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C4d – The Birmingham UK Experience

C4d – The Birmingham UK Experience. Desley Neil, Majid Mukadam, David Briggs* UHBNHSFT, NHSBT* Birmingham. Method. C4d staining performed routinely on all EMBs from May 2004. May 2004 – May 2008 1443 biopsies in 163 patients with 166 transplants reports for Grade of C4d staining

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C4d – The Birmingham UK Experience

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  1. C4d – The Birmingham UK Experience Desley Neil, Majid Mukadam, David Briggs* UHBNHSFT, NHSBT* Birmingham

  2. Method • C4d staining performed routinely on all EMBs from May 2004. • May 2004 – May 2008 • 1443 biopsies in 163 patients with 166 transplants • reports for Grade of C4d staining • 71 (4.9%) unreported – 14 missing , rest graded • Presence or absence DSA (luminex bead) – not routine • C3d staining on strong C4d cases • Pattern of inflammation reassessed in • Strong C4d bxV highest C4d neg/weak • Busy, no, focal or diffuse infiltrate, Cells in / around capillary

  3. Biopsy protocol • Protocol • Weekly x 6 • Fortnightly x 2 • Monthly x 2 • 6 weekly x 2 1year • 6 monthly x2 2 years • Yearly x1 3 years • Indication • Symptomatic or change in echo • Change of medication • 2-3 biopsy during transition and once established

  4. C4d (& C3d) grading system • 0 Negative • 1 Weak patchy staining • 2 Moderate staining • 3 Diffuse strong staining (Looks like CD31 at low power) • Immunoperoxidase Polyclonal Ab Biomedica

  5. C4d

  6. C3d

  7. Demographics 163 132 31 Age 49 (14-63) 44 (19-65) 49 (14-65)

  8. Biopsies • Timing of biopsies • 171 days (0-5806 days) post-tx • Number of biopsies / patient • 4 (1-40) biopsies

  9. C4d staining 60% 72% 15%

  10. Highest C4d grade / patient 35.6% 29.5% 22.1% 12.3%

  11. Death related to highest C4d 6.3% 11.1% 20.7% 35% Kruskal Wallis p<0.02

  12. Follow up time v highest C4d grade Kruskal Wallis p=0

  13. Strong C4d • 20 patients • 7 had DSA found • 6/7 (85.7%) with DSA died • 1 with lot of consecutive strong C4d • serum not sent till after Plasma exchange = negative • Retransplanted • Others only HLA Ab tested inconsistently

  14. DSA • 19 (11.7%) patients • Found 7.1 (0-12.9) years post-tx • 13 (68.6%) class II and 6 (31.4%) class I and II

  15. Demographics of DSA +/- NS Age: DSA + 46 (14-59) DSA – 49 (17-65)

  16. Symptoms • 5 (26.3%) asymptomatic • 14 (73.3%) symptomatic • 3 IHD/graft vasculopathy • 11 syncope, heart failure • 10 evidence of graft vasculopathy • 8 no evidence of graft vasculopathy • 1 don’t know

  17. Death related to DSA 10.5% 18.8% 47.4% Death v DSA Wilcoxin p=0.000

  18. Follow up time v DSA Kruskal Wallis NS • Death • 8.8 (3-12.9) yrs post tx • 215 (7-1188) days post DSA found

  19. DSA v highest C4d grade 2.1% 2.8% 17.2% 35% Kruskal Wallis p=0

  20. DSA v Strong C4d +C3d grade

  21. DSA /Patient with strong C4d +/- mod/strong C3d 60% P<0.05

  22. DSA in relation to C4d persistence • Persistent strong 4/6 (66.7%) • Intermittent mod/strong 4/17 (23.5%) • Single strong (others neg/weak) 4/18 (22.2%) • Single bx = strong (no others bx) 3/7 (42.9%) • Nothing much 3/111 (2.7%) Kruskal-Wallis p<0.02

  23. C3d staining in relation to persistence of C4d

  24. N=357 neg/weak N=42 strong

  25. BUSY “B” PATTERN

  26. Summary • C4d staining relatively uncommon • Both DSA and highest grade of C4d correlates with death • Correlation between C4d and DSA –? improved by C3d • Neither C4d or DSA in isolation is sensitive at a single time point • C4d - comes and goes, precede inflam and symptoms • Repeat DSAs (- to + in 4/7)

  27. Using ISHLT criteria will miss 2/3 C4d positive cases • same also if C3d mod/strong • Busy “B” with cells in or around vessels • C4d/C3d needs to be routine C4d grade

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