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CLINICAL SCIENCE

Cumulative exposure of TDF is associated with kidney tubulopathy whether it is currently used or discontinued

Nishijima, Takeshia; Mutoh, Yoshikazua; Kawasaki, Yoheib; Tomonari, Kiyomia; Kikuchi, Yoshimia; Gatanaga, Hiroyukia; Oka, Shinichia for the ACC Study Team

Author Information
doi: 10.1097/QAD.0000000000001667

Abstract

Introduction

Tenofovir disoproxil fumarate (TDF), one of the nucleotide reverse transcriptase inhibitors, is a prodrug of tenofovir and is a widely used antiretroviral agent for the treatment of HIV-1 infection as part of antiretroviral therapy (ART) in both resource rich and resource-limited settings [1,2]. TDF is also effective for treatment of hepatitis B infection [3] and used for prevention of sexual transmission of HIV-1 in uninfected individuals as preexposure prophylaxis [4].

TDF is renally excreted by the kidney through both glomerular filtration and via active tubular secretion at the proximal tubules, but can cause renal proximal tubular damage which can lead to decrement in estimated glomerular filtration rate (eGFR) and reduced bone mineral density [5–8]. The observed TDF-associated tubulopathy and renal dysfunction is thought to be because of mitochondrial toxicity in renal proximal tubular cells [9,10].

In TDF-induced nephrotoxicity, kidney tubular dysfunction (KTD) precedes decrement in renal function, indicating that tubular markers are more sensitive than eGFR calculated by serum creatinine [7,11,12]. Indeed, our group reported previously that measurement of urinary β2 microglobulin, a classic marker of tubular function, can predict long-term renal dysfunction in HIV-1-infected patients who started TDF-containing ART [13]. Other investigators also showed that tubular biomarkers are useful for early detection of acute kidney injury and renal function decrement in the general population [14] and HIV-1-infected patients [15,16], respectively. Only a few studies have analyzed the association between duration of TDF exposure and KTD [17–19]. Furthermore, little data are available from real-world settings whether patients with cumulative TDF exposure are at risk for KTD even after discontinuation of TDF. This is a clinically important question because KTD is a predictor of future renal function decrement [13,15] and a large number of HIV-1-infected patients have been and will be exposed to TDF in the future, although TDF use will likely phase out especially in resource-rich settings, following the advent of tenofovir alafenamide (TAF), another prodrug of tenofovir with favorable kidney and bone profiles [1,6].

Based on the above background, the present study was designed to investigate the association between KTD and cumulative TDF exposure in HIV-1-infected patients, especially focusing whether such association persists after discontinuation of TDF.

Methods

Study design and patients

We performed a cross-sectional study at AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo. The inclusion criteria were HIV-1-infected patients who gave a written informed consent for this study and those who visited our clinic between September and December 2016 and conducted protocol-defined blood and urine tests. We excluded patients aged less than 20 years and those with missing data on protocol-defined kidney tubular markers. This study aimed to enroll 1000 patients based on the scale of previous studies and research budget. The study was approved by the Human Research Ethics Committee of National Center for Global Health and Medicine, and was conducted according to the principles expressed in the Declaration of Helsinki.

Measurements

Protocol-defined blood and spot urine tests were conducted on the same day and the following clinical data were collected from the medical record: duration of TDF use, history of TDF use, current TDF use, time from the diagnosis of HIV-1 infection, duration of ART, current ART regimen, age, sex, height, body weight, BMI, history of AIDS [20], HIV-1 transmission route, laboratory data (CD4+ cell count, HIV-1 viral load, serum creatinine, uric acid, phosphate, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, hemoglobin A1c) and urine data [creatinine, phosphate, uric acid, β2 microglobulin, and N-acetyl-β-D-glucosaminidase (NAG), albumin, protein, and urine dipstick test], and presence or absence of other medical conditions (concurrent nephrotoxic drugs; diabetes mellitus; hypertension; dyslipidemia; hepatitis B infection; hepatitis C infection; and smoking; see supplemental method, http://links.lww.com/QAD/B174, Supplemental Digital Content 1, http://links.lww.com/QAD/B174, which describes details of the definitions of variables and data collection/measurement).

Definition of KTD was predefined as the presence of at least two abnormalities among the following five parameters: fractional excretion of phosphate (FEIP) {[(urine phosphate × serum creatinine)/(serum phosphate × urine creatinine)] × 100} more than 18%, fractional excretion of uric acid (FEUA) {[(urine uric acid × serum creatinine)/(serum uric acid × urine creatinine)] × 100)} more than 15%, β2-microglobulinuria (>1000 μg/g), high urinary NAG level in urine (NAG >5.93 U/g), and nondiabetic glycosuria defined as plasma glucose less than 126 mg/dl and urine glucose at least 1 and above by urine dipstick test [21,22]. Another tubular marker, tubular proteinuria was defined as proteinuria of more than 200 mg/g with a urine albumin-total protein ratio of less than 0.4 [23].

eGFR was calculated using the Japanese equation based on standardized serum creatinine, sex, and age, developed by the Japanese Society of Nephrology [24]. This equation performs better than the Chronic Kidney Disease Epidemiology Collaboration equation [25] in patients with small body stature, such as Japanese [8,26,27].

Statistical analysis

The study patients were categorized into three groups: current TDF users, those who discontinued TDF (past TDF users), and those who never used TDF (never TDF users). Characteristics of the patients were compared using the Kruskal–Wallis test for continuous variables and χ2 test for categorical variables.

A logistic regression model was used to estimate the effect of cumulative TDF exposure on KTD; two main analyses were performed. First, patients were categorized into current TDF users, past TDF users, and never TDF users, and uni and multivariate analyses were conducted. Basic demographics and related variables were incorporated into the univariate logistic regression model to estimate the association with KTD, and basic demographics, such as age and sex, established risk factors for KTD, such as diabetes mellitus and nephrotoxic drug use, and variables with P less than 0.05 in univariate analysis were incorporated into the multivariate model.

Second, patients were categorized into five groups; more than 5 years of TDF exposure and current TDF use, more than 5 years of TDF exposure and past TDF use, less than 5 years of TDF exposure and current TDF use, less than 5 years of TDF exposure and past TDF use, and no TDF exposure as reference, and the same multivariate model was constructed. Further analyses were conducted with cutoff values of 4, 3, and 2 years for the variable ‘duration of TDF exposure’ to estimate the effect of cumulative TDF exposure on KTD. Furthermore, alternative definition of KTD (the tubular marker with highest or lowest prevalence among the five markers was replaced with tubular proteinuria) was applied and the same logistic regression models were performed.

The correlation coefficient between cumulative TDF exposure and each tubular marker was evaluated with the Spearman test for markers with continuous value, and correlation ratio was evaluated for markers with dichotomous or ordinal values. We also constructed smoothing spline models where cross-validation was conducted to assess the coherence of spline fits across study participants to draw spline plots [28].

Statistical significance was defined with two-sided P value of less than 0.05. We used odds ratios (ORs) with 95% confidence intervals (95% CIs). All statistical analyses were performed with The Statistical Package for Social Sciences version 23.0 (Chicago, Illinois, USA), except for estimating spline plots for Fig. 1, which was conducted with SAS software, version 9.4 (SAS Institute, Cary, North Carolina, USA).

Fig. 1
Fig. 1:
Association between cumulative duration of TDF exposure and kidney tubular markers/number of abnormal tubular markers.Spline plot shows unadjusted association between duration of TDF exposure and each kidney tubular marker, calculated from generalized additive models. Solid line: predicted tubular marker level; shaded area: 95% confidence intervals. (a) Log-transformed urinary β2M, (b) FEIP, (c) nondiabetic glycosuria, (d) NAG, (e) FEUA, (f) number of abnormal tubular markers. β2M, β2 microglobulin; FEIP, fractional excretion of phosphate; FEUA, fractional excretion of uric acid; NAG, N-acetyl-β-D-glucosaminidase; TDF, tenofovir disoproxil fumarate.

Results

A total of 941 patients fulfilled the inclusion and exclusion criteria and were enrolled in the study (see supplemental Figure, http://links.lww.com/QAD/B174, Supplemental Digital Content 2, http://links.lww.com/QAD/B174, which describes patient enrollment). Their characteristics were very similar to those of the 1049 patients who visited our clinic during the study period but were not enrolled with regard to sex, age, race, CD4+ cell count, percentage of patient with suppressed HIV viremia, route of HIV-1 transmission, percentage of patients who were using TDF at the time of the study and who had history of TDF use, and eGFR (data not shown). Of the 941 patients, 882 (94%) were men with median age of 45 (interquartile range 40–54), and 927 (99%) were Asians (Table 1). In total, 80% were infected with HIV-1 through homosexual contact, and 922 (98%) patients were on ART and 94% had HIV-1 viral load of less than 50 copies/ml. 604 (64%) patients had ever used TDF, including 371 (39%) patients who were currently taking TDF and 233 (25%) who had discontinued TDF. Three hundred and thirty-seven (36%) patients had never used TDF. In total, 274 (29%) patients used TDF for more than 5 years, and of these, 199 (73%) continued to use TDF at study enrolment. For patients who discontinued TDF, the median time from discontinuation to enrolment was 1.2 years (0.2–3.6).

Table 1
Table 1:
Characteristics and tubular function according to status of tenofovir disoproxil fumarate use.

One hundred and sixteen patients (12%) had at least two abnormal tubular functions and satisfied the criteria for KTD. Thus, in this study prevalence of KTD was 16, 14, and 7% among current TDF users, past TDF users, and never TDF users, respectively (Table 1). Among the five tubular markers, prevalence of high NAG value was highest (29%), followed by high β2M (14%), high FEIP (12%), high FEUA (3%), and nondiabetic glycosuria (2%). On the other hand, protocol-defined tubular proteinuria was present in 4% of the patients.

As the number of abnormal tubular marker increased, patients were more likely to be currently using TDF and exposure to TDF was longer; also, patients were older, the CD4+ cell count and eGFR were lower, body weight was lighter, and were more likely to have diabetes mellitus and hypertension (Table 2). Other biomarkers, such as tubular proteinuria, urinary albumin, and protein also increased with increased number of abnormal tubular markers.

Table 2
Table 2:
Characteristics of the patients according to the number of markers positive for tubular dysfunction.

Using never TDF use group as reference, univariate analysis showed that both current TDF use (OR 2.4, 95% CI 1.44–3.87, P = 0.001), and past TDF use (OR 2.0, 95% CI 1.14–3.45, P = 0.015) were significantly associated with KTD (Table 3). Also, longer duration of TDF exposure (per 1-year increase, OR 1.1, 95% CI 1.08–1.20, P < 0.001) and more than 5 years of TDF exposure (OR 2.2, 95% CI 1.48–3.28, P < 0.001) were associated with KTD. Among those who discontinued TDF, the time from TDF discontinuation to the study enrolment was not associated with KTD (per 1-year increase, OR 1.1, 95% CI 0.98–1.24, P = 0.11). Apart from TDF-related variables, older age, history of AIDS, hypertension, and longer time from diagnosis of HIV-1 infection were associated with KTD, whereas heavier body weight, higher eGFR, and higher current CD4+ cell count were inversely associated with KTD (Table 3).

Table 3
Table 3:
The association between the status of tenofovir disoproxil fumarate use and kidney tubular dysfunction: multivariate analysis.

In the multivariate analysis, both current TDF use (OR 3.6, 95% CI 2.07–6.21, P < 0.001) and past TDF use (OR 2.5, 95% CI 1.36–4.51, P = 0.003) were significantly associated with KTD, using never TDF use as a reference (Table 3). Adjusted for the same variables, more than 5 years of TDF exposure (OR 2.4, 95% CI 1.54–3.66, P < 0.001) and longer duration of TDF exposure (per 1-year increase, OR 1.2, 95% CI 1.09–1.23, P < 0.001) were associated with KTD.

Furthermore, more than 5 years of TDF exposure and current TDF use (OR 4.4, 95% CI 2.46–7.99, P < 0.001), more than 5 years of TDF exposure and past TDF use (OR 2.4, 95% CI 1.08–5.39, P = 0.032), less than 5 years of TDF exposure and current TDF use (OR 2.5, 95% CI 1.24–4.98, P = 0.011), and less than 5 years of TDF exposure and past TDF use (OR 2.4, 95% CI 1.25–4.84, P = 0.009) were all significantly associated with KTD, with never TDF use as the reference in multivariate analysis (Table 4).

Table 4
Table 4:
The association between kidney tubular dysfunction and more than 5, 4, 3, and 2 years of tenofovir disoproxil fumarate use with current status of tenofovir disoproxil fumarate use: multivariate analysis.

The results were the same using 4 years or 3 years of TDF exposure as the cutoff value (Table 4). However, the model with 2 years of TDF exposure as the cutoff value showed that both less than 2 years of TDF exposure and current TDF use (OR 2.2, 95% CI 0.82–6.14, P = 0.12) and less than 2 years of TDF exposure and past TDF use (OR 1.9, 95% CI 0.74–5.05, P = 0.18) were not significantly associated with KTD, whereas both more than 2 years of TDF exposure and current TDF and more than 2 years of TDF exposure and past TDF use were associated with KTD (Table 4).

Additional analyses using the multivariate model applying the two alternative definitions of KTD (one replacing NAG with tubular proteinuria as one of five tubular markers and the other replacing nondiabetic glycosuria with tubular proteinuria) yielded very similar results; current TDF use and past TDF use, longer duration of TDF use, and more than 5 years of TDF exposure were all significantly associated with KTD; with 5, 4, and 3 years of TDF exposure as the cutoff value, regardless of current TDF use and duration of TDF exposure, patients with any TDF use were associated with KTD [except for those with more than 5 years of TDF exposure and past TDF use were only marginally associated with KTD; see Table S1, Supplemental Digital Content 3, http://links.lww.com/QAD/B174, which describes the association between KTD and more than 5, 4, 3, and 2 years of TDF use with current status of TDF use applying alternative definition of KTD (replacing NAG with tubular proteinuria), and Table S2, Supplemental Digital Content 4, http://links.lww.com/QAD/B174, which describes the association between KTD and more than 5, 4, 3, and 2 years of TDF use with current status of TDF use applying alternative definition of KTD (replacing nondiabetic glycosuria with tubular proteinuria)], whereas the use of 2 years as the cutoff value showed that less than 2 years of TDF exposure and current TDF was associated with KTD and less than 2 years of TDF exposure and past TDF use were not associated with KTD.

Figure 1 shows unadjusted association of cumulative TDF exposure with each urinary tubular marker. Cumulative use of TDF was significantly associated with β2 microglobulin (r = 0.33), FEIP (r = 0.20), and FEUA (r = 0.21), but not with NAG or nondiabetic glycosuria. Also, the number of abnormal tubular markers was significantly associated with cumulative TDF exposure (P < 0.0001, r = 0.14). Spline plots showed positive slopes for the association between cumulative TDF exposure and β2 microglobulin, FEIP, FEUA, and number of abnormal tubular markers.

Discussion

The results of this cross-sectional study showed strong and robust association between cumulative TDF exposure and KTD; the variables such as current TDF use and past TDF use (with never TDF use as reference), more than 5 years of TDF exposure, and longer duration of TDF use were all significantly associated with KTD in all multivariate models constructed in this study. Among the predefined five tubular markers for tubulopathy, three markers were linearly associated with cumulative TDF exposure, and the number of abnormal tubular markers was also linearly associated with cumulative duration of TDF exposure (Fig. 1). Interestingly, compared with never TDF users, long-term use of TDF followed by its discontinuation was significantly more likely to be associated with KTD, especially when used for more than 2 years. This finding might suggest that TDF-related KTD persists after discontinuation of TDF when the use exceeds 2 years. This is important considering that KTD is an early marker for future decrement in renal function [13–16].

The present study has three important strengths. First, it showed that the cumulative TDF exposure, regardless of current use of TDF, is strongly and robustly associated with KTD. This was shown with use of predefined definition of KTD using five tubular markers and also with alternative definitions of KTD replacing a tubular marker with highest or lowest prevalence with tubular proteinuria. This is important considering the definition of KTD in previous studies included haphazard combination of tubular markers and differed in each study [17,18,29]. It is particularly noteworthy that patients who had used TDF but discontinued were more likely to present with KTD than never TDF users, if cumulative exposure of TDF exceeded 2 years, even though never TDF users were more likely to have risk factors for KTD such as older age, hypertension, dyslipidemia, diabetes mellitus, longer time from HIV-1 diagnosis, and longer duration of ART than past TDF users [17,29,30] (Table 1). The above findings raise concern about reversibility of TDF-associated KTD in patients who discontinued or planned to discontinue TDF, especially considering that many patients have or will switch TDF to TAF as TAF becomes widely available in resource-rich setting.

Second, to our knowledge, this study enrolled the largest number of HIV-1-infected patients in whom a multitude of tubular markers were analyzed to evaluate tubulopathy [16–18,22]. It is also noteworthy that the study included a large number of never TDF users (n = 337), allowing us to perform various statistical comparisons between the groups. On the other hand, the cross-sectional study of Casado et al.[17] on 248 patients also evaluated the association between TDF use and prevalence of KTD. In comparison to our study, they included only a small number of patients who had either discontinued TDF (n = 26) or never TDF users (n = 22), making it difficult to perform appropriate comparisons between the groups, especially considering that 50% of never TDF users were treatment naïve for HIV-1.

Third, the association between each tubular marker and cumulative duration of TDF exposure were tested and spline plots were constructed. The results showed that, although association was weak, the duration of TDF exposure was significantly associated with β2 microglobulin, FEIP, and FEUA, but not with NAG and nondiabetic glycosuria (Fig. 1). To our knowledge, this is also the first study to show that the cumulative duration of TDF exposure was associated with the number of abnormal tubular markers (Fig. 1). Although the correlation coefficient is not very high (r = 0.14), the result that unadjusted association of cumulative TDF exposure with the number of abnormal tubular markers was significantly positive adds further support to the effect of cumulative TDF exposure on KTD.

With regard to the tubular markers, β2 microglobulin is considered a sensitive marker for TDF tubulopathy [11–13,31,32], and the present study further supports this finding. FEIP and FEUA, traditional tubular markers, were also found to be good markers for TDF tubulopathy (Fig. 1). On the other hand, NAG is not a sensitive marker of TDF tubulopathy, considering the lack of significant difference in the prevalence of high NAG value among the following three groups (current TDF users: 25%, past TDF users: 28%, never TDF users: 32%; Table 1).

Although clinical manifestations such as lipoatrophy and neuropathy caused by nucleotide reverse transcriptase inhibitor-induced mitochondria toxicity are difficult to reverse [33,34], whether TDF nephrotoxicity is reversible after discontinuation of TDF has been unknown and the results of few small studies that have examined this issue are contradictory [35–37]. However, Jose et al.[38] showed that a decline in the eGFR during TDF therapy was not fully reversible in one-third of patients from a large multicenter cohort in United Kingdom. The present study further adds a finding that the cumulative TDF exposure, regardless of current use of TDF, is strongly and robustly associated with KTD, to current knowledge on reversibility of TDF nephrotoxicity.

We need to acknowledge several limitations. First, the cross-sectional design allows estimation of association, but not causality. Also, possible residual confounding factors cannot be excluded despite the fact that the models were adjusted for multiple potential confounders. Second, there is no gold standard definition for KTD. The definition used in the present study as abnormality of at least two out of five tubular markers was used elsewhere [39], and the definition of KTD as at least multiple abnormal tubular markers among measured tubular markers has been commonly used in studies that evaluate TDF-associated tubulopathy, although they applied haphazard combination of tubular markers and measured tubular markers differed in each study [17,18,22,39,40]. There have also been a few studies which evaluated utility of a single tubular marker, such as urinary α1 microglobulin and β2 microglobulin, for TDF-associated KTD [13,19]. The present study selected five classic tubular markers (β2 microglobulin, FEIP, FEUA, NAG, and nondiabetic proteinuria) a priori, considering their common use in similar studies. It is notable that the results of the present study were confirmed irrespective of the terms used to define KTD (replacing a tubular marker with highest or lowest prevalence with tubular proteinuria). Third, the study population was mostly Asian men. Further studies are needed to confirm whether these findings are applicable to women and patients of other ethnic backgrounds.

In conclusion, this largest dataset of tubular markers of HIV-1-infected patients showed that the association between cumulative TDF exposure and KTD was strong and robust. Patients who used TDF for more than 2 years were significantly more likely to present with KTD even if they discontinued it later, compared with those who had never used TDF. This raises concern about reversibility of TDF-associated KTD in HIV-1-infected patients who had been treated with TDF.

Acknowledgements

The ACC Study Team included the following members:

Teruya Katsuji, Kunihisa Tsukada, Junko Tanuma, Ikumi Genka, Hirohisa Yazaki, Ei Kinai, Takahiro Aoki, Daisuke Mizushima, Taiichiro Kobayashi, Yasuaki Yanagawa, Haruka Uemura, and Shoko Matsumoto.

The authors thank Akiko Nakano, the study coordinator, and all other clinical staff at the AIDS Clinical Center for their help in completing the study.

T.N., H.G., and S.O. did the study design and conception. T.N., Y.M., K.T., Y. Kikuchi, H.G., and S.O. collected the data. T.N., and Y. Kawasaki, did the data management and the statistical analyses, and wrote first draft of article with help from H.G. and S.O. All authors participated in revising it critically for important intellectual content, and approved the final version for publication.

The work was supported by the Grant for National Center for Global Health and Medicine (25–106 and 27–6001), and a grants-in-aid of The IMAI MEMORIAL TRUST FOR AIDS RESEARCH.

Conflicts of interest

T.N. has received honoraria from MSD K.K., Janssen Pharmaceutical K.K., Torii Pharmaceutical, Co., and ViiV Healthcare, Co. Y.K. has received honoraria from Torii Pharmaceutical, Co. H.G. has received honoraria from MSD K.K., Janssen Pharmaceutical K.K., Torii Pharmaceutical, Co., and ViiV Healthcare, Co. S.O. has received honoraria and research grants from MSD K.K., has received honoraria from Torii Pharmaceutical, Co., Abbie GK, ViiV Healthcare, Janssen Pharmaceutical, and Japan Tobacco INC.

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* The ACC (AIDS Clinical Center) study team members are listed in the Acknowledgments section.

Keywords:

HIV-1 infection; kidney tubulopathy; tenofovir alafenamide; tenofovir disoproxil fumarate

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