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Year : 2002  |  Volume : 19  |  Issue : 1  |  Page : 58-62

Prospective randomized trial to evaluate the efficacy of single low dose ATG induction in renal transplant recipient with spousal kidney

Departments of Urology & Kidney Transplantation & Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Correspondence Address:
Anant Kumar
Department of Urology and Kidney Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014
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Source of Support: None, Conflict of Interest: None

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Objective: To see the efficacy and safety of single low dose ATG induction on graft survival, rejection, infection and development of malignancy in spousal renal trans­plant recipient.
Materials and Methods: A prospective randomized trial was conducted between July 1996-January 2000. Single dose (3.5-5 mg/kg) ATG induction was used in 30 patients while 30 patients were taken as control. Standard triple drug immunosuppression was given to both the groups, while study received additional single shot of rabbit ATG (Fresenius, Germany: 200 mg in 200 ml of saline). The patients were followed up for a mean of 30.4 months (range 19-46 months) in both groups. Graft function, rejections, episodes, anti-rejection therapy, infections and develop­ment of malignancy was analyzed at the last follow-up.
Result: There were 24 males and 6 females in control group with a mean age of'44.26 years and 26 males and 4 females in control group with a mean age of 41.26 years. Patients' characteristics in both the groups were compa­rable. A total of 26 (86.3%) patients in induction and 24(80%) patients in control group were evaluated at last follow-up (mean 30.4 vs. 30.2 months). Stable graft func­tion was present in 83.3% patients in induction versus 70% in control group. Impaired graft, function (serum creati­nine >2 mg%) was present only in 10% of control group and none of the patients in the study group at last follow­up. The total number of rejections were 23.3 and 43.3% in induction and control group respectively. 2 patients in each group who developed multiple episodes of rejection progressed to chronic rejection. Steroid resistant rejec­tions were less with induction therapy than with control group (14.4 vs. 30.7%). Apart from increased urinary tract infections in study group (46.7 vs. 23.3%), infection at other sites were comparable in both the groups. 2 patients in study group and 4 patients in control group died with, functioning graft due to medical problems. 2 patients were lost to follow-up in both the groups. I patient required graft nephrectomy in induction group, due to severe graft dysfunction with significant proteinuria.
Conclusion: Single shot low dose ATG induction therapy reduces the rejection episodes (p=0.05), but it has not shown any improvement in graft survival at 2'/z years. It is associated with higher urinary infection rates. How­ever, long-term, follow-up is needed to see any benefit of less rejection on long-term graft survival.

Keywords: Kidney Transplant; Spousal Donation; ATG Induction Therapy; Unrelated Transplant

How to cite this article:
Kumar A, Zaman W, Chaurasia D, Gupta A, Sharma RK, Gulati S. Prospective randomized trial to evaluate the efficacy of single low dose ATG induction in renal transplant recipient with spousal kidney. Indian J Urol 2002;19:58-62

How to cite this URL:
Kumar A, Zaman W, Chaurasia D, Gupta A, Sharma RK, Gulati S. Prospective randomized trial to evaluate the efficacy of single low dose ATG induction in renal transplant recipient with spousal kidney. Indian J Urol [serial online] 2002 [cited 2022 Jun 30];19:58-62. Available from:

   Introduction Top

Live related renal transplants have better outcome than unrelated renal transplant due to better HLA match. Spouses are completely mismatched and only accepted when no other related donor is available. Acute rejection in early posttransplant period is a bad prognostic factor in long-term graft survival. So, if we cut down the rejection rate, we can improve survival in spousal renal transplant. Induction therapy with polyclonal antibodies (for 10-14 days) have shown decrease in rejection rate and subse­quent improvement in graft outcome. [1],[2]

Single shot high dose (8-9 mg/kg) ATG induction has also shown better graft and patient survival in renal trans­plant recipient. [3] Such a high dose is economically not vi­able in developing countries, so we planned a low dose single shot induction in spousal (emotionally related) re­nal transplant recipient to see its efficacy and safety on graft survival, rejection, infection and the risk of malig­nancy.

   Materials and Methods Top

A prospective randomized trial was conducted between July 1996 and January 2000. A total of 60 emotionally related (spouse) patients were included in the study. Due to financial constraints randomization was based on afford­ability to bear the cost of ATG. Those who could afford the cost were included in the study group and those who couldn't became the control. Both groups were trans­planted in the same week by the same team. 30 patients were recruited in the study group (ATG induction) with 24 males and 6 females with a mean age of 44.26 years (range 27-57 yrs) and 30 patients were taken as control with 26 males and 4 females with a mean age of 41.26 years (range 20-62 yrs) [Table - 1]. Patients' characteristics were comparable in both the groups. All patients were transplanted at a single center and by the same team. Pa­tients' recruitment in the study was stopped in March 1998.

All recipients in both the groups received standard triple drug immunosuppression including prednisolone, azathio­prine and cyclosporine. Peroperatively patients received 500 mg of hydrocortisone before releasing the vascular clamp. Recipients in study group received an additional dose of 200 mg of ATG (Fresenius, Germany) which was dissolved in 200 ml of saline and the infusion was started at induction of anesthesia and was completed before revascularization of the graft. Since patients' weights were variable and dose of ATG was fixed, so the dose varied from 3.5 mg-5 mg/kg (mean 4.1 mg/kg).

Patients were followed up at regular intervals with re­nal function test, white cell counts, and hemoglobin and cyclosporine trough level. Whenever acute rejection was clinically suspected, a renal biopsy was performed in all cases except in those who refused, and antirejection treat­ment was started. All mild cellular rejections were treated with methylprednisolone while severe cellular and/or vas­cular rejections were treated with monoclonal or polyclonal antibodies. All patients were evaluated for rejection epi­sodes, infections, complications and development of ma­lignancy. The clinical characteristics and the differences in transplant outcome between the 2 groups were com­pared using the Fisher exact `Z' test and student `t' test. A p value of <0.05 was considered significant with all tests.

   Results Top

Out of 30 patients in each group, 26 patients (86.3%) in induction group and 24 patients (80%) in control group were evaluated at last follow-up with a mean follow-up of 30.4 months in induction and 30.2 months in control group. There were 6 deaths, 2 in induction and 4 in control group due to medical problems. 2 patients were lost to follow­up in each group and we presume they are dead or on maintenance dialysis. I patient in induction group required graft nephrectomy at 3 months due to severe graft dys­function and significant proteinuria. 25 patients (83.3%) in induction group while 21 patients (70%) in control group have stable graft function. 3 patients in control group have impaired graft function with a serum creatinine of >2 mg%. [Table - 2] The acute rejection episodes were more frequent in control group than in study group (43.3 vs. 23.3%). There were 9 (30%) and 8 (26.6%) biopsy proven rejec­tions in control and induction group respectively. 6 (20%) rejections in control group and 1 (3.3%) in induction group was treated on clinical suspicion, as these patients refused for biopsy. Most of these rejections occurred within first 3 months after transplant. 2 patients in each group, who de­veloped multiple episodes of rejection, progressed to bi­opsy proven chronic rejection [Table - 3]. Most of the rejection in induction group (85.7 vs. 69.3%) responded to antirejection treatment with steroid, while control group patients witnessed more steroid resistant rejections (30.7 vs. 14.3%) and subsequently required antirejection treat­ment with monoclonal or polyclonal antibodies [Table - 4]. More episodes of urinary tract infections were noted in induction group than in control group (46.7 vs. 23.3%) while infection at other sites were comparable in both the groups. 2 patients in each group developed pulmonary tu­berculosis. I patient in induction group, who was already suffering from pulmonary tuberculosis, developed meta­static bone tuberculosis at left ankle requiring prolonga­tion of antitubercular treatment and surgical drainage. 1 patient in induction group developed diabetic foot and was managed successfully with antibiotics and surgical exci­sion and drainage [Table - 5]. The follow-up ranged from a mean of 30.4 (range 24-46 months) and 30.2 (range 24­48 months) in induction and control group respectively [Table - 1]. The patient and graft survival at last follow-up was 86.3% vs. 83.3% in induction group and 80% vs. 70% in control group [Figure - 1].

   Discussion Top

The role of better matched HLA-graft is well established even in cyclosporine era. 6 antigen matched grafts do bet­ter than zero antigen matched grafts in live related as well as in cadaver renal transplant. [4] Live unrelated transplant has better outcome than six-matched cadaver graft, but its long-term graft outcome is still inferior to live related trans­plant. [5] Since live grafts are precious and spouses are taken only when no live related donor is available [6],[7],[8] we wished to increase long-term graft survival in this group of pa­tients as they are completely HLA-mismatched. To in­crease the graft survival, we should prevent the occurrence of acute rejections, which is a known prognostic factor for long-term graft survival. ATG induction has been shown to decrease rejection episode and thus improves long-term graft survival.

Kaden et al in 1992 introduced two forms of ATG pro­phylaxis along with standard triple drug immunosuppres­sion. High dose single bolus prophylaxis (9 mg/kg) in non sensitized patients (PRA <5 %) and a low dose 8 day prophy­laxis (1.5-3 mg/kg) in sensitized patients (PRA>5%).He reported low rejection episodes and improved 1-year pa­tient and graft survival in both the groups. The rationale was to produce maximal immuno-suppression when the recipient was most likely to respond to the new organ. [3] Zietse et al used single shot high dose (8 mg/kg) rabbit ATG for rejection prophylaxis 6 hours after kidney transplantation and reported that it is a cost-effective induction scheme.

With a low incidence of delayed graft function and acute rejection episodes but associated with a relatively high incidence of vascular thrombosis of the graft, [9] Kaden et al suggested shifting of the application of antilymphocytic antibodies from posttransplant to pretransplant period and hypothesized that sensitization of recipients begins with opening the anastomosis (i.e., removing of clamps) and basic immunosuppressive drugs need time to establish an efficient blood level. [10] One possibility to overcome this drawback is the application of antilymphocyte antibodies in a sufficient dosage that guarantee a strong and immedi­ate effect on the recipient's immune system before it rec­ognizes the foreign antigenic material. He reported significantly delayed onset of acute rejection as well as decrease in rejection episodes and increased methylpred­nisolone sensitivity of first rejection episodes. The 3-year graft survival was significantly better in ATG bolus group than in recipients without ATG induction (87.2% vs. 71.6%). High dose ATG bolus produced reduction in T­cell count at the time of completion of anastomosis. Un­der anaesthetic condition in the operation theatre along with steroid use, the ATG induced cytokine release did not lead to any serious side effect and ATG infusion did not need to be stopped in any of our patients.

Thibaudin et al in a randomized prospective trial com­pared induction with and without ATG in addition to a standard triple drug regimen in sensitized kidney allograft recipients and reported that low dose (0.5-1.3 mg/kg/day) ATG induction for 10 days is beneficial for all sensitized patients (regardless of their level of sensitization) with regard to acute rejection episodes, graft survival and graft function. ATG induction also delayed the onset of the first rejection episode. [11]

Szczech et al in a meta-analysis on the effect of ATG induction therapy on renal allograft survival reported a beneficial effect of induction therapy on allograft survivial. The allograft survival was prolonged with induction therapy compared with standard triple drug immunosup­pression. [12]

Same authors in 1998 published a meta-analysis of individual patient level data on the effect of ATG induction therapy on renal allograft survival and reported that ATG induction showed a benefit at 2 years, which had contin­ued at 5 years also. [13] As high dose or prolonged duration of induction with ATG is very expensive and could not be afforded by our patients, so we were looking for a less expensive modality like low dose single shot ATG induc­tion that may decrease the rejection rate without increas­ing other complications.

Our study showed no benefit in graft survival at 2½ years with ATG induction while it has reduced the rejec­tion episodes (P=0.05). Whether this will reflect in 5-10­year graft survival is difficult to say. We will follow these patients and will report long-term graft survival.

   Conclusions Top

Single shot low dose ATG induction therapy reduces the rejection episodes, but it has not shown any improve­ment in graft survival at 2½ year. It is associated with higher urinary infection rates. However, long-term follow­up is needed to see any benefit of less rejection on long­term graft survival.

   References Top

1.Kormos RL, Armitage JM, Dummer JS, Miyamoto Y, Griffith BP. Hardesty R. Optimal perioperative immunosuppression in cardiac transplantation using rabbit antilymphocyte globulin. Transplanation 1990; 49: 306-311.  Back to cited text no. 1    
2.Grino JM, Bas J. Gonzalez C, Castelav AM. Seron D, Mestre M. Buendia E. Sabate R, Diaz C, Alsina J. Low incidence of rejection and in vitro donor-specific hyporesponsiveness using pretransplant ALG, low dose cyclosporine and steroids in kidney cadaveric trans­plantation. Transplant Proc 1990; 22: 1368-1376.  Back to cited text no. 2    
3.Kaden J. May G, Schonemann C, Muller P, Goth J. Seeger W, Seibt F. Henkert M, Lippert J : Effect of ATG prophylaxis in sensi­tized and non-sensitized kidney graft recipient. Transplant Int 1992: 5 (suppl 1): 575-578.  Back to cited text no. 3    
4.Ponticelli C. Civati G, Tarantino A. Quarto di Palo F et al. Ran­domized study with cyclosporine in kidney transplantation: 10-year follow-up. J Am Soc Nephrol 1996: 7(5): 792-7.  Back to cited text no. 4    
5.Lowell JA, Bernnan DC, Shenoy S. Hagerty D, Miller S et al. Liv­ing unrelated renal transplantation provides comparable results to living related renal transplantation. Surgery 1996; 119(5): 538-43.  Back to cited text no. 5    
6.Dominguez J, Zayas E, Malave M. Gonzalez Z, Morales LA, Mora ER. Santiago Delpin EA. Living emotionally related donor trans­plantation as an approach to donor shortage. Transplant Proc 1997: 29: 187-189.  Back to cited text no. 6    
7.Cloix P. Marrast AC. Lefrancois N et al. Renal transplantation be­tween spouses. Transplant Proc 1996; 28(5): 2802.  Back to cited text no. 7    
8.Terasaki P1. Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated do­nors. N Engl J Med 1995: 10: 333-6.  Back to cited text no. 8    
9.Zietse R, Van Steenberge EPM, Hesse CJ, Vaessen LB et al. Sin­gle-shot. high-dose rabbit ATG for rejection prophylaxis after kid­ney transplantation. Transpl Int 1993; 6: 337-340.  Back to cited text no. 9    
10.Kaden J, May G, Strobelt V, Groth J, Muller P. Intraoperative T­cell depletion prior to completion of anastomosis by high dose sin­gle ATG bolus as a new approach to improve long-term results after kidney transplantation. Transplant Proc 1997: 344-347.  Back to cited text no. 10    
11.Thibaudin D. Alamartine E. de Filippis JP et al. Randomized pro­spective study comparing induction with and without ATG in sen­sitized kidney allograft recipient. Nephrol Dial Transplant 1998: 13: 711-715.  Back to cited text no. 11    
12.Szczech LA, Berlin JA, Aradhye SR, Grossman RA. Feldman HI. Effect of antilymphocyte induction therapy on renal allograft sur­vival : A meta-analysis. J Am Soc Nephrol 1997: 1771-1777.  Back to cited text no. 12    
13.Szczech LA, Berlin JA, Feldman HI. The effect of antilymphocyte induction therapy on renal allograft survival. A meta-analysis of individual patient-level data. Ann Intern Med 1998: 128: 817-826.  Back to cited text no. 13    


  [Figure - 1]

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

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