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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2021  |  Volume : 32  |  Issue : 2  |  Page : 348-354
Tacrolimus intrapatient variability in BK virus nephropathy and chronic calcineurin toxicity in kidney transplantation

1 Department of Internal Medicine, Division of Nephrology, Baskent University Ankara Hospital, Ankara, Turkey
2 Department of General Surgery, Division of Transplantation, Baskent University Ankara Hospital, Ankara, Turkey
3 Department of Biochemistry, Baskent University Ankara Hospital, Ankara, Turkey
4 Department of Pathology, Baskent University Ankara Hospital, Ankara, Turkey

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Date of Web Publication11-Jan-2022


Intrapatient variability (IPV) in tacrolimus has been increasingly acknowledged as a risk factor for poor graft survival after kidney transplantation. Although past studies have mainly accounted for IPV in acute or chronic rejection states as due to underimmunosuppression, this is not yet clear. So far, tacrolimus IPV for BK virus-associated nephropathy (BKVN) and chronic calcineurin inhibitor toxicity (CNIT) has not been investigated. Here, we evaluated IPV in tacrolimus for BKVN and chronic CNIT, which are mainly considered as overimmunosuppression states. In this case–control study, kidney allograft biopsies conducted between 1998 and 2018 were included, with patients grouped by biopsy results as BKVN alone group, CNIT alone group, and normal graft function (control group). IPV was estimated as mean absolute deviation. Our study groups included 25 kidney transplant recipients with BKVN alone, 91 patients with CNIT alone, and 60 patients with normal 5-year graft survival (control group). In analyses of IPV in tacrolimus six months before graft biopsy, IPV was highest in the BKVN group (P = 0.001). The BKVN group also had the highest IPV in tacrolimus at 12 months after biopsy (P = 0.001), with all pairwise comparisons statistically different between groups. At 12 months after biopsy, five patients (20%) in the BKVN group and 10 patients (10.9%) in the CNIT group had graft loss. Among other risk factors, BKVN and chronic CNIT are consequences related to high IPV. Quantification of IVP for tacrolimus in clinical practice would help to optimize kidney transplant outcomes.

How to cite this article:
Turgut D, Sayin B, Soy EA, Topcu D&, Ozdemir BH, Haberal M. Tacrolimus intrapatient variability in BK virus nephropathy and chronic calcineurin toxicity in kidney transplantation. Saudi J Kidney Dis Transpl 2021;32:348-54

How to cite this URL:
Turgut D, Sayin B, Soy EA, Topcu D&, Ozdemir BH, Haberal M. Tacrolimus intrapatient variability in BK virus nephropathy and chronic calcineurin toxicity in kidney transplantation. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jul 6];32:348-54. Available from: https://www.sjkdt.org/text.asp?2021/32/2/348/335446

   Introduction Top

Since its discovery, tacrolimus has been widely used in the world and in Turkey in kidney transplantation as a part of the immuno-suppressive regimen.[1],[2] However, therapeutic monitoring of tacrolimus remains complicated because a narrow margin exists between adequate immunosuppression and toxicity. Daily blood trough concentrations are currently used for dose adjustments in clinical practice. Because of its pharmacokinetics, high inter- patient variability and intrapatient variability (IPV) can limit the use of blood drug concentration to set the drug dosage. IPV is defined as the fluctuation in tacrolimus concentrations within an individual patient over a certain period during which the tacrolimus dose is unchanged.[2] High IPV is related to many factors, extending from diet to ethnic differences, and is associated with poor long-term outcomes.[2],[3],[4] Fluctuations in concentrations can result inpatients being at risk of underexposure and rejection or tacrolimus toxicity in cases of overexposure.

BK virus-associated nephropathy (BKVN) may be a good model to represent excessive immunosuppression, which predisposes eventually to graft loss.[5] Chronic calcineurin inhibitor toxicity (CNIT) is the other side of overexposure, resulting in irreversible damage to the renal architecture.[6]We hypothesized that fluctuations in tacrolimus blood trough levels may be associated with the coexistence of BKVN or CNIT. In this study, we aimed to investigate tacrolimus IPV in BKVN and CNIT as a surrogate marker for estimating over immunosuppression in the kidney transplant setting.

   Methods Top

Study population and laboratory data

Our retrospective cohort study included kidney transplant recipients who received transplants between 1998 and 2018 at the Baskent University Hospitals (Ankara, Turkey). We reviewed 1598 graft biopsy reports among our patients. Of total reports, there were 89 BKVN-related reports and 614 CNIT-related reports. The remaining 895 biopsy reports included acute humoral rejection, acute cellular rejection, transplant glomerulopathy, and others.

Patients were included in the analysis if (1) they were 18 years old or older at the time of the transplant, (2) they received a living kidney donation, (3) they had been maintained on tacrolimus + mycophenolate mofetil + steroid as immunosuppression at a stable dose for at least 12 months before the biopsy,(4) they had no rejection episodes during the preceding 12 months before graft biopsy, and (5) graft biopsies had been performed at least 12 months after transplant and did not include any rejection or other pathological findings concomitantly. Patients with missing data and who had <5 times of blood tacrolimus level measurements during the preceding six months and one year after graft biopsy were also excluded.

In total, 25 patients with BKVN alone and 91 patients with CNIT alone were included in our study. A flowchart diagram of patient election is presented in [Figure 1]. As a control group, we analyzed 60 patients who had 5-year graft survival and never had any rejection episodes. None of the patients in the control group needed a graft biopsy. We gathered demographic information and laboratory data from health records and analyzed laboratory data included serum creatinine, serum albumin, and C-reactive protein levels immediately before the biopsy. For patient outcomes, we assessed graft loss (defined as starting hemodialysis or peritoneal dialysis) over the 12 months.
Figure 1: Flow-chart diagram of study design.

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Tacrolimus blood levels and intrapatient variability

Mean tacrolimus blood concentration and mean daily drug dosage during the six months immediately before the graft biopsy were analyzed. To calculate the IPV for each patient, at least five tacrolimus blood samples had to be available in the preceding six months and the following 12 months after the graft biopsy. Tacrolimus IPV was quantified as the mean absolute deviation (MAD%). The MAD% was calculated as follows[3]:

X100, where m(X) represents average value of the data set, n represents the number of data values, and Xi represents data values in the set.

Compliance with ethical standards

This study was approved by Baskent University Institutional Review Board (Project No:KA21/66). Data had been obtained as a part of standard patient care and were analyzed in an anonymized fashion. Informed consent was taken from all patients when they applied to our hospital stating retrospective use of their data.

   Statistical Analyses Top

The distribution of baseline demographics was summarized using descriptive statistics. Continuous variables are expressed as median and interquartile range. To evaluate the differences between median values, we used Kruskal–Wallis test for three groups, with pairwise comparisons for posthoc analysis. Chi-square tests were used for categorical variables. P ≤0.05 was accepted as significant. Statistics were mainly calculated with the use of IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA).

   Results Top

Twenty-five patients with biopsy-proven BKVN, 91 patients with biopsy-proven chronic CNIT, and 60 patients with normal graft function were analyzed. Among the total patients analyzed (n = 176), the mean age was 34.39 ± 11.77 years, and time to graft biopsy from transplant was 54.92 ± 30.58 months. Mean tacrolimus dose in the six-months before biopsy was 4.18 ± 2.20 mg/day, and mean blood trough level was 7.41 ± 3.89 μg/L. For analysis of mean IPV in tacrolimus during the six months before biopsy, rate was 30.7% ± 8.5%. In the 12 months after biopsy, IPV rate was 34.3% ± 13.1%. According to study groups, serum creatinine was higher in both the BKVN group (P = 0.001) and CNIT group (P = 0.001) than in the control group but similar between BKVN and CNIT groups (P = 0.821). C-reactive protein and albumin levels were similar between the three groups. [Table 1] summarizes the demographic characteristics and laboratory data.
Table 1: Demographic and laboratory data of the study.

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In the analysis of drug use, tacrolimus daily dosage in the six months before biopsy was similar between the BKVN group and the control group (P = 0.792). However, in the CNIT group, dosages were lower compared with both the BKVN group (P = 0.033) and control group (P = 0.012). Tacrolimus blood trough level during the past six months before biopsy was similar between the three groups (P = 0.219). For all three groups, IPV in tacrolimus for the preceding six months before biopsy was, in descending order, highest in the BKVN group (P = 0.001), followed by the CNIT group (P = 0.001) and then the control group (P = 0.001). IPV in tacrolimus for the 12 months after biopsy was also highest in the BKVN group (P = 0.001), with all pair-wise comparisons statistically different between groups. For the 12 months after biopsy, five patients (20%) in the BKVN group and 10 patients (10.9%) in the CNIT group lost their graft. In patients who lost their graft, the IPV in tacrolimus was higher in the BKVN group than in the CNIT group (P = 0.013). IPV in tacrolimus results according to groups are shown in [Figure 2] and [Figure 3].
Figure 2: Intrapatient variability in tacrolimus during the preceding 6 months before biopsy according to patient groups.

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Figure 3: Intrapatient variability intacrolimus during the following 12 months after biopsy according to patient groups.

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   Discussion Top

In this retrospective case–control study, we tested the hypothesis that high IPV in tacrolimus levels is associated with an overimmunosuppression state, as observed in BKVN or CNIT of the kidney allograft. We found that, irrespective of tacrolimus daily dose or blood trough levels, fluctuations in tacrolimus blood levels were prominent in BKVN in the pre-period of infection. In the follow-up period of BKVN and chronic CNIT, high IPV was also shown.

Fluctuations in tacrolimus are common in the 1st weeks or months after transplant due to numerous factors, with changes in maintenance drug doses.[7] Generally, after a couple of weeks or months, patients reach a more stable blood druglevel.[8] However, nonadherence, genetic factors, drug–drug interactions, diet, and generic formulations may lead to exceeding or falling below the therapeutic range of tacrolimus, resulting in high IPV.[9] Highly fluctuating tacrolimus trough concentrations, despite a stable dose, can also occur with no reason. In our study, we tried to minimize the occasions, resulting in high IPV. We excluded all patients with <12-month duration since transplant and patients with any rejection episode during the past 12 months, to prevent any incidences of drug–drug interactions. All of our patients were using twice daily formulations of tacrolimus.

Many studies have reported that higher IPV of tacrolimus is related to worse graft survival.[2],[3],[4],[9],[10],[11] Some studies have reported a higher acute rejection rate in patients with a greater variation in intrapatient tacrolimus levels,[12],[13] although some did not.[14],[15] However, IPV in tacrolimus for those with BKVN and CNIT is still unknown. In their study, Shen et al analyzed BKVN and acute rejection together and reported that fluctuations in tacrolimus levels were noticeably associated with the coexistence of BKVN and acute rejection.[16] However, they compared BKVN alone with BKVN and acute rejection together and the immunosuppressant drug regimens used in their study were not standard as were ours. To our knowledge, our study is the first to analyze IPV in tacrolimus in patients with BKVN and CNIT separately and versus a control group to estimate whether high IPV is a predisposition to BKVN or chronic nephrotoxicity.

BKVN is a significant risk factor for premature allograft loss, with an incidence of up to 10%–15% after kidney transplant.[17] Beyond the many risk factors, the intensity of immunosuppression is the dominant risk for viral replication and nephropathy.[18] However, no specific immunosuppressive drug or regimen has been definitively associated with clinically significant infection.[19],[20],[21] In addition to the known risk factors related to BKVN,[22] the more obscure reasons for overimmunosuppression are still unclear. The pharmacokinetic changes of drugs rather than the blood levels might be responsible for uncontrolled immunosuppression without apparent toxic side effects.

In our study, living donor kidney transplant recipients with high IPV ended with BKVN after one year of graft function without complications. In addition, their tacrolimus daily dose and blood trough levels were similar to those shown in patients with normal graft function. Recent studies have shown that graft loss after BK virus infection is mainly related to increased risk of acute rejection due to decreased immunosuppression.[23] However, in the period before infection, it is enigmatic to see acute rejection concomitantly. In their study, Seifert et al[22] found that polyomavirus reactivation was associated with early de novo antibodies to kidney-specific self-antigens fibronectin and collagen IV. Although the exact pathway is unclear, the same mechanism increases the risk of acute rejection and infection.[24] The findings of Seifert et al were in agreement with our findings that high IPV during the BKVN course might be related to this unstable immune response. However, further studies are warranted to elucidate this argument.

In the other aspect of oversuppression, chronic nephrotoxicity cannot be disregarded because it can result in irreversible chronic progressive renal disease. However, the evidence of CNIT being associated with higher systemic drug dosages is not strong.[25] In fact, it was reported that low tacrolimus levels are highly associated with chronic tubulointerstitial damage.[6] Investigations have revealed that progression of chronic damage is more the result of local renal factors than of overexposure to drugs, with inter- and intra-variabilities of calcineurin inhibitors strengthening these local renal factors.[24] In the current literature, there is no study estimating IPV in patients with CNIT. We found that IPV was lower than in the BKVN group (P = 0.001) but higher than in the control group (P = 0.001) during the preceding six months. However, IPV was still high after 12 months, especially in patients who lost their graft due to CNIT. Prevention and eventually therapy for calcineurin inhibitor nephrotoxicity are aimed at lowering total systemic blood levels and decreasing local renal exposure to the calcineurin inhibitors or their metabolites.[26],[27] However, it is reasonable to speculate that high IPV might affect these local renal factors and should be corrected during routine posttransplant follow-up of kidney transplant recipients.

There are some limitations to the present study. Sample size was small in the BKVN group due to rareness of the disease. Second, due to our retrospective study design, we could not analyze patients for other reasons of kidney rejection during the 12-month follow- up. Third, the diagnoses were all based on kidney pathology instead of urine or blood examinations. However, this is the first study to identify that high drug level variability might be related to both BKVN and CNIT.

In conclusion, our results demonstrated that fluctuations in tacrolimus levels were relevant in BKVN and CNIT. Further studies are needed to better understand the interactions between infection, sensitization, and toxicity. Beyond routine therapeutic drug monitoring, IPV in tacrolimus is easy to determine, allowing testing to be routinely incorporated into everyday clinical practice as a tool for optimizing transplant outcomes.

Conflict of interest: None declared.

   References Top

Haberal M. Transplantation in Turkey. Clin Transpl 2013;175-80.  Back to cited text no. 1
Shuker N, Shuker L, van Rosmalen J, et al. A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation. Transpl Int 2016;29:1158-67.  Back to cited text no. 2
Whalen HR, Glen JA, Harkins V, et al. High intrapatient tacrolimus variability is associated with worse outcomes in renal transplantation using a low-dose tacrolimus immunosuppressive regime. Transplantation 2017;101:430-6.  Back to cited text no. 3
Shuker N, van Gelder T, Hesselink DA. Intra-patient variability in tacrolimus exposure: Causes, consequences for clinical management. Transplant Rev (Orlando) 2015;29:78-84.  Back to cited text no. 4
Wiseman AC. Polyomavirus nephropathy: A current perspective and clinical considerations. Am J Kidney Dis 2009;54:131-42.  Back to cited text no. 5
Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4:481-508.  Back to cited text no. 6
Prendergast MB, Gaston RS. Optimizing medication adherence: An ongoing opportunity to improve outcomes after kidney transplantation. Clin J Am Soc Nephrol 2010;5:1305-11.  Back to cited text no. 7
Sayin B, Ozdemir A, Ayvazoglu Soy EH, et al. Over 5 years of excellent graft kidney function determinants: Baskent university experience. Exp Clin Transplant 2019;17:75-7.  Back to cited text no. 8
Seibert SR, Schladt DP, Wu B, et al. Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney trans-plant recipients. Clin Transplant 2018;32: e13424.  Back to cited text no. 9
Borra LC, Roodnat JI, Kal JA, Mathot RA, Weimar W, van Gelder T. High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant 2010;25: 2757-63.  Back to cited text no. 10
Sapir-Pichhadze R, Wang Y, Famure O, Li Y, Kim SJ. Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure. Kidney Int 2014;85:1404-11.  Back to cited text no. 11
Mo H, Kim SY, Min S, et al. Association of intrapatient variability of tacrolimus concentration with early deterioration of chronic histologic lesions in kidney transplantation. Transplant Direct 2019;5:e455.  Back to cited text no. 12
Ro H, Min SI, Yang J, et al. Impact of tacrolimus intraindividual variability and CYP3A5 genetic polymorphism on acute rejection in kidney transplantation. Ther Drug Monit 2012;34:680-5.  Back to cited text no. 13
Prytula AA, Bouts AH, Mathot RA, et al. Intra-patient variability in tacrolimus trough concentrations and renal function decline in pediatric renal transplant recipients. Pediatr Transplant 2012;16:613-8.  Back to cited text no. 14
Taber DJ, Su Z, Fleming JN, et al. Tacrolimus trough concentration variability and disparities in African American kidney transplantation. Transplantation 2017;101:2931-8.  Back to cited text no. 15
Shen CL, Yang AH, Lien TJ, Tarng DC, Yang CY. Tacrolimus blood level fluctuation predisposes to coexisting BK virus nephropathy and acuteallograftrejection. Sci Rep 2017;7:1986.  Back to cited text no. 16
Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 2002;347:488-96.  Back to cited text no. 17
Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: Interdisciplinary analyses and recommendations. Transplantation 2005;791277-86.  Back to cited text no. 18
Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation 2009;87: 1019-26.  Back to cited text no. 19
Hirsch HH, Vincenti F, Friman S, et al. Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: A prospective, randomized, multi-center study. Am J Transplant 2013;13: 136-45.  Back to cited text no. 20
Schold JD, Rehman S, Kayle LK, Magliocca J, Srinivas TR, Meier-Kriesche HU. Treatment for BK virus: Incidence, risk factors and outcomes for kidney transplant recipients in the United States. Transpl Int 2009;22:626-34.  Back to cited text no. 21
Seifert ME, Gunasekaran M, Horwedel TA, et al. Polyomavirus reactivation and immune responses to kidney-specific self-antigens in transplantation. J Am Soc Nephrol 2017;28: 1314-25.  Back to cited text no. 22
Baek CH, Kim H, Yu H, Yang WS, Han DJ, Park SK. Risk factors of acute rejection in patients with BK nephropathy after reduction of immunosuppression. Ann Transplant 2018; 23:704-12.  Back to cited text no. 23
Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Chapman JR, Allen RD. Calcineurin inhibitor nephrotoxicity: Longitudinal assessment by protocol histology. Transplantation 2004;78:557- 65.  Back to cited text no. 24
Issa N, Kukla A, Ibrahim HN. Calcineurin inhibitor nephrotoxicity: A review and perspective of the evidence. Am J Nephrol 2013;37: 602-12.  Back to cited text no. 25
Naesens M, Lerut E, Damme BV, Vanrenterghem Y, Kuypers DR. Tacrolimus exposure and evolution of renal allograft histology in the first year after transplantation. Am J Transplant 2007;7:2114-23.  Back to cited text no. 26
Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357: 2562-75.  Back to cited text no. 27

Correspondence Address:
Didem Turgut
Department of Internal Medicine, Division of Nephrology, Baskent University Ankara Hospital, Ankara
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.335446

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