Ajay Kumar Sharma

 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.

Destination
Live longer
Via
Kidney Tx

 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

 Activation of T cell (CD4+ Th) needs 3 signal model
 Several immunological targets at various steps

 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

 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 We suggest that CNIs be continued rather than withdrawn.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)

 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.

 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




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.

 Dosing:
– Orally every 12 hrs at 4-8 mg/kg/day to achieve trough levels 250-
350 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

 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 -1/5 th of daily oral dose
 Major toxicities:
– Renal insufficiency
– Hypertension
– Diabetes much more than ciclosporin
– Dyslipidemia
– Hypomagnesemia
– Hyperkalemia
– Neurotoxicity such as tremors

Hypertension
Pancreatic islet toxicity
Neurotoxicity
Hirsutism
Hair loss
Gum hypertrophy
GI side effects
Gastric motility
Dyslipidemia
Hyperuricemia
↑K + /↓Mg 2+
Cyclosporine
++
+
+
+
-
-
-
+
+
++
+
Tacrolimus
+
++
++
-
+
+
+
-
-
+
+
Adapted from Danovitch, Handbook of Kidney Transplantation, Lippincott Williams & Wilkins, 2005

 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

 Inhibit CYP450
– Azoles
– Calcium channel blockers
– Amiodarone
– Grapefruit
 Potentiate CYP 450
– Rifampin
– Phenytoin
– St John’s Wort

Halloran, from Johnson (ed.), Comprehensive Clinical
Nephrology, Mosby Elsevier, 2003.





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.

 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

 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

mTOR inhibitors should not be initiated until allograft function is established and surgical wounds has healed

Halloran, N Eng J Med, 2004;351:3715

 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?

 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

 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.

 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.

 Weight gain
 Hypertension
 Osteopenia,
 Hyperglycemia,
 Poor wound healing,
 Cushingoid features,
 Proximal myopathy,
 Cataracts

Ajay Kumar Sharma

 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.

 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

 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.

 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.

• 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)

 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.

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

 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)

 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.

 Anti-thymocyte globulin (ATG) ( Thymoglobuline ) 1.5-
3mg/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 (0.050x10
9 /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

 £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)

 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

 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.

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
D+ve/R+ve
D+ve/R-ve
REQUIRED IF HAD ALEMTUZUMAB/ATG
REQUIRED IF HAD ALEMTUZUMAB/ATG
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).

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
.

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.

 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

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.