Continuing Education Activity

Acute transplant rejection occurs days to months after a transplant when the immune system identifies a grafted organ as foreign and attacks it. Acute transplant rejection is common and the prognosis is guarded. However, early diagnosis of acute transplant rejection and heightened monitoring may make graft preservation feasible. This activity reviews the etiology, pathophysiology, presentation, and management of acute transplant rejections, and highlights the role of the interprofessional team in caring for affected patients.

Objectives:

• Describe the signs and symptoms of acute transplant rejection.
• Explain how the diagnosis of acute transplant rejection is confirmed.
• Explain treatment considerations for patients with acute transplant rejection.
• Describe the roles of various interprofessional team members in caring for patients with acute transplant rejection and improving chances for survival and recovery.

Introduction

Transplantation is the only mode of therapy for most end-stage organ failure affecting kidneys, liver, heart, lungs, and pancreas. Acute transplantation rejection occurs days to weeks after transplantation. The immune system can see the grafted organ as foreign and attacks it; destroying it and leading to rejection. The difference between hyperacute and acute graft rejection lays 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, and the other one is the serum crossmatch. Using immunosuppressive drugs, for example, azathioprine and corticosteroids can prevent acute rejection. The induction of tolerance in alloreactive donor cells is a goal of transplantation and a method to prevent the rejection of organs and tissues. The deficit of donor organs limits the success of transplantation in humans, and an alternative is the use of pigs (xenotransplantation), and living donations is another way of tackling the problem.

Etiology

In renal transplantation, the matching of 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 there is a genetic disparity between donor and receptor, MHC class I and II can be seen as foreign by the immune system. 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 destroy the graft within days or weeks.

Epidemiology

In renal transplantation, acute rejection rates have dramatically fallen, chiefly due to the use of immunosuppressives such as calcineurin inhibitor regimes. The long-term outcome has improved. A delayed graft function is a preponderant risk factor for acute rejection that can be due to vulnerability or prolonged preservation times of allografts.[1]

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 a range of effector cells responsible for the damage of rejection including CD8+ T cells, macrophages, natural killer cells, and B cells. Foreign antigens can recognize these in the graft or the lymphoid tissue of the recipient. Another histopathologic mechanism is the participation of dendritic cells which are 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.[2][3] 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, and then the CTLs cause graft tissue damage, resulting in rejection. 

Acute rejection relates well with class I and class 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 below 24 months of age can accept an incompatible organ without rejecting it, known as an ABO-incompatible (ABOi) transplantation.[4] Immaturity of the immune system causes this unresponsive mechanism against graft tissues.[5]

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 that 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.[6]

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. A pathologist will make a diagnosis of 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 laboratory studies of blood 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. There may be an abnormal function of the organ or tissue graft, for example, in renal transplantation, this presents as anuria, an increasing serum creatinine levels, and metabolic problems including hyperkalemia.

A rejected pancreas may manifest by the production of only a small amount of insulin, which is not sufficient for healthy glucose metabolism. A rejected lung shows hypercapnia and hypoxia. Acute rejection can be associated with a high incidence of infections and other complications such as the lethal graft-versus-host disease. A single episode of acute rejection is diagnosed and promptly treated, often preventing organ or tissue failure, but the recurrence can lead to chronic rejection.

Evaluation

A clinical diagnosis of acute graft rejection is confirmed by a finding of lymphocytic infiltration of the renal cortex on fine-needle aspiration. If transplantation is unsuccessful, retransplantation surgery should be considered. The following tests should be done:

• Blood group testing: Both donor and recipient must be compatible with the blood type. Group O is the universal donor.
• Serum crossmatch: Donor cells and recipient serum are mixed. If there are antibodies against the graft they will attack and destroy the donor cells, which is a positive test, and the transplant surgery cannot be performed.
• HLA typing: It must test for histocompatibility between donor and recipient. The most critical loci are HLA-A, HLA-B, and HLA-DR.

Treatment / Management

Acute rejection occurs in all transplants, except between identical twins. Acute rejection begins as early as one week after transplant, with the risk being highest in the first three months. After clinical suspicion or histologic confirmation of acute renal rejection, therapy should start within a 3-day course of intravenous methylprednisolone, and periodically testing of serum creatinine levels. Subsequently, if the patient has similar rejection episodes post-operatively, the practitioner should treat with intravenous corticosteroids. In a patient that does well, cyclosporin-A should be discontinued after 9 months, but the patient still should take a daily maintenance dose of immunosuppressive drugs, for example, 50-mg azathioprine and 5-mg prednisolone.

Retransplantation should be considered on a clinical basis where there is not a definite improvement despite all efforts. 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.

Differential Diagnosis

Cytologic examination of voided urine is the simple diagnostic method for the differentiation between allograft rejection and CMV infection.[7] 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 (PCR) of the blood.[8]

Pertinent Studies and Ongoing Trials

Fingolimod (FTY 720) is an immunosuppressive agent that is highly effective in prolonging graft survival in clinical studies of transplantation. It is an immunomodulator and differs entirely from traditional immunosuppressants. Fingolimod is a new class of drugs named sphingosine 1-phosphate receptor (S1P-R) modulators.[9] This drug has shown promising results for the use of other immunological problems such as multiple sclerosis.

Prognosis

The prognosis of a patient with acute rejection is guarded. However, the long-term prognosis is good in individuals with minimal genetic mismatch, for example, identical twins. The prognosis in those with acute rejection that are non-genetically related can better with introducing immunosuppressive drugs. The prognosis of an autograft is the best and does not require the use of immunotherapy.

Complications

Graft-versus-host disease should be suspected after organ transplantation between genetically unrelated individuals. It is a complication of organ transplantation and 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. It often relates infection with CMV with 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, e.g., 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, among others. Patients should be educated to take their prescribed immunosuppressive drugs needed to avoid organ rejection and improve their quality of life. Rejection caused by non-adherence affects 50% of the adolescents in some countries.[10]

Pearls and Other Issues

• Liver transplantation: There is a tendency for bleeding. It is a complicated surgery in which the surgeon must revascularize a grafted liver. However, rejection episodes are milder and require less immunosuppression.
• Skin grafting: Used to treat severely burned patients; HLA typing is not done in practice because of the endogenous immunosuppressive effect of severe burns.
• Corneal grafting: There is no need for HLA typing. Corneas are obtained from cadaveric donors.
• Heart transplantation: The use of cyclosporin improves the survival of this graft. It requires ABO compatibility but not HLA typing. Serial endomyocardial biopsies that show increased HLA class I expression by myocardial cells suggest early rejection. It speeds up a major post-operative problem: atherosclerosis in the graft coronary arteries, which is a cause of death in those that survive over 1 year.
• Lung transplantation: It is indicated for chronic airways disease, cystic fibrosis, and other potentially fatal lung diseases. Acute rejection is a leading cause of death in this transplantation. Current immunosuppressive regimen and best practice surgical operation give a 3-year survival of over 50%. Infection is a common cause of death.
• Pancreatic transplantation: Graft survival correlates with HLA compatibility. Transplantation of isolated islets is more successful to reduce their immunogenicity.

Enhancing Healthcare Team Outcomes

An interprofessional team educates and manages the patient with acute rejection. Health care providers should advise the patient about treatment options and offer psychological support. Acute rejection is very common but if the diagnosis is made early, the graft can be preserved with treatment. However, constant monitoring is required to assess the function of the graft and to prevent further graft rejections.

Review Questions

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• Comment on this article.

References

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Moes DJ, Press RR, Ackaert O, Ploeger BA, Bemelman FJ, Diack C, Wessels JA, van der Straaten T, Danhof M, Sanders JS, Homan van der Heide JJ, Guchelaar HJ, de Fijter JW. Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients. Br J Clin Pharmacol. 2016 Jul;82(1):227-37. [PMC free article: PMC4917801] [PubMed: 27334415]

2.

Kim JY, Kang BM, Lee JS, Park HJ, Wi HJ, Yoon JS, Ahn C, Shin S, Kim KH, Jung KC, Kwon O. UVB-induced depletion of donor-derived dendritic cells prevents allograft rejection of immune-privileged hair follicles in humanized mice. Am J Transplant. 2019 May;19(5):1344-1355. [PubMed: 30500995]

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5.

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Yamada Y, Brüstle K, Jungraithmayr W. T Helper Cell Subsets in Experimental Lung Allograft Rejection. J Surg Res. 2019 Jan;233:74-81. [PubMed: 30502290]

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Winkelmann M, Grabensee B, Pfitzer P. Differential diagnosis of acute allograft rejection and CMV-infection in renal transplantation by urinary cytology. Pathol Res Pract. 1985 Aug;180(2):161-8. [PubMed: 2997762]

8.

Alquadan KF, Womer KL, Santos AH, Zeng X, Koratala A. Not all inflammation in a renal allograft is rejection. Clin Case Rep. 2018 Nov;6(11):2285-2286. [PMC free article: PMC6230630] [PubMed: 30455940]

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Budde K, Schütz M, Glander P, Peters H, Waiser J, Liefeldt L, Neumayer HH, Böhler T. FTY720 (fingolimod) in renal transplantation. Clin Transplant. 2006;20 Suppl 17:17-24. [PubMed: 17100697]

10.

Dobbels F, Hames A, Aujoulat I, Heaton N, Samyn M. Should we retransplant a patient who is non-adherent? A literature review and critical reflection. Pediatr Transplant. 2012 Feb;16(1):4-11. [PubMed: 22248250]