Signs and Symptoms of Acute Transplant Rejection

Organ transplantation offers life-saving treatment for end-stage organ failure, but the transplanted organ — carrying foreign antigens from a genetically distinct donor — faces continuous immune surveillance by the recipient's immune system. Acute rejection is the immune system's accelerated attack on the graft, typically occurring within the first year post-transplant but possible at any time. Early recognition is essential because prompt treatment can reverse most acute rejection episodes and preserve graft function.

What Triggers Acute Rejection

The recipient's T lymphocytes recognize donor HLA (human leukocyte antigen) molecules as foreign through either direct or indirect pathways of allorecognition. In direct allorecognition, recipient T cells react to intact donor MHC molecules on transplanted cells. In indirect allorecognition, donor antigens are processed by recipient antigen-presenting cells and presented as conventional peptide-MHC complexes. Both pathways activate a cascade of cellular and humoral immune responses that attack graft vasculature and parenchyma.

Antibody-mediated rejection (AMR) is increasingly recognized as a distinct and more treatment-resistant form, driven by donor-specific antibodies (DSA) that target donor HLA antigens on the graft endothelium, activating complement and causing endothelial injury, thrombosis, and graft dysfunction.

General Warning Signs

The classic signs of acute rejection — fever, graft tenderness, malaise, and acute deterioration in graft function — remain clinically relevant but are frequently muted or absent in the modern era of potent immunosuppression. Many patients experience "subclinical rejection" detectable only by protocol biopsy or laboratory markers. Nonetheless, the following symptoms should prompt urgent medical evaluation in any transplant recipient:

• Fever (temperature above 38°C / 100.4°F)
• Fatigue and flu-like malaise disproportionate to any apparent infection
• Decreased urine output (kidney transplant recipients)
• Rising creatinine or declining eGFR (kidney)
• Elevated liver enzymes AST, ALT, bilirubin (liver transplant)
• Declining lung function tests (FEV1 drop) or new dyspnea (lung transplant)
• New onset of congestive heart failure symptoms (heart transplant)
• Pain or tenderness over the graft site

Kidney Transplant Rejection Signs

The kidney is the most commonly transplanted solid organ, and kidney rejection provides the best-characterized clinical picture. Early signs include a rise in serum creatinine of 25% or more from baseline, reduced urine output, and occasionally graft tenderness. Hypertension may worsen as kidney function declines. In the era of modern immunosuppression, many episodes are entirely asymptomatic and detected only through routine monitoring. This underscores the importance of keeping all scheduled lab appointments — typically weekly for the first month, gradually spacing to monthly by year one.

Liver Transplant Rejection Signs

Acute cellular rejection of the liver presents with elevation of liver enzymes (typically ALT and AST rise first, followed by alkaline phosphatase and bilirubin), which may be accompanied by fever, graft tenderness, and fatigue. Jaundice can occur in moderate to severe rejection. Because elevated liver enzymes have many other causes (infection, drug toxicity, biliary complications), biopsy is required for definitive diagnosis. The Banff rejection activity index, scored on the biopsy, guides treatment intensity.

Heart and Lung Transplant Rejection Signs

Heart rejection can be insidious, with subtle changes in ventricular function detectable only on echocardiography or endomyocardial biopsy. Severe rejection may present as dyspnea, peripheral edema, arrhythmia, or hemodynamic instability. Many heart transplant programs perform protocol surveillance biopsies every few months in the first year. Lung rejection presents as declining spirometry (a fall in FEV1 of 10% or more), new infiltrates on chest imaging, hypoxia, or cough — but infection must be carefully excluded. Chronic lung allograft dysfunction (CLAD), primarily bronchiolitis obliterans syndrome, is a manifestation of chronic rejection and the leading cause of late lung transplant mortality.

Diagnostic Tests

Biopsy of the transplanted organ remains the gold standard for diagnosing acute rejection. Histological features on kidney biopsy include tubulitis, interstitial infiltrate, and endothelialitis (Banff classification). For antibody-mediated rejection, C4d staining and DSA detection are key diagnostic criteria. Blood tests including tacrolimus or cyclosporine trough levels help identify under-immunosuppression as a contributing factor. Novel biomarkers including donor-derived cell-free DNA (dd-cfDNA) and gene expression profiling assays offer non-invasive monitoring.

If you suspect rejection symptoms, do not wait for your next scheduled appointment — contact your transplant team immediately. Understanding the differences between acute and chronic rejection is covered in detail in our companion article on chronic versus acute rejection.

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