Immunosuppression Protocols

Report
POSTGRADUATE
SCHOOL OF MEDICINE
IMMUNOSUPPRESSION PROTOCOLS &
MAINTENANCE IMMUNOSUPPRESSION
A.K. Sharma
MDSC175: Transplantation Science for Transplant Clinicians
A MEMBER OF THE RUSSELL GROUP
CONTINUING PROFESSIONAL DEVELOPMENT
Immunosuppression Protocols
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Historical Perspective
In 1960s the maintenance immunosuppression was limited to total lymphoid
irradiation, massive doses of steroid and azathioprine.
It was rather non-specific and intense, and therefore, was associated with
overwhelming metabolic, infective and wound related complications. Not
many recipients of renal transplantation survived few months in that era.
Departures
Destination
Live longer
Via
Kidney Tx
Infection
Cardio-vacular
Cancer
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Clinical Immunosuppression
• Three phases –
a) Induction
b) Maintenance
c) Rescue therapy to treat acute rejection
• Combinations to achieve lower doses fine balance
between acute rejection and toxicity
Immunosuppression Protocols
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What are the targets?
• Activation of T cell (CD4+ Th) needs 3 signal model
• Several immunological targets at various steps
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Patients with higher risk of acute cellular
rejection
•
Younger recipient age
•
Panel reactive antibody (PRA) level >20%
•
Human leukocyte antigen (HLA) mismatch, especially at DR locus
•
ABO incompatibility
•
Presence of donor-specific antibody
•
Cold ischemia time greater than 24 hours
•
Delayed graft function
•
Afro- American ethnicity
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Maintenance Immunosuppression
•
To use combination of primary along with adjuvants to reduce the toxicity
of each
•
The incidence of ACR risk is maximum in first 6 weeks.
•
After 6 weeks, immunosuppression is reduced
•
Mainstay of immunosuppression: Calcineurine inhibitors – Cyclosporine
and Tacrolimus
•
ACR rate are lower with tacrolimus compared to cyclosporine
•
Other primary drugs are mTOR inhibitors – Sirolimus and Everolimus but
ACR rates are higher.
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Initial Maintenance Immunosuppressive
Medications: KDIGO recommendations
2.1: We recommend using a combination of immunosuppressive medications as maintenance
therapy including a CNI and an antiproliferative agent, with or without corticosteroids.
2.2: We suggest that tacrolimus be the first-line CNI used.
2.3: We suggest that mycophenolate be the first-line antiproliferative agent.
Immunosuppression Protocols
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Initial Maintenance Immunosuppressive
Medications: KDIGO recommendations
2.4: We suggest that, in patients who are at low immunological risk and who
receive induction therapy, corticosteroids could be discontinued during the
first week after transplantation.
2.5: We recommend that if mTOR inhibitors are used, they should not be
started until graft function is established and surgical wounds are healed.
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Long-Term Maintenance Immunosuppressive
Medications: KDIGO recommendation
•
We suggest using the lowest planned doses of maintenance
immunosuppressive medications by 2–4months after transplantation, if
there has been no acute rejection. (2C)
•
We suggest that CNIs be continued rather than withdrawn. (2B)
•
If prednisone is being used beyond the first week after transplantation, we
suggest prednisone be continued rather than withdrawn. (2C)
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Calcineurine Inhibitors (CNIs)
•
Used for maintenance immunosuppression.
•
Two agents in clinical practice:
•
•
Cyclosporine (Sandimmune®, Gengraf®, Neoral®, generic; CysA)
•
Tacrolimus (Prograf®, generic; FK506).
At present are key to maintenance immunosuppression
and a component of the majority of transplant protocols.
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Calcineurine Inhibitors (CNIs)
•
Lower ACR and improved short term graft survival but no
effect on long term survival
•
Nephrotoxicity is serious side effect – due to raised endothelin1 and TGFβ mediated fibrosis leading to arteriolar hyalinosis
•
Interstitial fibrosis set in all renal grafts by 10 yrs, median onset
6 months
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Calcineurin Inhibitors: Mechanism of Action
CsA: Cyclosporine
FK506: Tacrolimus
FKBP: FK Binding Protein
CpN: Cyclophilin
NF-AT: Nuclear Factor of
Activated T-cells (c- cytosolic
component; n- nuclear
component).
Stepkowski, Expert Rev
Mol Med, 2000;2(4):1
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Halloran, N Eng J Med, 2004;351:3715
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Calcineurine Inhibitors (CNIs)
• Hypertension and diabetes is more likely with
tacrolimus than with cyclosporine
• Infection and malignancy with any
immunosuppression
• As a group – 10 times risk of CVS death, 50% of death
with functioning graft.
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Cyclosporine (CsA)
• Orally every 12 hrs at 4-8 mg/kg/day
to achieve trough levels 250-350
Dosing:
ng/mL (< 6 mo), 200-250 ng/mL (6-12
mo), 100-200 ng/mL (> 1yr)
• IV: 12 hr infusions or continuous IV
infusion at 1/4 daily oral dose
Immunosuppression Protocols
Cyclosporine (CsA)
• Renal insufficiency
• HTN , though lesser than tacrolimus
Major
Toxicities:
• Dyslipidemia, though lesser than tacrolimus
• Hyperkalemia
• Hypomagnesemia
• Hyperuricemia
• Gingival hyperplasia
• Hirsutism
20
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Tacrolimus (Prograf)
• Prograf is given every 12 hr
dosing at 0.05-0.1 mg/kg/day,
Dosing:
Advagraf is given once a day
• IV: continuous infusion – 1/3 1/5th of daily oral dose
Immunosuppression Protocols
Tacrolimus (Prograf)
• Renal insufficiency
• Hypertension
Major
toxicities:
• Diabetes much more than ciclosporin
• Dyslipidemia
• Hypomagnesemia
• Hyperkalemia
• Neurotoxicity such as tremors
22
Immunosuppression Protocols
Calcineurine Inhibitors: Dosing and
Monitoring
23
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Calcineurine Inhibitors: Adverse Effects
Cyclosporine
Tacrolimus
Hypertension
++
+
Pancreatic islet toxicity
+
++
Neurotoxicity
+
++
Hirsutism
+
-
Hair loss
-
+
Gum hypertrophy
+
-
GI side effects
-
+
Gastric motility
-
+
Dyslipidemia
+
-
Hyperuricemia
++
+
↑K+/↓Mg2+
+
+
Adapted from Danovitch, Handbook of Kidney Transplantation, Lippincott Williams & Wilkins, 2005
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Advagraf (Slow-release Tacrolimus)
•
The author uses Advagraf once a day when there is neuro
toxicity due to Prograf (Tacrolimus)
•
It works by more constant levels of drug rather than peaks and
troughs
•
Once a day formulations allows more cautious reductions than
would be possible by tacrolimus when given in a daily dose of
< 3 mg per day
Immunosuppression Protocols
CNIs drug interactions
Inhibit
CYP450
Potentiate
CYP 450
•
•
•
•
Azoles
Calcium channel blockers
Amiodarone
Grapefruit
• Rifampin
• Phenytoin
• St John’s Wort
26
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CNIs drug interactions
Drug interactions with cyclosporine and tacrolimus
Increase cyclosporine or
tacrolimus blood levels
Decrease cyclosporine or
tacrolimus blood levels
Increase cyclosporine or
tacrolimus nephrotoxicity
Ketoconazole
Anticonvulsants: phenytoin,
phenobarbital
(phenobatbitone),
carbamazepine, others
Amphotericin B
Fluconazole
Erythromycin
Diltiazem
Antibiotics: rifampin
(rifamapicin) , rifabutin
Verapamil
Nonsteroidal antiinflammatory drugs
Aminoglycosides
Cisplatin
Nicardipine
Metoclopramide
Methylprednisolone
Sirolimus (increase
cyclosporine levels)
Halloran, from Johnson (ed.), Comprehensive Clinical Nephrology, Mosby Elsevier, 2003.
Immunosuppression Protocols
CNIs drug interactions
HAART
28
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Anti-proliferative agents are used as
adjuvants
•
Mycophenolic acid/MMF is the first line adjuvant
•
Azathioprine if MMF is not tolerated, is now a second line
adjuvant
•
Steroids for those with high immunological risk, and for those
who get severe ACR
•
If MMF are not tolerated well, Sirolimus is used as an adjunct.
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Azathioprine (Imurane)
• This gets hydrolyzed into 6- Mercaptopurine. It is a purine
analogue that is incorporated into the cellular DNA
interfering with the synthesis of RNA
• Dosing:
• Orally 1-1.5mg/kg/day (monitoring to keep WBC count > 4.0 )
• Drug levels not monitored
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Azathioprine (Imurane)
• Major Toxicities:
• Bone marrow suppression
• Hepatitis
• Pancreatitis
• Malignancy
• Always be cautious if the patient is already on allopurinol for
gout. A combination of these 2 drugs leads to severe bon
marrow depression
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Halloran, N Eng J Med, 2004;351:3715
Immunosuppression Protocols
Mycophenolate Mofetil (MMF)
•
This works by IMPDH dehydrogenase suppression
•
Dosing:
•
•
Orally 500 mg-1000 mg bd
•
Levels not done in usual clinical practice
Toxicity:
•
GI (nausea, gastritis, diarrhea)
•
Enteric coated mycophenolate Na (Myfortic) has been better
tolerated, but there is not much clinical evidence
•
Leukopenia and thrombocytopenia (dose-related)
33
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Halloran, N Eng J Med, 2004;351:3715
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Mammalian Target of Rapamycin Inhibitors
(mTOR inhibitors)
mTOR inhibitors should not be initiated until allograft
function is established and surgical wounds has healed
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Halloran, N Eng J Med, 2004;351:3715
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mTOR Inhibitors
•
•
Conversion to mTOR- based regimen is justified in those with: one of these
•
low immunological risk,
•
high risk of graft dysfunction,
•
history of malignancy and/or high CVS risk.
When?
•
Early – greatest improvement in function.
•
Late – more proteinuria
•
More infection, leucopoenia and hypercholesterolemia.
•
Anti-tumour effects against skin tumours
•
CMV protective?
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Sirolimus
Binds with FK receptors (like Tacrolimus)
independent of Calcineurine mechanism
Dosing:
• Once a day 1-3 mg daily with a target
of 24 hour trough of 4-8 ng/mL
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Sirolimus
Major
toxicities:
•
•
•
•
•
•
•
Oral ulcers
Dyslipidemia
Acne
Poor wound healing
Edema
Pneumonitis, alveolar hemorrhage
Bone marrow suppression (anemia and
thrombocytopenia)
• Proteinuria is a significant renal toxicity
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Steroids
•
Used for induction, maintenance and treatment of rejection.
•
Mechanism of action:
•
•
Inhibit function of dendritic cells.
•
Inhibit translocation to nucleus of NF-κB.
•
Suppress production of IL-1, IL-2, IL-3, IL-6, TNF-α, and γ-IFN.
Adverse effects numerous and well-known.
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Steroids
•
Nonspecific anti-inflammatory that interrupts multiple
steps in immune activation
•
A number of metabolic complications in long-term
•
A number of studies of steroid withdrawal – significant
increases in late rejection
•
Alemtuzumab induction – allows steroid avoidance
•
Steroid avoidance should be assessed carefully on
individual basis, with attention to risk-benefit profile.
Immunosuppression Protocols
Steroids
Weight gain
Hypertension
Osteopenia,
Hyperglycemia,
Poor wound healing,
Cushingoid features,
Proximal myopathy,
Cataracts
43
FACULTY OF HEALTH & LIFE SCIENCES – CPD
Institute for Learning & Teaching
Faculty of Health & Life Sciences
Room 2.16A, 4th Floor
Thompson Yates Building
Brownlow Hill
Liverpool
L69 3GB
www.liv.ac.uk/learning-and-teaching/cpd
A MEMBER OF THE RUSSELL GROUP
Immunosuppression Protocols
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CNI Avoidance: Options
•
mTORs and Mycophenolate Mofetil (MMF): high ACR rates, high rate of wound
complications
•
•
Belatacept – T cell co-stimulation blockade (CD80/CD28 interaction):
•
IV dosed monthly
•
higher rates of ACR
•
better CVS risk profiles
•
improved patient and graft survival in comparison to cyclosporine
•
CNS PTLD and PML
Conversion to the co-stimulation blocker Belatacept or an mTOR inhibitor may be
associated with an increased rate of ACR, but a benefit of this strategy is better renal
allograft function.
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CNI Minimisation
Low dose CNI with
high MMF or
Sirolimus: transient
or statistically
insignificant benefit
Low dose CNI with
Everolimus –
insignificant superior
renal function,
higher tolerance to
mTORs
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SMART
Aim: to compare the effect of an early CNI-free immunosuppression regimen
with a standard immunosuppression on renal function 36 months after
transplantation
Design: observational follow-up of patients followed within the SMART
framework for 36 mo (n=132)
Early conversion (10-24 d): CNI to SRL . Intention To Treat Analysis
End point: eGFR
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SMART
Outcome: At 36 mo, renal function continued to be superior in SRL-treated
patients eGFR at 36 mo: 60.88 vs 53.72 of CsA group P=0.031.
Significantly more patients discontinued therapy in the SRL group 59.4% vs
42.3% for CsA. Patient survival 99% in SRL group vs 97% CsA group and graft
survival 96% SRL group vs 94% CsA group survival at 36 months was excellent in
both arms.
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Spare the Nephron
Aim: hypothesis: the patients who are withdrawn from CNI-based
therapy early after transplantation and maintained on MMF in
combination with SRL will have improved GFR
Time to change: 30-180 days after transplant
Design: prospective, open-label, randomized, multicentre renal
transplant recipients (N=305)
Design: prospective, open-label, randomized, multicentre renal
transplant recipients (N=305)
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Spare the Nephron
End point: GFR
Outcome: Patients maintained on MMF + CNI for ≤6 m and then
converted to maintenance immunosuppression with MMF + SRL
had greater improvement in GFR vs patients remaining on MMF
+ CNI.
Immunosuppression Protocols
CONCEPT
Aim: to evaluate conversion from a CsA-based
regimen to a SRL-based regimen 3 months posttransplant
Design: prospective, open-label, randomized,
multicentre (N=237)
Design: prospective, open-label, randomized,
multicentre (N=237)
Early conversion (3 m): CsA to SRL
End point: e-GFR at wk 52
51
Immunosuppression Protocols
CONCEPT
Outcome: e-GFR at wk 52 was significantly
better in the SRL group (68.9 vs 64.4 mL/min,
P=.017).
Patient and graft survival rates were not
statistically different.
The incidence of ACR episode, mainly
occurring after withdrawal of steroids, was
not statistically higher in the SRL group (17%
vs 8%, P=.071)
52
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CONVERT
Aim: to evaluate
the efficacy and
safety of
converting
maintenance renal
transplant
recipients from
CNIs to SRL
Design:
prospective, openlabel, randomized,
single centre
(n=830)
Late (6-120 m)
conversion: CNI to
SRL
End points: e-GFR ,
cumulative rates of
BPAR, allograft
loss, or death at 12
m
Immunosuppression Protocols
CONVERT
Outcome: At 2 years, SRL
conversion among patients
with baseline e-GFR >40 ml
was associated with
excellent patient and
allograft survival, no
difference in BPAR,
increased urinary protein
excretion, and a lower
incidence of malignancy
compared with CNI
continuation.
Superior renal function was
observed among patients
who remained on SRL
through 12-24 m,
particularly in the subgroup
of patients with baseline eGFR >40 mL and UPr/Cr
≤0.11.
54
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Standard Risk Transplant: Liverpool Protocol
• All living related transplants with negative cross match and not sensitised i.e.
PRA<20%
• Heart-beating cadaveric transplants with no graft factors
• Better than 2 DR mismatch
•
In Theatre: 0.5-1 gm Methyl Prednisolone.
•
Induction: Basiliximab 20 mg Day 0 and Day 4.
•
Maintenance: Tacrolimus (0.1mg/kg starting dose)+ MMF (1.5-2 gm)
Tacrolimus
Level 8-12ng/ml
3 months
Level 4-7ng/ml
Afterwards
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High Risk Transplant: Liverpool Protocol
Patients with 2DR mismatch or PRA >20%
Re-transplants who had early loss of previous graft due to an immune cause
Extended criteria HBD transplants –
•
donors aged 60 or older
or
•
donors between 50-59 with at least 2 of – CVA as cause of death, renal insufficiency
(Cr>135 μmol/l), hypertension.
or
•
DCD transplants
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High Risk Transplant: Liverpool Protocol
•
In Theatre: Methyl Prednisolone 0.5-1 gm
•
Induction: Alemtuzumab 30mg SC Day 0 day 1 for patients <
60yrs, and Day 0 single dose for patients > 60yrs
•
Maintenance: Tacrolimus (level 5-8ng/ml) + MMF (1 gm)
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Treatment of Acute Rejection: Liverpool
Protocol
• Methylprednisolone 0.5-1g IV for 3 days
• Partial response (creatinine falls but still more than
20% over baseline on day 5): oral prednisolone
100mg reducing to 20mg over 8 days.
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Acute Vascular Rejection
• Anti-thymocyte globulin (ATG) (Thymoglobuline) 1.53mg/kg through a central line (unlicensed dose and
frequency), (following IV chlorphenamine10mg and
oral paracetamol 1g, and IV steroid if not already on a
steroid). The patient is re-dozed when CD3 count rises
to 50/microlitre (0.050x109/L) to cover a 14 day
period. (This is an unlicensed dose regime)
Immunosuppression Protocols
Acute Vascular Rejection
Tacrolimus and
mycophenolate
preparations are
stopped on initiation of
ATG and restarted on
day 10; oral
prednisolone 20mg
daily is started on
initiation
60
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Use of Ecluzimab in Acute Vascular Rejection
•
£3150 per 30ml vial
•
1 dose=90ml=£9450
•
Not licenced for AMR so individual patient approval required
•
Humanised (mouse) monoclonal antibody acts on C5 to inhibit
latter part compliment cascade reducing inflammation.
•
Prevents the generation of the terminal complement
membrane attack complex (MAC)
•
(See induction immunosuppression)
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Treatment of Steroid-Resistant Acute
Rejection
•
Aim: to deplete CD3+ lymphocytes from peripheral blood.
•
There are 3 options have been used:
1.
Rabbit Anti-Thymocyte Globulin (ATG)
2.
Horse Anti-Lymphocyte Globulin (ALG) not in use now
3.
OKT3 not much used for this indication
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Disease Processes Requiring Modification in
Immunosuppression
•
Steroids should be minimized in transplant recipients who
have evidence of viral infections or have metabolic
complications
•
Patients with intractable systemic infection especially CMV
disease in transplant recipients requires reduction in
immunosuppression especially MMF
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Disease Processes Requiring Modification in
Immunosuppression
•
Compliance is a serious issue in young patients, especially
adolescent females may stop taking cyclosporine and
prednisolone due to their effect on body image
•
Infection should be ruled out before embarking on
steroid pulse therapy, however, these 2 conditions may be comanifest
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Disease Processes Requiring Modification in
Immunosuppression
•
During pregnancy, the dose of Tacrolimus/Cyclosporine
needs to be increased, as the volume in which the drug
is redistributed is much bigger
•
Pediatric patients, who already face growth retardation due to
chronic end-stage organ failure, would remain stunted if
continued on inadvertent doses of steroids.
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Disease Processes Requiring Modification in
Immunosuppression
•
Patients who develop skin tumors require change over from
Azathioprine based immunosuppression to Sirolimus based
immunosuppression.
•
Transplant patients with hepatitis C positivity are considered to
have lesser proliferation of virus when on Cyclosporine than on
Tacrolimus
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Surgical Problems in Immunosuppressed
Patients
•
Involve the transplant team from the start
•
Immunosuppressive drugs down the NGT if possible
•
Immunosuppressive drugs IV (1/4 of the oral Cya dose & 1/5 of the oral Tac
dose)
•
Steroid cover (Suppressed suprarenal gland)
•
Antibiotic cover
•
IV fluid
•
Careful monitoring of urine out put and renal function (daily)
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Surgical Problems in Immunosuppressed
Patients
•
Careful monitoring of CNIs drug level
•
Avoid nephrotoxic drugs
•
Be aware of drug interaction with CNI (discuss with the Tx
team)
•
Delayed wound healing and wound-related complications
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Prophylaxis of Infection
•
Pneumocystis Carinii pneumonia
•
Co-trimoxazole 480mg daily to all patients for 6 months
•
A three month course should be initiated after this period
if a transplant patient has their immunosuppression
changed or increased.
•
If patients are allergic to Co-trimoxazole, or this causes
dyscrasias, Dapsone 50mg BD may be used.
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Prophylaxis of Infection
•
Cytomegalovirus (CMV) prophylaxis
•
CMV status of potential recipients is to be tested for every six
months. After transplant, valganciclovir is prescribed for
100days as below.
•
Donor(D)/Recipient(R) combinations:
•
D-ve/R-ve
Not required
•
D-ve/R+ve
REQUIRED IF HAD ALEMTUZUMAB/ATG
•
D+ve/R+ve
REQUIRED IF HAD ALEMTUZUMAB/ATG
•
D+ve/R-ve
REQUIRED FOR ALL TRANSPLANT PATIENTS
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Diffuse peri-hilar infiltrate secondary to cytomegalovirus infection in an 18 year old
man with a rapidly deteriorating febrile condition 5 weeks post-transplant, after a
course of antilymphocyte globulin (for rejection).
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Prophylaxis of Infection
Prevention of hepatitis B virus (HBV)
•
There is UK protocol for screening and vaccinating dialysis and pre-dialysis
patients against hepatitis B virus (HBV).
•
The earlier in the chronic kidney disease process a patient is vaccinated the
more likely vaccination is to achieve adequate immune response.
•
Vaccination can be carried out during immune suppression but is much less
effective.
•
Patients listed for transplant must have their HBV immune status
documented at the time of listing.
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Prophylaxis of Infection
Prevention of varicella zoster virus (VZV) by vaccination
•
VZV can carry the risk of producing life-threatening illness in
the immunocompromised. It is thus important to ensure that
all patients awaiting transplantation are screened to ensure
immunity (usually conferred by childhood chicken pox) and
offered vaccination BEFORE TRANSPLANT if appropriate,
although contraindications may preclude this.
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Prophylaxis of Infection
If a patient is unsuitable for or declines
vaccination, full documentation should be made
in the case notes. These patients should be
warned to avoid contact with patients with
chickenpox or shingles if they are transplanted
and immunosuppressed. Any contact requires
hospital referral; suspicion of varicella or shingles
contact should be treated as an emergency and
discussed with a Consultant Medical Virologist.
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Summary
• The incidence and severity of acute rejection has
come down significantly
• Nonetheless, the chronic allograft nephropathy
remains the major obstacle in the long term outcome,
and that has not changed
• The ultimate goal of ‘tolerance’ continues to be
elusive
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Summary
•
With ever growing understanding of the mechanisms of
the process of rejection, the aim is to evolve a situation
when the need for immunosuppression is specific and
minimized
•
Clinical immunosuppression is rather complex.
•
At times, it may be difficult to strike a fine balance
between hazards of over-immunosuppression and
protecting allograft from immunological onslaught.
FACULTY OF HEALTH & LIFE SCIENCES – CPD
Institute for Learning & Teaching
Faculty of Health & Life Sciences
Room 2.16A, 4th Floor
Thompson Yates Building
Brownlow Hill
Liverpool
L69 3GB
www.liv.ac.uk/learning-and-teaching/cpd
A MEMBER OF THE RUSSELL GROUP

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