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SIGNIFICANCE OF FOCAL C4d DEPOSTIS IN THE KIDNEY

Understand the clinical significance, management issues, and association of focal C4d deposits in the kidney. Explore guidelines for C4d interpretation, detection of DSA, and biologic explanations for C4d-positive and DSA-negative cases.

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SIGNIFICANCE OF FOCAL C4d DEPOSTIS IN THE KIDNEY

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  1. SIGNIFICANCE OF FOCAL C4d DEPOSTIS IN THE KIDNEY P.Randhawa, A. Girnita, A. Zeevi, R. Shapiro, I. Batal, Departments of Pathology, Surgery, University of Pittsburgh

  2. OUTLINE OF TALK • Definition of focal C4d • Clinical significance • Management issues • Occurrence of DSA –ve cases • Association with Dx other than AMR

  3. GUIDELINES FOR C4d INTERPRETATION • Minimum 5 hpf Cortex or medulla (concordant in 75% graft nephrectomy). • Necrotic/scarred area exclude ( intensity) • Linear, circumferential, finely granular • Intensity at least 1+ intensity on FS • HCHO weak stain may be significant

  4. Neg Neg Neg Unknown Unknown ?Pos Pos Pos BANFF 2007 DEFINITION OF C4d STAINING PATTERNS % biopsy area Interpretation according to technique (cortex and medulla) IF IHC • C4d0 Negative: 0% • C4d1 Minimal 1-10% • C4d2 Focal 10-50% • C4d3 Diffuse >50%

  5. : BANFF 2001 MEETING Only C4d + and – categories recognized. Positive staining was defined as bright linear staining along capillary basement membranes typically involving OVER HALF OF SAMPLED peritubular capillaries NUMBER of capillaries expressed as a percentage, rather than SURFACE AREA of biopsy was the defining criterion Racusen et al. Am J Transplant 2003: 3: 708

  6. % CAPILLARY SCORING • % PTC score used in many studies >2001 • Difficult to apply IF (dark field evaluation) • Can not take in account loss of sensitivity of C4d staining on formalin fixed tissue • Underestimates extent of C4d staining in bxs with IFTA & capillary loss

  7. PTC C4d STAINING PATTERNS (106 BX WITH AR & C4d STAIN) Kayler et al. Transplantation 2008; 85: 813

  8. ANTI-HLA ANTIBODIES

  9. RESPONSE TO STEROIDS

  10. C4D PATTERNS IN F/U BIOPSIES <1 YR (WORST C4d SCORE)

  11. EFFECT OF TISSUE FIXATION :C4D PATTERNS IN DSA + PTS (n=14)

  12. MANAGEMENT OF FOCAL C4d+ BIOPSIES AT PITTSBURGH • Correlate with presence of DSA • Pure Acute AMR with DSA, rising creatinine, get IVIG &/or PP • Treat any concurrent T-cell mediated AR • Assess degree of histologic chronicity

  13. C4d + DSA –VE CASES:Technical Issues • Technical problems with C4d staining -high background, necrotic or scarred area • Technical problems with antibody testing (a) Date (b) Rare antigen not present in testing panel (c) Incorrect HLA Typing of donor HLA (d) Incomplete donor typing (anti-DP, DQ)

  14. DETECTION OF DSA DEPENDS ON SENSITIVITY OF TECHNIQUE • 41 biopsies focal C4d, ELISA PRA screening test for anti-HLA antibody -ve • 11/41= 27% had DSA by Luminex • 7/41 = 17% antibodies to MICA

  15. BIOLOGIC EXPLANATIONS FOR C4d + DSA –VE CASES: • Adsorption of DSA to graft • Non-donor specific antibodies • Non-HLA antibodies • C4d deposition in dx other than AMR

  16. NON-DONOR SPECIFIC HLA ABS • Statistically more AR & worse outcome • Marker for high immune responsiveness • DSA may actually be present but absorbed • Monitor carefully Hourmant et al. JASN2005;16;2804

  17. NON-HLA ANTIBODIES • AECA: anti-endothelial antibodies • Anti-GSTT1 Glutathione S-Transferase T1 • MICA, MICB • AT1R ab: Angio II type I receptor ab • Anti-VIM/ICAM-1 ab assoc GAX in heart • Anti-AGRIN (GBM) ab associated cg • Anti-HY ab products of Y chromosome

  18. POTENTIAL TARGETS OF AECA • MHC antigens • ABO antigens • AT1R receptors • MICA (Mhc class I related Chain Ag) • Other unknown polymorphic ags

  19. PROBLEMS WITH AECA STUDIES • Most assays do not attempt to define ag. • Studies cross sectional: cause & effect? • Some AECA definitely 20 vascular injury - due to rejection (intimal arteritis) - viral infection (CMV)

  20. AECA & ANTI-HLA CAN CO-EXIST • FCM assay XM-ONE Kit PBL endoth progenitors -35/147 (24%) pre-tx sera had donor reactive ab -Acute rejection 16/35 (46%) vs 13/112 (12%); -6/16 C4d +, ALL had confounding HLA ab Breimer et al. Txn 2008; 87: 549:

  21. SOME AEC ASSAYS DO MEASURE COMPLEMENT FIXING AB • EUROIMMUN indirect IF reagent kit and HUVEC deposited on BIOCHIPs • AECA in 13/47 patients vascular rejection • 6/13 C4d+ (46%); 1/6 anti-HLA + • Plasma cell infiltrate 54% AEC-AR vs 12%no AR • Overall 1 yr graft loss 46% AEC vs 19 % no AEC Sun et al. CJASN 2008; 3; 1479

  22. ANTI-GLUTATHIONE S-TRANSFERASE T1 ANTIBODIES • Donor has GSTT1 gene, recipient does not • Incidence of GSTT1 mismatch ~ 20% • Initial associative studies severe liver dysfunction • Ktx: one study reported 4 cases of CHRONIC AMR with C4d in peritubular capillaries • 1 case report acute AMR is also available Aguilera et al NDT 2008; 23; 1393

  23. BANFF CATEGORIES OTHER THAN AMR WITH C4d DEPOSITS • Recurrent antiGBM • Post-tx IgA 16/66 PTC Cho et al Clin Tx 2007:21:159 • Colvin: USCAP 38% Denovo 17% rMGN • Feucht 2001: 6/10 GN 11/19 ATN • Feucht 2003: ATN C3d, not C4d Feucht et al. KI 2001:5934; AJT 2003:3:646

  24. C4d DESCRIBED IN NATIVE KIDNEY DISEASES • Lupus nephritis (31/455, D) • -Li et al. Lupus 2007:16:875 • - granular, EM immune complex deposits • 2/2 Bacterial endocarditis GN • Scleroderma renal crisis • -diffuse 1/11, focal 3/11 • Two donor, 1 DIC kidney (F) • C activation multiple paths

  25. SUMMARY • Focal C4d PTC <50% surface area • Staining pattern affected by tissue fixation • Significance: correlate histology & DSA • % patients with DSA intermediate • DSA–ve: technical issues, non-HLA abs, diseases other than AMR

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