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C4d – The Birmingham UK Experience

This study explores the routine use of C4d staining on kidney transplant biopsies in Birmingham, UK from 2004 to 2008. The presence of C4d staining, along with the presence of donor-specific antibodies (DSA), is correlated with patient outcomes. The study also examines the pattern of inflammation in cases of strong C4d staining. The results suggest that C4d staining and DSA, when considered together with C3d staining, can provide valuable information about transplant outcomes.

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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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