Download Maintenance ImmunosuppressionMScFinal6_10_2014

Maintenance
Immunosuppression
Ajay Kumar Sharma
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
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
What are the targets?
 Activation of T cell (CD4+ Th) needs 3 signal
model
 Several immunological targets at various steps
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
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.
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.
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.
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)
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.
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 endothelin-1 and TGFβ mediated
fibrosis leading to arteriolar hyalinosis
 Interstitial fibrosis set in all renal grafts by
10 yrs, median onset 6 months
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
Halloran, N Eng J Med, 2004;351:3715
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.
Cyclosporine (CsA)
 Dosing:
– Orally every 12 hrs at 4-8 mg/kg/day to achieve trough levels 250350 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
 Major Toxicities:
–
–
–
–
–
–
–
–
Renal insufficiency
HTN , though lesser than tacrolimus
Dyslipidemia, though lesser than tacrolimus
Hyperkalemia
Hypomagnesemia
Hyperuricemia
Gingival hyperplasia
Hirsutism
Tacrolimus (Prograf)
 Dosing:
– Prograf is given every 12 hr dosing at 0.05-0.1 mg/kg/day, Advagraf is
given once a day
– IV: continuous infusion – 1/3 -1/5th of daily oral dose
 Major toxicities:
–
–
–
–
–
–
–
Renal insufficiency
Hypertension
Diabetes much more than ciclosporin
Dyslipidemia
Hypomagnesemia
Hyperkalemia
Neurotoxicity such as tremors
Calcineurine Inhibitors: Dosing and
Monitoring
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
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
CNIs drug interactions
 Inhibit CYP450
–
–
–
–
Azoles
Calcium channel blockers
Amiodarone
Grapefruit
 Potentiate CYP 450
– Rifampin
– Phenytoin
– St John’s Wort
CNIs drug interactions
Halloran, from Johnson (ed.), Comprehensive Clinical
Nephrology, Mosby Elsevier, 2003.
CNIs drug interactions
HAART
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.
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
 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
Halloran, N Eng J Med, 2004;351:3715
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)
Halloran, N Eng J Med, 2004;351:3715
Mammalian Target of
Rapamycin Inhibitors
(mTOR inhibitors)
mTOR inhibitors should not be initiated until
allograft function is established and surgical
wounds has healed
Halloran, N Eng J Med, 2004;351:3715
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?
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
 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
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 wellknown.
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.
Steroids








Weight gain
Hypertension
Osteopenia,
Hyperglycemia,
Poor wound healing,
Cushingoid features,
Proximal myopathy,
Cataracts
Immunosuppression
Protocols
Ajay Kumar Sharma
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.
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
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
 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.
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)
 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.
CONCEPT
• Aim: to evaluate conversion from a CsA-based regimen to a SRLbased regimen 3 months post-transplant
• 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
• 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)
CONVERT
 Aim: to evaluate the efficacy and safety of converting maintenance
renal transplant recipients from CNIs to SRL
 Design: prospective, open-label, 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
 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 e-GFR >40 mL and UPr/Cr ≤0.11.
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
Level 4-7ng/ml
3 months
Afterwards
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
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)
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.
Acute vascular rejection
Liverpool Protocol
 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)
 Tacrolimus and mycophenolate preparations are stopped
on initiation of ATG and restarted on day 10; oral
prednisolone 20mg daily is started on initiation
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)
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
(See induction immunosuppression)
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
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 co-manifest
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.
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
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)
 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
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.
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
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).
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.
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.
 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.
Conclusions
 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
 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
 The ultimate goal of ‘tolerance’ continues to be elusive
Conclusion
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.