Immunosuppression in Kidney Transplantation PDF

Immunosuppressants use in kidney transplantation  The recipient recognizes the transplanted graft as either self or foreign. This recognition is based on the recipient’s reaction to histocompatibility antigens. Histocompatibility antigens  The panel-reactive antibody (PRA) In thi...

Immunosuppressants use in kidney transplantation  The recipient recognizes the transplanted graft as either self or foreign. This recognition is based on the recipient’s reaction to histocompatibility antigens. Histocompatibility antigens  The panel-reactive antibody (PRA) In this test, the recipient’s serum is tested against a cell panel of known HLA specificities that are representative of possible donors in the general population. The percentage of cell reactions (recipient with potential donor) determines a recipient’s PRA The potential recipient with a higher percentage of PRA (>20%–50%) is at higher risk for rejection and will generally a have longer wait time for a kidney than patients with PR A cytotoxic and/or flow cytometry lymphocyte cross-match the potential recipient’s serum is cross-matched to determine whether preformed antibodies to the donor’s lymphocytes are present. A positive cross-match indicates the presence of recipient cytotoxic IgG antibodies to the donor. In kidney transplantation, a positive cross-match is usually considered a contraindication. ABO blood typing ABO blood typing is one of the most critical of all evaluations Transplantation of an organ with ABO incompatibility typically results in a hyperacute rejection and destruction of the graft, although in kidney transplant, newer therapeutic approaches to overcome ABO incompatibility have been successful. Desenstization Recently, a number of transplant programs have utilized desensitization strategies to reduce the level of HLA antibodies present in potential recipients as a mechanism to reduce likelihood of a positive cross-match with either identified living donors or future potential deceased donors. Common strategies to reduce these preformed HLA antibodies include serial delivery of plasmapheresis coupled with rituximab. Another strategy includes antigen immunosuppression  Immunosuppressives Thymocyte globulin Antireceptor IL-2, Baciliximab Azathioprine antibody CTLA, Belatacept Antimetabolites CD20, Rituximab Mycophenolate Calcineurin Cyclosporine corticosteroids prednisolone inhibitors Tacrolimus mTOR Sirulamus inhibitors Everolimus Drugs that inhibits T-cell activation T-cell depleting drugs Others Rejection Rejection episodes can be categorized as Hyperacute accelerated acute chronic. cellular and/or antibody mediated Clinically, the patient presents with anuria, hyperkalemia, hypertension, metabolic acidosis, pulmonary edema, and, in some cases, disseminated intravascular coagulopathy. Kidney biopsy is considered the gold standard for making the diagnosis of rejection after kidney transplant. Hyperacute rejection Within minutes to hours after transplantation of the allograft This type of rejection is rare because of ABO matching and improved HLA typing before transplant, but it remains associated with a poor prognosis. Accelerated rejections Accelerated rejections of transplanted kidneys occur primarily in recipients who have had prior transplantation, multiple pregnancies, or blood transfusions. These patients usually maintain good renal function for a few days before developing acute renal failure. Accelerated organ rejections generally are more resistant to pharmacologic therapy Acute rejection Acute rejection often occurs in the first week to months after kidney transplantation. The prophylactic use of antibody induction may, however, delay the onset for several weeks. If acute rejection occurs, its onset is generally within the first year, with most episodes occurring within the first 60 days after transplantation. Acute rejection can, however, also occur at any time after transplant and can be a result of patient nonadherence (also called noncompliance) to medications and monitoring Chronic rejection It occurs slowly in most cases over several years. The characteristic signs of chronic rejection are hypertension, proteinuria, and a progressive decline in renal function leading to renal failure. Because no specific treatment exists, therapy is supportive (e.g., dialysis in the case of kidney transplantation). It can be either cellular- or antibody-mediated. The diagnosis of chronic rejection is determined by clinical signs and biopsy findings indicative of fibrosis of hollow structures and vessels within the graft Chronic allograft injury Chronic allograft injury (CAI) is a term that has been used, generally, as a diagnosis of exclusion that indicates a slow deterioration of renal function over months to years after kidney transplant, where the exact cause is unknown and results in graft loss Immunologic factors that increase the likelihood of CAI include a history of acute rejection, inadequate immunosuppression, nonadherence with immunosuppressive therapy, and previous infection, such as CMV. Nonimmunologic factors are donor-related (age, hypertension, diabetes), increased ischemic times, recipient hypertension, hyperlipidemia, CNI nephrotoxicity, and elevated body mass index. Immunosuppressive therapy Induction therapy  ATG  Basiliximab Maintainane therapy  Calcinorin inhibitors  Antimetabolite  Corticosteroid Treatment of Rejection Antibody-Mediated Rejection Plasma exchange: 3 to 5 sessions daily on every other day is used for antibody removal followed by IVIG and rituximab IVIG: IV immunoglobulin (100 to 200 mg/kg) is used followed by the last session of plasma exchange when used in combination with plasmapheresis or a higher dose of 2g/kg after the final session of plasmapheresis. Rituximab: Anti CD20 cell antibody rituximab (375 mg/m^2) is used in combination with IVIG followed by plasma exchange Bortezomib: Plasma cell inhibitor bortezomib (1.3 mg/m^2) is also used in combination with plasma exchange and IVIG Splenectomy: A splenectomy is very rarely an option, but there are anecdotal reports of successful treatment of refractory rejections Optimize the dose and the level of the maintenance immunosuppressive drugs. T Cell-Mediated rejection Methyl prednisone IV (250 to 1000 mg daily) targeting T cells, B cells, and macrophages; given for 3 to 5 days rATG - rabbit anti-thymocyte globulin IV (1 to 1.5 mg/kg) targeting T cell receptors. The duration varies among different transplant centers, but in general, it is for 7 to 14 doses based on the response and Cd3 level. Optimize the dose and the level of the maintenance immunosuppressive drugs. Chronic rejection: Since the antibody-mediated rejection mechanism is a major cause of chronic rejection, the same therapy as ABMR has been used, but generally, these measures are ineffective when serum creatinine is over 3 mg/dl and/or heavy proteinuria is present. Therapeutic use of ATG Induction of immunosuppression to prevent transplant rejection in patients:  High immunological risk of rejection 1. Recipients with greater than 80% calculated panel-reactive antibodies 2. previously rejected one or more transplants within 1 year posttransplant 3. Due to DCD or ECD donors.  Low and intermediate immunological risk patients are generally treated with basiliximab for induction.  Treatment of acute rejection. ATG Basiliximab: Therapeutic use Basiliximab is indicated for prophylaxis of kidney transplant rejection immediately post-transplant: in patient with “low” and “intermediate” risk. Although data is limited, basiliximab is well tolerated. However, hypersensitivity reactions can occur. Medications for hypersensitivity reactions should be available for immediate use during the administration of these agents. Mycophenolic acids Mycophenolic acids are used in combination post-transplant immunosuppressive regimens to prevent solid organ transplant rejection. Mycophenolic acids  Azathioprine : Therapeutic use Maintenance therapy in conjunction with other immunosuppressive agents to prevent organ transplant rejection in patients who are Unable to tolerate the gastrointestinal effects of mycophenolic acids  Have an increased incidence of infection while on mycophenolic acids  Female transplant recipients who are considering pregnancy. Azathioprine: Interaction with allopurinol Cyclosporine Cyclosporine is approved for solid organ transplant rejection prophylaxis and treatment. Cyclosporine may be used alone or in combination with other immunosuppressants. Cyclosporine Has a narrow therapeutic index, needs monitoring Tacrolimus Tacrolimus IMMEDIATE release is indicated for prophylaxis and treatment of rejection following renal, liver, heart, lung and pancreas transplantation when used in combination with other immunosuppressants. Tacrolimus Sirulamus S.E: 1. Delayed wound healing 2. Affects lipid profile Prednisone Prednisone is used in conjunction with other immunosuppressive medications for transplant rejection prophylaxis and treatment. Prednisone Special Outpatient Medications Required to Maintain Transplant Management of comorbidities Management of infection