Continuing Education Activity
Various factors merit consideration to match the donor kidney with the recipient, as the donor kidney act as an alloantigen. In general, when transplanting tissue or cells from a genetically different donor to the graft recipient, the alloantigen of the donor induces an immune response in the recipient against the graft. This response can destroy the graft if not controlled. The whole process is called allograft rejection. This activity describes and defines the types of rejections. It also describes the pathophysiology, histopathology, and staging of the rejections very briefly. It also describes the risk factors, prognosis, and differential diagnosis, along with the clinical presentation, evaluation, and treatment.
- Identify the etiology and epidemiology of renal transplant rejection.
- Review the appropriate history, physical, and evaluation of renal transplant rejection.
- Summarize the treatment and management options available for renal transplant rejection.
- Describe some interprofessional team strategies for improving care coordination and communication to advance renal transplant rejection and improve outcomes.
Kidney transplantation is the treatment of choice in patients with end-stage renal disease or severe chronic kidney disease as it improves the quality of life and has better survival advantages compared to dialysis. Various factors merit consideration to match the donor kidney with the recipient, as the donor kidney act as an alloantigen. In general, when transplanting tissue or cells from a genetically different donor to the graft recipient, the alloantigen of the donor induces an immune response in the recipient against the graft. This response can destroy the graft if not controlled. The whole process is called allograft rejection.
Allograft rejection is inflammation with specific pathologic changes in the allograft, due to the recipient’s immune system recognizing the non-self antigen in the allograft, with or without dysfunction of the allograft.
Both innate and adaptive immune systems play a significant role in rejection, But the T lymphocytes are the principal cells that recognize the allograft. There are other costimulatory molecules, and cytokines also play a major role in this reaction. Depending on the histopathology and immunological characteristics, the renal transplant rejections can be classified broadly under the following categories :
1) Hyperacute rejection: Happens minutes after transplant, and it is related to the preformed antibody or ABO incompatibility; this is rarely seen now due to the very sensitive cross-match tests performed before the transplant.
2) Acute rejection: This can happen any time after transplant, usually within days to weeks after transplant. It classifies into the following:
A) Antibody-mediated rejection- ABMR: which usually demonstrates evidence of circulating donor-specific alloantibodies and immunological evidence of antibody-mediated injuries to the kidney. Like inflammation of glomeruli (Glomerulitis) or peritubular capillary (peritubular capillaritis).
B) Acute T-cell mediated rejection- TCMR: which characterized by lymphocytic infiltration of the tubules, interstitium, and sometimes the arterial intima.
3) Chronic rejection: It usually develops more than three months post-transplant. It can either be chronic antibody-mediated rejection or chronic T cells mediated rejection.
4) A mixture of acute rejection superimposed on chronic rejection.
Certain factors correlate with an increased risk of rejection of the renal allograft after the transplantation. These factors are:
- Prior sensitization - high panel reactive antibodies
- Type of transplant: Deceased donor has a higher rejection than a living transplant
- Advanced age of the donor
- Prolonged cold ischemia time
- HLA mismatch
- Positive B cell crossmatch
- ABO incompatibility
- Recipient’s age: Younger recipients have more rejection than older ones
- Recipient’s race: African American race greater than White race
- Delayed Graft function
- Therapy non-compliance
- Previous episodes of rejections
- Inadequate immunosuppression
The overall incidence and prevalence of acute allograft rejection have decreased, and graft survival has improved with the use of more advanced and potent immunosuppressive agents for induction and maintenance therapy. The incidence of acute rejection within the first year is around 7.9%. Overall, the rate of acute rejection is lower in living-donor than deceased-donor kidney transplants; this is likely related to better matching and less cold ischemia time.
Renal transplant rejection, as stated earlier, is an immunological response that leads to inflammation with specific pathological changes in the allograft, due to the recipient’s immune system recognizing the non-self (foreign) antigen in the allograft. There are different mechanisms postulated depending on the type of rejection, as follows:
- Hyperacute rejection: It is related to preexisting circulating antibodies in the recipient’s blood against the donor antigen (usually ABO blood group or HLA antigen), which is present at the time of transplantation. These antibodies attack and destroy the transplanted organ as soon as or within a few hours after allograft is revascularized.
- Acute T cell-mediated rejection: in which the recipient’s lymphocytes become activated by recognition of foreign [non-self] donor antigens in the transplanted organ by antigen-presenting cells (APC) through direct, semi-direct or indirect pathways, which leads to activation and infiltration of the T cells and damage to the allograft.
- ABMR: It is related to antibodies against foreign [non-selfx] donor antigens, mainly HLA antigen, which leads to damage to the allograft through activation of the complement-dependent pathway as well as independent mechanisms recruiting NK cells, polymorphonuclear cells, platelets and macrophages to attack the allograft. These antibodies can be either preexisting at a low level before the transplant or synthesized de novo post-transplant.
- Chronic rejection: it is related to both immune and nonimmune mediated factors. The primary risk factor for chronic rejection is non-compliance with immunosuppressive medication. It can be either chronic antibody-mediated rejection, which is mainly related to the presence of donor HLA-antigens donor Specific Antibody (DSA) or Chronic cellular rejection, which is uncommon.
The standard way to detect rejection is a renal allograft biopsy, which serves to accurately grade the severity of rejection, differentiate between different types, and guide the treatment.
There are two major classifications for the histopathological diagnosis of renal allograft biopsy: the Banff classification system and the Cooperative Clinical Trials in Transplantation (CCTT). Later, both were incorporated into the Banff 97 classification, to standardize the histopathological diagnosis of renal allograft biopsy. Subsequently, Banff has had updates at regular intervals; the last one was in 2017.
When performing a kidney biopsy, it should have adequate tissue to give a definitive interpretation. Adequate core biopsy must contain ten glomeruli and two arteries and section thickness 3 to 4 microns (marginal if 7 to 10 glomeruli and one artery; unsatisfactory if less than seven glomeruli or no arteries).
The histological characteristics of each type of rejection are as follows:
- Hyperacute rejection: The transplanted kidney turns mottled, dusky, and black as soon as it revascularized. Severe endothelial injury, PMN infiltration, whispered thrombosis, ischemic tissue necrosis will appear on biopsy.
- ABMR: Histological features of ABMR include: arteriolar fibrinoid necrosis, fibrin thrombi in glomerular capillaries, glomerulitis, and peritubular Capillaritis, interstitial hemorrhage. Also, the presence of peritubular Capillary linear staining for C4d, which is a degradation product of the complement pathway that binds covalently to the endothelium, is highly suggestive of ABMR.
- Acute T Cell-Mediated Rejection: Characterized by diffuse lymphocytic infiltration in the tubule, interstitium of the kidney, and in severe cases, vessels of the allograft
- Chronic rejection lesions like interstitial fibrosis, tubular atrophy, vascular fibrous intimal thickening, glomerular basement membrane double contouring (transplant glomerulopathy), arteriolar hyalinosis, hyaline arteriolar thickening
Banff system uses scores to assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies. It focuses mostly, but not exclusively, on the diagnostic features seen in rejection. According to the scoring of the various lesions described above, the staging is as below.
- Category 1: Normal biopsy or nonspecific changes
- Category 2: Antibody-mediated rejection - AMR: depending on the features of lesion further divided into acute AMR, chronic AMR active chronic AMR
- Category 3: Suspicious (borderline) for acute T cell-mediated rejection - TCMR.
- Category 4: TCMR. Depending on the score of chronic lesions, it further divides into acute TCMR, chronic TCMR, acute, chronic TCMR
- Category 5: Interstitial fibrosis and tubular atrophy - IFTA
- Category 6: Other changes not considered to be the result of acute or chronic rejection
History and Physical
Most patients who have acute rejection episodes are asymptomatic and have abnormal allograft dysfunction evidence from the routine blood workups; when there is a sudden rise of serum creatinine to more than 25% of the baseline value, the clinicians should suspect allograft rejection. Even when the creatinine is not trending down as expected in the early post-transplant phase, the possibility of rejection should be a consideration. Any new-onset or worsening proteinuria and new-onset or worsening hypertension should raise the suspicion for rejection.
Sometimes a rejecting graft may present with fever, pain at the graft site, hematuria, dysuria, hypertension, fluid retention, and decreased urine output.
The approach for elevated serum creatinine in a renal transplant recipient would be the same as evaluating for AKI with added workup for the rejection.
The specific workup for evaluating allograft dysfunction should include the following:
- Rule out prerenal causes: Check orthostatic vital sign, blood pressure, and volume status
- Rule out post-renal causes mainly obstructive uropathy in older adults by bladder scan, renal US
- CBC: Look for anemia and thrombocytopenia to rule out TMA
- Electrolyte abnormality related to CKD, AKI
- UA and urine culture: It is essential to rule out infection as a cause of AKI
- Check for proteinuria: Either UPCR or 24-hour urine collection as nephrotic range proteinuria correlates with the presence of extensive transplant glomerulopathy
- Check BK Virus, CMV PCR in clinically indicated patients
- Testing for donor-specific antibodies
- Transplant renal ultrasound with doppler for renal arterial and venous indices
- Many transplant centers use testing for donor-derived free DNA testing. This test can be positive even before the actual rise in serum creatinine, suggesting possible rejection.
Treatment / Management
The treatment plan determination uses multiple factors, including the type of rejection, the severity of the histological lesion, the chronicity score, and the recipient comorbidity. So what will be discussed is a general guideline, but tailoring medical treatment of individual characteristics is needed.
1. Hyperacute rejection: No effective therapy usually leads to early allograft nephrectomy, and so prevention is the key by assuring through the following
- i) ABO-compatibility between donor and recipient. Sometimes, it is advisable to address ABO incompatibility under specific criteria, and careful pre-transplant preparation of recipient with the removal of anti-ABO antibodies by plasmapheresis is an option, IVIG with or without rituximab
- ii) Pre-transplant cross-match [complement cell cytotoxicity test]: Recipient serum is added to donor lymphocytes. If the test is positive (which means the recipient has an antibody that reacts with the donor HLA antigens on lymphocyte), one should not proceed with transplant unless these antibodies are removable pre-transplant.
2. Antibody-Mediated Rejection:
The treatment of acute antibody-mediated rejection also depends on the level of the antibody levels. Higher antibody levels need plasma exchange for the removal of the antibodies. The following are the different modalities used for AMR:
- i) Plasma Exchange: 3 to 5 sessions daily on every other day is used for antibody removal followed by IVIG and rituximab
- ii) 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 higher dose 2g/kg after the final session of plasmapheresis.
- iii) Rituximab: Anti CD20 cell antibody rituximab (375 mg/m^2) is used in combination with IVIG followed by plasma exchange
- iv) Bortezomib: Plasma cell inhibitor bortezomib (1.3 mg/m^2) is also used in combination with plasma exchange and IVIG
- v) Splenectomy: Splenectomy is very rarely an option, but there are anecdotal reports of successful treatment of refractory rejections
- vi) Optimize the dose and the level of the maintenance immunosuppressive drugs.
3. T Cell-Mediated rejection: They receive treatment with the following agents based on the severity of the lesion.
- i) Methyl Prednisone IV (250 to 1000 mg daily) targeting T cells, B cells, and macrophages; given for 3 to 5 days
- ii) rATG - Rabit 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.
- iii) Optimize the dose and the level of the maintenance immunosuppressive drugs.
4. 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 Scr is over 3 mg/dl and/or heavy proteinuria.
While dealing with renal allograft dysfunction, equal weight should be given to find out the possible etiologies other than the rejection.
The following are the most common reasons for allograft dysfunctions other than the allograft rejection.
A. Immediate Post Transplant (less than one week):
1. Postischemic acute tubular necrosis or Ischemia-reperfusion injury.
2. Volume depletion leading to pre-renal AKI
3. Surgical complications:
- Fluid collection – urinoma, perinephric hematoma or lymphocele
- Vascular thrombosis - arterial and venous
- Multiple renal arteries from the donor's kidney - infarction of the part of the allograft or necrosis of the ureter leading to urinary obstruction or urinary leak.
- Calcium oxalate crystals deposits in renal allograft
B. Early (1 week to 3 months) and Late Post Transplant (over three months):
1. Volume depletion
2. Acute tubular necrosis
3. Calcineurin inhibitor nephrotoxicity - manifesting as acute azotemia as well as chronic progressive renal disease.
4. Urinary obstruction
- Bacterial pyelonephritis
- Viral infections - BK ( polyomavirus) and CMV
6. Acute and chronic interstitial nephritis
7. Recurrent primary glomerular diseases
- Primary membranous nephropathy
- Diabetic nephropathy
- Ig A nephropathy
- C3 GN
8. De novo glomerular disease
9. Thrombotic microangiopathy
- In patients with a prior history of TTP, HUS, antiphospholipid antibody syndrome
- Associated with calcineurin inhibitor nephrotoxicity
10. Transplant renal artery stenosis
11. Post-transplant lymphoproliferative disease
Pertinent Studies and Ongoing Trials
- Small trials are ongoing for cell therapies to modulate the immune system.
- AntiCD40 monoclonal antibody (CFZ533) has the potential to block the co-stimulatory CD40–CD154 pathway is a possible upcoming clinical treatment for acute rejection.
- There are a few clinical trials underway for checking the safety and efficacy and safety of immunomodulatory medicines for desensitization and antibody medicated rejections.
The acute rejections predispose to chronic graft dysfunction.
T Cell-Mediated rejections have better graft survival, especially when they respond to therapy, and the serum creatinine reaches near to the previous baseline after the treatment.
Acute rejections occurring after three months, vascular rejections, and the rejections not responding to therapy ( serum creatinine not reaching 75% of baseline value) are associated with poor graft survival.
The appearance of de novo DSAs at any time post-transplant is associated with 5% poor graft outcome per year as compared to recipients without these antibodies.
Due to the above-mentioned graft outcomes, each episode of acute rejection needs to be treated and monitored thoroughly with optimizing the Maintainance immunosuppressive regimen.
The complication associated with acute rejection is graft failure if not treated appropriately and timely fashion. And even after the treatment, there is an association of poor graft survival after each episode of rejection.
The treatment of acute rejection, as described above, results in a severely immunocompromised state and puts the recipient at an increased risk from the side effects of the agents. There are many side effects associated with these immunosuppressive agents.
- Increased cardiovascular risk
- Development of post-transplant diabetes mellitus
- Various malignancies (squamous cell carcinoma, post-transplant lymphoproliferative disease, more common among them)
- Various opportunistic infections (viral- CMV, BK; fungal- Histoplasmosis, coccidiomycosis, etc. and other atypical organisms)
CMV infection itself is associated with an increased risk of rejection as well. It is always a double-edged sword to manage immunosuppressive agents post rejection episodes. The physician has to manage wisely while weighing risk-benefits.
Deterrence and Patient Education
As treatment noncompliance is one of the critical risk factors for the development of rejection, patient educations and awareness is a key factor for the prevention of allograft rejection.
Pearls and Other Issues
Renal transplant rejections are either acute or chronic, and depending on the immunohistopathology, they are either antibody-mediated rejections or T cell-mediated rejections.
Acute rejections usually present as an abrupt onset of allograft dysfunction, while chronic rejections present as a slow allograft dysfunction over time.
Tissue biopsy is still the key for diagnosis, although donor-derived free DNA detection test is emerging as a noninvasive tool for diagnosing rejections but not validated to date.
Treatment of rejection depends on the type of rejection and managed with more immunosuppression and optimizing baseline immunosuppressive regimen post rejection.
Although many factors are playing a role, patient awareness, and education regarding the compliance to the anti-rejection medication is still very important for the prevention of rejection.
Enhancing Healthcare Team Outcomes
Renal transplant patients require a comprehensive approach in post-transplant care, including the clinicians from different disciplines, nurses, social workers, and other health professionals. Together as a team, they play a significant role in better outcomes of renal allograft survival.
While the transplant surgeon is the chief clinician involved, the specialty-trained transplant nurse will provide invaluable support. This includes patient preparation, assisting during the surgery, and providing post-operative care. As the patient starts on post-procedure pharmacotherapy, a board-certified pharmacotherapy pharmacist should consult on the case to optimize agent selection, dosing, and provide patient counsel. The transplant nurse will also monitor the patient and inform the treating clinician of any concerns or significant status changes. Given the lifelong follow-up necessary after a transplant, these players functioning as an interprofessional team on behalf of the patient will optimize the outcomes with the new organ, and minimize the chances for organ rejection. [Level 5]