Tailoring immunosuppressive treatment in kidney transplantation

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Tailoring immunosuppressive treatment in kidney
transplantation where do we stand at present?

• Goce Spasovski Department of Nephrology
• University of SkopjeR. Macedonia

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Organ transplantation at present
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Transplant activity
USA 2009 2003 / pmp
Heart 2,163 Spain - 34
Liver 6,319 Belgium - 24 Austria - 23
Kidney 16,518 310 53,3 pmp USA - 22
Kidney Pancreas Pancreas 837 436 Ireland - 21
Lungs 1,478 Norway - 19
Intestine 185 France 18
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Graft survival (UNOS USA)
1 year () 5 years ()
Heart 87.1 71.5
Liver 83.4 67.4
Kidney 91.9 71.9
Kidney Pancreas 91.8 76.2
Lungs 83.1 46.3
Intestine 77.9 39.7

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What are the determinants of long term allograft
results ?
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Factors influencing long-term outcome
Pre - Tx
Post - Tx

• DONOR
• age
• source
• HLA-match

RECIPIENT
age preformed Ab immune reactivity waiting time viral status specific diseases calcineurin-inhibitors factors progression tx glomerulopathy chronic rejection
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Effect of donor age on chronic renal damage
n500
Howie et al. Transplantation 2004 771058-1065
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Effect of donor glomerular sclerosis on graft
function
GS0 n129
n210
GS 0.1-10 n42
GS 10-20 n22
GS gt 20 n17
Escofet et al. Transplantation 2003 75344-346
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Age is a risk factor for acute rejection and death
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Why response with Acute Rejection (AR)

• Without immunosuppression
• Immediate AR unless homozygous twins
  transplantation
• If immunosuppression is stopped
• Acute rejection no immunological tolerance
• Immunosuppression in organ transplantation
• Strong in the first 6 months posttransplantation
  (AR)
• then lighter - avoid complications/infections,
  cancers
• No available in-vitro test to assess the degree
  of immunosuppression
• Therapeutical adjustments according to
• Immunosuppressant trough levels (C2)
• Side effects

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Patient survival at one year
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Graft survival at one year
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Incidence of acute rejection
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Main causes of graft lost
ANZDATA Registry Report 2004
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Causes of late allograft loss in kidney
transplant patients
Donor specific alloantibodies (DSA detected by
Luminex)
Pascual et al. NEJM 2002346580
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Factors that lead to Chronic Graft Dysfunction
Chapman JR et al. JASN 2005 16 3015-26
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Estimatated cumulative prevalence (Kaplan-Meier)
Nankivell et al., NEJM 2003
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Immunosuppressants

• Steroids
• Azathioprine Imuran (Glaxo-Welcome)
• Ciclosporine Sandimmune/Neoral (Novartis)
• Tacrolimus Prograf/Advagraf (Astellas)
• Mycophenolate Mofetil CellCept (Roche)
• Mycophenolate sodium Myfortic (Novartis)
• Sirolimus/Rapamycine Rapamune (Pfizer)
• Everolimus Certican (Novartis)
• Leflunomide Arava (Aventis)
• Bioreagents
• Polyclonal antibodies
• ATG/ALG (Thymoglobulins Genzyme -
  Lymphoglobulins - Fresenius)
• Monoclonal antibodies
• Chimeric Basiliximab, Simulect (Novartis)
• Humanized Daclizumab, Zenapax (Roche)

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Immunosuppressants

• Ideal immunosuppressant
• Save security margin between toxic dose and
  therapeutic dose
• Selective effect upon lymphoid cells
• Efficacy on cells implicated in the targeted
  immune response
• Drug is efficient against engaged immune
  response(s)
• Hazards of immunosuppressants
• Over immunodepression
• infectious problems (bacterial, virological -
  cytomegalovirus, or fungal - candida,
  aspergillus)
• De novo cancers
• posttransplant lymphoproliferative disorders
  induced by EBV,
• Kaposi sarcoma - HHV8
• cutaneous and cervix cancers induced by
  papillomavirus
• risk for de novo cancer

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How to chose the immunosuppressive regime?
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Choice of immunosuppression

• ? We HAVE to block the T-cell response
• calcineurin inhibitor OR
• mTOR in ASSOCIATION with MPA which blocks T-
  and B-cell responses
• /- steroids
• /- induction therapy

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To evaluate patients at risk

• 1st graft vs iterative graft
• Old recipient (gt 60 years) vs child
• caucasian vs african
• No anti-HLA Ab vs anti-HLA Ab ()
• Living donor vs deceased donor
• History of
• Chronic viral disease (hepatitis B or C)
• Cancer
• ? Light or heavy immunosuppression
• Initial phase (lt 3 months) to prevent acute
  rejection
• Later on (gt 6 months) to prevent chronic
  rejection

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Anti-HLA antibodies

1. Indicative of anti-HLA memory T and B cells
2. Sensitisation ?
3. Pregnancies
4. Blood transfusions
5. Previous grafts
6. Risk factors for graft loss

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AJT 2009
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DACLIZUMAB versus THYMOGLOBULIN IN RENAL
TRANSPLANT RECIPIENTS WITH A HIGH IMMUNOLOGICAL
RISK A MULTICENTER, PROSPECTIVE, CONTROLLED, RCT
Noel C, Abramowicz D, et al., JASN 2009

• To compare the incidence of biopsy-proven acute
  rejection in high immunological risk renal
  transplant patients receiving either ATG or
  Zenapax as induction therapy
• (Maintenance th Tac, MMF, steroids)
• Inclusion criterias (N227)
• Current PRA gt 30
• and/or Peak PRA gt 50
• and/or Rapid (lt 2 years) immunological loss of a
  first graft
• and/or Third or fourth renal transplantation
• ? 50 of patients received a 2nd and 20 a 3rd
  or 4th graft
• ? Peak PRA was 70 and current PRA was 35

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DACLIZUMAB versus THYMOGLOBULIN IN RENAL
TRANSPLANT RECIPIENTS WITH A HIGH IMMUNOLOGICAL
RISK A MULTICENTER, PROSPECTIVE, CONTROLLED, RCT
Noel C, Abramowicz D, et al., JASN 2009
15.0 vs 27.2 P0.016
NS
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Choice according to profiles

• ? cholesterol, ? triglycerides
• Glucose intolerance
• Osteopenia
• Hypertension ? less Neoral/Prograf
• Leucopenia ? ? Imurel or
  Cellcept
• Cutaneous cancers ? Introduce mTOR
  inhibitors (sirolimus/everolimus)

Avoid steroids
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Side-effects of calcineurin inhibitors
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MPAs Cellcept / Myfortic

• Prodrugs of mycophenolic acid (MPA)
• Mycophenolate mofetil Cellcept gastric
  absorption
• Mycophenolate sodium Myfortic intestinal
  absorption ? better exposition of MPA
• Inhibit purine synthesis (T and B lymphocytes)
  decrease T-cell response as well as antibody
  synthesis
• Twice a day
• Side effects
• Leucopenia
• Thrombocytopenia
• Anemia
• Gastrointestinal disorders diarrhea, nausea,
  villous atrophy ? malabsorption syndrome
• Dosage
• Trough level of no value
• Area under the curve (AUC) to optimize MPA
  efficacy and to decrease side effects

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Sirolimus (Rapamune) / Everolimus (Certican)

• Inhibit mTOR protein in T lymphocytes ?
  inhibition of cellular proliferation
• Acute rejection prevention
• Active on endothelial cells/myocytes
• Inhibition of vascular proliferation
• Chronic rejection prevention
• Prevent intra-stent restenosis
• Anti-tumoral properties
• Antiangiogenic properties

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Choice of immunosuppression

• Use of mTOR inhibitors with CsA synergistic
  effects
• Use of mTOR inhibitors with tacrolimus or MPAs
  additive effects
• Once (sirolimus) or twice (everolimus) a day
• Trough levels 7 to 15 ng/mL
• Side effects (dose-dependent)
• Leucopenia
• Thrombocytopenia
• Microcytic anemia
• Dyslipidemia
• ? total cholesterol (LDL)
• ? triglycerids
• ? LDH
• Kidney
• Tubular disorders (hypokaliemia,
  hypophosphatemia)
• Glomerular and tubulointerstitial damage when
  administered in the long-term with CNIs

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B-cells targeting-immunosuppressants

• Steroids
• Cyclophosphamide Cytoxan
• Cellcept / Myfortic
• Rituximab (Mabthera)
• (anti-CD20 monoclonal Ab) antibody mediated AR

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Complications of immunosuppressants

• Infectious
• Neoplastic
• Cardiovascular
• Metabolic
• Bone

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EMERGENCY SITUATIONS - It is a TRANSPLANT patient

• Any fever gt 385
• Acute rejection
• Acute pyelonephritis
• Opportunistic infection
• Any bullous cutaneous lesions
• Varicella
• Any febrile cough
• Any profuse diarrhea gt 24 hours
• Prolonged vomiting
• Dehydration
• management of immunosuppressants

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Interactions between immunosuppressants and other
drugs

• Avoid Cyt P450 enzymatic inducers or inhibitors
• Many transplant patients are on ACEIs and/or ARBs
  
• Avoid NSAID steroids if necessary
• To be stopped in case of fever or profuse
  diarrhea
• Many transplant patients are diabetic

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Graft survival at one year