such as diabetes, cryoglobulinemia, and end-stage liver disease were also not reported in most studies. In conclusion, HCV coinfection in HIV-positive patients is associated with an increased risk of kidney disease. Healthcare providers should be aware of this risk, and future studies should investigate the mechanism of the observed association to allow for targeted interventions in susceptible patients. In the interim, patients with HIV–HCV coinfection should be regarded as being at increased risk for acute and chronic kidney disease, regardless of the presence of traditional kidney disease risk factors.

Acknowledgements

The authors wish to acknowledge the contribution of the investigators who have generously provided or confirmed data from the included studies. Systematic review and data abstraction were performed by C.W. and C.M. All authors participated in the analysis and interpretation of data and critical revision of the manuscript.

Sponsorship: This work was supported in part by NIH grants K23 DK077568 (C.W.), F32 DK076318 (S.C.), K23 DK64689 (C.P.), and P01DK56492-05 (C.W., P.K.).

Disclosures: C.M.W. has received honoraria from Gilead Sciences and Research support from the Gilead Foundation. P.E.K. is on the scientific advisory board of Gilead Sciences.

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Keywords:

hepatitis C; hepatitis coinfection; HIV; kidney disease; nephrotoxicity

© 2008 Lippincott Williams & Wilkins, Inc.