Abstract
The association between donor specific antibodies (DSA) and renal transplant rejection has been generally established, but there are cases when a DSA is present without rejection. We examined 73 renal transplant recipients biopsied for transplant dysfunction with DSA test results available: 23 patients diffusely positive for C4d (C4d+), 25 patients focally positive for C4d, and 25 patients negative for C4d (C4d−). We performed C1q and IgG subclass testing in our DSA+ and C4d+ patient group. Graft outcomes were determined for the C4d+ group. All 23 C4d+ patients had IgG DSA with an average of 12,500 MFI (cumulative DSA MFI). The C4d− patients had average DSA less than 500 MFI. Among the patients with C4d+ biopsies, 100% had IgG DSA, 70% had C1q+ DSA, and 83% had complement fixing IgG subclass antibodies. Interestingly, IgG4 was seen in 10 of the 23 recipients' sera, but always along with complement fixing IgG1, and we have previously seen excellent function in patients when IgG4 DSA exists alone. Cumulative DSA above 10,000 MFI were associated with C4d deposition and complement fixation. There was no significant correlation between graft loss and C1q positivity, and IgG subclass analysis seemed to be a better correlate for complement fixing antibodies in the C4d+ patient group.
Highlights
In Humoral Theory of Transplantation [1] Terasaki argued against Sir Peter Medawar’s evidence for cellular rejection through thymus directed T-cell immunity that had for decades biased the transplantation community against antibodies as a cause of transplant rejection and loss
IgG subclass analysis and how it is determined is a critical issue with regard to the interpretation of complement fixing
It is reasonable to suspect that patients biopsied for cause would have a higher incidence of donor specific antibodies (DSA) than patients without cause for biopsy
Summary
In Humoral Theory of Transplantation [1] Terasaki argued against Sir Peter Medawar’s evidence for cellular rejection through thymus directed T-cell immunity that had for decades biased the transplantation community against antibodies as a cause of transplant rejection and loss. Antibody mediated rejection (AMR) assumed a prominent role in allograft dysfunction and loss with the discovery of the complement protein C4d on the peritubular capillaries [2,3,4] and the principles described in Humoral Theory of Transplantation [1]. 30% of the patients showed AMR only, 45% exhibited AMR plus cell mediated rejection (CMR), 15% CMR only, and only 10% acute tubular necrosis [11]. There are commercially available kits for identifying C1q-binding HLA antibodies, IgG subclasses of HLA antibodies were measured by using several murine antibody clones recognizing human IgG subclasses These clones have been tested by several other investigators with variable outcomes and correlations to the different subclasses [12,13,14,15]. Data is presented that suggests indirect “sandwich” assays could give a more specific result
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