|Year : 2002 | Volume
| 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
Anant Kumar, Waheed Zaman, Dilip Chaurasia, Amit Gupta, Raj Kumar Sharma, Sanjeev Gulati
Departments of Urology & Kidney Transplantation & Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
Department of Urology and Kidney Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014
Source of Support: None, Conflict of Interest: None
| Abstract|| |
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 2020 Oct 22];19:58-62. Available from: https://www.indianjurol.com/text.asp?2002/19/1/58/20293
| Introduction|| |
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. ,
Single shot high dose (8-9 mg/kg) ATG induction has also shown better graft and patient survival in renal transplant recipient.  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|| |
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|| |
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|| |
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.  Live unrelated transplant has better outcome than six-matched cadaver graft, but its long-term graft outcome is still inferior to live related transplant.  Since live grafts are precious and spouses are taken only when no live related donor is available ,, 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.  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,  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.  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. 
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. 
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.  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|| |
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|| |
|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. |
|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. |
|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. |
|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. |
|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. |
|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. |
|7.||Cloix P. Marrast AC. Lefrancois N et al. Renal transplantation between spouses. Transplant Proc 1996; 28(5): 2802. |
|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. |
|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. |
|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. |
|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. |
|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. |
|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. |
[Figure - 1]
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]
|This article has been cited by|
||Efficacy and safety of single and multiple dose antithymocyte globulin induction treatment in living related renal transplantation
| ||RadivojeviÄ‡, D. and BlagojeviÄ‡-LaziÄ‡, R. and RistiÄ‡, S. and LauÅ¡eviÄ‡, M. and LeÅ¾aiÄ‡, V. |
| ||Biomedicine and Aging Pathology. 2011; 1(2): 78-83 |