Continuing Education Activity

Acute transplant rejection is a condition that occurs within a transplant recipient days to months after transplantation, secondary to the recipient's immune system identifying the grafted organ as foreign and mounting a defense. The etiology, pathophysiology, presentation, and management of this commonly occurring transplantation complication are complex. The diagnosis of acute rejection is based on clinical features involving the grafted organ and is confirmed by diagnostic laboratory studies, including tissue biopsy. Treatment primarily involves immunosuppressive medications to induce tolerance of alloreactive donor cells and avert rejection. Early diagnosis and intervention of acute transplantation rejection are critical to prevent the loss of donor organs and tissues. The limitations of current risk prediction algorithms and biomarkers have paved the way for understanding the implications of DNA methylation changes in immune pathways, enabling clinicians to tailor personalized prevention and treatment strategies in solid organ transplantation. 

This activity for healthcare professionals aims to enhance learners' competence in selecting appropriate diagnostic tests, identifying acute rejection promptly, enabling timely intervention to preserve graft function, minimizing systemic immunosuppression-related adverse effects, and emphasizing the crucial role of the interprofessional team in providing holistic care to affected patients.

Objectives:

• Identify the clinical features of acute transplant rejection.
• Select appropriate confirmatory diagnostic studies for acute transplant rejection.
• Compare treatment options for patients with acute transplant rejection.
• Apply interprofessional team strategies to improve care coordination and outcomes in patients with acute transplant rejection.

Introduction

Transplantation is the only mode of therapy for most end-stage organ failure affecting the kidneys, liver, heart, lungs, and pancreas. Acute transplantation rejection occurs days to weeks after transplantation. The immune system recognizes the grafted organ as foreign and mounts an immune response, resulting in organ rejection and destruction. The difference between hyperacute and acute graft rejection lies in the presence of preformed antibodies that cause rejection immediately. Human leukocyte antigen (HLA) matching is 1 of 2 critical methods for preventing rejection of allografts, the other being serum crossmatch. Immunosuppressive drugs (eg, azathioprine and corticosteroids) may also prevent acute rejection. Treatment primarily involves immunosuppressive medications to induce tolerance of alloreactive donor cells and avert rejection. Early diagnosis and intervention of acute transplantation rejection are critical to prevent the loss of donor organs and tissues. The deficit of donor organs limits human transplantation success; therefore, using pigs (ie, xenotransplantation) and living donations are alternative strategies employed.

Etiology

Acute transplantation rejection is an immune response against the donor graft that causes tissue impairment and potential failure.[1] T-cell and antibody-mediated rejection are the primary mechanisms leading to acute transplantation rejection.[2] In renal transplantation, matching major histocompatibility complex (MHC) class II antigens is more critical than MHC class I antigen compatibility in determining graft survival. Matching of the ABO blood group system is also essential since A and B antigens can be expressed on the endothelium. When genetic disparity between donor and receptor is present, the immune system can identify MHC class I and II as foreign. CD4+ T cells react to these donor antigens presented by antigen-presenting cells (APC) or themselves and produce cytokines that stimulate a robust immune reactivity that destroys the graft within days or weeks.

Epidemiology

The risk of acute transplantation is highest in the first weeks following a transplantation procedure, with an estimated incidence of 50% to 70%.[1] In renal transplantation, acute rejection rates have dramatically fallen, chiefly due to immunosuppressive (eg, calcineurin inhibitor) regimens. The long-term outcome has improved. Delayed graft function is a significant risk factor for acute rejection due to vulnerability or prolonged preservation times of allografts.[3]

Pathophysiology

Acute rejection has been associated with increased expression of HLA class I and class II antigens in inflamed grafts and with early infiltration of CD8+ T cells. Fine-needle aspiration can help recognize rejection from cyclosporin toxicity. CD4+ T cells orchestrate rejection by recruiting various effector cells responsible for the rejection damage, including CD8+ T cells, macrophages, natural killer cells, and B cells. Foreign antigens can recognize these in the recipient's graft or lymphoid tissue. Another histopathologic mechanism is the participation of dendritic cells, antigen-presenting cells of the donor tissue or organ that migrate to the recipient's lymphoid follicles and present peptides to the recipient's adaptive immune system, causing acute rejection.[4][5] Alloreactive cytotoxic T lymphocytes (CTLs) have CD8 molecules that bind to the transplanted tissue's MHC class I proteins that express the donor's self-peptides. The CTLs then cause graft tissue damage, resulting in rejection. Acute rejection relates well to class I and II HLA gene disparity between donor and receptor. ABO matching protects against hyperacute transplantation rejection, which cannot be prevented with the use of immunosuppressive drugs. However, children aged younger than 24 months can accept an incompatible organ without rejection, known as an ABO-incompatible (ABOi) transplantation, due to immune system immaturity causing this unresponsive mechanism against graft tissues.[6][7]

Furthermore, memory cells against the graft alloantigens differentiate into Th1 and Th2 lymphocytes. Th1 cells produce IL-2 and gamma interferon that mediates cellular immune responses, including activation of macrophages against the allograft and xenograft. Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13, which stimulate humoral responses mediated by antibodies against the graft. However, Th1 cells orchestrate the acute graft rejection. Other T cell subsets that may be involved in rejection are Th9, Th17, and Th22 through participation in the inflammatory response.[8]

Histopathology

Histologically, there is a mononuclear infiltrate in the renal cortex and necrosis of arterial walls; after successful treatment, the inflammatory infiltrate clears. Graft-versus-host disease is a usual complication of an allograft; skin biopsy shows lymphocytic infiltration with vascular cuffing and basal cell degeneration. Pathologists diagnose acute rejection based on infiltrating T cells, structural compromise of tissue anatomy that varies by the graft used, and blood vessel damage.

History and Physical

The diagnosis of acute rejection is based on clinical data, including the patient's symptoms and signs, and confirmed by serum laboratory studies and a tissue biopsy. After a few days or weeks of successful transplantation surgery, the patient complains about tenderness at the site of the graft and pyrexia. Clinical features secondary to the abnormal function of the transplanted organ or tissue graft are frequently characteristic. For instance, in renal transplantation, clinical features of renal dysfunction, including anuria, increasing serum creatinine levels, and metabolic abnormalities (eg, hyperkalemia), may result due to acute rejection. Similarly, an acute rejection of a transplanted pancreas may manifest as minimal insulin production, insufficient for normal glucose metabolism, whereas a patient with acute rejection of a lung may primarily present with hypercapnia and hypoxia. Furthermore, acute rejection can be associated with a high incidence of infections and other complications, including lethal graft-versus-host disease. Prompt diagnosis and treatment of a single acute rejection episode often prevent organ or tissue failure. However, a recurrent episode can lead to chronic rejection.

Evaluation

Laboratory Studies

Prevention of a transplantation rejection response is the standard of care for transplant procedures, which involves assessing the compatibility between the recipient and the donor tissue. The following laboratory studies are performed for this evaluation:

• Blood group testing: Both the donor and recipient must have compatible blood types. Group O is the universal donor.
• Serum crossmatch: In this test, donor T and B cells are mixed with recipient serum. A transplant surgery cannot be performed if the serum crossmatch is positive, which occurs when anti-graft antibodies, if present, attack and destroy the donor cells. A "virtual crossmatch" is another method that can be performed that compares recipient anti-HLA antibodies against donor HLA antigens; detected anti-HLA antibodies meeting established adverse response thresholds is considered a positive test. Virtual crossmatching is sometimes preferred due to the ability to obtain results faster and with greater sensitivity than serum crossmatch testing.[9] 
• HLA typing: Histocompatibility is vital between donor and recipient, which is assessed with HLA typing. The most critical loci are HLA-A, HLA-B, and HLA-DR.

Following transplantation procedures, patients with suspected acute rejection may be evaluated with laboratory studies to exclude differential diagnoses or assess organ function. However, these tests are not diagnostic of acute rejection, though they may be supportive. Diagnostic confirmation of acute graft rejection is typically obtained with tissue biopsy demonstrating histologic inflammatory changes (eg, lymphocytic infiltration or cellular damage).[10][1][2] If transplantation is unsuccessful, retransplantation surgery should be considered.

Imaging Studies

Imaging studies are utilized to monitor donor tissue following transplantation for pathologic changes suggestive of acute rejection, though not diagnostic.[11] Various modalities may be preferred depending on the area being imagined. Ultrasound has become the most commonly used monitoring method after kidney transplantation, as renal blood perfusion can be optimally visualized with this modality.[12] However, following lung transplantation, chest x-ray or computed tomography imaging are better studies to demonstrate perihilar and basilar consolidations, interstitial opacities, pleural effusions, and nodules findings associated with acute rejection. Imaging studies may also help differentiate acute transplantation from differential diagnoses associated with the donor organ (eg, acute tubular necrosis, reimplantation response, infection).[11]

Treatment / Management

Acute rejection occurs in all transplants except between identical twins. Acute rejection begins as early as 1 week after transplant, with the risk being highest in the first 3 months. After clinical suspicion or histologic confirmation of acute renal rejection, therapy should start within a 3-day course of intravenous methylprednisolone and periodic testing of serum creatinine levels. Subsequently, if the patient has similar rejection episodes postoperatively, the clinician should treat with intravenous corticosteroids. In a patient with a good response, cyclosporin-A should be discontinued after 9 months; however, a daily maintenance dose of immunosuppressive drugs should be continued. Common maintenance regimens include azathioprine 50 mg daily or prednisolone 5 mg daily.

Retransplantation should be considered on a clinical basis in patients with no definite improvement despite treatment. Primary cytomegalovirus (CMV) infection in the recipient due to transplantation of a CMV-positive kidney into a CMV-negative recipient can be treated with a combination of ganciclovir and CMV-specific immune globulin. Cases refractory to immunosuppressive therapy or intravenous antibodies can be treated with extracorporeal photoimmune therapy to inactivate graft-specific immunoglobulins.[13]

Additionally, emerging monoclonal antibodies offer promising avenues for treating acute transplantation rejection. These antibodies target specific immune pathways implicated in rejection, enhancing graft tolerance and minimizing adverse effects. The following novel monoclonal antibodies are some of the acute transplantation rejection treatments that offer targeted immunomodulation, potentially improving graft survival and minimizing systemic immunosuppression-related adverse effects:

• Anti-CD3 antibodies: Targeting T-cell activation and proliferation, antibodies, eg, muromonab-CD3, can rapidly suppress rejection in various solid organ transplants.
• Anti-CD25 antibodies (IL-2 Receptor Antagonists): Agents (eg, basiliximab and daclizumab) selectively inhibit IL-2 receptors on activated T cells, effectively suppressing immune responses without global immunosuppression.
• Anti-CD52 antibodies: Alemtuzumab targets CD52 on T and B cells, inducing profound lymphocyte depletion and suppressing rejection, especially in renal transplantation.
• Anti-CD20 antibodies: Rituximab depletes B cells, reducing alloantibody production and preventing antibody-mediated rejection. This antibody is commonly used in kidney and heart transplants.
• Anti-CD40 antibodies: Agents (eg, CFZ533) block CD40-CD154 costimulation, inhibiting T-cell activation and B-cell differentiation and potentially reducing the risk of rejection.
• Anti-IL-6 receptor antibodies: Tocilizumab inhibits IL-6 signaling, attenuating inflammatory responses and graft damage. These antibodies show promise in preventing acute rejection in liver transplants.
• Anti-CCR5 antibodies: Maraviroc targets CCR5 on memory T cells, reducing infiltration into grafts and mitigating rejection, particularly in kidney transplantation.
• Anti-TNF-α antibodies: Infliximab and Etanercept neutralize TNF-α, dampening inflammatory cascades and mitigating graft damage, explored in various transplant settings.

Differential Diagnosis

Depending on the transplanted tissue or organ involved, various differential diagnoses that may present with similar clinical features following a graft procedure should be considered when evaluating acute transplantation rejection. For instance, following lung transplantation, conditions including reimplantation response and infection should be excluded, while acute tubular necrosis should be considered following renal transplants.[11] Furthermore, cytologic examination of voided urine is the simple diagnostic method for differentiating allograft rejection and CMV infection.[14] IgM anti-CMV antibodies can be detected and confirm the diagnosis of CMV infection. Adenovirus nephropathy may mimic allograft rejection and can be ruled out by polymerase chain reaction of the blood.[15]

Pertinent Studies and Ongoing Trials

Fingolimod is an immunosuppressive agent highly effective in prolonging graft survival in clinical transplantation studies. Fingolimod is an immunomodulator and differs entirely from traditional immunosuppressants. This new class of drugs was named after sphingosine 1-phosphate receptor (S1P-R) modulators and has shown promising results for using other immunological problems (eg, multiple sclerosis).[16] 

Prognosis

The prognosis of a patient with acute rejection is guarded. However, the long-term prognosis is good in individuals with a minimal genetic mismatch, eg, identical twins. The prognosis in those with acute rejection who are nongenetically related is improved with immunosuppressive drugs. Autografts result in the best prognosis and do not require immunotherapy.

Complications

Graft-versus-host disease should be suspected after organ transplantation between genetically unrelated individuals. This can result following organ transplantation and is clinically characterized by rash, fever, bloody diarrhea, hepatosplenomegaly, and breathlessness 7 to 14 days after transplantation. The rash can progress to exfoliative dermatitis. Susceptibility to infection is also a complication of acute rejection that can be a cause of death. Infection may be bacterial, viral, fungal, protozoal, or mixed. Immunosuppression is often associated with CMV infection and graft rejection. A late complication of particular renal transplantation is the recurrence of the original disease that should be suspected when alternating functional deterioration with long periods of stable graft function. Malignancy in the recipient is another late complication, eg, the incidence of lymphoma and skin cancer is higher in transplant recipients.

Deterrence and Patient Education

Patients must comply with the treatment of comorbidities, including renal disease, diabetes mellitus, and cystic fibrosis. Patients should be educated to take their prescribed immunosuppressive drugs needed to avoid organ rejection and improve their quality of life. Rejection caused by nonadherence affects 50% of the adolescents in some countries.[17]

Pearls and Other Issues

The following factors should be kept in mind during acute transplantation reaction management:

• In cases of liver transplantation, bleeding is prevalent as the procedure is complicated. Surgeons are required to revascularize a grafted liver. However, rejection episodes are milder and require less immunosuppression.
• In patients undergoing skin grafting (eg, severely burned patients), HLA typing is not done in practice because of the endogenous immunosuppressive effect of severe burns.
• HLA typing for corneal grafts is unnecessary as corneas are obtained from cadaveric donors.
• For heart transplantation, cyclosporin improves the survival of this graft. Heart transplantation requires ABO compatibility but not HLA typing. Serial endomyocardial biopsies that show increased HLA class I expression by myocardial cells suggest early rejection and speed up a major postoperative problem of atherosclerosis in the graft coronary arteries, which is a cause of death in those that survive >1 year.
• Lung transplantation is indicated for chronic airway disease, cystic fibrosis, and other potentially fatal lung diseases. Acute rejection is a leading cause of death in this transplantation. The current immunosuppressive regimen and best-practice surgical operation result in a 3-year survival rate of over 50%. Infection is a common cause of death.
• Graft survival correlates with HLA compatibility in pancreatic transplantation. Transplantation of isolated islets is more successful in reducing their immunogenicity.

Enhancing Healthcare Team Outcomes

An interprofessional team approach is pivotal in educating and managing patients with acute transplantation rejection. Physicians, advanced practitioners, nurses, pharmacists, and other health professionals collaborate to provide comprehensive care, advising patients on treatment options and offering psychological support. Regular monitoring ensures early diagnosis and intervention, optimizing graft preservation and preventing further rejection episodes. Clear communication and coordinated efforts among team members enhance patient-centered care, improve outcomes, ensure patient safety, and optimize overall team performance in managing acute transplantation rejection.

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Disclosure: Angel Justiz Vaillant declares no relevant financial relationships with ineligible companies.

Disclosure: Subhasis Misra declares no relevant financial relationships with ineligible companies.

Disclosure: Brian Fitzgerald declares no relevant financial relationships with ineligible companies.