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The role of thymoglobulin in renal transplantation


5 June, 2009  

Thymoglobulin’s ability to decrease ischaemic reperfusion injury, improve early graft function and decrease the rate of delayed graft function in kidney
transplantation means it could grab attention in the field

Hamidreza Fonouni MD Mohammad Golriz MD Jan Schmidt MD Arianeb Mehrabi MD Department of General, Visceral
and Transplantation Surgery Martin Zeier MD Department of Nephrology University of Heidelberg Heidelberg, Germany

Among numerous attempts to minimise graft damage in transplantation through the application of new immunosuppressive agents, thymoglobulin (TG), a rabbit derived polyclonal antibody, offers considerable benefits. With its anti-inflammatory effects and immunosuppressive potential, it decreases ischaemic reperfusion injury and the rate of delayed graft function and improves early graft function in kidney transplantation. Preserving a good functioning graft is one of the most important aspects of organ transplantation. Ischaemia reperfusion injury (IRI), which causes poor functioning grafts, increases length  of hospitalisation and decreases long-term graft survival, is among the most important causes of organ failure and can be minimised through different kinds of modalities. Using thymoglobulin is  one of them and offers potential benefits.

The mechanism of TG

Thymoglobulin is a cytotoxic antibody with antiinflammatory
effect and immunosuppressive potential directed against antigens expressed on human T-lymphocytes. It is obtained by immunising rabbits with human thymocytes and, since
1984, has been used in different fields such as transplantation, prevention and treatment of acute rejection, treatment of  plastic anaemia and prevention and treatment of graft versushost disease. With a direct and indirect effect, it reduces the degree of leukocyte rolling and adhering along capillary endothelial surfaces, inflammatory mediators and inhibits leukocyte chemotaxis or chemokine receptor expression.[1] Furthermore, inhibition of leukocyte homing and trafficking to the graft by binding to chemokine receptors is another way in which TG affects IRI.

Through inducing T-cell depletion, complement- related lysis or activation-associated apoptosis, TG reduces the number of peripheral lymphocytes from the circulating pool. Anergy and functional impairment of non-depleted lymphocytes and prevention of memory T-cell migration are some other effects. Preventing delayed graft function (DGF) and minimising the IRIrelated problems in the transplanted organ can be done using TG as a polyclonal agent, directed against molecules participating in IRI. In heart transplantation models, TG treatment induced a dose-dependent lymphocytopenia and T-cell depletion in spleen and lymph nodes due to T-cell apoptosis. Beiras-Fernandez et al could show that TG not only increased the rate of apoptosis in leukocyte but also protected the reperfused tissue against IRI.[1]

The role of TG in reducing IRI in kidney
transplantation
In 1999, Brennan et al stated that a brief (sevenday) induction therapy with TG in renal transplant recipients significantly decreased the incidence and severity of acute rejection and led to a better event-free survival than Atgam. Furthermore, less post-transplant cytomegalovirus (CMV) infection and fewer serious adverse events were seen in TG-treated patients.[1] However, in another study the limited dosing regimen of daclizumab with mycophenolate mofetil (MMF), steroids and delayed cyclosporine A introduction in comparison to TG has not shown significant difference in incidence of CMV infection.[2]

Research in 2006 showed that induction therapy consisting of a five-day course of TG, as compared with basiliximab, reduced the incidence and severity of acute rejection.[3] Moreover, Agha et al showed that a three-day course of TG induction was as effective as a seven-day course treatment without any significant differences in acute rejection, graft and patient survival. Peddi et al found that intermittent TG therapy was safe and associated with a low acute rejection rate, which results in a significant reduction of the total cumulative dose and costs.[1] TG has also been considered safe and effective as induction therapy in paediatric renal transplant patients by Colleen Hastings et al.[2]

According to Khosroshahi et al, prophylactic administration of a single- and low-dose TG the night before kidney transplantation (KTx) could reduce the risk of acute allograft rejection in renal transplant recipients.[4] Wong et al showed that after six months’ monitoring of three-day TG-based therapy the induction therapy of TG with different dosages in addition to maintenance immunosuppression was efficacious in both groups, with a significantly sustained T-cell clearance in the higher doses of TG.[5] Moudgi et al believe that in patients at high risk of graft loss TG may be the preferred choice for induction therapy, while for all other patients IL-2 receptor antagonists should be considered the first-line choice for induction therapy.[2]

In another study by Requião-Moura et al, immunological induction with TG produced excellent graft survival after one year.[6] In addition, Matas et al showed that intraoperative TG induction therapy in 51 patients allowed rapid steroid withdrawal without significant differences in six-month and 12-month patient and graft survival. Goggins et al mentioned that intraoperative TG administration was beneficial regarding DGF and length of hospitalisation.

In a further study by Knight et al, they suggested that the strategy of treatment should be a combination of basiliximab with sirolimus for low-immunological-risk recipients and TG with sirolimus for high-immunological-risk recipients. In other research, Cravedi et al concluded that in recipients with delayed graft function early TG treatment with delayed cyclosporine administration accelerated kidney function recovery and significantly decreased the rate of acute rejection, leading to shorter hospitalisation time and reduced treatment cost.

In 2006, for the first time, the benefits of TG in improving clinical outcome and reducing the complications in living donor KTx were declared.[1] In KTx alemtuzumab with lower-dose maintenance, immunosuppression has been reported to be less effective than either TG or daclizumab with higher maintenance immunosuppression.[7] In the short term, after kidney and pancreas transplantation, alemtuzumab and TG induction therapies were shown to be similarly safe and effective.[8] Finally, in a study on HIVinfected renal transplant recipients who received TG as induction therapy, it appeared to be safe at
a median follow-up of 24 months.[9]

Side-effects of thymoglobulin
Anaemia, thrombosis, thrombocytopenia and neutropenia can occur due to cross-reaction of TG with antibodies. Leukopenia has been reported when TG was used to reverse rejection. Some authors reported prophylactic hydrocortisone and heparin administration before peripheral TG induction for decreasing the risk of thrombosis.

As with other antibody preparations, cytokine release syndrome (fever, chills, tachycardia and hypotension) and serum sickness can occur, with the overall incidence of adverse events and infections appearing similar to other T-cell-depleting antibody agents.[1] However, TG usage has been considered to be associated with increased infectious complications after transplantation in some other studies.[10] Although controversial, the development of post-transplant lymphoproliferative disorder (PTLD) is another proposed side-effect of TG usage.

It has been shown that patients treated with TG had a significantly increased risk of developing lymphoma. This reaction is probably caused by inhibition of T-cell control, which allows the uninhibited proliferation of B-cells. However, treatment with lower doses of polyclonal antibodies such as TG, unlike OKT3 and high-dose steroid therapy, has not been accompanied by subsequent development of PTLD.[1]

Conclusion

In summary, as TG can decrease IRI, improve early graft function and decrease the rate of DGF in KTx as well as the chance of subsequent graft failure, it could gradually achieve scientists’ consideration in the field of transplantation. A reduction in the incidence of acute rejection in KTx recipients and a decrease in length of hospitalisation and costs could be other benefits. Through improving long-term graft and patient survival rates, increasing the possibility of using marginal donors, TG might play an important role in expansion of the donor pool

References
1. Mehrabi A, Mood ZhA, Sadeghi M, et al. Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. Nephrol Dial Transplant 2007;22 Suppl 8:viii54-viii60.
2. Abou-Ayache R, Büchler M, Lepogamp P, et al. CMV infections after two doses of daclizumab versus thymoglobulin in renal transplant patients receiving mycophenolate mofetil, steroids and delayed cyclosporine A. Nephrol Dial Transplant 2008;23(6):2024-32.
3. Moudgil A, Puliyanda D. Induction therapy in pediatric renal transplant recipients: an overview. Paediatr Drugs 2007;9(5):323-41.
4. Khosroshahi HT, Tubbs RS, Shoja MM, et al. Effect of prophylaxis with low-dose anti-thymocyte globulin on prevention of acute kidney allograft rejection. Transplant Proc 2008;40(1):137-9.
5. Wong W, Agrawal N, Pascual M, et al. Comparison of two dosages of thymoglobulin used as a short-course for induction in kidney transplantation. Transpl Int 2006;19(8):629-35.
6. Requião-Moura LR, Durão MS, Tonato EJ, et al. Effect of thymoglobulin in graft survival and function 1 year after kidney transplantation using deceased donors. Transplant Proc 2006;38(6):1895-7.
7. Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of thymoglobulin vs. alemtuzumab (with lower dose maintenance immunosuppression) vs. daclizumab in renal transplantation at 24 months of follow-up. Clin Transplant 2008;22(2):200-10.
8. Farney A, Sundberg A, Moore P, et al. A randomized trial of alemtuzumab vs. anti-thymocyte globulin induction in renal and pancreas transplantation. Clin Transplant  008;22(1):41-9.
9. Trullas JC, Cofan F, Cocchi S, et al. Effect of thymoglobulin induction on HIV-infected renal transplant recipients: differences between HIV-positive and HIV-negative patients. AIDS Res Hum Retroviruses 2007;23(10):1161-5.
10. Clesca P, Dirlando M, Park SI, et al. Thymoglobulin and rate of infectious complications after transplantation. Transplant Proc 2007;39(2):463-4.