pediatric renal transplants

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RENAL TRANSPLANTATION IN CHILDHOOD Lynne P. Yao, M.D. INOVA Fairfax Hospital for Children Fairfax, VA

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Page 1: Pediatric Renal Transplants

RENAL TRANSPLANTATION IN CHILDHOOD

Lynne P. Yao, M.D.INOVA Fairfax Hospital for Children

Fairfax, VA

Page 2: Pediatric Renal Transplants

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

Page 3: Pediatric Renal Transplants
Page 4: Pediatric Renal Transplants

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

Page 5: Pediatric Renal Transplants

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

Page 6: Pediatric Renal Transplants

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

Page 7: Pediatric Renal Transplants

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

Page 8: Pediatric Renal Transplants

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

Page 9: Pediatric Renal Transplants

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

Page 10: Pediatric Renal Transplants

T lymphocyte activation

from Arakelov, Lakkis, Semin. Nephrol., 20:2, 2000

Page 11: Pediatric Renal Transplants

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)

Page 12: Pediatric Renal Transplants

From Semin. Nephrol., 20:2, 2000

Stimulation of IL-2 production after T cell activation

Page 13: Pediatric Renal Transplants
Page 14: Pediatric Renal Transplants

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

Page 15: Pediatric Renal Transplants
Page 16: Pediatric Renal Transplants

need slide of cell cycle

Page 17: Pediatric Renal Transplants

Break slide

Page 18: Pediatric Renal Transplants

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

Page 19: Pediatric Renal Transplants

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

Page 20: Pediatric Renal Transplants

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

Page 21: Pediatric Renal Transplants

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

Page 22: Pediatric Renal Transplants
Page 23: Pediatric Renal Transplants

Age at transplantation

6.4 420>18

38.7252713-17

34.522566-12

15.3 9982-5

5.1 3330-1

Age Number Percent

Page 24: Pediatric Renal Transplants

Cadaveric donor Living related donor

Patient survival by age at primary transplantation

Page 25: Pediatric Renal Transplants

Graft survival by bi-annual cohort

Page 26: Pediatric Renal Transplants

Primary graft survival by age at time of transplantation

Cadaveric donor Living related donor

Page 27: Pediatric Renal Transplants

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

Page 28: Pediatric Renal Transplants

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

Page 29: Pediatric Renal Transplants

Time to first rejection episode

% R

ejec

tion

Page 30: Pediatric Renal Transplants

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

Page 31: Pediatric Renal Transplants

Cadaveric donor Living related donorTime in years

Primary graft survival by race

Page 32: Pediatric Renal Transplants

Significant complications

◆ Growth failure◆ Infection◆ Posttransplant lymphoproliferative disorder

(PTLD)◆ Diabetes mellitus

Page 33: Pediatric Renal Transplants

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

Page 34: Pediatric Renal Transplants

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

Page 35: Pediatric Renal Transplants

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

Page 36: Pediatric Renal Transplants

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

Page 37: Pediatric Renal Transplants

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

Page 38: Pediatric Renal Transplants

Future directions

◆ Steroid withdrawal or steroid avoidance protocols◆ Designer immunosuppression ◆ Tolerance◆ Xenotransplantation

Page 39: Pediatric Renal Transplants

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

Page 40: Pediatric Renal Transplants

Xenotransplantation

Page 41: Pediatric Renal Transplants

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

Page 42: Pediatric Renal Transplants

Last slide

Page 43: Pediatric Renal Transplants

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

Page 44: Pediatric Renal Transplants

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

Page 45: Pediatric Renal Transplants

Cadaveric donor Living related donor

% G

raft

sur

viva

l

Primary graft survival by use of induction antibody

Time in years

Page 46: Pediatric Renal Transplants

Cadaveric donor Living related donorTime in years

Primary graft survival by number of transfusions

Page 47: Pediatric Renal Transplants

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

Page 48: Pediatric Renal Transplants

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

Page 49: Pediatric Renal Transplants

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

Page 50: Pediatric Renal Transplants

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

Page 51: Pediatric Renal Transplants
Page 52: Pediatric Renal Transplants

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

Page 53: Pediatric Renal Transplants

Monoclonal antibodies

◆ OKT3 (targets CD3 receptor on T cells)◆ Anti-IL-2 receptor (IL-2R) Ab◆ Anti ICAM-1 Ab◆ Anti CD40 Ab

Page 54: Pediatric Renal Transplants

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

Page 55: Pediatric Renal Transplants

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%)

Page 56: Pediatric Renal Transplants

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