In a large population of HIV-uninfected and HIV-infected men of similar social risk behaviors, we demonstrated that GFR estimates differed by the biomarker used and by kidney function level. Estimates of GFR based on serum cystatin C differed by HIV status. Among HIV-infected men, estimates of GFR based on serum cystatin C classified a larger proportion of individuals with moderate to severe CKD compared with GFR estimates based on serum creatinine. These discordant classifications are clinically relevant as drug dosing and the institution of a multitude of CKD management strategies are advocated at the threshold of eGFR below 50 to 60 mL/min/1.73m2
by national guidelines (25
The differences between these two GFR-estimating methods and therefore CKD classification reflect the differential factors associated with the respective biomarkers. We observed that more clinical factors correlated with eGFRCYSC than eGFRSCR, supporting ongoing concerns of cystatin C’s utility as an uninfluenced biomarker of kidney function. Since HIV infection can be accompanied by systemic inflammation and multiple non-AIDS co-morbidities that may alter markers of kidney function independently of kidney function, our study is an important step in understanding the relationship of these concurrent factors with indicators of renal function among HIV-infected persons and may help with interpretation of GFR estimates in this patient population.
Similar to prior studies, we demonstrated that HIV-infected individuals have higher serum cystatin C levels compared with social and demographically similar HIV-uninfected individuals (28
). Whether these elevated serum cystatin C levels in HIV-infected persons necessarily reflect decrements in kidney function, however, remains unclear. In the Study of Fat Redistribution and Metabolic Change (FRAM) study, HIV-infected individuals who had traditional CKD risk factors (older age, higher baseline or greater increase in HIV RNA levels, higher serum glucose levels, and dyslipidemia) were more likely to have a decline in eGFRCYSC
). Conversely, individuals with improved HIV RNA levels had improvement in eGFRCYSC
. While these findings by Longenecker and colleagues suggests that elevated serum cystatin C levels seen in HIV-infected individuals may be explained by subclinical kidney disease, our data suggest that additional factors occurring in HIV-infected persons are differentially associated with serum creatinine and cystatin C, and thus their corresponding estimates of kidney function. While some clinical factors, such age and proteinuria, were consistent in their influence across GFR-estimating methods, others factors affected only one or the other method. For example, ACEi or ARB use and higher serum albumin levels were inversely associated with eGFRSCR
but not eGFRCYSC
; in this context, ACEi or ARB use may reflect a drug-related reduction in true GFR via vasodilatation of the renal efferent arteriole or may serve as a surrogate for hypertension, a risk factor for CKD. On the other hand, serum albumin’s effect on serum creatinine may be reflective of one’s nutritional state and protein stores rather than kidney function. Prior studies comparing various GFR-estimating equations to an exogenous indicator of GFR have shown that both eGFRSCR
are considerably biased (−10 to −29 mL/min/1.72 m2
) in HIV-infected persons (31
). Moreover, Barraclough and colleagues demonstrated that cystatin C-based estimates of kidney function were less accurate than those based on serum creatinine, with 41% versus 89% falling within 30% of the measured GFR, respectively (31
). These studies, however, consisted of no more the 30 participants, limiting their generalizability to the HIV-infected population at large. While our study also underscores the need for large studies which rigorously validate GFR-estimating equations in the HIV-infected population, clinicians currently rely on available GFR-estimating equations (which were developed in studies excluding HIV-infected persons) to inform management of their HIV-infected patients. Therefore, recognition and understanding of extra-renal factors which affect these estimates are important in the application of these GFR-estimating equations to HIV-infected persons.
Our study has several limitations to consider. Results of the agreement between eGFRSCR
should be interpreted cautiously at the extremes of eGFR since we had few individuals with either very high or low eGFRs; therefore, these results may have been unduly influenced by the few participants at the eGFR extremes. In addition, we relied upon only one time point for GFR estimation. Our calibration of the original serum creatinine values to standardized serum creatinine across sites may have introduced bias or additional measurement error which may have affected our results; however, the high correlation and excellent agreement between the original and repeated serum creatinine values across sites indicate that these potential effects were minimal. A systematic downward drift in cystatin C values due to changes in the assay has been noted since the development of the CKD-EPI eGFRCYSC
). This may have led to an underestimation of the CKD prevalence based on eGFRCYSC
in our study. Direct comparisons of cystatin C concentrations from our study to previous studies of HIV-infected populations should account for the change in the assay over time.
Kidney function estimates based on serum creatinine versus cystatin C differentially classified individuals with CKD. This discordance in identifying some individuals with CKD may be due to the effects of extra-renal factors on both serum creatinine and cystatin C. Until GFR-estimating equations are rigorously validated among HIV-infected individuals, current estimates of kidney function based on these biomarkers should be interpreted cautiously in this patient population in light of these potential extra-renal influences.