T-Cell-Mediated Rejection

The contract between this chapter and the reader.

1. 1. Define T-cell-mediated rejection and its mechanism.
2. 2. Recognise how TCMR presents.
3. 3. Apply the Banff lesions and grades for TCMR.
4. 4. Distinguish borderline changes and vascular rejection.
5. 5. Treat tubulointerstitial TCMR.
6. 6. Treat steroid-resistant or vascular TCMR.
7. 7. Distinguish TCMR from other causes of graft dysfunction.
8. 8. Recognise the BK nephropathy trap.
9. 9. Understand the prognosis and prevention of TCMR.

A sixty-second reading. Each bullet stands alone.

• T-cell-mediated rejection is cellular rejection: recipient T cells infiltrate and attack the graft.
• It targets the tubules (tubulitis) and interstitium (inflammation), and in severe cases the arteries (arteritis).
• It is driven by under-immunosuppression — low calcineurin-inhibitor levels or non-adherence — especially early.
• It usually presents as an asymptomatic rising creatinine, or is found on biopsy.
• Biopsy is the gold standard, graded by the Banff lesions of interstitial inflammation, tubulitis, and arteritis.
• Borderline changes are inflammation and tubulitis below the diagnostic threshold.
• Banff grades run from tubulointerstitial (I) to intimal (II) and transmural (III) arteritis.
• Tubulointerstitial TCMR is treated with pulse corticosteroids and optimised maintenance immunosuppression.
• Steroid-resistant or vascular TCMR is treated with a lymphocyte-depleting antibody.
• Most T-cell-mediated rejection responds well to treatment, unlike chronic antibody-mediated rejection.
• A rising creatinine has a wide differential including calcineurin-inhibitor toxicity, BK nephropathy, obstruction, and recurrence.
• BK nephropathy mimics rejection but requires reduced, not increased, immunosuppression.
• Prevention rests on adequate immunosuppression, adherence, induction, and HLA matching.

The medical core. An expert should agree T-cell-mediated rejection is fully covered here.

Why it matters at the bedside

If antibody-mediated rejection is the quiet killer, T-cell-mediated rejection is the one you can usually beat. It is the classic acute rejection — a T-cell assault on the graft, most often triggered by too little immunosuppression — and, caught on biopsy and treated, it generally responds. The two skills are recognising it (against a wide differential) and grading it (because grade dictates treatment).

What TCMR is and its mechanism

• T-cell-mediated rejection is cellular rejection: recipient T cells — CD4 helper and CD8 cytotoxic — recognise donor alloantigen (the direct pathway dominating early), infiltrate the graft, and attack it. They invade the tubules (tubulitis) and interstitium (interstitial inflammation), and in severe forms the arteries (arteritis). The usual trigger is under-immunosuppression — a low calcineurin-inhibitor level or non-adherence — especially in the early months when the alloresponse is strongest.

How it presents

• TCMR is usually clinically silent, declaring itself only as an asymptomatic rising creatinine or being found on a surveillance or for-cause biopsy. (In a graft with delayed function, where the creatinine is already uninformative, rejection is detected only by biopsy — the masking problem of the DGF chapter.) There is rarely pain or fever; the kidney is attacked quietly.

Banff lesions and grades

• Biopsy is the gold standard, read by the Banff classification. The defining lesions are interstitial inflammation (i), tubulitis (t), and arteritis (v). Grades escalate by what is attacked: Banff I (IA/IB) is tubulointerstitial — inflammation plus tubulitis; Banff II (IIA/IIB) adds intimal arteritis; Banff III is transmural arteritis with fibrinoid necrosis, the most severe. The grade is not academic — it sets the treatment.

Borderline and vascular rejection

• Two categories deserve emphasis. ‘Borderline changes’ are inflammation and tubulitis that fall just below the diagnostic threshold — often treated, sometimes observed, depending on context and graft function. At the other extreme, vascular (arteritic) rejection — Banff II and III — behaves more aggressively, is often steroid-resistant, and needs stronger therapy; missing arteritis is a serious error.

Treating tubulointerstitial TCMR

• Tubulointerstitial rejection (Banff I, and treated borderline changes) responds to pulse corticosteroids — high-dose intravenous methylprednisolone — alongside optimisation of maintenance immunosuppression, since the rejection usually reflects inadequate exposure or non-adherence. The calcineurin inhibitor is brought to target and the adherence problem addressed, or the rejection simply recurs.

Treating steroid-resistant or vascular TCMR

• Rejection that does not respond to steroids, or that shows arteritis (Banff II/III), needs a lymphocyte-depleting antibody — anti-thymocyte globulin — to remove the attacking T cells. Vascular rejection in particular is treated this way from the outset rather than with steroids alone, because it is both more dangerous and frequently steroid-resistant.

Distinguishing from other causes

• A rising creatinine is not synonymous with rejection — the differential is wide: calcineurin-inhibitor toxicity, BK polyomavirus nephropathy, obstruction or a vascular problem, recurrent or de novo disease, dehydration, and antibody-mediated rejection. Biopsy distinguishes them — tubulitis and interstitial inflammation for TCMR, arteriolar hyalinosis for CNI toxicity, SV40 staining for BK, microvascular inflammation and C4d for AMR — which is why rejection is confirmed histologically rather than assumed and treated blindly.

The BK trap

• The most dangerous mimic is BK nephropathy (its own chapter): it inflames the graft and raises the creatinine, looking like rejection — but its treatment is the opposite. Reducing immunosuppression treats BK; increasing it (as one would for rejection) feeds the virus and destroys the graft. This is the cardinal reason to biopsy and stain for SV40 before escalating immunosuppression for presumed rejection.

Prognosis

• The encouraging contrast with antibody-mediated rejection is that most T-cell-mediated rejection responds to treatment and carries better graft survival. The exceptions are recurrent or steroid-resistant TCMR and vascular (arteritic) rejection, which do worse — and TCMR can herald or accompany AMR, so a rejection biopsy is always read for both.

Prevention

• Because the usual cause is too little immunosuppression, prevention is mostly about maintaining adequate exposure and adherence — the themes of the monitoring chapter — supported by induction at transplant and, where feasible, better HLA matching to lower the alloimmune stimulus.

Five fully-built tables.

Table A — Banff TCMR lesions and grades

Table B — Treatment by type

Table C — Differential of a rising creatinine

Table D — TCMR versus AMR

Table E — Prevention

Visualise & Map

Causal chains, each ending in a named action.

Chain 1 — The trigger

Under-immunosuppression / non-adherence → T cells escape suppression → graft infiltration → tubulitis and inflammation → ACTION: treat the rejection and restore adequate immunosuppression.

Chain 2 — Tubulointerstitial attack

T cells invade tubules and interstitium → Banff I lesions → a steroid-responsive rejection → ACTION: give pulse corticosteroids.

Chain 3 — Vascular attack

T cells attack the artery wall → intimal/transmural arteritis (Banff II/III) → an aggressive, often steroid-resistant rejection → ACTION: use a lymphocyte-depleting antibody.

Chain 4 — The wide differential

A rising creatinine has many causes → rejection is only one → blind treatment may be wrong → ACTION: biopsy to diagnose before escalating.

Chain 5 — The BK reversal

BK nephropathy inflames the graft and mimics rejection → but is driven by over-immunosuppression → increasing immunosuppression worsens it → ACTION: stain for SV40 and reduce immunosuppression if BK.

Numbered rules. These numbers are the cross-reference handle for the cases and flowcharts.

Clinical Reasoning

Five cases. Each stops you at a decision before it answers it.

Every mechanism from Level 3 earns a bedside consequence and an action.

Exhaustive. Every rule in the chapter is here.

Safety & Evidence

Panel A — Red flags

Panel B — NEVER DO

Anti-patterns clinicians fall into. Each becomes a Level 22 distractor.

The grade reflects strength of evidence, not importance.

Patient Decisions

Outcomes as natural frequencies. Figures are representative; the direction of effect is given where precise numbers are uncertain.

Apply & Test

Copy-paste chart notes that map to the real decisions in this chapter.

Template 1 — TCMR diagnosis note

• Indication: rising creatinine / surveillance; biopsy date ___.
• Banff lesions: interstitial inflammation (i) ___; tubulitis (t) ___; arteritis (v) ___.
• Grade: borderline / Banff I (IA/IB) / II (IIA/IIB) / III.
• AMR assessed: C4d ___; microvascular inflammation ___; DSA ___.
• Other causes excluded: CNI level ___; BK / SV40 ___; obstruction ___.

Template 2 — TCMR treatment note

• Treatment: pulse corticosteroids / lymphocyte-depleting antibody (ATG).
• Rationale (grade; steroid-resistant; vascular): ___.
• Maintenance optimised: CNI to target; adherence addressed ___.
• Coexistent AMR treated (if present): ___.
• Response (creatinine trend) and follow-up: ___.

Pre-rounds compression. Rules only.

Active recall. At least one card per objective.

Micro-teaching for rounds. Two scenarios, five steps each.

Nine items, each anchored in this chapter. At least one per objective.