The tacrolimus metabolism rate influences renal function after kidney transplantation

Gerold Thölking, Christian Fortmann, Raphael Koch, Hans Ulrich Gerth, Dirk Pabst, Hermann Pavenstädt, Iyad Kabar, Anna Hüsing, Heiner Wolters, Stefan Reuter, Barbara Suwelack, Gerold Thölking, Christian Fortmann, Raphael Koch, Hans Ulrich Gerth, Dirk Pabst, Hermann Pavenstädt, Iyad Kabar, Anna Hüsing, Heiner Wolters, Stefan Reuter, Barbara Suwelack

Abstract

The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient's risk management strategies.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Histogram of the distribution of…
Figure 1. Histogram of the distribution of the Tac C/D ratio (ng/mL*1/mg).
The patients showed a symmetric distribution relating to their C/D ratio and were categorized in three groups: slow, intermediate and fast metabolizers. Intermediate metabolizers were grouped around the mean C/D ratio value (1.05–1.54). Patients showing a C/D ratio

Figure 2. eGFR value comparison between the…

Figure 2. eGFR value comparison between the three metabolism groups (a).

Fast and intermediate Tac…

Figure 2. eGFR value comparison between the three metabolism groups (a).
Fast and intermediate Tac metabolizers showed statistically noticeable lower eGFR values compared to slow metabolizers one month after RTx. P-values refer to the linear mixed model. Renal function in a 24 months follow-up (b). The differences between the follow-up eGFR values (month 2, 3, 6, 12, 24) and the eGFR value and the eGFR value at month 1 are shown for every metabolism group.
Figure 2. eGFR value comparison between the…
Figure 2. eGFR value comparison between the three metabolism groups (a).
Fast and intermediate Tac metabolizers showed statistically noticeable lower eGFR values compared to slow metabolizers one month after RTx. P-values refer to the linear mixed model. Renal function in a 24 months follow-up (b). The differences between the follow-up eGFR values (month 2, 3, 6, 12, 24) and the eGFR value and the eGFR value at month 1 are shown for every metabolism group.

References

    1. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, et al. (2007) Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 357: 2562–2575.
    1. Naesens M, Kambham N, Concepcion W, Salvatierra O Jr, Sarwal M (2007) The evolution of nonimmune histological injury and its clinical relevance in adult-sized kidney grafts in pediatric recipients. Am J Transplant 7: 2504–2514.
    1. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, et al. (2003) The natural history of chronic allograft nephropathy. N Engl J Med 349: 2326–2333.
    1. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, et al. (2004) Evolution and pathophysiology of renal-transplant glomerulosclerosis. Transplantation 78: 461–468.
    1. Jacobson PA, Schladt D, Israni A, Oetting WS, Lin YC, et al. (2012) Genetic and clinical determinants of early, acute calcineurin inhibitor-related nephrotoxicity: results from a kidney transplant consortium. Transplantation 93: 624–631.
    1. Tsuchiya T, Ishida H, Tanabe T, Shimizu T, Honda K, et al. (2013) Comparison of pharmacokinetics and pathology for low-dose tacrolimus once-daily and twice-daily in living kidney transplantation: prospective trial in once-daily versus twice-daily tacrolimus. Transplantation 96: 198–204.
    1. Stratta P, Quaglia M, Cena T, Antoniotti R, Fenoglio R, et al. (2012) The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation. Eur J Clin Pharmacol 68: 671–680.
    1. Gijsen V, Mital S, van Schaik RH, Soldin OP, Soldin SJ, et al. (2011) Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients. J Heart Lung Transplant 30: 1352–1359.
    1. Tavira B, Coto E, Diaz-Corte C, Ortega F, Arias M, et al. (2011) Pharmacogenetics of tacrolimus after renal transplantation: analysis of polymorphisms in genes encoding 16 drug metabolizing enzymes. Clin Chem Lab Med 49: 825–833.
    1. Kim IW, Noh H, Ji E, Han N, Hong SH, et al. (2012) Identification of factors affecting tacrolimus level and 5-year clinical outcome in kidney transplant patients. Basic Clin Pharmacol Toxicol 111: 217–223.
    1. Kuypers DR (2008) Influence of interactions between immunosuppressive drugs on therapeutic drug monitoring. Ann Transplant 13: 11–18.
    1. Metalidis C, Lerut E, Naesens M, Kuypers DR (2011) Expression of CYP3A5 and P-glycoprotein in renal allografts with histological signs of calcineurin inhibitor nephrotoxicity. Transplantation 91: 1098–1102.
    1. Joy MS, Hogan SL, Thompson BD, Finn WF, Nickeleit V (2007) Cytochrome P450 3A5 expression in the kidneys of patients with calcineurin inhibitor nephrotoxicity. Nephrol Dial Transplant 22: 1963–1968.
    1. Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, et al. (2010) Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant 10: 464–471.
    1. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, et al. (2006) Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145: 247–254.
    1. Anglicheau D, Flamant M, Schlageter MH, Martinez F, Cassinat B, et al. (2003) Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation. Nephrol Dial Transplant 18: 2409–2414.
    1. Mourad M, Wallemacq P, De Meyer M, Brandt D, Van Kerkhove V, et al. (2006) The influence of genetic polymorphisms of cytochrome P450 3A5 and ABCB1 on starting dose- and weight-standardized tacrolimus trough concentrations after kidney transplantation in relation to renal function. Clin Chem Lab Med 44: 1192–1198.
    1. Kuypers DR, de Jonge H, Naesens M, Lerut E, Verbeke K, et al. (2007) CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther 82: 711–725.
    1. Ji E, Choi L, Suh KS, Cho JY, Han N, et al. (2012) Combinational effect of intestinal and hepatic CYP3A5 genotypes on tacrolimus pharmacokinetics in recipients of living donor liver transplantation. Transplantation 94: 866–872.
    1. Acott P, Babel N (2012) BK virus replication following kidney transplant: does the choice of immunosuppressive regimen influence outcomes? Ann Transplant 17: 86–99.
    1. Borni-Duval C, Caillard S, Olagne J, Perrin P, Braun-Parvez L, et al. (2013) Risk factors for BK virus infection in the era of therapeutic drug monitoring. Transplantation 95: 1498–1505.
    1. Watanabe Y, Sato M, Abe Y, Yamamoto T, Kashu Y, et al. (1998) Enteric absorption of FK 506: estimation by a block liver perfusion technique in rats. Transplant Proc 30: 3777–3778.
    1. Karamperis N, Povlsen JV, Hojskov C, Poulsen JH, Pedersen AR, et al. (2003) Comparison of the pharmacokinetics of tacrolimus and cyclosporine at equivalent molecular doses. Transplant Proc 35: 1314–1318.
    1. Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y (2004) The rate of gastric emptying determines the timing but not the extent of oral tacrolimus absorption: simultaneous measurement of drug exposure and gastric emptying by carbon-14-octanoic acid breath test in stable renal allograft recipients. Drug Metab Dispos 32: 1421–1425.
    1. Ekberg H, Bernasconi C, Tedesco-Silva H, Vitko S, Hugo C, et al. (2009) Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation. Am J Transplant 9: 1876–1885.

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