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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 Skopje – PowerPoint PPT presentation

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Title: Tailoring immunosuppressive treatment in kidney transplantation


1
Tailoring immunosuppressive treatment in kidney
transplantation where do we stand at present?
  • Goce Spasovski Department of Nephrology
  • University of SkopjeR. Macedonia

2
Organ transplantation at present
3
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
4
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

5
What are the determinants of long term allograft
results ?
6
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
7
Effect of donor age on chronic renal damage
n500
Howie et al. Transplantation 2004 771058-1065
8
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
9
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12
Age is a risk factor for acute rejection and death
13
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

14
Patient survival at one year
15
Graft survival at one year
16
Incidence of acute rejection
17
Main causes of graft lost
ANZDATA Registry Report 2004
18
Causes of late allograft loss in kidney
transplant patients
Donor specific alloantibodies (DSA detected by
Luminex)
Pascual et al. NEJM 2002346580
19
Factors that lead to Chronic Graft Dysfunction
Chapman JR et al. JASN 2005 16 3015-26
20
Estimatated cumulative prevalence (Kaplan-Meier)
Nankivell et al., NEJM 2003
21
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)

22
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

23
How to chose the immunosuppressive regime?
24
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

25
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

26
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

27
AJT 2009
28
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

29
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
30
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
31
Side-effects of calcineurin inhibitors
32
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

33
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

34
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

35
B-cells targeting-immunosuppressants
  • Steroids
  • Cyclophosphamide Cytoxan
  • Cellcept / Myfortic
  • Rituximab (Mabthera)
  • (anti-CD20 monoclonal Ab) antibody mediated AR

36
Complications of immunosuppressants
  • Infectious
  • Neoplastic
  • Cardiovascular
  • Metabolic
  • Bone

37
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

38
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

39
Graft survival at one year
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