Paediatric Nephrology Trainees Meeting

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Paediatric Nephrology Trainees Meeting
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'If I were to stick my organ in you, you'd
probably reject it'
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• Blood Groups
• Immunofluorescent staining has revealed blood
  group substance in the cell membranes of all
  vascular endothelial cells, and certain
  epithelial cells. Szulman, A. E. Chemistry,
  distribution, and function of blood group
  substances.Ann. Rev. Med. 17307-322, 1966
• Normal individuals have naturally occurring
  anti-A or anti-B isoagglutinins
• Poor outcome of transplants performed between
  blood group incompatible individuals.

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Transfusion Rules
Donor A B AB O A Y N N Y
B N Y N Y Recipient
AB Y Y Y Y O N N N Y
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First and Second Set Rejection Medawar Rabbit
skin graft model Recipient Donor Graft
loss strain strain X
Y 10-14 days 1st set rejection X'
Y 5-7 days 2nd set rejection X'
Z 10-14 days 1st set rejection
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Major Histocompatibility Antigens ? HLA Class I
(HLA-A, B, Cw) ? HLA Class II (HLA-DR, DQ,
DP) ? 6p21.3 ? Heterodimeric molecules
? Heavy and light chain non-covalently
associated
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Membrane bound glycoproteins HLA CI A,B,C
molecules composed of MHC encoded 45kd heavy
chain non-covalently associated with
non-polymorphic B2 microglobulin HLA CII DR, DQ,
DP molecules composed of MHC encoded 31-34 kd
associated a chain non-covalently associated with
26-29 kd B chain
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HLA CI bound peptides usually 8-9 aa in length.
CII generally longer and more variable in length
14-21 aa. Polymorphic residues encoded by
different alleles are found in this peptide
binding groove
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Principal CI genes are those encoding heavy
chains of the six CI isoforms HLA-A,B,C, E,F,G.
The gene encoding B2 microglobulin is located on
Chr. 15 There are five isotypes of the CII
protein HLA-DM, DO, DP,DQ,DR. Genes for both
the CII a and B chains are located in the CII
region
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HLA Polymorphism (DNA vs Serology) HLA Class
I HLA-A 414 (18) HLA-B 788 (35) HLA-Cw 210 (8)
HLA Class II HLA-DRB1 506 (14) HLA-DQB1 100 (6)
HLA-DPB1 143
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Major Histocompatibility Antigens Class I
antigens found on all nucleated cells Class II
antigens primarily expressed on B lymphocytes but
expression can be induced on T lymphocytes and
other cells
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Inheritance ? Mendelian inheritance ? En-bloc
from each parental chromosome (HLA- A,B,Cw, DR,
DQ,DP). Each individual inherits two antigens
at a given locus. ? Codominant expression. All
of the inherited antigens are displayed on the
cell surface (HLA phenotype). ? Haplotype
segregation (HLA genotype) ab x
cd ac ad
bc bd
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Terasaki (Transplantation 1969 7
246-250) Transplants between HLA-identical
siblings have best outcome.
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HLA-DR HLA-B gt HLA-A
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Terminology of Mismatching HLA A B
DR 0 0 0 Matched 1 0
0 0 1 0 Favourable mismatch
1 1 0 1 1
1 Non-favourable mismatch
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Direct and Indirect Antigen Presentation
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Renal Rejection Hyperacute Pre-existing
DSA Hidden Hyperacute Low level pre-existing
DSA Accelerated acute Memory
humoral/cellular Acute de-novo
humoral/cellular Chronic smouldering
humoral/cellular non- immune
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Acute Cellular Rejection Chronic Allograft
Nephropathy

• Cellular Infiltrate - Arterial fibrosis
• - Intimal thickening

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Sensitisation Any event which elicits
an HLA directed immune response
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Origins of Patient Sensitisation Pregnancy Bloo
d transfusion Transplantation
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Kissmeyer-Nielson ( Lancet 1966 2 662-665)
Hyperacute rejection of kidney allografts
associated with pre-existing humoral antibodies
against donor cells.
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Antibody-Mediated Rejection
Antibody reacts with the endothelial lining of
the blood vessel wall
Complement fixation leads to neutrophil
recruitment and endothelial destruction
Damaged endothelium causes platelet
accumulation and thrombus formation
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Hyperacute Rejection
- fibrin accumulation - thrombosis - vessel
occlusion - necrosis
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Effect of Sensitisation on Waiting Time to
Transplantation Sensitisation
Size of Median Status group
waiting time unsensitised
2027 353 sensitised 510
553 highly sensitised 42
716 Statistics prepared by UK Transplant from
the National Database maintained on behalf of
transplant services in the UK and ROI
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• Reasons for gt Waiting Times in Sensitised
  Patients
• Eligibility gt opportunity for transplant
• Unacceptable antigens gt opportunity for
  transplant
• Positive crossmatch gt opportunity for transplant

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UKT Allocation Rules Allocation in priority
order 000 HSP or DR hom paeds gt 000 non-HSP paeds
gt 000 HSP or DR hom adults gt 000 non-HSP adults
and 100,010,110 paeds gt all others Paediatric
patients in first two groups sorted on wait
time In other groups points score used to sort
rank order points score waiting time points
HLA match and age points combined age
difference points location points HLA-B
homozygous points HLA-DR homozygous points
local priority points