Chronic Kidney Disease & Transplantation. Paediatrics : 2004 FRACP

Transcription

1 Chronic Kidney Disease & Transplantation Paediatrics : 2004 FRACP

2 ANZDATA Registry Mode of First Treatment - Paediatric y 5-9 y y y Hospital CAPD Hospital HD Hospital PD Transplant-no Dx

3 ANZDATA Registry Paediatric patients PD HD Tx 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Tx HD PD 0-4 yrs yrs 0-4 yrs yrs

4 Paediatric CKD Anaemia Growth Bone Disease

5 Cardiovascular mortality in CKD patients Annual Mortality (%) Levey et al AJKD 1998;32:853 Dialysis Male Dialysis Female Control Male Control Female >85 Age (years)

6 Failure to respond to erythropoietin in CKD is due to A. More common in patients pre-dialysis than post dialysis B. Severe hyperparathyroidism C. More likely in patients recovering from surgery D. Increased transferrin level to 20% E. Desferrioxamine therapy for aluminium toxicity

7 Hyperphosphatemia in renal failure A. Does not occur if GFR >50ml/min/1.73 m 2 B. Primarily due to bone resorption C. Causes decreased 1.25 Vit D ( > 1.25) D. Is associated with increased PTH levels

8 Cause of death Cause of death Total Cardiac & vascular Infective Malignant Other Total

9 Early Experience of Paediatric Transplantation Virtually everyone on dialysis was offered a transplant CKD Dialysis Transplant

10 Survival and time to transplantation Kaplan-Meier survival estimates, by txdelaycat Preemptive Never transplanted analysis time

11 Risk factors for early death Parameter estimate Hazard Hazard ratio ratio HD PD Transpla Predictors Transplant PD HD Year of RRT start RRT modality Age at RRT start

12 Figure 10.1 Country Number of Grafts Performed Over The Twenty Year Period 1-Jan-1983 to 31-Dec-2002 Donor Source First Graft Subsequent Graft Total Australia New Zealand Both Cadaveric Living Total Cadaveric Living Total Cadaveric Living Total Both Countries by Age Groups <5 years 5-9 years years years Cadaveric Living Total Cadaveric Living Total Cadaveric Living Total Cadaveric Living Total

13 Graft Survival 50 % at 1 year virtually all losses due to Acute Rejection

14 Immunosuppression before Cyclosporine Corticosteroids (Prednisolone) Azathioprine (Imuran)

15 Figure 10.3 Cadaveric and Living Graft Survival Initial and Subsequent Transplants 1-Jan-1983 to 31-Dec-2002 Source Graft survival after Survival (95% CI) First Cadaveric Graft Subsequent Cadaveric Graft First Living Graft Subsequent Living Graft 1 year 0.83 (0.79, 0.87) 2 years 0.76 (0.71, 0.80) 5 years 0.60 (0.55, 0.65) 10 years 0.42 (0.37, 0.48) 1 year 0.74 (0.64, 0.82) 2 years 0.66 (0.55, 0.75) 5 years 0.43 (0.33, 0.53) 10 years 0.36 (0.26, 0.46) 1 year 0.92 (0.89, 0.94) 2 years 0.88 (0.85, 0.91) 5 years 0.80 (0.76, 0.84) 10 years 0.66 (0.59, 0.71) 1 year 0.96 (0.75, 0.99) 2 years 0.95 (0.72, 0.98) 5 years 0.75 (0.53, 0.88) 10 years 0.46 (0.20, 0.68)

16 Figure 10.6 Patient Survival Following Cadaveric and Living Graft Initial and Subsequent Transplants 1-Jan-1983 to 31-Dec-2002 Source Patient survival after Survival (95% CI) First Cadaveric Graft Subsequent Cadaveric Graft First Living Graft Subsequent Living Graft 1 year 0.97 (0.95, 0.99) 2 years 0.96 (0.94, 0.98) 5 years 0.91 (0.88, 0.94) 10 years 0.83 (0.79, 0.87) 1 year 0.95 (0.88, 0.98) 2 years 0.94 (0.86, 0.97) 5 years 0.83 (0.73, 0.89) 10 years 0.77 (0.66, 0.85) 1 year 0.98 (0.96, 0.99) 2 years 0.97 (0.95, 0.98) 5 years 0.95 (0.92, 0.97) 10 years 0.93 (0.89, 0.95) 1 year 1 2 years 0.96 (0.74, 0.99) 5 years 0.92 (0.71, 0.98) 10 years 0.80 (0.55, 0.92)

17 Kaplan-Meier graft survival estimates of Australia and NZ combined st Jan st Dec 2002: First graft-cadaveric donor 0.90 Proportion surviving Age = <5 Age = 5-9 Age = Age = Survival time

18 Kaplan-Meier graft survival estimates of Australia and NZ combined 1st Jan st Dec 2002: First graft-live donor 0.90 Proportion surviving Age = <5 Age = 5-9 Age = Age = Survival time

19 Figure 10.9 Point Prevalent Paediatric Patients at 31-Dec-2002 Country Age at 31-Dec-2002 Peritoneal Dialysis APD CAPD Haemodialysis Functioning Transplant Total Australia New Zealand <1 year years years years years Total <1 year years years years years Total

20 Figure Incident Paediatric Patients 1-Jan-2002 to 31-Dec-2002 Age at Initial Treatment Qld NSW ACT Vic Tas SA NT WA AUST. N.Z. Total <1 year years years years years Total

21 Figure Primary Renal Disease Incidence in Paediatric Patients 1-Jan-2002 to 31-Dec-2002 Country Primary Renal Disease Age Groups < Total Australia Other Glomerulonephritis Reflux Hypoplasia and Dysplasia Medullary Cystic Haemolytic Uraemic Posterior Urethral Valves Total New Zealand Other Glomerulonephritis Reflux Medullary Cystic Total

22 Figure Transplant Operations on Paediatric Patients 1-Jan-2002 to 31-Dec-2002 Age at Transplant CD First CD Subsequent LD First LD Subsequent Total Australia New Zealand <1 year years years years years Total <1 year years years years years Total

23 Figure Time from Replacement Therapy to First Graft Donor of first graft Pre-emptive <6 months 6-24 months >2 years Total Australia New Zealand Cadaveric Living Total Cadaveric Living Total

24 Causes of Graft Loss Figure 8.38 Year of Graft Loss Due to Death or Failure By Country of Transplant Loss Cause of Failure Total Australia Death Rejection - Acute Rejection - Chronic Rejection - Hyperacute Rejection - Subacute Fa ile d Vascular Technical Problem s Recurrence Primary Disease Non Com pliance Other Total

25 Acute Cellular Rejection

26 Acute Cellular Rejection - Tubulitis

27 A 4-year-old girl develops a cough, dyspnoea and a fever 7 days following renal transplantation. She was seropositive for CMV prior to transplant. CXR shows sign of consolidation at the right lung base. She is receiving cyclosporin-a and prednisolone to prevent graft rejection. The transplanted kidney shows no signs of rejection. Which one of the following is most likely to be the cause of the pneumonia? A. Cytomegalovirus B. Gram negative bacteria C. Streptococcus pneumoniae D. Aspergillus fumigatus E. Pneumocystis carinii

28 6-yo boy, day 8 post living related renal transplant is febrile and tender over the graft site, MSU shows increased white cells, no organisms are seen. Cyclosporin levels from day 6 were at desirable targets. CMV status: CMV +ve kidney, CMV-ve patient. DTPA scans shown from day 3 good uptake (normal) day 8 no uptake in renal graft The explanation for these findings is: A. Vascular thrombosis B. Ureteric obstruction C. CMV infection D. Acute rejection E. Cyclosporin-A toxicity

29 IMMUNOSUPPRESSION The optimal maintenance immunosuppressive therapy in solid organ transplantation is not established There are still no absolute criteria that enable the clinician to predict who will do well with a low level of immunosuppression

30 IMMUNOSUPPRESSION Until recently, there had been very few well controlled trials comparing different regimens.

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32 Immunology of Allograft Rejection IL2 APC Tcell MHC Ag TCR 1 3 IL2R + B7 CD28 2 CD40 CD40L Proliferation Activation Signal 1 - Antigen Presentation Signal 2 - Co-stimulation Signal 3 - IL-2 stimulation REJECTION

33 Pharmaceutical Intervention in Rejection APC + MHC OKT3 ATG Ag B7 CD28 TCR CSA TAC 1 Tcell 2 3 CD25 IL2R IL2 anticd25 CD40 CD40L Rapamycin(SRL) CTLA4-Ig anticd154 Activation Proliferation MMF AZA Depletion - OKT3, ATG Signal 1 -CSA, TAC Signal 2 - CTLA4-Ig, anticd154 Signal 3 - anticd25, Rapamycin Late - MMF, AZA, Prednisolone Prednisolone REJECTION

34 Acute Rejection Biologicals

35 Rejection without Antibody Induction CSA + PNL 60% CSA + PNL + AZA 50% RAPA + PNL 50% CSA + PNL + MMF 30% TAC + PNL 30% TAC + PNL + AZA 30% TAC + PNL + MMF 15% CSA + PNL + RAPA 10% + ATG!50% + anti-il2r!33%

36 Regarding renal transplant and mouse OKT 3 A. Patients on cyclosporin do not produce anti-mouse antibodies B. Causes a serum sickness like illness C. Decreases IL.2 levels D. Increases calcium levels E. Binds alpha subunit of T cell receptor

37 Currently available Biologic Agents AGENT ANTIBODY TARGETS ATGAM Equine Polycolonal Multiple CD specificities Thymoglobulin Rabbit Polycolonal OKT3 Murine IgG2a CD3 Basiliximab Daclizumab Chimeric (Murine/Human) Humanised (MurineCDR) CD25

38 Antiproliferative Agents

39 Pharmaceutical Intervention in Rejection APC + MHC OKT3 ATG Ag B7 CD28 TCR CSA TAC 1 Tcell 2 3 CD25 IL2R IL2 anticd25 CD40 CD40L Rapamycin(SRL) CTLA4-Ig anticd154 Activation Proliferation MMF AZA Depletion - OKT3, ATG Signal 1 -CSA, TAC Signal 2 - CTLA4-Ig, anticd154 Signal 3 - anticd25, Rapamycin Late - MMF, AZA, Prednisolone Prednisolone REJECTION

40 Immunosuppression before Cyclosporine Corticosteroids (Prednisolone) Azathioprine (Imuran)

41 Increasing Use of MMF as a Component of Primary Immunosuppression in Pediatric Renal Transplantation (NAPRTCS data) Use in New Transplant Recipients 70% MMF Azathioprine % of All Trans- plants % 37% %

42 Increasing Use of MMF as a Component of Primary Immunosuppression in Pediatric Renal Transplantation (NAPRTCS data) Use in New Transplant Recipients MMF Azathioprine % of All Trans- plants

43 MYCOPHENOLATE MOFETIL Decreased incidence of acute rejection compare to azathioprine/placebo Steroid-free and steroid sparing protocols Rescue therapy Chronic rejection

44 The Long Term Use of Mycophenolate Mofetil in Pediatric Renal Transplantation Robert Ettenger et al Mattel Children s Hospital at UCLA 1. In pediatric renal transplantation, MMF in combination with CsA and Prednisone provide effective long-term immunosuppression. 2. Patient and graft survival are excellent. 3. The relatively low rate of rejection episodes is maintained through 3 years posttransplant. 4. The use of MMF appears to be generally well tolerated through 3 years posttransplant.

45 MYCOPHENOLATE MOFETIL Smith KG et al: Nephrol, Dial Transpl 13(1);1998; % Responding to 3 Ags % Responding to no Ags Control Aza MMF Control Aza MMF

46 Calcineurin Inhibitors

47 Pharmaceutical Intervention in Rejection APC + MHC OKT3 ATG Ag B7 CD28 TCR CSA TAC 1 Tcell 2 3 CD25 IL2R IL2 anticd25 CD40 CD40L Rapamycin(SRL) CTLA4-Ig anticd154 Activation Proliferation MMF AZA Depletion - OKT3, ATG Signal 1 -CSA, TAC Signal 2 - CTLA4-Ig, anticd154 Signal 3 - anticd25, Rapamycin Late - MMF, AZA, Prednisolone Prednisolone REJECTION

48 Cyclosporine and Tacrolimus Should the use of Calcineurin inhibitors be uniform or individualised?

49 Comparing cyclosporine to tacrolimus which of the following statements are true about cyclosporine A. Only patients on cyclosporin develop nephrotoxicity B. C 0 compared to C 2 monitoring is preferred C. Diabetes is more common D. Gingival enlargement and hirsutism are features E. Hyperlipidaemia is less common

50 Cyclosporine and Tacrolimus Criticisms of Phase III trials Tacrolimus compared to Cyclosporine (Sandimmune) not Neoral Open label bias Adjustment to trough levels and not C2 for Cyclosporine

51 Cyclosporine and Tacrolimus :Toxicity CsA TAC " Islet cell toxicity "" " Neurotoxicity "" "" Hyperlipidemia " "" Hypertension " " GI "" "" Cosmetic " " Polyoma/BK virus ""

52 Cyclosporine and Tacrolimus Safety edge to cyclosporine Ease of use edge to tacrolimus Efficacy??

53 Cyclosporine and Tacrolimus Cyclosporine Low Immunologic Risk Older Patients Primary Patients At risk of Diabetes mellitus Polyoma /BK risk Tacrolimus Children Young Women African Americans High Immunologic Risk

54 TACROLIMUS Low incidence of acute rejection Side-effect profiles Steroid-free and steroid sparing protocols Rescue therapy for refractory rejection

55 TACROLIMUS Shapiro et al Transpl 1999;67(2): Incidence of Adverse Events PTLD : EBV related 9% CMV 13% New onset IDDM 10%

56 Conclusions TACROLIMUS Excellent short/medium term Patient and Graft Survival Options for Steroid Withdrawal Decreasing Rates of Acute Rejection Decreased Incidence of Gum Enlargement and Hirsutism

57 RAPAMYCIN

58 Pharmaceutical Intervention in Rejection APC + MHC OKT3 ATG Ag B7 CD28 TCR CSA TAC 1 Tcell 2 3 CD25 IL2R IL2 anticd25 CD40 CD40L Rapamycin(SRL) CTLA4-Ig anticd154 Depletion - OKT3, ATG Signal 1 -CSA, FK506 Signal 2 - CTLA4-Ig, anticd154 Signal 3 - anticd25, Rapamycin Late - MMF, AZA, Prednisolone Prednisolone Activation Proliferation REJECTION MMF AZA

59 RAPAMYCIN # Lipids " Cholesterol " Triglycerides " Peak 2-4 months Reversible after drug cessation (takes 1-2 months)

60 Novel Immunosuppression FTY 720

61 FTY720 Mechanism of Action: Alteration of Lymphocyte Homing/Sequestration Microvasculature Chemokines ELC SLC Cytokines FTY720 CCR7 X FTY720 Sequestration Migration X FTY720 SLC = Secondary Lymphoid-Tissue Chemokine ELC = EBI1 ligand Chemokine Graft FTY720 may activate the cell mobility machinery via S1P receptors and thereby accelerate the response to chemokines

62 FTY720 Homing of lymphocytes

63 Intervention in the immunology of rejection APC + MHC OKT3 ATG Ag B7 CD28 TCR CSA FK506 1 Tcell 2 3 CD25 IL2R IL2 anticd25 CD40 CD40L Rapamycin CTLA4-Ig acd154 Depletion - OKT3, ATG Signal 1 - CSA, FK506 Signal 2 - CTLA4-Ig, acd154 Signal 3 - acd25, Rapamycin Late - MMF, AZA, Pred Pred Activation Proliferation REJECTION FTY720 MMF AZA Migration

64 Calcineurin Inhibitor Avoidance

65 A RANDOMIZED TRIAL OF SIROLIMUS VS. CYCLOSPORINE IN KIDNEY TRANSPLANTATION 61 patients randomised Cyclosporine ( ng/ml troughs Sirolimus (10-12 ng/ml troughs Flechner et al Mycophenolate (1000 mg bid) Prednsiolone (tapering doses) Basiliximab (20 mg X 2 doses) Patient Survival Graft Survival Ac Rejection Cyclosporine 100% 96.0% 16.6% Sirolimus 96.7% 96.7% 6.4% Comparable transplant outcomes

66 KIDNEY TRANSPLANTATION WITHOUT CALCINEURIN-INHIBITORS: A RANDOMIZED TRIAL OF SIROLIMUS VS TACROLIMUS Larson TS et al, Rochester, MN Protocol Tacrolimus Sirolimus Mycophenolate Prednsiolone Thymoglobuline Induction CONCLUSIONS low rejection rates acceptable tolerability excellent renal function with CNI free immunosuppression Results Patients Graft Losses Rejections Creatinine CLR Tacrolimus (0%) 56 +/- 12 ml/min/bsa Sirolimus (12%) 62 +/- 20 ml/min/bsa

67 ADVERSE EFFECTS OF SIROLIMUS ON WOUND HEALING IN KIDNEY TRANSPLANTATION David S. Seaman,et al, Cleveland, OH. Mycophenolate Sirolimus Tacrolimus Prednsiolone Retrospective review of 175 kidney transplants TAC/MMF TAC/SRL Number of patients Serious wound infection 0 11 Fascial dehiscence 0 2 Symptomatic fluid collection 0 1 Symptomatic lymphocele 3 10 Hematoma 1 0 Total wound complications 4(4%) 24(35%)

68 Chronic Rejection Chronic Allograft Nephropathy

69 Cyclosporine Withdrawal Chronic Allograft Nephropathy (CAN) Chronic Renal Allograft Dysfunction Syndrome (CRAD) After the first year of transplantation, 4% - 8% of grafts fail annually

70 Prolonging Survival in Chronic Renal Allograft Dysfunction 143 patients (6 month follow up) 73 treated with MMF 70 continued on CSA MMF CsA Improved 58% 32% Deteriorated 42% 68% P =.0003

71 Prolonging Survival in Chronic renal Allograft Dysfunction

72 Cyclosporine Withdrawal Safe Withdrawal Stabilisation in function Improvement on BP and Cholesterol

73 IMMUNOSUPPRESSION STEROID WITHDRAWAL early (within three months) cessation of steroids is associated with a increased incidence of acute rejection possible decrease in long-term (more than two years) graft survival

74 Confused?

75 Cardiovascular mortality in CKD patients Annual Mortality (%) Levey et al AJKD 1998;32:853 Transplanted Dialysis Male Dialysis Female Control Male Control Female >85 Age (years)

76 IMMUNOSUPPRESSION ANZDATA REGISTRY 1997 INCIDENCE OF CANCER POST RENAL TRANSPLANT 10 years 25 years Any Cancer 38% 78% Skin Cancer 35% 73% Non-Skin 8% 23% (Non-Skin) (4% 7%)

77 IMMUNOSUPPRESSION ANZDATA REGISTRY 1997 Causes of Death in Renal Transplant Patients n = 109 Cardiac 36 (33%) Infection 16 (15%) Vascular 17 (16%) Social 8 (7%) Malignancy 25 (23%) Miscellaneous 7 (6%)

78 What final take home message do we want to get across?