| Abstract|| |
Inadequate cyclosporine blood levels may cause acute rejection in transplanted renal graft, and its increase is accompanied with graft toxicity. Cyclosporine has variable bioavailability and pharmacokinetics among patients at different times after transplantation. In this study, we compared the effects of cyclosporine blood levels (trough versus 2-hour peak, C2) on renal graft function during the first six months after transplantation in order to find better methods for drug levels assessment in our patients. We studied 50 patients who received grafts at Mashhad transplant centers from October 2006 to May 2007. Drug levels were monitored seven times during the study; in each assessment, more than 80% of the patients did not reach the therapeutic C2 levels. There was no significant correlation between age, sex, times of transplantation and acute rejection with drug C2 levels. There was no difference between graft function in patients with therapeutic C2 level and those with inadequate C2 levels. However, we found a significant correlation between trough levels and acute rejection (P <0.05). Only during the 6 th month after transplantation was the drug dosage significantly higher in patients with therapeutic C2 level than that in other patients (P >0.05). Apparently, peak levels were not a suitable method in drug monitoring in our patients, or peak levels might have occurred at a different time (like 1.5 or 3 or 4 h after ingestion of the drug) in our population. Based on this study, trough level may be a better method of evaluation of cyclosporine effects on renal allografts than 2-h peak levels in our patients.
|How to cite this article:|
Hami M, Naghibi M, Mojahedi MJ, Sharifipour F, Shakeri MT. Graft function based on two hours peak level monitoring of cyclosporine a during the first six months of renal transplantation. Saudi J Kidney Dis Transpl 2012;23:1169-74
|How to cite this URL:|
Hami M, Naghibi M, Mojahedi MJ, Sharifipour F, Shakeri MT. Graft function based on two hours peak level monitoring of cyclosporine a during the first six months of renal transplantation. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2014 Sep 23];23:1169-74. Available from: http://www.sjkdt.org/text.asp?2012/23/6/1169/103555
| Introduction|| |
Cyclosporine has been used as a back bone in solid organ transplantation until now.  Its usage, in organ transplantation, was associated with a significant reduction in the incidence of acute rejection. 
Blood level monitoring of cyclosporine must be done whenever it is used, especially in organ transplantation, as it has a narrow therapeutic index. ,, Although assessment of cyclosporine blood levels was done for more than two decades,  there are many debates about the best time of sampling for drug monitoring. Different methods for evaluation of drug blood levels were evaluated, such as trough level (C0), peak 2-h levels (C2) and area under the curve (AUC), etc. 
Trough level (C0) and drug levels before the next dose have been used to monitor routinely in most transplant centers.  In some studies, it has been demonstrated that drug side-effects and acute rejection occur in the patients, even in therapeutic trough levels. ,,,
Another way for drug monitoring is assessment of AUC 0-12 , and an easier one is the assessment of AUC 0-4 . ,,, However, it remains impractical in the clinic as they need hourly sampling. ,, Based on studies, an alternative method for AUC assessment is the more practical 2-h peak levels (C2 level) of the drug.  Some studies reported this method of drug monitoring as suitable and nearly similar to AUC 0-4 . ,,, In contrast, some studies disagreed with this finding and preferred the C0 levels to guide cyclosporine therapy. ,
The aim of our study was to evaluate the trough and the C2 levels and compare their effects on drug monitoring in the renal transplant patients during the first six months of cyclosporine usage in our centers.
| Materials and Methods|| |
This study was performed in two transplant centers in the Mashhad University Medical Sciences-related hospitals (Ghaem and Imam Reza) as a prospective, cohort trial of newly adult renal transplant recipients who received an immunosuppressive regimen consisting of cyclosporine (Neoral®), Mycophenolate mofetile (Cellcept®) and Prednisolone. All adult renal transplant recipients who received grafts from October 2006 to May 2007 were considered for enrolment. The patients were excluded if they had severe cardiovascular or hepatic diseases, hyper-acute rejection, acute rejection in the first week after transplantation, urologic problems or drugs that affect cyclosporine blood level.
All the patients received cyclosporine 9-10 mg/kg on the first day and then 5-6 mg/kg/day that was adjusted based on the trough level, Cellcept 2 g/day, methylprednisolone succinate (Solumedrole®) 500-1000 mg/day IV on the first three days, followed by 1 mg/kg/day orally, which was tapered over three months to 10-15 mg/day. They were followed in the first six months after transplantation. The laboratory method of measuring cyclosporine levels was radio-immunoassay in whole blood sample.
During the study, trough levels and C2 levels were assessed seven times (4 th day, the 1 st week, the 2 nd week, the 1 st month, the 2 nd month, the 4 th month and the 6 th month) after transplantation.
Basically, the accepted C0 target levels in the first two months ranged from 250 to 300 ng/mL and from 100 to 250 ng/mL in the reminder four months. The accepted C2 levels ranged from 1500 to 2000 ng/mL in the first two months and from 1100 to 1500 ng/mL in the next four months.
Serum creatinine, fasting blood sugar (FBS), glomerular filtration rate (GFR) (calculated by MDRD equation) and Neoral® dosage were assessed at each visit. If there was any rise in creatinine or reduction in GFR, it would be assessed for acute rejection or cyclosporine toxicity by methods including DTPA isotope scan and renal biopsy. Based on the results, treatment such as pulse of methylprednisolone and/or ATG was to be initiated.
| Statistical Analysis|| |
Continuous variables are expressed as mean ± standard deviation (SD), and means were compared by independent sample "t " test and one way ANOVA. Nominal variables are expressed as percentages, and were analyzed by chi-square and Fisher exact tests. For repeatedly assessed parametric data, groups were compared using the repeated measure analysis and paired "t " test. Statistical significance was considered at P <0.05.
| Results|| |
A total of 106 patients received grafts from October 2006 to May 2007. Only 70 patients fulfilled the inclusion criteria, and were entered to the study. Finally, 50 patients finished the study, some of them excluded as urologic problem in the graft (three patients), severe infection after transplantation (five patients) and non-compliance (12 patients).
Patients' demographic characteristics based on their C2 levels are shown in [Table 1]. In our data, there was no significant relation between age, sex and times of transplantation with C2 levels (P >0.05). We found a significant correlation between type of donor and C2 levels only on the 4 th day after transplantation (P <0.05).
|Table 1: Patients' demographic characteristics based on C2 levels at first (4th day) and in the end (6th month) of study.|
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The correlation of C0 levels, FBS, creatinine and Neoral® dosage with C2 level are summarized in [Table 2]. There was a significant correlation only between Neoral® dosage at 6 th month and C2 level, and more drug usage was associated with higher C2 level. We also found a significant correlation between C2 and C0 levels in the 2 nd and 6 th months after transplantation. Therefore, higher C2 level was associated with higher C0 levels. Another significant finding was a correlation between FBS and C2 level only on the 4 th day after transplantation.
|Table 2: Serum creatinine, blood sugar, cyclosporine (CsA) dose, GFR, C0 levels in accordance with the means of C2 levels on the 4th day and at the end 6th month of the study.|
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As shown in [Table 2], none of the patients at the beginning of the study had C2 levels more than the therapeutic levels, and also at other times that almost only one patient had C2 level more than the therapeutic level. In spite of low C2 levels, most of them had therapeutic C0 level.
During the study, 12 patients had a period of acute rejection, which was confirmed in all of them by DTPA scans and biopsies [Table 3]. We found that there was no significant correlation between C2 levels and rejection. However, the mean of C2 levels in nearly all the patients was less than the therapeutic level [Figure 1]. On the other hand, there was a significant correlation between C0 levels and rejection only in the 2 nd month; patients with lower C0 levels experienced a higher rejection rate than those who were within the therapeutic range.
|Figure 1: Correlation between number of patients with acute rejection and C2 levels during the 2nd and 6th months after transplantation. Only one patient with therapeutic C2 level had acute rejection.|
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|Table 3: Correlation between drug blood levels and acute rejection in the 2nd month and at the end of the 6th month of the study.|
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| Discussion|| |
In our study, we evaluated the best method of drug monitoring in our patients. The drug dosages were regulated based on C0 level, and the C2 levels were assessed as well. Few patients achieved therapeutic C2 levels; through the first two months, none of them achieved therapeutic C2 levels. After two months, there was concordance between C2 levels and C0 levels in more patients. Higher C2 level was associated with higher C0 level. In the first two months, in spite of low C2 level in all patients, some of them had high C0 levels.
Even though, based on some studies, the correlation between cyclosporine trough levels and graft function is low, this method of drug monitoring is commonly used in many transplant centers. ,, Furthermore, it was reported that C0 levels on the second day after transplantation were the strongest predictors of acute rejection,  and despite twice higher doses of cyclosporine in C2-monitored patients, the incidence of rejection failed to show any predictive value for C2 levels.  On the other hand, Nashan et al concluded that C0 correlated only poorly with AUC 0-4 and that C2 was the most accurate single-sample marker for AUC 0-4 . 
This disparity between the different -blood levels can be explained by the changed absorption of cyclosporine through time after transplantation. The pharmacokinetics and pharmacodynamics of cyclosporine improve not only during the time after transplantation but also there is a circadian rhythm of the drug as fasting sample is associated with better absorption of drug. , Furthermore, -the uremic environment after successful transplantation and time of eating foods affect the peak more than affecting the trough levels.
In our study, we assessed the correlation of parameters such as FBS, creatinine and GFR with C2 levels; there was no significant correlation among them, in contrast with other studies that found that higher blood sugar was a dose-dependent complication of cyclosporine toxicity. ,
In our study, there was only a significant correlation between C0 levels and acute rejection in the 2 nd month, as in patients with graft rejection the average of C0 levels was less than the therapeutic levels, while they were within the therapeutic range in the group without rejection; none of them achieved therapeutic C2 levels. This may be due to having different peak level in our patients, or due to having different drug metabolism in them. Pescovitz et al found lower accepted C2 levels in their patients in the first six months post-transplantation,  and with increasing drug dosage many patients experienced symptoms of drug toxicity such as tremor, headache and elevation of creatinine.
Ethnicity may have an effect on cyclosporine blood levels by different metabolism of drug, and, in Iranians, the peak levels occur at different times (such as 1.5 or 3 or 4 h after taking the drug). We conclude that peak levels of the drug are not a suitable method for drug monitoring in our patients and that trough levels correlate better with the drug levels and clinical outcome of the patients.
| References|| |
|1.||Hardinger KL, Schnitzler MA, Koch MJ, et al. Cyclosporine minimization and cost reduction in renal transplant recipients receiving a C2-monitored, cyclosporine-based quadruple immunosuppressive regimen. Transplantation 2004;78:1198-203. |
|2.||Brunet M, Millan O, Jimenez O, et al. New concepts in cyclosporine pharmacokinetic and dynamic monitoring: The impact of concomitant immunosuppression on target C2 concentration. Transplant Proc 2004;36(Suppl 2S):437S-41. |
|3.||Morris RG. Cyclosporine therapeutic drug monitoring- an established service revisited. Clin Biochem Rev 2003;24:33-46. |
|4.||Birsan T, Loinig C, Bodingbauer M, et al. Comparison between C0 and C2 monitoring in denovo renal transplant recipients: Retrospective analysis of a single-center experience. Transplantation 2004;78:1787-91. |
|5.||Citterio F. Evolution of the therapeutic drug monitoring of cyclosporine. Transplant Proc 2004;36(Suppl 2S):420S-5. |
|6.||Konstadinidou I, Boletis JN. Experience with conversion from Sandimmun to Neoral cyclos-porine and the correlation of C2 levels with Renal Function. Trasplant Proc 2004;36:163S-6. |
|7.||Braun F, Armstrong VW, Lorf T, et al. Comparison of trough level and C2 cyclosporine blood concentration monitoring in outpatient kidney transplant recipients. Transplant Proc 2001;33:3108-9. |
|8.||Citterio F, Scata MC, Romagnoli J, Nanni G, Castagento M. Results of a three-year prospective study of C2 monitoring in long-term renal transplant recipients receiving cyclosporine microemulsion. Clin Transplant 2005;79:802-6. |
|9.||Cattaneo D, Gaspari F, Zenoni S, et al. Two-hour pot-dose cyclosporine monitoring does not fit all in kidney transplantation. Therapy 2005;2:95-105. |
|10.||Morris RG. Cyclosporine theraputic drug monitoring- an established service revisited. Clin Biochem Rev 2003;24:33-46. |
|11.||Paul LC, de Fijter JH. Cyclosporine- induced renal dysfunction. Transplant Proc 2004;36 (Suppl 2S):224S-8. |
|12.||Gadela SR, Varma PP, Baliga KV. 3 year prospective evaluation of conversion to C2 monitoring of renal transplantation recipient. Army Hospital (R&R). Indian J Nephrol. 2004;14:141. |
|13.||Keown PA. New concepts in cyclosporine monitoring. Curr Opin Nephrol Hypertens 2002;11:619-26. |
|14.||Citterio F, Scata MC, Borzi MT, Pozzetto U, Castagento M. C2 single- point sampling to evaluate Cyclosporine Exposure in long-term renal transplant recipients. Transplant Proc 2001;33:3133-6. |
|15.||Narula AS, Murthy MS, Patrulu KS, Saxena VK. Routine cyclosporine concentration-C2 level monitoring. Is it helpful during the early post Transplant Period? Medical Journal Armed Forces India 2004;60:326-8. |
|16.||Sandrini S, Bossini N, Setti G, Mazzucchelli C, Maiorca P, Cancarini G. Neoral dose adjustment after conversion from C0 to C2 monitoring in stable renal transplant recipients: A prospective single center study. J Nephrol 2004;17:284-91. |
|17.||Nashan B, Cole E, Levy G, Therver E. Clinical validation studies of Neoral C2 monitoring: A review. Transplantation 2002;73:S3-11. |
|18.||Mahalati K, Kahan BD. Advancing the art of immunosuppression with the science of pharmacology. Transplant 2000;5:255-62. |
|19.||Curtis JJ, Jones P, Barbeito R. Large with in-day variation in cyclosporine absorption: Circadian variation or food effect? Clin J Am Soc Nephrol 2006;17:462-6. |
|20.||Perico N, Ruggeenti P, Gotti E, et al. Dialysis-Transplantation. In Renal transplantation blood cyclosporine levels soon after surgery act as a major determinant of rejection: Insights from the MY.S.S. Trial. Kidney Int 2004;65:1084-93. |
|21.||Danovitch GM. Immunosuppressive medications and protocols for kidney transplantation. Handbook of Kidney Transplantation. 4 th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 122-4. |
|22.||Pescovitz MD, Barbeito R. Two-hour postdose cyclosporine level is a better predictor than through level of acute rejection of renal allografts. Clin Transplant 2002;16:378-82. |
Assistant Professor of Nephrology, Kidney Transplantation Complications Research Center, Department of Internal Medicine, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad
[Table 1], [Table 2], [Table 3]