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Frequent injection cocaine use increases the risk of renal impairment among hepatitis C and HIV co-infected patients.
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"In conclusion, we found evidence to suggest that cumulative exposure and frequent cocaine use is associated with CRI [chronic renal impairment ] progression among HIV-HCV co-infected patients. The role of substance use in contributing to renal disease in co-infection has been underappreciated and should be taken into consideration when evaluating impaired renal function in this setting......Cocaine itself has been associated with rhabdomyolysis and acute kidney injury, and is a known nephropathic drug [23, 24]."
"This is the first cohort study to examine the effect of injection cocaine use, a known nephropathic drug [23, 24, 36], on renal function among HIV or co-infected populations......It is notable that in our analysis, chronic HCV infection was not associated with an increased risk of CRI
Results from this study are consistent with clinical studies that demonstrate pathogenic effects of cocaine on the kidney [40]. Cocaine is known to have strong vasoconstrictive effects on smooth muscle tissue which may accelerate hypertensive nephrosclerosis. Furthermore, kidney epithelial cells exposed to cocaine experienced a reduction in intracellular glutathione, an antioxidant and important component of cellular homeostasis, increasing oxidative stress and may reduce normal kidney function [24]. Results of our analysis were appreciably similar for non-injection cocaine use, suggesting the nephropathic potential of cocaine is drug-specific and not related to route of administration."
"It is notable that in our analysis, chronic HCV infection was not associated with an increased risk of CRI. As HCV has been associated with specific glomerular diseases, such as MPGN, it has been hypothesized that patients with a chronic HCV infection may be at a greater risk for CKD, compared to those who have spontaneously cleared the virus or developed a sustained virologic response to HCV treatment [41]. Indeed, in studies of patients enrolled in the SMART and ESPRIT trials, as well as the EuroSIDA cohort, co-infected patients with HCV viral loads ≥ 800,000 IU/mL and 500,000 IU/mL, respectively, had larger CKD incidence rates compared to those with resolved HCV infections [42, 43]."
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Frequent injection cocaine use increases the risk of renal impairment among hepatitis C and HIV co-infected patients.
AIDS Feb 2016
Rossi, Carmine; Cox, Joseph; Cooper, Curtis; Martel-Laferriere, Valerie; Walmsley, Sharon; Gill, John; Sapir-Pichhadze, Ruth; Moodie, Erica E.M.; Klein, Marina B.; for the Canadian Co-infection Cohort Investigators
Abstract
Objective: To examine the association between injection cocaine use, hepatitis C virus (HCV) infection and chronic renal impairment (CRI).
Design: Prospective observational cohort study of HIV-HCV co-infected patients.
Methods: Data from 1,129 participants in the Canadian Co-Infection Cohort with baseline and follow-up serum creatinine measurements between 2003-2014 were analyzed. Prevalent and incident cohorts were created to examine the association between self-reported past, current, and cumulative cocaine use and chronic HCV with CRI. CRI was defined as an estimated glomerular filtration rate <70 mL/min/1.73m2. Multivariate logistic regression was used to calculate odds ratios (ORs) and discrete-time proportional hazards models were used to calculate hazard ratios (HRs) for cocaine use, in the two respective cohorts, adjusted for HCV RNA and important demographic, HIV disease stage, and comorbidity confounders.
Results: Eighty-seven participants (8%) had prevalent CRI. Past injection cocaine use was associated with a two-fold greater risk of prevalent CRI [OR 2.03, 95% confidence interval (CI): 0.96, 4.32]. During follow-up, 126 of 1,061 participants (12%) developed incident CRI (31 per 1,000 person-years). Compared to non-users, heavy (>= 3 days/week) and frequent injection cocaine users (>= 75% of follow-up time) experienced more rapid progression to CRI [HR 2.65, 95% CI: 1.35, 5.21 and HR 1.82, 95% CI: 1.07, 3.07, respectively]. There was no association between chronic HCV and CRI in either cohort.
Conclusions: After accounting for HCV RNA, frequent and cumulative injection cocaine abuse were associated with CRI progression and should be taken into consideration when evaluating impaired renal function in HIV-HCV co-infection.
Introduction
Chronic kidney disease (CKD) is a prevalent comorbidity among HIV-infected persons [1, 2]. It is estimated that 5% to 11% of people living with HIV have mild to moderately reduced kidney function [3-5], increasing their risk of cardiovascular disease and premature mortality [6, 7]. HIV-associated nephropathy (HIVAN), which is associated with rapid progression to end-stage renal disease (ESRD), is the classic kidney disease presentation among HIV patients, particularly in African Americans [8]. With the introduction of antiretroviral therapy (ART), which has been effective in the prevention and treatment of HIVAN [9, 10], the spectrum of CKD among HIV-infected persons has changed. Of late, the increasing CKD burden among HIV-infected persons has been attributed to aging, metabolic changes associated with a greater prevalence of diabetes and hypertension, and direct nephrotoxic complications from prolonged ART use [1, 11].
Hepatitis C virus (HCV) co-infection has also been implicated as an important risk factor for CKD and ESRD among HIV patients [12-16]. Due to shared routes of transmission, approximately 25% of people living with HIV are also co-infected with HCV [17]. Membranoproliferative glomerulonephritis (MPGN) is more common in HCV co-infected compared to HIV mono-infected patients [18, 19]. MPGN is associated with type II mixed cryoglobulinemia which may represent a pathway by which HCV affects the kidney [20]. A recent epidemiologic study, however, found no association between HCV RNA and CKD, suggesting that the excess risk associated with HCV infection may be attributable to other exposures in this population [21].
Injection drug use (IDU), the primary route of HCV infection, remains a common behavior for many co-infected individuals [22]. Cocaine itself has been associated with rhabdomyolysis and acute kidney injury, and is a known nephropathic drug [23, 24]. However, there is little epidemiological evidence about the role that cocaine has on renal function or whether its use may explain the observed association between HCV and CKD. The aim of this study was to examine the association between injection cocaine use and chronic renal impairment (CRI) among HIV-HCV co-infected patients receiving clinical care.
Discussion
In this prospective study of HIV-HCV co-infected patients, past injection cocaine increased the risk of CRI, independent of chronic HCV infection, ART use, and other traditional kidney disease risk factors. Furthermore, frequent injection cocaine use of three or more times per week was associated with rapid progression to CRI. We also found that regular use of injection cocaine was associated with CRI progression. Relative effect estimates for cocaine use in this analysis were large. For example, past injection cocaine use was associated with an approximately two-fold greater risk of prevalent CRI. Similar associations were also observed for frequent and cumulative injection and non-injection cocaine in the incident cohort. We also found important clinical differences in annual rates of change in eGFR between injection cocaine users and non-users. Given that the prevalence of injection drug use in this population is high, cocaine use may be an important modifiable risk factor for CKD among co-infected patients [22]. These results support that screening guidelines for CKD among HIV-infected populations should be expanded to include cocaine users as a high-risk group for kidney disease, as has previously been suggested [34, 35].
This is the first cohort study to examine the effect of injection cocaine use, a known nephropathic drug [23, 24, 36], on renal function among HIV or co-infected populations. Previous research in non-HIV-infected populations has been limited by small sample sizes, poor exposure ascertainment and the use of non-longitudinal study designs, which have led to inconsistent results. For example, in a case-control study of recreational drug use and ESRD, cocaine use was not associated with being on dialysis; however, the effect estimate lacked precision as the population controls reported no past illicit drug use [37]. In a cohort of 647 hypertensive men, past cocaine use was strongly associated with mild increases in SCr concentrations [38]. However, because of the retrospective cohort design, drug use may have occurred after follow-up time in the analysis began for many participants. Results from this study are similar to results from a longitudinal analysis of acute kidney disease among a cohort of 367 HCV-infected patients, which have characteristics comparable to our co-infected cohort [39]. Garg et al. reported that recent injection or non-injection cocaine use was associated with a two-fold greater risk of a concomitant rise in SCr, which may be a marker for future chronic disease [39]. Our study supports that elevations in creatinine associated with cocaine use are not transient but rather lead to chronic kidney dysfunction as the vast majority of those developing CRI never returned to normal renal function.
Results from this study are consistent with clinical studies that demonstrate pathogenic effects of cocaine on the kidney [40]. Cocaine is known to have strong vasoconstrictive effects on smooth muscle tissue which may accelerate hypertensive nephrosclerosis. Furthermore, kidney epithelial cells exposed to cocaine experienced a reduction in intracellular glutathione, an antioxidant and important component of cellular homeostasis, increasing oxidative stress and may reduce normal kidney function [24]. Results of our analysis were appreciably similar for non-injection cocaine use, suggesting the nephropathic potential of cocaine is drug-specific and not related to route of administration.
It is notable that in our analysis, chronic HCV infection was not associated with an increased risk of CRI. As HCV has been associated with specific glomerular diseases, such as MPGN, it has been hypothesized that patients with a chronic HCV infection may be at a greater risk for CKD, compared to those who have spontaneously cleared the virus or developed a sustained virologic response to HCV treatment [41]. Indeed, in studies of patients enrolled in the SMART and ESPRIT trials, as well as the EuroSIDA cohort, co-infected patients with HCV viral loads ≥ 800,000 IU/mL and 500,000 IU/mL, respectively, had larger CKD incidence rates compared to those with resolved HCV infections [42, 43].
In the larger NA-ACCORD cohort, however, rates of incident CKD did not differ between co-infected patients with any quantifiable or undetectable HCV viral load [21]. None of these studies accounted for cocaine use. It is therefore possible that some or much of the effect attributed to HCV may instead be related to cocaine abuse rather than to HCV itself. Due to the lack of quantitative measures for all participants, we were unable to determine if HCV RNA levels may impact risk of renal impairment at higher thresholds. Among the subset of participants with available quantitative HCV RNA measures, the median HCV RNA was high (median 1.3 million IU/mL) and there was no evidence that cocaine use was associated with level of HCV RNA, suggesting our findings were not confounded by HCV viremia.
As reported previously, past exposure to tenofovir was associated with prevalent CRI [13, 44]. Consistent with findings from an assessment of the effect of cumulative ART exposure, past use of lopinavir and atazanavir, two protease inhibitors, and current atazanavir use were also associated with CRI in this study [26]. We found no evidence of interaction between any of these nephrotoxic ART agents and injection cocaine use, suggesting that renal safety of these medications is not affected by cocaine use.
This study has several important strengths. First, the cohort collected detailed, time-updated information on the use of specific illicit drugs, as well as their frequency of use. This information is typically not recorded in clinical databases used for other HIV cohort studies on CKD. Previous studies have also ascertained drug exposure retrospectively or at only one time point. Second, with regular HCV RNA testing, this study isolated the effect of HCV viremia from the effect of specific injection drug use, which has not previously been done in HIV-infected cohorts. Finally, we used a validated kidney function equation to measure eGFR and required two consecutive measurements, at least three months apart, to confirm incident CRI and rule out acute kidney injury.
Our study has also several potential limitations. First, although data were obtained from a large cohort of co-infected patients, study power was limited to detect smaller effect sizes and interactions between exposure and covariates. Therefore, we only considered CRI as our outcome rather than traditional CKD (eGFR < 60 mL/min/1.73 m2), as there were few CKD events. While it is possible that risk factors for CRI may differ from CKD, there is increasing interest in identifying patients at earlier risk for CKD so interventions and modifications of treatment can be implemented [26]. Our analysis of CRI may help to achieve this aim. Second, drug history was measured by self-report and may result in misclassification if some patients failed to report drug use. We do not expect the degree of misclassification to be biased, however, as drug use history was collected independently of objective serum creatinine measures. Third, as only 3% of the study participants were black, we were unable to adequately evaluate race as a confounder or effect modifier. Finally, HCV viremia was measured using a combination of qualitative and quantitative molecular assays. As a result, we were unable to assess a dose-response relationship between viremia and CRI as we classified all those with any detectable HCV viral load as being viremic.
In conclusion, we found evidence to suggest that cumulative exposure and frequent cocaine use is associated with CRI progression among HIV-HCV co-infected patients. The role of substance use in contributing to renal disease in co-infection has been underappreciated and should be taken into consideration when evaluating impaired renal function in this setting.
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