Individuals infected with HIV had substantially worse kidney function, as measured by cystatin C level, compared with HIV-negative controls, even after adjustment for demographic characteristics and clinical factors. After multivariable adjustment, the HIV-infected participants had more than a 9-fold increased odds of having a cystatin C level greater than 1.0 mg/L, a level that was demonstrated to be associated with an increased risk for death and cardiovascular and kidney disease in an elderly cohort.23
In contrast, there was little difference in creatinine levels between HIV-positive individuals and controls. Creatinine level may not adequately capture kidney function because of its strong associations with ethnicity, sex, and body composition. While eGFR equations are often used to adjust for these factors, eGFRs were also similar in HIV infection and in controls. In participants with HIV, hypertension and low HDL-C level—potentially modifiable risk factors for kidney disease—were associated with worse kidney function, as were lower CD4 lymphocyte count and coinfection with HCV.
Several studies have noted an increased prevalence of kidney disease in the HIV-infected population, as well as an increased prevalence of HIV-infection in the population with end-stage renal disease.1-5
The majority of studies of HIV and kidney disease have focused on end-stage renal disease or HIV-associated nephropathy, a condition marked by proteinuria and glomerulopathy, but few have compared kidney function in HIV-infected individuals and noninfected controls. One prior study from the FRAM cohort found approximately a 5-fold odds for microalbuminuria in HIV-infected individuals compared with controls, and predictors of microalbuminuria included both risk factors for kidney disease and markers of HIV severity.10
Our findings expand on a small study of HIV-infected individuals (n=77) and HIV-negative volunteers (n=18) in Poland. The investigators found that cystatin C levels were elevated in HIV infection and were correlated with viral load; however, there were no significant differences in eGFR levels26
A recent study described elevated cystatin C level (>1.0 mg/L) in the setting of normal eGFR as “preclinical kidney disease,” and this condition has been associated with increased risk of progression to CKD, cardiovascular disease, and death.23
Participants without CKD who had cystatin C concentrations greater than 1.0 mg/L had a 4-fold risk for progressing to CKD after 4 years of follow-up compared with participants without elevated cystatin C level. Using this cystatin C-based definition, we found that approximately one-third of persons with HIV have pre-clinical kidney disease, a condition that was undetected by creatinine-based measures. If truly reflective of underlying kidney dysfunction, elevated cystatin C concentrations may identify persons with a greater risk for kidney toxic effects from medication use, worsening kidney disease, cardiovascular disease, or death. Since only 2% had an eGFR lower than 60 mL/min/1.73 m2
, this potential risk would be missed using traditional measures of kidney function.
Although the present study did not include a direct measure of kidney function, there is substantial evidence that a higher cystatin C level reflects worse kidney function.11,14,27
Several studies have reported the superiority of cystatin C over creatinine measurement for detecting early changes in kidney function, especially in the setting of chronic disease or aging.13,14,23,28
One cross-sectional study compared HIV-positive patients using antiretroviral regimens with or without tenofovir and found that tenofovir use was associated with reduced kidney function using measurements of cystatin C level or 24-hour creatinine clearance but found no significant difference in kidney function when measured by the MDRD formula.29
The authors concluded that the mild nephrotoxic effects may have been missed by the simple formula-based estimation of kidney function. The insensitivity of creatinine measurement for capturing small changes in kidney function may explain why few studies have reported an association of HIV infection with impaired kidney function.
Several risk factors for kidney disease were more prevalent in persons with HIV infection. Hypertension, hypertriglyceridemia, inflammation, diabetes, hyperuricemia, and microalbuminuria are all well-described risk factors for reduced kidney function that were associated with a higher cystatin C level in HIV-infected participants.30-35
Adjustment for risk factors moderately reduced the magnitude of the association between HIV and cystatin C level in the linear models, suggesting that some of the elevated renal risk observed in HIV infection may be due to the increased levels of these factors. If these findings are confirmed, then future studies should evaluate whether therapies that target modifiable risk factors can delay the progression of kidney disease in HIV-infected persons.
Risk factors associated with HIV were also strongly and independently associated with higher cystatin C level, including lower CD4 lymphocyte count, which is indicative of immune dysfunction, and HCV. This suggests that in addition to the adverse metabolic effects of HIV, severity of HIV infection and HCV coinfection may exacerbate the diminished kidney function observed in these participants. Consistent with other literature, heroin use was associated with worse kidney function, although the prevalence of heroin use was low in this population and thus would not explain much of the HIV effect.36
Total duration of 2 antiretroviral therapies, efavirenz and indinavir, were also modestly associated with worse kidney function; this association may be due to direct pathogenic effects of the medications or may be a surrogate for longer or more severe HIV infection. It is important to note that our study population was recruited before the widespread use of tenofovir, the most widely cited therapy with potential nephrotoxic effects.
An alternative explanation for elevated cystatin C level may be altered production or secretion of cystatin C in HIV infection. Without a gold standard for kidney function, we are unable to conclude definitively that the observed elevations in cystatin C concentrations are indicative of diminished kidney function in HIV infection. Finally, there may have been incomplete or inadequate control for factors that confound the association of HIV infection and cystatin C level.
In conclusion, HIV infection appears to be associated with substantially worse kidney function when measured by cystatin C level, whereas creatinine levels and eGFRs were similar in HIV-infected individuals and controls. Future studies that use a direct measure of kidney function could help to define the optimal role of cystatin C for detecting reduced kidney function in HIV or other chronic infection. Early identification of kidney dysfunction may permit actions that prevent or reduce the risk of toxic effects from medication use, further renal complications, or cardiovascular outcomes. Longitudinal studies may better elucidate the HIV-associated physiologic processes that accompany declines in kidney function and thus facilitate the development of preventive therapies.