The history of renal transplantation dates back to 1954, when in Boston a surgery was performed on identical twins following a report of an unsuccessful renal transplantation attempted earlier. The recipient survived for one year, which is much a longer period when compared with the previous one which lasted for only 3 days. The subsequent development in the field of biochemistry like the HLA antigen description in 1958, and better understanding of immunology, in 1959, an attempt was made to prevent the loss of the kidney graft by the total body irradiation to remove the immune cells attacking the grafted allogenic kidney. In 1961, thanks to the efforts made by the scientific community, the first immunosuppressant was made available to the rescue of the patient. In the subsequent year, the corticosteroid was also added to the regimen to prevent the graft rejection.
In 1966, the direct cross-matching between the donor lymphocytes and recipient's serum was done before attempting the transplantation. During the mid-1970s, the knowledge of the scientific community grown to such an extent that brain death was legalised in America.
1978 is the golden year as far as the transplantation community is concerned. This is the year the first clinical trial in Cyclosporine was initiated. After that the biotechnology also paved its entry in this field offering the first monoclonal antibody to prevent the hyper acute rejection that was a menace, even after a series of clinical tests like HLA matching, ABO matching, Cross-matching, etc., to confirm the success of renal transplantation in the recipient.
Around 300 patients per million populations begin to dialysis on a year. The predisposing factors include a history of hypertension, diabetes mellitus, and glomerulonephritis. Transplantation of the kidneys is the preferred one, because of increased survival observed when compared with the dialysis. On comparing the transplantation with the dialysis, the former enjoys the patient friendly benefits like cost effectiveness, near normal lifestyle, and improved survival.
The histocompatibility of the donor and the recipient should be done in order to prevent the graft rejection episodes is a hard learned lesson in the field of transplantation. The following are matched between the donor and recipient.
1. ABO blood group
2. Major Histocompatibility Complex (MHC)
3. Panel Reactive Antibody (PRA) and
4. Cross-matching
Out of these the panel reactive antibody reflected as a percentage which relates to presence of antibodies (recipient) to HLA molecules of the donor. The higher the PRA, the more "sensitized" the recipient is and more likely to get a positive cross match and rejection after transplantation.
This may be due to prior pregnancy, blood transfusions, and transplantations, and the patients are termed as "high risk" for rejection.
In cross-matching, the B cell of the recipient is cross-matched with the T cell of the donor. This is the easiest procedure to find out the cross-match, by incubating the donor lymphocytes with the recipient's serum. This procedure had virtually eliminated the hyper-acute rejection episodes.
The following kinds of immune reactions are said to occur in the transplantation.
Cell mediated immunity: Cell to cell contact resulting in mature T cell activity.
Humoral mediated immunity: This occurs by virtue of the antibodies produced by the B lymphocytes.
Antigen Presenting Cells: (AP cells), Natural Killer cells (NK cells), Polymorphonuclear cells (PMN cells), monocytes, and macrophages also can pick up antigens and present them to the T cells, stimulating an immune response.
Types of rejection
Hyper-acute rejection: Occurs within minutes to hours of release of clamps of the circulatory system of kidneys during the surgical procedure. The effects produced as so fast that the damage caused is irreversible. This may be a result of preformed circulating antibodies. This is a very rare if the cross-match is negative. This results in activation of complement, leading to thrombosis or vascular injury, ischemia, and finally grafts loss. Some times, this may be fatal to the patient too.
Accelerated acute rejection: Occurs within 24 hours to 4 days after transplant. This also occurs due to the prior sensitisation of the recipient to the donor antigens due to transfusions and/or prior transplants. This is mediated by both cellular and humoral mechanisms. This condition is very difficult to treat.
Acute rejection: Occurs days to weeks after transplant. Approximately 90% are cellular mediated and easier to treat. 5 to 10% of these cases are due to humoral mediated. These patients present the constitutional symptoms of cytokine release (TNF a, IL-1 and 2, etc.,) The majority of patient follow the path tubulitis, vasculitis and perivascular infiltration.
Chronic rejection: Occurs over months to years with progressive graft loss associated with the diminished renal functioning. Etiology is not clearly known, but probably multi-factorial elements may predispose this kind of rejection. This may involve immune, non-immune mechanisms, drug toxicity, chronic ischemia, repeated bouts of acute rejection, etc.
Immunosuppressantas
The main stay of treatment for the post-transplant complications is by the immunosuppressant drugs like the following:
i. Steroids
ii. Calcineurin inhibitors
iii. Target of Rapamycin (TOR) inhibitors
iv. Anti-lymphocyte antibodies
v. Anti-IL-2 receptor antibodies
vi. Anti-proliferative agents
vii. Allo-antibody modulation.
Calcineurin inhibitors
The critical example for this class of drugs is Cyclosporine (Sandimmune and Neoral), which is a small polypeptide of fungal origin. This binds to cyclophillin (the receptor protein for cyclosporine) to form a complex, which inhibits the cytokine production by binding to the calcineurin. The latest addition to the same class that claimed to have reduced side effects to cyclosporines is the Tacrolimus (Prograf, and FK 506). This is a macrolide compound, which specifically binds to the binding protein, FKBP, and this complex then deactivates the calcineurin, thereby the cytokine production is hindered.
The problem with this class of drugs is that their serum levels have to be monitored continuously because of their potential to cause renal toxicity by themselves, due to the vasoconstrictive properties. Other side effects include hyperkalemia, hyperlipidemia, tremor, diabetogenesis, gingival hyperplasia, and renal insufficiency. They are inactivated by the Cytochrom P 450 enzyme systems and care should be exercised in patients taking enzyme inducers.
TOR inhibitor
They are a class of drugs similar to tacrolimus, bind to FKBP, but does not block calcineurin. Instead, engages to a regulatory protein called target of rapamycin (TOR), whose inhibition reduces cytokine dependent cellular proliferation at the G1 to S phase of the cell division cycle. The example of this class of drug is Sirolimus (Rapamune). It has been proven that this drug produces less nephrotoxicity compared to the cyclosporines or Prograf. They are also inactivated by Cytochrom P 450 enzyme and the precaution for Calcineurin holds good here too.
Anti-lymphocyte antibodies
Antibodies like OKT3 and Thymoglobulin (Atgam) are used for induction treatment of rejection, not for maintenance of immunosuppression, because of the well know side effect of inducing the immune reaction and causing the rejection of the graft.
Anti-IL-2 antibodies:
Daclizumab (Zenapax) and Basiliximab (Simulect) are the typical examples of this class of drug. They inhibit the IL-2 receptors and thereby activation of the T cells. Since the former is more humanized, they have a long half life of more than 7 days. They too are used only for induction treatment and not for maintenance.
Anti-proliferative agents
Mycophenolate mofetil (Cellcept) and Azathioprine (Imuran) belong to this class. MMF is a reversible inhibitor of the IMP dehydrogenase (IMPDH), which is a critical enzyme of the de novo pathway of purine and guanosine synthesis. Lymphocytes rely only on the de novo synthesis more than other cells and they are selectively inhibited by these drugs. The target is down stream from antigen recognition or signal transduction. Essentially blocks the proliferation of lymphocytes. Greater immunosuppression is observed in the Indian population as compared to the Western population and low doses are preferred in India.
The second drug, Azathioprine, is used for almost 30 years in the transplantation and has widely accepted efficacy profile. The cause of concern is the bone marrow depression that is caused by this drug and now-a-days are not much preferred due to this effect, as well as the availability of newer forms of therapy with reduced side effects. The treatment and management of renal transplant is a separate specialty and more emphasis is done in finding out new targets and new lines of therapy.
Some useful resources
1. www.medscape.com/px/transplant.htm
2. www.kidneyinternational.com/transplantation.htm
3. www.mayoclinic.com/123487.htm
(The authors are from Pharmacy Group, Birla Institute of Technology and Science, Pilani 333031. anantha@bits-pilani.ac.in)