Transplant Rejection & Immunosuppression

"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." "Acute rejection occurs in all transplants except between identical twins."

T cells lead the attack. "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." "CD4+ T cells orchestrate rejection by recruiting various effector cells responsible for the rejection damage, including CD8+ T cells, macrophages, natural killer cells, and B cells." Antibody-mediated rejection "usually demonstrates evidence of circulating donor-specific alloantibodies."

Matching lowers the risk. "Human leukocyte antigen (HLA) matching is 1 of 2 critical methods for preventing rejection of allografts, the other being serum crossmatch." "A transplant surgery cannot be performed if the serum crossmatch is positive." Rejection risk rises with prior sensitization, "A deceased donor has a higher rejection than a living transplant," HLA mismatch, ABO incompatibility, "Younger recipients have more rejection than older ones," delayed graft function, "Therapy non-compliance," previous rejections and "Inadequate immunosuppression."

Hyperacute — minutes. It "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." "The transplanted kidney turns mottled, dusky, and black as soon as it is revascularized." There is "No effective therapy" — it "usually leads to early allograft nephrectomy, so prevention is the key." ABO matching "protects against hyperacute transplantation rejection, which cannot be prevented with the use of immunosuppressive drugs."

Acute — days to weeks. It "can happen any time after transplant, usually within days to weeks," and "Acute rejection begins as early as 1 week after transplant, with the risk being highest in the first 3 months." In kidney transplants, "The incidence of acute rejection within the first year is around 7.9%." "Prompt diagnosis and treatment of a single acute rejection episode often prevent organ or tissue failure. However, a recurrent episode can lead to chronic rejection."

Chronic — months to years. It "usually develops more than 3 months after transplant," with "interstitial fibrosis, tubular atrophy, vascular fibrous intimal thickening." "The primary risk factor for chronic rejection is non-compliance with immunosuppressive medication." "Acute rejections usually present as an abrupt onset of allograft dysfunction, while chronic rejections present as a slow allograft dysfunction over time."

Combination therapy. Tacrolimus "is typically administered in combination with one or, most commonly, two other immunosuppressive agents." NIDDK: "Without medicine, your immune system may treat your donor kidney as foreign, or not your own, and attack your new kidney." "A kidney transplant is a treatment for kidney failure; it’s not a cure."

The price. PROGRAF’s boxed warning: "Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death." Patients "are most heavily immune-suppressed in the first 3-6 months post-operatively, putting them at heightened risk of infection during that window," (StatPearls, kidney transplant) and "Anti-rejection medicines can dull symptoms of problems such as infection." The cancer risk "appears to be related to the intensity and duration of immunosuppression rather than to any specific drug."

A narrow balance. "Tacrolimus is a drug with a narrow therapeutic index"; its levels are affected by food and by many interacting drugs, and it can harm the kidney it protects — "acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal blood vessels." "It is advisable to monitor for infection and adjust the immunosuppressive regimen to balance the risk of rejection with that of infection." Treating rejection with more immunosuppression "is always a double-edged sword."