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 

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 HLA locus Mother Father Patient  

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

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 

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 

Side Effects – Heme: – Endocrine: – NO NEPHROTOXICITY