Transplantation

1
Transplantation

• Jeffrey J. Kaufhold, MD FACP
• Nephrology Associates
• December 2003

2
TransplantationSummary

• 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

3
Scope of problem

• 300,000 dialysis patients in US
• 55,000 patients on waiting List
• 17,000 recovered kidneys per year
• 11000 from deceased donors
• 6000 from living related donors
• 1000 kidneys not used after recovery
• Average waiting time 5 years !

4
History of Transplants

• 1950s First attempted in Twins
• Still rejected due to minor antigen differences
• 1960s 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.

5
Survival after Transplant2003

• Patient Survival 1 yr
• LRD 98
• DD 95
• Allograft Survival 1 yr
• LRD 95
• DD 89
• Allograft half-life
• LRD 21 years

• 5 yrs
• LRD 91
• DD 81
• 5 years
• LRD 76
• DD 61
• DD 13.8 years

6
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

7
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

8
Transplant Update

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

9
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

10
Recipient Preparation

• Dialysis or near Dialysis
• GFR lt 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.

11
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

12
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?

13
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 lt 45 min
• Cold ischemia time up to 72 hours!

14
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

15
Surgical Transplantation

• Cold Storage limits for organs
• Heart 6 hours
• Lung 6 hours
• Pancreas 12 hours
• Liver 24 hours
• Kidney 72 hours
• Primary graft failure rate higher after 72 hrs.
• Tissue weeks to months!
• Bone, skin, cornea, dura mater, etc.

16
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)

17
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

18
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

19
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.

20
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 gt 80
• 4 pts for Age lt 11, 3 pts for age 11-18
• National sharing of 0 mismatch kidneys
• 17-20 of all transplants

21
Transplant Costs

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

22
Typical Kidney Course
Creat
Days after Transplant
23
Delayed Graft Function Course
Biologic agent used first 10-14 days
Creat
Days after Transplant
24
Rejection

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

25
Rejection Biopsy findings
Cellular Rejection
Normal
26
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)

27
Pattern of Acute Renal Failureafter Transplant
Relative frequency
Month after transplant
28
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.

29
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

30
Rejection and Complement

• Circulating Proteins in blood
• 1 Albumin
• 2 Immunoglobulin
• 3 Complement, esp C 3.
• Triggers of Complement fixation
• Ischemia reperfusion injury (IP - 10)
• Brain injury in donor
• Dialysis after transplant
• Infection

31
Basic Immunology

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

32
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.

33
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

34
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 PMNs
• PMNs attack with lysozyme

35
Basic Immunology
Antigen Presenting Cell
Antigen plus HLA, coreceptors
Humoral
Cell Mediated
T lymphocytes
B cell
Fc receptor
comp
C3b
Cytotoxic Helper Suppressor Memory
Pmns
36
Memory cell formation
37
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?

38
Immunology of Rejection

• HLA A and B are constitutive antigens
• HLA D is inducible antigen
• Infection, ischemia induce D antigen expression
• D antigen expression leads to vascular rejection
  which is worst type
• Bactrim SS MWF reduces bacteriuria

39
Immunology of Rejection

• HLA A and B are constitutive antigens
• HLA D is inducible antigen
• Infection, ischemia induce D antigen expression
• D antigen expression leads to vascular rejection
  which is worst type
• Bactrim SS MWF reduces bacteriuria
• What is Acyclovir used for after Txp?

40
Immunology of Rejection

• HLA A and B are constitutive antigens
• HLA D is inducible antigen
• Infection, ischemia induce D antigen expression
• D antigen expression leads to vascular rejection
  which is worst type
• Bactrim SS MWF reduces bacteriuria
• Acyclovir reduces shedding of Herpes Simplex
  virus in urine

41
Induction Immunosuppression

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

42
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

43
Induction Immunosuppression

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

44
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

45
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

46
Regulation of T-Cell Activation
IL-2
APC
CD 40
CD 80/86
CD 25
CTL4
T-Cell
Negative stimulatory
Positive stimulation
IL -2 Receptor
47
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

48
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)

49
Where the drugs work

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

50
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

51
Where the drugs work

• Imuran, Cellcept
• Antimetabolite blocks purine synthesis
• Interupt cell cycling/proliferation

S Phase
G 2
G 1
Mitosis
52
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.

53
Maintenance Immunosuppression

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

54
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

55
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.

56
Drug Conversion for Cause

• Refractory Rejection CyA -gt Tac
• Cardiovasc Dz CyA -gt Tac
• Rapa -gt MMF
• Diabetes decrease steroid dose
• Tac -gt CyA may be helpful
• Hirsuitism CyA -gt Tac
• Gout Azo -gt MMF
• Gingival Hyperplasia CyA -gt Tac
• Stop dihydropyridines (procardia XL)

57
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

58
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

59
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

60
Tolerance

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

61
Complications of Transplant

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

62
Complications of Transplant

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

63
Complications of Transplant

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

64
Complications of Transplant

• Infections
• Pattern of infectious complications
• First 30 days
• Period from 1 6 months
• After 6 months

65
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

66
Complications of Transplant

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

67
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.

68
Complications after Transplant

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

69
Complications after Transplant

• Malignancy
• Due to reduced immune Surveillance, chronic virus
  affects
• Most common is ?
• Skin followed by
• Colon
• Lymphoma (Burkitts)
• Hepatoma (Hep B)

70
Complications of Transplant

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

71
Complications of Transplant

• Hypertension
• Target SBP lt 130
• Chronic Allograft Nephropathy
• Proteinuria
• Target BP 125 / 75
• Recommended Drugs
• B blockers
• ACE inhibitors
• CCBs and diuretics as needed.

72
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!

73
Complications of Transplant

• Hyperlipidemia
• Assume CV risk is present
• LDL target lt 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.

74
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

75
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

76
Complications of Transplant

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

77
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.

78
TransplantationSummary

• 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

79
Kidney Pancreas Transplant
80
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

81
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.

82
Kidney Pancreas Transplant

• Surgical Complication rate 10 at 1 yr.
• Immunologic Failure Rates
• Type of Txp graft loss at 1 yr.
• PAK 7
• PTA 8
• SPK 2
• Gruessner, Clinical Transplantation 2002, p 52

83
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.

84
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.

85
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 wont answer due to debtors
• Higher PRA, fewer AA donors
• Mistrust of system

86
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.

87
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
• Dont 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

88
Immunology of RejectionThe Future

• Protein Tyrosine Kinases
• Src
• FAK
• Paxillin
• Akt
• PPARS peroxisome proliferator activated
  receptors
• Ligands for PPARs tend to decrease inflammatory
  response
• Include Piaglitizone, Lopid

89
Immunology of RejectionThe Future

• Chemokine receptors
• CXC R3 antibody prolongs graft survival in monkey
  models
• Also in clinical trials CCR-1, CCR-5 which bind
  CKs and prevent activation of receptor.
• Soluble Complement Receptor CR-1
• Trypriline decreases synthesis of complement
• WY14643 ligand for PPAR

90
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