The investigation of correlation between Iminoral concentration and neurotoxic levels after kidney transplantation


1 Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

2 Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

3 Department of Clinical Biochemistry, Isfahan University of Medical Sciences, Isfahan, Iran

4 Isfahan Neurosciences Research Center; Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran


Background: Neurotoxicity side effects related to cyclosporine kinetics could lead to dysfunction of kidney graft and patient outcome after transplantation. The aim of this study was evidence-based pharmacotherapy of kidney transplant recipients and to investigate neurotoxic levels of Iminoral.
Materials and Methods: The results of 2239 cyclosporine trough levels obtained from 743 patients were studied. Seventy-five adult kidney recipients who received Iminoral were studied for neurotoxicity symptoms. Demographic, clinical, hematology and biochemical data were recorded in d-base and analyzed using SPSS application for windows.
Results: The mean value related to cyclosporine C 0 was 246.3 μg/l. In the 48% the signs of neurotoxicity such as tremor and headache were noted, but only in 9% the levels of cyclosporine C 0 were >400 μg/l. Further studies on 75 patients showed that the incidence of neurotoxic side effects were as follows: Tremor in 35, headache in 24 and anxiety in 34 recipients of kidney. The prescribed drug regimens from the day of transplant in most patients were based on mycophenolic acid or cellcept, pulse therapy using methylprednisolone (daily from kidney transplant up to 3 days after transplant), cyclosporine or Iminoral plus other drugs related to each individual. Administrations of ganciclovir, thymoglobulin, clotrimazol and prednisolone were also distinguished with immunosuppressant-based therapy simultaneously.
Conclusion: Evidence-based study related to pharmacotherapy of Iminoral showed that clinical presentation related to neurotoxic side effects such as tremor, headache and anxiety might be due to many factors such as polypharmacy. Planning immunosuppression to individual patients based on programmed therapeutic Iminoral monitoring, avoiding polypharmacy in terms of removal or drug minimization and focusing on first week after transplant seem to be a realistic option.


Thierry A, Mourad G, Büchler M, Choukroun G, Toupance O, Kamar N, et al. Three-year outcomes in kidney transplant patients randomized to steroid-free immunosuppression or steroid withdrawal, with enteric-coated mycophenolate sodium and cyclosporine: The infinity study. J Transplant 2014;2014:171898.  Back to cited text no. 1
Arnold R, Pussell BA, Pianta TJ, Lin CS, Kiernan MC, Krishnan AV. Association between calcineurin inhibitor treatment and peripheral nerve dysfunction in renal transplant recipients. Am J Transplant 2013;13:2426-32.  Back to cited text no. 2
Kahan BD. The evolution of therapeutic immunosuppression and the potential impact of drug concentration monitoring. Ther Drug Monit 1995;17:560-3.  Back to cited text no. 3
Tolou-Ghamari Z, Palizban AA. Laboratory monitoring of cyclosporin pre-dose concentration (C 0 ) after kidney transplantation in Isfahan. Iran J Med Sci 2003;28:81-5.  Back to cited text no. 4
Tolou-Ghamari Z, Palizban AA, Gharavi M. Cyclosporin trough concentration rejection relationship after kidney transplantation. Indian J Pharmacol 2003;35:395-6.  Back to cited text no. 5
Tolou-Ghamari Z, Palizban AA. The history of liver and renal transplantation. Internet J Pharmaco 2003;2:24.  Back to cited text no. 6
Gabe SM, Bjarnason I, Tolou-Ghamari Z, Tredger JM, Johnson PG, Barclay GR, et al. The effect of tacrolimus (FK506) on intestinal barrier function and cellular energy production in humans. Gastroenterology 1998;115:67-74.  Back to cited text no. 7
Tolou-Ghamari Z, Wendon J, Tredger JM. In vitro pentamer formation as a biomarker of tacrolimus-related immunosuppressive activity after liver transplantation. Clin Chem Lab Med 2000;38:1209-11.  Back to cited text no. 8
Fahr A. Cyclosporine clinical pharmacokinetics. Clin Pharmacokinet 1993;24:472-95.  Back to cited text no. 9
Akhlaghi F, Trull AK. Distribution of cyclosporine in organ transplant recipients. Clin Pharmacokinet 2002;41:615-37.  Back to cited text no. 10
Toledo Perdomo K, Navarro Cabello MD, Pérez Sáez MJ, Ramos Pérez MJ, Agüera Morales ML, Aljama García P. Reversible acute encephalopathy with mutism, induced by calcineurin inhibitors after renal transplantation. J Nephrol 2012;25:839-42.  Back to cited text no. 11
Tolou-Ghamari Z. Antiepileptic drugs (AEDs) polypharmacy could lead to buried pharmacokinetic interactions due to CYP450. Drug Metab Lett 2012;6:207-12.  Back to cited text no. 12
Sereno J, Rodrigues-Santos P, Vala H, Rocha-Pereira P, Alves R, Fernandes J, et al. Transition from cyclosporine-induced renal dysfunction to nephrotoxicity in an in vivo rat model. Int J Mol Sci 2014;15:8979-97.  Back to cited text no. 13
Nafar M, Roshan A, Pour-Reza-Gholi F, Samadian F, Ahmadpoor P, Samavat S, et al. Prevalence and risk factors of recurrent cytomegalovirus infection in kidney transplant recipients. Iran J Kidney Dis 2014;8:231-5.  Back to cited text no. 14
Arnold R, Pussell BA, Pianta TJ, Lin CS, Kiernan MC, Krishnan AV. Association between calcineurin inhibitor treatment and peripheral nerve dysfunction in renal transplant recipients. Am J Transplant 2013;13:2426-32.  Back to cited text no. 15
Bayers SL, Arkin L, Bohaty B, Paller AS. Neurotoxicity in the setting of pediatric atopic dermatitis treated with modified cyclosporine and itraconazole. J Am Acad Dermatol 2013;69:e177-8.  Back to cited text no. 16
Lamarche F, Carcenac C, Gonthier B, Cottet-Rousselle C, Chauvin C, Barret L, et al. Mitochondrial permeability transition pore inhibitors prevent ethanol-induced neuronal death in mice. Chem Res Toxicol 2013;26:78-88.  Back to cited text no. 17
Berntsen HF, Wigestrand MB, Bogen IL, Fonnum F, Walaas SI, Moldes-Anaya A. Mechanisms of penitrem-induced cerebellar granule neuron death in vitro: Possible involvement of GABAA receptors and oxidative processes. Neurotoxicology 2013;35:129-36.  Back to cited text no. 18
Lischke R, Simonek J, Stolz AJ, Schützner J, Belsan T, Marusic P, et al. Cyclosporine-related neurotoxicity in a patient after bilateral lung transplantation for cystic fibrosis. Transplant Proc 2004;36:2837-9.  Back to cited text no. 19
Ponticelli C, Campise MR. Neurological complications in kidney transplant recipients. J Nephrol 2005;18:521-8.  Back to cited text no. 20
Thamer M, Chan JK, Ray NF, Vassalotti JA, Kimmel PL. Drug use concomitant with cyclosporine immunosuppressive therapy for 3 years after renal transplantation. Am J Kidney Dis 1998;31:283-92.  Back to cited text no. 21
Iyer RS, Chaturvedi A, Pruthi S, Khanna PC, Ishak GE. Medication neurotoxicity in children. Pediatr Radiol 2011;41:1455-64.  Back to cited text no. 22
Wang YY, Zhang M, Lu FM, Jiao Z, Qiu XY. CYP3A4 genetic polymorphisms predict cyclosporine-related clinical events in Chinese renal transplant recipients. Chin Med J (Engl) 2012;125:4233-8.  Back to cited text no. 23
García M, Macías RM, Cubero JJ, Benítez J, Caravaca F, Gervasini G. ABCB1 polymorphisms are associated with cyclosporine-induced nephrotoxicity and gingival hyperplasia in renal transplant recipients. Eur J Clin Pharmacol 2013;69:385-93.  Back to cited text no. 24
Tolou-Ghamari Z, Najafi MR, Habibabadi JM, Zare M. Preliminarily analysis of carbamazepine (CBZ) C0 in patients visited Isfahan Epileptic Clinics. Int J Prev Med 2013;4(Suppl 2):S343-6.  Back to cited text no. 25
Tolou-Ghamari Z, Zare M, Habibabadi JM, Najafi MR. Antiepileptic drugs: A consideration of clinical and biochemical outcome in patients with epilepsy. Int J Prev Med 2013;4(Suppl 2):S330-7.  Back to cited text no. 26
Tolou-Ghamari Z, Zare M, Mehvari-Habibabadi J, Najafi MR. A quick outlook to the world of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012. J Res Med Sci. 2013 Mar;18(Suppl 1):S81-5.  Back to cited text no. 27
Kuypers DR. Immunotherapy in elderly transplant recipients: A guide to clinically significant drug interactions. Drugs Aging 2009;26:715-37.  Back to cited text no. 28
de Jonge H, de Loor H, Verbeke K, Vanrenterghem Y, Kuypers DR. In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. Clin Pharmacol Ther 2011;90:414-22.  Back to cited text no. 29
Hadjistavropoulos T, Kaasalainen S, Williams J, Zacharias R. Improving pain assessment practices and outcomes in long-term care facilities: A mixed methods investigation. Pain Manag Nurs 2013. [Epub ahead of print].  Back to cited text no. 30