Renal Transplant Flashcards
HLA and renal transplant
• The human leucocyte antigen (HLA) system is the name given to the major histocompatibility complex (MHC) in humans. It is coded for on chromosome 6. -Some basic points on the HLA system ○ class 1 antigens include A, B and C. ○ Class 2 antigens include DP,DQ and DR
when HLA matching for a renal transplant the relative importance of the HLA antigens are as follows DR > B > A
What are the 3 steps of acute allograft rejection
- Antigen presentation: antigen presenting cell that presents an antigen to T cell
- Co-stimulation: that enhances that interaction
- IL-2 stimulation
- APC present peptide/antigen to MHC and generate signal 1
- Costimulatory molecules such as B7 and CD40 generate IL-2
- Signal 2 and 3 activated, causing proliferation and activation of T cells and B cells leading to rejection.
- T cells respond to MHC
1. APC presents to T cell (via mHC/peptide -TCR+CD3 contact)
▪ Initiates calcineurin pathway - Calcineurin Inhibitors, eg; tacrolimus, cyclosporin
- APC presents to T cell (via CD86/CD28) - COSTIMULATION
a. Co-stimulates with [1], helps make IL2
Belatacept - IL2 binds to IL2-Ra (aka CD25) - basiliximab
a. Activate mTOR - mTOR inhibitors like everolimus, sirolimus –> T cell activation
b. Further downstream joins with nucleotide synthesis (blocked by MMF) which both input to cell cycle (blocked by AZA
Immunosuppression classes
Antilymphocyte
○ T cell non-depleting: BASILIXIMAB (anti-CD25/anti-IL2Ra)
T cell depleting: ALEMTUZUMAB (anti-CD52), THYMOGLOBULIN/rATG -
Often used as induction therapy
Immunosuppression Classes
[1] Calcineurin Inhibitors: tacrolimus, cyclosporin
[2] Belatacept: fusion protein composed of Fc fragment of IgG1 linked to the extracellular domain of CTLA-4 which inhibits T cell activation
[3] Mammalian target of rapamycin inhibitors (mTORi): everolimus, sirolimus
[all] Corticosteroid: methylprednisone, prednisone
[LATE]
Antiproliferative: mycophenolate, azathioprine
[B CELL/AB]
Rituximab, IVIg
Usual regime: tacrolimus, mycophenolate/azathioprine, prednisone
Cardiovascular events post renal transplant
Compared with the general population, renal transplant recipients have:
– Almost 50 times higher annual risk of death from CVD
– A more than 3-fold higher incidence of congestive heart failure
– A 3-fold higher incidence of strokes due to cerebral haemorrhage
Histological characteristics of chronic allograft nephropathy [CAN]
- Tubular atrophy
- Interstitial fibrosis
- Patchy infiltrate
- Reduplication of GBM - GBM double contours
Occurs due to calcineurin inhibitors toxicity, HTN, diabetes, GN nephrotoxins, ischaemia, time
Belatacept
CTLA4Ig
• Fusion protein: Fc portion of Ig prolongs half-life, fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, which is a molecule crucial in the regulation of T cell costimulation, selectively blocking the process of T-cell activation.
Issues with EBV PTLD - if EBV positive, should not be on belatacept
• Co-stimulatory blockade
– Theoretical potential for tolerance, not realised in man
• Equal efficacy to CSA in Phase II trial
– Vincenti NEJM 2005
– Phase III trials –more AR, better function
Vincenti et al, NEJM 2005
Note – this is the opposite of PD-1 inhibition in oncology
Newer studies underway – anti-CD40
MOA of calcineurin inhibitors - cyclosporin and tacrolimus
MOA: IL-2 inhibitor
Immunosuppression: binding of cyclophilin → inhibition of calcineurin → inhibition of NFAT activation → ↓ IL-2 transcription → ↓ activation of T cells
NFAT: nuclear factor of activated T cells
Signal 1 Inhibition: Antigen presentation
- Inhibit IL-2
- Tacrolimus more potent, preferred
Key clinical issues:
- Cytochrome P450 metabolism – multiple interactions
- Concentration dependent action & toxicities, therefore need to monitor levels (concentrations)
- CSA – measure peak (C2), tacrolimus trough (C0).
- Both nephrotoxic – key contributors to CAN
- Aim for high exposure early, minimise exposure late
Side Effects
- Hypertension
Caused by renal vasoconstriction and sodium retention
Usually develops within first few weeks of therapy
- Neurotoxicity
Mild tremor common - 35-55% patients
Rarely, severe headache, visual abnormalities, seizures - Posterior reversible encephalopathy syndrome (PRES)
confusion, headache, altered LOC, visual changes, seizures
characteristic posterior cerebral white matter oedema on neuroimaging - TAC>CYC: ↑ NODAT/DM, ↑ CVS dx, ↑ tremor, ↑ alopecia, NO gum hypertrophy
- Both: nephrotoxicity (biopsy: striped fibrosis), ↑ HTN, ↑K, ↓Mg, TMA/aHUS, PRES, NODAT, CVS dx, tremor/neurotoxicity, alopecia
Anti-proliferatives: mycophenolate, azathioprine
Mycophenolates more potent in first 12 months and relatively leukocyte specific:
- inhibits IMPDH(II), preferential action lymphocytes, involved in purine synthesis
IMPDH: Inosine-5′-monophosphate dehydrogenase
- blocks de novo purine synthesis - G1 ARREST
- Dose controlled
- Mycophenolate sodium absorbed more distally, less GI tox
- Synergies with other Immunosuppressives
- Interactions – mycophenolate levels lower with CSA
Bone marrow suppression
- additive to sirolimus, everolimus, valgancyclovir
- azathioprine accumulation with allopurinol (4-fold)
Mycophenolate
- MMF>AZA: ↓ Rejection
- Side Effects: ↓ BM suppression, GIT upset (diarrhoea)
- NOT for pregnancy
AZA
- Side Effects: ↓ BM suppression, GIT upset, ↑LFT, ↑Cx, ↑pneumonitis, pancreatitis
- SAFE in pregnancy
- ↑ levels: allopurinol, febuxostat
m-TOR inhibitors
Sirolimus, Everolimus
Signal 3: IL2 stimulation
- Binds to FKBP-12
- mTORi-FKBP complex binds to mTOR
- Inhibits IL-2/co-stimulatory triggered cell signalling inhibits:
• DNA synthesis - P27 - cdk2 interference - G1 arrest
• Protein synthesis - IL-2, IFNg, IL-4, IL-10 (lesser)
SE:
- Hyperlipidemia
- Stomatitis
- EVE>SIR: everolimus has no interstitial pneumonitis, sirolimus causes interstitial pneumonitis
- Side Effects: ↑↑ proteinuria, poor wound healing, ↓ BM suppression, ↑lipid, interstitial pneumonitis, mouth ulcers, GIT upset, ↓fertility
- mTORi>CNI: ↓ skin complications (especially SCCs), no NODAT/DM2, “weaker” immunosuppression (used for BKVAN, CMV or infections generally)
Mtor: acts a central regulator of cell growth and proliferation
- block signal transduction - cell cycle arrest in G1
- Inhibits proliferation and clonal expansion of IL-2 stimulated T cells
- Concerns with proteinuria and wound healing
- If significant proteinuria - won’t use MTOR
Tend not to use early on during transplant
- BENEFIT IN MALIGNANCY - ESPECIALLY SKIN
Management of acute rejection
- Tissue diagnosis essential
- differential diagnosis
- histological severity and nature - IV Methylprednisolone - >90% effective
- OKT3 ( Muromonab-CD3) or ATG ( Anti-thymocyte globulin) lymphocyte depleting antibodies
- Steroid resistant or vascular rejection
- 95% reversibility
- Non-depleting antibodies not useful
- adjust other immunosuppressants - Plasma-exchange, IVIG – Ab-mediated rejection
- Rescue: Refractory or recurrent rejection
- high dose tacrolimus and mycophenolate - Reversal provides good prognosis
- Number of episodes correlates with mortality
Complications of kidney transplant
Early
- Infection: bacterial, viral (CMV, polioma, BK)
- Acute rejection
- Tumours: Post transplant lymphoproliferative disorder
- General: surgical post transplant DM
- Drugs: tremor, acute renal failure, GI, mood, bone
Late
- Viral: HSV, HZV
- Chronic rejection, chronic allograft nephropathy (reduplication of BM)
- Tumours: Carcinoma, lymphoma
- General: CVS disease, recurrence
- Drugs: hair, skin, kidney, bone, CVS
Time course of infections post renal transplant
- UTI: early or late
- CMV: 2-12 months - fever, colitis, LFT, lung
- PJP: 3-12 months - dyspnoea, fever
- BK virus: 4-24 months - graft dysfunction
- HSV/Varicella/fungus/pneumonia: anytime
Basiliximab
- Human/mouse chimeric Ab
- Binds to IL-2 receptor (anti-CD25) on ACTIVATED T cells
- Reduction in acute rejection vs placebo
- Minimal SE except cost
Anti thymocyte globulin
- Rabbit (thymoglobulin) polyclonal Ab
- Targets T cells
- Reduction in acute rejection - superior vs IL2R Ab in high immunological risk group
- Elevated risk of infections and malignancies
- Used for treatment of steroid resistance rejection.
Causes of
- graft loss (death with graft function)
- Death censored graft loss
Causes graft loss (death with graft function) Early (1st year) - Cardiovascular - Infection - Cancer
Late (beyond 1st year)
- Cancer
Cardiovascular
- Infection
Death censored graft loss Early (1st year) - Graft thrombosis - Rejection - GN
Late (beyond 1st year)
- Chronic allograft nephropathy
- GN
- Acute rejection
What are recurrent GN after transplant?
Recurrent disease
- Early: 1º FSGS, aHUS; MPGN, ANCA
- Late: IgAN, membranous; MPGN
What are the 2 types of rejection?
TCMR (T cell mediated rejection) vs AbMR (antibody mediated rejection)
T Cell Mediated Rejection (TCMR)
- Lymphocytes (T cells and other cells) invade tubules/interstitium + vessels to cause damage
- Ix: renal biopsy
- Prevention: induction therapy
- Treatment: depends on severity
Mild: IV methylprednisone Mod-Severe: add thymoglobulin/rATG if steroid resistant
Ab Mediated Rejection (AbMR)
- Circulating donor specific Abx (DSAs) recognise graft → invades peritubular capillaries + glomerulus → inflammation + complement cascade → damage
- Ix: Renal biopsy, measuring DSAs profile
- Prevention: desensitisation (pre-transplant PLEX/IVIG/RTX)
- Treatment:
PLEX (plasma exchange)/IVIG
Other (severe): eculizumab, bortezomib, splenectomy
