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



98%
95
Allograft Survival 1 yr



LRD
DD
LRD
DD

95%
89
5 yrs



LRD
21 years
91 %
81
5 years

LRD
DD

DD 13.8 years

Allograft half-life

LRD
DD
76%
61
Transplant survival

Relative risk of death
 Transplanted
in 1993 = 1.0
 Transplanted in
1998 = 0.74
 Currently on Wait list
= 1.7
 These
 Patients
are the healthy ones!
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
 Screen
tests and colonoscopy
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
 Liver
 Kidney
 Primary
 Tissue
 Bone,
6 hours
6 hours
12 hours
24 hours
72 hours +
graft failure rate higher after 72 hrs.
weeks to months!
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


Lower Risk
Living donor
 Recipient under 60
 Donor under 60
 Recipient race

Black / Hispanic
Long Cold Ischemic
time
 Previous Txp
 High PRA






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
7
5
2
4
4

pt per year on list
pts for 0 mismatch with B, DR antigens
pts for 1 mm with B, DR
pts for 2 mm with B, DR
pts for match in pt with PRA > 80 %
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
Typical Kidney Course
Creat
8
7
6
5
Typical
4
3
2
1
0
1
2
3
4
5
6
7
Days after Transplant
8
9
10
Delayed Graft Function Course
Biologic agent used first 10-14 days
Creat
8
7
6
5
4
Delayed
3
2
1
0
1
2
3
4
5
6
7
Days after Transplant
8
9
10
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
rejection
Drug tox
surgical
ATN
Recurrent
1st
Month
2nd to
6th
6 to 12 after 12
Month after transplant
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
 Must
Type or Chronic Rejection
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
Antigen Presenting Cell
Antigen plus HLA, coreceptors
Humoral
Cell Mediated
T lymphocytes
Fc receptor
comp
Cytotoxic
Helper
Suppressor
Memory
Pmn’s
B cell
C3b
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
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
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?
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
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
to


 LEA
a
CTL4 coreceptor on T cell which leads
Decreased activation
Apoptosis of the activated cell line
29 Y
second generation CTL4 Ig
Regulation of T-Cell Activation
IL-2
APC
CD 40
CD 80/86
CD 25
CTL4
Negative stimulatory
T-Cell
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

Cyclosporine, Tacrolimus, Prograf
 Adjuvant
Agents
 Interfere



signal modifiers
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
G2
G1
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:
 Tac
decrease steroid dose
-> 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


Peripheral T- Cell deletion





Thy – 1 cells lead to rejection
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
 First
of infectious complications:
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

C-Dif, CMV, Herpes simplex
 Infection

infections in recipient
carried from donor
CMV, West Nile Virus
Complications of Transplant

Infections
 Period
 Here
from 1 – 6 months
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
B
Drugs:
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:
 Non
diabetics:
 Contributing
 Renal
40-50 %
10-15 %
Factors:
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.
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
Kidney – Pancreas Transplant
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
PAK
PTA
SPK
of Txp
% 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
 Military
of Rationing by Inconvenience
patients demonstrate NO disparity in
rates of transplant or Graft survival.
Ethnic Disparities in Transplant

Immunologic Factors
 Once
 AA
transplanted, AA pts fare worse
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