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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 4  |  Page : 564-571
Comparative Analysis of Azathioprine versus Cyclosporine-based Therapy in Primary Haplo-identical Live-Donor Kidney Transplantation: A 20-Year Experience


Urology and Nephrology Center, Mansoura University, Egypt

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   Abstract 

Chronic allograft nephropathy (CAN) remains a major cause of graft failure over the long term, second only to patient mortality. The main adverse effects of cyclosporine A (CsA) include nephrotoxicity, hypertension, symptomatic hyperuricemia, hirsutism, and gum hyperplasia. Available studies among live related donor renal transplants lack adequate information regarding the long-term efficacy and safety of primary CsA-based immunosuppressive regimens. This prospective randomized study is aimed at evaluating the long-term results of CsA-based immunosuppressive protocols in live­donor kidney transplantation. The follow-up data of 444 renal transplant recipients operated at the Urology and Nephrology Center, Mansoura University, prior to 1996 were reviewed. Primary immuno­suppressive protocols included: steroids and azathioprine (group I, 130 cases); steroids and CsA (group II, 75 cases); and steroids, CsA, and azathioprine (group III, 239 cases). Only adult primary renal transplant recipients with age ranging between 18 and 60 years and one haplotype HLA mismatch with the donor were included. All patients received kidneys from living related donors with previous donor non-specific blood transfusions. The percentage of cases with chronic rejection was significantly higher in group III. Living cases with graft failure were significantly higher in group III, whereas mortality was significantly higher in group I. Diabetic patients and those with serious bacterial infections were significantly more prevalent in group II. Hypertensive patients were significantly more common in groups I and II. Liver disease was more prevalent among patients in group III. Our study suggests that the long-term results of treatment with steroids and azathioprine are satisfactory in live related donor kidney transplant recipients. Chronic rejection was significantly higher in patients in group III, possibly due to the risk of CsA nephrotoxicity. Groups with CsA-based protocols experienced many adverse reactions of CsA such as hypertension, diabetes mellitus, and chronic rejection

How to cite this article:
Gheith OA, Bakr MA, Fouda MA, Shokeir AA, Sobh M, Ghoneim M. Comparative Analysis of Azathioprine versus Cyclosporine-based Therapy in Primary Haplo-identical Live-Donor Kidney Transplantation: A 20-Year Experience. Saudi J Kidney Dis Transpl 2008;19:564-71

How to cite this URL:
Gheith OA, Bakr MA, Fouda MA, Shokeir AA, Sobh M, Ghoneim M. Comparative Analysis of Azathioprine versus Cyclosporine-based Therapy in Primary Haplo-identical Live-Donor Kidney Transplantation: A 20-Year Experience. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2019 Nov 11];19:564-71. Available from: http://www.sjkdt.org/text.asp?2008/19/4/564/41315

   Introduction Top


The improvement achieved in short-term graft survival since the introduction of cyclos­porine (CsA) has not been matched by im­provement in the long-term graft function. Chronic allograft nephropathy (CAN) remains the second commonest cause of graft loss over time after patient mortality. [1] The main adverse reactions of CsA include nephro­toxicity, hypertension, symptomatic hyper­uricemia, hirsutism, and gum hyperplasia. [2] To alleviate these adverse reactions, many trials have been conducted to optimize CsA utilization. [3] Co-administration of calcium cha­nnel blockers, [4] or ketoconazole [5] was fa­shioned to decrease the dose and achieve acceptable therapeutic levels. Reduction and possible withdrawal of calcineurin inhibitors may be necessary to slow the rate of prog­ressive loss of renal function. [3]

Grimbert et al [6] concluded that a 12-year graft survival of 56% and a graft half-life of 15 years could be achieved without the use of a calcineurin inhibitor in low-risk patients who received anti-lymphocyte globulin (ALG) induction. Patients treated with CsA had poorer graft function at 12 years. In addi­tion, Opelz and Dohler [7] confirmed that main­tenance immunosuppression with azathioprine and steroids resulted in good long-term kid­ney graft survival, provided azathioprine was administered at a daily dose of > 1.5 mg/kg.

However, the available information on the long-term efficacy and safety of primary CsA­based immunosuppressive regimens among live related donor renal transplant recipients is scanty. This prospective randomized study was performed to evaluate the long­term results of CsA-based immunosuppre­ssive protocols in live-donor kidney trans­plantation.


   Study Population Top


The follow-up data of 444 renal transplant recipients operated at the Urology and Neph­rology Center, Mansoura University, prior to 1996 were reviewed. Primary immunosu­ppressive protocols included: steroids and azathioprine (group I, 130 cases); steroids and CsA (group II, 75 cases); and steroids, CsA, and azathioprine (group III, 239 cases). Only adult primary renal transplant recipients with age ranging between 18 and 60 years and one haplotype HLA mismatch with the donor were included. All patients received kidneys from living related donors with pre­vious donor non-specific blood transfusions.

Comparative analyses included patient and graft survival rates, condition at the last fo­llow-up, rejection episodes (acute and chro­nic), and graft function. The cases were cla­ssified according to the serum creatinine levels into three groups:

  1. less than 1.5 mg/dl,
  2. between 1.5 and 3 mg/dl and
  3. more than 3 mg/dl. The survivors with functioning graft after 10 years were eva­luated regarding demography, rejection episodes, and other medical complications.



   Methods Top


Clinical data of all kidney transplant pa­tients were reviewed. Demographic data in­cluded recipient age and gender, donor age and gender, cause of end-stage renal di­sease, human leukocyte antigens (HLA)-A, B, and DR mismatching and medical com­plications such as hypertension, diabetes mel­litus (DM), and infections.

Prednisolone was started on the day before transplantation at a dose of 8.5 mg/kg and was reduced gradually till the smallest main­tenance dose of 0.15 mg/kg/day was achieved by the end of the ninth month after trans­plantation. Patients in group I were given azathioprine at a dose of 3 mg/kg/day and those in group III received a dose of 1.5 mg/kg/day. Cyclosporine was administered at a dose of 12 mg/kg/day to patients in group II and at a dose of 8.5 mg/kg/day to patients in group III; the dose was adjusted to keep the trough level between 200 and 400 ng/ml in the first two months and between 125 and 175 ng/ml thereafter. CsA trough level was measured initially using radio-immune assay kits (Sandoz, Basel, Switzerland) and sub­sequently using monoclonal-specific antibody (Abbott, USA). All acute rejection episodes were biopsy proven and treated with 500­mg methylprednisolone, given intravenous (IV) for five days. Steroid-resistant rejection was treated with anti-thymocyte globulin or OKT3. Plasmapheresis was added to the treatment plan as an adjuvant therapy in cases of accelerated or vascular rejections.

Statistical analysis

Statistical analysis was carried out using IBM-compatible SPSS for windows version 11.5 (spss Inc., Chicago, IL, USA). All values were expressed as means ± SD for con­tinuous parametric data, median for con­tinuous non-parametric data, and frequent­cies for categorical data. Kaplan-Meier actua­rial curves were constructed for patient and graft survival. Patients who lost their grafts were excluded at the time of graft loss, and when evaluating graft survival, patients who died with functioning graft were excluded at the date of death. Values of p< 0.05 were considered significant.


   Results Top


[Table 1] illustrates the donors' and recipients' characteristics. Majority of recipients were males in their second decade of life, where­as nearly half of the donors were females in their third decade of life. Also, all groups were homogenous in terms of donor's age and sex, recipient's age and sex, causes of renal failure, prior blood transfusion(s), and pre-transplant hypertension. In addition, no preformed antibodies against donor antigens were detected in the pre-transplant cross­match of any of the study patients. HLA matching among patients in group I was significantly superior to the other two groups; however, no significant difference was seen in DR matching. The techniques employed for re-establishment of urinary continuity were also essentially similar. The survivors with functioning grafts were comparable in the three groups [Table 2].

Rejection episodes

We found no significant difference between the three groups regarding rejection-free cases and those who experienced one or more re­jection episodes (p> 0.05); however, the per­centage of cases with chronic rejection was significantly higher in group III (p= 0.01; [Table 3]).

Outcome

There was no statistically significant diffe­rence in the percentage of survivors with functioning grafts at the last follow-up bet­ween the three groups (p> 0.05). However, the number of patients surviving with graft failure was significantly higher in group III, whereas mortality was significantly higher in group I (p< 0.05). Graft survival rates were 85.3%, 79.8%, and 92.4% at one year; 69.9%, 58.7%, and 71.9% at five years; and 52.5%, 36.6%, and 50.8% at 10 years in the three groups I, II, and III, respectively ([Figure 1]; p= 0.03). The corresponding patient survival rates were 89.2%, 86.3%, and 95.7% at one year; 75.7%, 77.5%, and 85% at five years; and 60.9%, 58.1%, and 72.8% at 10 years in groups I, II, and III, respectively ([Figure 2]; p= 0.01).

Graft function

There was no statistically significant diffe­rence between the three groups regarding the number of patients with grade-a graft function both at one year and at the last follow-up [Table 4]. However, cases with grade-b graft function were significantly higher in group III at one year and at the last follow-up com­pared with the other two groups (p=0.001).

Complications

No significant differences were encountered between the three groups regarding post­transplant malignancies; however, diabetic patients and those with serious bacterial infections were significantly more prevalent in group II. Hypertensive patients were significantly more common among cases on CsA-based protocols (groups I and II). Liver disease was more prevalent among patients in group III (p< 0.05).


   Discussion Top


Several strategies have been adopted toimprove allograft survival. The introduction of CsA has been reported to improve graft survival and decrease the incidence and/or severity of rejection episodes. [8]

Long-term studies among live related do­nor renal transplant recipients are lacking. Our study was performed to evaluate the long-term results of CsA-based protocols after live-donor kidney transplantation.

We found no significant difference between the three groups regarding rejection-free cases and those who experienced one or more rejection episodes (p > 0.05). In addition, we found comparable graft survival between groups I and III (69.9% vs. 71.9% at five years and 52.5% vs. 50.8% at 10 years), which can be attributed to higher prevalence of CAN in group III and better HLA mat­ching in group I. This is in accordance with the report of Bakker [9] who found, at 15 years, that graft survival tended to be lower in the CsA group (64% vs.76.5%), with a higher relative risk of CAN in this group, a finding attributing a role of CsA nephro­toxicity in development of CAN. The con­clusion was to replace azathioprine by myco­phenolate mofetil (MMF) due to its higher protective effect in prevention of worsening of chronic interstitial fibrosis, either directly or through its immunologic pathway. [8]

Moreover, patients treated with CsA had poorer graft function at 12 years. [6] Experi­mental work failed to prove significant diffe­rences between azathioprine and CsA in development of CAN. However, it is diffi­cult to be certain as to what extent this mo­del reflects the human disease. [10]

The patient survival rates were significant­ly lower in group II at one, five, and 10 years, which may be attributed to medical com­plications including serious bacterial infec­tions, DM, and hypertension.

We found no significant difference between the three groups regarding rejection episodes (p> 0.05); however, the percentage of cases with chronic rejection was significantly higher in group III (p= 0.01) and this is matched with our primary report about the same groups. [11]

We found no statistically significant diffe­rence between the three groups regarding the number of patients with grade-a graft function both at one year and at the last follow-up [Table 4]. However, cases with grade-b graft function were significantly higher in group III at one year and at the last follow-up when compared with the other two groups (p= 0.001).

In addition, we found no significant diffe­rence between the three groups regarding post-transplant malignancies [Table 5]. How­ever, diabetic patients and those with serious bacterial infections were significantly more prevalent in group II. Patients with hepatic impairment were more prevalent in group I, possibly due to toxic effects of immuno­suppression and in group III, possibly due to both viral reactivation and toxic effects of immunosuppression (p< 0.05). Meanwhile, the number of hypertensive cases in the CsA groups (groups I and II) was significantly higher than that in the azathioprine group, and this is in accordance with Thiel et al, who reported that the main benefit of CsA was better graft survival up to five years and the chance to stay free of steroids. [2]

From this study, we can conclude that the long-term results of conventional therapy (ste­roid/azathioprine) without induction are satis­factory for live-donor kidney transplant. Chro­nic allograft nephropathy was significantly higher in group III, possibly due to the risk of CsA neph-rotoxicity. Groups with CsA­based protocols experienced many adverse reactions of CsA such as hypertension, DM, and chronic rejection. Nowadays, it is possible to achieve excellent calcineurin inhibitor-free regimen after introduction of induction therapy and utilization of newer maintenance immunosu-ppressive agents as MMF and rapamycin.

 
   References Top

1.Afzali B, Taylor AL, Goldsmith DJ. What we CAN do about chronic allograft nephro­pathy: Role of immunosuppressive modulations. Kidney Int. 2005;68(6):2429-43.  Back to cited text no. 1    
2.Thiel G, Bock A, Spondlin M, et al. Long-term benefits and risks of cyclosporin A (sandimmun)-an analysis at 10 years. Transplant Proc 1994;26(5):2493-8  Back to cited text no. 2    
3.Weir MR, Ward MT, Blahut SA, et al. Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy. Kidney Int 2001;59(4):1567-73.  Back to cited text no. 3    
4.Wahlberg J, Hanas E, Bergstrom C, Fellstrom B, Skarp-Orberg I, Frodin L Diltiazem treatment with reduced dose of cyclosporine in renal transplant recipients. Transplant Proc 1992;24(1):311-2.  Back to cited text no. 4    
5.el-Agroudy AE, Sobh MA, Hamdy AF, Ghoneim MA. A prospective, randomized study of coadministration of ketoconazole and cyclosporine in kidney transplant reci­pients: ten-year follow-up. Transplantation 2004;77(9):1371-6.  Back to cited text no. 5    
6.Grimbert P, Baron C, Fruchaud G, et al. Long-term results of a prospective rando­mized study comparing two immunosup­pressive regimens, one with and one without CsA, in low-risk renal transplant recipients. Transplant Int 2002;15(11):550-5.  Back to cited text no. 6    
7.Opelz G, Dohler B, for the Collaborative Transplant Study. Critical threshold of aza­thioprine dosage for maintenance immuno­suppression in kidney graft reci-pients: daily versus intermittent adminis-tration based on T-Cell monitoring. Transplantation 2000;69: 818-821.  Back to cited text no. 7    
8.Morales JM. Immunosuppressive treatment and progression of histologic lesions in kidney allografts. Kidney Int 2005;68(suppl 99):124-30.  Back to cited text no. 8    
9.Bakker RC, Hollander AA, Mallat MJ, et al. Conversion of cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy. Kidney Int 2003;64:1027-34.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Hamar P, Liu S, Viklicky O, et al, Cyclos­porine A and azathioprine are equipotent in chronic kidney allograft rejection. Trans­plantation 2000;69:1290-5.  Back to cited text no. 10    
11.Ghoneim MA, Sobh MA, Shokeir AA, Bakr MA, Elsherif A, Fouda MA. Prospective Randomized study of azathioprine vs. cyclosporine in live-donor kidney trans­plantation. Am J Nephrol 1993;13:437-41.  Back to cited text no. 11    

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Correspondence Address:
Osama A Gheith
Consultant of Internal Medicine and Nephrology, Urology and Nephrology Center, Mansoura University
Egypt
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PMID: 18580014

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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