transplantation

TransplantationTransplantation

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

Nephrology AssociatesNephrology Associates

December 2003December 2003

TransplantationTransplantationSummarySummary

Trends in Survival after transplantTrends in Survival after transplant Donor and Recipient preparationDonor and Recipient preparation HLA MatchingHLA Matching Surgical ProcedureSurgical Procedure Rejection diagnosis and treatmentRejection diagnosis and treatment Immunosuppression Immunosuppression Infectious complications after TransplantInfectious complications after Transplant Other complications after TransplantOther complications after Transplant Kidney Pancreas UpdateKidney Pancreas Update Immunology and ToleranceImmunology and Tolerance

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 !

History of TransplantsHistory of Transplants

1950’s First attempted in Twins1950’s First attempted in TwinsStill rejected due to minor antigen Still rejected due to minor antigen

differencesdifferences1960’s First success 1960’s First success

Imuran and Prednisone, ATGImuran and Prednisone, ATG1983 Cyclosporine A introduced1983 Cyclosporine A introduced

Dramatic improvement in graft survivalDramatic improvement in graft survivalOpened the era for success in Heart, Opened the era for success in Heart,

lung, liver and other arenas.lung, liver and other arenas.

Survival after TransplantSurvival after Transplant20032003

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

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

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

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.

Donor CriteriaDonor Criteria

Living related preferredLiving related preferredLiving unrelated next Living unrelated next Deceased Donor means longer waitDeceased Donor means longer wait

Brain death requiredBrain death requiredNo InfectionNo InfectionNo malignancy (except CNS lymphoma)No malignancy (except CNS lymphoma)Preferrably under 60 years oldPreferrably under 60 years oldNormal renal function Normal renal function

Recipient PreparationRecipient Preparation

Dialysis or near DialysisDialysis or near DialysisGFR < 15 ml/minGFR < 15 ml/minCompliant with meds and treatmentCompliant with meds and treatmentScreen for infection, malignancyScreen for infection, malignancy

Blood tests and colonoscopyBlood tests and colonoscopyScreen for Heart DiseaseScreen for Heart Disease

Higher risk for dialysis ptsHigher risk for dialysis pts25 y.o. on dialysis has same risk as 55 y.o.25 y.o. on dialysis has same risk as 55 y.o.Risk for dialysis pt 10 fold higher at any age.Risk for dialysis pt 10 fold higher at any age.

Surgical TransplantationSurgical Transplantation

Procedure time 2 - 4 hoursProcedure time 2 - 4 hoursHernia incision to expose Iliac A and Hernia incision to expose Iliac A and

V, extend to expose bladderV, extend to expose bladderRetroperitoneal so recovery time Retroperitoneal so recovery time

from surgery is minimalfrom surgery is minimalAnastomose Artery and VeinAnastomose Artery and VeinTunnel ureter into bladderTunnel ureter into bladder

Lich, LedbetterLich, Ledbetter


The native kidneys are left intactThe native kidneys are left intactUnless problems with infection, HTNUnless problems with infection, HTN

Allograft is easy to palpate, biopsyAllograft is easy to palpate, biopsyUreter length is kept shortUreter length is kept short

Where does the ureter get its blood Where does the ureter get its blood supply?supply?


The native kidneys are left intactThe native kidneys are left intactUnless problems with infection, HTNUnless problems with infection, HTN

Allograft is easy to palpate, biopsyAllograft is easy to palpate, biopsyUreter length is kept shortUreter length is kept short

Dual Blood supply from renal artery and Dual Blood supply from renal artery and from cystic artery. Ischemic ureter leads from cystic artery. Ischemic ureter leads to stricture or leak.to stricture or leak.

Warm ischemia time is kept to < 45 Warm ischemia time is kept to < 45 minmin

Cold ischemia time up to 72 hours! Cold ischemia time up to 72 hours!


Typical Scenario:Typical Scenario:Multiple organ donor identified, blood typedMultiple organ donor identified, blood typedOrgan recovery team takes abdominal Organ recovery team takes abdominal

organs first, heart and lungs last. (bone organs first, heart and lungs last. (bone skin corneas may be taken after heart skin corneas may be taken after heart stops).stops).

Organs are perfused and stored in Organs are perfused and stored in preservative solutionpreservative solutionMixture of high K, antioxidantsMixture of high K, antioxidantsKept cold on ice.Kept cold on ice.

Lymph Nodes, spleen used for HLA typingLymph Nodes, spleen used for HLA typing


Cold Storage limits for organs:Cold Storage limits for organs:Heart Heart 6 hours6 hoursLungLung 6 hours6 hoursPancreas Pancreas 12 hours12 hoursLiver Liver 24 hours24 hoursKidneyKidney 72 hours +72 hours +

Primary graft failure rate higher after 72 hrs.Primary graft failure rate higher after 72 hrs.Tissue Tissue weeks to months!weeks to months!

Bone, skin, cornea, dura mater, etc.Bone, skin, cornea, dura mater, etc.


UNOS master list used to determine where UNOS master list used to determine where organs sent, which pts are best matchorgans sent, which pts are best match

Primary patient, plus a standby are calledPrimary patient, plus a standby are called Crossmatch takes 6 hoursCrossmatch takes 6 hours Standby used if CM + or primary not Standby used if CM + or primary not

availableavailable A single Txp team could then doA single Txp team could then do

SPK first (4-6 hours)SPK first (4-6 hours) Liver next (8-12 hours)Liver next (8-12 hours) Kidney last (2-4 hours)Kidney last (2-4 hours)

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

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

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 DMost important antigens are B and DA and B are constitutive (always A and B are constitutive (always

expressed)expressed)D antigen is inducible and responsible for D antigen is inducible and responsible for

more serious (vascular) rejections when more serious (vascular) rejections when it gets expressed.it gets expressed.

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

Transplant CostsTransplant CostsCost: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

LOS for uncomplicated Kidney:LOS for uncomplicated Kidney:5-7 days5-7 days

Typical Kidney CourseTypical Kidney Course

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7 8 9 10

Typical

Creat

Days after Transplant

Delayed Graft Function Delayed Graft Function CourseCourse

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7 8 9 10

Delayed

Creat

Days after Transplant

Biologic agent used first 10-14 days

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

Rejection Biopsy findingsRejection Biopsy findingsNormal Cellular Rejection

RejectionRejection

Differential DiagnosisDifferential DiagnosisNot all ARF is rejection!Not all ARF is rejection!

Drug toxicityDrug toxicityUreter complicationUreter complicationRenal Artery StenosisRenal Artery StenosisContrast, Aminoglycoside toxicityContrast, Aminoglycoside toxicityTubulo-interstitial NephritisTubulo-interstitial NephritisPre or Post renal causesPre or Post renal causesRecurrent disease (late)Recurrent disease (late)

Pattern of Acute Renal FailurePattern of Acute Renal Failureafter Transplantafter Transplant

05

1015202530354045

1stMonth

2nd to6th

6 to 12 after 12

rejectionDrug toxsurgicalATNRecurrent

Relativefrequency

Month after transplant

RejectionRejection

4 Types:4 Types:Hyperacute (preformed antibody)Hyperacute (preformed antibody)

Screened for with Lymphocyte crossmatchScreened for with Lymphocyte crossmatchImmediate/on the OR tableImmediate/on the OR tableRare due to testingRare due to testing

ADCCADCCAntibody dependent cellular cytotoxicityAntibody dependent cellular cytotoxicity1-4 days post op1-4 days post opRare occurance.Rare occurance.

RejectionRejection

4 Types:4 Types:AcuteAcute

Most commonMost commonDue to Antigen presentation to an awakened Due to Antigen presentation to an awakened

immune systemimmune systemCellular or VascularCellular or Vascular

Delayed Type or Chronic RejectionDelayed Type or Chronic RejectionMust be differentiated from drug Must be differentiated from drug

nephrotoxicitynephrotoxicity

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

Basic ImmunologyBasic Immunology

Antigen presenting cellsAntigen presenting cellsMacrophagesMacrophagesMesangial cellsMesangial cellsDendritic/Kupfer cellsDendritic/Kupfer cellsReticuloendothelial system (RES)Reticuloendothelial system (RES)Endothelial cells and others once injuredEndothelial cells and others once injured

D antigen expressionD antigen expression


Cell mediated ImmunityCell mediated Immunity Antigens:Antigens:

Viruses, fungi, parasites, intracellular organismsViruses, fungi, parasites, intracellular organisms T cell lymphocytesT cell lymphocytes

CytotoxicCytotoxic Directly attack and kill APC, Organism usuallyDirectly attack and kill APC, Organism usually

Helper/ inducer cells Helper/ inducer cells Recruit more immune cells to respondRecruit more immune cells to respond IL-1 and IL-2IL-1 and IL-2

Suppressor cellsSuppressor cells Feedback to modulate immune responseFeedback to modulate immune response Important for tolerance.Important for tolerance.


Humoral / Neutrophil systemHumoral / Neutrophil systemParallel to Cell mediated systemParallel to Cell mediated systemAntigens:Antigens:

Usually bacterial cell polysaccharideUsually bacterial cell polysaccharideAntibodiesAntibodies

Produced by B lymphocytesProduced by B lymphocytesMay be specific or nonspecificMay be specific or nonspecificIgG, IgM, othersIgG, IgM, others


Humoral / Neutrophil systemHumoral / Neutrophil systemImmune complex formationImmune complex formation

Occurs when Antigen fixed by antibodyOccurs when Antigen fixed by antibodySpecificity of ab for ag determines size and Specificity of ab for ag determines size and

solubility of Immune complex formedsolubility of Immune complex formed• Immune complex fixes complementImmune complex fixes complement• Complement activation increases Complement activation increases

clearance of I-C by spleen, etcclearance of I-C by spleen, etc• C3b chemotactic factor for PMN’sC3b chemotactic factor for PMN’s• PMN’s attack with lysozymePMN’s attack with lysozyme

Basic ImmunologyBasic ImmunologyAntigen Presenting Cell

Antigen plus HLA, coreceptors

Cell Mediated Humoral

Cytotoxic Helper Suppressor Memory

B cellFc receptor

comp C3b

Pmn’s

T lymphocytes

Memory cell formationMemory cell formation

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?





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





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?


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

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


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


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


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


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

Regulation of T-Cell Regulation of T-Cell ActivationActivation

APC

T-Cell

CD 40

CTL4

Negative stimulatory

CD 80/86

CD 25

Positive stimulation

IL -2 Receptor

IL-2


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

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)

Where the drugs workWhere the drugs work

Steroids:Steroids:Toxic to lymphocytesToxic to lymphocytesStops rejectionStops rejectionInhibits release of IL-1 and IL-2Inhibits release of IL-1 and IL-2Inhibits chemotaxisInhibits chemotaxis


Cyclosporin A, TacrilimusCyclosporin A, TacrilimusNeoral, PrografNeoral, PrografCalcineurin Inhibitors (CNI)Calcineurin Inhibitors (CNI)Multiple effects on proliferating immune Multiple effects on proliferating immune

cellscellsInhibits m-RNA producing IL-2Inhibits m-RNA producing IL-2Negligible effect on pre-sensitized cellsNegligible effect on pre-sensitized cellsDoes not stop ongoing rejectionDoes not stop ongoing rejection


Imuran, CellceptImuran, CellceptAntimetabolite – blocks purine synthesisAntimetabolite – blocks purine synthesisInterupt cell cycling/proliferationInterupt cell cycling/proliferation

G 1

S Phase

G 2

Mitosis


RapamicinRapamicinSirolimusSirolimus

Calcineurin inhibitor with novel effectsCalcineurin inhibitor with novel effectsReceptor is called TORReceptor is called TORSimilar side effects to CYA and TACSimilar side effects to CYA and TACMay be used in conjunction with TAC and May be used in conjunction with TAC and

CYA.CYA.

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

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

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.

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)


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

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

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

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

Complications of TransplantComplications of Transplant

SurgicalSurgicalDrug Side EffectsDrug Side Effects InfectionsInfectionsMalignanciesMalignanciesCardiovascularCardiovascularBone Disease/hypercalcemiaBone Disease/hypercalcemiaPolycythemia Polycythemia When to remove the allograftWhen to remove the allograft


SurgicalSurgicalWound infection, dehiscenceWound infection, dehiscenceUreter stricture or leakUreter stricture or leakBladder rupture if atrophicBladder rupture if atrophicRenal artery StenosisRenal artery StenosisRenal Vein thrombosisRenal Vein thrombosisDVTDVTUTI, PneumoniaUTI, Pneumonia


Drug Side EffectsDrug Side EffectsHypertensionHypertensionDiabetesDiabetesHirsuitismHirsuitismTremorTremorRenal FailureRenal FailureTTPTTPAnemia/marrow suppressionAnemia/marrow suppressionGI side effects N/V/DGI side effects N/V/D


InfectionsInfectionsPattern of infectious complications:Pattern of infectious complications:

First 30 daysFirst 30 daysPeriod from 1 – 6 monthsPeriod from 1 – 6 monthsAfter 6 monthsAfter 6 months


InfectionsInfectionsFirst 30 daysFirst 30 days

Surgical complicationsSurgical complicationsUTI, wound, IV sitesUTI, wound, IV sites

Pre-existing infections in recipientPre-existing infections in recipientC-Dif, CMV, Herpes simplexC-Dif, CMV, Herpes simplex

Infection carried from donorInfection carried from donorCMV, West Nile VirusCMV, West Nile Virus


InfectionsInfectionsPeriod from 1 – 6 monthsPeriod from 1 – 6 months

Here There be MonstersHere There be MonstersCould be anythingCould be anythingNeed to be aggressive and thorough in Need to be aggressive and thorough in

approachapproach


InfectionsInfectionsAfter 6 months, again divides into 3 After 6 months, again divides into 3

groups:groups:Low risk groupLow risk group

Low IS load, no serious rejection or infectionLow IS load, no serious rejection or infection Will mirror general population for the most part.Will mirror general population for the most part.

High risk groupHigh risk group Serious or recurrent bouts of rejectionSerious or recurrent bouts of rejection More prone to fungal, CMV infectionsMore prone to fungal, CMV infections

Chronic infection groupChronic infection group Need to consider withdrawal of ImmunosuppressionNeed to consider withdrawal of Immunosuppression Hepatitis B, C, Difficult CMV, Virus associated Hepatitis B, C, Difficult CMV, Virus associated

Malignancy.Malignancy.

Complications after Complications after TransplantTransplant

MalignancyMalignancyDue to reduced immune Surveillance, Due to reduced immune Surveillance,

chronic virus affectschronic virus affectsMost common is ?Most common is ?

Complications after Complications after TransplantTransplant

MalignancyMalignancyDue to reduced immune Surveillance, Due to reduced immune Surveillance,

chronic virus affectschronic virus affectsMost common is ?Most common is ?

SkinSkin followed byfollowed byColonColonLymphoma (Burkitt’s)Lymphoma (Burkitt’s)Hepatoma (Hep B)Hepatoma (Hep B)


HypertensionHypertensionCorrelates with AgeCorrelates with AgeDiabetesDiabetesRaceRaceGraft FunctionGraft FunctionCNI useCNI useSteroidsSteroids

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


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.


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!


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.


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


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.

Hypercalcemia also commonHypercalcemia also common


PolycythemiaPolycythemiaDue to extra erythropoietin productionDue to extra erythropoietin productionHigh Hct, hypertensiveHigh Hct, hypertensiveTreatmentTreatment

PhlebotomyPhlebotomyACE inhibitor useACE inhibitor use

When to remove AllograftWhen to remove Allograft

Allograft Nephrectomy is indicated:Allograft Nephrectomy is indicated:Unusual – some pts have more than one Unusual – some pts have more than one

allograft!allograft!For refractory infectionFor refractory infectionMost commonly for terminal rejection, Most commonly for terminal rejection,

after graft has failed and pt is back on after graft has failed and pt is back on dialysisdialysisFUO, FTT, may thrombose or rupture.FUO, FTT, may thrombose or rupture.

TransplantationTransplantationSummarySummary

Trends in Survival after transplantTrends in Survival after transplant Donor and Recipient preparationDonor and Recipient preparation HLA MatchingHLA Matching Surgical ProcedureSurgical Procedure Rejection diagnosis and treatmentRejection diagnosis and treatment Immunosuppression Immunosuppression Infectious complications after TransplantInfectious complications after Transplant Other complications after TransplantOther complications after Transplant Kidney Pancreas UpdateKidney Pancreas Update Immunology and ToleranceImmunology and Tolerance

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


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.


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


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.

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.


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


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.


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

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

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


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

transplantation

Documents

dialysis patients

recovery time

wait list

allograft survival

heart diseasehigher

mincold ischemia time

warm ischemia time

recovered kidneys