Update in Transplantation

Transcript Update in Transplantation

Transplantation

Jeffrey J. Kaufhold, MD FACP Nephrology Associates December 2003

Transplantation Summary           Trends in Survival after transplant Donor and Recipient preparation HLA Matching Surgical Procedure Rejection diagnosis and treatment Immunosuppression Infectious complications after Transplant Other complications after Transplant Kidney Pancreas Update Immunology and Tolerance

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 !

History of Transplants

 1950’s First attempted in Twins  Still rejected due to minor antigen differences   1960’s First success  Imuran and Prednisone, ATG 1983 Cyclosporine A introduced  Dramatic improvement in graft survival  Opened the era for success in Heart, lung, liver and other arenas.

Survival after Transplant 2003  Patient Survival 1 yr   LRD DD 98% 95  5 yrs   LRD DD 91 % 81  Allograft Survival 1 yr   LRD DD 95% 89  Allograft half-life  LRD 21 years  5 years   LRD DD 76% 61  DD 13.8 years

Transplant survival

 Relative risk of death  Transplanted in 1993 = 1.0

 Transplanted in 1998 = 0.74

 Currently on Wait list = 1.7

 These are the healthy ones!

 Patients not on wait list = 2.6

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

Transplant Update

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

Donor Criteria

 Living related preferred  Living unrelated next  Deceased Donor means longer wait  Brain death required  No Infection  No malignancy (except CNS lymphoma)  Preferrably under 60 years old  Normal renal function

Recipient Preparation

 Dialysis or near Dialysis  GFR < 15 ml/min  Compliant with meds and treatment  Screen for infection, malignancy  Blood tests and colonoscopy  Screen for Heart Disease  Higher risk for dialysis pts  25 y.o. on dialysis has same risk as 55 y.o.

 Risk for dialysis pt 10 fold higher at any age.

Surgical Transplantation

 Procedure time 2 - 4 hours  Hernia incision to expose Iliac A and V, extend to expose bladder  Retroperitoneal so recovery time from surgery is minimal  Anastomose Artery and Vein  Tunnel ureter into bladder  Lich, Ledbetter

Surgical Transplantation

 The native kidneys are left intact  Unless problems with infection, HTN  Allograft is easy to palpate, biopsy  Ureter length is kept short  Where does the ureter get its blood supply?

Surgical Transplantation

     The native kidneys are left intact  Unless problems with infection, HTN Allograft is easy to palpate, biopsy Ureter length is kept short  Dual Blood supply from renal artery and from cystic artery. Ischemic ureter leads to stricture or leak.

Warm ischemia time is kept to < 45 min Cold ischemia time up to 72 hours!

Surgical Transplantation

 Typical Scenario:    Multiple organ donor identified, blood typed Organ recovery team takes abdominal organs first, heart and lungs last. (bone skin corneas may be taken after heart stops).

Organs are perfused and stored in preservative solution   Mixture of high K, antioxidants Kept cold on ice.

 Lymph Nodes, spleen used for HLA typing

Surgical Transplantation

 Cold Storage limits for organs:       Heart Lung Pancreas 6 hours 6 hours 12 hours Liver Kidney  24 hours 72 hours + Primary graft failure rate higher after 72 hrs.

Tissue  weeks to months!

Bone, skin, cornea, dura mater, etc.

Surgical Transplantation

     UNOS master list used to determine where organs sent, which pts are best match Primary patient, plus a standby are called Crossmatch takes 6 hours Standby used if CM + or primary not available A single Txp team could then do  SPK first (4-6 hours)   Liver next (8-12 hours) Kidney last (2-4 hours)

Risk of Graft Loss

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

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

Transplant Update

  HLA Matching    Main HLA groups A B C D C not important for transplant survival Host of minor antigens Most important antigens are B and D   A and B are constitutive (always expressed) D antigen is inducible and responsible for more serious (vascular) rejections when it gets expressed.

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

Transplant Costs

 Cost:     Kidney Txp: Islet cells Panc Txp alone SPK (K-P) $ 60,000 53,000 105,000 130,000   Each year on dialysis: $27,000 LOS for uncomplicated Kidney:  5-7 days

Creat

Typical Kidney Course

8 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7

Days after Transplant

8 9 10 Typical

Creat

Delayed Graft Function Course

Biologic agent used first 10-14 days

8 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7

Days after Transplant

8 9 10 Delayed

Rejection

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

Rejection Biopsy findings

Normal Cellular Rejection

Rejection

  Differential Diagnosis Not all ARF is rejection!

 Drug toxicity       Ureter complication Renal Artery Stenosis Contrast, Aminoglycoside toxicity Tubulo-interstitial Nephritis Pre or Post renal causes Recurrent disease (late)

Relative frequency Pattern of Acute Renal Failure after Transplant

45 40 35 30 25 20 15 10 5 0 1st Month 2nd to 6th 6 to 12 after 12

Month after transplant

rejection Drug tox surgical ATN Recurrent

Rejection

 4 Types:  Hyperacute (preformed antibody)  Screened for with Lymphocyte crossmatch  Immediate/on the OR table  Rare due to testing  ADCC  Antibody dependent cellular cytotoxicity  1-4 days post op  Rare occurance.

Rejection

 4 Types:  Acute  Most common  Due to Antigen presentation to an awakened immune system  Cellular or Vascular  Delayed Type or Chronic Rejection  Must be differentiated from drug nephrotoxicity

Rejection and Complement

  Circulating Proteins in blood:    #1 #2 #3 Albumin Immunoglobulin Complement, esp C 3.

Triggers of Complement fixation     Ischemia reperfusion injury (IP - 10) Brain injury in donor Dialysis after transplant Infection

Basic Immunology

 Antigen presenting cells  Macrophages  Mesangial cells  Dendritic/Kupfer cells  Reticuloendothelial system (RES)  Endothelial cells and others once injured  D antigen expression

Basic Immunology

 Cell mediated Immunity   Antigens:  Viruses, fungi, parasites, intracellular organisms T cell lymphocytes    Cytotoxic  Directly attack and kill APC, Organism usually Helper/ inducer cells   Recruit more immune cells to respond IL-1 and IL-2 Suppressor cells   Feedback to modulate immune response Important for tolerance.

Basic Immunology

 Humoral / Neutrophil system  Parallel to Cell mediated system  Antigens:  Usually bacterial cell polysaccharide  Antibodies  Produced by B lymphocytes  May be specific or nonspecific  IgG, IgM, others

Basic Immunology

 Humoral / Neutrophil system  Immune complex formation Occurs when Antigen fixed by antibody Specificity of ab for ag determines size and solubility of Immune complex formed • • • • Immune complex fixes complement Complement activation increases clearance of I-C by spleen, etc C3b chemotactic factor for PMN’s PMN’s attack with lysozyme

Basic Immunology

Cell Mediated T lymphocytes Antigen Presenting Cell Antigen plus HLA, coreceptors Humoral Fc receptor comp B cell C3b Cytotoxic Helper Suppressor Memory Pmn’s

Memory cell formation

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?

Immunology of Rejection

Induction Immunosuppression

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

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

Induction Immunosuppression

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

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

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

Regulation of T-Cell Activation

IL-2 APC CD 40 CD 80/86 CTL4 Negative stimulatory T-Cell CD 25 Positive stimulation IL -2 Receptor

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

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)

Where the drugs work

 Steroids:  Toxic to lymphocytes  Stops rejection  Inhibits release of IL-1 and IL-2  Inhibits chemotaxis

Where the drugs work

 Cyclosporin A, Tacrilimus  Neoral, Prograf  Calcineurin Inhibitors (CNI)  Multiple effects on proliferating immune cells  Inhibits m-RNA producing IL-2  Negligible effect on pre-sensitized cells  Does not stop ongoing rejection

Where the drugs work

 Imuran, Cellcept  Antimetabolite – blocks purine synthesis  Interupt cell cycling/proliferation S Phase G 2 G 1 Mitosis

Where the drugs work

 Rapamicin  Sirolimus  Calcineurin inhibitor with novel effects  Receptor is called TOR  Similar side effects to CYA and TAC  May be used in conjunction with TAC and CYA.

Maintenance Immunosuppression

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

Drug Dosages

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

Drug Dosages

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

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)

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

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

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

Tolerance

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

Complications of Transplant

        Surgical Drug Side Effects Infections Malignancies Cardiovascular Bone Disease/hypercalcemia Polycythemia When to remove the allograft

Complications of Transplant

 Surgical  Wound infection, dehiscence  Ureter stricture or leak  Bladder rupture if atrophic  Renal artery Stenosis  Renal Vein thrombosis  DVT  UTI, Pneumonia

Complications of Transplant

 Drug Side Effects         Hypertension Diabetes Hirsuitism Tremor Renal Failure TTP Anemia/marrow suppression GI side effects N/V/D

Complications of Transplant

 Infections  Pattern of infectious complications:  First 30 days  Period from 1 – 6 months  After 6 months

Complications of Transplant

 Infections  First 30 days  Surgical complications  UTI, wound, IV sites  Pre-existing infections in recipient  C-Dif, CMV, Herpes simplex  Infection carried from donor  CMV, West Nile Virus

Complications of Transplant

 Infections  Period from 1 – 6 months  Here There be Monsters  Could be anything  Need to be aggressive and thorough in approach

Complications of Transplant

 Infections  After 6 months, again divides into 3 groups:  Low risk group   Low IS load, no serious rejection or infection Will mirror general population for the most part.

  High risk group  Serious or recurrent bouts of rejection  More prone to fungal, CMV infections Chronic infection group   Need to consider withdrawal of Immunosuppression Hepatitis B, C, Difficult CMV, Virus associated Malignancy.

Complications after Transplant

 Malignancy  Due to reduced immune Surveillance, chronic virus affects  Most common is ?

Complications after Transplant

 Malignancy  Due to reduced immune Surveillance, chronic virus affects  Most common is ?

 Skin followed by  Colon  Lymphoma (Burkitt’s)  Hepatoma (Hep B)

Complications of Transplant

 Hypertension  Correlates with Age  Diabetes  Race  Graft Function  CNI use  Steroids  Graft Survival reduced if hypertension +

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.

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!

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.

Complications of Transplant

 Post Transplant Bone Disease  Osteoporosis in 40- 60 % of pts  BMD decreases 6-10 % per year  Fractures occurrence Rate  Diabetics: 40-50 %  Non diabetics: 10-15 %  Contributing Factors:  Renal osteodystrophy, Immunosuppressives  PTH, Age, Gender, Gonadal Status

Complications of Transplant

 Post Transplant Bone Disease  Treatment  Calcium 1200 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.

 Hypercalcemia also common

Complications of Transplant

 Polycythemia  Due to extra erythropoietin production  High Hct, hypertensive  Treatment  Phlebotomy  ACE inhibitor use

When to remove Allograft

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

 For refractory infection  Most commonly for terminal rejection, after graft has failed and pt is back on dialysis  FUO, FTT, may thrombose or rupture.

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

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.

Kidney – Pancreas Transplant

 Surgical Complication rate 10% at 1 yr.

 Immunologic Failure Rates:  Type of Txp PAK PTA SPK % graft loss at 1 yr.

7 % 8 2 Gruessner, Clinical Transplantation 2002, p 52

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.

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.

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

Ethnic Disparities in Transplant

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

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

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

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 WY14643 ligand for PPAR

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