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. 2023 May 18;55(2):226–236. doi: 10.3947/ic.2023.0001

Incidence and Risk Factors of Tenofovir Disoproxil Fumarate Induced Nephrotoxicity and Renal Function Recovery, a Hospital Case-Control Study

Sirikan Srisopa 1,2, Akarawat Kornjirakasemsan 3, Pornpit Treebupachatsakul 4, Paveena Sonthisombat 2,✉
PMCID: PMC10323539  PMID: 37272235

Abstract

Background

The incidence of tenofovir disoproxil fumarate (TDF)-induced nephrotoxicity ranges from 15.8 to 19.3 percent. Following cessation of TDF, approximately one-half of patients with nephrotoxicity regained full renal functions. This study aimed to determine the incidence and risk factors for nephrotoxicity, as well as the complete recovery of renal function, in human immunodeficiency virus (HIV)-infected patients receiving TDF regimens.

Materials and Methods

This was a retrospective case-control study of HIV-positive patients who received TDF regimens from 2 tertiary hospitals between 2012 and 2018. Signs of TDF-induced renal dysfunction, defined as having estimated glomerular filtration rate (eGFR) decline of greater than 25%, and proximal renal tubulopathy (PRT) were followed for 48 months. After discontinuing TDF due to nephrotoxicity, the renal parameters of patients were monitored for 48 months. Univariate and multivariate regression analyses were used to determine the factors associated with TDF-induced nephrotoxicity and renal function recovery.

Results

Twelve percent of 3,214 TDF-treated patients were diagnosed with renal dysfunction, whereas 303 patients (15.20%) were diagnosed with PRT. TDF-induced renal dysfunction was associated with older age (odds ratio [OR] = 2.851), smoking (OR = 1.972), and TDF use for more than 3 years (OR 1.928). Receiving trimethoprim-sulfamethoxazole (TMP/SMX) or nonsteroidal anti-inflammatory drugs (NSAIDs) and being elderly were associated with PRT (OR = 4.727, 4.313, and 3.357, respectively). Following the discontinuation of TDF, 12.96% of patients regained full renal function. Elderly patients and those taking renin-angiotensin-aldosterone system (RAAS) inhibitors or protease inhibitors (PIs) had a lower likelihood of full recovery (OR = 0.811, 0.793, 0.582, respectively). One-third experienced PRT recovery, whereas RAAS inhibitors use, old age, and receiving PIs decreased the likelihood of PRT recovery (OR = 0.709, 0.504, 0.311, respectively). TDF cessation at an eGFR greater than 60 mL/min/1.73 m2 increased the likelihood of renal function recovery and PRT by 4.07 and 2.11 times, respectively.

Conclusion

Twelve percent and 15 percent of patients receiving TDF developed renal dysfunction and PRT, respectively. Age, TMP/SMX, NSAIDs, and long-term TDF exposure were independent risk factors for TDF-induced nephrotoxicity. Thirteen and thirty-three percent of patients with renal dysfunction and PRT recovered from their conditions, respectively. The discontinuation of TDF at an eGFR greater than 60 mL/min/1.73 m2 was advantageous for the recovery of renal function and PRT.

Keywords: Tenofovir disoproxil fumarate, Nephrotoxicity, Proximal tubular dysfunction, Recovery of renal function

Graphical Abstract

graphic file with name ic-55-226-abf001.jpg

Introduction

Tenofovir disoproxil fumarate (TDF) is one of a backbone drug for human immunodeficiency virus (HIV) infection treatment regimens, as recommended by the World Health Organization (WHO), Department of Health and Human Services (DHHS), European AIDS Clinical Society (EACS), Korean Society for AIDS, and Department of Disease Control, Ministry of Public Health, Thailand, and other national organizations [1,2,3,4,5]. There were many reports of nephrotoxicity after prolonged use of TDF, and the reported incidence of TDF ranged from 0.6% to 17.7% [6,7,8,9,10,11,12,13,14,15]. According to the Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia) and the HIV Observational Database (TAHOD), after 2.07 years of drug usage, 4.2% of 2,425 TDF-treated patients had an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2 or decreased by at least 30% relative to the baseline value [6]. Currently, available data on TDF-induced nephrotoxicity is linked to proximal tubular dysfunction. With drug-drug interactions, organic anion transporters (OAT) and multidrug resistance proteins (MRP) at the proximal tubule cells accumulate more TDF [16,17]. However, studies did not adhere to the same diagnostic criteria for TDF-induced nephrotoxicity. The most common indicator of nephrotoxicity was a reduction in eGFR to less than 25.0 – 50.0% of the pretreatment value or less than 30 - 90 mL/min/1.73 m2. Recently, the presence of proteinuria, albuminuria, metabolic acidosis, glucosuria, phosphaturia, hypokalemia, and/or hypophosphatemia has been required to identify proximal tubular dysfunction, whereas serum creatinine (SCr) and creatinine clearance (CrCl) declines have become obsolete. Within 22 (13 - 49.5) months of discontinuing TDF due to nephrotoxicity, 59.0% of the patient's renal parameters, including serum creatinine, serum phosphate, urine phosphate, and urine glucose, returned to normal, 9.8% improved but did not return to normal, and 31.2% remained unchanged [18]. In a recent study conducted in Korea, after switching from TDF to tenofovir alafenamide fumarate (TAF), 57.9% of the patients exhibited some level of renal function recovery, 26.3% were above the baseline level, and 26 (86.6%) had recovered from tubulopathy [19]. The review found that the following factors contributed to TDF-induced nephrotoxicity: age over 50 - 60 years old, underweight, long-term exposure to TDF, and concurrent use of nephrotoxic drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and protease inhibitors (PIs) [6,9,10,11,12,20]. The discontinuation of TDF at an eGFR less than 60 mL/min/1.73 m2 resulted in a 13.18-fold increase in the incomplete recovery of renal functions [21]. Although TDF-induced nephrotoxicity has been evaluated in a large number of studies, the majority of them have consisted of small sample sizes or short-term monitoring. Consequently, there is limited evidence of their actual clinical impact. Moreover, there is a paucity of information regarding the variables that affect the recovery of renal function in patients. Thus, we investigated the incidence and factors influencing TDF-induced nephrotoxicity and the recovery of renal function.

Materials and Methods

1. Study design

This was a two-phase, case-controlled study that collecting electronic data of TDF-treated patients who visited outpatient clinics at two tertiary hospitals between 2012 and 2018. After TDF initiation and discontinuation, the renal parameters of patients were monitored for 48 months.

2. Ethics statement

The study was approved by the Institutional Review Board of Naresuan University (IRB No. 661/2018), Buddhachinaraj Phitsanulok hospital (IRB No. 002/62), and Nakornping hospital (IRB No. 035/62). As this was a retrospective study, patient informed consent was not obtained.

3. Outcomes and definitions

The primary outcome measure was the incidence of TDF-induced nephrotoxicity, which was categorized as renal dysfunction and proximal renal tubulopathy (PRT).

1) TDF-induced nephrotoxicity

Patients with HIV infection according to ICD-10 codes B20, 21, 22, and 24 who were at least 20 years old and had received a TDF-containing regimen for at least 3 months met the inclusion criteria. Patients with co-infected hepatitis B and/or C were permitted to participate in the study. After TDF administration, the eGFR of the patient was monitored every 3 to 4 months for 48 months. Time to renal dysfunction was defined as the interval between the initiation of TDF and the decline in eGFR to greater than 25% of the pretreatment level. The renal dysfunction case group included patients whose eGFR decreased by more than 25% of the pretreatment value for no discernible reason. The patients who did not meet the criteria for renal dysfunction constituted the control group. Time to PRT was defined as the interval between the initiation of TDF and the discovery of abnormal PRT findings (see definition of PRT). A patient was considered to have PRT if any two of the following abnormalities were present: phosphaturia (fractional excretion of phosphate [FePi] >20%), uricosuria (fractional excretion of uric acid of >10%), normoglycemic glycosuria (a urine dipstick reading of ≥1+ with blood glucose <180 mg/dl), and proteinuria (urinary reagent strips reading of ≥1+). The specified laboratory values were monitored every 6 months until a PRT event occurred or TDF treatment lasted 48 months. The control group consisted of patients who did not meet the PRT criteria.

2) Recovery of renal dysfunction

When patients were diagnosed with renal dysfunction or PRT, TDF was discontinued and replaced with an alternative antiretroviral agent. The eGFR was then monitored every 3 - 4 months for 48 months.

Recovery from renal dysfunction was separated into two groups: complete and incomplete recovery.

Time to complete renal function recovery was defined as the interval between TDF cessation and eGFR returning to at least 95% of stable pre-TDF levels.

Complete renal function recovery was defined as the eGFR returning to at least 95.0% of pre-TDF treatment levels and remaining stable since then. Incomplete renal function recovery was defined as the eGFR not meeting the criteria for complete recovery within 48 months of follow-up.

Time to PRT recovery was defined as the time between cessation of TDF and normalization of abnormal tubular function markers.

Recovery from PRT was defined as the return of abnormal tubular function markers to normal levels, whereas no recovery was the failure to meet the criteria for full recovery within 48 months.

The secondary outcome were the factors that contributed to nephrotoxicity and renal function recovery.

4. Statistical analyses

This study was designed as a case-control study. Based on the Nishijima study (22) with a 22.1% of the incidence of TDF-induced eGFR decline of at least 25.0% and a 20.0% required error margin, it was estimated that each group would need a minimum of 372 participants. The demographic and clinical characteristics of the sample were described by percentage, mean, and median values. The Chi-square test, the Fisher exact test, and the Student t-test were used to appropriately analyze variables appropriately. Wilcoxon sign-rank test was used to compare the serum creatinine levels or eGFR, proteinuria, glucosuria, and phosphaturia events prior to and after TDF administration. To determine the relationship between risk factors and TDF-induced nephrotoxicity, as well as between risk factors and renal function recovery, odds ratios (OR) with 95% confidence intervals (CI) were calculated. All covariates with a P-value < 0.10 in the univariate regression analysis were considered for inclusion in the multivariate regression analysis, where P-value <0.05 was considered statistically significant. The SPSS (version 17, SPSS, Inc., Chicago, IL, USA) was utilized for statistical analysis. P ≤0.05 (two-sided) was deemed statistically significant.

Results

1. Patient characteristics in the TDF-induced nephrotoxicity study

Included were 3,214 TDF-treated patients, of whom 2,224 and 990 were from Buddhachinaraj Phitsanulok and Nakornping hospitals, respectively. On account of TDF exposure, renal dysfunction and proximal tubular dysfunction were detected in 378 (11.76%) and 303 (15.20%) participants, respectively (Table 1). On average, renal dysfunction and PRT manifested at 39.72 and 37.23 months, respectively. In each group, the average age, weight, and body mass index were identical. Patients with renal dysfunction and renal tubular dysfunction had a significantly higher prevalence of smoking and alcohol dependence compared to those without these conditions. Approximately 95% of patients were on non-nucleoside reverse transcriptase inhibitor regimens, but only two-thirds of each group was TDF-naïve. Serum creatinine and eGFR levels at baseline were normal for all patients. Over eighty percent of each group had undetectable levels of HIV RNA despite varying CD4 counts. The prevalence of patients with dyslipidemia, hypertension, and diabetes was higher among those with renal or renal tubular dysfunction. Trimethoprim-sulfamethoxazole (TMP/SMX), renin-angiotensin-aldosterone system (RAAS) inhibitors, and NSAIDs were more frequently co-administered in patients with renal dysfunction and PRT (Table 1).

Table 1. Demographic and laboratory baseline data for TDF recipients.

Variables Patient with renal dysfunction (n = 378) Patient without renal dysfunction (n = 2,836) P-value Patient with PRT (n = 303) Patient without PRT (n = 1,690) P-value
Demographics
Age, years (mean ± SD) 43.84 ± 10.46 38.51 ± 10.41 0.105 43.24 ± 10.37 37.95 ± 10.06 0.273
Female gender, % 44.59 44.06 0.088 41.64 49.50 0.033
Weight, kg (mean ± SD) 57.73 ± 11.51 58.48 ± 11.68 0.898 58.18 ± 11.77 59.39 ± 11.88 0.188
BMI, kg/m2 (mean ± SD) 21.82 ± 3.39 22.04 ± 3.91 0.297 21.88 ± 3.51 21.98 ± 3.96 0.078
Smoking, n (%) 126 (33.33) 396 (13.96) <0.001 124 (40.92) 202 (11.95) <0.001
Alcohol dependence, n (%) 146 (38.62) 486 (17.14) <0.001 134 (44.22) 245 (14.50) <0.001
Antiretroviral therapy
TDF naïve, n (%) 264 (69.84) 1,921 (67.74) 0.057 208 (68.65) 1,115 (65.98) 0.057
TDF use duration, months (mean ± SD) 39.72 ± 8.46 48.00 0.072 37.23 ± 10.77 48.00 0.053
PI-based, n (%) 12 (3.17) 108 (3.81) 0.127 14 (4.62) 111 (6.57) 0.091
Laboratory data
SCr, mg/dL (mean ± SD) 0.83 ± 0.20 0.80 ± 0.87 0.069 0.82 ± 0.60 0.80 ± 0.20 0.398
eGFR, mL/min/1.73 m2 (mean ± SD) 106.45 ± 20.83 109.00 ± 16.70 <0.001 105.90 ± 20.42 106.58 ± 15.62 0.051
Triglyceride, mg/dL (mean ± SD) 202.21 ± 95.42 163.68 ± 82.43 <0.001 196.56 ± 94.42 156.58 ± 74.09 <0.001
LDL-cholesterol, mg/dL (mean ± SD) 120.48 ± 34.65 113.70 ± 39.01 0.730 122.77 ± 37.33 111.69 ± 36.74 0.352
HDL-cholesterol, mg/dL (mean ± SD) 53.24 ± 12.60 50.90 ± 12.63 0.707 52.37 ± 12.38 50.53 ± 12.84 0.732
CD4, cell/mm3 (mean ± SD) 383.65 ± 274.03 395.03 ± 241.02 0.141 397.95 ± 247.93 398.93 ± 251.42 0.236
Undetectable HIV RNAa, n (%) 306 (80.95) 2,256 (79.55) 0.845 252 (83.17) 1,396 (82.60) 0.064
Comorbidities
Dyslipidemia, n (%) 103 (27.25) 343 (12.09) <0.001 108 (35.64) 336 (19.88) <0.001
Hypertension, n (%) 102 (26.98) 452 (15.94) <0.001 101 (33.33) 236 (13.96) <0.001
Diabetes, n (%) 30 (7.94) 138 (4.87) 0.001 31 (10.23) 68 (4.02) <0.001
concurrent medications taken during TDF exposureb
TMP/SMX, n (%) 66 (17.37) 272 (9.59) <0.001 72 (23.76) 158 (9.35) <0.001
Fluconazolec, n (%) 40 (10.53) 292 (10.30) 0.116 47 (15.51) 166 (9.82) 0.012
RAAS inhibitors, n (%) 72 (18.95) 221 (7.79) <0.001 75 (24.75) 152 (8.99) <0.001
NSAIDs, n (%) 125 (32.89) 270 (9.52) <0.001 113 (37.29) 186 (11.01) <0.001
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aHIV RNA <40 copies/mL.

bMedication lists were extracted from the hospital outpatient prescription database. Concurrent medications were taken during TDF exposure.

cFluconazole 400 mg weekly for primary prophylaxis of cryptococcal meningitis.

TDF, tenofovir disoproxil fumarate; PRT, proximal renal tubulopathy; SD, standard deviation; BMI, body mass index; PI, protease inhibitors; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HIV, human immunodeficiency virus; TMP/SMX, trimethoprim-sulfamethoxazole; RAAS, renin-angiotensin-aldosterone system; NSAIDs, non-steroidal anti-inflammatory drugs.

2. Factors associated with TDF-induced nephrotoxicity

According to multivariate regression analysis, age over 60 years (OR = 2.851), smoking (OR = 1.972), duration of TDF use greater than 3 years (OR = 1.928), PI-based regimen (OR = 1.513), TMP/SMX exposure (OR = 1.500), concurrent NSAIDs use (OR = 1.466), and BMI less than 18 kg/m2 (OR = 1.475) increase the likelihood of TDF-induced renal dysfunction (Table 2). Intriguingly, taking TMP/SMX (OR = 4.727), using NSAIDs (OR = 4.313), being elderly (OR = 3.357), using TDF for more than three years (OR = 2.183), and smoking increased the risk of PRT as well. In addition, hypertension (OR = 1.993), and female gender (OR = 1.471) were identified as PRT risk factors.

Table 2. Univariate and multivariate logistic regression analyses of the variables associated with TDF-induced nephrotoxicity.

Variables Patients with renal dysfunction Patients with PRT
Univariate logistic regression Multivariate logistic regression Univariate logistic regression Multivariate logistic regression
Odd ratio (95% CI) P-value Odd ratio (95% CI) P-value Odd ratio (95% CI) P-value Odd ratio (95% CI) P-value
Female gender 0.800 (0.646 - 0.991) 0.041 0.992 (0.549 - 1.020) 0.062 1.374 (1.073 - 1.758) 0.012 1.471 (1.100 - 1.968) 0.009
Elderly (age >60 years old) 2.844 (1.704 - 4.747) <0.001 2.851 (1.660 - 4.897) <0.001 3.960 (2.244 - 6.990) <0.001 3.357 (1.643 - 6.857) 0.001
BMIa <18 kg/m2 1.553 (1.145 - 2.105) 0.005 1.475 (1.069 - 2.035) 0.018 1.207 (0.837 - 1.739) 0.313
CD4 a >200 cell/mm2 0.958 (0.747 - 1.229) 0.735 1.193 (0.888 - 1.604) 0.242
Undetectable HIV RNAa,b (<40 copies/mL) 0.581 (0.438 - 0.770) <0.001 0.527 (0.357 - 1.007) 0.061 1.281 (1.088 - 1.728) 0.011 1.002 (0.988 - 1.086) 0.051
TDF-naive 1.057 (0.846 - 1.321) 0.624 1.126 (0.957 - 1.892) 0.054 1.029 (0.861 - 1.297) 0.810
Duration of TDF use >3 years 2.031 (1.627 - 2.535) <0.001 1.928 (1.532 - 2.426) <0.001 2.206 (1.707 - 2.851) <0.001 2.183 (1.642 - 2.935) <0.001
Diabetes 1.320 (0.853 - 2.051) 0.212 2.700 (1.733 - 4.208) <0.001 1.514 (0.841 - 2.725) 0.167
Hypertension 1.713 (1.332 - 2.203) <0.001 1.387 (0.992 - 1.940) 0.056 3.052 (2.318 - 4.020) <0.001 1.993 (1.320 - 3.010) 0.001
Dyslipidemia 1.363 (1.073 - 1.732) 0.011 1.194 (0.895 - 1.594) 0.228 2.211 (1.699 - 2.877) <0.001 1.420 (0.988 - 2.039) 0.058
RAAS inhibitorsc use 1.758 (1.314 - 2.352) <0.001 1.148 (0.794 - 1.660) 0.463 3.302 (2.423 - 4.499) <0.001 1.497 (0.966 - 2.320) 0.071
TMP/SMXc use 1.676 (1.252 - 2.244) 0.001 1.500 (1.039 - 2.165) 0.030 2.998 (2.197 - 4.092) <0.001 4.727 (3.136 - 7.124) <0.001
NSAIDsc prescribed 1.979 (1.529 - 2.561) <0.001 1.466 (1.113 - 1.930) 0.006 4.762 (3.602 - 6.237) <0.001 4.313 (3.133 - 5.938) <0.001
PI-basedc regimen 1.496 (1.014 - 2.209) 0.042 1.513 (1.007 - 2.273) 0.046 0.685 (0.387 - 1.211) 0.193
Smoking 2.701 (2.122 - 3.438) <0.001 1.972 (1.327 - 2.930) 0.001 5.050 (3.849 - 6.626) <0.001 2.166 (1.367 - 3.432) 0.001
Alcohol dependence 2.325 (1.840 - 2.937) <0.001 1.337 (0.915 - 1.955) 0.134 4.625 (3.553 - 6.020) <0.001 2.478 (1.583 - 3.880) <0.001
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aData was collected within 6 months prior to the initiation of the TDF.

bHIV RNA <40 copies/mL.

c Pre-TDF and concurrent TDF medications were extracted from the hospital outpatient prescription database.

TDF, tenofovir disoproxil fumarate; PRT, proximal renal tubulopathy; CI, confidence interval; BMI, body mass index; HIV, human immunodeficiency virus; RAAS, renin-angiotensin-aldosterone system; TMP/SMX, trimethoprim-sulfamethoxazole; NSAIDs, non-steroidal anti-inflammatory drugs; PI, protease inhibitors.

3. Patient characteristics in the renal recovery study

Three hundred seventy-eight patients discontinued TDF due to an eGFR decline of more than 25.00%, and 303 participants met the criteria for PRT. Following TDF cessation for 48 months, 12.96% of patients' renal function returned to pre-TDF levels, whereas 33.33% of them recovered from PRT (Table 3). The time required to recover renal function and PRT was 26.72 ± 13.44 and 22.76 ± 9.03 months, respectively. At the time of TDF discontinuation, the complete and incomplete renal function recovery groups had comparable age, sex ratio, weight, BMI, lipid profile, CD4 counts, percent of those with undetectable HIV RNA, comorbidity diseases, and concurrent medications, including TMP/SMX, RAAS inhibitors, and NSAIDs. Surprisingly, the latter had lower serum creatinine levels (1.03 vs. 1.21 mg/dL) and a lower eGFR (59.57 vs. 53.54 mL/min/1.73m2) than the former. Additionally, the percentages of smokers and alcohol users were higher in the incomplete recovery group. The characteristics of the recovery and non-recovery PRT groups were similar, with the exception that the first group had a lower proportion of PI-based regimens (14.29 vs.18.27%) (Table 3).

Table 3. Demographic and laboratory data of patients at the time of TDF cessation.

Variables Complete recovery of renal function (n = 49) Incomplete recovery of renal function (n = 329) P-value Recovery of PRT (n = 101) No recovery of PRT (n = 202) P-value
Demographics at discontinuation of TDF
Age, years (mean ± SD) 42.62 ± 11.42 41.32 ± 16.99 0.051 41.45 ± 10.31 43.35 ± 15.01 0.071
Female gender, % 43.22 42.18 0.532 44.55 48.51 0.065
Weight, kg (mean ± SD) 64.54 ± 1.16 62.67 ± 1.35 0.673 61.64 ± 1.35 62.70 ± 1.79 0.630
BMI, kg/m2 (mean ± SD) 25.82 ± 1.75 24.28 ± 0.70 0.072 26.72 ± 3.75 25.88 ± 4.70 0.082
Smoking, n (%) 20 (40.82) 188 (57.14) 0.039 32 (31.68) 68 (33.66) 0.256
Alcohol dependence, n (%) 23 (49.94) 208 (63.22) 0.025 56 (55.45) 108 (53.47) 0.948
Laboratory data at discontinuation of TDF
SCr, mg/dL (mean ± SD) 1.03 ± 0.11 1.21 ± 0.23 0.048 0.99 ± 0.17 1.11 ± 0.12 0.051
eGFR, mL/min/1.73m2 (mean ± SD) 59.57 ± 16.21 53.54 ± 24.01 0.049 60.23 ± 12.91 59.54 ± 14.81 0.052
Triglyceride, mg/dL (mean ± SD) 267.54 ± 71.22 209.32 ± 81.52 0.290 259.34 ± 91.02 246.02 ± 49.69 0.340
LDL-cholesterol, mg/dL (mean ± SD) 113.69 ± 23.57 109.67 ± 56.47 0.411 116.65 ± 81.52 119.54 ± 61.79 0.598
HDL-cholesterol, mg/dL (mean ± SD) 55.84 ± 11.72 56.20 ± 11.98 0.821 57.84 ± 81.52 54.71 ± 9.90 0.807
CD4, cell/mm3 (mean ± SD) 416.29 ± 104.32 397.22 ± 147.22 0.568 411.29 ± 104.32 407.47 ± 97.12 0.460
Undetectable HIV RNAa, n (%) 43 (87.76) 298 (90.58) 0.079 89 (88.12) 183 (90.59) 0.064
Switching regimens
ABC/3TC, n (%) 39 (79.59) 251 (76.29) 0.056 90 (89.11) 169 (83.66) 0.064
AZT/3TC, n (%) 10 (20.41) 74 (22.49) 0.091 11 (22.45) 33 (16.34) 0.071
Switching regimens
Switching to others, n (%) 0 4 (1.22) 0.053 0 0 0
PIs-based, n (%) 7 (14.29) 72 (18.27) 0.058 7 (14.29) 72 (18.27) <0.001
Comorbidity at discontinuation of TDF
Dyslipidemia, n (%) 16 (32.65) 147 (44.68) 0.089 21 (20.79) 39 (19.31) 0.076
Hypertension, n (%) 17 (34.69) 144 (43.77) 0.069 32 (31.68) 67 (33.17) 0.059
Diabetes, n (%) 6 (12.24) 45 (13.68) 0.159 14 (13.86) 29 (14.36) 0.099
Concurrent medication during TDF exposurea
TMP/SMX, n (%) 4 (8.16) 39 (11.85) 0.053 11 (10.89) 26 (12.87) 0.156
Fluconazoleb, n (%) 4 (8.16) 33 (10.03) 0.056 9 (8.91) 20 (9.90) 0.113
RAAS inhibitors, n (%) 13 (26.53) 113 (34.34) 0.079 36 (35.64) 100 (49.50) 0.732
NSAIDs, n (%) 7 (14.29) 56 (17.02) 0.907 21 (20.79) 43 (21.29) 0.094
Time to recovery, months 26.72 ± 13.44 - - 22.76 ± 9.03 - -
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aHIV RNA <40 copies/mL.

bMedication lists were extracted from the hospital outpatient prescription database.

TDF, tenofovir disoproxil fumarate; PRT, proximal renal tubulopathy; SD, standard deviation; BMI, body mass index; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HIV, human immunodeficiency virus; ABC, abacavir; 3TC, lamivudine; AZT, zidovudine; PI, protease inhibitors; TMP/SMX, trimethoprim-sulfamethoxazole; RAAS, renin-angiotensin-aldosterone system; NSAIDs, non-steroidal anti-inflammatory drugs.

4. Factors associated with the recovery of renal parameters

Using univariate and multivariate logistic regression analysis, we found that discontinuing TDF when eGFR was greater than 60 mL/min/1.73 m2 (OR = 4.075 vs. 2.115) increased the likelihood of achieving complete renal function and PRT recovery. In contrast, being at least 60 years of age (OR = 0.811 vs. 0.504), receiving RAAS inhibitors (OR = 0.793 vs. 0.709), and taking Pls (OR = 0.582 vs. 0.311) were associated with a decreased likelihood of complete renal function and PRT recovery (Table 4).

Table 4. Univariate and multivariate analyses of factors associated with recovery of renal parameters after TDF cessation.

Variables Complete vs. Incomplete recovery of renal function Recovery vs. Non-recovery of PRT
Univariate logistic regression analysis Multivariate logistic regression analysis Univariate logistic regression analysis Multivariate logistic regression analysis
Odd ratio (95% CI) P-value Odd ratio (95% CI) P-value Odd ratio (95% CI) P-value Odd ratio (95% CI) P-value
Female gender 1.009 (0.899 - 1.113) 0.574 1.502 (0.673 - 1.764) 0.476
Elderly (age >60 years old) 0.894 (0.650 - 0.932) 0.031 0.811 (0.701 - 0.967) 0.012 0.357 (0.121 - 0.672) 0.011 0.504 (0.384 - 0.871) 0.002
BMIa <18 kg/m2 0.733 (0.118 - 1.994) 0.117 0.162 (0.029 - 0.803) 0.038 0.691 (0.135 - 1.004) 0.053
CD4 a >200 cell/mm2 1.214 (1.007 - 2.004) 0.048 1.09 (0.846 - 1.988) 0.069 1.409 (1.279 - 2.690) 0.049 1.06 (0.893 - 4.116) 0.064
Undetectable HIV RNAb 1.008 (0.735 - 2.056) 0.519 1.609 (0.869 - 2.068) 0.196
TDF-discontinuation while eGFR > 60 mL/min/1.73 m2 3.164 (1.648 - 4.893) <0.001 4.075 (1.997 - 5.783) <0.001 1.842 (1.399 - 3.693) <0.001 2.115 (1.904 - 4.799) <0.001
Switching TDF to ABC regimen 1.001 (0.772 - 1.385) 0.094 1.539 (0.892 - 1.844) 0.415
Switching TDF to AZT regimen 0.976 (0.511 - 1.387) 0.335 0.988 (0.721 - 1.953) 0.671
PI-based 0.796 (0.116 - 0.936) <0.001 0.582 (0.210 - 0.889) <0.001 0.467 (0.196 - 0.671) <0.001 0.311 (0.109 - 0.461) <0.001
Diabetes 0.564 (0.437 - 1.103) 0.145 0.650 (0.396 - 1.784) 0.077
Hypertension 1.378 (0.874 - 1.941) 0.831 1.064 (0.702 - 1.739) 0.508
Dyslipidemia 1.568 (0.965 - 2.799) 0.326 1.386 (0.893 - 2.009) 0.081
RAAS inhibitors 0.469 (0.185 - 0.472) <0.001 0.793 (0.458 - 0.819) 0.001 0.439 (0.221 - 0.599) <0.001 0.709 (0.258 - 0.991) 0.001
TMP/SMX 0.131 (0.157 - 1.008) 0.078 0.324 (0.122 - 1.013) 0.051
NSAIDs 0.742 (0.601 - 1.793) 0.508 0.602 (0.419 - 1.599) 0.098
Smoking 0.767 (0.504 - 1.930) 0.099 0.746 (0.409 - 1.311) 0.143
Alcohol dependence 1.562 (0.972 - 1.867) 0.098 1.014 (0.684 - 1.693) 0.068
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adata was recorded within 6 months of the initiation of the TDF treatment.

bHIV RNA <40 copies/mL.

TDF, tenofovir disoproxil fumarate; PRT, proximal renal tubulopathy; CI, confidence interval; BMI, body mass index; CD4, cluster of differentiation 4; HIV, human immunodeficiency virus; eGFR, Estimated glomerular filtration rate; ABC, abacavir; AZT, zidovudine; PI, protease inhibitors; RAAS, renin-angiotensin-aldosterone system; TMP/SMX, trimethoprim-sulfamethoxazole; NSAIDs, non-steroidal anti-inflammatory drugs.

Discussion

Our study found renal dysfunction in 11.76% of TDF-treated patients, which was within the range of incidences (5.68 - 19.3%) reported by other studies that defined renal dysfunction as a decrease in eGFR of more than 25.0% from baseline [23,24,25,26]. This diagnostic criterion is recommended by well-known guidelines, such as the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents (2022) and the Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for Management of Chronic Kidney Disease in HIV-Infected Patients (2014) [2,27]. This study also detected 15.20% of patients with PRT, which is comparable to the previous study in Thailand (15.8%) [28], which used the same criteria as a few findings of proteinuria and albuminuria, metabolic acidosis with a normal anion gap, hypophosphatemia, elevated urinary phosphate, or urinary α-1, β-2-microglobulin [16,17,29].

Over 60 years of age, smoking, use of TDF for more than 3 years, PI-based therapy, TMP/SMX exposure, concurrent NSAIDs use, and a body mass index (BMI) of less than 18 kg/m2 were found to be risk factors for TDF-induced renal dysfunction, defined as a decrease in eGFR by more than 25% from pretreatment level, in this study.

A study conducted in Vietnam revealed that the likelihood of having an eGFR of less than 60 mL/min/1.73 m2 increased with age over 60. (OR = 26.75) [30]. Similarly, an Asian and a Thai studies discovered a 5.39- and 1.97-fold increased risk of TDF-induced eGFR declines greater than 25% from baseline in patients aged 50 and older (P <0.05) [6,25].

In this study, age over 60 was also associated with a 3.357-fold increased risk of proximal tubulopathy. One Thai study, however, failed to find a correlation between age and proximal tubulopathy [28].

According to a previous study, the use of TMP/SMX to prevent pneumocystis pneumonia had no effect on the probability of proximal tubule nephrotoxicity [28]. However, 1.7% and 7.5% of HIV-infected patients receiving a high dose of TMP/SMX experienced crystalluria, renal colic, and acute renal failure due to the precipitation of sulfonamides in the urine [31,32].

The use of NSAIDs has 1.73-fold increased the likelihood of acute kidney injury [33]. NSAIDs inhibit the activity of cyclooxygenase, which converts arachidonic acid to prostaglandins (PG) I2 and PGE2 causing constriction of the afferent arterioles and impairing renal function as a result [34].

Similar to our research, a social behavior study conducted in Japan found that smoking increased the likelihood of nephrotoxicity by a factor of 1.65 [35]. It was found that smoking decreased renal nephropathy and PRT by 1.972 and 2.166 times, respectively. In addition to increasing blood pressure, smoking stimulates the release of nicotine and catecholamines from the adrenal medulla, resulting in a decrease in eGFR [36].

Long-term administration of TDF increased the probability of nephrotoxicity 1.16-fold [12]. While a study conducted in the United States revealed that using TDF longer than three years increased the annual decrease of 3 mL/min/1.73 m2 or more for two consecutive years and proteinuria by 1.04 and 2.17 times, respectively [37].

A Japanese study discovered that a body weight of less than 60 kilograms increased the risk of an eGFR decline by more than 25.0% [22]. Due to the fact that tenofovir is a dose-dependent medication, underweight people may be susceptible to nephrotoxicity when taking high doses. The risk of proximal tubular dysfunction was found to be 2.02 times greater in subjects weighing 55 kg with serum TDF levels greater than 160 ng/mL [38]. Our study found a correlation between a BMI of less than 18 kg/m2 and a decline in eGFR, but not PRT.

The addition of PIs to antiretroviral regimens multiplied the likelihood of an eGFR decline of more than 30.0% by 1.93 (P = 0.005) [6]. The primary mechanism for increasing TDF levels is the inhibition of the intestinal p-glycoprotein activity [39]. The administration of PIs was only associated with renal dysfunction, but not PRT, according to our research.

The mean renal function recovery time in this study was 19.23 months, which was comparable to the results of studies conducted in the United States and Spain, where the mean renal function recovery time was 12 and 22 months, respectively [18,27].

According to a study conducted in Korea, 57.9% of TDF-treated patients who were switched to TAF regained baseline renal function, and 26.3% regained renal function above baseline. In addition, 86.6% of patients with tubulopathy recovered after TAF replacement [19]. TAF was not easily accessible in Thailand, so our patients with TDF-induced nephrotoxicity were switched to abacavir or zidovudine .

According to a study conducted in Spain, 59% of 183 patients with TDF-induced renal impairment had normalized renal parameters, including serum creatinine, eGFR, absence of proteinuria, hypophosphatemia, or glycosuria, after discontinuing TDF for 13 - 49.54 months, with time to renal impairment ranging from 22 - 63 months [18]. A Korean study found that renal function and tubulopathy recovery to baseline was observed in 57.9% (11 of 19 patients) and 86.6% (26 of 30 patients) of patients with more than a 25.0% decrease in the estimated glomerular filtration rate (eGFR) compared to baseline and tubulopathy, respectively [19]. Our study revealed that only 12.96% and 33.33% of 378 and 303 patients with these disorders recovered complete renal function and PRT, respectively. To confirm the recovery rate in the big picture, a larger sample of patients should be studied.

All studies, including our own, on renal function recovery have demonstrated that discontinuing TDF as soon as possible, especially in patients with a normal eGFR, allows patients to regain normal renal function. A British study found that discontinuing TDF at an eGFR below 60 mL/min/1.73 m2 (as calculated by the CKD EPI equation) increased the risk of incomplete renal function recovery by 13.18 - fold [21].

The use of PIs, RAAS inhibitors, and advanced age reduce the likelihood of renal function recovery. This result may be attributable to the fact that taking these medications during renal dysfunction increases the risk of nephrotoxicity and older individuals are able to repair cells more slowly than younger individuals, resulting in a slower renal function recovery rate [40].

Among the patients who required close renal monitoring during TDF therapy were those aged 60 and older, those receiving TMP/SMX and/or NSAIDs, and those who smoked. Long-term use of nephrotoxic medications during TDF exposure should be avoided if possible. When TDF-induced nephrotoxicity is diagnosed, the drug must be discontinued immediately, even if the patient's eGFR is still greater than 60 mL/min/1.73 m2.

After initiating TDF for 39.72 and 37.23 months, 11.76 and 15.20% of 3,214 and 1,993 patients, respectively, had renal dysfunction and PRT. Shared risk factors between TDF-induced renal dysfunction and TDF-induced PRT included age over 60, smoking, duration of TDF use greater than 3 years, TMP/SMX exposure, and concurrent use of NSAIDs. After discontinuing TDF for 26.72 and 22.76 months, 12.96 and 33.33% of patients, respectively, had recovered full renal function and PRT. Elderly patients and those taking RAAS inhibitors or PIs were associated with a lower probability of both complete renal function and PRT recovery. Patients who discontinued TDF at an eGFR greater than 60 mL/min/1.73 m2 have a greater chance of regaining complete renal function and PRT recovery.

Footnotes

Funding: None.

Conflict of Interest: No conflict of interest.

Author Contributions:
  • Conceptualization: SS, AK, PT, PS.
  • Data curation: SS, PS.
  • Formal analysis: SS, PS.
  • Investigation: SS, AK, PT, PS.
  • Methodology: SS, PS.
  • Project administration: SS.
  • Resources: SS, AK, PT.
  • Software: SS, PS.
  • Supervision: SS, PS.
  • Validation: SS, PS.
  • Visualization: SS, PS.
  • Writing - original draft: SS, PS.
  • Writing - review & editing: SS, AK, PT, PS.

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