Pre-Transplantation Guidelines

Approach and Workflow

1. Early Screening – identify compatibility
   • ABO blood group typing
   • HLA typing (donor and recipient)
   • Virtual crossmatch (using latest HLA antibody profile)
2. Full donor workup
   • Medical, surgical and psychosocial assessments
3. Structured immunological monitoring
   • Recipient HLA antibody screening
   • Direct crossmatch performed

Compatibility

ABO Compatibility

Compatible ABO blood group is required.

HLA Compatibility

HLA compatibility is assessed using a mismatch grading system:

• 0.0.0 (perfect match): no mismatch at the 3 key loci HLA-A, -B, and -DR
• 2.2.2 (full mismatch): 2 mismatches at all 3 key loci HLA-A, -B, and -DR (6 mismatches in total)

In short, 0.0.0 (perfect HLA match) is preferred and has the best prognosis.

Management of Incompatibility

1st line option for ALL incompatible donor-recipient pairs: consider for UKLKSS (UK Live Kidney Sharing Scheme)

If no suitable match in UKLKSS: consider AIT (antibody incompatible transplantation) in an experienced centre

Protocol for ABO-Incompatible (ABOi) Transplant

Can only proceed in centres with ≥5 ABOi transplants / year

Pre-transplantation management:

• Titration of isohaemagglutinins (anti-A or anti-B)
• Desensitisation (plasmapheresis or immunoadsorption)
• Pre-treatment with rituximab

Protocol for HLA-Incompatible (HLAi) Transplant

Pre-transplantation management:

• Pre-treatment with rituximab + IVIG +/- antithymocyte globulin
• Desensitisation (plasmapheresis or immunoadsorption)

Donor Work Up – Core Investigations

Routine Screening Test

• Blood tests: FBC, U&Es, LFTs, fasting glucose, lipid profile, coagulation profile
• Infection screening: HIV, HBV, HCV, CMV/EVC IgG, HTLV-1/2, syphilis, HEV (if at risk), TB
• Urinalysis 

Anatomical and Functional Imaging

• GFR measurement: Isotope (mGFR) or iohexol clearance if eGFR < 90
• Renal anatomy: CT-angiography or MRA
• Cardiac risk: ECG +/- ECHO, stress test if cardiovascular risk present
• Bone density: DEXA if osteopenia suspected

Targeted Assessment

• Hypertension, obesity (BMI >30), diabetes
• Malignancy risk or family history of renal disease
• Donors with prior pregnancy, liver or haematological conditions

Structured Immunological Monitoring

• HLA antibody screening every 3 months
• Detect donor-specific antibodies
• Re-screen after any sensitising event (e.g. transfusion, pregnancy, change in immunosuppression)

• Perform direct cross-matching using recipient serum within 14 days of transplant

Post-Transplantation Guidelines

Immunosuppression – Preventing Rejection

Induction Therapy

Induction therapy should be started before or at the time of renal transplantation.

All patients should receive a biological induction agent:

• Low immunological risk: generally IL2-RA (e.g. basiliximab)
• High immunological risk: consider for T-cell depleting antibodies (e.g. antithymocyte globulin)

Maintenance Therapy

1st line triple therapy in low / medium immunological risk:

• Calcineurin inhibitor – tacrolimus preferred over ciclosporin
• Anti-proliferative agent – mycophenolic acid-based (MPA) drugs preferred
• +/- Corticosteroids

2nd line options:

• Calcineurin inhibitor alternatives (if tacrolimus not appropriate)
  • Ciclosporin (calcineurin inhibitor)
  • Sirolimus (mTOR inhibitor)
  • Everolimus (mTOR inhibitor)
  • Belatacept (CTLA4-Ig inhibitor)
  • Modified-release tacrolimus (if peak dose side effects are problematic)

• Anti-proliferative agent alternatives (if MPA drugs not appropriate)
  • Azathioprine – in fertile patients who are unwilling to use reliable contraception

Monitoring Immunosuppression

Long-term monitoring of the following is recommended:

• Tacrolimus – trough level
• Ciclosporin – trough level or 2-hour post-dose
• Sirolimus – trough level

BTS guidelines state that the utility of monitoring MPA drugs is uncertain.

Acute Rejection

Investigation and Diagnosis

To diagnose acute rejection:

• Renal biopsy with C4d and SV40 staining (ideally before starting treatment unless this would cause significant delay or risk)
• Serum sample at time of biopsy to check for HLA-specific antibodies

Management

There are 2 types of acute rejections:

Hyperacute Rejection

Hyperacute rejection is very rare and involves pre-formed antibodies against HLA or antigens of the donor.

BTS guidelines do not specify the management of hyperacute rejection as the pre-transplant screening practices and protocols effectively prevents it.

If hyperacute rejection happens, management involves immediate removal of the graft.

Acute Cellular Rejection

1st line: high-dose IV corticosteroids + add or restart steroids into maintenance therapy

If refractory or aggressive vascular rejection: consider lymphocyte-depleting agents

Antibody-Mediated Rejection

Treat with one or more of the following:

• Steroids
• Plasma exchange
• IVIG
• Anti-CD20 antibody
• Lymphocyte-depleting antibody
• Bortezomib

MPA drugs are effective in preventing antibody-mediated rejection and should be part of the maintenance therapy:

• If patient is on azathioprine → switch to MPA drugs
• If patient is already on MPA drugs  → maximise the existing dose

Chronic Allograft Injury

Investigation and Diagnosis

Screen for chronic allograft injury by monitoring renal function at each clinic visit by:

• Serum creatinine
• Urine dipstick and ACR / PCR
  • Look for new-onset proteinuria

To diagnose chronic allograft injury:

• Renal biopsy with C4d + SV40 staining – gold standard
• Serum sample at time of biopsy to check for HLA-specific antibodies

Management

• If there is histological evidence of calcineurin inhibitor toxicity or non-specific interstitial fibrosis and tubular atrophy → stop calcineurin inhibitors (tacrolimus / ciclosporin)
• If there is evidence of ongoing immune injury (cellular rejection and/or humoral rejection) → intensify immunosuppression
• Manage similarly to other patients with CKD

Long-Term Management

The BTS guideline outlines a broad range of recommendations to support the long-term health and graft survival of kidney transplant recipients. Key management priorities are summarised below.

Cardiovascular and Metabolic Health

• Strict hypertension control
• Annual fasting lipid profile
• Screen regularly for post-transplant diabetes mellitus

Also offer general lifestyle recommendations like any other:

• Encourage a healthy diet
• Maintain BMI ≤25 kg/m²
• Promote regular physical activity
• Advice on smoking cessation and moderate alcohol intake
• Avoid unsupervised over-the-counter medications

Cancer Surveillance

Immunosuppression increases the risk of non-melanoma skin cancer, especially squamous cell carcinoma:

• Biannual skin checks for the first 5 years post-transplant, then annually
• Advice on sun protection measures

Infection Prevention and Management

Patients should:

• Avoid live attenuated vaccines
• Otherwise, receive inactivated vaccines per standard schedules
• Annual influenza vaccination is recommended

The following extra infection prophylaxis is recommended

• VZV vaccination in IgG-negative patients prior to transplantation
• CMV prophylaxis for 3-6 months post-transplant or until immunosuppression is reduced to maintenance levels
• PJP prophylaxis with co-trimoxazole for 3-6 months post-transplant

• Monitor high-risk patients for EBV viral load post-transplant
• Screen for BK virus in cases of unexplained renal dysfunction and confirm diagnosis with renal biopsy + SV40 staining

Conception Advice

Female patients:

• Discontinue MPA drugs prior to conception and replace with azathioprine
• Wait at least 1 year post-transplant with stable graft function before attempting conception
• Consider low-dose aspirin to reduce pre-eclampsia risk

Male patients:

• Mycophenolate mofetil and enteric-coated mycophenolate sodium (Myfortic®) have theoretical teratogenic potential
• mTOR inhibitors may reduce sperm count

References