Our study demonstrates that established CKD at HAART initiation is associated with higher mortality risk independent of HIV-related risk factors for death (Model 1), consistent with the prior WIHS study in the early HAART era that was conducted through March 31, 20021
. Attenuation of the association between CKD and mortality after adjustment for diabetes (Model 2) suggests that CKD may mediate some of the effects of diabetes on mortality; however, we were unable to confirm this explanation due to lack of temporal data on diabetes in relation to kidney function in a large number of WIHS participants. Alternatively, exclusion of women who were missing diabetes data in the adjusted model may have diminished our ability to detect smaller increases in mortality risk associated with CKD. The statistical significance of the risk estimate for CKD upon inclusion of women missing diabetes data supports the latter explanation.
We also found that eGFR at HAART initiation was inversely, but weakly associated with mortality risk in women with prior AIDS and that proportion of women dying of heart disease and malignancy differed between those with and without CKD. In the general HIV-uninfected population, the risk of all-cause mortality increases progressively with lower eGFR; Go and colleagues showed that the risk of death was 1.2-, 1.8-, 3.2- and 5.8-fold higher in those with eGFRs of 45–59, 30–44, 15–29, and <15 ml/min/1.73 m2
. This increased risk of death associated with CKD in the general population is driven primarily by cardiovascular death, with individuals who have CKD having more than 50% increased risk of death due to cardiovascular disease compared to persons with normal kidney function10, 11
. Many of the same risk factors that lead to CKD also lead to cardiovascular disease. These CKD risk factors and CKD itself may lead to activation of the renin-angiotensin system, inflammation, extra-skeletal calcification, and dyslipidemia which, in turn, culminate in endothelial dysfunction11
. This may explain why we observed a higher proportion of deaths from heart disease in HIV-infected women with CKD compared to women without CKD. In contrast, there is no apparent physiologic mechanism by which CKD is associated with the risk of malignancy to explain the disparity in cancer-related deaths between women with and without CKD in our study. Perhaps, women with CKD were more likely to die of other causes prior to having the opportunity to develop cancer.
Although HAART has greatly improved the survival of HIV-infected individuals12
, prior studies suggest that HIV-infected persons with CKD may not have the same degree of survival benefit as those without CKD13
. Underutilization of HAART and improper dose adjustments of antiretroviral medications may partially explain the impact of kidney dysfunction on mortality among HAART-users that we observed14
. Due to lack of data on drug dosages within WIHS, we were unable to explore this further. However, the mechanism by which HAART dose may mediate the effect of CKD on mortality may be more complex. A detailed pK study of atazanavir among 122 women in WIHS showed that the area under the curve of atazanavir concentration following its administration was increased by 1.58-fold (CI: 1.05 – 2.38) in women with CKD compared to those without CKD15
, suggesting that individuals with CKD may be exposed to higher concentrations of certain antiretroviral drugs than anticipated.
Our study has several limitations to consider. WIHS consists only of women; however, there is no evidence to date that the impact of CKD on mortality differs by gender in HIV infection. Selection bias may have occurred when women with missing serum creatinine values at HAART initiation were excluded. Although women who were excluded were less likely to die, we were unable to compare their CKD and immunological status to those of women included in our study due to missing data on these characteristics among the former. The MDRD equation has not been thoroughly validated in HIV-infected persons; therefore, misclassifications for CKD may have occurred. However, most of the published data linking kidney disease to death are based on eGFR by the MDRD equation9, 10, 16
, and current evidence suggests that the MDRD equation is more accurate than other currently available estimates of GFR in HIV-infected individuals17
. We also used two sequential eGFRs to define CKD status to minimize misclassifications.
In summary, our study suggests that pre-existing CKD at the time of HAART initiation leads to increased risk of death. Furthermore, kidney function level at HAART initiation is independently associated with mortality in those with a history of AIDS. Our study underscores the importance of early screening for kidney disease in HIV-infected women prior to HAART initiation.