Kidney Transplant Rejection
Kidney transplant rejection is a significant immunological complication following renal transplantation, characterized by the recipient's immune system recognizing the transplanted kidney as foreign and initiating an immune response against it. The pathogenesis involves both cellular and humoral immune mechanisms, wherein T lymphocytes and antibodies target donor antigens, particularly human leukocyte antigens (HLA), leading to graft inflammation, injury, and possible graft loss. The process can be acute or chronic, with distinct immunopathological pathways. The impact of rejection is profound, as it can result in graft dysfunction, decreased graft survival, and, in severe cases, return to dialysis or increased mortality. Rejection episodes are associated with increased morbidity, higher healthcare costs, and reduced quality of life for transplant recipients.
Hyperacute rejection occurs within minutes to hours after transplantation and is mediated by preformed recipient antibodies against donor antigens, most commonly ABO blood group or HLA antigens. These pre-existing antibodies rapidly bind to the endothelium of the transplanted kidney, activating the complement cascade and resulting in immediate vascular thrombosis and graft necrosis. Hyperacute rejection is now rare due to improved pre-transplant crossmatching and antibody screening.
Acute cellular rejection typically arises within the first few weeks to months post-transplant and is primarily mediated by recipient T lymphocytes that recognize donor antigens presented by antigen-presenting cells. This leads to infiltration of the graft by cytotoxic T cells and macrophages, resulting in tubulitis, interstitial inflammation, and varying degrees of vascular involvement. Acute cellular rejection is a major cause of early graft dysfunction but is often reversible with prompt immunosuppressive therapy.
Antibody-mediated rejection (AMR), also known as humoral rejection, is characterized by the presence of donor-specific antibodies (DSAs) that bind to antigens on the vascular endothelium of the transplanted kidney. This triggers complement activation, endothelial injury, and microvascular inflammation. AMR can occur acutely or chronically, and is associated with C4d deposition in peritubular capillaries and evidence of microvascular injury on biopsy. AMR is often more resistant to standard immunosuppression and poses a significant threat to long-term graft survival.
Chronic rejection, or chronic allograft nephropathy, develops over months to years and is characterized by progressive decline in renal function, often accompanied by hypertension and proteinuria. The pathology includes interstitial fibrosis, tubular atrophy, and vascular changes such as transplant glomerulopathy. Chronic rejection results from ongoing immune-mediated injury, both cellular and humoral, as well as non-immunological factors such as hypertension and drug toxicity. It is a leading cause of late graft loss.
Kidney transplant rejection remains a significant clinical challenge despite advances in immunosuppressive therapy. The incidence of acute rejection has declined over the past two decades, with current rates reported at approximately 10–15% within the first year post-transplant in developed countries. Hyperacute rejection is rare, occurring in less than 1% of cases due to rigorous pre-transplant screening. Antibody-mediated rejection is reported in 5–10% of renal allografts, while chronic rejection is a leading cause of late graft loss, affecting up to 40% of recipients within 10 years. Risk factors for rejection include HLA mismatch, sensitization to donor antigens, non-adherence to immunosuppressive regimens, and certain recipient demographics such as younger age and African ancestry. Global disparities exist, with higher rejection rates reported in regions with limited access to advanced immunosuppression and monitoring.
The diagnosis of kidney transplant rejection is multifaceted, involving clinical assessment, laboratory tests, imaging, and histopathological evaluation. Clinically, rejection is suspected in patients presenting with graft dysfunction, manifested as rising serum creatinine, reduced urine output, or new-onset hypertension and proteinuria. Laboratory investigations include measurement of renal function, detection of donor-specific antibodies, and assessment of inflammatory markers. Imaging modalities such as Doppler ultrasound may reveal increased graft resistance or perfusion abnormalities. The gold standard for diagnosis remains renal allograft biopsy, which allows for direct visualization of inflammatory infiltrates, vascular lesions, and evidence of complement deposition. The Banff classification provides standardized criteria for grading the type and severity of rejection based on histological and immunopathological findings, including the presence of tubulitis, arteritis, interstitial inflammation, and C4d staining for antibody-mediated rejection. Ancillary tests such as gene expression profiling and molecular diagnostics are increasingly used to enhance diagnostic accuracy and guide therapy.
Imlifidase is an enzyme that cleaves immunoglobulin G (IgG) antibodies, thereby reducing circulating donor-specific antibodies and facilitating desensitization in transplant recipients at risk for antibody-mediated rejection. Belatacept is a fusion protein that selectively inhibits T-cell activation by blocking the CD80/CD86:CD28 costimulatory pathway, providing an alternative to calcineurin inhibitors for maintenance immunosuppression in kidney transplant recipients. Everolimus is an mTOR inhibitor that suppresses T-lymphocyte proliferation and is utilized as part of immunosuppressive regimens to prevent acute rejection and preserve renal function. Mycophenolate sodium is an immunosuppressant that inhibits inosine monophosphate dehydrogenase, thereby blocking lymphocyte proliferation and reducing the risk of both cellular and humoral rejection. Sirolimus, also known as rapamycin, is another mTOR inhibitor that impedes T-cell activation and proliferation, and is used in maintenance immunosuppression, particularly in patients at risk for chronic allograft nephropathy. Basiliximab is a monoclonal antibody targeting the interleukin-2 receptor alpha chain (CD25) on activated T lymphocytes, used for induction therapy to prevent early acute rejection. Rituximab is a monoclonal antibody against CD20, depleting B cells and thus reducing antibody-mediated immune responses in cases of antibody-mediated rejection or desensitization protocols. Mycophenolate mofetil is a prodrug of mycophenolic acid and functions similarly by inhibiting lymphocyte proliferation, forming a cornerstone of maintenance immunosuppression. Gusperimus hydrochloride, also known as 15-deoxyspergualin, is an immunosuppressive agent that modulates both cellular and humoral immune responses and has been used in refractory cases of rejection. Tacrolimus, also referred to as fujimycin, is a calcineurin inhibitor that suppresses T-cell activation and is widely used for both induction and maintenance immunosuppression to prevent allograft rejection.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| imlifidase (USAN) | 1947415-68-0 | |||
| belatacept (Prop INN; USAN) | 706808-37-9 | |||
 | everolimus (Rec INN; USAN) | 159351-69-6 | C53 H83 N O14 | 958.224 |
 | mycophenolate sodium (USAN); mycophenolic acid sodium salt (Rec INNM; BANM) | 24280-93-1 (free acid); 37415-62-6 | C17 H19 O6 . Na | 342.319 |
 | (-)-rapamycin; rapamycin; sirolimus (Rec INN; USAN; BAN) | 53123-88-9 | C51 H79 N O13 | 914.172 |
| basiliximab (Prop INN; USAN) | 179045-86-4 | |||
| rituximab (Prop INN; USAN) | 174722-31-7 | |||
 | mycophenolate mofetil (USAN; BAN) | 128794-94-5 | C23 H31 N O7 | 433.495 |
 | 15-deoxyspergualin; deoxyspergualin hydrochloride; gusperimus hydrochloride (Rec INNM; JAN); gusperimus trihydrochloride (USAN) | 85468-01-5 | C17 H37 N7 O3 . 3 Cl H | 496.904 |
 | fujimycin; tacrolimus (Rec INN; USAN; BAN) | 104987-11-3 | C44 H69 N O12 | 804.018 |
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