Complement-Binding Anti-HLA Antibodies and Kidney-Allograft Survival

Key Takeaways

• The presence of complement-binding donor HLA-specific antibodies (DSA+ C1q+) after transplantation was associated with greater than fourfold risk of graft loss
• These patients had the lowest five-year graft survival compared with either non-complement-binding DSA or no DSA recipients
• Patients with complement-binding DSA had an increased rate and severity of antibody mediated rejection
• Adding complement-binding DSA improves risk stratification post-kidney transplantation

Summary Statement

The C1q-binding assay significantly increases the ability to predict antibody mediated rejection and graft loss. C1q is a useful addition to the tools available to manage renal patients post-transplantation.

Background

The complement-dependent cytotoxicity (CDC) test was introduced by Patel and Terasaki in 1969 and demonstrated that the complement cascade is a key component of antibody mediated rejection. Whilst antibody can be detected in in vivo and in vitro, it is not always detrimental to graft function.

C1q forms the first part of the complement cascade, and the C1q test is a measure of the complement-binding ability of donor HLA-specific antibody in the sample.

Summary

1,016 consecutive patients from two hospitals were enrolled in the study between 2005 and 2011 and followed post-transplant until 2012. All patients were ABO-compatible with the donor, gave informed consent, and were transplanted following a negative T and B cell CDC crossmatch.

Retrospectively, patients were tested for donor HLA-specific antibodies (DSA) on day-of transplant samples, and samples taken at the time of suspected rejection. Kidney biopsy was taken either at presentation with suspected rejection or as a protocol biopsy at one year. Clinical data was recorded at days 0 and 6 months post-transplantation, and annually thereafter up to 7 years post-transplant. Samples positive for DSA were blinded and tested for C1q-binding properties using the C1q-binding test (C1qScreen, One Lambda).

The patients could be stratified into three groups based on DSA and C1q-binding capacity: Post-transplant, 18% of DSA+ C1q+ patients had biopsy proven T cell mediated rejection, compared with 13% DSA+ C1q- and just 7% of DSA- patients (p<0.001). Antibody mediated rejection occurred in 48% of DSA+ C1q+ patients compared to just 16% DSA+ C1q- patients (p<0.001).

Kidney function at one year was lowest in DSA+ C1q+ patients (42 mL/min/1.73 m² vs. 51 mL/min/1.73 m² for DSA+ C1q- and 54 mL/min/1.73 m² for DSA- , p<0.001), as was 5-year graft survival at just 54% for DSA+ C1q+ patients.

The highest risk to transplant loss was shown to be for patients who were C1q- at time of transplant but subsequently developed C1q+ antibodies post-transplant, and this remained significant whether the antibodies were detected following for-cause or surveillance testing (Hazzard ration 9.23, p<0.001). C1q-binding ability was also associated with biopsy proven determinants of rejection, including microvascular inflammation, C4d deposition, transplant glomerulopathy, and tubulitis.

Conclusion

The C1q-binding test, used alongside DSA testing, provides an additional level of sensitivity when stratifying for risk of graft loss. Whether measured at the time of suspected rejection, or as part of routine surveillance, patients with a positive C1q test had just a 54% 5-year graft survival compared to patient who were either DSA+ (93%) or DSA- (94%).

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