Humoral Rejection: Status and Questions

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Humoral Rejection Status and Questions

• Robert B. Colvin, M.D.
• Department of Pathology
• Massachusetts General Hospital
• Harvard Medical School
• Boston MA 02114
• 7th Banff Conference
• Aberdeen
• June 15, 2003

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ACUTE REJECTION Cellular / Humoral
Cellular
Humoral
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Thioester Defense Proteins
Ancient Opsonins
C4 (shark-Ig) C3 (sea urchin) a2-macroglobul
in (mollusc/lobster)
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• Classical complement pathway activation
• Antibody Antigen
• C1
• C4 C4a C4b

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C4d Immunofluorescence Acute Cellular Rejection
Acute Humoral Rejection
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Acute Humoral Rejection
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Acute Humoral Rejection
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Morphologic Diagnoses in Acute Rejection

• C4d C4d-
• n20 n47
• AHR 30 0
• AHR ACR 45 9
• ACR 15 91
• ATI 10 0
• 25 of AHR misdiagnosed by histology alone
• 60 of AHR assoc. with ACR

Mauiyyedi et al, JASN 13779,2002
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Day 9 Oliguria
C4d
HE
01E55740
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C4d vs. Histology in diagnosis of AHR

• Sensitivity Specificity
• 1. Serum DSA as standard
• Histology 68 96
• C4d in PTC 95 96

2. C4d in PTC as standard DSA in serum 90 98
Mauiyyedi et al, JASN 13779,2002
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Consensus

• C4d deposition in PTC is a robust marker of
  humoral antibody to graft endothelial antigens
  (HLA class I or II, ABO)
• Humoral rejection is common and occurs often with
  cellular rejection
• Acute humoral rejection has a poor prognosis
  unless treated appropriately

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KIDNEY Acute Humoral Rejection
Trpkov Mauiyyedi Nickeleit Regele Herz
enberg Lederer Prevalence
(24/44) (20/67) (94/265) (31/61) (34/93) (
50/100) C4d PTC - 30 35
51 37 50 One-year graft loss
50 30 14 10 38 50
Mauiyyedi
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C4d Predicts Accelerated Graft Loss
Herzenberg et al JASN 2002, 13234
Mauiyyedi
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Question 1

• Do the Banff criteria of humoral rejection need
  refinement?

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Acute Antibody Mediated Rejection

• Immunpathologic evidence for antibody action,
  such as
• C4d and/or (rarely) immunoglobulin in peritubular
  capillaries
• immunoglobulin and complement in arterial
  fibrinoid necrosis
• Serologic evidence of circulating antibodies to
  donor HLA or other anti-donor antigens

Racusen et al, Am J Transplant 31, 2003
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Acute Antibody Mediated Rejection

• Morphologic evidence of acute tissue injury, such
  as
• acute tubular injury
• neutrophils in capillaries and/or glomeruli
  and/or capillary thrombosis
• intimal arteritis/fibrinoid necrosis/intramural
  or transmural inflammation in arteries

Why not just fibrinoid necrosis? Should we add
macrophages in glomeruli?
Racusen et al, Am J Transplant 31, 2003
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Magil and Tinckham Monocytes and peritubular
capillary C4d deposition in acute renal
allograft rejectionKidney International,
631888, 2003
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Day 5
CD68
C4d
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Day 9 Oliguria
C4d
CD68
01E55740
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Question 2

• Does C4d deposition always lead to graft damage?
• ?Accommodation?
• Evidence from ABO incompatible grafts
• (Tuesday afternoon session)

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Question 3

• Does ischemia alone cause C4d deposition?
• Heart
• Kidney

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• Ischemia alone does not cause C4d deposition in
  kidney PTC

2/35 intra-operative biopsies had C4d
PTC Both developed AHR later (d5, 34) Both
presensitized (historical crossmatch) Haas
, Modern Pathol, 15 276A, 2002

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Asystolic donor kidney, severe ATN, anuric on Day
10
C4d
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Question 4

• Are there other forms of humoral rejection?

Chronic Subclinical
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Chronic Allograft Arteriopathy
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Chronic Allograft Glomerulopathy
PAS
EM
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C4d in Chronic Rejection

• C4d- C4d
• Chronic Rejection 15 23 61
• (Arteriopathy or Glomerulopathy)
• Allograft Controls
• Chronic CsA Tox 20 1 5
• Interstitial Fibrosis 10 0 0
• Native Kidneys ESRD 15 0 0
• plt.001 vs controls
• Mauiyyedi et al, JASN, 12574, 2001

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C4d correlates with donor specific antibodies in
chronic rejection

• C4d DSA
• 88 (15/17)
• - 0 (0/8)

plt.001
100 of DSA cases had C4d 12 of C4d cases
lacked DSA
Mauiyyedi et al, JASN, 12574, 2001
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C4d in Late Biopsies

• 213 transplant biopsies gt12 months
• 34 C4d
• C4d associated with
• lamination of PTC
• chronic allograft glomerulopathy
• Regele et al (Vienna), JASN 132371,2002

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C4d in late biopsies correlates with chronic
allograft glomerulopathy (CAG)

• of cases
• with CAG
• Bx gt12mo C4d 53
• C4d- 14
• Regele et al JASN 132371,2002

Also correlates with later development of
CAG If bx lt12 mo later bx C4d
46 CAG C4d- 6
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DRAFT PROPOSAL KIDNEYCHRONIC HUMORAL REJECTION

• 1. Clinical evidence of chronic graft
  dysfunction
• 2. Histologic evidence of chronic injury need 3
  of 4
• Arterial intimal fibrosis
• Duplication of glomerular basement membrane
• Interstitial fibrosis / tubular atrophy
• Laminated PTC basement membrane
• 3. Evidence for Ab action / deposition in tissue
• C4d in PTC
• 4. Serologic evidence of anti-HLA antibody

AST/ASTS Conference on Humoral Rejection Bethesday
, April 2003
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Question 5

• Is it useful to designate stages of humoral
  rejection?
• Stages
• - measurable period of time
• - probability of going to next stage or back
• - clinicopathologic criteria

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• Circulating anti-HLA antibodies detected before
  evidence of graft dysfunction
• Terasaki
• Worthington

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Subclinical Humoral Rejection

• Protocol biopsies from stable patients stained
  for C4d (paraffin)
• N C4d
• Non-presensitized 47 17
• Nickerson, Regele et al (Manitoba) ASN 2002
  (abstr)
• Also reported by Mengel et al (Hanover) - lower

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Transplant Biopsy Day 370 Monkey 1900 Mixed
Chimerism/aCD40L Tolerance Protocol
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