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
Which conditions have the highest recurrence rates?
Highest Recurrence Risks - Primary oxalosis Oxalosis is a rare metabolic disorder in which the kidneys are unable to eliminate calcium oxalate crystals through the urine. Oxalate is a by-product of normal metabolism. There are no enzymes in the human body that can break down oxalate. Oxalate must be excreted from the body through urine - DM Nephropathy - Membranoloproliferative GN - aHUS - IgA nephropathy - Membranous nephropathy - Fibrillary/immunotactoid GN
Sometimes: FSGS, ANCA-associated vasculitis
Uncommon: Lupus nephritis, anti-GBM, fabry’s (x linked disease due to deficiency of alpha-galactosidase).
Never: genetic (PCKD)
BK associated nephropathy
- BK polyomarvirus, naturally lives in kidneys + urothelium
- BK = TOO MUCH IMMUNOSUPPRESION
Multiple Mechanism of Reactivation
- Immunosuppresion
- Hormonal change - pregnancy, DM
- Tissue injury
- Coinfection by HIV/CMV/HHV6
Clinical Features:
- asymptomatic, gradual or acute ↑Cr
- Viruria → Viraemia → Nephropathy (correlates with serum viral lode)
- Prevention better than cure - screening by serum PCR usually in the first 12 months
- Reduce immunosuppression with viraemia (especially anti-metabolite)
Ix:
- Serum BK Virus PCR (qualitative + quantitative)
High BK Levels > 10,000
- Renal Biopsy: interstitial nephritis, tubular injury, - IHC: SV40+ive immunohistochemistry stain
- EM: intranuclear inclusions
- Biopsy if graft dysfunction to confirm nephropathy and exclude rejection BUT
- Can mimic rejection - interstitial nephritis, tubular injury, interstitial fibrosis
- Intranuclear viral inclusions and SV40 (staining) - missed if no medulla tissue (BK normally found in medulla)
- Not useful: urine cytology, urinary BK PCR
Treatment: nonspecific
- Immunosuppression: ↓ dose overall (especially CNI), change CNI to mTOR, change MMF to leflunomide - rejection possible
- IV cidofovir
- IVIG/steroid if concomitant inflammation when rejection not excluded
Long term complications
- Graft failure
- Ureteric cancers
CMV infection
Definitions:
- CMV viremia: detectable virus
- CMV syndrome: + fever, malaise, arthraglia
- CMV disease : + tissue invasion (Bx proven)
- Increased risk if Donor + and Recipient -
- CMV infection is associated with rejection
Clinical Features: affects any organ but especially lung, liver, retina, GIT
Prophylaxis: valganciclovir, duration of prophylaxis is limited by neutropenia.
- D+ R-: prophylaxis 6 months
- D-R+ or D+R+: ~3 months
- D-R-: no prophylaxis unless ATG use.
Treatment
- Mild: PO Valganciclovir (Sfx= GIT upset, ↓ BM suppression, ↑LFTs)
- Moderate-Severe: IV ganciclovir
- Other: CMV specific IVIG, foscarnet
A 66-year-old man received a deceased donor kidney transplant 7 months ago. The CMV serostatus is donor positive recipient negative. Valganciclovir as primary prophylaxis was ceased 2 months ago due to neutropenia (which has resolved). He is currently on prednisolone 5 mg daily, mycophenolate 750 mg BD and tacrolimus 2 mg BD. His eGFR is 80 ml/min/1.73m2 with no proteinuria or previous rejection. Regular serum CMV viral load showed new onset viraemia (9,800 copies/L) associated with lethargy and elevated ALT of 85 but no other symptoms of organ involvement. Which one of the following is not appropriate?
A. Commence oral valganciclovir 900 mg BD and monitor CMV viral load weekly
B. Commence oral valganciclovir 450 mg daily (reduced dose) and titrate upwards to avoid recurrence of neutropenia
C. Reduce mycophenolate dose
D. Switch mycophenolate to everolimus
E. Continue PJP prophylaxis
B. Commence oral valganciclovir 450 mg daily (reduced dose) and titrate upwards to avoid recurrence of neutropenia - Not appropriate as this will promote the development of resistance and treatment failure
Cancer post renal transplant
Highest Risk
- Skin SCC (+ other SCCs)
□ Most common cause of cancer related death post transplant
□ Strategies include skin check, sun protection, immunosuppression modification (change CNI to mTOR, decrease CNI dose, avoid AZA and reduce overall immunosuppression)
- Kaposi’s sarcoma (rarer now)
- Post-transplant lymphoproliferative disorder (PTLD) especially in EBV D+/D-
- Urothelial (especially in BKV)
Metabolic complications post transplant
• Cardiovascular Disease
○ ↑ weight, ↑HTN, ↑lipid
○ Usual risk factor modification
• New onset diabetes after transplant (NODAT)
• Osteoporosis
○ Caltrate 600mg daily, calcitriol 0,25 micrograms daily
• Chronic Kidney Disease
○ Same as native kidney management
• Gastric Ulcers
PPI
Graft failure progression
Post-op Problems
- ATN of graft
- vascular thrombosis
- urine leakage
- UTI
Hyperacute Rejection (minutes to hours)
• due to pre-existing antibodies against ABO or HLA antigens and is IgG mediated
• an example of a type II hypersensitivity reaction
• leads to widespread thrombosis of graft vessels → ischaemia and necrosis of the transplanted organ
• no treatment is possible and the graft must be removed
Acute Graft Failure (< 6 months)
• usually due to mismatched HLA. Cell-mediated (cytotoxic T cells)
• other causes include cytomegalovirus infection
• may be reversible with steroids and immunosuppressants
Causes of Chronic Graft Failure (> 6 months)
• both antibody and cell mediated mechanisms cause fibrosis to the transplanted kidney (chronic allograft nephropathy)
• recurrence of original renal disease (Goodpasture > MCGN > IgA > FSGS)
Agents that induce T cell lysis include:
a. thymoglobulin
b. eculizumab
c. Basiliximab
d. mycophenolate
e. sirolimus
f. tacrolimus
g. cyclosporin
a. thymoglobulin
- T cell non-depleting: basiliximab (anti-CD25/anti-IL2Ra)
Basiliximab does not induce T cell lysis, it only blocks CD25 - T cell depleting: alemtuzumab (anti-CD52), thymoglobulin/rATG
Agents that primarily interrupt signal 1 of T cell activation during allograft rejection include: a. thymoglobulin b. CTLA4Ig/belatacept c. basiliximab d. mycophenolate e. everolimus f. tacrolimus g. cyclosporin
f. tacrolimus
g. cyclosporin
Immunology of acute allograft rejection
- Antigen presentation
- Co-stimulation
- 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.
- Thymoglobulin: depletes T cells
- CTLA4IG/belatacept: blocks signal 2
- Basiliximab: Blocks signal 3
- Mycophenolate: blocks T cell proliferation
- Everolimus: blocks signal 3
Serum creatinine increases from 100 to 130 umol/L from day 7 to day 8 post-renal transplant - the most unlikely cause would be: a. acute rejection b. tacrolimus toxicity c. sepsis d. mycophenolate toxicity e. ureteric obstruction
d. mycophenolate toxicity
MMP is not nephrotoxic
A patient develops fever, abnormal LFTs and diarrhoea on day 60 post-renal transplant - the most likely cause would be: a. acute rejection b. graft versus host disease c. tacrolimus toxicity d. mycophenolate toxicity e. CMV disease
e. CMV disease
The type of glomerulonephritis least likely to recur posttransplant
and cause graft failure:
a. IgA nephropathy
b. MPGN Type 1
c. Post-streptococcal glomerulonephritis
d. Focal and segmental glomerulosclerosis
e. Membranous glomerulonephritis (primary)
c. Post-streptococcal glomerulonephritis
A 45 year old woman with ESRD due to MPGN Type II
(Dense Deposit Disease) presents 8 years following
renal transplantation with a slowly rising serum
Creatinine (80 to 160umol/L over past 12 months).
Rx – cyclosporin 75mg bd, azathioprine, prednisolone
BP 150/90, examination otherwise normal.
Dipstick urine 2+ protein only. MSU no cells seen.
24h urine – creat. clearance 35ml/min, protein 1.0gm/day
The most likely diagnosis is:
a. Recurrent glomerulonephritis
b. De novo glomerulonephritis
c. Acute rejection
d. Chronic allograft nephropathy
e. Transplant renal artery stenosis
d. Chronic allograft nephropathy
With recurrent MPGN, would expect haematuria
A 45 year old, Chinese born man with liver failure due to
HCV induced cirrhosis had a liver transplant in 2000.
His eGFR is now 15ml/min. Which of the following
statements is least likely to be true:
a. AKI requiring dialysis following liver transplant indicated
an increased risk of chronic renal failure (CRF).
b. Asian recipients are more likely to develop CKD
following liver transplantation
c. Cyclosporin use may be a contributor to his CKD
d. Renal transplantation should be considered and may
improve his life expectancy
e. HCV positivity placed him at increased risk of CKD
b. Asian recipients are more likely to develop CKD
following liver transplantation
Being asian is protective
The least likely medication to contribute to the development of diabetes after transplantation is: a. mycophenolate b. sirolimus c. tacrolimus d. Cyclosporin e. prednisone
a. mycophenolate
Which of the following are a risk factor for CAN?
a. Excess CNI exposure
b. Inadequate CNI exposure
c. Prior acute rejection
d. Presence of DSA (donor specific antibodies)
e. All of the above
e. All of the above
Agents that are effective in the treatment of acute renal allograft rejection include: a. thymoglobulin b. CTLA4Ig/Belatacept c. basiliximab d. mycophenolate e. everolimus f. tacrolimus g. cyclosporin
a. thymoglobulin
d. mycophenolate
e. everolimus
f. tacrolimus
- In kidney or other solid organ transplant, what confers the greatest risk of CMV post transplant?
a. Past CMV infection
b. Continued immune suppression with tacrolimus
c. Methylprednisone pulse for acute rejection
d. CMV +ve organ donor and CMV naïve recipient
e. ATG for acute rejection.
d. CMV +ve organ donor and CMV naïve recipient
Medications that increase or decrease cyclosporin levels
Substances that increase cyclosporine levels
- Calcium channel blockers: diltiazem, nicardipine, verapamil
- Antibiotics or antifungals: erythromycin, clarithromycin, doxycycline, fluconazole, itraconazole, ketoconazole
- Others: colchicine, cimetidine, tacrolimus, tamoxifen, metoclopramide, grapefruit juice
Substances that decrease cyclosporine levels
- Anticonvulsants: carbamazepine, phenobarbital, phenytoin
- Antibiotics: rifabutin, rifampin, nafcillin
- Others: omeprazole, sulfinpyrazone
Which of the following drugs is least likely to increase the serum level of cyclosporine if co-administered with cyclosporine?
a. Fluconazole
b. Erythromycin
c. Diltiazem
d. Ramipril
e. Cimetidine
d. Ramipril
What are examples of antigen presenting cells?
dendritic cells, macrophages, Langerhans cells and B cells.
Contraindications to renal transplant
ABSOLUTE
- Malignancy
- Uncontrolled/untreated infection
- Chronic infection
- Unacceptable anaesthetic risk
- Smoking, alcohol, psychological
RELATIVE
- Severe sun damage
- Severe vascular disease
- Non-adherence
Rejection
- HYPERACUTE - rare, early, untreatable
Pre-formed ab, on table/black kidney, anuria
Predictable by cytotoxic cross match
Pathology: vascular thrombosis, PMNs, infarction - Acute (common, early, treatable)
- T cell mediated (classical)
- Antibody mediated (when donor specific Ab develops)
- Diagnosed by biopsy (DDx: ATN, drugs, obstruction)
- Path
cellular: tubulitis, interstitial infiltrate
Vascular; endothelialitis, glomerulitis, haemorrhage
Antibody mediated: PMNs, CD4 - Chronic
Reduplication of BM
Mx of acute rejection
- Tissue diagnosis
- IV methylpred
- Lymphocyte depleting ab
- Plasma exchange, IVIG - Ab mediated rejection
- Rescue: refractory/recurrent rejection
High dose tacrolimus, mycophenolate - Reversal provides good prognosis
- No of episodes correlates with mortality
A patient develops fever, abnormal LFT and diarrhoea day 60 post renal transplant. The most likely cause would be: A. Acute rejection B. Graft vs host disease C. Tacrolimus toxicity D. Mycophenolate toxicity E. CMV disease
E. CMV disease
- Acute rejection: doesn’t really affect LFTs and diarrhoea
- TAC: doesn’t affect LFT
- Mycophenolate: gut problems, LFTs but don’t develop fever
- CMV: evidence of organ disease
45yo woman with ESRD due to mesangiocapillary GN type II (dense deposit disease) presents 8 years post renal transplantation with a slowly rising serum creatinine (90-130 over past 12 months). Tx: Cyclosporin 75mg BD, azathioprine, pred BP 150/90, examination otherwise normal Dipstick urine: 2+ protein MSU: no cells seen 24 hour: creatinine clearance 35ml/min, protein 1g/day The most likely diagnosis is: A. Recurrent GN B. De novo GN C. Acute rejection D. Chronic allograft nephropathy E. Transplant renal artery stenosis
D. Chronic allograft nephropathy
Recurrent GN - would normally have haematuria
Acute - unlikely 8 years post
