Introduction
(Article introduction authored by Conquest Editorial Team)
Despite advances in immunosuppressive treatments-, kidney transplant rejection remains a significant challenge impacting graft longevity. This article provides an overview of the diagnosis and management of acute T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR).
TCMR is diagnosed through kidney biopsy and treated with corticosteroids, with severe cases requiring T-cell-depleting agents like Thymoglobulin.
ABMR results from antibody binding to graft endothelial cells and is commonly treated with plasmapheresis, although its effectiveness is debated. Other therapies like intravenous immunoglobulins, anti-CD20 antibodies, complement inhibitors, and proteasome inhibitors are used with uncertain efficacy. Management decisions depend on rejection timing and chronic changes.
Optimizing immunosuppression and addressing adherence is crucial, but further research is needed to explore and assess new therapies.
T-Cell-Mediated Rejection (TCMR)
DIAGNOSIS
The gold standard for diagnosing acute T-cell-mediated rejection is through histological examination of kidney biopsy samples.
The biopsy samples typically reveal infiltration of mononuclear cells in the interstitium, tubules, and/or vessels (t, i, or v). caTCMR is characterized by chronic changes that include ct, ci, and/or cv lesions, in addition to acute inflammation changes (t, i, or v) [7]. The severity of aTCMR is graded into IA, IB, IIA, IIB, and III, which are outlined in Table 1 according to the Banff 2019 classification [7].
The majority of biopsy-proven acute rejections (BPARs) occurring within the first year post-transplant are typically TCMR
CURRENT THERAPIES:
Corticosteroids
Corticosteroids are the primary treatment for acute inflammation in TCMR, administered intravenously (IV) at 3-5 mg/kg of methylprednisolone over 3-6 days, followed by an oral prednisone taper.
They work by inhibiting cytokine transcription through factors like NF-kβ and activator protein-1, leading to T-cell depletion, T-Helper 1 inhibition, apoptosis, eosinophil apoptosis, and macrophage dysfunction.
The response to TCMR treatment varies based on severity, typically assessed by histological improvements and kidney function. Banff grade II TCMR responds less to steroids, with a 36% success rate, while 86% of non-responders benefit from anti-lymphocyte antibody therapy.
Response criteria vary among studies, but pooled data suggests similar responses for Banff IA, IB (44-73%), and Banff IIA (52-80%), while Banff IIB has a lower response rate (10%).
T-Cell-Depleting Agents
KDIGO recommends T-cell-depleting agents for treating steroid-resistant cellular rejection. Thymoglobulin, the most common agent, is a polyclonal product that interacts with various T cell and shared receptors on B cells, monocytes, and neutrophils.
It works through lymphocyte depletion, complement-dependent lysis, and T-cell activation-induced apoptosis.
There are two preparations: Thymoglobulin, made by immunizing rabbits with human thymocytes, and anti-thymocyte globulin (rATG), made by immunizing rabbits with Jurkat T-cell leukemia line lymphocytes.
Thymoglobulin is typically used at 1-1.5 mg/kg per dose for 4-6 doses, often causing leukopenia and thrombocytopenia.
Peripheral CD3 counts help monitor the response. In cases of thymoglobulin antibodies, ATGAM (horse anti-thymocyte globulin) can be used at 1 gm IV for 10 days, with dosing based on CD2-positive T-cell measurement.
However, ATGAM has more side effects, including serum sickness and cytokine release, and is less well tolerated than thymoglobulin.
Approach to Treatment
TCMR diagnosis can be clinical or subclinical through biopsies. Treatment is recommended for both types unless contraindications exist. Approaches vary, with high-dose steroids for TCMR IA and IB, thymoglobulin for grade II or III TCMR, and follow-up biopsies at 2-4 weeks. CaTCMR is usually treated with high-dose steroids.
Monitoring for DeNovo DSA is essential. Optimizing maintenance immunosuppression is key, considering drug adjustments and nonadherence. Response monitoring includes kidney function tests and follow-up biopsies.
ANTIBODY-MEDIATED REJECTION (ABMR)
DIAGNOSIS
ABMR is caused by recipient antibodies binding to donor alloantigens on graft endothelial cells, including HLA, ABO, and other antigens.
Criteria for diagnosing active ABMR (aABMR) are outlined in Table 2, while chronic ABMR (caABMR) results from ongoing antibody damage.
New Banff 2022 subtypes include probable ABMR with sub-threshold microvascular inflammation lesions and MVI exceeding the threshold but without circulating DSA and negative C4d staining in peritubular capillaries.
CURRENT THERAPIES
Plasmapheresis
Plasmapheresis, used since 1979 in ABMR, directly removes DSAs from the serum but has limitations as DSAs re-equilibrate with the interstitium over time. It’s often performed every 48 hours.
Plasmapheresis may have an immuno-modulatory effect by reducing B cells and NK cells while increasing T regulatory cells and T-suppressor-cell function. Studies vary in their results; one showed a significant benefit in graft survival, while another found no improvement.
Discrepancies may result from differing inclusion criteria, endpoints, follow-up durations, and historical variations in immunosuppression. Current immunosuppressive therapies are more effective and safer than earlier regimens.
Immunoadsorption
Immunoadsorption (IA) directly removes IgG proteins from the serum using high-affinity absorbers in adsorption columns.
A study by Bohmig et al. found IA to be highly effective in treating severe C4d-positive ABMR, with all IA-treated patients responding within 3 weeks, compared to poor outcomes in the control group.
The study was terminated early due to high graft loss in the control group. Although there are limited high-quality trials comparing IA and plasmapheresis, a retrospective study indicated a positive trend in 5-year graft survival with IA. It’s worth noting that IA therapy is not available in the United States.
Intravenous Immunoglobulin
IVIG is often used alongside plasmapheresis for managing ABMR, with different dosages. Low-dose IVIG (100 mg/kg) inhibits endogenous antibody rebound and restores antimicrobial IgGs.
High-dose IVIG (2 g/kg) has immunomodulatory effects on T and B cells, inducing B-cell apoptosis and modulating B-cell signaling. In late ABMR, IVIG can improve graft survival. A study by Lee et al. found that patients who received IVIG had better graft survival than those who did not. Graft survival was also higher in a small retrospective study comparing high-dose IVIG to plasmapheresis/IVIG/anti-CD20 therapy.
However, due to variations in doses, biopsy findings, time from transplantation, and maintenance immunosuppression, comparing these studies can be challenging.
Anti-CD20 Monoclonal Antibodyntravenous Immunoglobulin
Rituximab is used to treat ABMR and is recommended by KDIGO guidelines (grade 2C). It depletes B cells, which produce DSA. There’s no consensus on the optimal dosing regimen, and side effects include infusion reactions, infections, and rare but severe complications like hepatitis B reactivation. Evidence supporting its effectiveness is limited.
The RITUX-ERAH study found no significant differences in outcomes between rituximab and a placebo for aABMR, except for more side effects in the rituximab group.
A prospective study in caABMR also found no significant differences in outcomes with or without rituximab.
However, some retrospective studies showed benefits, with one achieving successful treatment in 24 out of 27 patients, and another reporting higher graft survival in patients who received plasmapheresis plus rituximab.
Systematic reviews haven’t provided clear evidence for rituximab’s effectiveness in improving ABMR outcomes.
Complement Inhibitors
The activation of the classical complement pathway plays a significant role in ABMR. Complement inhibitors like Eculizumab and complement 1 esterase inhibitors (C1 INHs) have been used for AMR treatment.
Eculizumab blocks complement protein C5 and may have side effects.
Case reports suggest success in some severe ABMR cases. A combination of splenectomy and eculizumab has shown promise in HLA-incompatible kidney transplants. However, the routine use of eculizumab for AMR lacks robust evidence.
C1 INH has also been studied, with some positive results in improving eGFR and reducing anti-HLA DSA C1q status.
A study with Cinryze as add-on therapy for early ABMR showed promising results in six-month biopsies.
However, a larger study evaluating Cinryze for ABMR treatment was terminated early due to futility. Personalized approaches based on DSA characteristics require further investigation.
Proteasome Inhibitors
Bortezomib, a proteasome inhibitor used in multiple myeloma treatment, has been employed in ABMR management.
It targets elevated protein synthesis in differentiated plasma cells, inducing plasma cell apoptosis.
While case reports indicated its efficacy in ABMR when combined with other therapies, side effects include gastrointestinal symptoms, peripheral neuropathy, and thrombocytopenia. Retrospective studies have shown its effectiveness.
However, a trial investigating its use in late DSA-positive ABMR found that bortezomib did not significantly improve outcomes and was associated with gastrointestinal and hematologic toxicity.
Splenectomy
Surgical splenectomy is not commonly performed for ABMR but may be considered as a salvage procedure for refractory cases.
Case series have shown immediate improvements in urine output and serum creatinine after laparoscopic splenectomy in some patients with severe, refractory ABMR.
In cases where patients developed ABMR after living-donor kidney transplantation, splenectomy followed by plasmapheresis and IVIG led to the return of allograft function within 48 hours.
However, the lack of supporting evidence regarding the safety and efficacy of splenectomy compared to medical therapy means it is not routinely recommended.
Approach to Treatment
ABMR, like TCMR, can be diagnosed clinically via for-cause or subclinically through protocol biopsies. Management varies by transplant centers and usually includes high-dose steroids, plasmapheresis, and IVIG, with variation in other therapies.
Consensus guidelines by the transplant society guide management. Timing and chronic changes in ABMR are crucial. Plasmapheresis, though occasionally used, doesn’t address the root cause and should be used sparingly.
Plasmapheresis and IVIG are standard treatments despite some uncertainty, while rituximab is ineffective, and the role of bortezomib and complement inhibitors is unclear. Figure 2 outlines an algorithm combining consensus recommendations and clinical experience.
Conclusions
In summary, rejection is a significant concern in kidney transplantation, impacting long-term outcomes. Treatment varies for T-cell-mediated and antibody-mediated rejection, with the Banff classification system aiding diagnosis.
TCMR is treated with corticosteroids and T-cell-depleting agents. ABMR involves therapies like corticosteroids, plasmapheresis, and IVIG. Efficacy varies. Maintaining immunosuppression is crucial to prevent further rejection.
Emerging therapies like IL-6 inhibitors, carfilzomib, and Daratumumab hold promise. Combining therapies may be necessary, but their use should be rigorously tested in controlled trials to balance infection risk with benefits.
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