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Update in Transplantation

Update in Transplantation. Jeffrey J. Kaufhold, MD FACP Nephrology Associates July 2015. Update in Transplantation Summary. Trends in Survival after transplant Expanded Donor Kidneys Waiting list Management changes Trends in IS protocols Kidney Pancreas Update

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Update in Transplantation

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  1. Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates July 2015

  2. Update in TransplantationSummary • Trends in Survival after transplant • Expanded Donor Kidneys • Waiting list Management changes • Trends in IS protocols • Kidney Pancreas Update • Ethnic Disparities in Transplants • Immunology and Tolerance • New approach to Complications

  3. Scope of problem • 300,000 dialysis patients in US • 55,000 patients on waiting List • 17,000 recovered kidneys per year • 11000 from “deceased donors” • 6000 from living related donors • 1000 kidneys not used after recovery • Average waiting time 5 years !

  4. Patient Survival 1 yr LRD 98% DD 96.5 Allograft Survival 1 yr LRD 95% DD 96.5 Allograft half-life LRD 21 years 5 yrs LRD 91 % DD 81 5 years LRD 76% DD 92% at 3 yrs DD 13.8 years Survival after Transplant

  5. Transplant survival • Relative risk of death • Transplanted in 1993 = 1.0 • Transplanted in 1998 = 0.74 • Currently on Wait list = 1.7 • These are the healthy ones! • Patients not on wait list = 2.6

  6. Transplant Update • Annual Death Rates • Pts on list 6.3 % • Diabetic pts on list 10.8 % • Pts not on list 21 % • Note that “death censored graft loss” is standard measure used in transplant outcome reports since this is desired outcome.

  7. Higher risk Deceased donor Recipient over 60 Donor over 60 Recipient race* Black / Hispanic Long Cold Ischemic time Previous Txp High PRA Lower Risk Living donor Recipient under 60 Donor under 60 Recipient race Asian Short cold ischemia Higher HLA match Low PRA Risk of Graft Loss

  8. Impact of Race on Allograft Survival • Registry data show that African American allograft survival now matches the white population for DDKT or LDKT since 2012. • Reasons for the improvement: • Change in UNOS scoring that eliminated the HLA B matching bias • Shorter time on dialysis (which may be one of the biggest risk factors for allograft and pt survival) • Improved insurance coverage for Txp meds.

  9. Expanded Donor Kidneys • Used when risk of Txp is better than life expectancy on dialysis • Criteria • Recipient/donor over 60 • Diabetics over 40 • Failing access for dialysis • Patient with poor Quality of Life

  10. Transplant Update • HLA Matching • Main HLA groups A B C D • C not important for transplant survival • Host of minor antigens • Most important antigens are B and D • D antigen is inducible and responsible for more serious (vascular) rejections

  11. Waiting list management • Old Point system for UNOS Wait list • 1 pt per year on list • 7 pts for 0 mismatch with B, DR antigens • 5 pts for 1 mm with B, DR • 2 pts for 2 mm with B, DR • 4 pts for match in pt with PRA > 80 % • 4 pts for Age < 11, 3 pts for age 11-18 • National sharing of 0 mismatch kidneys • 17-20 % of all transplants

  12. Wait list Management • Ethnic disparity in rates of transplant • Due to smaller pool of B antigens in AA population • UNOS is changing point system to reflect this • Eliminating points for B antigen reduces the ethnic disparity in points awarded.

  13. UNOS Waiting list Update 2015 • candidate Kidney Allocation Score (KAS): • 1. Life Years from Transplant (LYFT): Determines the estimated survival that a recipient of a specific donor kidney may expect to receive versus remaining on dialysis. LYFT is primarily a measure of utility.

2. Dialysis Time (DT): Time spent on dialysis allows candidates to gain priority over the period they receive this treatment, adding the essential element of justice into the allocation system.

3. Donor Profile Index (DPI): Provides a continuous measure of organ quality based on clinical information. DPI increases individual autonomy by providing a better metric for deciding which organs are appropriate for which candidates. LYFT, DPI, and DT are incorporated so that kidneys are matched to candidates based on the expected survival of both the kidney and the recipient.

  14. Trends in Transplantation • Rejection rates and Creatinine at 6 months are now surrogates for allograft survival • Due to improved survival, a study of a new drug would need over 9000 enrollees to show a difference. • Rejection rates are down 50 % • Cardiovascular death rate improving.

  15. Trends in Transplantation • Overall Mortality is unchanged! • Death with functioning graft increasing • Donor Age older • Recipient age is older • Time on waiting list is longer • Older, sicker patients are getting transplants

  16. Induction Immunosuppression • Biological Agents • Steroid use vs steroid sparing • Cellcept used in place of Imuran • Calcineurin Inhibitors / Sirolimus

  17. Induction Immunosuppression • Biological Agents • OKT-3 rarely used • Thymoglobulin (rabbit) • ATG (polyclonal) • Basiliximab (Simulect) Chimeric • Anti CD 25/ anti IL-2 receptor monoclonal • Daclizumab (Zenapax) Humanized • Anti CD 25 Monoclonal

  18. Induction Immunosuppression • Biological Agents • Expensive, complex to use • Use in high risk patients: • High PRA • Second transplant • African American recipient • Delayed Graft function

  19. Induction Immunosuppression • Biological Agents • Basiliximab and Daclizumab • Anti CD 25 monoclonals • Do not deplete lymphocytes • Will not stop ongoing rejection • Other immunosuppression (CNI, steroid, MMF) should continue during use • OKT-3, ATG • Deplete lymphocytes, stop rejection, • reduce or withhold other immunosuppression while in use

  20. Induction Immunosuppression • New Biological Agents coming soon: • CTL4 Ig • stimulates CTL4 coreceptor on T cell which leads to • Decreased activation • Apoptosis of the activated cell line • LEA 29 Y • a second generation CTL4 Ig

  21. Regulation of T-Cell Activation IL-2 APC MHC CD 40 CD 80/86 Antigen TCR CD 25 CTL4 T-Cell Negative stimulatory Positive stimulation IL -2 Receptor

  22. T cell Costimulation

  23. Induction Immunosuppression • Biological Agents recommendations • Low risk patient: • IL-2 receptor antibody, consider steroid sparing regimen • High Risk patient • Thymoglobulin plus 3 drug regimen • CNI, Steroids, MMF

  24. Maintenance Immunosuppression • Categories of Agents: • Steroids • Calcineurin Inhibitors • Intracellular signal modifiers • Cyclosporine, Tacrolimus, Prograf • Adjuvant Agents • Interfere with cell cycling • Sirolimus, Rapamicin • Cellcept (MMF) • Imuran (azothioprine)

  25. Maintenance Immunosuppression • Three Drug Regimen: • Steroid - prednisone • Calcineurin Inhibitor • Cyclosporine, Tacrolimus (Prograf) • Adjuvant Agent • Cellcept (MMF) • Steroid Sparing Regimen: • Prograf + MMF or Rapamicin

  26. Drug Dosages • Steroid • 10 mg daily or every other day • CyA • 4-6 mg/Kg/day usually 100 - 150 BID • Levels 1-6 months: 250 - 400 • Level after 6 months: 100 – 250 • Imuran • 50 – 100 mg daily at bedtime

  27. Drug Dosages • Prograf • 0.1 – 0.2 mg/kg/day • Usually about 5 mg BID • Levels 5-15 by ELISA • Rapamicin • 6 mg po load then 2 mg po daily • Cellcept (MMF) • 1000 mg BID, taper if low WBC or anemia, GI intolerance.

  28. Drug Conversion for Cause • Refractory Rejection: CyA -> Tac • Cardiovasc Dz: CyA -> Tac • Rapa -> MMF • Diabetes: decrease steroid dose • Tac -> CyA may be helpful • Hirsuitism: CyA -> Tac • Gout: Azo -> MMF • Gingival Hyperplasia: CyA -> Tac • Stop dihydropyridines (procardia XL)

  29. Kidney – Pancreas Transplant

  30. Kidney – Pancreas Transplant • Cost: • Kidney Txp: $ 60,000 • Islet cells 53,000 • Panc Txp alone 105,000 • SPK (K-P) 130,000 • Each year on dialysis: $27,000

  31. Kidney – Pancreas Transplant • Rejection rates improved • Options for pancreas placement: • Attach to bladder • Dumps lots of bicarb, Cystitis • Easy to identify rejection by measuring urine amylase • Attach to intestine (enteric anastomosis) • Eliminates problems with acidosis and cystitis • Rejection harder to identify early.

  32. Kidney – Pancreas Transplant • Rejection Diagnosis: • Hyperglycemia • May also occur in face of high steroids, sepsis • Increased serum amylase level • Decreased urine amylase level in bladder anastomosis patients. • Maintenance immunosuppression • Tacrolimus/Cellcept preferred combo • Avoid steroids if possible

  33. Kidney – Pancreas Transplant • Surgical Complication rate 10% at 1 yr. • Immunologic Failure Rates: • Type of Txp % graft loss at 1 yr. PAK 7 % PTA 8 SPK 2 Gruessner, Clinical Transplantation 2002, p 52

  34. Kidney – Pancreas Transplant • Effect of Pancreas Txp on outcomes • No significant QOL improvement compared to kidney alone • Insulin free for diabetics 50 – 90 % • Neuropathy improves • Microvasculature improves • Retinopathy – no improvement • Survival improved compared to wait list pts • May be slightly better than kidney alone.

  35. Ethnic Disparities in Transplant • Rate of transplantation for AA lower than any other ethnic group • % of AA patients hearing about the option of transplant is only about 70% of other groups • Rate of referral once they hear about transplant is only about 70% of other groups.

  36. Ethnic Disparities in Transplant • Socioeconomic Factors: • 70% of AA children born into single parent homes • Less likely to have insurance • Barriers to travelling to appts • Less likely to be available when called • No phone or won’t answer due to debtors • Higher PRA, fewer AA donors • Mistrust of system

  37. Ethnic Disparities in Transplant • Insurance Impact on Transplant: • Compared to pts of other ethnic groups with same insurance, 70-80 % of eligible AA pts get to transplant • HMO rates 70-80 % of eligible pts get to transplant, evenly across races • Example of Rationing by Inconvenience • Military patients demonstrate NO racial disparity in rates of transplant or Graft survival.

  38. Ethnic Disparities in Transplantmay be changing…. • Immunologic Factors • Once transplanted, AA pts fare worse • AA with 0 MM does about as well as Caucasian with 6 MM and 1 rejection episode in first year. • Require higher doses of Immunosuppression • Don’t tolerate steroid or other drug withdrawal nearly as well as other groups • Higher levels of IL-6, CD-80, TGF-B, Endothelin, Renin. • More Hypertensive, which worsens overall survival

  39. Rejection • Clinical Diagnosis: • Hypertension • Increased Creatinine • Decreased urine output • Biopsy findings: • Tubulitis – usual Vasculitis - bad • Interstitial infiltration • Fixing of C 4 d

  40. Rejection Biopsy findings rejection Normal

  41. Rejection and Complement • Circulating Proteins in blood: • #1 Albumin • #2 Immunoglobulin • #3 Complement, esp C 3. • Triggers of Complement fixation • Ischemia reperfusion injury (IP - 10) • Brain injury in donor • Dialysis after transplant • Infection

  42. Immunology of Rejection • HLA A and B are constitutive antigens • HLA D is inducible antigen • Infection, ischemia induce D antigen expression • D antigen expression leads to vascular rejection which is worst type • How does Bactrim SS MWF help?

  43. Immunology of Rejection • HLA A and B are constitutive antigens • HLA D is inducible antigen • Infection, ischemia induce D antigen expression • D antigen expression leads to vascular rejection which is worst type • Bactrim SS MWF reduces bacteriuria

  44. Immunology of Rejection • HLA A and B are constitutive antigens • HLA D is inducible antigen • Infection, ischemia induce D antigen expression • D antigen expression leads to vascular rejection which is worst type • Bactrim SS MWF reduces bacteriuria • What is Acyclovir used for after Txp?

  45. Immunology of Rejection • HLA A and B are constitutive antigens • HLA D is inducible antigen • Infection, ischemia induce D antigen expression • D antigen expression leads to vascular rejection which is worst type • Bactrim SS MWF reduces bacteriuria • Acyclovir reduces shedding of Herpes Simplex virus in urine

  46. Immunology of Rejection • Chemoattractant Cytokines (chemokines) • Leukocyte recruitment • Most important CK is CXC • Receptor is CXC-R3 • Transmembrane protein • Activation of CXC R3 activates rejection pathway • IP-10 Activates CXC R3 • Both CXC R3 and IP-10 are present in urine of pts who are rejecting

  47. Immunology of RejectionThe Future • Chemokine receptors: • CXC R3 antibody prolongs graft survival in monkey models • Also in clinical trials: CCR-1, CCR-5 which bind CK’s and prevent activation of receptor. • Soluble Complement Receptor CR-1 • Trypriline decreases synthesis of complement • WY14643 ligand for PPAR

  48. Immunology of RejectionThe Future • Protein Tyrosine Kinases • Src • FAK • Paxillin • Akt • PPARS peroxisome proliferator activated receptors • Ligands for PPARs tend to decrease inflammatory response • Include Piaglitizone, Lopid

  49. Immunology of Rejection • Tolerance is the best immunosuppression • Has been known for years • First seen in pts treated with Steroids/Imuran • Patients present off all IS with stable renal function, normal biopsy. • Cyclosporine seems to impair development of tolerance • Has lead to research about T-Cell coreceptors

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