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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
Historical perspectives 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
A B DR
Mother 3/29 13/44 5/7
Father 2/1 8/42 4/3
Patient 3/1 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
HLA locus
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)
From Semin. Nephrol., 20:2, 2000
Stimulation of IL-2 production after T cell activation
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
Gender
Male 2549 56.1
Female 1997 43.9
Race/ethnicity
White 2261 49.7
Black 1074 23.6
Hispanic 925 20.3
Other 286 6.3
Age at initiation
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
Number Percent
From Neu, Pediatr. Nephrol., 17:2002
Characteristics of Pediatric Dialysis Patients
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
OTHER DISEASES
Diabetic glomerulonephritis 5 0.1
Sickle cell nephropathy 14 0.4
Unknown 255 6.8
Total transplants 6534 100Cadaveric 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
NAPRTCS registry 1987-1999
Number Percent
Age at transplantation
0-1 333 5.1
2-5 998 15.3
6-12 2256 34.5
13-17 2527 38.7
>18 420 6.4
Age Number Percent
Cadaveric donor Living related donor
Patient survival by age at primary transplantation
Graft survival by bi-annual cohort
Primary graft survival by age at time of transplantation
Cadaveric donor Living related donor
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
Number Percent
Causes of graft failure in primary transplant
Risk factors for chronic rejection
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
Relative risk increase p-value
Time to first rejection episode
% R
ejec
tion
Risk factors for acute rejection
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
HLA-DR mismatch
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
From McDonald, Amer. J. Transplan., 1:2001
Characteristics Living donor Cadaver donor
RR p-value RR p-value
Cadaveric donor Living related donorTime in years
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– 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
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
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
UNOS scoring system
Cadaveric donor Living related donor
% G
raft
sur
viva
l
Primary graft survival by use of induction antibody
Time in years
Cadaveric donor Living related donorTime in years
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, IL-6, IF-, TNF-) 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
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-expression which inhibits IL-2
Side effects– Renal: nephrotoxicity due to renal vasoconstriction, interstitial fibrosis, de-
novo 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 (FK-binding 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
Side Effects– Heme:– Endocrine:– NO NEPHROTOXICITY
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