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