Background: Previous studies in persons with an initially normal eGFR have been underpowered to assess whether the incidence of CKD increases immediately after starting potentially nephrotoxic ARVs and then remains stable or continues to increase with duration of exposure.
Methods: D:A:D study participants were followed from baseline until earliest of CKD, last eGFR, 1/1/2013 or last visit plus 6 months. Baseline was defined as the first eGFR after 1/1/2004; persons with <2 eGFRs after baseline or where baseline eGFR <90 ml/min/1.73m2 were excluded. CKD was defined as confirmed (>3 months apart) eGFR <60 ml/min/1.73m2 and chronic renal impairment (CRI) as confirmed (>3 months apart) eGFR <70 ml/min/1.73m2. Poisson regression was used to estimate the incidence of CKD associated with cumulative exposure to or time since stopping tenofovir (TDF),ritonavir-boosted atazanavir (ATV/r), lopinavir (LPV/r), other ritonavir-boosted protease inhibitors (BPI) or abacavir (ABC).
Results: 23560 persons were included with median baseline eGFR 110ml/min/1.73m2 (IQR 100–125), age 39 years (IQR 33–45) and CD4 440/mm3 (IQR 293–629). During a median follow-up of 6.3 years (IQR 4.4–8.0), 210 persons developed CKD (0.9%; incidence 1.48/1000 PYFU; 95% CI 1.28–1.68). The crude incidence of CKD increased as exposure to TDF, LPV/r and ATV/r increased, but not as clearly for BPI and ABC (Figure). After adjustment, there was a significant increase in CKD associated with increasing exposure to TDF, ATV/r and LPV/r (all p<0.0001) but not other BPI (p=0.44) or ABC (p=0.12; Figure). Results were consistent for CRI and when limited to those currently on ARVs. There was a decrease in the incidence of CKD as time since stopping TDF increased, with no clear picture for the other ARVs. Those who had stopped TDF for >2 years had a significantly raised incidence of CKD (adjusted incidence rate ratio 2.47; 95% CI 1.36–4.48) compared to those never exposed to TDF.
Conclusions: The association between TDF, ATV/r, LPV/r and CKD in persons with an initially normal eGFR was not limited to an increased incidence immediately after starting the ARV, but clearly persisted with increasing exposure to TDF, LPV/r and ATV/r. After 6 years exposure, the relative risk of CKD was increased by 97%, 320% and 140% for TDF, ATV/r and LPV/r respectively. A clear decrease in the incidence of CKD after stopping ARVs was only observed for TDF; but the incidence remained significantly higher 2 years after stopping compared to those who had never started TDF.