In this analysis, AKI incidence was 2.2 times higher in subjects with HIV/HCV coinfection than in HCV monoinfection. In comparison to Franceschini's study,5
in which subjects with HIV/HCV coinfection and HIV monoinfection had a combined incidence of first AKI event of 4.3 per 100 person-years, AKI incidence was twofold higher (8.74 per 100 person-years) among HIV/HCV-coinfected subjects in our current analysis. After adjusting for the elevated risk of AKI attributed to HIV coinfection, additional significant risk factors for AKI included decompensated liver cirrhosis and cocaine use. These risk factors remained significant among HIV/HCV-coinfected subjects, even after adjustment for CD4 cell count and HIV VL.
In contrast to findings that higher HIV VL is associated with increased risk of AKI, we did not find an association between HCV VL and AKI incidence in our analysis. While several studies have demonstrated that HIV infection may be linked to renal disease through direct viral infection of renal parenchyma,16
a similar mechanism has not been demonstrated for HCV infection. HCV has been linked to several types of glomerular lesions including membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy. These pathologic lesions appear to result from deposition of circulating immune complexes that contain HCV and anti-HCV antibody. Although a few reports of immunohistochemical localization of HCV antigen in renal tissue have been published, results have not been consistently demonstrated.16,17
Although in our study, higher HCV VL and genotype were not associated with AKI, these findings add important information to currently available data as other epidemiologic studies examining the relationship between HCV and renal disease have not included HCV VL or genotype data.11–14
In addition to HIV/HCV coinfection and decompensated liver cirrhosis, cocaine but not heroin use was strongly associated with AKI. Indeed, the entity previously known as heroin nephropathy has greatly decreased in recent years and likely represented primary focal and segmental glomerulosclerosis (FSGS) rather than a consequence of heroin use.18
FSGS is now the most common cause of nephrosis in African American individuals in the United States. In contrast, cocaine clearly causes deleterious effects on the kidney and can lead to AKI both from rhabdomyolysis and malignant hypertension.19,20
This study further supports the existence of an association between cocaine use and AKI among persons with HIV/HCV coinfection.
Among the HIV/HCV-coinfected subjects, there was only a single case of HIV-associated nephropathy identified. No cases of other diagnoses attributable to HIV infection, such as HIV immune complex kidney disease, IgA nephropathy or thrombotic thrombocytopenic purpura (TTP), were found. The bulk of cases were related to prerenal azotemia or drug toxicity. In multivariable analyses, lower CD4 cell count and higher HIV VL were both associated with AKI, although only CD4 cell count less than 200 was statistically significant. Lower CD4 count may have been associated with AKI through higher rates of nephrotoxic drug use for opportunistic infections and ARV toxicity. Indinavir-associated renal dysfunction is well documented and there is also growing evidence of an association between tenofovir use and loss of renal function.22–27
In a recent meta-analysis that included 17 studies to assess the renal safety of tenofovir in HIV-infected patients, a statistically significant greater loss in creatinine clearance was observed among tenofovir recipients compared to control subjects, as well as a significantly greater risk of acute renal failure among tenofovir recipients.22
Of subjects on ARVs at the time of AKI, 45% were receiving indinavir or tenofovir-containing regimens, reflecting evolving drug availability and prescribing practices during the study period. However, sufficient data were not available to examine the independent association between tenofovir use and AKI. The interrelationships between CD4 cell count, HIV VL, exposure to ARVs, and the subsequent development of AKI warrant further investigation among HIV/HCV-coinfected subjects.
There were several limitations to this analysis. Serial HIV antibody testing was not performed as part of the research protocol after study entry, and could have resulted in misclassification of some dually infected subjects as having HCV monoinfection. Such a misclassification may have dampened the true impact of HIV coinfection on the incidence of AKI among subjects with HCV infection. HCV VL and genotype data was missing for 12% of the cohort and may have diminished the power to detect a true association between HCV VL and AKI. Furthermore, kidney biopsies were not performed in this study to look for direct HCV viral effects on renal tissue. Data on tenofovir use were not consistently collected for the cohort and the data presented likely underestimates the true proportion, of individuals that were taking tenofovir. Due to concerns with the quality of the tenofovir data and associated biases, we did not adjust for tenofovir use in the final multivariable analyses. Thus, tenofovir use may have been a potential confounder of the association between variables of interest and AKI among coinfected subjects. As no standard definition for AKI exists, a traditional definition of AKI, which has been shown to affect mortality in hospitalized patients without HIV or HCV, was utilized.4
Recently, smaller changes in serum Cr have been found to be of clinical import, such that a rise in Cr of 0.5
mg/dL is utilized in the RIFLE criteria (Risk Injury Failure Loss End Stage) and a rise of only 0.3
mg/dL is utilized in the AKIN criteria (Acute Kidney Injury Network).28
In our study, we chose to utilize the more conservative definition of AKI to capture the most serious events.
The findings of the association between AKI and decompensated liver cirrhosis, HIV coinfection, and cocaine use in this study, highlight the importance of controlling HIV infection in coinfected individuals and preventing liver disease progression and cocaine use in persons with both HIV/HCV coinfection and HCV monoinfection. While the relationship between AKI and other substances of abuse, including heroin and hazardous alcohol, was not statistically significant after adjusting for cocaine use, intermediate multivariable models did demonstrate a positive association between these agents and AKI. Thus, targeted interventions to reduce heroin and alcohol use may further reduce the burden of renal disease among these individuals. Further studies are required to determine the association between HCV VL and AKI, and whether lowering HCV VL may impact AKI incidence. By addressing the identified modifiable risk factors, a reduction in AKI-associated morbidity and mortality, including rates of hospitalization, transient hemodialysis and death, may potentially be achieved in this population.