Transcript RENAL TRANSPLANTATION IN CHILDHOOD: Something for

RENAL TRANSPLANTATION
IN CHILDHOOD
Lynne P. Yao, M.D.
INOVA Fairfax Hospital for Children
Fairfax, VA
Overview
Review basic transplantation immunology
 Review immunosuppressive agents used in children
 Review clinical renal transplantation outcomes in
children
 Review specific complications of renal transplantation
in children
 Review the role of the general pediatrician in the care
of a child with a renal transplant
 Review future directions in renal transplantation
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Historical perspectives
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1902: First experimental kidney transplantation by
Emerich Ullmann
1933: First human kidney transplant by Voronoy
1950-53: First functioning human kidney transplant
(2 centers)
1961: Azathioprine first used successfully
1962: First use of tissue matching to select a donor
1963: Prednisolone and Azathioprine combination
produced longer graft survival
1972: Successful transplantation into a 9 month-old girl
1978: First clinical use of cyclosporine A
Transplant immunology

ABO group matching
– Blood group mismatches result in hyperacute rejection in
most cases
– ABO incompatible donor protocols underway in children
Human Leukocyte Antigen (HLA) matching
 Panel Reactive Antibodies (PRA) and Crossmatching
 Rejection

– an immune response raised by the recipient against foreign
(donor) alloantigens
– allograft rejection is a coordinated event
HLA (Human Leukocyte Antigen) matching
 HLA system
is divided into 2 classes
 Class I: HLA-A, HLA-B, HLA-C
– Expressed on most cell surfaces
 Class
II: HLA-DR, HLA-DP, HLA-DQ
– Expressed predominantly on antigen presenting cells
 HLA-A,
HLA-B, HLA-DR most important in clinical
transplantation
 HLA genes located on short arm of chromosome 6
 HLA antigens are inherited in a Mendelian fashion as
codominant alleles
Example of HLA matching
HLA locus
Mother
Father
Patient
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A
3/29
2/1
3/1
B
DR
13/44
5/7
8/42
4/3
8/44
5/3
Result: Patient is a 3/6 antigen match with each parent
(haplotype match)
Haplotype matching improves graft survival because minor
(unidentified) HLA loci are also matched
Crossmatching
 Used
to detect presence of preformed HLA antibodies
against donor tissues
 Lymphocytes from donor are incubated with recipient
serum, complement added, and cell lysis is detected
 Positive crossmatch is associated with high risk for
hyperacute rejection
 Prevents development of hyperacute rejection
Panel reactive antibodies (PRA)
 PRA
– Used to assess likelihood of positive crossmatch
– Lymphocytes from a “representative” panel of donors are
incubated with serum from patient
– Expressed as a percentage of panel cells showing activity
– High PRA levels are associated with greater likelihood of
positive crossmatch
– Major risk factors for high PRA are prior blood
transfusion, pregnancy, and prior transplant
T lymphocyte activation
from Arakelov, Lakkis, Semin. Nephrol., 20:2, 2000
CD4 and CD8 interactions
CD4 and B cell interactions
Other CD4 interactions
Interactions mediated by CD40 costimulatory pathway
(from Arakelov, Lakkis, Semin. Nephrol., 20:2, 2000)
Stimulation of IL-2 production after T cell activation
From Semin. Nephrol., 20:2, 2000
The “paradigms” of transplant immunosuppression
 The
Proliferation Paradigm
– drugs that prevent immune cell proliferation prevent rejection
– Prednisone, Azathioprine, Mycophenolate Mofetil
 The
Depletion Paradigm
– drugs that decrease immune cell numbers prevent rejection
– polyclonal and monoclonal antibodies
 The
Cytokine Paradigm
– drugs that modify cytokine production prevent rejection
– Calcineurin inhibitors, Prednisone, IL-2R monoclonal
antibodies
need slide of cell cycle
Break slide
Pediatric Renal Transplantation
 NAPRTCS
(North American Pediatric Renal
Transplant Cooperative Study)
– Voluntary, collaborative effort
– 150 participating centers in US, Canada, Mexico, and Costa
Rica
– Registry for pediatric renal transplants since 1987
– Registry for ESRD since 1992
– Registry for chronic renal insufficiency since 1995
Characteristics of Pediatric Dialysis Patients
Number
Percent
Gender
Male
2549
56.1
Female
1997
43.9
White
2261
49.7
Black
1074
23.6
Hispanic
925
20.3
Other
286
6.3
0-1 years
568
12.5
2-5 years
467
10.3
6-12 years
1407
31.0
13-17 years
1739
38.3
>17 years
365
8.0
Race/ethnicity
Age at initiation
From Neu, Pediatr. Nephrol., 17:2002
DIAGNOSIS
No. of Patients
Percent
Aplastic, hypoplastic, or dysplastic
kidneys
571
15.2
Obstructive uropathy
476
12.7
Reflux nephropathy
129
3.4
Focal segmental glomerulosclerosis
526
14.0
Systemic immunological disease
282
7.5
Chronic glomerulonephritis
143
3.8
Hemolytic uremic syndrome
122
3.3
Polycystic kidney disease
114
3.0
Congenital nephrotic syndrome
Medullary cystic disease
88
79
2.3
2.1
MPGN Type II
75
2.0
MPGN Type I
38
1.0
Diabetic glomerulonephritis
5
0.1
Sickle cell nephropathy
14
0.4
Unknown
255
6.8
OTHER DISEASES
NAPRTCS registry 1987-1999
Number
Percent
Total transplants
6534
100
Cadaveric donor
3328
51
Living related donor
3206
49
Primary transplant
5436
83.2
Repeat transplant
1098
16.8
Male
3556
59.7
Female
2402
40.3
Caucasian
3747
62.9
Age at transplantation
Age
Number
Percent
0-1
333
5.1
2-5
998
15.3
6-12
2256
34.5
13-17
>18
2527
420
38.7
6.4
Cadaveric donor
Living related donor
Patient survival by age at primary transplantation
Graft survival by bi-annual cohort
Cadaveric donor
Living related donor
Primary graft survival by age at time of transplantation
Causes of graft failure in primary transplant
Number
Percent
Total
1399
100
Chronic rejection
437
31.2
Acute rejection
230
16.4
Vascular thrombosis
169
12.1
Death
141
10.1
Recurrence of disease
79
5.7
Primary nonfunction
36
2.6
Malignancy
17
1.2
Patient discontinued medication
50
3.6
Risk factors for chronic rejection
Relative risk increase
p-value
Acute rejection
1.5
0.005
> 2 rejection episodes
4.1
0.006
Late initial acute rejection
2.6
< 0.001
Prior transplant
2.4
< 0.001
African-American race
2.3
< 0.001
Cadaver donor
1.5
< 0.001
Recent transplant (after 1994)
0.66
< 0.001
Time to first rejection episode
Risk factors for acute rejection
Characteristics
Living donor
Cadaver donor
RR
p-value
RR
Recipient race
(black vs. nonblack)
1.34
0.07
1.37
0.004
Recipient age (< 24 months)
0.67
0.04
0.83
0.453
One mismatch vs. none
2.03
<0.001
0.93
0.597
Two mismatches vs. none
1.64
0.01
0.94
0.644
No induction therapy
1.42
0.001
1.31
0.001
p-value
HLA-DR mismatch
From McDonald, Amer. J. Transplan., 1:2001
Time in years
Cadaveric donor
Living related donor
Primary graft survival by race
Significant complications
 Growth
failure
 Infection
 Posttransplant lymphoproliferative disorder
(PTLD)
 Diabetes mellitus
Growth failure
 Growth
fails to improve after renal transplantation in
several studies
– Improvement in growth occurs only in the younger age
groups (age 0-5 years)
– Long term steroid therapy is implicated
– Change to alternate day dosing of prednisone has shown to
improve growth
– Growth hormone improves growth
– Growth hormone not associated with increased risk of
rejection or significant graft
– Theoretical risk of malignancy
Infectious complications
 Bacterial
– Generally more likely in early posttransplant period
 Viral
– CMV and other Herpes viruses
– CMV infections relative common and symptoms may be
severe
– CMV infection may increase risk of chronic rejection
 EBV
– Infection can produce spectrum of disease
 Varicella
– Risk significantly decreased with immunization
pretransplant
PTLD
 Malignancy
associated with polyclonal expansion
of B cells associated with rise in EBV titers
 Incidence of PTLD in pediatric renal transplants is
1.2% overall
 Incidence has increased slightly
 Increased incidence with use of tacrolimus, white
race, and cadaver donor
 Treatment generally involves reduction in
immunosuppression dose and antiviral agents
Posttransplant diabetes mellitus (PTDM)
Occurs in small number (2.6%) of pediatric renal
transplant patients
 Higher risk groups
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– African American race
– Use of tacrolimus
 No
differences based on overweight, presence of
specific HLA antigens, family history, or
prednisone dose
 Increased incidence of acute rejection in PTDM
group
Role of general pediatrician
 Growth
and development
 Surveillance for infection
 Immunizations
– Live virus vaccines can be given if prednisone dose is low
– Influenza vaccine and pneumococcal vaccine are
recommended
 Awareness
of potential drug interactions
– drugs that increase activity of CYP450 will increase
metabolism of calcineurin inhibitors
– Tegretol, Dilantin, INH, Phenobarbital, Rifampin
– drugs that compete for metabolism by CYP450 will decrease
the metabolism of calcineurin inhibitors
– Cimetidine, ketoconazole, erythromycin, diltiazem
Future directions
 Steroid
withdrawal or steroid avoidance protocols
 Designer immunosuppression
 Tolerance
 Xenotransplantation
Transplant tolerance
 A state
where the immune system does not respond
to a specific antigen: A Way to Peace
 Strategies to induce tolerance
– CD28 and CD40L blockade
– CTLA4 and FasL blockade
 Studies
in nonhuman primates are promising
 No data on long term effects, or long term graft
function
Xenotransplantation
Xenotransplantation
 The
need: 12,000 renal transplants were
performed, but 42,000 patients remained on
waiting lists
 The solution: xenotransplantation
– Major obstacles: hyperacute rejection, delayed
xenograft function, and “xenoses”
– Search for the suitable species
Last slide
Kidney allocation and distribution
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1984: US Congress passes National Organ Transplant Act
(NOTA)
NOTA provides for the establishment and operation of an Organ
Procurement and Transplantation Network (OPTN)
1986: United Network of Organ Sharing (UNOS) was awarded
the contract to develop OPTN
US is divided into regions each with a separate Organ
Procurement Organization (OPO)
Washington Regional Transplant Consortium (WRTC) is the
Washington metropolitan area OPO
Allocation of cadaveric kidneys
UNOS scoring system
Time waiting
Longest wait time for each ABO
group
1 point
Each additional year on wait list
0.5
Quality of HLA match
0 mismatch
1 B/ 1 DR mismatch
0 B/ 1 DR mismatch
2 B/ 1 DR mismatch
*
7
5
2
PRA
> 79% PRA with negative
crossmatch
4
Pediatric recipient Age
0-11 years
11-17 years
3
2
% Graft survival
Time in years
Cadaveric donor
Living related donor
Primary graft survival by use of induction antibody
Cadaveric donor
Time in years
Living related donor
Primary graft survival by number of transfusions
Prednisone
 First
immunosuppressive agent used
 Several immunosuppressive effects
– inhibit gene transcription of several cytokines ( IL-1, IL-2, IL6, IF-g, TNF-a) by binding to 5’ glucocorticoid response areas
of DNA
– produces lympholysis by direct effects on lymphocyte
membrane
– causes sequestration of circulating T cells
– antagonizes neutrophil and monocyte chemotaxis
Prednisone
 Side effects
– Cardiovascular: hypertension
– ID: infection and delayed wound healing
– GI: peptic ulcer disease, pancreatitis
– Endocrine: hyperglycemia, growth failure, obesity,
hyperlipidemia
– Ortho: osteoporosis, aseptic necrosis
– Ophtho: cataracts
– Derm: acne, hypertrichosis
– Psych: psychosis, pseudotumor cerebri
Azathioprine
 History
– Derivative of 6-MP but can be given orally
– First drug widely used for maintenance immunosuppression
 Immunosuppressive
effects
– metabolized to 6-thioinosinic acid and is incorporated into
strands of DNA and RNA and causes chromosome breaks
– 6-thioinosinic inhibits purine (adenine and guanine) synthesis
from inosine
 Side
effects
– Hematologic: bone marrow suppression, megaloblastic anemia
– Derm: alopecia
– GI: hepatic dysfunction
Mycophenolate Mofetil
 History
– semi-synthetic derivative of mycophenolic acid produced by fungus
Penicillium
– approved by the FDA in 1995 for use in rejection prophylaxis in renal
transplantation
 Immunosuppressive effects
– irreversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) that
converts IMP to GMP
– prevents de novo synthesis of GMP from IMP. GMP is essential nucleoside
for purine synthesis
– lymophcytes use de novo synthesis of purines exclusively
 Side effects
– GI: diarrhea, GI discomfort, GI bleeding (12%)
– Cardiovascular: hypertension
– Hematologic: leukopenia, thrombocytopenia
– ID: increased risk of CMV infection (10%)
– none developed PTLD
Polyclonal antibodies
 ATGAM
– Equine antilymphocyte antibody
 Thymoglobulin
– Rabbit antilymphocyte antibody
– used for induction and treatment of acute rejection
 Side
effects
– anaphylaxis: hypotension, fever, pulmonary edema,
bronchospasm, diarrhea
– PTLD
Monoclonal antibodies
 OKT3
(targets CD3 receptor on T cells)
 Anti-IL-2 receptor (IL-2R) Ab
 Anti ICAM-1 Ab
 Anti CD40 Ab
Cyclosporine A
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History
– isolated from 2 strains of fungi imperfecti
– 1200 kD, 11 amino acid hydrophobic protein

Immunosuppressive effects
– forms heterodimeric complex with a cytoplasmic receptor protein
(cyclophilin)
– This complex binds calcineurin and inhibits its phosphatase activity
– also enhances TGF-b expression which inhibits IL-2
 Side effects
– Renal: nephrotoxicity due to renal vasoconstriction, interstitial fibrosis, denovo thrombotic microangiopathy, hypomagnesemia, type IV RTA
(hyperkalemia), hyperuricemia
– Cardiovascular: hypertension
– GI: hepatotoxicity, cholestasis
– Neuro: seizures, coma, cortical blindness, tremor, dysesthesia
– Derm: hypertrichosis, gingival hyperplasia, acne
Tacrolimus
 History
– a macrolide antibiotic derived from the fungus Streptomyces tsukubaensis
– first used on liver transplant recipients in 1989
 Immunosuppressive effects
– mechanism of action similar to cyclosporine A
– forms heterodimeric complex with a cytoplasmic receptor protein (FKbinding protein)
– This complex binds calcineurin and inhibits its phosphatase activity
 Side
–
–
–
–
–
–
effects
Renal: similar nephrotoxicity profile as cyclosporine A
Endo: hyperglycemia, overt diabetes (10%)
GI: anorexia, diarrhea, nausea
Neuro: similar to cyclosporine A
Oncologic: post-transplantation lymphoproliferative disease (PTLD) (5-10%)
ID: increased incidence of CMV infection (13%)
Sirolimus
 History
– structure very similar to tacrolimus, also a macrolide antibiotic derived
from the fungus Streptomyces hydroscopicus
– also known as rapamycin, named after a fungus found on the island of
Rapa Nui (Easter Island)
 Immunosuppressive effects
– binds to FK-binding protein
– inhibits co-stimulatory path (CD28) translocation of transcription factor
– may be synergistic with cyclosporine A and tacrolimus
– no nephrotoxicity or hyperglycemia
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Side Effects
– Heme:
– Endocrine:
– NO NEPHROTOXICITY