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OverviewAetiologyPathophysiologyClinical features and red flagsInvestigationsDifferential diagnosisManagementComplicationsMonitoring and follow-upSpecial situationsCommon pitfallsQuestionsSources
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Educational draft · awaiting clinical reviewThe full textbook explains uncertainty but does not replace live national or local guidance, specialist advice, or current prescribing information.

Transplant rejection and infection

Renal · UK scope · Sources checked 27 Aug 2026 · Clinical review pending

RapidFull
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Time-critical presentation

A transplant recipient with sepsis, oliguria, rapidly rising creatinine, hyperkalaemia, pulmonary oedema, graft pain, major drug-level abnormality or suspected rejection needs same-day discussion with the transplant nephrology service and acute assessment. Never stop tacrolimus, mycophenolate or steroid independently unless the transplant team directs it during a life-threatening reaction.

Overview

Assess acute kidney-allograft dysfunction without anchoring, recognise infection despite blunted signs, and protect both patient and graft through immediate transplant-centre coordination.

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.

Aetiology

01

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.

02

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.

03

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.

Pathophysiology

  1. 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. 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. 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. 4
    Competing graft injuries

    BK viral tubular injury, infection-related inflammation and calcineurin vasoconstriction can all raise creatinine, yet require opposing changes in immunosuppression.

Clinical features and red flags

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.

Investigations

  1. 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.
  2. 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.
  3. 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.
  4. 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.

Differential diagnosis

01

Hypovolaemic or septic AKI

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

02

Obstruction or vascular complication

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

03

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.

04

BK nephropathy

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

05

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.

Management

01Creatinine riseAssess graft dysfunction in parallelFirst stepCreatinine exceeds the recipient's established baseline or urine output falls.+
  1. 1Contact the transplant centre, confirm timeline, baseline, adherence, recent illness and interacting medicines, and assess ABCDE, fluid state, blood pressure and urine output.
  2. 2Obtain electrolytes, cultures, urinalysis, drug trough, viral PCR and urgent ultrasound-Doppler according to presentation, treating sepsis or life-threatening electrolyte disturbance immediately.
  3. 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.+

Complications

01

Irreversible graft failure

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

02

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.

03

BK-associated graft injury

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

04

Medicine toxicity and interaction

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

05

Malignancy from chronic immunosuppression

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

Monitoring and follow-up

  • 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.

Special situations

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.

Common pitfalls

  1. 01

    Calling every creatinine rise rejection and giving steroid before infection review.

  2. 02

    Reassuring from absence of fever in an immunosuppressed septic patient.

  3. 03

    Stopping maintenance immunosuppression independently during infection.

  4. 04

    Interpreting a tacrolimus concentration without checking trough timing and formulation.

  5. 05

    Using normal ultrasound to exclude rejection or BK nephropathy.

  6. 06

    Missing private, community or newly prescribed macrolide and azole interactions.

  7. 07

    Treating BK viraemia with more immunosuppression because creatinine is rising.

  8. 08

    Ignoring mycophenolate contraception and pregnancy planning until conception occurs.

Practice

Two practice questions

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Question 1 of 2
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RenalOriginal SBA

Unexplained allograft dysfunction

A kidney transplant recipient has a rising creatinine, normal ultrasound and no fever. BK PCR is positive and rejection remains possible. What is the safest next principle?

Choose one answer, then submit
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Sources and review status5 sources · checked 27 Aug 2026 · clinical review pending+
Sources

Sources and review status

National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.

  • NICE TA481 kidney transplant immunosuppressionRecommended maintenance immunosuppressive options in adult kidney transplantation.
  • NHSBT kidney transplant medicinesLifelong immunosuppression, common toxicities and prophylaxis context.
  • NHSBT kidney rejection informationRejection types, biopsy and specialist treatment principles.
  • BNF tacrolimus prescribing monographFormulation, monitoring, interactions and toxicity.
  • MHRA mycophenolate contraception adviceCurrent reproductive risk and contraception safeguards.

Editorial contact: Doctor’s Passport editorial team. Source-check date is separate from clinical approval. Report a content problem · Content changes

Authoring stateComplete draft

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.
  • 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.
    • 1
    Follow 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.+
    1. 1Classify T-cell versus antibody-mediated injury, severity, chronicity, DSA and infection burden before selecting rescue treatment and prognosis.
    2. 2EscalationUse centre-protocol intravenous steroid for suitable cellular rejection, escalating steroid-resistant cases to lymphocyte-depleting therapy only with infection prophylaxis and monitoring.
    3. 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.+
    1. 1For BK, confirm trend and consider biopsy; the transplant team usually reduces selected immunosuppression stepwise while watching closely for rejection.
    2. 2For CMV syndrome or organ disease, begin renal-adjusted valganciclovir or intravenous ganciclovir according to severity, absorption, resistance and specialist virology advice.
    3. 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.

    Clinical stateAwaiting review
    JurisdictionUnited Kingdom
    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.
    • 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.