Objective

To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART.

Methods

Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes.

Results

Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from -2.18 to -1.37 ml/min per 1.73 m per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m: 3.35 (95% confidence interval (CI) = 1.40-8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type.

Conclusion

ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI.

Rationale and objective

Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFR_cr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFR_cr or eGFR_cys, respectively), but the inclusion of creatinine in eGFR_cr-cys requires specification of a person's race. β₂-Microglobulin (B2M) and β-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.

Study design

Study of diagnostic test accuracy.

Setting and participants

Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants.

Tests compared

Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race.

Outcomes

GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [⁵¹Cr]EDTA.

Results

Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m², and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFR_cys (percentage of estimates greater than 30% different from measured GFR [1 - P₃₀] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFR_cr-cys (1 - P₃₀ of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.

Limitations

No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.

Conclusions

The 4-marker panel eGFR is as accurate as eGFR_cr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.