In this large, national sample of predominantly male HIV-infected veterans receiving combination antiretroviral therapy, we found that exposure to tenofovir was associated with increased risk for proteinuria, rapid decline (a ≥3 unit annual decrease) in kidney function, and development of CKD. Even after accounting for demographics, HIV-related factors, comorbidities, and other antiretroviral drugs, tenofovir remained independently associated with elevated risk for each kidney disease outcome. These associations were in general similar across subgroups based on baseline comorbidities and characteristics, and few statistically significant interactions were observed. Presence of traditional CKD risk factors at baseline such as pre-existing CKD, diabetes, and hypertension did not appear to worsen the effects of tenofovir. Together, these findings provide strong evidence that tenofovir may cause clinically significant toxicity to the kidney that is not reversible.
It is noteworthy that tenofovir was associated with both proteinuria and CKD in our study. These outcomes are not highly inter-correlated, and each is independently
associated with cardiovascular disease and death in the setting of HIV infection.[3
] The primary mechanism by which tenofovir causes renal toxicity may involve drug accumulation within proximal renal tubules, leading to mitochondrial injury and depletion.[28
] Individuals with certain variants of the ABCC2
gene, the multidrug resistance protein which facilitates tenofovir efflux from proximal tubular cells, may be more prone to tenofovir toxicity.[29
] Furthermore, inhibition of tenofovir entry into proximal tubular cells via the organic anion transporter by probenecid prevents recurrent tenofovir renal toxicity.[30
] Consistent with this proposed mechanism of drug accumulation in the renal proximal tubule, most case reports describe tenofovir renal toxicity presenting as partial or full Fanconi syndrome characterized by sub-nephrotic proteinuria with or without hyperphosphaturia and normoglycemic glycosuria.[31
] However, tenofovir renal injury may also present as acute tubular necrosis,[34
] eventually leading to tubulointerstitial scarring, which may account for the lack of reversibility of tenofovir renal toxicity in some individuals.[5
Few previous large, nationally representative studies in HIV-infected patients have looked at associations of tenofovir with kidney disease outcomes. Tenofovir was the only antiretroviral drug that showed statistically significant associations with all three kidney disease outcomes in our study. A study of 10,343 patients designed to evaluate the safety of tenofovir over the first four years of use reported that less than 1% of patients experienced a serious renal adverse event;[35
] however, all subjects were taking tenofovir, so its effects on renal function could not be compared with other drugs.
A recent longitudinal study of 6,843 HIV-infected persons found that tenofovir, indinavir, and atazanavir were associated with a higher incidence of CKD, even after controlling for traditional CKD risk factors and other antiretroviral drugs.[36
] In our study, atazanavir was associated with increased risk of rapid decline, but not with CKD.
By contrast, efavirenz was associated with a lower risk of both proteinuria and CKD. Similarly, a recent prospective study of 62 HIV-infected patients found lower rates of proteinuria and higher levels of eGFR among those who were treated with tenofovir/lamivudine/efavirenz compared to those treated with tenofovir/lamivudine/nevirapine.[37
] Mechanisms accounting for this potential beneficial effect of efavirenz are unknown.
Among those who discontinued tenofovir use in our study, time following cessation was not significantly associated with either higher or lower risks of proteinuria, or rapid decline, and appeared to be weakly associated with increased CKD risk. Past users of tenofovir remained at increased risk of outcomes, compared to those never exposed to tenofovir. Proteinuria appeared to be similarly persistent among users, current and former, as non-users, suggesting that TDF-induced proteinuria is not uniquely transient. A small study of HIV-infected men found little recovery on average in eGFR following tenofovir cessation.[10
] Similarly, both current and past tenofovir use were associated with increased risk of proximal renal tubular dysfunction in a cross-sectional study of 399 HIV-infected persons.[38
] These findings suggest that kidney damage and loss of function do not quickly reverse after cessation of tenofovir use.
A major strength of our study is the large number of participants, which gave us power to detect relatively small hazard ratios for the risk of renal outcomes per year of tenofovir exposure. Previous studies may have been less powered to detect statistically significant associations between tenofovir use and kidney disease. Assuming 5 years of follow-up and a type I error rate of 5% with equal allocation to treatment arms (tenofovir versus no tenofovir), a study would need to enroll 3,544 participants to achieve 80% power to detect a hazard ratio of 1.3 or greater (the TDF effect observed in our study for CKD and proteinuria).
Study limitations include our inability to measure GFR directly, similar to all large studies of kidney disease. There may have been incomplete or inadequate control for factors that may confound or explain the association between tenofovir and kidney disease. However, we utilized marginal structural models to account for the possibility that the decision to prescribe a particular antiretroviral drug may change over time due to changes in a patient’s covariates. Mean exposure to tenofovir in our study was 1.3 years, and among those who discontinued tenofovir, mean follow-up time was 1.2 years; this limits our ability to extrapolate risk of longer exposure. Antiretroviral drugs other than tenofovir showed inconsistent associations with kidney disease risk; the few results reaching statistical significance may be due to chance despite meeting the conventional cutoff for statistical significance. Prospective studies should be undertaken to validate our findings. Additionally, our results may not generalize to non-veterans, women, or patients not receiving regular clinical care. However, our population includes those who are often excluded from clinical trials and do not qualify or volunteer for cohort studies. Finally, our analyses excluded patients with inadequate data collection, and these persons on average were healthier than patients included in our study; we cannot discern whether this would have a bias on our findings.
In conclusion, this large, national sample of 10,841 HIV-infected persons indicates that tenofovir is associated with increased risk of proteinuria, rapid decline, and CKD. Clinicians treating HIV-infected patients should recognize that while traditional risk factors such as hypertension, older age, and diabetes may increase the risk for kidney disease, tenofovir is associated with elevated risk even in patients without pre-existing kidney risk factors. Despite tenofovir’s association with progressive kidney disease, it is an important component of effective antiretroviral therapy that may be required in many patients to control viral load. The balance between its efficacy and probable adverse effects requires further study.