Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection

Background. Capillary deposition of complement split product C4d has been suggested to be a valuable marker for humoral rejection. In this retrospective study we evaluated the clinical impact of C4d deposition in renal allografts with special emphasis on associations between C4d staining patterns and histological features of acute rejection. Methods. One hundred and two allograft biopsies obtained from 61 kidney transplants (1-532 days after transplantation, median 14 days) were examined by immunohistochemistry on routine paraffin sections using a novel anti-C4d polyclonal antibody (C4dpAb). Results. Fourty-two of 102 biopsies showed endothelial C4d deposits in peritubular capillaries (PTC). Histopathological analysis revealed a significantly lower frequency of positive C4d staining in biopsies with rather than in those without acute cellular rejection defined by the Banff grading schema (P <0.01). For clinical evaluation, patients were classified according to C4d staining in allografts C4d(PTC) positive in at least one biopsy, n=31 vs C4d(PTC)( negative in all biopsies, n = 30). C4d(PTC) positive patients had significantly higher serum creatinine levels than C4d negative patients. Even in the absence of morphological evidence for rejection, differences in serum creatinine levels between C4dPTC positive and negative recipients were significant (6 months: 2.01 +/- 0.75 rs 1.41 +/- 0.27 mg/dl; 12 months: 1.95 +/- 0.60 vs 1.36 +/- 0.34 me dl, 18 months: 1.98 +/- 0.50 vs 1.47 +/- 0.31 mg, dl. P <0.05). All patients with rejection resistant to conventional therapy (n=4) were in the C4d(PTC) positive subgroup. All recipients with panel reactive antibodies (PRA) > 50% (n = 8) were C4dPTC positive. Conclusions. Our data indicate that endothelial C4d deposition is associated with inferior graft outcome. We provide evidence that this immunohistochemical finding and its clinical impact are not associated with morphological signs of cellular rejection.