update in transplantation jeffrey j. kaufhold, md facp nephrology associates december 2003

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

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

Update in Update in TransplantationTransplantation

Jeffrey J. Kaufhold, MD FACPJeffrey J. Kaufhold, MD FACP

Nephrology AssociatesNephrology Associates

December 2003December 2003

Page 2: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Update in TransplantationUpdate in TransplantationSummarySummary

Trends in Survival after transplantTrends in Survival after transplantExpanded Donor KidneysExpanded Donor KidneysWaiting list Management changesWaiting list Management changesTrends in IS protocolsTrends in IS protocolsKidney Pancreas UpdateKidney Pancreas UpdateEthnic Disparities in TransplantsEthnic Disparities in Transplants Immunology and ToleranceImmunology and ToleranceNew approach to ComplicationsNew approach to Complications

Page 3: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Scope of problemScope of problem

300,000 dialysis patients in US300,000 dialysis patients in US 55,000 patients on waiting List55,000 patients on waiting List 17,000 recovered kidneys per year17,000 recovered kidneys per year

11000 from “deceased donors” 11000 from “deceased donors” 6000 from living related donors6000 from living related donors 1000 kidneys not used after recovery1000 kidneys not used after recovery

Average waiting time 5 years !Average waiting time 5 years !

Page 4: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Survival after TransplantSurvival after Transplant

Patient Survival 1 yr Patient Survival 1 yr LRDLRD 98%98% DDDD 9595

Allograft Survival 1 Allograft Survival 1 yryr LRDLRD 95%95% DDDD 8989

Allograft half-lifeAllograft half-life LRD LRD 21 years21 years

5 yrs5 yrs LRD LRD 91 %91 % DDDD 8181

5 years5 years LRDLRD 76%76% DDDD 6161

DD 13.8 yearsDD 13.8 years

Page 5: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Transplant survivalTransplant survival

Relative risk of deathRelative risk of deathTransplanted in Transplanted in 1993 = 1.01993 = 1.0Transplanted inTransplanted in 1998 = 0.741998 = 0.74Currently on Wait listCurrently on Wait list = 1.7= 1.7

These are the healthy ones!These are the healthy ones!Patients not on wait list = 2.6Patients not on wait list = 2.6

Page 6: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Transplant UpdateTransplant Update

Annual Death RatesAnnual Death RatesPts on listPts on list 6.3 %6.3 %Diabetic pts on list Diabetic pts on list 10.8 %10.8 %Pts not on listPts not on list 21 %21 %

Note that “death censored graft loss” Note that “death censored graft loss” is standard measure used in is standard measure used in transplant outcome reports since this transplant outcome reports since this is desired outcome.is desired outcome.

Page 7: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Risk of Graft LossRisk of Graft Loss

Higher riskHigher risk Deceased donorDeceased donor Recipient over 60Recipient over 60 Donor over 60Donor over 60 Recipient raceRecipient race

Black / HispanicBlack / Hispanic Long Cold Ischemic Long Cold Ischemic

timetime Previous TxpPrevious Txp High PRAHigh PRA

Lower RiskLower Risk Living donorLiving donor Recipient under 60Recipient under 60 Donor under 60Donor under 60 Recipient raceRecipient race

AsianAsian Short cold ischemiaShort cold ischemia Higher HLA matchHigher HLA match Low PRALow PRA

Page 8: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Expanded Donor KidneysExpanded Donor Kidneys

Used when risk of Txp is better than Used when risk of Txp is better than life expectancy on dialysislife expectancy on dialysis

CriteriaCriteriaRecipient/donor over 60Recipient/donor over 60Diabetics over 40Diabetics over 40Failing access for dialysisFailing access for dialysisPatient with poor Quality of LifePatient with poor Quality of Life

Page 9: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Transplant UpdateTransplant Update

HLA MatchingHLA MatchingMain HLA groupsMain HLA groups A B C DA B C DC not important for transplant survivalC not important for transplant survivalHost of minor antigensHost of minor antigens

Most important antigens are B and Most important antigens are B and DDD antigen is inducible and responsible D antigen is inducible and responsible

for more serious (vascular) rejectionsfor more serious (vascular) rejections

Page 10: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Waiting list managementWaiting list management

Point system for UNOS Wait listPoint system for UNOS Wait list1 pt per year on list1 pt per year on list7 pts for 0 mismatch with B, DR antigens7 pts for 0 mismatch with B, DR antigens5 pts for 1 mm with B, DR5 pts for 1 mm with B, DR2 pts for 2 mm with B, DR2 pts for 2 mm with B, DR4 pts for match in pt with PRA > 80 %4 pts for match in pt with PRA > 80 %4 pts for Age < 11, 3 pts for age 11-184 pts for Age < 11, 3 pts for age 11-18

National sharing of 0 mismatch kidneysNational sharing of 0 mismatch kidneys17-20 % of all transplants17-20 % of all transplants

Page 11: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Wait list ManagementWait list Management

Ethnic disparity in rates of transplantEthnic disparity in rates of transplantDue to smaller pool of B antigens in AA Due to smaller pool of B antigens in AA

populationpopulationUNOS is changing point system to UNOS is changing point system to

reflect thisreflect thisEliminating points for B antigen reduces Eliminating points for B antigen reduces

the ethnic disparity in points awarded.the ethnic disparity in points awarded.

Page 12: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Trends in TransplantationTrends in Transplantation

Rejection rates and Creatinine at 6 Rejection rates and Creatinine at 6 months are now surrogates for months are now surrogates for allograft survivalallograft survival

Due to improved survival, a study of Due to improved survival, a study of a new drug would need over 9000 a new drug would need over 9000 enrollees to show a difference.enrollees to show a difference.

Rejection rates are down 50 %Rejection rates are down 50 %Cardiovascular death rate improving.Cardiovascular death rate improving.

Page 13: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Trends in TransplantationTrends in Transplantation

Overall Mortality is unchanged!Overall Mortality is unchanged!Death with functioning graft increasingDeath with functioning graft increasingDonor Age olderDonor Age olderRecipient age is olderRecipient age is olderTime on waiting list is longerTime on waiting list is longer

Older, sicker patients are getting Older, sicker patients are getting transplantstransplants

Page 14: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Induction Induction ImmunosuppressionImmunosuppression

Biological AgentsBiological AgentsSteroid use vs steroid sparingSteroid use vs steroid sparingCellcept used in place of ImuranCellcept used in place of ImuranCalcineurin Inhibitors / SirolimusCalcineurin Inhibitors / Sirolimus

Page 15: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Induction Induction ImmunosuppressionImmunosuppression

Biological AgentsBiological AgentsOKT-3 rarely usedOKT-3 rarely usedThymoglobulin (rabbit) Thymoglobulin (rabbit) ATG (polyclonal)ATG (polyclonal)Basiliximab (Simulect) ChimericBasiliximab (Simulect) Chimeric

Anti CD 25/ anti IL-2 receptor monoclonalAnti CD 25/ anti IL-2 receptor monoclonal

Daclizumab (Zenapax) HumanizedDaclizumab (Zenapax) HumanizedAnti CD 25 MonoclonalAnti CD 25 Monoclonal

Page 16: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Induction Induction ImmunosuppressionImmunosuppression

Biological AgentsBiological AgentsExpensive, complex to useExpensive, complex to useUse in high risk patients:Use in high risk patients:

High PRAHigh PRASecond transplantSecond transplantAfrican American recipientAfrican American recipientDelayed Graft functionDelayed Graft function

Page 17: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Induction Induction ImmunosuppressionImmunosuppression

Biological AgentsBiological Agents Basiliximab and Daclizumab Basiliximab and Daclizumab

Anti CD 25 monoclonalsAnti CD 25 monoclonalsDo not deplete lymphocytesDo not deplete lymphocytesWill not stop ongoing rejectionWill not stop ongoing rejectionOther immunosuppression (CNI, steroid, MMF) should Other immunosuppression (CNI, steroid, MMF) should

continue during usecontinue during use

OKT-3, ATG OKT-3, ATG Deplete lymphocytes, stop rejection,Deplete lymphocytes, stop rejection, reduce or withhold other immunosuppression while reduce or withhold other immunosuppression while

in usein use

Page 18: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Induction Induction ImmunosuppressionImmunosuppression

New Biological Agents coming soon:New Biological Agents coming soon:CTL4 Ig CTL4 Ig

stimulates CTL4 coreceptor on T cell which stimulates CTL4 coreceptor on T cell which leads to leads to

Decreased activation Decreased activation Apoptosis of the activated cell lineApoptosis of the activated cell line

LEA 29 Y LEA 29 Y a second generation CTL4 Iga second generation CTL4 Ig

Page 19: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Regulation of T-Cell Regulation of T-Cell ActivationActivation

APC

T-Cell

MHC

TCR

CD 40

CTL4

Negative stimulatory

CD 80/86

CD 25

Positive stimulation

IL -2 Receptor

IL-2

Antigen

Page 20: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

T cell CostimulationT cell Costimulation

Page 21: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003
Page 22: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Induction Induction ImmunosuppressionImmunosuppression

Biological Agents recommendationsBiological Agents recommendationsLow risk patient:Low risk patient:

IL-2 receptor antibody, consider steroid IL-2 receptor antibody, consider steroid sparing regimensparing regimen

High Risk patientHigh Risk patientThymoglobulin plus 3 drug regimenThymoglobulin plus 3 drug regimen

CNI, Steroids, MMFCNI, Steroids, MMF

Page 23: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Maintenance Maintenance ImmunosuppressionImmunosuppression

Categories of Agents:Categories of Agents:SteroidsSteroidsCalcineurin InhibitorsCalcineurin Inhibitors

Intracellular signal modifiersIntracellular signal modifiersCyclosporine, Tacrolimus, PrografCyclosporine, Tacrolimus, Prograf

Adjuvant AgentsAdjuvant AgentsInterfere with cell cyclingInterfere with cell cycling

Sirolimus, RapamicinSirolimus, RapamicinCellcept (MMF)Cellcept (MMF) Imuran (azothioprine)Imuran (azothioprine)

Page 24: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Maintenance Maintenance ImmunosuppressionImmunosuppression

Three Drug Regimen:Three Drug Regimen:Steroid - prednisoneSteroid - prednisoneCalcineurin InhibitorCalcineurin Inhibitor

Cyclosporine, Tacrolimus (Prograf)Cyclosporine, Tacrolimus (Prograf)Adjuvant AgentAdjuvant Agent

Cellcept (MMF)Cellcept (MMF)

Steroid Sparing Regimen:Steroid Sparing Regimen:Prograf + MMF or RapamicinPrograf + MMF or Rapamicin

Page 25: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Drug DosagesDrug Dosages

Steroid Steroid 10 mg daily or every other day10 mg daily or every other day

CyACyA4-6 mg/Kg/day usually 100 - 150 BID4-6 mg/Kg/day usually 100 - 150 BIDLevels 1-6 months: 250 - 400Levels 1-6 months: 250 - 400Level after 6 months: 100 – 250Level after 6 months: 100 – 250

ImuranImuran50 – 100 mg daily at bedtime50 – 100 mg daily at bedtime

Page 26: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Drug DosagesDrug Dosages

PrografPrograf0.1 – 0.2 mg/kg/day0.1 – 0.2 mg/kg/dayUsually about 5 mg BIDUsually about 5 mg BIDLevels 5-15 by ELISALevels 5-15 by ELISA

RapamicinRapamicin6 mg po load then 2 mg po daily6 mg po load then 2 mg po daily

Cellcept (MMF)Cellcept (MMF)1000 mg BID, taper if low WBC or 1000 mg BID, taper if low WBC or

anemia, GI intolerance.anemia, GI intolerance.

Page 27: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Drug Conversion for CauseDrug Conversion for Cause

Refractory Rejection: CyA -> TacRefractory Rejection: CyA -> TacCardiovasc Dz: CyA -> TacCardiovasc Dz: CyA -> Tac

Rapa -> MMFRapa -> MMFDiabetes:Diabetes: decrease steroid dosedecrease steroid dose

Tac -> CyA may be helpfulTac -> CyA may be helpfulHirsuitism: CyA -> TacHirsuitism: CyA -> TacGout: Azo -> MMFGout: Azo -> MMFGingival Hyperplasia: CyA -> TacGingival Hyperplasia: CyA -> Tac

Stop dihydropyridines (procardia XL) Stop dihydropyridines (procardia XL)

Page 28: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Kidney – Pancreas TransplantKidney – Pancreas Transplant

Page 29: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Kidney – Pancreas TransplantKidney – Pancreas TransplantCost:Cost:

Kidney Txp:Kidney Txp: $ 60,000$ 60,000Islet cellsIslet cells 53,000 53,000Panc Txp alonePanc Txp alone 105,000 105,000SPK (K-P)SPK (K-P) 130,000 130,000

Each year on dialysis: Each year on dialysis: $27,000$27,000

Page 30: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Kidney – Pancreas TransplantKidney – Pancreas Transplant

Rejection rates improved Rejection rates improved Options for pancreas placement:Options for pancreas placement:

Attach to bladderAttach to bladderDumps lots of bicarb, CystitisDumps lots of bicarb, CystitisEasy to identify rejection by measuring urine Easy to identify rejection by measuring urine

amylaseamylaseAttach to intestine (enteric anastomosis)Attach to intestine (enteric anastomosis)

Eliminates problems with acidosis and Eliminates problems with acidosis and cystitiscystitis

Rejection harder to identify early.Rejection harder to identify early.

Page 31: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Kidney – Pancreas TransplantKidney – Pancreas Transplant

Rejection Diagnosis:Rejection Diagnosis:HyperglycemiaHyperglycemia

May also occur in face of high steroids, May also occur in face of high steroids, sepsissepsis

Increased serum amylase levelIncreased serum amylase levelDecreased urine amylase level in Decreased urine amylase level in

bladder anastomosis patients.bladder anastomosis patients.Maintenance immunosuppressionMaintenance immunosuppression

Tacrolimus/Cellcept preferred comboTacrolimus/Cellcept preferred comboAvoid steroids if possibleAvoid steroids if possible

Page 32: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Kidney – Pancreas TransplantKidney – Pancreas Transplant

Surgical Complication rate 10% at 1 Surgical Complication rate 10% at 1 yr.yr.

Immunologic Failure Rates:Immunologic Failure Rates:Type of TxpType of Txp % graft loss at 1 yr.% graft loss at 1 yr.

PAKPAK 7 %7 %

PTAPTA 88

SPKSPK 22

Gruessner, Clinical Transplantation 2002, p 52Gruessner, Clinical Transplantation 2002, p 52

Page 33: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Kidney – Pancreas TransplantKidney – Pancreas Transplant

Effect of Pancreas Txp on outcomesEffect of Pancreas Txp on outcomesNo significant QOL improvement compared No significant QOL improvement compared

to kidney aloneto kidney aloneInsulin free for diabetics 50 – 90 %Insulin free for diabetics 50 – 90 %Neuropathy improvesNeuropathy improvesMicrovasculature improvesMicrovasculature improvesRetinopathy – no improvementRetinopathy – no improvementSurvival improved compared to wait list ptsSurvival improved compared to wait list pts

May be slightly better than kidney alone.May be slightly better than kidney alone.

Page 34: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Ethnic Disparities in Ethnic Disparities in TransplantTransplant

Rate of transplantation lower than Rate of transplantation lower than any other ethnic groupany other ethnic group

% of AA patients hearing about the % of AA patients hearing about the option of transplant is only about option of transplant is only about 70% of other groups70% of other groups

Rate of referral once they hear about Rate of referral once they hear about transplant is only about 70% of other transplant is only about 70% of other groups.groups.

Page 35: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Ethnic Disparities in Ethnic Disparities in TransplantTransplant

Socioeconomic Factors:Socioeconomic Factors:70% of AA children born into single parent 70% of AA children born into single parent

homeshomesLess likely to have insuranceLess likely to have insuranceBarriers to travelling to apptsBarriers to travelling to apptsLess likely to be available when calledLess likely to be available when called

No phone or won’t answer due to debtorsNo phone or won’t answer due to debtorsHigher PRA, fewer AA donorsHigher PRA, fewer AA donorsMistrust of systemMistrust of system

Page 36: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Ethnic Disparities in Ethnic Disparities in TransplantTransplant

Insurance Impact on Transplant:Insurance Impact on Transplant:Compared to pts of other ethnic groups Compared to pts of other ethnic groups

with same insurance, 70-80 % of eligible with same insurance, 70-80 % of eligible AA pts get to transplantAA pts get to transplant

HMO rates 70-80 % of eligible pts get to HMO rates 70-80 % of eligible pts get to transplant, evenly across racestransplant, evenly across racesExample of Rationing by InconvenienceExample of Rationing by Inconvenience

Military patients demonstrate NO Military patients demonstrate NO disparity in rates of transplant or Graft disparity in rates of transplant or Graft survival.survival.

Page 37: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Ethnic Disparities in Ethnic Disparities in TransplantTransplant

Immunologic FactorsImmunologic FactorsOnce transplanted, AA pts fare worseOnce transplanted, AA pts fare worse

AA with 0 MM does about as well as Caucasian AA with 0 MM does about as well as Caucasian with 6 MM and 1 rejection episode in first year.with 6 MM and 1 rejection episode in first year.

Require higher doses of ImmunosuppressionRequire higher doses of ImmunosuppressionDon’t tolerate steroid or other drug withdrawal Don’t tolerate steroid or other drug withdrawal

nearly as well as other groupsnearly as well as other groupsHigher levels of IL-6, CD-80, TGF-B, Endothelin, Higher levels of IL-6, CD-80, TGF-B, Endothelin,

Renin.Renin.More Hypertensive, which worsens overall More Hypertensive, which worsens overall

survivalsurvival

Page 38: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

RejectionRejection

Clinical Diagnosis:Clinical Diagnosis:HypertensionHypertensionIncreased CreatinineIncreased CreatinineDecreased urine outputDecreased urine output

Biopsy findings:Biopsy findings:Tubulitis – usual Vasculitis - badTubulitis – usual Vasculitis - badInterstitial infiltrationInterstitial infiltrationFixing of C 4 dFixing of C 4 d

Page 39: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Rejection Biopsy findingsRejection Biopsy findings

Page 40: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Rejection and ComplementRejection and Complement

Circulating Proteins in blood:Circulating Proteins in blood:#1#1 AlbuminAlbumin#2#2 ImmunoglobulinImmunoglobulin#3#3 Complement, esp C 3.Complement, esp C 3.

Triggers of Complement fixationTriggers of Complement fixationIschemia reperfusion injury (IP - 10)Ischemia reperfusion injury (IP - 10)Brain injury in donorBrain injury in donorDialysis after transplantDialysis after transplantInfectionInfection

Page 41: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Immunology of RejectionImmunology of Rejection

HLA A and B are constitutive HLA A and B are constitutive antigensantigens

HLA D is inducible antigen HLA D is inducible antigen Infection, ischemia induce D antigen Infection, ischemia induce D antigen

expressionexpressionD antigen expression leads to vascular D antigen expression leads to vascular

rejection which is worst typerejection which is worst typeHow does Bactrim SS MWF help? How does Bactrim SS MWF help?

Page 42: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Immunology of RejectionImmunology of Rejection

HLA A and B are constitutive HLA A and B are constitutive antigensantigens

HLA D is inducible antigen HLA D is inducible antigen Infection, ischemia induce D antigen Infection, ischemia induce D antigen

expressionexpressionD antigen expression leads to vascular D antigen expression leads to vascular

rejection which is worst typerejection which is worst typeBactrim SS MWF reduces bacteriuria Bactrim SS MWF reduces bacteriuria

Page 43: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Immunology of RejectionImmunology of Rejection

HLA A and B are constitutive HLA A and B are constitutive antigensantigens

HLA D is inducible antigen HLA D is inducible antigen Infection, ischemia induce D antigen Infection, ischemia induce D antigen

expressionexpressionD antigen expression leads to vascular D antigen expression leads to vascular

rejection which is worst typerejection which is worst typeBactrim SS MWF reduces bacteriuria Bactrim SS MWF reduces bacteriuria What is Acyclovir used for after Txp?What is Acyclovir used for after Txp?

Page 44: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Immunology of RejectionImmunology of Rejection

HLA A and B are constitutive antigensHLA A and B are constitutive antigensHLA D is inducible antigen HLA D is inducible antigen

Infection, ischemia induce D antigen Infection, ischemia induce D antigen expressionexpression

D antigen expression leads to vascular D antigen expression leads to vascular rejection which is worst typerejection which is worst type

Bactrim SS MWF reduces bacteriuria Bactrim SS MWF reduces bacteriuria Acyclovir reduces shedding of Herpes Acyclovir reduces shedding of Herpes

Simplex virus in urineSimplex virus in urine

Page 45: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Immunology of RejectionImmunology of Rejection

Chemoattractant Cytokines Chemoattractant Cytokines (chemokines)(chemokines)Leukocyte recruitmentLeukocyte recruitmentMost important CK is CXCMost important CK is CXCReceptor is CXC-R3Receptor is CXC-R3

Transmembrane proteinTransmembrane proteinActivation of CXC R3 activates rejection pathwayActivation of CXC R3 activates rejection pathwayIP-10 Activates CXC R3IP-10 Activates CXC R3Both CXC R3 and IP-10 are present in urine of pts Both CXC R3 and IP-10 are present in urine of pts

who are rejectingwho are rejecting

Page 46: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Immunology of RejectionImmunology of RejectionThe FutureThe Future

Chemokine receptors:Chemokine receptors:CXC R3 antibody prolongs graft survival CXC R3 antibody prolongs graft survival

in monkey modelsin monkey modelsAlso in clinical trials: CCR-1, CCR-5 Also in clinical trials: CCR-1, CCR-5

which bind CK’s and prevent activation which bind CK’s and prevent activation of receptor.of receptor.

Soluble Complement Receptor CR-1Soluble Complement Receptor CR-1Trypriline decreases synthesis of Trypriline decreases synthesis of

complementcomplementWY14643 ligand for PPAR WY14643 ligand for PPAR

Page 47: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Immunology of RejectionImmunology of RejectionThe FutureThe Future

Protein Tyrosine KinasesProtein Tyrosine Kinases SrcSrc FAKFAK PaxillinPaxillin AktAkt

PPARS peroxisome proliferator activated PPARS peroxisome proliferator activated receptorsreceptors Ligands for PPARs tend to decrease Ligands for PPARs tend to decrease

inflammatory responseinflammatory response Include Piaglitizone, LopidInclude Piaglitizone, Lopid

Page 48: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Immunology of RejectionImmunology of Rejection

Tolerance is the best immunosuppressionTolerance is the best immunosuppressionHas been known for yearsHas been known for yearsFirst seen in pts treated with Steroids/ImuranFirst seen in pts treated with Steroids/ImuranPatients present off all IS with stable renal Patients present off all IS with stable renal

function, normal biopsy.function, normal biopsy.Cyclosporine seems to impair development of Cyclosporine seems to impair development of

tolerancetoleranceHas lead to research about T-Cell coreceptorsHas lead to research about T-Cell coreceptors

Page 49: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Tolerance Inducing Tolerance Inducing MechanismsMechanisms

T- Cell deletion in ThymusT- Cell deletion in ThymusThy – 1 cells lead to rejectionThy – 1 cells lead to rejection

Peripheral T- Cell deletionPeripheral T- Cell deletion IL-2 dependentIL-2 dependentFAS dependentFAS dependentVeto CellsVeto CellsSo immune system activation is required but So immune system activation is required but

apoptosis is favored over rejectionapoptosis is favored over rejection

Peripheral Non-deletional mechanismPeripheral Non-deletional mechanismAnergy – loss of response to antigenAnergy – loss of response to antigenThy 2 cells – regulatory/suppressor cellThy 2 cells – regulatory/suppressor cell

Page 50: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Tolerance in Practice TodayTolerance in Practice Today

For high PRA and Positive Crossmatch For high PRA and Positive Crossmatch pts:pts:IVIG/plasmapheresis before and after TXPIVIG/plasmapheresis before and after TXPLeads to decrease % Anti-donor antibodyLeads to decrease % Anti-donor antibodyAfter Txp, Antidonor Ab returns but does After Txp, Antidonor Ab returns but does

not lead to rejection not lead to rejection AnergyAnergyIncrease in Bcl - 2Increase in Bcl - 2

Page 51: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

ToleranceTolerance

““Tolerogenic Immunosuppression”Tolerogenic Immunosuppression”Rapamicin, Tacrilimus seem to be OKRapamicin, Tacrilimus seem to be OKCyclosporine blocks tolerance pathwayCyclosporine blocks tolerance pathway

Starzl Lancet 2003Starzl Lancet 2003Sayegh Annals of Surgery 2003Sayegh Annals of Surgery 2003

Page 52: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Complications of TransplantComplications of Transplant

HypertensionHypertensionCorrelates with AgeCorrelates with AgeDiabetesDiabetesRaceRaceGraft FunctionGraft FunctionCNI useCNI useSteroidsSteroids

Graft Survival reduced if hypertension Graft Survival reduced if hypertension ++

Page 53: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Complications of TransplantComplications of Transplant

HypertensionHypertensionTarget SBP < 130Target SBP < 130Chronic Allograft NephropathyChronic Allograft Nephropathy

ProteinuriaProteinuriaTarget BP 125 / 75Target BP 125 / 75

Recommended Drugs:Recommended Drugs:B blockersB blockersACE inhibitorsACE inhibitorsCCB’s and diuretics as needed.CCB’s and diuretics as needed.

Page 54: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Complications of TransplantComplications of Transplant

New Onset Diabetes after Txp New Onset Diabetes after Txp NODATNODATDecrease steroids if possibleDecrease steroids if possibleConsider Change from TAC to CyA.Consider Change from TAC to CyA.

Cardiovascular Risk of a 25 y.o. Cardiovascular Risk of a 25 y.o. recipientrecipientEqual to the risk for a 55 y.o. without Equal to the risk for a 55 y.o. without

renal disease.renal disease.10 fold higher at any age!10 fold higher at any age!

Page 55: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Complications of TransplantComplications of Transplant

HyperlipidemiaHyperlipidemiaAssume CV risk is presentAssume CV risk is presentLDL target < 100LDL target < 100Consider decreasing SteroidsConsider decreasing SteroidsRecommend changing CyA or Rapa to TAC.Recommend changing CyA or Rapa to TAC.

Thrombin Activatable Fibrinolysis Thrombin Activatable Fibrinolysis InhibitorInhibitorTAFI levels are increased in Txp and DiabetesTAFI levels are increased in Txp and DiabetesIncrease risk of DVT, Unstable Angina.Increase risk of DVT, Unstable Angina.

Page 56: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Complications of TransplantComplications of Transplant

Post Transplant Bone DiseasePost Transplant Bone DiseaseOsteoporosis in 40- 60 % of ptsOsteoporosis in 40- 60 % of ptsBMD decreases 6-10 % per yearBMD decreases 6-10 % per yearFractures occurrence RateFractures occurrence Rate

Diabetics:Diabetics: 40-50 %40-50 %Non diabetics:Non diabetics: 10-15 %10-15 %

Contributing Factors:Contributing Factors:Renal osteodystrophy, ImmunosuppressivesRenal osteodystrophy, ImmunosuppressivesPTH, Age, Gender, Gonadal StatusPTH, Age, Gender, Gonadal Status

Page 57: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Complications of TransplantComplications of Transplant

Post Transplant Bone DiseasePost Transplant Bone DiseaseTreatmentTreatment

Calcium 1200 mg DailyCalcium 1200 mg DailyVit D 400 – 800 mcg dailyVit D 400 – 800 mcg dailyExercise, Tai ChiExercise, Tai ChiQuit smoking!Quit smoking!Fosamax 70 mg week or 5 mg daily for 6-12 Fosamax 70 mg week or 5 mg daily for 6-12

months.months.

Page 58: Update in Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Update in TransplantationUpdate in TransplantationSummarySummary

Trends in Survival after transplantTrends in Survival after transplantExpanded Donor KidneysExpanded Donor KidneysWaiting list Management changesWaiting list Management changesTrends in IS protocolsTrends in IS protocolsKidney Pancreas UpdateKidney Pancreas UpdateEthnic Disparities in TransplantsEthnic Disparities in Transplants Immunology and ToleranceImmunology and ToleranceNew approach to ComplicationsNew approach to Complications