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.
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:
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:
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.
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:
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
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:
3. T Cell-Mediated rejection: They receive treatment with the following agents based on the severity of the lesion.
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:
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
6. Acute and chronic interstitial nephritis
7. Recurrent primary glomerular diseases
8. De novo glomerular disease
9. Thrombotic microangiopathy
10. Transplant renal artery stenosis
11. Post-transplant lymphoproliferative disease
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.
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.
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.
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.
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.
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]
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