Presentation on theme: "Update in Transplantation"— Presentation transcript:
1 Update in Transplantation Jeffrey J. Kaufhold, MD FACPNephrology AssociatesDecember 2003
2 Update in Transplantation Summary Trends in Survival after transplantExpanded Donor KidneysWaiting list Management changesTrends in IS protocolsKidney Pancreas UpdateEthnic Disparities in TransplantsImmunology and ToleranceNew approach to Complications
3 Scope of problem 300,000 dialysis patients in US 55,000 patients on waiting List17,000 recovered kidneys per year11000 from “deceased donors”6000 from living related donors1000 kidneys not used after recoveryAverage waiting time 5 years !
5 Transplant survival Relative risk of death Transplanted in 1993 = 1.0 Currently on Wait list = 1.7These 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 60Donor over 60Recipient raceBlack / HispanicLong Cold Ischemic timePrevious TxpHigh PRALower RiskLiving donorRecipient under 60Donor under 60Recipient raceAsianShort cold ischemiaHigher HLA matchLow PRA
8 Expanded Donor Kidneys Used when risk of Txp is better than life expectancy on dialysisCriteriaRecipient/donor over 60Diabetics over 40Failing access for dialysisPatient with poor Quality of Life
9 Transplant Update HLA Matching Most important antigens are B and D Main HLA groups A B C DC not important for transplant survivalHost of minor antigensMost important antigens are B and DD antigen is inducible and responsible for more serious (vascular) rejections
10 Waiting list management Point system for UNOS Wait list1 pt per year on list7 pts for 0 mismatch with B, DR antigens5 pts for 1 mm with B, DR2 pts for 2 mm with B, DR4 pts for match in pt with PRA > 80 %4 pts for Age < 11, 3 pts for age 11-18National sharing of 0 mismatch kidneys17-20 % of all transplants
11 Wait list Management Ethnic disparity in rates of transplant Due to smaller pool of B antigens in AA populationUNOS is changing point system to reflect thisEliminating 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 survivalDue 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 increasingDonor Age olderRecipient age is olderTime on waiting list is longerOlder, sicker patients are getting transplants
14 Induction Immunosuppression Biological AgentsSteroid use vs steroid sparingCellcept used in place of ImuranCalcineurin Inhibitors / Sirolimus
15 Induction Immunosuppression Biological AgentsOKT-3 rarely usedThymoglobulin (rabbit)ATG (polyclonal)Basiliximab (Simulect) ChimericAnti CD 25/ anti IL-2 receptor monoclonalDaclizumab (Zenapax) HumanizedAnti CD 25 Monoclonal
16 Induction Immunosuppression Biological AgentsExpensive, complex to useUse in high risk patients:High PRASecond transplantAfrican American recipientDelayed Graft function
17 Induction Immunosuppression Biological AgentsBasiliximab and DaclizumabAnti CD 25 monoclonalsDo not deplete lymphocytesWill not stop ongoing rejectionOther immunosuppression (CNI, steroid, MMF) should continue during useOKT-3, ATGDeplete lymphocytes, stop rejection,reduce or withhold other immunosuppression while in use
18 Induction Immunosuppression New Biological Agents coming soon:CTL4 Igstimulates CTL4 coreceptor on T cell which leads toDecreased activationApoptosis of the activated cell lineLEA 29 Ya second generation CTL4 Ig
23 Maintenance Immunosuppression Categories of Agents:SteroidsCalcineurin InhibitorsIntracellular signal modifiersCyclosporine, Tacrolimus, PrografAdjuvant AgentsInterfere with cell cyclingSirolimus, RapamicinCellcept (MMF)Imuran (azothioprine)
24 Maintenance Immunosuppression Three Drug Regimen:Steroid - prednisoneCalcineurin InhibitorCyclosporine, Tacrolimus (Prograf)Adjuvant AgentCellcept (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 BIDLevels 1-6 months:Level after 6 months: 100 – 250Imuran50 – 100 mg daily at bedtime
26 Drug Dosages Prograf Rapamicin Cellcept (MMF) 0.1 – 0.2 mg/kg/day Usually about 5 mg BIDLevels by ELISARapamicin6 mg po load then 2 mg po dailyCellcept (MMF)1000 mg BID, taper if low WBC or anemia, GI intolerance.
27 Drug Conversion for Cause Refractory Rejection: CyA -> TacCardiovasc Dz: CyA -> TacRapa -> MMFDiabetes: decrease steroid doseTac -> CyA may be helpfulHirsuitism: CyA -> TacGout: Azo -> MMFGingival Hyperplasia: CyA -> TacStop dihydropyridines (procardia XL)
29 Kidney – Pancreas Transplant Cost:Kidney Txp: $ 60,000Islet cells ,000Panc Txp alone ,000SPK (K-P) ,000Each year on dialysis: $27,000
30 Kidney – Pancreas Transplant Rejection rates improvedOptions for pancreas placement:Attach to bladderDumps lots of bicarb, CystitisEasy to identify rejection by measuring urine amylaseAttach to intestine (enteric anastomosis)Eliminates problems with acidosis and cystitisRejection harder to identify early.
31 Kidney – Pancreas Transplant Rejection Diagnosis:HyperglycemiaMay also occur in face of high steroids, sepsisIncreased serum amylase levelDecreased urine amylase level in bladder anastomosis patients.Maintenance immunosuppressionTacrolimus/Cellcept preferred comboAvoid 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 8SPK 2Gruessner, Clinical Transplantation 2002, p 52
33 Kidney – Pancreas Transplant Effect of Pancreas Txp on outcomesNo significant QOL improvement compared to kidney aloneInsulin free for diabetics 50 – 90 %Neuropathy improvesMicrovasculature improvesRetinopathy – no improvementSurvival improved compared to wait list ptsMay 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 groupsRate 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 homesLess likely to have insuranceBarriers to travelling to apptsLess likely to be available when calledNo phone or won’t answer due to debtorsHigher PRA, fewer AA donorsMistrust 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 transplantHMO rates % of eligible pts get to transplant, evenly across racesExample of Rationing by InconvenienceMilitary patients demonstrate NO disparity in rates of transplant or Graft survival.
37 Ethnic Disparities in Transplant Immunologic FactorsOnce transplanted, AA pts fare worseAA with 0 MM does about as well as Caucasian with 6 MM and 1 rejection episode in first year.Require higher doses of ImmunosuppressionDon’t tolerate steroid or other drug withdrawal nearly as well as other groupsHigher levels of IL-6, CD-80, TGF-B, Endothelin, Renin.More Hypertensive, which worsens overall survival
38 Rejection Clinical Diagnosis: Biopsy findings: Hypertension Increased CreatinineDecreased urine outputBiopsy findings:Tubulitis – usual Vasculitis - badInterstitial infiltrationFixing of C 4 d
40 Rejection and Complement Circulating Proteins in blood:#1 Albumin#2 Immunoglobulin#3 Complement, esp C 3.Triggers of Complement fixationIschemia reperfusion injury (IP - 10)Brain injury in donorDialysis after transplantInfection
41 Immunology of Rejection HLA A and B are constitutive antigensHLA D is inducible antigenInfection, ischemia induce D antigen expressionD antigen expression leads to vascular rejection which is worst typeHow does Bactrim SS MWF help?
42 Immunology of Rejection HLA A and B are constitutive antigensHLA D is inducible antigenInfection, ischemia induce D antigen expressionD antigen expression leads to vascular rejection which is worst typeBactrim SS MWF reduces bacteriuria
43 Immunology of Rejection HLA A and B are constitutive antigensHLA D is inducible antigenInfection, ischemia induce D antigen expressionD antigen expression leads to vascular rejection which is worst typeBactrim SS MWF reduces bacteriuriaWhat is Acyclovir used for after Txp?
44 Immunology of Rejection HLA A and B are constitutive antigensHLA D is inducible antigenInfection, ischemia induce D antigen expressionD antigen expression leads to vascular rejection which is worst typeBactrim SS MWF reduces bacteriuriaAcyclovir reduces shedding of Herpes Simplex virus in urine
45 Immunology of Rejection Chemoattractant Cytokines (chemokines)Leukocyte recruitmentMost important CK is CXCReceptor is CXC-R3Transmembrane proteinActivation of CXC R3 activates rejection pathwayIP-10 Activates CXC R3Both 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 modelsAlso in clinical trials: CCR-1, CCR-5 which bind CK’s and prevent activation of receptor.Soluble Complement Receptor CR-1Trypriline decreases synthesis of complementWY ligand for PPAR
47 Immunology of Rejection The Future Protein Tyrosine KinasesSrcFAKPaxillinAktPPARS peroxisome proliferator activated receptorsLigands for PPARs tend to decrease inflammatory responseInclude Piaglitizone, Lopid
48 Immunology of Rejection Tolerance is the best immunosuppressionHas been known for yearsFirst seen in pts treated with Steroids/ImuranPatients present off all IS with stable renal function, normal biopsy.Cyclosporine seems to impair development of toleranceHas lead to research about T-Cell coreceptors
49 Tolerance Inducing Mechanisms T- Cell deletion in ThymusThy – 1 cells lead to rejectionPeripheral T- Cell deletionIL-2 dependentFAS dependentVeto CellsSo immune system activation is required but apoptosis is favored over rejectionPeripheral Non-deletional mechanismAnergy – loss of response to antigenThy 2 cells – regulatory/suppressor cell
50 Tolerance in Practice Today For high PRA and Positive Crossmatch pts:IVIG/plasmapheresis before and after TXPLeads to decrease % Anti-donor antibodyAfter Txp, Antidonor Ab returns but does not lead to rejectionAnergyIncrease in Bcl - 2
51 Tolerance “Tolerogenic Immunosuppression” Rapamicin, Tacrilimus seem to be OKCyclosporine blocks tolerance pathwayStarzl Lancet 2003Sayegh Annals of Surgery 2003
52 Complications of Transplant HypertensionCorrelates with AgeDiabetesRaceGraft FunctionCNI useSteroidsGraft Survival reduced if hypertension +
53 Complications of Transplant HypertensionTarget SBP < 130Chronic Allograft NephropathyProteinuriaTarget BP 125 / 75Recommended Drugs:B blockersACE inhibitorsCCB’s and diuretics as needed.
54 Complications of Transplant New Onset Diabetes after TxpNODATDecrease steroids if possibleConsider Change from TAC to CyA.Cardiovascular Risk of a 25 y.o. recipientEqual to the risk for a 55 y.o. without renal disease.10 fold higher at any age!
55 Complications of Transplant HyperlipidemiaAssume CV risk is presentLDL target < 100Consider decreasing SteroidsRecommend changing CyA or Rapa to TAC.Thrombin Activatable Fibrinolysis InhibitorTAFI levels are increased in Txp and DiabetesIncrease risk of DVT, Unstable Angina.
56 Complications of Transplant Post Transplant Bone DiseaseOsteoporosis in % of ptsBMD decreases 6-10 % per yearFractures occurrence RateDiabetics: %Non diabetics: %Contributing Factors:Renal osteodystrophy, ImmunosuppressivesPTH, Age, Gender, Gonadal Status
57 Complications of Transplant Post Transplant Bone DiseaseTreatmentCalcium mg DailyVit D 400 – 800 mcg dailyExercise, Tai ChiQuit smoking!Fosamax 70 mg week or 5 mg daily for 6-12 months.
58 Update in Transplantation Summary Trends in Survival after transplantExpanded Donor KidneysWaiting list Management changesTrends in IS protocolsKidney Pancreas UpdateEthnic Disparities in TransplantsImmunology and ToleranceNew approach to Complications