In this large contemporary cohort of HIV-infected persons, 28% of participants had either albuminuria or eGFRSCysC <60 mL/min/1.73m2. These markers of kidney damage and reduced kidney function, respectively, were each independently associated with a nearly two-fold increase in mortality risk, whereas eGFRSCr did not have a significant association with mortality. Albuminuria and eGFRSCysC <60 mL/min/1.73m2 provided complementary prognostic information, collectively accounting for 17% of the population-level mortality in HIV-infected persons. These findings suggest that kidney disease, marked by albuminuria and decreased eGFRSCysC, is an important source of mortality in HIV-infected individuals, and that a substantial proportion of this risk is unrecognized because of the current reliance on serum creatinine to estimate kidney function in clinical practice. Alternatively, the mortality associations of either albuminuria, decreased eGFRSCysC, or both in HIV-infected persons may in part reflect an unknown process that is unrelated to the kidney.
Few studies have jointly assessed the risk of death associated with reduced kidney function and albuminuria in the contemporary era of antiretroviral therapy. While we and others have observed a graded, independent relationship between eGFRSCr
levels and mortality, these studies lacked information on albuminuria and were unable to account for important characteristics such as HIV viral load, blood pressure, or inflammatory markers.30, 31
Our results are consistent with studies that have analyzed both eGFRSCr
and albuminuria as risk factors for mortality among individuals receiving antiretroviral therapy, and found that albuminuria is independently associated with death, but eGFRSCr
is not.14, 15
Our study builds on these prior reports, which were limited to women, by establishing the independent association of both kidney damage (albuminuria) and reduced kidney function (eGFRSCysC
) with mortality in a diverse population of antiretroviral treated patients. We also describe the population attributable risk associated with joint measures of kidney disease to help understand its relevance to the HIV-infected population at large, given the high prevalences of albuminuria and reduced eGFRSCysC
and their strong associations with mortality. Collectively, these findings strongly suggest that kidney disease is a critical source of mortality in patients with HIV and demand further investigations into underlying mechanisms.
To our knowledge, no prior study has reported an association between cystatin C levels and mortality in HIV-infected persons. A strength of this study is the demonstration of this relationship in a large, geographically and ethnically diverse, population-based sample of HIV-infected persons, and the availability of comprehensive clinical information and specialized measures of physiologic status which allowed us to test the robustness of this association. Consistent with findings in HIV-uninfected persons, cystatin C appears to capture mortality risk not characterized by established measures of kidney function, such as creatinine.10, 12
Interestingly, this result was not affected by adjustment for lean body mass, which has been hypothesized to confound the association between creatinine and mortality, since creatinine is a derivative of muscle mass. We have previously shown that cystatin C levels are not associated with muscle mass.3
While studies of eGFRSCysC
in HIV-uninfected patients have revealed that it is a sensitive test of kidney disease and an accurate predictor of gold standard GFR, no studies of adequate sample size have been conducted in HIV-infected persons. 5–9
It is unknown, therefore, whether abnormal levels of cystatin C are predominantly a manifestation of reduced GFR or if there is a substantial contribution from non-GFR determinants of cystatin C. In addition, the impact of muscle mass on the validity of serum creatinine as a marker of kidney function has not been definitively addressed. To date, neither of the currently available measures of kidney function, cystatin C or creatinine, has been validated in an HIV-infected population using gold standard techniques. Such studies are urgently needed to aid the interpretation of increased cystatin C levels in the HIV-infected population.
Some have expressed concern that cystatin C may be confounded by increased cell turnover, leading to excessive cystatin C production in high inflammatory states such as HIV infection. 32, 33
In addition, inflammation itself is associated with mortality in HIV-infected persons, which raises the possibility of a spurious association between eGFRSCysC
and mortality due to confounding. 34
However, it is notable that inflammation had similar attenuating effects on the associations of reduced kidney function defined by eGFRSCr
with mortality. Furthermore, both eGFRSCysC
and albuminuria remained independent predictors of mortality despite adjustment for inflammatory factors. These results do not rule out the possibility that the mortality associations of cystatin C or albuminuria could still be subject to residual confounding by inflammation or other unmeasured factors, but they suggest that eGFRSCr
may be differentially affected by inflammation or associated malnutrition and muscle wasting. Further study is needed to identify determinants of serum creatinine and cystatin C in HIV-infected persons in conjunction with measurements of gold standard GFR.
In this study, markers of kidney disease were independent risk factors for mortality in HIV-infected persons after accounting for traditional and HIV-related risk factors for mortality, including comorbid illnesses, health behaviors, physiologic measurements, CD4 count, HIV viremia, hepatitis C virus co-infection, and medication exposures. It is plausible that kidney disease could lead to increased mortality among HIV-infected individuals through a number of different pathways. Both albuminuria and decreased kidney function are associated with cardiovascular disease in studies conducted among both HIV-infected and uninfected persons.13,35
Cardiovascular disease has become a leading cause of death in the HIV-infected population36–38
and both kidney and heart complications have become increasingly common as the HIV-infected population ages.31, 39–42
In addition, several studies conducted in vitro
and in humans have established an association between uremia and immune activation, which is widely accepted as an important mechanism by which HIV disease progresses.43, 44
Similarly, other studies have suggested that kidney disease is associated with progression to AIDS and loss of CD4+ T cells.15, 45
Finally, another report suggested that the effectiveness of antiretroviral therapy may be compromised in the setting of kidney disease because of decreased renal clearance of these medications, inadequate dose adjustments, and increased side effects.30
The next key step will be to investigate causes of death associated with kidney disease and to determine whether mortality is due to cardiovascular causes, immune-related mechanisms, or interactions between the host and the reservoir of HIV residing in the kidney.
The most important limitation of the study was the analytic challenge presented by limited vital status information. We used a number of statistical methods to deal with this problem, including multivariable logistic regression with an offset term for follow-up time and inverse probability of censor weights to account for those with missing vital status. In addition, we performed a number of sensitivity analyses to test our analytic approach, which further supported a significant association between eGFRSCysC with mortality. Unfortunately, cause of death information was not available to us to provide additional evidence that these deaths were related to kidney disease. Our data support the concept that cystatin C should be measured in future studies of HIV-infected cohorts in which cause of death can be ascertained.
In this nationally representative cohort of HIV-infected persons, kidney disease marked by albuminuria and impaired kidney function was common, and strongly associated with mortality. Cystatin C based estimates of kidney function appear to improve the prognostic value of eGFR, compared with serum creatinine based estimates of kidney function that are the current clinical standard. Further study is needed to confirm these findings and to determine whether cystatin C may be a useful tool for detecting unrecognized kidney disease and identifying HIV-infected persons at increased risk for mortality.