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Transplantation
Immunosuppressive Drugs After Renal Transplant
Antonio Dal Canton and Ciro Esposito
Unit of Nephrology, University of Pavia School of Medicine
The introduction of cyclosporine into clinical practice in the 1980s has rejections is maximal during the first four to six months after
dramatically improved one-year kidney transplant survival and reduced transplantation. These considerations have led to the concept of
rejection episodes. However, improvement of long-term outcomes has temporal intensity of immunosuppression with higher levels of
not changed and five-year graft survival rates are still far below 80%; in immunosuppression at the moment of kidney transplant and during the
fact, data from the European Renal Assosciation – European Dialysis and early phase after transplantation, which are then tapered over time.
Transplant Association (ERA-EDTA) registry showed only modest Induction therapy has significantly reduced the incidence of acute
improvement in actual kidney graft half-lives. Several studies have rejection in kidney transplanted patients.
5
indicated chronic allograft nephropathy (CAN) and death with a
functional graft
1–3
as principal causes of late kidney graft loss. Although Early induction protocols used polyclonal antilymphocyte globulin (ALG)
the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus remain the and antithymocyte globulin (ATG) with high-dose steroids. In the 1980s
cornerstones of immunosuppressive therapy, they are both characterised OKT3, a murine antiCD3 monoclonal antibody, and Thymoglobulin, a
by chronic nephrotoxicity and can contribute to chronic allograft rabbit antithymocite globulin (RATG), became available. However,
nephropathy. These considerations have prompted the development of during the last decade there has been a shift towards the use of
new immunosuppressive agents and protocols, the goal of which has humanised and chimeric anti-interleukin-2 (IL-2R) monoclonal
shifted from acute rejection prophylaxis to management of chronic antibodies, which has opened a new era in the induction therapy of solid
allograft nephropathy and minimisation of total immunosuppression. The organ transplantation.
6,7
aim of strategies focused on minimising total immunosuppression would
be the reduction of unwanted side effects and the preservation of graft Polyclonal Lymphocyte-depleting Antibody
function without any increase in rejection rate. The newer therapeutic Antilymphocyte and antithymocyte polyclonal antibodies suppress T-cell-
approaches have included steroid minimisation or withdrawal and CNI mediated immune response by binding to a wide range of antigens on
dose reduction or replacement with new drugs such as rapamycin. In this T-cell membrane, leading to prolonged depletion of T cells. In addition,
brief overview we will attempt to provide a critical analysis of current they prevent the activation of B cells by different stimuli. As
developments in immunosuppressive drugs and protocols in the demonstrated by the United Network for Organ Sharing (UNOS),
induction and manteinance of therapy in renal transplantation. lymphocyte-depleting antibodies are preferentially used in patients at
high immunological risk such as immunised patients or patients with
Induction Therapy delayed graft function.
5
Several non-randomised studies have shown a
Acute rejection during the first year post-transplant is a predictor of graft reduction in the rate of rejection with polyclonal antibodies.
8,9
Although
survival after renal transplantation.
4
Furthermore, the rate of acute they share a common immunosuppressive mechanism, their potency
varies and significant differences in outcome have been reported.
10
According to the majority of the literature, Thymoglobulin as induction
Antonio Dal Canton is a Professor of Nephrology at the
University of Pavia School of Medicine, Policlinico San
therapy offers better results than other polyclonal antibodies. In fact, as
Matteo, Pavia, Italy. In 1996 he became Head of the reported by Brennan et al.,
11
fewer patients experienced acute rejection
Department of Internal Medicine and Nephrology in Pavia.
with Thymoglobulin than with ATGAM. Furthermore, death, graft
He was previously Head of Nephrology in Catanzaro in
1987, after becoming Full Professor in 1986. Professor Dal
survival and rejection episodes were still lower at five years in patients
Canton serves on the Editorial Board of many journals and
treated with Thymoglobulin. However, the drawbacks of this class of
is also a member of many nephrology societies. He
graduated in medicine from the Parma School of Medicine
lymphocyte-depleting antibodies are the common adverse effects: fever,
in 1971. leucopoenia, thrombocytopoenia, tachycardia, their immunogenicity
E: dalcanton@smatico.pv.it
with the emergence of anti-isotypic antibodies and the short half-life
requiring daily administration (which increases their cost). Finally,
Ciro Esposito is a Professor of Nephrology at the University
of Pavia School of Medicine, Policlinico San Matteo, Pavia,
polyclonal antibodies increase the risk of lymphoma and solid tumours.
Italy. He became Associate Professor of Nephrology in 2000,
having first specialised in nephrology in 1986. Professor
Monoclonal Lymphocyte-depleting Antibody Therapy
Esposito serves on the Editorial Board of the Journal of
Nephrology and Giornale Italiano di Nefrologia and is a Unfortunately, the first and only monoclonal antibody introduced in
member of many societies, including the European Dialysis
clinical practice, muronobam CD3 (OKT3), did not prove to be better
and Transplant Association (EDTA), the American Society of
Nephrology (ASN) and the International Society of
than polyclonals. OKT3 deactivates the CD3 portion of the T-cell
Nephrology (ISN). He graduated in medicine in 1982. receptor blocking the rejection response, thus it can prevent and
reverse acute rejection. However, as an induction agent it
70 © TOUCH BRIEFINGS 2007
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