Tacrolimus intrapatient variability and latent virus reactivation after kidney transplantation: A retrospective study comparing prolonged-release and immediate-release tacrolimus formulations

Abstract

Objective

This study explored the differences in intrapatient variability of tacrolimus between prolonged-release and immediate-release formulations and evaluated the association between tacrolimus intrapatient variability and reactivation of BK virus and cytomegalovirus in kidney transplant recipients.

Methods

This retrospective observational study included 270 kidney transplant recipients receiving either prolonged-release tacrolimus or immediate-release tacrolimus. Receiver operating characteristic curve analysis identified tacrolimus intrapatient variability cutoff values associated with viral reactivation. Logistic regression analyses identified predictors of BK virus and cytomegalovirus reactivation.

Results

The prolonged-release tacrolimus group had significantly lower tacrolimus intrapatient variability than the immediate-release tacrolimus group (p < 0.001). No significant differences were observed in BK virus and cytomegalovirus reactivation rates. Receiver operating characteristic curve analysis identified tacrolimus intrapatient variability cutoffs of 0.268 for BK virus and 0.261 for cytomegalovirus. High tacrolimus intrapatient variability was significantly associated with increased BK virus and cytomegalovirus reactivation. Logistic regression showed that high tacrolimus intrapatient variability was significantly associated with BK virus and cytomegalovirus reactivation. Multivariate analysis confirmed an independent association between high tacrolimus intrapatient variability and cytomegalovirus reactivation.

Conclusions

Tacrolimus intrapatient variability may predict reactivation of latent viral infection after kidney transplantation. Although viral reactivation rates were similar between tacrolimus formulations, prolonged-release tacrolimus showed lower tacrolimus intrapatient variability levels, suggesting that fluctuations in tacrolimus exposure might increase the risk of viral reactivation.

Keywords

Kidney transplantation tacrolimus intrapatient variability tacrolimus formulations latent viral infections BK virus cytomegalovirus

Introduction

Kidney transplantation remains the primary treatment modality for patients with end-stage kidney disease (ESKD), as it offers significantly improved survival rates and a better quality of life compared with long-term dialysis.¹ Despite substantial advances in surgical techniques and immunosuppressive therapies, long-term graft survival remains suboptimal because of several factors, including acute and chronic rejection, toxicity associated with immunosuppressive medications, infectious complications, and nonadherence to immunosuppressive medication.^1,2

Calcineurin inhibitors (CNIs) constitute the cornerstone of maintenance immunosuppressive therapy in most kidney transplantation protocols. The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines and the 2019 Kidney Data Report of the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) recommend tacrolimus as the first-line CNI in kidney transplant recipients.^1,3–6 However, tacrolimus has a narrow therapeutic index, making it challenging to maintain optimal therapeutic levels in clinical practice.⁴

Traditionally, therapeutic drug monitoring of tacrolimus has focused on measuring trough blood concentrations. However, trough levels may not adequately reflect fluctuations in tacrolimus exposure over time. Consequently, increasing attention has been directed toward tacrolimus intrapatient variability (Tac-IPV), which reflects the degree of fluctuation in tacrolimus concentrations within an individual patient over a specified period.^2,3,7–14 Tac-IPV is multifactorial and may be influenced by medication adherence, drug–drug interactions, gastrointestinal disturbances, pharmacogenetic variability, food intake, circadian variation, and the pharmacokinetic characteristics associated with tacrolimus formulations.^9,13,14 In addition to its impact on graft outcomes, high Tac-IPV may also contribute to periods of excessive immunosuppression, potentially increasing the risk of opportunistic viral infections, including BK virus (BKV) and cytomegalovirus (CMV) reactivation.^2,15–18 Conversely, excessive variability may also reflect underimmunosuppression and immunologic instability. High Tac-IPV has been associated not only with excessive immunosuppression and infectious complications but also with underimmunosuppression, acute rejection, donor-specific antibody formation, and inferior graft survival. Therefore, Tac-IPV may represent an overall marker of immunosuppressive instability after transplantation.^13,14

Tacrolimus is available in both immediate-release (IR-Tac) and prolonged-release (PR-Tac) formulations, which have different pharmacokinetic profiles and absorption characteristics that may affect Tac-IPV. Some observational and conversion studies have evaluated differences in Tac-IPV between PR-Tac and IR-Tac formulations in renal transplant recipients; however, their findings have been heterogeneous and inconclusive.^3,19–21 In addition, evidence regarding the relationship among tacrolimus formulations, Tac-IPV, and viral reactivation after kidney transplantation remains limited.

Therefore, the present study aimed to compare Tac-IPV between PR-Tac and IR-Tac formulations and to investigate whether Tac-IPV is associated with the reactivation of latent viral infections, specifically BKV and CMV, in kidney transplant recipients during the post-transplant period.

Materials and methods

Study design and population

This retrospective observational study was conducted at a single tertiary transplantation center in Turkey. The study was approved by the Institutional Review Board of Izmir Tepecik Research and Education Hospital, Health Sciences University, Izmir, Turkey (Approval Number: 2026/01–10). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki of 1975, as revised in 2024. Patients who underwent kidney transplantation at our center between 2013 and 2023 and were routinely followed between 6 and 24 months post-transplantation were retrospectively evaluated. Consecutive kidney transplant recipients meeting the eligibility criteria were included. All patient data were deidentified to ensure confidentiality and privacy protection. Demographic, clinical, and laboratory data, including age, sex, donor type (living or deceased), panel-reactive antibody (PRA) status, induction therapy, pre-transplant dialysis status, and time since transplantation, were retrieved from hospital medical records. Patients were eligible for inclusion if they were aged >18 years, had received a first kidney transplant, had a follow-up period of 6–24 months on stable tacrolimus-based maintenance immunosuppressive treatment, and had sufficient therapeutic drug monitoring data to calculate Tac-IPV. Patients with missing tacrolimus trough-level measurements or incomplete clinical data were excluded.

A total of 270 kidney transplant recipients were included in the final analysis. Patients were divided into two groups according to the tacrolimus formulation used for maintenance immunosuppression: PR-Tac and IR-Tac.

Immunosuppressive protocol

All patients received tacrolimus-based maintenance immunosuppression consisting of tacrolimus, mycophenolate mofetil, and corticosteroids. Mycophenolate mofetil was generally administered at a dose of 1–2 g/day. Tacrolimus was administered either as PR-Tac (once daily) or IR-Tac (twice daily) according to the clinical preference of the treating physician. Target tacrolimus trough concentrations were 8–12 ng/mL during the first 3 months after transplantation, 6–8 ng/mL between months 3 and 12, and 4–6 ng/mL subsequently, according to institutional protocols. Induction therapy consisted of either basiliximab or anti-thymocyte globulin, depending on the recipient's immunological risk profile.

Renal allograft function was assessed using the estimated glomerular filtration rate (eGFR), which was calculated using the Modification of Diet in Renal Disease (MDRD) equation.²²

Calculation of Tac-IPV

Tac-IPV was calculated using the coefficient of variation (CV) of tacrolimus trough levels. Four consecutive tacrolimus trough levels (C0) obtained during routine follow-up between 6 and 24 months post-transplantation were used for the calculations. Tacrolimus trough concentrations were measured in whole-blood samples by chemiluminescent microparticle immunoassay (CMIA) on the ARCHITECT i1000SR (Abbott Laboratories; Chicago, IL, USA) analyzer at the hospital's central laboratory. The CV was calculated using the equation CV = σ/μ × 100, which indicates the proportion of the SD (σ) to the mean (μ), expressed as a percentage.^13,14

Assessment of BKV and CMV reactivations

Reactivation of latent viral infections was evaluated by routine surveillance for BKV and CMV. According to institutional protocol, viral monitoring was performed monthly for the first 9 months after transplantation and then every 3 months until 2 years post-transplantation. Plasma CMV DNA levels were quantified using a real-time quantitative polymerase chain reaction (qPCR) assay (cobas^® CMV, Roche Diagnostics) on the Cobas 6800 system (Roche Diagnostics; Mannheim, Germany), performed in the institutional virology laboratory. The BKV viral load was measured by a qPCR assay using the Artus BK Virus RG PCR Kit (QIAGEN; Hilden, Germany) on the Rotor-Gene Q system.

BKV reactivation was defined as plasma BKV-DNA >104 copies/mL.^17,23 CMV reactivation was defined as the detection of CMV DNA in blood with nucleic acid quantification >10³ IU/mL, regardless of the presence of clinical symptoms.²⁴

Statistical analysis

The distribution of continuous variables was assessed using histogram analysis together with skewness and kurtosis statistics. Variables demonstrating an approximately normal distribution were expressed as mean ± SD, whereas non-normally distributed variables were presented as median and interquartile range (IQR). Categorical variables are presented as frequencies and percentages. Comparisons between patients receiving PR-Tac and IR-Tac were performed using the unpaired Student's t-test for normally distributed continuous variables and the Mann–Whitney U test for non-normally distributed variables. Categorical variables were compared using the chi-squared or Fisher's exact test, as appropriate.

Receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminatory ability of Tac-IPV in predicting BKV and CMV reactivation. Optimal cutoff values for Tac-IPV were determined using the Youden index to maximize sensitivity and specificity for predicting viral reactivation.

Logistic regression analysis was performed to evaluate factors associated with BKV and CMV reactivation. The assessed variables included Tac-IPV (based on ROC-derived cutoff values), tacrolimus formulation, age, sex, donor type, PRA positivity, induction therapy, pre-transplant dialysis status, and time since transplantation. The results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was set at p <0.05.

All statistical analyses were performed using IBM Statistical Package for the Social Sciences (SPSS) Statistics for Windows (version 27.0; IBM Corp.; Armonk, NY, USA).

The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.²⁴

Results

A total of 270 kidney transplant recipients were included in the analysis, including 122 who received PR-Tac and 148 who received IR-Tac.

The baseline demographic characteristics, including age and sex distribution, were comparable between the two groups (Table 1). Donor type and pre-transplant clinical characteristics did not differ significantly between the PR-Tac and IR-Tac groups. Regarding immunological risk, the prevalence of PRA positivity was similar between the two groups. In addition, maintenance immunosuppressive regimens and induction strategies were comparable, indicating a balanced distribution of baseline immunological and therapeutic factors.

Table 1.

Baseline characteristics of the patients in the PR-Tac and IR-Tac groups.

Variable	PR-Tac group n (%)	IR-Tac group n (%)	p-value
Sex
Male	76 (62.3%)	87 (58.8%)	0.617
Female	46 (37.7%)	61 (41.2%)
Age (years, mean ± SD)	46.5 ± 12.60	45.3 ± 13.34	0.463
Dialysis before transplantation
Yes	92 (75.4%)	111 (75.0%)	0.887
No	30 (24.6%)	37 (25.0%)
Donor type			1.000
Deceased	42 (34.4%)	50 (33.8%)
Living	80 (65.6%)	98 (66.2%)
Induction treatment
ATG	98 (80.3%)	122 (82.4%)	0.753
Basiliximab	24 (19.7%)	26 (17.6%)
Time from transplantation (months, mean ± SD)	12.74 ± 4.89	13.26 ± 4.33	0.362
Tac-IPV (CV%) (mean ± SD)	0.165 ± 0.08	0.267 ± 0.13	<0.001
Creatinine (mg/dl, mean ± SD)	1.42 ± 0.52	1.57 ± 1.29	0.202
e-GFR (ml/min/1.73 m²) (mean ± SD)	63.74 ± 25.88	58.48 ± 17.56	0.048
CMV reactivation
Positive	3 (2.5%)	9 (6.1%)	0.235
Negative	119 (97.5%)	139 (93.9%)
BKV reactivation
Positive	2 (1.6%)	8 (5.4%)	0.119
Negative	120 (98.4%)	140 (94.6%)
PRA
Positive	11 (12.0%)	20 (17.7%)	0.328
Negative	81 (88.0%)	93 (82.3%)

PR-Tac: prolonged-release tacrolimus; IR-Tac: immediate-release tacrolimus; ATG: antithymocyte globulin; Tac-IPV: tacrolimus intrapatient variability; CV: coefficient of variation; eGFR: estimated glomerular filtration rate; CMV: cytomegalovirus; BKV: BK virus; PRA: panel-reactive antibody.

Tac-IPV was significantly lower in the PR-Tac group than in the IR-Tac group (0.165 ± 0.080 vs 0.267 ± 0.137, p < 0.001). Renal function assessment, estimated using the eGFR calculated by the MDRD formulation, was significantly better in the PR-Tac group (p = 0.048).

BKV reactivation was observed in 1.6% of patients in the PR-Tac group and 5.4% of patients in the IR-Tac group; however, this difference was not statistically significant (p = 0.119). Similarly, CMV reactivation occurred in 2.5% of patients treated with PR-Tac and 6.1% of patients treated with IR-Tac, but the difference was not statistically significant (p = 0.235).

Results of ROC curve analyses

ROC curve analysis demonstrated that Tac-IPV had moderate discriminatory ability for predicting BKV reactivation (area under the curve (AUC) = 0.708). The optimal cutoff value of Tac-IPV for BKV reactivation was 0.268, with a sensitivity of 70.0% and specificity of 72.3% (Figure 1). Using the ROC-derived cutoff value of 0.268, BKV reactivation was significantly more frequent in patients with high Tac-IPV levels than in those with lower variability (8.9% vs 1.6%, OR = 6.09, p = 0.008).

Figure 1.

ROC curve for Tac-IPV-BKV.

ROC curve analysis demonstrated that Tac-IPV had good discriminatory ability for predicting CMV reactivation (AUC = 0.769). The optimal cutoff value of Tac-IPV for CMV reactivation was 0.261, with a sensitivity of 75% and specificity of 71% (Figure 2). Using the ROC-derived cutoff value of 0.261, CMV reactivation occurred significantly more frequently in patients with higher Tac-IPV than in those with lower Tac-IPV (10.7% vs. 1.6%, OR = 7.32, p = 0.002).

Figure 2.

ROC curve for Tac-IPV-CMV.

When patients were stratified according to Tac-IPV using ROC-derived cutoff values (0.268 for BKV and 0.261 for CMV) within each tacrolimus formulation group (Table 2), BKV reactivation among patients receiving PR-Tac occurred in 0.9% of patients with low Tac-IPV and 8.3% of those with high Tac-IPV (OR = 9.91, p = 0.188). Similarly, CMV reactivation was observed in 1.9% of patients with low Tac-IPV and in 7.1% of those with high Tac-IPV (OR = 4.08, p = 0.309). In patients receiving IR-Tac, BKV reactivation occurred in 2.5% of patients with low Tac-IPV and 9.0% of those with high Tac-IPV (OR = 3.89, p = 0.141). In contrast, CMV reactivation was significantly more frequent in IR-Tac recipients with high Tac-IPV than in those with low Tac-IPV (11.4% vs. 1.3%; OR = 9.94; p = 0.013).

Table 2.

Viral reactivation rates according to Tac-IPV cutoff values within tacrolimus formulation groups*.

Tacrolimus formulation	Low Tac-IPV n/N (%)	High Tac-IPV n/N (%)	Odds ratio (OR)	p-value
PR-Tac-BKV	1/110 (0.9%)	1/12 (8.3%)	9.91	0.188
PR-Tac-CMV	2/108 (1.9%)	1/14 (7.1%)	4.08	0.309
IR-Tac-BKV	2/81 (2.5%)	6/67 (9.0%)	3.89	0.141
IR-Tac-CMV	1/78 (1.3%)	8/70 (11.4%)	9.94	0.013

*Data are presented as the number of events/total patients (%). Tac-IPV cutoff values were derived from ROC analyses: 0.268 for BKV reactivation and 0.261 for CMV reactivation. ORs and p-values were calculated using Fisher's exact test.

Tac-IPV: tacrolimus intrapatient variability; PR-Tac: prolonged-release tacrolimus; IR-Tac: immediate-release tacrolimus; ROC: receiver operating characteristic; BKV: BK virus; CMV: cytomegalovirus.

Results of the logistic regression analysis

Variables with p <0.10 in the univariable analysis were included in the multivariable logistic regression model. The results for BKV and CMV reactivation are presented in Tables 3 and 4, respectively. For BKV reactivation, high Tac-IPV, defined by the ROC-derived cutoff value of 0.268, was significantly associated with BKV reactivation (OR = 6.09, 95% CI: 1.53–24.21, p = 0.010). Tacrolimus formulation (IR vs PR) showed a nonsignificant trend toward a higher risk (OR = 3.43, 95% CI: 0.71–16.46, p = 0.124). PRA positivity also showed a borderline association with BKV reactivation (OR = 3.55, 95% CI: 0.87–14.52, p = 0.078). Age, sex, donor type, induction therapy, and pre-transplant dialysis status were not significantly associated with BKV reactivation (all p > 0.05). Time since transplantation demonstrated a borderline inverse association with BKV reactivation (OR = 0.86, 95% CI: 0.73–1.01, p = 0.070).

Table 3.

Logistic regression analyses for predicting BKV reactivation.

Factors	Univariable OR (95% CI)	p-value	Multivariable OR (95% CI)	p-value
High Tac-IPV ≥0.268	6.09 (1.53–24.21)	0.010	5.44 (1.28–23.01)	0.021
IR-Tac vs PR-Tac	3.43 (0.71–16.46)	0.124	–	–
PRA positivity	3.55 (0.87–14.52)	0.078	_	_
Age	0.99 (0.94–1.04)	0.68	–	–
Male sex	2.36 (0.65–8.57)	0.19	–	–
Donor type	0.5 (0.14–1.78)	0287	–	–
Induction therapy	0.48 (0.06–3.87)	0.489	–	–
Pre-transplant dialysis	1.31 (0.27–6.34)	0.735	–	–
Transplant duration	0.86 (0.73–1.01)	0.07	–	–

BKV: BK virus; OR: odds ratio; CI: confidence interval; Tac-IPV: tacrolimus intrapatient variability; IR-Tac: immediate-release tacrolimus; PR-Tac: prolonged-release tacrolimus; PRA: panel-reactive antibody.

Table 4.

Logistic regression analyses for predicting CMV reactivation.

Factors	Univariable OR (95% CI)	p-value	Multivariable OR (95% CI)	p-value
High Tac-IPV ≥0.261	7.32 (1.93–27.79)	0.003	6.38 (1.59–25.54)	0.009
IR-Tac vs PR-Tac	2.57 (0.68–9.71)	0.164	–	–
PRA positivity	1.58 (0.33–7.57)	0.567	–	–
Age	1.01 (0.97–1.06)	0.55	–	–
Male sex	1.55 (0.49–4.95)	0.46	–	–
Donor type	0.16 (0.04–0.60)	0.006	0.15, (0.04–0.59)	0.007
Induction therapy	0.00 (0.00–0.00)	0.999	–	–
Pre-transplant dialysis	3.72 (0.47–29.41)	0.212	–	–
Transplant duration	1.03 (0.91–1.16)	0.665	–	–

CMV: cytomegalovirus; OR: odds ratio; CI: confidence interval; Tac-IPV: tacrolimus intrapatient variability; IR-Tac: immediate-release tacrolimus; PR-Tac: prolonged-release tacrolimus; PRA: panel-reactive antibody.

For BKV reactivation, the multivariable analysis included high Tac-IPV, PRA positivity, and time since transplantation.

For CMV reactivation, high Tac-IPV, defined by the ROC-derived cutoff value of 0.261, was significantly associated with CMV reactivation (OR = 7.32, 95% CI: 1.93–27.79, p = 0.003). Living-donor transplantation was associated with a significantly lower risk of CMV reactivation than deceased-donor transplantation (OR = 0.16, 95% CI: 0.04–0.60, p = 0.006). Tacrolimus formulation, PRA positivity, age, sex, induction therapy, pre-transplant dialysis status, and time since transplantation were not significantly associated with CMV reactivation (all p > 0.05).

In the multivariable logistic regression analysis including Tac-IPV and donor type, high Tac-IPV (≥0.261) remained independently associated with CMV reactivation (adjusted OR = 7.56, 95% CI: 1.94–29.37, p = 0.003). Living-donor transplantation was associated with a significantly lower risk of CMV reactivation than deceased-donor transplantation (adjusted OR = 0.15, 95% CI: 0.04–0.59, p = 0.007).

Discussion

The present study highlights Tac-IPV as an important predictor of viral reactivation after kidney transplantation. Although BKV and CMV reactivation rates were comparable between PR-Tac and IR-Tac, Tac-IPV was significantly lower in the PR-Tac group, suggesting that pharmacokinetic stability, rather than tacrolimus formulation per se, may play a more important role in viral reactivation risk. Monitoring tacrolimus blood levels is essential for transplant recipients because of the drug's concentration–effect relationship, narrow therapeutic index, and potential nephrotoxicity. Medication adherence is considered a major determinant of Tac-IPV; however, pharmacokinetic and pharmacogenetic factors, dietary composition, gastrointestinal disturbances, potential drug interactions, and genetic polymorphisms may also substantially contribute to variations in tacrolimus levels.^3,17 Although tacrolimus trough concentrations of 4–6 ng/mL are generally considered an acceptable maintenance target beyond the first post-transplant year, trough levels obtained during routine monitoring represent isolated measurements and may not fully reflect overall tacrolimus exposure. Additionally, substantial fluctuations in tacrolimus concentrations may occur in the same patient, even with the same dosing regimen. Consequently, transient overimmunosuppression that goes undetected by routine therapeutic drug monitoring, along with periods of higher tacrolimus exposure despite the same dosing regimen, may contribute to viral reactivation. Tac-IPV has emerged as a key pharmacokinetic marker reflecting fluctuations in blood levels and has been associated with adverse outcomes, including rejection, development of donor-specific antibodies, and overall graft dysfunction.^9,14,25 Given the clinical significance of Tac-IPV, several studies have explored the potential effects of various formulations on tacrolimus variability. The literature remains inconsistent regarding the effects of prolonged-, extended-, and immediate-release formulations on Tac-IPV, highlighting the need for further research to optimize patient outcomes.^9,20,26 Pharmacokinetic studies indicate that modified tacrolimus formulations can attenuate peak–trough fluctuations, resulting in more consistent drug exposure than immediate-release tacrolimus. The ASTCOFF crossover study highlighted that extended-release tacrolimus exhibited lower peak concentrations and reduced intraday fluctuations than immediate-release tacrolimus, offering a more stable pharmacokinetic profile.²¹ Conversion studies have suggested that switching from twice-daily tacrolimus to prolonged-release formulations may improve the stabilization of tacrolimus trough levels in kidney transplant recipients.^20,25 In contrast, Shuker, et al.²⁶ reported that conversion from twice-daily to once-daily tacrolimus did not significantly decrease intrapatient variability in tacrolimus exposure, suggesting that formulation alone may not entirely account for fluctuations in tacrolimus levels. In a large observational study, no significant reduction in within-patient variability was observed after conversion to once-daily tacrolimus; however, higher variability remained strongly associated with adverse graft outcomes, including an increased risk of graft failure.³

The pharmacokinetic characteristics of extended-release tacrolimus formulations may contribute to a more stable drug exposure in kidney transplant recipients. Once-daily tacrolimus formulations have been developed to simplify dosing regimens and potentially improve medication adherence. Pharmacokinetic studies have demonstrated that extended-release tacrolimus exhibits prolonged absorption, lower peak concentrations, and reduced peak-to-trough fluctuations compared with IR-Tac.^27,28 These pharmacokinetic properties may result in more stable tacrolimus exposure over time, thereby decreasing Tac-IPV. Consistent with this concept, the present study demonstrated significantly lower Tac-IPV in patients who received PR-Tac than in those who received IR-Tac. Therefore, our findings support previous observations suggesting that PR-Tac provides greater pharmacokinetic stability than IR-Tac.

In the present study, we found a significant association between elevated Tac-IPV and viral reactivation after kidney transplantation. Patients with Tac-IPV values above the cutoff determined by ROC analysis had higher rates of BKV and CMV reactivation than those with lower values. These findings suggest that variations in tacrolimus exposure may be important pharmacokinetic indicators of immunosuppressive instability. Moreover, several studies have reported an association between variations in tacrolimus levels and reactivation of latent viruses.^15,16,29 A study from Turkey demonstrated that Tac-IPV was significantly higher in patients with BKV-associated nephropathy than in controls, suggesting that fluctuations in tacrolimus exposure may reflect periods of excessive immunosuppression that predispose patients to viral replication.¹⁵ Nafar et al.² reported a significant association between elevated BKV and higher Tac-IPV among transplant recipients, even among those who consistently adhered to immunosuppressive treatment. This finding emphasizes the importance of variability in tacrolimus exposure for BKV reactivation, irrespective of medication adherence. Similarly, Shen et al.¹⁷ showed that a greater variability in tacrolimus trough levels was associated with BKV nephropathy and acute rejection, underscoring the impact of inconsistent immunosuppressive exposure on adverse graft outcomes.

A biologically plausible mechanism for the reactivation of latent viruses after kidney transplantation involves compromised virus-specific cellular immunity under conditions of unstable immunosuppression. Research by Schachtner et al.³⁰ showed that recipients who developed BKV viremia had significantly fewer BKV-specific T cells, together with lower cluster of differentiation (CD) CD3+, CD4+, and CD8+ T-cell counts and reduced interferon-γ levels, indicating impaired antiviral immune control. Experimental data indicate that tacrolimus and common combination immunosuppressive regimens impair antiviral T-cell activation and cytokine production, providing a mechanistic basis for reduced antiviral surveillance and a diminished ability to respond to viral interventions in this setting.¹⁸ Although appropriate immunosuppression is necessary to prevent rejection, inadequate or excessive immunosuppression can compromise antiviral defense and increase the risk of viral reactivation. Our findings support these data by suggesting that Tac-IPV may serve as a clinically useful marker for identifying patients at increased risk of viral reactivation after kidney transplantation.

This study has some limitations. First, this was a retrospective single-center study, which may limit the generalizability of the findings. Second, the overall sample size was relatively small, potentially reducing the statistical power to detect differences between tacrolimus formulations. Finally, potential factors influencing tacrolimus variability, including medication adherence, genetic polymorphisms affecting tacrolimus metabolism, and drug–drug interactions, were not systematically assessed.³¹

Conclusion

High Tac-IPV may be associated with an increased risk of reactivation of latent viral infections following kidney transplantation. PR-Tac demonstrated significantly lower Tac-IPV than IR-Tac, whereas the reactivation rates of latent viruses did not differ significantly between the two groups. These findings suggest that enhanced pharmacokinetic stability may contribute to more consistent immunosuppressive exposure after transplantation. Monitoring Tac-IPV in clinical practice may help identify transplant recipients at increased risk of viral reactivation and guide individualized immunosuppressive management strategies.

Footnotes

Acknowledgments

We would like to thank the SAGE editing service for professional English-language editing.

ORCID iDs

Sibel Ersan

Gursel Ersan

Sibel Akkurt

Ethical consideration

This study was approved by the Institutional Review Board of Izmir Tepecik Research and Education Hospital, Health Sciences University, Izmir, Turkey (approval no.: 2026/01–10). This study was conducted in accordance with the principles of the Declaration of Helsinki.

Consent to participate

Informed consent was obtained from all the participants.

Consent for publication

Not applicable.

Author contributions

Gulin Kavakalan: Investigation, Methodology, and Review and Editing

Gursel Ersan: Conceptualization, Methodology, and Review and Editing

Gozde Buhur Sari: Conceptualization, Investigation, and Review and Editing

Sibel Akkurt: Conceptualization, Methodology, and Original Draft Preparation

Mehmet Tanrisev: Investigation and Review and Editing

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The authors will provide the research data upon request.

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