Can occur immediately following vascular anastomosis or within minutes to hours after graft revascularization
Uniformly results in graft loss requiring allograft nephrectomy
With the current cytotoxic crossmatch and the advent of the single-antigen bead-based Luminex assays (see chapter 1), hyperacute rejection has become virtually nonexistent.2
Caused by preformed antidonor human leukocyte antigen (HLA) antibodies (or cytotoxic antibodies against the graft)
Preformed antidonor HLA antibodies bind to graft endothelial antigens and activate complement leading to severe vascular injury, thrombosis, coagulative necrosis, and obliteration of the graft vasculature.
In the setting of ABO incompatible transplantation, hyperacute rejection occurs due to preformed anti-ABO antibodies (ABO isoagglutinins).
Histopathology (see chapter 9)
Banff classification of TCMR and ABMR and their histopathologic features are discussed in chapter 9.1
Generally occurs after the first posttransplant week and most commonly within the first 3 to 6 months after transplantation. In unsensitized patients with low levels of preformed anti-HLA antibodies, acute TCMR rarely occurs in the first week.2
Most patients present with asymptomatic acute rise in serum creatinine.
In the early posttransplant period, acute rejection may also manifest as plateauing of serum creatinine at a creatinine level that is higher than expected (also referred to as “high baseline creatinine”).
In the era of potent immunosuppression, fever, malaise, oliguria, and graft tenderness are usually absent unless immunosuppression is completely discontinued.
Caused by T cells reacting to donor histocompatibility antigens expressed in the tubules, interstitium, and vessels to various extent
Studies suggest that TCMR is a risk factor for the development of de novo antibodies against the allograft and subsequent ABMR.3
Generally occurs early after transplantation
ABMR can occur alone or concomitantly with TCMR.
Clinical manifestations: allograft dysfunction frequently more severe than that of acute cellular rejection
ABMR can occur under two clinical scenarios4:
ABMR type 1: caused by persistent preexisting donor-specific antibodies and/or anamnestic or “memory” humoral response against an antigen present on the graft to which the recipient had been previously exposed (eg, through blood transfusion, pregnancy, or previous transplant). Type 1 ABMR is often seen in highly sensitized recipients who underwent pretransplant desensitization protocol to remove antibodies against the donor kidney and most often occurs early after transplantation.
ABMR type 2: caused by de novo donor-specific antibodies (dnDSAs), most often occurring after the first posttransplant year (frequently seen in the context of medical nonadherence or inadequate immunosuppression)
Caused by DSA against HLA. Less commonly, other non-HLA antibodies have been implicated in ABMR.
Non-HLA are further classified as alloantigens, such as MHC class I-related chain A (MICA) and MHC class I-related chain B (MICB), or as tissue-specific autoantigens, such as the angiotensin II type 1 receptor (AT1R), anti-endothelin-1 type A receptor (ETAR), vimentin, cardiac myosin, collagen V, or agrin (see chapter 1).
Graft deterioration in the late posttransplant period can be due to alloimmune or nonalloimmune causes or both. Diagnosis requires allograft biopsy. The 2017 Banff classification of chronic active TCMR, chronic active ABMR, and chronic ABMR and their histopathologic features are discussed in chapter 9.1
Chronic rejection is an alloimmune-dependent process associated with T cell-mediated and/or antibody-mediated injury.
Risk factors: prior acute rejection episodes (TCMR or ABMR or both),5,6 poor HLA matching,7 prior sensitization or posttransplant development of HLA antibodies (de novo or anamnestic response),8 underimmunosuppression, or medical nonadherence
Clinical manifestations: Patients generally present with gradual deterioration in kidney allograft function with or without various degrees of proteinuria.
Chronic rejection of the kidney transplant is the most common cause of graft loss in the late posttransplant period.
Chronic ABMR is a process in which donor-specific anti-HLA antibodies develop, followed by immune-mediated injury to the kidney allograft. Continuous antibodymediated injury can lead to separation of the endothelial cells from the underlying basement membrane. These cells will, in turn, lay down new basement membrane matrix resulting in the so-called basement membrane duplication and the histologic appearance of transplant glomerulopathy (TG).3
Interstitial inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) is considered a potential lesion of chronic active TCMR. However, the pathogenesis of i-IFTA and to what extent this represents a manifestation of TCMR remains to be studied.
Suspicious for rejection
Decision to treat with corticosteroid pulse is generally based on clinical history such as severity of acute kidney injury, immunologic risk, history of medical nonadherence, and/or subtherapeutic calcineurin inhibitor levels. Examples
Low immunologic risk, 25% (or less) rise in serum creatinine
Observation alone and close follow-up of serum creatinine trend. Consider oral or intravenous corticosteroid pulse if creatinine does not improve or increases on serial measurements.
More than 25% to 30% rise in serum creatinine, subtherapeutic calcineurin inhibitor levels
Banff grade 1A
High-dose intravenous corticosteroid, usually referred to as “pulse steroid” or “Solu-Medrol pulse” (methylprednisolone pulse) at 5 mg/kg body weight for 3 days. Higher dose such as 500 to 1,000 mg for 3 days does not appear to be more effective. The dose of prednisone can be continued at its previous level after completion of the pulse steroid. Some centers may elect to follow various oral steroid tapering protocols.
Antithymocyte globulin (ATG) should be considered in TCMR refractory to corticosteroid therapy (refractory can be arbitrarily defined as failure of serum creatinine to improve or deterioration of graft function despite three “daily methylprednisolone pulse”). Note that there may be a delay in serum creatinine improvement by 2 to 5 days following completion of steroid pulse. Clinical judgment is required.
Banff grade 1B
Choice of high-dose intravenous corticosteroid versus ATG such as Thymoglobulin generally requires clinical correlation. ATG is generally employed in patients with moderately severe to severe acute kidney injury (arbitrarily defined as ≥100% increase in serum creatinine) or in those who develop acute TCMR in the early posttransplant period. ATG should also be considered in those who fail to respond to pulse corticosteroid (particularly when there is rapid deterioration of renal function).
Banff grade 2A or 2B
Antithymocyte globulin (eg, Thymoglobulin)
Banff grade 3
The optimal management of chronic active TCMR remains to be defined. Consider maximizing antimetabolite therapy as tolerated if applicable (ie, CellCept 1,000 mg twice a day or Myfortic 720 mg twice a day). Table 3-1 summarizes the pathogenesis and treatment strategies for acute and chronic TCMR (opinion based).
Treatment of acute ABMR may vary among centers. Suggested guidelines for the treatment of ABMR are shown in Table 3-3.
Plasmapheresis or plasma exchange (PLEX) removes circulating alloantibodies or DSA. There is no consensus on the mean fluorescence intensity (MFI) cutoff whereby PLEX is indicated. Furthermore, the threshold to perform PLEX and the number of PLEX sessions may differ depending on the clinical scenarios and histopathologic findings (see Table 3-3). DSA testing after PLEX to assess treatment response is discussed in a later section.
TABLE 3-1 T cell-Mediated Rejection Treatment Strategies
PATHOGENESIS: Recipient T cells react to donor human leukocyte antigens (HLAs) expressed in tubules, interstitium, vessels
Suspicious for acute TCMR
Type 1 acute TCMR
Type 2 acute TCMR
Type 3 acute TCMR
Chronic active TCMR
Observe and follow creatinine trend vs oral or IV steroid pulse per risk (such as degree of acute kidney injury, history of medical nonadherence, and immunologic risk).
Banff 1A: IV steroid pulse (5 mg/kg body weight, see text)
Banff 1B: IV steroid pulse or antithymocyte globulin (such as Thymoglobulin) per risk
Banff 2A: antithymocyte globulin such as Thymoglobulin
Banff 2B: antithymocyte globulin
There is no standardized protocol for the treatment of chronic active TCMR.
Consider maximizing antimetabolite therapy if applicable. Consult transplant center.
Abbreviations: IV, intravenous; TCMR, T cell-mediated rejection.
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