ETV and TDF are the two first-line NAs for preventing HBV recurrence after LT. However, limited data exist regarding the renal safety of TDF and ETV in liver transplant recipients, who are more susceptible to nephrotoxicity [7, 8, 18]. In the present study, we evaluated the renal effects of TDF and ETV in 804 liver transplant patients. Multivariable analysis showed that the risk of renal dysfunction was significantly higher in the TDF group than in the ETV group, and development of renal dysfunction after LT was independently associated with increased mortality. To our knowledge, this is the first nationwide cohort study evaluating the renal safety of TDF and ETV in liver transplant patients.
TDF, a prodrug of tenofovir diphosphate, is widely prescribed for the treatment of HIV and HBV infections. Although TDF is generally well tolerated, there are increasing concerns about its nephrotoxicity [9–11]. The mechanism of TDF nephrotoxicity involves mitochondrial toxicity in renal proximal tubule cells . There have been conflicting results regarding the effects of TDF on renal function. In HIV patients, the authors of a meta-analysis concluded that patients treated with TDF experienced a small but significant loss of renal function during treatment, compared with controls . However, findings in HIV patients should be extrapolated to other populations with caution because of HIV-associated nephropathy and concomitant use of antiretroviral agents .
In HBV patients, several randomized clinical trials have shown that TDF has no significant effects on renal function [24, 25]. In contrast, some real-world observational studies reported that TDF significantly increases the risk of renal dysfunction, compared with ETV [26, 27]. Possible reasons for these discrepancies include the use of different definitions for renal dysfunction and differences in inclusion/exclusion criteria. As a reflection of these conflicting results, recent international guidelines for selecting antiviral agents differ in their recommendations related to renal safety issues. The European Association for the Study of the Liver guidelines recommended selecting ETV or tenofovir alafenamide fumarate (TAF) over TDF for patients with an old age (> 60 years), eGFR < 60 mL/min per 1.73 m2, or albuminuria, as well as for patients receiving hemodialysis . By contrast, the American Association for the Study of Liver Disease guidelines suggest no preference for TDF or ETV regarding renal safety issues . Of note, there is a distinct paucity of data regarding the renal safety of TDF and ETV in liver transplant recipients, who are particularly susceptible to nephrotoxicity because of concomitant use of calcineurin inhibitors. Considering that liver transplant patients with HBV require lifelong use of antiviral agents in combination with calcineurin inhibitors, there is an urgent need for comprehensive research regarding the renal safety of these agents in this patient population [18, 19].
Our results suggest that TDF significantly increases the risk of renal dysfunction after LT. Previous studies revealed that older age, diabetes mellitus, low BMI, worse baseline renal function, and use of nephrotoxic agents are associated with TDF-induced nephrotoxicity [22, 28]. In agreement with these findings, we also found that older age, low BMI, and worse baseline renal function were significantly associated with renal dysfunction in liver transplant recipients. Therefore, TDF should be used with caution in these patients.
Renal dysfunction is a common and serious complication after LT [15, 16]. Despite advances in perioperative management and reduction of calcineurin inhibitor exposure, the risk of renal dysfunction following LT has substantially increased in the MELD era . Our data confirmed that the development of renal dysfunction after LT is significantly associated with increased mortality. Since post-LT renal dysfunction has a significant impact on patient survival, it is important to carefully evaluate the risk for renal dysfunction.
Despite its higher risk of renal dysfunction, TDF cannot be totally replaced by ETV . Prior exposure to other NAs increases ETV resistance, whereas TDF is effective for treating HBV strains resistant to ETV, lamivudine, telbivudine, or even multiple drugs [7, 8, 29]. Although TAF has shown better renal safety than TDF, limited data exist regarding its use in liver transplant recipients . Thus, TDF continues to have an important role in the treatment of liver transplant patients, and more attention should be given to patients at risk for renal dysfunction.
The present study has several limitations. First, as with any registry study, selection bias and confounders are the major limitations of this study. Although reimbursement criteria for ETV and TDF are identical in South Korea, patients at higher risk for renal dysfunction might be more likely to receive ETV rather than TDF. In addition, it is difficult to determine the specific effects of TDF on renal dysfunction in liver transplant patients receiving calcineurin inhibitors. To minimize potential confounding factors as much as possible, we adjusted for tacrolimus serum trough levels, as well as other well-known risk factors for renal dysfunction. Second, this study included a large number of living donor transplant recipients with a low MELD Na score. Thus, our results may not be generalizable to deceased donor transplant patients with a high MELD Na score. Third, we were unable to obtain data about tubular dysfunction, such as urinary β2 microglobulin and fractional excretion of phosphate. However, these tests are not commonly used in real-world practice.
Despite these limitations, the study design involving use of data from a nationwide registry has enabled us to analyse a large patient cohort. This study includes real-world clinical data in liver transplant patients receiving first-line antiviral agents with calcineurin inhibitors. Previous scientific evidence is limited regarding the renal safety of TDF in this patient population, which has resulted in inconsistencies between recent international guidelines. Thus, our data provide valuable insights into the renal safety of TDF in liver transplant recipients.
In conclusion, use of TDF in liver transplant recipients was associated with a higher risk of renal dysfunction, when compared with ETV. TDF should be used with caution in this patient population, especially in individuals with other risk factors for renal dysfunction.