The most recent guidelines from the European Association for the Study of the Liver (EASL) recommend ETV or tenofovir alafenamide (TAF) over ETV in CHB patients with renal insufficiency or its risk factors. Although there have been several studies reporting no difference in renal function between patients treated with TDF and those treated with ETV during a relatively short observation period,[14,15,24,25] TDF has the inherent potential to be nephrotoxic. Because TDF accumulates in the proximal tubule during its excretion through the kidney, it causes nephrotoxicity through direct proximal tubular cell and mitochondrial damage.[26,27] In this study, we confirmed that eGFR significantly decreased in the TDF group (AAPC −0.88%, p < .001) during the 6-year observation period after the commencement of AVT, in contrast to the ETV group wherein the eGFR was maintained (AAPC −0.09%, p = .322).
Our findings have several strengths. First, we provide robust evidence to support the above EASL guidelines based on real-world data, emphasizing that special attention needs to be paid to serial changes in renal function, especially in the group receiving TDF, given that AVT treatment is usually life-long.[16,17,28,29] Second, compared with previous studies, our study has the advantage of a longer follow-up duration (up to 6 years) and a larger sample size (n = 3033) from three independent academic teaching hospitals in a real-world setting. Furthermore, from a statistical perspective, we focused on annual changes in the eGFR. In fact, in most previous studies, the occurrence of CKD of or eGFR reduction by ≥20% was adopted as the major study endpoint.[16,24,30] However, given that the annual decline in eGFR among the TDF group, although progressive, was not so rapid, the actual number of events fulfilling the occurrence of overt CKD, i.e. eGFR<60 ml/min/1.73 m2 or eGFR reduction by ≥20% was very small (3.7%–6.8% in other studies; 3.7% in our study).[16,24,30] In such circumstances, there may be a statistically significant concern leading to the false negativity of the type II error. For this reason, we focused on the AAPC in eGFR during the long-term AVT, using Joinpoint regression and adopted a negative slope of the mean change in eGFR during the AVT (n = 681, 22.4%) as the major clinical endpoint in the logistic regression. To the best of our knowledge, this study is the first to assess AAPC in eGFR during long-term AVT in patients with CHB.
Notably, in contrast to the ETV group, even patients without diabetes mellitus or hypertension in the TDF group showed significantly decreased eGFR, with AAPCs of −0.80% and −0.87%, respectively. As expected, when diabetes mellitus or hypertension was present in the TDF group, the decline in eGFR showed a trend toward more accelerated patterns: an AAPC of −1.59% and −1.00%, respectively. Physicians should monitor patients' renal function more closely, considering that therapy with TDF is almost life-long. Although patients in the ETV group with diabetes mellitus or hypertension may also experience a significant decline in eGFR, this may be due to the natural history of the accompanying comorbidities rather than an ETV-related adverse event. Nevertheless, given that patients with CHB are aging, and their comorbidities (e.g., diabetes, hypertension, and chronic kidney disease) are also increasing,[9,31] the early recognition of individual risk factors and correspondingly careful monitoring are also required.
The eGFR decrease in patients receiving TDF occurred consistently every year after the first year of AVT. There are conflicting opinions regarding whether the renal impairment induced by TDF is prominent early since the beginning of AVT or progressive after several years of AVT. Therefore, further research is needed to investigate the timing of the development of renal toxicity in patients receiving TDF, its degree, and annual progress rate. Specifically, a long-term study of up to 10 years or longer is needed to determine whether the eGFR will continue to drop or there will be a quiescent period. This would provide an important clinical insight into whether TDF should be sustained or replaced with safer oral NUCs that is, ETV or TAF at a certain time point.
An eGFR <60 ml/min/1.73 m2 and a low albumin level at 1 year of AVT as well as hypertension were independent predictors of ongoing renal dysfunction in our study. Diabetes mellitus was a significant univariate predictor, but did not prove to be independently associated with ongoing renal dysfunction in the multivariate analysis; this is different from the general hypothesis that diabetes mellitus is a well-known risk factor for progression to CKD. This is most likely due to the multi-collinearity of diabetes with hypertension. Indeed, patients with diabetes mellitus were more likely to have hypertension than those without (31.6% vs. 6.9%; OR, 6.20; 95% CI, 4.57–8.42; p < .001). Consistent with the findings of previous studies, baseline eGFR <60 ml/min/1.73 m2 was a poor prognostic factor in our study,[24,32] indicating that more caution is required in such a population during follow-up. In addition, albumin synthesis decreases as a result of liver dysfunction in patients with chronic liver disease, and may lead to decreased effective intravascular blood volume, compensatory activation of the renin-angiotensin system and sympathetic nervous system, sodium and water retention, and finally, reduction in renal perfusion and eGFR.[33,34] Finally, the analyses of new biomarkers for CHB (e.g., serum quantitative hepatitis B surface antigen, serum hepatitis B core-related antigen, serum HBV-RNA, or specific HBV mutants), and for renal insufficiency (i.e., cystatin C, β2-microglobulin, or neutrophil gelatinase-associated lipocalin) may provide more precise predictions in the future.[13,35]
This study has several limitations. First, the retrospective design may have led to an inherent selection bias, which we tried to overcome by recruiting a homogeneous study population with a statistically reliable large sample size and event number, providing a longer follow-up duration, gathering data from multiple centers (three independent teaching hospitals), and applying optimized statistical approaches. Indeed, clinical characteristics at patients 1 year of AVT (i.e., age, male gender, liver cirrhosis, albumin, total bilirubin, creatinine, and eGFR by CKD-EP), and the proportion of patients with ongoing renal dysfunction, were statistically similar among three hospitals. However, additional studies are required to validate this hypothesis. Second, the Joinpoint regression method for assessment of eGFR through AAPC does not adjust other confounding factors for eGFR changes. Therefore, comparison between the changes of eGFR in ETV and TDF group may not be a firm data, and therefore, we further analyzed if AVT was an independent factor for ongoing renal dysfunction from a multivariate regression analysis. Finally, while eGFR showed a gradually decreasing pattern over the years, serum creatinine did not change significantly during the same time (Table S2). This phenomenon might be explained in several ways. Above all, since eGFR was calculated based upon age and gender in addition to creatinine, simple "creatinine' might not reflect the minute change or renal function. Furthermore, it might be in part due to the difference of units between eGFR and creatinine; the former has usually a double-digit value, whereas the latter has a value of <1 with one decimal place. Thus, it suggests that clinicians should monitor the occurrence and progress of renal dysfunction using calculated eGFR rather than creatinine, even though creatinine is more widely used in the routine practice.
In conclusion, compared with the ETV group, the TDF group experienced slow, but progressive renal dysfunction. Although the annual eGFR change was small in the TDF group, careful monitoring of renal function is necessary to allow timely intervention, especially in patients requiring life-long AVT.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author, if appropriate. The data are not publicly available due to privacy or ethical restrictions.
J Viral Hepat. 2022;29(4):289-296. © 2022 Blackwell Publishing