Acute kidney graft rejection is an immune-mediated injury to a transplanted kidney that occurs when the recipient’s immune system recognizes the donor kidney as foreign and mounts an immune response against the graft. It is a major cause of early kidney transplant dysfunction and can threaten long-term graft survival if not recognized and treated promptly.

Acute rejection is suspected when there is an unexplained increase in serum creatinine after excluding other causes of graft dysfunction such as dehydration, urinary obstruction, infection, medication toxicity, or recurrence of the original kidney disease. Kidney biopsy remains the gold standard for diagnosis and classification of rejection.

Early diagnosis, appropriate immunosuppressive treatment, and close monitoring are essential to preserve kidney graft function and improve transplant outcomes.

Epidemiology

Acute kidney graft rejection is most common during the first months following kidney transplantation, particularly within the first six months after transplantation. The incidence has decreased with modern immunosuppressive regimens; however, rejection remains an important complication, especially among patients with increased immunological risk.

The risk of rejection varies depending on factors such as human leukocyte antigen (HLA) mismatch, presence of donor-specific antibodies, poor adherence to immunosuppressive therapy, blood group incompatibility, delayed graft function, and prolonged cold ischemia time.

Risk factors

Risk factors associated with acute kidney graft rejection include:

• Human leukocyte antigen (HLA) mismatches between donor and recipient

• Presence of donor-specific antibodies (DSA)

• Positive panel reactive antibody (PRA)

• Blood group incompatibility

• Younger recipient age with older donor age

• Delayed onset of graft function after transplantation

• Cold ischemia time greater than 24 hours

• Reduced adherence to immunosuppressive medication

• Inadequate immunosuppression

• Previous transplant rejection episodes

• Infections affecting immune regulation

• Failure to attend regular transplant follow-up

Pathophysiology

Acute kidney graft rejection occurs when recipient immune cells recognize donor antigens expressed on the transplanted kidney. This activates cellular and antibody-mediated immune responses leading to inflammation and injury of graft tissues. Two major types of acute rejection occur:

i. Acute cellular rejection

This is mainly mediated by recipient T lymphocytes. Activated T cells infiltrate the kidney graft, causing inflammation and damage to renal tubules and blood vessels. Histological diagnosis and grading are based on the Banff classification.

ii. Antibody-mediated acute rejection

This occurs due to antibodies directed against donor antigens, particularly donor-specific anti-HLA antibodies. These antibodies activate complement pathways, causing endothelial injury and vascular inflammation. Complement component C4d staining on biopsy supports the diagnosis.

Untreated rejection can lead to progressive graft injury, chronic rejection, graft fibrosis, and eventual transplant failure.

Clinical presentation

Patients with acute kidney graft rejection may present with:

• Occurrence commonly within the first six months after transplantation

• Fever

• Malaise

• Reduced urine output (oliguria)

• Pain or tenderness over the transplanted kidney

• Worsening hypertension

• Unexplained rise in serum creatinine

• Reduced kidney graft function

Some patients may have minimal symptoms, and graft dysfunction may only be detected during routine laboratory monitoring.

Diagnostic criteria

Acute kidney graft rejection should be suspected in a transplant recipient with:

• Increased serum creatinine without another identifiable cause

• Evidence of graft dysfunction

• Histological evidence of rejection on kidney biopsy

Kidney biopsy is required to confirm diagnosis and determine the type of rejection unless performing biopsy would significantly delay life-saving treatment.

Differential diagnosis

Conditions that should be considered in a kidney transplant recipient with rising creatinine include:

1. Acute kidney graft rejection

2. Acute tubular necrosis due to delayed graft function or ischemic injury

3. Calcineurin inhibitor nephrotoxicity (tacrolimus or cyclosporine toxicity)

4. Urinary tract obstruction or ureteric complications

5. Acute pyelonephritis or other graft infections

6. BK polyomavirus nephropathy

7. Cytomegalovirus (CMV) infection affecting graft function

8. Recurrent primary kidney disease

9. Dehydration or reduced circulating volume

10. Renal artery or vein thrombosis/stenosis

Investigations

Recommended investigations include:

Kidney graft assessment

• Kidney biopsy (gold standard for diagnosis)

• Repeat kidney biopsy if there is failure to respond to treatment

• Kidney ultrasound

• Doppler ultrasound of the transplanted kidney

• Nuclear medicine renal scans where indicated

Laboratory investigations

• Serum creatinine

• Blood urea nitrogen (BUN)

• Estimated glomerular filtration rate (eGFR)

• Urinalysis

• Urine biochemistry

• Urine microscopy

• BK polyomavirus testing

• Cytomegalovirus (CMV) testing

Additional investigations may include:

• Tacrolimus or cyclosporine drug levels

• Full blood count

• Inflammatory markers where infection is suspected

Management

Management aims to:

• Restore kidney graft function

• Suppress harmful immune responses

• Prevent irreversible graft injury

• Identify and treat contributing factors

Non-pharmacological treatment

Management measures include:

• Close monitoring of kidney function and urine output

• Assessment and improvement of adherence to immunosuppressive therapy

• Identification and treatment of infections

• Avoidance of nephrotoxic medications

• Regular transplant clinic follow-up

• Patient education regarding lifelong immunosuppressive medication use

Pharmacological treatment

Treatment depends on the type and severity of rejection.

Acute cellular rejection

Treatment should follow Banff classification severity.

For acute cellular rejection:

Methylprednisolone (IV) 300–500 mg once daily for 3–5 days, followed by gradual prednisolone tapering.

If corticosteroid treatment fails:

Rabbit anti-thymocyte globulin (IV) 1.5 mg/kg/day for 4–7 days.

For children and adolescents:

Anti-thymocyte globulin (ATGam) (IV) 10–15 mg/kg/dose once daily for 14 days. If required, doses may be continued on alternate days up to a maximum of 21 doses within 28 days.

Antibody-mediated acute rejection

Diagnosis is based on:

• Histological evidence of graft injury

• Vascular endothelial injury

• Positive C4d staining

• Serological evidence of donor-specific antibodies

Treatment includes:

Methylprednisolone (IV) 300–500 mg daily for 3–5 days.

AND one or more of the following:

Plasma exchange every 24 hours or on alternate days until serum creatinine improves to within 30% of previous baseline (maximum 5 sessions).

OR

Rituximab 200–375 mg/m² after completion of plasmapheresis and intravenous immunoglobulin therapy.

OR

Rabbit anti-thymocyte globulin (IV) 1.5 mg/kg/day for 4–7 days.

For children and adolescents:

Anti-thymocyte globulin (ATGam) (IV) 10–15 mg/kg/dose daily for 14 days, with possible extension to alternate-day dosing up to 21 doses.

Other important conditions in kidney transplant recipients

Recurrent kidney disease

Evaluation

• Urine protein assessment

• Serum creatinine

• Kidney biopsy

• ANCA testing where indicated

• Anti-GBM antibodies where indicated

• Full blood count

• Lactate dehydrogenase (LDH)

Treatment

Management depends on the underlying disease and may include:

• Plasmapheresis

• Cyclophosphamide

• Corticosteroids

• ACE inhibitors or angiotensin receptor blockers for proteinuria control where appropriate

Vaccination in kidney transplant recipients

Recommendations

• Hepatitis B vaccination should be completed before transplantation where possible.

• Hepatitis B surface antibody levels should be checked 12 weeks after completing vaccination.

• Inactivated vaccines are generally acceptable.

• Live vaccines should be avoided after transplantation.

• Vaccination is generally avoided during the first six months unless specifically indicated.

• Influenza vaccination may be considered during the first six months.

• Pneumococcal vaccination is recommended.

Viral infections

BK polyomavirus infection

Investigation

• BK viral nucleic acid testing

• Kidney biopsy where indicated

Treatment

• Reduction of immunosuppressive therapy

Cytomegalovirus (CMV) infection

Investigation

• CMV serology in donor and recipient before transplantation

• CMV plasma nucleic acid testing for diagnosis and monitoring

Treatment

Prophylaxis:

Valganciclovir (PO) 900 mg once daily for 3 months.

For life-threatening disease:

Ganciclovir (IV) 6 mg/kg every 12 hours until clinical improvement.

Then:

Valganciclovir (PO) 900 mg twice daily until symptoms resolve.

Epstein-Barr virus (EBV) and post-transplant lymphoproliferative disease

Investigation

• EBV nucleic acid testing

Management

• Reduction of immunosuppressive medication in patients with increasing EBV viral load

• Specialist management for post-transplant lymphoproliferative disease

Herpes simplex virus and varicella zoster virus infection

Management:

Superficial disease:

• Oral acyclovir or valacyclovir until lesions resolve.

Systemic disease:

• Reduce immunosuppressive therapy.

• Intravenous acyclovir.

Frequent attacks:

• Consider antiviral prophylaxis.

Pneumocystis jirovecii pneumonia

Diagnosis

• Bronchoalveolar lavage

• Lung biopsy where indicated

Prevention

Trimethoprim-sulfamethoxazole prophylaxis for 3–6 months.

Additional prophylaxis should be considered after treatment of acute rejection requiring corticosteroids.

Candida infection

Prevention:

• Clotrimazole oral lozenges

• Nystatin

• Fluconazole where indicated

Cardiovascular complications

Kidney transplant recipients have increased cardiovascular risk due to chronic kidney disease, immunosuppressive medication effects, hypertension, and metabolic complications.

Management includes:

• Cardiovascular risk assessment

• Blood pressure control

• Lipid management

• Diabetes screening and treatment

For atherosclerotic cardiovascular disease:

Acetylsalicylic acid (PO) 75 mg once daily may be used after balancing bleeding risk and cardiovascular benefit.

New onset diabetes after transplantation (NODAT)

Investigation

• Fasting plasma glucose

• HbA1c

• Oral glucose tolerance testing

Screening should follow transplant monitoring schedules and should also be performed after initiation or modification of immunosuppressive medication.

Management follows diabetes treatment recommendations in CKD patients.

Malignancy after transplantation

Kidney transplant recipients have increased risk of malignancies due to chronic immunosuppression.

Management includes:

• Patient education on self-examination

• Routine cancer screening

• Specialist management according to cancer type

For Kaposi sarcoma:

• Consider conversion to mammalian target of rapamycin (mTOR) inhibitors.

Referral

Refer kidney transplant recipients to a transplant specialist/nephrologist when there is:

• Suspected acute rejection

• Rising serum creatinine without clear cause

• Failure to respond to rejection therapy

• Severe infection

• Suspected malignancy

• Immunosuppressive drug toxicity

• Progressive graft dysfunction

Complications

Potential complications include:

• Chronic kidney graft dysfunction

• Permanent graft failure

• Increased risk of infections

• Opportunistic infections

• Drug toxicity

• Cardiovascular disease

• Malignancy

• Post-transplant lymphoproliferative disease

• Increased mortality

Prognosis

The prognosis depends on:

• Severity and type of rejection

• Time to diagnosis and treatment

• Baseline graft function

• Adherence to immunosuppressive therapy

• Presence of infections or complications

Early recognition and appropriate treatment improve the likelihood of preserving kidney graft function. Delayed treatment may result in irreversible graft injury and transplant failure.

Prevention

Preventive strategies include:

• Appropriate immunological matching before transplantation

• Adequate induction and maintenance immunosuppression

• Regular monitoring of kidney function

• Strict adherence to immunosuppressive medication

• Infection prevention and vaccination

• Early detection of drug toxicity

• Regular transplant clinic follow-up

• Patient and family education