Transplantation and Immunosuppression

Last updated 17 August 2026.

Key points

Kidney transplantation: the treatment of choice for suitable patients with end stage renal disease, giving better survival and quality of life than dialysis. A live donor graft outlasts a deceased donor graft.
Surgical placement: the graft is placed extraperitoneally in the iliac fossa and anastomosed to the external iliac vessels, with the ureter implanted into the bladder. The native kidneys are usually left in situ.
Matching: ABO compatibility is essential, plus HLA matching (at HLA-A, -B and -DR) and a negative crossmatch to exclude preformed donor-specific antibodies.
Hyperacute rejection: occurs within minutes to hours, mediated by preformed antibodies causing complement activation and thrombosis. The graft is unsalvageable and must be removed - now rare because of crossmatching.
Acute rejection: occurs over days to months and is usually T-cell mediated. Presents with a rising creatinine, sometimes fever and graft tenderness. Diagnosed by biopsy and usually reversible with high-dose steroids.
Standard immunosuppression: induction with basiliximab (or ATG), then maintenance with a calcineurin inhibitor (tacrolimus) plus an antiproliferative (mycophenolate) plus or minus prednisolone.
Key drug toxicities: tacrolimus and ciclosporin are nephrotoxic; ciclosporin causes gum hypertrophy and hirsutism, tacrolimus causes diabetes and tremor. Both interact heavily via CYP3A4.
Long-term risks: infection (CMV, BK virus, PCP), malignancy (especially skin cancer and post-transplant lymphoproliferative disorder), cardiovascular disease and chronic allograft failure.

Introduction

Kidney transplantation is the optimal form of renal replacement therapy for patients who are fit enough for surgery and lifelong immunosuppression. Compared with remaining on dialysis it offers substantially better survival, better quality of life, restoration of fertility, freedom from dialysis schedules and fluid restriction, and lower long-term cost to the health service.¹

Around 3,000 to 3,500 kidney transplants are performed annually in the UK. Roughly a third come from living donors and the remainder from deceased donors. The median wait for a deceased donor kidney is two to three years, and longer for patients with unusual blood groups or high levels of pre-existing antibody sensitisation.

Donors, matching and assessment

Types of donor

Donor types and their characteristics.
Donor type	Detail	Outcome
Living related or unrelated donor	A healthy volunteer (family member, friend, spouse, or an altruistic stranger) donates one kidney, usually laparoscopically. Allows elective, planned surgery and pre-emptive transplantation. The UK Living Kidney Sharing Scheme enables paired and pooled exchange where a willing donor is incompatible with their intended recipient.	Best graft and patient survival
Deceased donor after brain death (DBD)	Donation following confirmation of death by neurological criteria, with the circulation maintained until organ retrieval	Good, with shorter ischaemic times than DCD
Deceased donor after circulatory death (DCD)	Donation following death confirmed by cardiorespiratory criteria; the kidney sustains a period of warm ischaemia before retrieval	Higher rates of delayed graft function, but long-term outcomes approach those of DBD

Matching and immunological assessment

ABO blood group compatibility - essential, as ABO antibodies are naturally occurring and would cause hyperacute rejection (ABO-incompatible transplantation is possible in specialist centres with antibody removal, but is not routine)
HLA (human leucocyte antigen) matching - the closer the match at HLA-A, HLA-B and HLA-DR, the better the long-term graft survival. HLA-DR mismatch matters most. A '000 mismatch' is ideal but rarely achieved.
Crossmatching - recipient serum is tested against donor lymphocytes. A positive crossmatch indicates preformed donor-specific antibodies and is an absolute contraindication, because it predicts hyperacute rejection.⁴
Panel reactive antibody / calculated reaction frequency - quantifies how sensitised a recipient is. Sensitisation results from previous transplants, blood transfusions and pregnancy, which is why unnecessary transfusion is avoided in potential transplant candidates.
Virology - CMV, EBV, hepatitis B and C, HIV and varicella status in both donor and recipient, to guide prophylaxis

The operation

The graft is placed heterotopically and extraperitoneally in the iliac fossa - usually the right, because the iliac vessels are more superficial there - through a curved 'hockey stick' incision. The renal artery and vein are anastomosed to the external iliac artery and vein, and the donor ureter is implanted into the bladder over a temporary stent.

Anatomical diagram showing a transplanted kidney positioned low in the right iliac fossa, with its artery and vein joined to the external iliac vessels and its ureter connected to the bladder, alongside the two native kidneys left in place. — Position of a transplanted kidney. The graft sits **superficially in the iliac fossa**, anastomosed to the **external iliac vessels**, with the ureter implanted into the bladder. The **native kidneys are left in situ** unless there is a specific reason to remove them.Wiremu Stadtwald Demchick, CC BY 3.0, via Wikimedia Commons

The native kidneys are usually left in place - removing them adds morbidity for no benefit. Native nephrectomy is reserved for specific indications: massively enlarged polycystic kidneys needing space, refractory hypertension, chronic infection or stones, or suspected malignancy.
The superficial position has a practical consequence - the graft is palpable in the iliac fossa and can be examined for tenderness and, with a stethoscope, for a bruit. Any transplant patient with graft tenderness needs assessment.
A functioning graft usually produces urine immediately; delayed graft function (needing dialysis in the first week) is common after DCD donation and usually reflects acute tubular injury from ischaemia rather than rejection
Immediate surgical complications include bleeding, renal artery or vein thrombosis (a surgical emergency presenting with sudden anuria and graft pain), urine leak, ureteric stenosis, lymphocoele and wound infection

Rejection

Rejection is an immune response of the recipient against donor antigens. It is classified by timing and mechanism, and the distinction is heavily examined because the treatment and prognosis differ completely.

Types of rejection.
Type	Timing	Mechanism	Features and management
Hyperacute	Minutes to hours - often on the operating table	Preformed recipient antibodies (ABO or anti-HLA) bind donor endothelium, activating complement and causing thrombosis and infarction - a type II hypersensitivity reaction	The graft becomes mottled, dusky and swollen and never functions. It is unsalvageable and must be removed (graft nephrectomy). Now rare, because ABO matching and crossmatching prevent it.
Acute T-cell mediated (cellular)	Days to months, most often in the first 6 months	T-lymphocyte-mediated infiltration of the graft interstitium and tubules	Rising creatinine, sometimes with fever, oliguria, hypertension and a tender, swollen graft. Diagnosed on biopsy. Usually reversible with high-dose intravenous methylprednisolone; resistant cases receive ATG.
Acute antibody-mediated (humoral)	Days to months, or later	Donor-specific antibodies developing after transplantation, causing complement-mediated endothelial injury; C4d staining on biopsy	Rising creatinine. Treated with plasma exchange, intravenous immunoglobulin and rituximab. Worse prognosis than cellular rejection.
Chronic allograft injury	Months to years	Multifactorial - chronic antibody-mediated injury, calcineurin inhibitor toxicity, hypertension, recurrent disease and interstitial fibrosis with tubular atrophy	Gradual creatinine rise with proteinuria and hypertension. Largely irreversible; management is to optimise blood pressure, minimise calcineurin inhibitor exposure and prepare for return to dialysis or re-transplantation.

Approaching a rising creatinine in a transplant recipient

This is a very common exam scenario, and the differential is broader than rejection alone. Work through it systematically:

Pre-renal - dehydration, diarrhoea, over-diuresis, NSAIDs or an ACE inhibitor
Drug toxicity - calcineurin inhibitor nephrotoxicity; check the tacrolimus or ciclosporin trough level and review for interacting drugs
Rejection - cellular or antibody-mediated; suggested by graft tenderness and confirmed by biopsy
Infection - urinary tract infection, pyelonephritis of the graft, or BK virus nephropathy (which mimics rejection but is treated by reducing immunosuppression - getting this the wrong way round is harmful)
Obstruction - ureteric stricture, stent problem or lymphocoele; arrange an ultrasound with Doppler
Vascular - transplant renal artery stenosis (consider if there is refractory hypertension and a creatinine rise on an ACE inhibitor), or thrombosis in the early period
Recurrence of the original disease - particularly FSGS, IgA nephropathy and membranous nephropathy
The investigation sequence is: bloods with drug levels, urine dipstick and culture, ultrasound with Doppler, then biopsy - biopsy is the only way to diagnose rejection definitively

Immunosuppression

Immunosuppression has two phases: induction at the time of transplantation, and lifelong maintenance. The aim is to prevent rejection while minimising the infective, malignant and metabolic consequences of over-immunosuppression - a balance that has to be individualised and revisited.

Induction

Basiliximab - a monoclonal antibody against the IL-2 receptor (CD25) on activated T cells; the standard induction agent, well tolerated
Anti-thymocyte globulin (ATG) - a polyclonal T-cell depleting antibody, used in higher immunological risk recipients and to treat steroid-resistant rejection; causes cytokine release and profound lymphopenia
High-dose corticosteroid at induction

Maintenance

Standard UK maintenance is a calcineurin inhibitor plus an antiproliferative agent, with or without a corticosteroid - typically tacrolimus, mycophenolate mofetil and prednisolone.²

Maintenance immunosuppressive drugs, their mechanisms and characteristic toxicities.
Drug	Mechanism	Characteristic adverse effects
Tacrolimus	Calcineurin inhibitor - binds FKBP-12, inhibiting calcineurin and so blocking IL-2 transcription and T-cell activation	Nephrotoxicity (dose-dependent, and a major cause of chronic graft dysfunction), new-onset diabetes after transplantation, tremor and neurotoxicity, hypertension, hyperkalaemia, hypomagnesaemia, alopecia. Narrow therapeutic index - requires trough level monitoring.
Ciclosporin	Calcineurin inhibitor - binds cyclophilin, same downstream effect	Nephrotoxicity, hypertension, gum (gingival) hypertrophy, hirsutism, tremor, hyperlipidaemia, hyperuricaemia and gout, hyperkalaemia. Also needs level monitoring.
Mycophenolate mofetil	Inhibits inosine monophosphate dehydrogenase, blocking de novo purine synthesis on which lymphocytes uniquely depend	Bone marrow suppression (leucopenia, anaemia), diarrhoea and gastrointestinal intolerance, increased infection risk. Teratogenic - strictly contraindicated in pregnancy, and effective contraception is mandatory.
Azathioprine	A purine analogue; its metabolite inhibits DNA synthesis	Myelosuppression, hepatotoxicity, pancreatitis. Catastrophic interaction with allopurinol and febuxostat - xanthine oxidase inhibition blocks azathioprine metabolism and causes profound myelosuppression. Check TPMT activity before starting.
Prednisolone	Broad anti-inflammatory and immunosuppressive effects through altered gene transcription	Cushingoid features, diabetes, osteoporosis, weight gain, hypertension, cataracts, poor wound healing, mood disturbance, adrenal suppression - hence the drive to steroid-sparing regimens
Sirolimus / everolimus	mTOR inhibitors - block IL-2 signal transduction and cell cycle progression	Impaired wound healing and lymphocoele (so usually avoided immediately post-operatively), proteinuria, pneumonitis, mouth ulcers, hyperlipidaemia. Not nephrotoxic, so useful where calcineurin inhibitor toxicity is a problem; may also reduce skin cancer risk.
Belatacept	Fusion protein blocking CD80/86 co-stimulation of T cells	Avoids calcineurin nephrotoxicity, but increased risk of post-transplant lymphoproliferative disorder, especially in EBV-seronegative recipients, in whom it is contraindicated

Calcineurin inhibitor interactions - a common cause of avoidable graft loss

Tacrolimus and ciclosporin are metabolised by CYP3A4 and have a narrow therapeutic index. Prescribing an interacting drug without adjusting the dose and rechecking levels can precipitate either rejection or acute nephrotoxicity.

CYP3A4 inhibitors raise levels (risking nephrotoxicity) - macrolides (clarithromycin, erythromycin), azole antifungals (fluconazole, itraconazole), diltiazem and verapamil, protease inhibitors, and grapefruit juice
CYP3A4 inducers lower levels (risking rejection and graft loss) - rifampicin, phenytoin, carbamazepine, and St John's wort, which patients may buy without telling anyone
Always check with the transplant team before adding or stopping any drug, and recheck the trough level after any change⁵
Avoid NSAIDs entirely - additive nephrotoxicity on an already vulnerable single functioning kidney
Take the trough level immediately before the next dose, and be sure the patient has not already taken it that morning

Infection and prophylaxis

Infection is the price of immunosuppression and the second commonest cause of death after transplantation. The likely organism depends on how long ago the transplant was.

Timeline of post-transplant infection.
Period	Typical infections
First month	Conventional post-surgical infections - wound infection, urinary tract infection, hospital-acquired pneumonia, line sepsis, Clostridioides difficile; also donor-derived infection
1 to 6 months	Opportunistic infections, when immunosuppression is at its most intense - CMV, Pneumocystis jirovecii, BK virus, EBV, reactivated tuberculosis, Nocardia, Listeria, fungal infection, and reactivated hepatitis B
Beyond 6 months	Community-acquired infections predominate again, but with atypical severity; plus late CMV, and chronic viral infections including BK nephropathy and EBV-driven disease

Co-trimoxazole for around 6 months as Pneumocystis prophylaxis (also covers some urinary and Nocardia infection)
Valganciclovir for CMV prophylaxis in at-risk pairings - the highest risk being a CMV-positive donor into a CMV-negative recipient; CMV presents with fever, malaise, leucopenia, hepatitis, colitis, pneumonitis or retinitis, and is monitored by CMV PCR viral load
BK virus - a polyomavirus causing BK nephropathy with a rising creatinine that mimics rejection. Monitored by plasma BK PCR, and treated by reducing immunosuppression - the opposite of rejection treatment, which is why biopsy matters
Nystatin or fluconazole for candidiasis in the early period
Vaccination before transplantation where possible - live vaccines are contraindicated after transplantation (MMR, varicella, yellow fever, BCG, live attenuated influenza); inactivated influenza, pneumococcal and COVID-19 vaccines are recommended
A low threshold for investigation - immunosuppressed patients mount blunted inflammatory responses, so fever may be absent and peritonitis may present without guarding

Long-term complications

Long-term complications after kidney transplantation.
Category	Detail
Malignancy	Overall risk is increased two- to fourfold by chronic immunosuppression. Skin cancer is by far the commonest - squamous cell carcinoma (which behaves more aggressively than in the general population), basal cell carcinoma and melanoma - hence lifelong sun protection and annual skin surveillance. Post-transplant lymphoproliferative disorder (PTLD) is an EBV-driven B-cell proliferation, treated by reducing immunosuppression, with rituximab or chemotherapy as needed. Also increased Kaposi sarcoma, anogenital and cervical cancer (HPV-related) and renal cell carcinoma in native kidneys.
Cardiovascular disease	The leading cause of death with a functioning graft. Driven by pre-existing CKD risk plus steroid- and calcineurin inhibitor-induced hypertension, dyslipidaemia and diabetes. Managed with statins, blood pressure control and lifestyle measures.
New-onset diabetes after transplantation	Common, particularly with tacrolimus and corticosteroids; requires screening and standard diabetes management
Chronic allograft dysfunction	Progressive interstitial fibrosis and tubular atrophy from combined immunological and non-immunological injury; the commonest cause of late graft loss
Recurrence of original disease	Particularly FSGS (which can recur within days and cause early graft loss), IgA nephropathy, membranous nephropathy, and atypical HUS
Bone disease	Steroid-induced osteoporosis and persistent hyperparathyroidism; needs bone protection and monitoring
Drug-specific toxicity	As tabulated above - calcineurin inhibitor nephrotoxicity is the most important
Non-adherence	A leading and under-recognised cause of late graft loss, especially in adolescents and young adults transitioning to adult services

Red flags

Act on these

Sudden anuria with graft pain in the early post-operative period - suspect renal artery or vein thrombosis; needs immediate Doppler ultrasound and surgical exploration, as the graft can be lost within hours
Rising creatinine with a tender, swollen graft - suspect acute rejection; check drug levels, exclude infection and obstruction, and arrange urgent biopsy
Rising creatinine in a transplant patient - never assume rejection. Distinguishing rejection (needs more immunosuppression) from BK nephropathy or calcineurin toxicity (need less) requires levels, virology and biopsy
Fever in a transplant recipient - a broad and urgent differential; the usual inflammatory signs are blunted, so investigate thoroughly and involve the transplant team
A new or changing skin lesion - squamous cell carcinoma is common and behaves aggressively; refer promptly
Lymphadenopathy, night sweats or weight loss - consider PTLD; check EBV viral load and image
Prescribing clarithromycin, fluconazole, diltiazem or rifampicin to a patient on tacrolimus or ciclosporin - a major interaction; adjust the dose and recheck levels, or choose another agent
Prescribing allopurinol to a patient on azathioprine - risks life-threatening myelosuppression; avoid the combination
Any live vaccine in a transplant recipient - contraindicated
A young adult transplant recipient missing clinic appointments - non-adherence is a leading cause of graft loss; address it actively rather than discharging them

Prognosis

Outcomes are good and continue to improve. One-year graft survival exceeds 90% for both living and deceased donor transplants in the UK, and around 85 to 90% of living donor grafts are still functioning at 5 years.³ Median graft survival is roughly 12 to 15 years for a deceased donor kidney and 15 to 20 years or more for a living donor kidney, so many recipients - particularly those transplanted young - will need a second transplant or a return to dialysis during their lifetime.

Patient survival is markedly better than on dialysis, roughly doubling life expectancy for a transplanted patient compared with an equivalent patient remaining on the waiting list. The benefit is greatest in younger patients and those with diabetes.

Factors associated with better graft survival include a living donor, a close HLA match, short cold ischaemic time, pre-emptive transplantation, low sensitisation, younger donor age, and good adherence to immunosuppression. Acute rejection episodes, delayed graft function, recurrent disease and non-adherence all predict earlier graft loss.

The pattern of death after transplantation has shifted: with rejection now largely controlled, patients die with a functioning graft more often than they lose one, principally from cardiovascular disease, infection and malignancy. Long-term care is therefore as much about cardiovascular risk reduction, cancer surveillance and vaccination as about immunology - and this is precisely where general medical clinicians contribute most to a transplant recipient's outcome.

References

NICE NG107. Renal replacement therapy and conservative management. 2018. Available here
KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Available here
NHS Blood and Transplant. Annual report on kidney transplantation. Available here
British Transplantation Society. Clinical guidelines. Available here
BNF. Tacrolimus, ciclosporin, mycophenolate mofetil and azathioprine. Available here
Wiremu Stadtwald Demchick, CC BY 3.0, via Wikimedia Commons. Available here

This article is written for revision and education. It is not clinical guidance and must not be used to make decisions about the care of a patient. Always check current NICE guidance and local protocols.