Transplant rejection and infection

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Kidney transplantation trades kidney failure for lifelong immunological and medicine management. T-cell-mediated rejection, antibody-mediated rejection, opportunistic infection and drug toxicity can present with the same finding: a creatinine above the patient's usual baseline. The safest initial stance is parallel evaluation with the transplant centre, not empirical steroid or antibiotic treatment in isolation.

Time after transplant changes probability but does not create absolute rules. In the first month, leaks, collections, thrombosis, obstruction, wound and hospital infection dominate. Between roughly one and six months, immunosuppression is often greatest and CMV, BK, Pneumocystis and fungal disease become more likely. Later, community infections dominate in stable recipients, while opportunistic infection re-emerges after rejection treatment or augmented immunosuppression.

Histology and immune evidence direct rejection treatment. Acute T-cell-mediated rejection often receives intravenous glucocorticoid, with lymphocyte-depleting treatment for selected resistant disease. Antibody-mediated rejection may require plasma exchange, immunoglobulin and other centre-selected therapy. Every intensification increases infection risk, so microbiology, prophylaxis and baseline viral screening are integrated into the plan.

Key points

An allograft creatinine rise has a broad differential: rejection, infection, hypovolaemia, obstruction, vascular compromise, calcineurin toxicity, recurrent disease and other AKI causes.
Contact the patient's transplant centre early; timing, induction regimen, donor-recipient virology, previous rejection, antibodies and usual creatinine change interpretation.
Rejection may be asymptomatic and is not reliably distinguished from infection or tacrolimus toxicity by examination or creatinine pattern alone.
Fever and inflammatory responses can be muted by immunosuppression, so confusion, hypotension, breathlessness, diarrhoea or unexplained graft dysfunction may be the infection signal.
Urinary infection may lack dysuria or graft pain because the allograft is denervated; obtain cultures before antibiotics when this does not delay sepsis care.
Early infection is often surgical or healthcare-associated; later opportunistic risk includes CMV, BK polyomavirus and Pneumocystis, shaped by prophylaxis and net immunosuppression.
Ultrasound with Doppler assesses hydronephrosis, collections and major vascular flow but cannot rule out cellular or antibody-mediated rejection.
Allograft biopsy usually establishes rejection type, while donor-specific antibody testing supports antibody-mediated disease and guides centre-specific treatment.
Tacrolimus has a narrow therapeutic range and major azole, macrolide, anticonvulsant, herbal and grapefruit interactions; measure a correctly timed trough and call renal pharmacy.
BK nephropathy treatment commonly requires supervised immunosuppression reduction, whereas rejection requires intensification; guessing between them can damage the graft.
Keep prophylaxis, vaccination and reproductive plans current; live vaccines are generally avoided during clinically significant immunosuppression and mycophenolate is a major teratogen.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Cellular or antibody-mediated rejection

Recipient T cells or donor-specific antibodies attack allograft tissue, with risk shaped by immunological history, adherence, drug exposure and time from transplantation.

Healthcare and opportunistic infection

Surgical and device-related infections predominate early, while CMV, BK polyomavirus, Pneumocystis and other opportunistic pathogens reflect cumulative immunosuppression and prophylaxis.

Altered immunosuppressant exposure

Vomiting, diarrhoea, missed doses and major medicine or food interactions can create underexposure that permits rejection or overexposure that increases infection and toxicity.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Alloreactive immune recognition
Recipient T-cell and antibody responses recognise donor antigens, producing cellular or antibody-mediated injury that requires biopsy and immune evidence to distinguish.
2
Microvascular and tubular injury
Cellular rejection inflames tubules and interstitium, while antibody-mediated rejection injures glomerular and peritubular microcirculation through complement and endothelial activation.
3
Impaired infection control
Immunosuppression reduces T-cell, B-cell and innate responses, allowing common pathogens to present subtly and latent viruses to reactivate.
4
Competing graft injuries
BK viral tubular injury, infection-related inflammation and calcineurin vasoconstriction can all raise creatinine, yet require opposing changes in immunosuppression.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Silent graft dysfunctionRed flag

A reproducible creatinine rise, new proteinuria or falling urine output may be the only rejection sign; normal temperature and a non-tender graft do not make it benign.

Sepsis under immunosuppressionRed flag

Hypotension, tachypnoea, confusion, hypoxia, rigors or lactate elevation can occur with little fever or leukocytosis and requires immediate cultures, antimicrobials and transplant advice.

CMV syndrome or disease

Fever, malaise, cytopenias, transaminitis, diarrhoea, pneumonitis or graft dysfunction after prophylaxis or treatment escalation suggests CMV; tissue-invasive disease may need endoscopic or organ-specific confirmation.

BK polyomavirus nephropathy

A gradual otherwise unexplained creatinine rise with BK viraemia, often without systemic illness, can mimic rejection; biopsy may be needed because management moves immunosuppression in the opposite direction.

Calcineurin inhibitor toxicity

Creatinine rise with tremor, headache, hypertension, hyperkalaemia, hypomagnesaemia, diabetes or a high trough suggests tacrolimus effect, often after an interacting drug or diarrhoea.

Urological or vascular complicationRed flag

Oliguria, anuria, graft swelling, haematuria, new hypertension, bruit or abrupt severe dysfunction raises obstruction, leak, collection, artery stenosis or thrombosis and needs urgent imaging.

Mycophenolate reproductive risk

Planned or possible pregnancy during mycophenolate treatment needs immediate transplant and specialist reproductive review; abrupt withdrawal can precipitate rejection, while continued exposure is teratogenic.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Serial creatinine, electrolytes and urine outputFirst step
Why
Quantify allograft dysfunction and detect dialysis-threatening complications.
Interpretation and limitations
Compare with the personal baseline and trajectory; hyperkalaemia, acidosis, pulmonary oedema or oliguria changes urgency regardless of rejection probability.
02
Urinalysis, microscopy and culture
Why
Find infection, haematuria, proteinuria and recurrent glomerular disease clues.
Interpretation and limitations
Pyuria and culture support UTI but symptoms may be absent; casts or rising proteinuria can suggest parenchymal disease and require nephrology interpretation.
03
Blood cultures and infection screen
Why
Identify bacterial, respiratory, gastrointestinal or line-related infection before treatment.
Interpretation and limitations
Take appropriate cultures without delaying antimicrobials in sepsis; negative early tests do not exclude opportunistic infection under blunted immunity.
04
Tacrolimus or ciclosporin trough
Why
Detect underexposure, toxicity, non-adherence or medicine interaction.
Interpretation and limitations
Confirm exact formulation, dose and sample timing before interpreting; target ranges depend on centre, time and immune risk, so call the transplant pharmacist.
05
Transplant ultrasound with Doppler
Why
Assess obstruction, collections, gross perfusion and vascular resistance or stenosis clues.
Interpretation and limitations
Hydronephrosis or absent flow needs urgent surgical action, but a normal scan cannot exclude rejection, BK nephropathy or calcineurin toxicity.
06
CMV and BK quantitative PCR
Why
Assess common viral causes according to donor risk, symptoms and surveillance protocol.
Interpretation and limitations
Viral-load trend is more useful than one low value; BK viraemia does not alone prove nephropathy, and CMV organ disease may occur with variable blood load.
07
Donor-specific HLA antibody testing
Why
Support evaluation of antibody-mediated allograft injury.
Interpretation and limitations
New or rising DSA strengthens concern but is not synonymous with histological rejection; integrate biopsy, microvascular injury and complement or molecular evidence.
08
Ultrasound-guided allograft biopsy
Why
Distinguish T-cell rejection, antibody-mediated rejection, viral nephropathy, recurrent disease and other injury.
Interpretation and limitations
Pathology is classified using current transplant criteria and directs therapy; correct blood pressure, anticoagulation and bleeding risk before the procedure.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Hypovolaemic or septic AKI

Vomiting, diarrhoea, hypotension or systemic infection can reduce graft perfusion without rejection, although infection may be present without fever.

Obstruction or vascular complication

Hydronephrosis, collections or abnormal Doppler flow support a surgical or post-renal cause; a normal scan cannot exclude microscopic rejection.

Calcineurin-inhibitor toxicity

A correctly timed high trough, interacting medicine, hypertension or neurotoxicity supports tacrolimus or ciclosporin exposure, but levels alone do not exclude rejection.

BK nephropathy

BK viral load and biopsy features distinguish viral tubular injury from rejection because reducing versus intensifying immunosuppression has opposite consequences.

Recurrent or de novo renal disease

New proteinuria, characteristic serology or biopsy deposits may reveal recurrence of the original glomerulopathy or a new allograft disease.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Creatinine riseAssess graft dysfunction in parallelFirst stepCreatinine exceeds the recipient's established baseline or urine output falls.

1Contact the transplant centre, confirm timeline, baseline, adherence, recent illness and interacting medicines, and assess ABCDE, fluid state, blood pressure and urine output.
2Obtain electrolytes, cultures, urinalysis, drug trough, viral PCR and urgent ultrasound-Doppler according to presentation, treating sepsis or life-threatening electrolyte disturbance immediately.
3If no rapidly reversible cause explains dysfunction, arrange transplant-team biopsy and DSA testing; do not give empirical rejection steroids before infection and histology discussion unless directed.

02SepsisTreat infection without abandoning the graftA transplant recipient has physiological infection or sepsis features.

1Follow the local sepsis bundle, collect cultures promptly, start renal-adjusted broad antimicrobial therapy and involve microbiology and transplant nephrology at presentation.
2Review source, donor-recipient viral risk, prophylaxis, neutrophils and prior resistant organisms, adding CMV, fungal or Pneumocystis evaluation when the syndrome supports it.
3Change immunosuppression only through the transplant team, balancing infection control against rejection and monitoring drug levels as diarrhoea, AKI and antimicrobials alter exposure.

03RejectionTreat the biopsy-defined mechanismHistology and transplant review diagnose acute allograft rejection.

1Classify T-cell versus antibody-mediated injury, severity, chronicity, DSA and infection burden before selecting rescue treatment and prognosis.
2EscalationUse centre-protocol intravenous steroid for suitable cellular rejection, escalating steroid-resistant cases to lymphocyte-depleting therapy only with infection prophylaxis and monitoring.
3For antibody-mediated rejection, use transplant-selected plasma exchange, immunoglobulin and adjunct strategy, while following antibody, creatinine, proteinuria and treatment complications.

04BK or CMVUse virus-specific managementQuantitative PCR and clinical findings suggest clinically important viral replication.

1For BK, confirm trend and consider biopsy; the transplant team usually reduces selected immunosuppression stepwise while watching closely for rejection.
2For CMV syndrome or organ disease, begin renal-adjusted valganciclovir or intravenous ganciclovir according to severity, absorption, resistance and specialist virology advice.
3Monitor viral load, counts, renal function and immunosuppression exposure until response and secondary prophylaxis decisions are complete.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Calcineurin inhibition prevents T-cell activation and acute allograft rejection as part of combination maintenance therapy.

Tacrolimus maintenance immunosuppression

Use the recipient-specific immediate- or modified-release oral regimen at fixed times, adjusted only by the transplant team to a correctly timed trough target that varies with post-transplant stage and immune risk.

Formulations are not interchangeable. Monitor creatinine, potassium, magnesium, glucose, blood pressure and neurotoxicity; macrolides, azoles, anticonvulsants, St John's wort and grapefruit can cause dangerous exposure changes.

Antimetabolite maintenance therapy reduces lymphocyte proliferation and rejection risk alongside tacrolimus and steroid.

Mycophenolate mofetil

Use the transplant-centre twice-daily oral dose, commonly 1 g twice daily initially in adults, reduced or interrupted only for protocol-defined toxicity, infection or reproductive planning under specialist direction.

Causes diarrhoea, cytopenia and infection and is a major human teratogen. Follow current MHRA contraception and pregnancy testing advice; do not stop independently because under-immunosuppression can lose the graft.

Prevents or treats cytomegalovirus according to donor-recipient risk, viral load and organ involvement.

Valganciclovir or intravenous ganciclovir

Use the transplant virology protocol with dose and interval adjusted to measured renal function; select oral valganciclovir for reliable absorption and intravenous ganciclovir for severe or tissue-invasive disease.

Can cause neutropenia, anaemia, thrombocytopenia and renal accumulation. Monitor full blood count, creatinine and CMV PCR, review resistance with virology and apply current reproductive precautions.

Prevents Pneumocystis jirovecii pneumonia and may reduce selected urinary or opportunistic infections.

Co-trimoxazole prophylaxis

Use the transplant-centre prophylactic tablet strength and schedule, often 480 mg once daily for a defined early post-transplant or post-rejection period, with renal and blood-count adjustment.

Review sulfonamide allergy, hyperkalaemia, cytopenia, renal function, methotrexate and warfarin interactions. Prophylaxis duration varies with centre and augmented immunosuppression; breakthrough respiratory illness still needs urgent investigation.

Reverses acute cellular or antibody-mediated immune injury and preserves allograft function when benefit remains plausible.

Rejection rescue therapy

Use only the transplant-centre biopsy-specific intravenous glucocorticoid, lymphocyte-depleting, plasma-exchange or immunoglobulin regimen, with pharmacy verification and infection prophylaxis before each treatment phase.

Intensification can cause severe bacterial, viral and fungal infection, cytopenia, infusion reaction and malignancy risk. Exclude important infection, screen appropriately and never select a regimen from creatinine alone.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Irreversible graft failure

Untreated rejection, severe infection or repeated injuries can produce interstitial fibrosis, tubular atrophy and permanent loss of allograft function.

Sepsis and opportunistic organ disease

Muted infection may progress to shock, pneumonitis, gastrointestinal disease or disseminated viral and fungal illness before conventional inflammatory signs appear.

BK-associated graft injury

Persistent viral replication can destroy tubular cells and scar the graft, while excessive immunosuppression reduction may provoke rejection.

Medicine toxicity and interaction

Altered calcineurin-inhibitor exposure can cause renal vasoconstriction, neurological toxicity or under-immunosuppression, particularly during diarrhoea or interacting antimicrobial treatment.

Malignancy from chronic immunosuppression

Reduced immune surveillance increases skin, lymphoid and other cancer risk, adding the need for sun protection, screening and specialist review.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Trend creatinine, electrolytes, urine protein and blood pressure against the recipient's own stable baseline, not only the laboratory reference range.
Measure tacrolimus or ciclosporin trough at the centre-defined frequency and after interacting medicine, formulation change, diarrhoea, adherence concern or unexplained dysfunction.
Follow full blood count, liver profile and infection symptoms during antimetabolite, antiviral and prophylactic therapy, escalating cytopenia rather than stopping all agents blindly.
Use CMV and BK PCR surveillance according to donor risk, time from transplant and centre policy, and intensify after rejection treatment when indicated.
Maintain non-live vaccination, skin and malignancy surveillance, cardiovascular risk and bone health through transplant follow-up; avoid live vaccine without specialist approval.
Review contraception and pregnancy plans at relevant visits, converting mycophenolate to a pregnancy-compatible transplant regimen well before conception through the specialist team.
After rejection, document histological type, rescue treatment, prophylaxis and a clear plan for DSA, creatinine, proteinuria and infection monitoring.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Creatinine does not name the lesion

Rejection, BK nephropathy and tacrolimus toxicity can produce nearly identical laboratory trajectories but require opposite changes in immunosuppression.

Denervation hides symptoms

A transplanted kidney and ureter may not produce ordinary pyelonephritis or obstruction pain, so urine, physiology and function deserve greater weight.

Diarrhoea changes two risks

It can indicate CMV or mycophenolate toxicity while also raising tacrolimus exposure unpredictably; drug level and infection assessment belong together.

Normal ultrasound is incomplete

Ultrasound answers obstruction, collection and major perfusion questions; it cannot clear microscopic immune, viral or toxic graft injury.

Never promise no rejection

Excellent adherence greatly lowers risk but does not eliminate it; unexplained dysfunction still needs timely assessment without blaming the recipient.

11Common pitfallsFrequent interpretation and management errors.

01
Calling every creatinine rise rejection and giving steroid before infection review.
02
Reassuring from absence of fever in an immunosuppressed septic patient.
03
Stopping maintenance immunosuppression independently during infection.
04
Interpreting a tacrolimus concentration without checking trough timing and formulation.
05
Using normal ultrasound to exclude rejection or BK nephropathy.
06
Missing private, community or newly prescribed macrolide and azole interactions.
07
Treating BK viraemia with more immunosuppression because creatinine is rising.
08
Ignoring mycophenolate contraception and pregnancy planning until conception occurs.