Solid Organ Transplant Basics

GENERAL PRINCIPLES

• Solid organ transplantation is a treatment, not a cure, for end-stage organ failure of the kidney, liver, pancreas, heart, and lung. Small intestine and vascularized composite allografts are performed in smaller numbers at specialized centers throughout the country.

• Organs from deceased donors remain in short supply, with increasing waiting times for potential recipients. Living donor transplants are common in kidney transplantation and are being evaluated in liver and lung transplantations as a partial solution to this shortage. Xenotransplantation (transplantation of animal tissue into humans) is not currently a viable option.

• Immunologic considerations between donor and recipient prior to the transplant must be fully evaluated including ABO compatibility, HLA typing, cross-matching, and some degree of immune response testing for the proposed donor. Newer protocols using desensitization techniques have had some success in overcoming these immunologic barriers, such as a desensitization protocol for ABO incompatibility in living donor kidney transplantations.

DIAGNOSIS

• For indications and contraindications of heart, lung, kidney, and liver transplantations, see chapters devoted to these organs.

• Transplant recipient patient evaluation: Evaluation of a transplant recipient with medical or surgical problems should encompass details of the patient's organ transplant and treatment. Thus, the following should always be reviewed when taking a history from an organ transplant recipient:

î Cause of organ failure

î Treatment for organ failure prior to transplantation

î Type and date of transplant

î Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serology of donor and recipient

î Induction immunosuppression, particularly use of antibody-based induction therapy

î Initial allograft function (e.g., nadir creatinine, forced expiratory volume in 1 second [FEV₁], ejection fraction, synthetic function, and transaminases)

î Current allograft function

î Complications of transplantation (e.g., surgical problems, acute rejection, delayed graft function, infections, chronic organ dysfunction)

î Current immunosuppression regimen and recent drug levels

TREATMENT

• Immunosuppression: Immunosuppressive medications are used to promote acceptance of a graft (induction therapy), to prevent rejection (maintenance therapy), and to reverse episodes of acute rejection (rejection therapy).

• Glucocorticoids: Glucocorticoids are immunosuppressive and anti-inflammatory. Their mechanisms of action include inhibition of cytokine transcription, induction of lymphocyte apoptosis, downregulation of adhesion molecules and major histocompatibility complex expression, and modification of leukocyte trafficking.

î Side effects of chronic glucocorticoid therapy are well-known.

î Steroids are tapered rapidly in the immediate posttransplant period to achieve maintenance doses of 0.1 mg/kg or less.

î Steroid-free immunosuppression, rapid steroid tapering, and steroid withdrawal are developed to minimize side effects.

° For most long-term transplant recipients, increases in glucocorticoid therapy (i.e., stress dosing) are not indicated for routine surgery or illness.³

• Calcineurin inhibitors (CNIs): CNIs inhibit T-lymphocyte activation and proliferation. They remain the most commonly used immunosuppressant, despite their side effect of nephrotoxicity (Table 17-1). IV CNIs should be avoided because of their extreme toxicity.

and rarely, thrombotic microangiopathy

tremors and, rarely, thrombotic microangiopathy

• Antimetabolites: Inhibition of DNA synthesis

î Azathioprine (AZA) is a purine analog that is metabolized by the liver to 6-mercaptopurine (active drug), which in turn is catabolized by xanthine oxidase.

î Mycophenolic acid (MPA) inhibits inosine monophosphate dehydrogenase selectively in monocytes. This enzyme is the rate-limiting enzyme of guanine nucleotide synthesis, which is critical for de novo purine synthesis in both T and B lymphocytes. Two forms are available: mycophenolate mofetil (which is converted to the active metabolite, MPA) and enteric-coated mycophenolate sodium. Adverse effects of MPA commonly include gastrointestinal disturbances (nausea, diarrhea, and abdominal pain) and hematopoietic side effects (leukopenia and thrombocytopenia).

î Antacids that contain magnesium and aluminum interfere with the absorption of MPA.

î Proton pump inhibitors can also interfere with the bioavailability of mycophenolate mofetil, but not enteric-coated MPA, which is absorbed in the small intestine.

° MPA is not used in pregnancy because of its teratogenicity.

î The usual dose is 1-2 g daily in divided doses, although lesser doses may be used with concomitant tacrolimus compared with cyclosporine (CsA), because of enterohepatic circulation affecting MPA levels. Additionally, the dosage of MPA should be reduced in chronic renal impairment. Drug levels can be measured, but the clinical utility of monitoring MPA levels has not been determined.

• Antiproliferative agents: mTOR inhibitors

î Sirolimus and everolimus inhibit the activation of a regulatory kinase, the mammalian target of rapamycin (mTOR), thus prohibiting T-cell progression from the G₁ to the S phase of the cell cycle.

î Unlike the CNIs, mTOR inhibitors do not affect cytokine transcription but inhibit cytokine- and growth factor-induced cell proliferation.

î The major adverse effects include hyperlipidemia (hypertriglyceridemia), anemia, proteinuria, impaired wound healing, cytopenias, peripheral edema, oral ulcers, and gastrointestinal symptoms.

î Although not directly nephrotoxic, mTOR inhibitors may enhance the vasoconstriction of CNIs and potentiate their nephrotoxicity.

î Sirolimus interacts with CsA metabolism, making monitoring of both drugs difficult.

î The typical dose of sirolimus is 2-5 mg daily in a single dose. Everolimus is administered at 0.75­1.50 mg twice daily. Therapeutic drug monitoring is being perfected, with current trough levels between 5 and 15 ng/mL for sirolimus and 3 and 8 ng/mL for everolimus most commonly being used.

î Sirolimus should be avoided if SCr is more than 2 mg/dL and urine protein is more than 500 mg. It should also be avoided immediately postoperatively because it is associated with poor wound healing, delayed graft function (kidney transplant), anastomotic bronchial dehiscence (lung transplant), and hepatic artery thrombosis (liver transplant). Limited data are available regarding use

of everolimus in the immediate postoperative period.

î Sirolimus is not used in pregnant women because of teratogenicity in animal models.

î mTOR inhibitors have been effective in reducing intimal proliferation and obliterative vasculopathy in heart transplantation and have been approved as chemotherapy in advanced renal cell, breast, and other malignancies.

• Biologic agents

î Polyclonal antibodies

#9632; Antithymocyte globulin is produced by injecting human thymocytes into animals and collecting sera.

#9632; Important adverse effects include fever, chills, arthralgias, myelosuppression, serum sickness, and, rarely, anaphylaxis. Two preparations are available: horse antithymocyte globulin (ATGAM) and rabbit antithymocyte globulin (Thymoglobulin). Current literature suggests that rabbit antithymocyte globulin is more efficacious. These drugs can be used at the time of transplantation to promote engraftment (“induction”) or as a subsequent treatment for acute rejection. The long­term risk of increased malignancy, particularly lymphoma, remains a concern.

#9632; IV immunoglobulin (IVIG) is pooled from several thousand plasma donors to create a product that is IgG rich. Immunomodulatory and anti-inflammatory effects are associated with high dose (1-2 g/kg), but common mechanisms including direct binding to natural antibodies, immunomodulatory proteins, pathogens, inhibition of complement fixation on target tissue, and stimul ation of anti­inflammatory pathways are also involved. Because of these effects, IVIG is used in the treatment of antibody-mediated rejection and desensitization of preformed HLA or ABO antibodies. Side effects include flushing, myalgias, chills, headache, and, rarely, anaphylaxis.

î Monoclonal antibodies

#9632; Alemtuzumab (Campath 1H) is a humanized monoclonal antibody against CD52, which is present on B and T cells, macrophages, and NK cells. It can cause significant lymphopenia for up to 6-12 months after dosing, which has led to its use in B-CLL and multiple sclerosis. In kidney transplants, it was used off label as an induction agent.

#9632; Basiliximab (Simulect) is a humanized anti-interleukin-2 receptor (IL-2 receptor or CD25) monoclonal antibody that competitively inhibits the IL-2 receptor and thereby inhibits proliferation of activated T cells.

#9632; Belatacept is a fusion protein (human IgG bound to CTLA4), which competitively binds to CD80/86 on antigen-presenting cells (APCs). This agent blocks T-cell co-stimulation between CD80/86 on APCs and CD28 on T cells and downregulates the T cell response. This agent is FDA indicated for use as a substitute for CNIs for long-term use as rejection prophylaxis posttransplant. It is contraindicated for use in liver transplantation and in recipients seronegative for EBV because of increased posttransplant lymphoproliferative disease (PTLD) in EBV- seronegative recipients.

#9632; Rituximab, a chimeric monoclonal antibody against the B-cell protein CD20, leads to B cell depletion through complement-dependent cytotoxicity, growth arrest, and apoptosis. This medication can suppress B cell counts for up to 6-9 months. Side effects such as fever, bronchospasm, and hypotension are attributed to cytokine release. Rituximab also carries the risk of hepatitis B reactivation in patients positive for hepatitis B surface antigen or hepatitis B core antibody. Therefore, prior to starting treatment, patients should be screened for hepatitis B by checking hepatitis B surface antigen and core antibody.

î Infection prophylaxis

#9632; Immunization: Pneumococcal and hepatitis B vaccination should be given to the recipient at the time of pretransplant evaluation. Influenza A vaccination should be administered yearly. Live vaccines should be avoided after transplantation and also in a live donor if organ donation is imminent. Varicella vaccination in seronegative patients if no contraindication for live vaccine and hepatitis A vaccination (particularly in liver transplant candidates) should be considered before transplant. A new inactivated varicella vaccine can be given prior to and after transplantation. Vaccination against SARS-CoV-2 should be encouraged to all pre- and posttransplant patients.

#9632; Trimethoprim-Sulfamethoxazole prevents urinary tract infections, Pneumocystis jirovecii pneumonia, and Nocardia infections. Prophylaxis is recommended for 6-12 months posttransplant. In sulfa-allergic patients, dapsone, aerosolized pentamidine, and atovaquone are suitable alternatives.

#9632; Acyclovir prevents reactivation of herpes simplex virus (HSV) and varicella-zoster virus but is less effective in CMV prophylaxis. HSV can be a serious infection in immunosuppressed individuals, and some form of prophylaxis should be used during the first year. Patients with recurrent HSV infections (oral or genital) should be considered candidates for long-term prophylaxis. Lifetime acyclovir should be considered in EBV-seronegative patients who receive an EBV-positive organ.

#9632; Ganciclovir or valganciclovir prevents reactivation of CMV infection when administered to patients who were previously CMV seropositive, received a CMV-positive organ, or both. Typically, these antivirals are administered for 3-12 months following transplantation. CMV hyperimmune globulin or IV ganciclovir can also be used for this purpose. Alternatively, patients can be monitored for the presence of CMV replication in the bloodstream by polymerase chain reaction before symptoms develop and can be treated preemptively.

#9632; Fluconazole can be given to patients with a high risk of systemic fungal infections or recurrent localized fungal infections. Fluconazole increases CsA and tacrolimus levels (see “Treatment” under the “Solid Organ Transplant Basics” section).

#9632; Nystatin suspension, clotrimazole troches, or weekly fluconazole are used to prevent oropharyngeal candidiasis (thrush).