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Update in Transplantation

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Presentation on theme: "Update in Transplantation"— Presentation transcript:

1 Update in Transplantation
Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

2 Update in Transplantation Summary
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 Survival after Transplant
Patient Survival 1 yr LRD 98% DD 95 Allograft Survival 1 yr LRD 95% DD 89 Allograft half-life LRD 21 years 5 yrs LRD 91 % DD 81 5 years LRD 76% DD 61 DD 13.8 years

5 Transplant survival Relative risk of death Transplanted in 1993 = 1.0
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 % Diabetic pts on list % 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 Risk of Graft Loss Higher risk Lower 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

8 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

9 Transplant Update HLA Matching Most important antigens are B and D
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

10 Waiting list management
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

11 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.

12 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.

13 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

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

15 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

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

17 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

18 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

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

20 T cell Costimulation

21

22 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

23 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)

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

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

26 Drug Dosages Prograf Rapamicin Cellcept (MMF) 0.1 – 0.2 mg/kg/day
Usually about 5 mg BID Levels 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.

27 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)

28 Kidney – Pancreas Transplant

29 Kidney – Pancreas Transplant
Cost: Kidney Txp: $ 60,000 Islet cells ,000 Panc Txp alone ,000 SPK (K-P) ,000 Each year on dialysis: $27,000

30 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.

31 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

32 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

33 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.

34 Ethnic Disparities in Transplant
Rate of transplantation 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.

35 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

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

37 Ethnic Disparities in Transplant
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

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

39 Rejection Biopsy findings

40 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

41 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?

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 Bactrim SS MWF reduces bacteriuria

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 What is Acyclovir used for after Txp?

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 Acyclovir reduces shedding of Herpes Simplex virus in urine

45 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

46 Immunology of Rejection The 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 WY ligand for PPAR

47 Immunology of Rejection The Future
Protein Tyrosine Kinases Src FAK Paxillin Akt PPARS peroxisome proliferator activated receptors Ligands for PPARs tend to decrease inflammatory response Include Piaglitizone, Lopid

48 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

49 Tolerance Inducing Mechanisms
T- Cell deletion in Thymus Thy – 1 cells lead to rejection Peripheral T- Cell deletion IL-2 dependent FAS dependent Veto Cells So immune system activation is required but apoptosis is favored over rejection Peripheral Non-deletional mechanism Anergy – loss of response to antigen Thy 2 cells – regulatory/suppressor cell

50 Tolerance in Practice Today
For high PRA and Positive Crossmatch pts: IVIG/plasmapheresis before and after TXP Leads to decrease % Anti-donor antibody After Txp, Antidonor Ab returns but does not lead to rejection Anergy Increase in Bcl - 2

51 Tolerance “Tolerogenic Immunosuppression”
Rapamicin, Tacrilimus seem to be OK Cyclosporine blocks tolerance pathway Starzl Lancet 2003 Sayegh Annals of Surgery 2003

52 Complications of Transplant
Hypertension Correlates with Age Diabetes Race Graft Function CNI use Steroids Graft Survival reduced if hypertension +

53 Complications of Transplant
Hypertension Target SBP < 130 Chronic Allograft Nephropathy Proteinuria Target BP 125 / 75 Recommended Drugs: B blockers ACE inhibitors CCB’s and diuretics as needed.

54 Complications of Transplant
New Onset Diabetes after Txp NODAT Decrease steroids if possible Consider Change from TAC to CyA. Cardiovascular Risk of a 25 y.o. recipient Equal to the risk for a 55 y.o. without renal disease. 10 fold higher at any age!

55 Complications of Transplant
Hyperlipidemia Assume CV risk is present LDL target < 100 Consider decreasing Steroids Recommend changing CyA or Rapa to TAC. Thrombin Activatable Fibrinolysis Inhibitor TAFI levels are increased in Txp and Diabetes Increase risk of DVT, Unstable Angina.

56 Complications of Transplant
Post Transplant Bone Disease Osteoporosis in % of pts BMD decreases 6-10 % per year Fractures occurrence Rate Diabetics: % Non diabetics: % Contributing Factors: Renal osteodystrophy, Immunosuppressives PTH, Age, Gender, Gonadal Status

57 Complications of Transplant
Post Transplant Bone Disease Treatment Calcium mg Daily Vit D 400 – 800 mcg daily Exercise, Tai Chi Quit smoking! Fosamax 70 mg week or 5 mg daily for 6-12 months.

58 Update in Transplantation Summary
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


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