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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 DRMother 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
10.34672-5 years
8.0365>17 years
38.3173913-17 years
31.014076-12 years
12.55680-1 years
Age at initiation
6.3286Other
20.3925Hispanic
23.61074Black
49.72261White
Race/ethnicity
43.91997Female
56.12549Male
Gender
Number Percent
From Neu, Pediatr. Nephrol., 17:2002
Characteristics of Pediatric Dialysis Patients
6.8 255 Unknown
0.4 14Sickle cell nephropathy
0.1 5Diabetic glomerulonephritis
OTHER DISEASES
1.0 38MPGN Type I
2.0 75MPGN Type II
2.3
2.1
88
79
Congenital nephrotic syndrome
Medullary cystic disease
3.0114Polycystic kidney disease
3.3122Hemolytic uremic syndrome
3.8143Chronic glomerulonephritis
7.5282Systemic immunological disease
14.0526Focal segmental glomerulosclerosis
3.4129Reflux nephropathy
12.7476Obstructive uropathy
15.2571Aplastic, hypoplastic, or dysplastic kidneys
PercentNo. of PatientsDIAGNOSIS
62.93747Caucasian
40.32402Female
59.73556Male
16.8
83.2
49
51
100
1098Repeat transplant
5436Primary transplant
3206Living related donor
3328Cadaveric donor
6534Total transplants
NAPRTCS registry 1987-1999
Number Percent
Age at transplantation
6.4 420>18
38.7252713-17
34.522566-12
15.3 9982-5
5.1 3330-1
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
1001399Total
16.4230Acute rejection
3.6 50Patient discontinued medication
1.2 17Malignancy
2.6 36Primary nonfunction
5.7 79Recurrence of disease
10.1141Death
12.1169Vascular thrombosis
31.2437Chronic rejection
Number Percent
Causes of graft failure in primary transplant
Risk factors for chronic rejection
< 0.0010.66Recent transplant (after 1994)
< 0.0011.5Cadaver donor
< 0.0012.3African-American race
< 0.0012.4Prior transplant
< 0.0012.6Late initial acute rejection
0.0064.1> 2 rejection episodes
0.0051.5Acute rejection
Relative risk increase p-value
Time to first rejection episode
% R
ejec
tion
Risk factors for acute rejection
0.0011.310.0011.42No induction therapy
0.6440.940.011.64Two mismatches vs. none
0.5970.93<0.0012.03One mismatch vs. none
HLA-DR mismatch
0.4530.830.040.67Recipient age (< 24 months)
0.0041.370.071.34Recipient race
(black vs. nonblack)
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
0.5Each additional year on wait list
3
2
0-11 years
11-17 years
Pediatric recipient Age
4> 79% PRA with negative crossmatch
PRA
*
7
5
2
0 mismatch
1 B/ 1 DR mismatch
0 B/ 1 DR mismatch
2 B/ 1 DR mismatch
Quality of HLA match
1 pointLongest wait time for each ABO group
Time waiting
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-γ, TNF-α) 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-β 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