Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts

Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts.BackgroundThe contribution of humoral alloreactivity to the rejection of renal allografts is not well defined because humoral antigraft reactions are not easily detectable in transplant biopsies, and serial measurements of circulating allo-antibodies in the post-transplantation period are not routinely performed. We have developed diagnostic techniques that improve the assessment of humoral alloreactivity in vivo and in vitro.MethodsHumoral alloreactivity in transplant biopsies derived from 218 single kidney grafts was detected by assessing the deposition of complement fragment C4d in interstitial capillaries. Circulating alloantibodies were determined in corresponding serum samples by flow cytometry using lymphoblastoid cell lines of donor DR-type as target cells and by a conventional microcytotoxicity test. The impact of capillary C4d and other selected variables on renal graft survival was calculated by univariate and multivariate analysis.ResultsCapillary C4d, present in 46% of biopsies from first grafts and 72% of regrafts, is related to circulating alloantibodies. Grafts with capillary C4d have a markedly shorter survival than grafts without capillary C4d (50% graft survival, 4 vs. 8 years, P = 0.0001). Among several risk factors, capillary C4d is the strongest predictor of subsequent graft loss in a multivariate analysis (relative risk, 2.1, 95% CI, 1.4 to 3.1). Humoral alloreactivity detectable within six months after transplantation has a much stronger impact on graft survival than alloreactivity detected beyond this period.ConclusionsHumoral alloreactivity, manifested by the capillary deposition of complement C4d in about 50% of biopsied renal grafts, exerts a strong impact on graft survival when it operates within six months after transplantation

Detection of both isotypes of complement C4, C4A and C4B, in normal human glomeruli

Detection of both isotypes of complement C4, C4A and C4B, in normal human glomeruli. Monoclonal antibodies reactive against the complement C4A and C4B isotypic components were used in an immunoper-oxidase technique for the histological study of normal human renal tissue. Prominent staining with both antibodies was seen in the mesan-gial areas of all normal kidney sections investigated. Occasional staining of arteriolar walls of the same tissues, however, was also observed. In contrast, no mesangial staining was seen using monoclonal antibodies reactive against other ‘early’ complement components, such as Clq and C3. Specificity of the glomerular staining with the anti-C4 reagents was demonstrated in two patients possessing only the C4A serum component but lacking genetically the C4B locus products. As would be predicted, glomerular staining with the anti-C4A reagent, but not anti-C4B, was clearly demonstrable. It is concluded that both isotypes of complement C4 are present in normal human glomeruli and thus might be operative for normal mesangial function