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Saudi Journal of Kidney Diseases and Transplantation
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RENAL DATA FROM THE ASIA - AFRICA Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 6  |  Page : 1101-1104
Is short term outcome of Iranian renal transplant recipients affected by mean first 6 months C2 level?


1 Medicine and Health Promotion Institute, Tehran; Clinical Research Unit, Baqiyatallah Medical Sciences University, Tehran, Iran
2 Clinical Research Unit, Baqiyatallah Medical Sciences University, Tehran; Nephrology and Urology Research Center, and Kidney Transplant Department, Tehran, Iran
3 Nephrology and Urology Research Center, and Kidney Transplant Department, Tehran, Iran

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Date of Web Publication27-Oct-2009
 

   Abstract 

International Consensus Conference (ICC) has suggested that the whole blood level of Cyclosporine (CsA) be kept strictly at a certain level. However, it is not well understood whether failing to maintain these levels will affect the short term outcome in different patient populations or not. We aimed to assess if the short term outcome of Iranian renal transplant recipients will be affected by first 6 months C2 level. In a retrospective cohort, 265 consecutive kidney transplant recipients were categorized as group with mean C2 lower than recommended range (mean C2 levels in the first 6 month after transplantation lower than the recommended ranges; n=213) and group with mean C2 within recommended range (mean C2 levels in the first 6 month after transplantation within the recommended range; n=52). All recipients were negative for panel reactive antibody, and had received their first (living unrelated) kidney transplantation in Baqiyatallah hospital, between 2002 and 2003. The groups were similar in characteristics and 6 months, 1, 2, and 3 years patient and graft survival rates were considered as outcome. No significant difference was observed in patient and graft survival rates between the two groups (P> 0.05). The patient survival rate in group with mean C2 lower than recommended range and group with mean C2 within recommended range were: 6 months: 98% vs. 98, 1 year: 97% vs. 98%, 2 years: 97% vs. 98% and 3 years: 97% vs. 98%. The graft survival rate in the above groups were as follows: 6 months: 93% vs. 91%, 1 year: 92% vs. 91%, 2 years: 92% vs. 77% and 3 years: 89% vs. 69%, respectively. The result of our study showed that lower mean C2 levels was not necessarily accompanied with a worse short term outcome in our patients. This finding suggests that the optimal level of C2 may be different in ethnic populations.

How to cite this article:
Assari S, Lankarani MM, Panahi Y, Einollahi B. Is short term outcome of Iranian renal transplant recipients affected by mean first 6 months C2 level?. Saudi J Kidney Dis Transpl 2009;20:1101-4

How to cite this URL:
Assari S, Lankarani MM, Panahi Y, Einollahi B. Is short term outcome of Iranian renal transplant recipients affected by mean first 6 months C2 level?. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2019 Dec 12];20:1101-4. Available from: http://www.sjkdt.org/text.asp?2009/20/6/1101/57277

   Introduction Top


Cyclosporine (CsA) has a narrow therapeutic window. Although introduction of microemul­sion formulation (Neoral) has shown a good promise in reducing intrapersonal variability [1] but close monitoring with the aim of maintai­ning therapeutic effects as well as preventing nephrotoxicity is still necessary. [2]

International Consensus Conference (ICC) have proposed recommended C2 levels to enhance the patients' outcome based on the results of transplantation in north America, [3] but a num­ber of recent studies from different ethnicities have reported satisfactory outcomes in their patient populations despite having a lower C2 values than those recommended by ICC. [4],[5]

A study from Iran, showed that the initial ad­ministered doses are lower than the recommen­ded values. [6] Another recent study by Pourfar­ziani et al reported good outcomes despite sig­nificantly lower level of C2 in Iranian kidney transplant recipients. [7] To the best of our know­ledge, no study has ever evaluated C2 blood levels of the Iranian kidney recipients in com­parison to the recommended levels of the in­ternational consensus conference. In this multi­center study, we designed a retrospective co­hort to investigate the short term effect of lo­wer than recommended C2 levels on patient and graft survival rates, in Iranian renal trans­plant recipients.


   Methods Top


In a retrospective cohort, we included 265 consecutive kidney recipients, transplanted in Baqiyatallah hospital, Tehran, Iran from 2002 to 2003. Inclusion criteria were receiving the first allograft from a living unrelated donor and being negative for panel reactive antibody. All recipients were under triple therapy with prednisolone, mycophenolate mofetil and cy­closporine microemulsion (Neoral). Induction immunotherapy was used in none of the pa­tients. The groups were not significantly diffe­rent in terms of donor and recipient age, donor and recipient gender, ischemia time, follow-up time, and number of HLA missmatchs.

Post-transplant immunosuppressive monito­ring was done based on patients clinical status and also the serial measurements of serum crea­tinine, calculated creatinine clearance, liver func­tion tests and the C2 level was not used for changing of the dose of Cyclosporin.

According to the whole blood mean C2 levels in the first 6 months after transplantation, pa­tients were divided into two groups: group I with mean C2 lower than recommended range (n=213) [3] and group II with mean C2 within recommended range (n=52). (None of the pa­tients represented a higher than recommended C2 level).

We then retrospectively followed the patients for a period of 3 years for patient and graft survival. 6 months, 1, 2, and 3 years patient and graft survival rates were considered as out­come and compared between the two groups.

We used SPSS version 13.0 for Windows for data analysis. Survival analysis was performed using Log-rank test. P-values < 0.05 were con­sidered significant.


   Results Top


In the study population, 178 (67.2%) were male and 87(32.8%) were female. The mean age at the time of transplantation was 37 ± 17 year. Patients in the two groups were not sig­nificantly different regarding age, sex and cause of end stage renal disease (ESRD). The groups were also not significantly different in terms of donor and recipient age difference, donor and recipient gender, ischemia time, follow-up time, and number of HLA mismatch (P >0.05).

The mean C2 level for the first six months was 801.9 ± 237.1 ng/mL in group I and 1120.2 ± 259.0 ng/mL in group II with mean C2 with­in recommended range.

The patient survival rate in different time in­tervals after transplantation in group I and group II were: 6 months: 98% vs. 98, 1 year: 97% vs. 98%, 2 years: 97% vs. 98% and 3 years: 97% vs. 98% respectively (P >0.05).

The graft survival rate in different times post transplantation in group I and group II were as follows: 6 months: 93% vs. 91%, 1 year: 92% vs. 91%, 2 years: 92% vs. 77% and 3 years: 89% vs. 69% respectively. Again, there was no significant difference between the two groups.


   Discussion Top


According to the results of this study, having mean first 6 months post transplantation whole blood C2 levels lower than the target ranges of ICC is not essentially associated with worse 3 years patient and graft survival.

Our findings provide a higher level of evi­dence for previous claims regarding achieving a good patient and graft outcomes with lower than recommended C2 levels. [2],[4] Einecke et al has observed excellent long-term results with a C2 measure as low as 500-600 ng/mL, [2] and Ahmadi et al has also observed improved renal function, dyslipidemia and hypertension with such strategies. [4]

Pourfarziani by reviewing data regarding C2 measurement for patients who underwent kid­ney transplantation between 2001 and 2005 in 3 major transplantation centers in Tehran (Sha­heed Labbaf inejad, Baqiyatallah, and Shaheed Hasheminejad hospitals) included those patients who had at least 1 follow-up C2 measurement. Good overall patient and graft survival rates were reported for the Iranian population des­pite obvious lower blood levels of C2, com­pared to the consensus recommendations. In that report, 57% of transplanted population, C2 levels never met the target levels in all their posttransplant measurements that were studied. [7]

In a study of German renal transplanted pa­tients, in 68% C2 values were lower than the recommended levels in the first 2 months post­transplantation and in 55% at late post trans­plant period. 2 In an Australian transplanted study, a C2 level of less than the recommen­ded value on the 7th day after transplantation was linked to complete elimination of acute rejection incidence for the first month post­transplantation. [8] In France, kidney transplant re­cipients had good outcomes despite a low cy­closporine dose. [5] The same was reported from Iran. [9]

Some factors may explain these results inclu­ding different immunosuppression regimens than those at the time of publishing the guidelines may be a possible factor, as some later studies with different immunosuppression strategies [2],[5] have reduced the cyclosporine dose effectively with no adverse effect on the out­comes. Differences in the pharmacokinetic pa­rameters of cyclosporine in different patients [9] and racial and ethnic populations [8],[10] may be the other contributing factors to cyclosporine metabolism and may result in different plasma cyclosporine levels due to the genetic diffe­rences. [10]

Slow cyclosporine absorbers demonstrate lower levels of C2 compared to other longer interval measures like C6. [3] While reports showed that between 10% and 20% of the patients are slow absorbers during the early post-transplant pe­riod, many of them revert over time to the nor­mal pattern, [11] a large portion of the population (80.3%) in our study at the first 6 months post­transplantation with low C2 levels seems to have normal absorption pattern however, future studies must elucidate this.

Our study had some limitations, including small sample size and lack of long term patient and graft survival. Nevertheless, this may be the first comparative study and the hypothesis's presented should be tested in multi-ethnic groups. [12],[13],[14],[15]

In conclusion, we found that having a mean whole blood C2 level lower than the recom­mendation during the first 6 months post renal transplant is not accompanied with poor short term patient or graft survival for Iranian renal transplant recipients. Further investigations for determining a more precise target range for cyclosporine blood levels in different ethnic kidney recipient populations seems to be necessary.


   Acknowledgement Top


This study was fully supported and funded by Baqiyatallah Medical Sciences University.

 
   References Top

1.Neumayer HH, Farber L, Haller P, et al. Subs­titution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year. Nephrol Dial Transplant 1996;11:165-72.  Back to cited text no. 1      
2.Einecke G, Mai I, Fritsche L, et al. The value of C2 monitoring in stable renal allograft recipients on maintenance immunosuppression. Nephrol Dial Transplant 2004;19:215-22.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Levy G, Thervet E, Lake J, Uchida K. Patient management by Neoral C(2) monitoring: an international consensus statement. Transplantation 2002;73:S12-8.  Back to cited text no. 3      
4.Ahmadi F, Lessan Pezeshki M, Khatami M, et al. Beneficial effect of low dose cyclosporine with mmf in renal allograft recipients. Clin Exp Transpl 2004. XLIII ERA-EDTA Congress. July 15-18, 2006. Glasgow, United Kingdom. 0July%2016%20posters.pdf.  Back to cited text no. 4      
5.Loichot C, tue-Ferrer D, Bernard N, et al. Cy­closporine monitoring in renal transplant reci­pients with induction therapy: C2 levels in pa­tients monitored on C0. Fundam Clin Pharmacol 2006;20:91-6.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Kahan BD, Welsh M, Schoenberg L, et al. Va­riable oral absorption of cyclosporine. A bio­pharmaceutical risk factor for chronic renal allograft rejection. Transplantation 1996;62: 599-606.  Back to cited text no. 6      
7.Pourfarziani V, Nemati E, Taheri S, Khoddami­Vishte HR, Azizabadi Farahani M. Satisfactory outcome despite low 2-hour post dose cyclos­porine level in Iranian Kidney Recipients. Iranian J Kidney Dis 2008;2(2):99-101.  Back to cited text no. 7      
8.Morris RG, Russ GR, Cervelli MJ, Juneja R, McDonald SP, Mathew TH. Comparison of trough, 2-hour, and limited AUC blood sam­pling for monitoring cyclosporin (Neoral) at day 7 post-renal transplantation and incidence of rejection in the first month. Ther Drug Monit 2002;24:479-86.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Ghafari A, Makhdoomi K, Ahmadpour P, Afshari AT, Fallah MM, Rad PS. Low-dose versus high-dose cyclosporine induction proto­cols in renal transplantation. Transplant Proc 2007;39:1219-22.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.Azarpira N, Aghdaie MH, Behzad-Behbahanie A, et al. Association between cyclosporine concentration and genetic polymorphisms of CYP3A5 and MDR1 during the early stage after renal transplantation. Exp Clin Transplant 2006;4:416-9.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Nashan B, Bock A, Bosmans JL, et al. Use of Neoral C monitoring: a European consensus. Transpl Int 2005;18:768-78.  Back to cited text no. 11      
12.Oellerich M, Armstrong VW, Schiitz E, Shaw LM. Therapeutic drug monitoring of cyclos­porine and tacrolimus. Update on Lake Louise Consensus Conference on cyclosporin and tacrolimus. Clin Biochem 1998;31:309-16.  Back to cited text no. 12      
13.Belitsky P, Levy GA, Johnston A. Neoral absorption profiling: an evolution in effective­ness. Transplant Proc 2000;32:45S-52S.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Oellerich M, Armstrong VW. Two-hour cyclosporine concentration determination: an appropriate tool to monitor neoral therapy? Ther Drug Monit 2002;24:40-6.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]  
15.Nemati E, Einollahi B, Taheri S, et al. Cyclos­porine trough (C0) and 2-hour postdose (C2) levels: which one is a predictor of graft loss? Transplant Proc 2007;39(4):1223-4.  Back to cited text no. 15      

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Correspondence Address:
Shervin Assari
Medicine and Health Promotion Institute, Tehran
Iran
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PMID: 19861884

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    Abstract
    Introduction
    Methods
    Results
    Discussion
    Acknowledgement
    References
 

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