We conducted a systematic review and series of meta-analyses to calculate the pooled relative risk of renal disease for PLHIV across available sources of evidence. Our analysis suggests that PLHIV have increased risk of renal disease. Specifically, the relative risk of renal disease for PLHIV was found to be 3.87 times greater than in HIV-uninfected people. The relative risk of renal disease for late-stage HIV infection (AIDS) was found to be 3.32 times more than that of PLHIV at earlier stages of infection. The relative risk of renal disease among PLHIV treated with ART was found to be decreased by 46% compared to treatment-naïve PLHIV. This indicates that ART could have a protective effect against renal disease in PLHIV. We also found that the risk of renal disease for HIV-infected people receiving TDF-based treatment was found to be 56% greater than the risk for HIV-infected people who are treated with non-TDF-based ART.
Our estimates are consistent with earlier reviews of specific associations with renal disease. A Multicentre AIDS Cohort Study by Palella et al. [35
] found the relative risk of proteinuria with GFR decreased rate was 5.0 (p < 0.001) among PLHIV without AIDS compared to HIV-uninfected people and 2.18 (p = 0.02) among people with AIDS compared to other PLHIV, respectively. A review of TDF conducted by Cooper et al. found a non-significant effect of TDF-based ART of 0.7% (0.02-1.2) [36
]. We also found that the duration of exposure to ART and age are important contributors to the risk of acquiring renal disease: specifically, each year of ART increased the relative risk by an estimated 29% and each 10-year increment in age increased the risk of renal disease by 54%.
One study identified in our search strategy, by Crane et al. [4
], did not have similar comparator groups with other studies and thus could not be pooled in these estimates. The study reported estimates in various age groups and within ART groups. They found the risk of CKD among people receiving tenofovir was greater if the patients also received didanosine and amprenavir antiretrovirals, were of greater age, and lower baseline weight [4
The underlying reason for development of CKD in HIV-infected patients is likely that HIV can cause direct injury to the kidneys as manifested by HIVAN [37
]. The CKD can be developed by drug-induced nephrotoxicity to prevent HIV-infection, dependent on exposure to antiretroviral drug regimen. TDF-induced regimens are more likely to increase CKD than non-TDF-based regimen. There are other mechanisms of developing CKD among PLHIV as described in a recent study [37
In our analyses we attempted to eliminate bias and confounding wherever possible. Individual studies controlled for certain confounders between the treatment and control groups but not all studies controlled for the same variables. Due to differences between study categorizations it is possible that our analysis may have some bias due to misclassification error. This may be particularly relevant for comparisons between HIV-infected people receiving ART versus treatment-naïve people because some of the people with unknown treatment exposure could have been classified as treatment-naïve. It is possible that there are other important characteristics beyond the effects of antiretroviral drugs that differ between populations of people who are given and take ART and those who are not treated. We were unable to conduct an analysis based on duration of ART, which may be an important determining factor. For individual studies in which there was some uncertainty in definitions of populations in any arm we conducted a sensitivity analysis by performing the meta-analysis without the questioned study, but we found our pooled estimates to be relatively robust. Our meta-analysis ended up with relatively small numbers in each grouping with reasonable amounts of heterogeneity. However, estimates from our meta-analyses provided no significant evidence of publication bias. Our effect measures were relatively consistent among the trials. Also, abstracts did not provide final, peer-reviewed, data and that the GFR equations have not been validated in HIV populations. Given these potential limitations, we believe our pooled estimates are accurate indications of the relative risk of CKD for HIV-infected people based on the available empirical evidence. However, it is important to note the importance of race/ethnicity, as it pertains to HIV-associated kidney disease. We were unable to conduct sub-analyses by race. However, a number of studies reported that people of African descent among HIV-infected population known to have high risk, as HIV-associated nephropathy (HIVAN) occurs disproportionately among those of African descent [9
]. hepatitis C co-infection is also associated with kidney disease which was not included in our analysis [38