Chronic Transplantation Rejection

Etiology

The cause of chronic transplant rejection is not fully understood. Glinton et al reported that a significant factor in the development of chronic complications in solid organ transplants is the presence of a vascular disease in the transplanted organ.[1] However, their review specifically focused on cardiac transplantation. In cardiac allograft vasculopathy, histological evidence suggests that the accumulation and activation of phagocytes, such as macrophages, monocytes, and immature dendritic cell subsets, may contribute to chronic rejection. Additionally, these myeloid phagocytes interact with B and T lymphocytes and signal and activate vascular smooth muscle cells and fibroblasts, leading to fibrous intimal thickening.[1] Chronic renal allograft rejection is characterized by interstitial fibrosis and tubular atrophy, reflecting its underlying histology and cause. Currently, chronic rejection is considered the primary etiology of graft rejection.

Epidemiology

The overall incidence and prevalence of chronic allograft nephropathy in renal allograft biopsies vary based on the timing and indications for such graft biopsies. In protocol biopsies conducted within the first year after transplantation, the prevalence of grade 1 chronic allograft nephropathy can be as high as 94%, reaching up to 100% after 10 years. 

In the United States, mortality rates for patients on chronic hemodialysis are significantly higher in winter compared to summer. Whether a similar seasonal difference affects mortality or graft failure among kidney transplant recipients is not well-established. However, a report indicated significant annual variation in deaths related to graft failures.[2]

Pathophysiology

Chronic allograft rejection can be caused by antibody-dependent complement activation and cell-mediated arteritis, leading to the development of interstitial fibrosis and tubular atrophy.[3] This injury can manifest early after transplantation. By 1 year posttransplant, over 81% of kidneys show minimal interstitial fibrosis and tubular atrophy lesions, which tend to progress over time, affecting more than 50% of transplanted kidneys with severe lesions by 5 years.

The 2011 Banff meeting focused on diagnostic criteria for late antibody-mediated rejection. During this review, CD4-negative antibody-mediated rejection was recognized, and endothelial activation and natural killer (NK) cells were identified as primary contributors to chronic rejection.[4] Other proposed pathophysiological mechanisms include:

• Calcineurin inhibitors toxicity
• Chronic dysfunction of the solid organ causing premature graft loss
• Alloimmunization to minor HLA antigens
• Production of interferon-γ and interleukin-2 by T_H1 lymphocytes
• Secretion of cytokines by endothelial cells

Liver transplantation, a standard treatment for end-stage liver disease, relies heavily on immunosuppressive drugs for immune control. Despite the liver's inherent tolerance capacity, significant immune activity occurs in the early posttransplant period. Successfully identifying and managing different types of rejection—T-cell–mediated, antibody-mediated, and chronic—is crucial. Prescribing immunosuppressants to patients often depends more on clinical judgment than evidence-based criteria. As operational tolerance mechanisms are still unclear, lifelong immunosuppression is common. A deeper understanding of immune responses and drug targets enables customized treatment, improving patient care. However, consensus on optimal immunosuppressive regimens remains elusive, highlighting the need for ongoing research and clinical expertise in liver transplant immunosuppression.[5]

Histopathology

The main histological finding in biopsies of rejected organs is arteriosclerosis, which causes a progressive luminal narrowing of graft vessels, typically referred to as a vasculopathy or graft vascular disease. Graft vascular disease is often accompanied by graft tissue (parenchymal) fibrosis.[6] For example, livers with chronic rejection show a decreased number of bile ducts on biopsy and obliteration of small arteries. Correspondingly, lung rejection is characterized by bronchiolitis obliterans. The presence of endothelial injury and subsequent inflammation has been suggested as the inciting cause of this vascular dysfunction.

History and Physical

Individuals with chronic transplant rejection typically have a history of chronic organ or tissue pathology (such as kidney, liver, and lung) that was treated with transplantation. The symptoms and signs of rejection vary depending on the transplanted organ; for example, chronic kidney rejection may present with fatigue, fever, flu-like symptoms, anuria or decreased urine output, generalized edema, and pain or tenderness at the transplantation site.

Additional clinical features of organ rejection can include:

• Jaundice
• Dark urine
• Itching
• Nausea and vomiting
• Abdominal swelling or tenderness
• Cough and shortness of breath
• Recurrent infections
• Arterial hypertension
• Proteinuria
• Fatigue
• Weight gain 
• Premature death
• Anorexia
• Anemia
• Opportunistic neoplasia
• Pulmonary edema
• Atherosclerosis

Evaluation

When evaluating chronic rejection in organ transplantation, the assessment must be guided by the patient's clinical history, with various laboratory tests being ordered as needed. These tests may include a 24-hour urine collection, a comprehensive metabolic panel, complete blood counts, and histological studies. Additionally, HLA typing can be performed to assess histocompatibility between the donor and recipient, focusing on critical loci such as HLA-A, HLA-B, and HLA-DR. Serology may also be used to screen for hepatitis B and C and HIV. 

Certain laboratory studies may be indicated based on the organ being evaluated. For example, urinary samples can be useful in renal transplantation in determining rejection. Findings such as tubular epithelial cells, casts, oxalate crystals (sand-glass–shaped), a dirty background, increased erythrocyturia, mixed cell clusters, lymphocytes, and mitoses may be observed. The presence of "owl-eye" cells with milk-glass nuclei and eosinophilic condensation typically characterizes voided urine in cytomegalovirus (CMV) infection during cytologic examination.[7] Serological tests can further help differentiate CMV infection from allograft rejection.

Additional diagnostic studies may be used to identify findings of transplantation rejection in various organs. These methods include electrocardiograms, chest radiography, computed tomography (CT) of the abdomen, and abdominal ultrasonography, with the preferred modality depending on the specific organ being assessed.

Treatment / Management

The treatment of organ rejection depends on the type of injury and underlying etiology. For instance, in chronic kidney rejection, complications such as arterial hypertension, pulmonary edema, and uremia should be managed through various therapeutic options, including hemodialysis, hemofiltration, and the use of diuretics. Most infectious causes should be addressed with specific, targeted antimicrobials. In managing diabetic nephropathy, the albumin-to-creatinine ratio is a key indicator for therapy. If this ratio exceeds 3, renin-angiotensin system inhibition with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker is recommended, even if blood pressure is normal, to help protect the donor's kidney.

Tight glucose control is recommended in the setting of hyperglycemia. Type 1 diabetes is typically treated with insulin, while non–insulin-dependent diabetes is usually managed with biguanides or sulfonylureas. In end-stage rejection cases, organ or tissue retransplantation may be considered.

Additional Management Considerations

Managing chronic transplant rejection presents significant challenges, often necessitating a multifaceted approach to suppress ongoing immune responses and address specific pathological features. Common strategies include:

Immunosuppressive therapy optimization: Immunosuppressive regimens are adjusted and tailored to enhance immunomodulation while minimizing drug toxicity. This often involves combining various classes of immunosuppressants, such as calcineurin inhibitors, mTOR inhibitors, and corticosteroids.

Monoclonal antibodies: Monoclonal antibodies targeting specific immune pathways involved in chronic rejection are used. For example, agents such as rituximab (anti-CD20) can deplete B cells, which is implicated in chronic antibody-mediated rejection.

Anti-inflammatory agents: Anti-inflammatory drugs are administered to mitigate ongoing inflammation within the graft. This may include corticosteroids or other anti-inflammatory agents to suppress cytokine-mediated damage.

Antifibrotic therapies: Antifibrotic agents are used to reduce fibrosis and tissue remodeling within the graft. Drugs that target profibrotic cytokines or signaling pathways, such as transforming growth factor-β inhibitors, may be considered.

Biological therapies: The potential of biological therapies, such as mesenchymal stem cell transplantation or regulatory T-cell infusions, to induce graft tolerance and mitigate chronic rejection processes is currently being investigated.

Targeted therapies: Therapies targeting specific molecular pathways involved in chronic rejection, such as endothelin receptor antagonists to inhibit vascular remodeling or inhibitors of fibrosis-promoting pathways, are currently under development.

Antiviral therapies: When chronic rejection is associated with viral infections, such as CMV or Epstein-Barr virus, antiviral treatment may be necessary to suppress viral replication and reduce immune-mediated damage.

Adjunctive therapies: Clinicians may consider adjunctive therapies to support graft function and minimize complications associated with chronic rejection, such as antihypertensive agents, lipid-lowering drugs, or anticoagulants.

Lifestyle modifications: Lifestyle modifications, such as smoking cessation, dietary changes, and regular exercise, are implemented to optimize overall health and potentially reduce factors contributing to chronic rejection, such as cardiovascular risk factors.

Close monitoring and surveillance: Rigorous surveillance protocols should be used to detect early signs of graft dysfunction or rejection, allowing for prompt intervention and adjustment of treatment strategies.

While these approaches hold promise, managing chronic transplantation rejection remains a formidable clinical challenge, highlighting the need for continued research into novel therapeutic modalities and personalized treatment strategies.

Differential Diagnosis

The differential diagnosis for chronic rejection is broad and includes acute rejection, infection, medication toxicity (eg, immunosuppressants), posttransplant lymphoproliferative disease, and technical issues such as vascular or structural anastomotic complications.

Pertinent Studies and Ongoing Trials

FTY720 (fingolimod) is a novel immunosuppressive agent investigated over the past few decades. FTY has proven highly effective in prolonging graft survival in preclinical models of transplantation and multiple sclerosis. Unlike traditional immunosuppressants, FTY720 is an immunomodulator with a unique mechanism of action, classified as a sphingosine 1-phosphate receptor (S1P-R) modulator.[8][9] In laboratory animals, activating S1P receptors with fingolimod triggers anti-inflammatory and anti-apoptotic pathways, enhancing myocardial salvage by reducing cardiac fibrosis.[10]

ASP0028, an S1P1/S1P5-selective agonist with comparable efficacy to FTY720 and a broader safety profile, demonstrated both efficacy and safety when coadministered with a suboptimal dose of tacrolimus in a monkey renal transplantation model. ASP0028 administration remarkably reduced peripheral lymphocytes, including subsets of CD4+ or CD8+ naive and central memory cells, CD4+ Treg cells, and B cells, while not affecting CD4+ or CD8+ effector memory cells and NK cells. These findings suggest that ASP0028, in combination with tacrolimus, effectively prolongs renal allograft survival in primates.[8]

Staging

The Banff grading system, first introduced in 1997, is used to classify the severity of chronic renal allograft nephropathy and has been updated in 2005, 2007, 2009, 2013, and 2017.[3][4] The system categorizes disease severity based on interstitial fibrosis, atrophy, and loss of tubules into the following grades:

• Grade I: This grade is characterized by mild fibrosis of the interstitium and mild atrophy of the tubules, with or without specific glomerular or vascular findings, which may suggest chronic allograft nephropathy.

• Grade II: This grade shows moderate interstitial fibrosis (affecting 25%-50% of the cortical area) and moderate tubular atrophy (involving 26%-50% of the area of the cortical tubules).

• Grade III: This grade indicates severe interstitial fibrosis (affecting >50% of the cortical area) and tubular atrophy (involving >50% of the area of the cortical tubules).

Prognosis

Up to one-third of recipients of cadaveric kidney transplants may experience graft loss within 5 years. Unfortunately, advances in immunotherapy have had limited impact on altering the prognosis for patients with established chronic allograft nephropathy. Efforts should focus on prevention, early diagnosis, and the management of comorbidities and complications associated with chronic kidney disease to improve survival for those with transplant failure.

Complications

The success of organ transplantation relies on immunosuppressive drugs to manage the alloimmune response. For kidney transplantation, a common regimen includes a combination of 3 types of medications—a drug that inhibits T-cell activation (such as cyclosporine, tacrolimus, or sirolimus), an antiproliferative agent (such as 6-mercaptopurine or mycophenolic acid), and an anti-inflammatory agent (such as corticosteroids). 

Chronic organ rejection can be associated with a high mortality rate and lead to various complications, including kidney failure, liver failure, chronic pulmonary disease, pancreatic insufficiency, arteriosclerosis, and blood dyscrasias. Additional complications include CMV infection and infectious diseases of bacterial, viral, fungal, protozoal, or mixed etiologies. Excessive immunosuppression may lead to the emergence of BK polyomavirus, causing BK nephropathy, which accounts for 1% to 10% of allograft failures.

A late complication of renal transplantation can be the recurrence of the original disease, such as diabetic nephropathy. The development of malignancy is a late complication of chronic organ rejection, with the incidence of lymphoma approximately 40 times higher in transplant recipients than in the general population. Other tumors that may be observed include skin cancer, Kaposi sarcoma, and lymphoma due to Epstein-Barr virus activation.