Is Tenofovir-Related Renal Toxicity Incompletely Reversible?

Abstract

To the Editors: Wever et al1 report “incomplete reversibility of tenofovir (TDF)-related renal toxicity in HIV-infected men”. The authors' report highlights that TDF-related renal toxicity may not always be fully reversible, particularly in those with gradual decline in estimated glomerular filtration rate (eGFR). The study describes 24 patients who ceased TDF for suspected renal toxicity and compared serum creatinine with eGFR (Cockcroft-Gault and Modification of Diet in Renal Disease) before initiating TDF, at the time of stopping TDF, and the most improved value after stopping TDF. The median age of the patients was 56 years, the median duration of TDF exposure 30 months, the median eGFR at TDF initiation 74 ml·min−1·1.73 m−2, and most patients received protease inhibitors and had good virological control. At the time of TDF discontinuation, the eGFR (Modification of Diet in Renal Disease) had declined to 51, with subsequently improvement to 64 ml·min−1·1.73 m−2 (most improved value) and 58 ml·min−1·1.73 m−2 (most recent measurement). The authors conclude that TDF-associated renal toxicity was not fully reversible in 58% of subjects. Although this may be correct, it should be appreciated that many patients with reduced eGFR (<90 or <75 ml·min−1·1.73 m−2) may have underlying chronic kidney disease, the natural history of which may be progressive in nature. Consequently, over a 3-year period (30 months of TDF exposure and 5 months of recovery), eGFR declines that are observed in the setting of drug-induced renal injury may not recover fully after drug discontinuation when the underlying renal disease has progressed during this time. This would be more likely if drug exposure has been prolonged and if drug-induced kidney injury was insidious in onset. We propose that eGFR slopes may provide better insight into the potential reversibility of TDF-associated nephrotoxicity, as they allow estimation of the rate of CKD progression before TDF initiation, during TDF exposure, and after TDF discontinuation. We analyzed renal function using eGFR slopes in 843 patients who initiated TDF-containing cART, and of whom 26 (3.1%) developed CKD (defined as an eGFR <60 ml·min−1·1.73 m−2 for >3 months). Compared with patients who did not develop CKD, those who developed CKD were older (53.6 vs 39.9 years, P < 0.001) and had significantly lower eGFR at TDF initiation (69 vs 102 ml per minute, P < 0.001). In addition, 85% had other risk factors for CKD progression including underlying cardiovascular disease or exposure to other potentially nephrotoxic drugs.2 When changes in renal function over time were examined, patients who developed CKD already experienced modest eGFR decline (−2.3 ml·min−1·year−1) before TDF initiation. Accelerated decline in eGFR (median -8.5 ml·min−1·year−1) was observed during TDF exposure, with subsequent return to the pre-TDF eGFR slope of -2.2 ml·min−1·year−1 after TDF discontinuation. In patients who did not develop CKD, a similar, but much more modest decline in eGFR was observed (Table 1).TABLE 1: eGFR Slopes in Patients With and Without CKD (eGFR <60 mL·min− 1·1.73m−2 for >3 Months)Even though our data suggest that TDF-related renal toxicity may be largely reversible, it clearly is best avoided by monitoring changes in renal function over time. Although the optimal frequency of monitoring is unknown, the modest rate of renal disease progression in patients on TDF would support annual or biannual assessment of renal function. Although we agree with Wever et al1 that an eGFR >60 ml·min−1·1.73 m−2 may lead to consideration of TDF discontinuation, it may be important to identify those at greatest risk of TDF-associated renal toxicity, including those aged >50 (odds ratio: 5.4) and patients who have eGFR <75 ml·min−1·1.73 m−2 at TDF initiation (odds ratio: 17.2),2 and either avoid TDF if suitable alternatives are available, or use TDF with more close monitoring of renal function. Lucy J. Campbell, MSc Lisa Hamzah, MBChB Frank A. Post, MD PhD FCP(SA) Department of Renal Sciences King's College London School of Medicine, London, United Kingdom