Complement‐fixing donor‐specific antibodies identified by a novel C1q assay are associated with allograft loss

Sutherland, Scott M.; Chen, Ge; Sequeira, Flavia; Lou, Calvin D.; Alexander, Steven R.; Tyan, Dolly B.

doi:10.1111/j.1399-3046.2011.01599.x

Cited by 163 publications

(117 citation statements)

References 24 publications

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“…113 Cumulative prevalence at 3 years post-transplant is similarly varied from 6% 116 to 38%, 113 with lifetime cumulative prevalence even more disparate. Class II antibodies predominate in most [115][116][117][118][119][120][121][122][123][124][125] but not all reports. [111][112][113][114] With differences in antibody MFI cutoffs, baseline immunosuppression, and frequency of testing, definitive conclusions remain elusive.…”

Section: Utility Of Hla Antibody Testing Pretransplantmentioning

confidence: 99%

Utility of HLA Antibody Testing in Kidney Transplantation

Konvalinka¹,

Tinckam

2015

Journal of the American Society of Nephrology

157

131

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HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donorspecific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre-and post-transplant clinical outcomes.

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Section: Utility Of Hla Antibody Testing Pretransplantmentioning

confidence: 99%

Utility of HLA Antibody Testing in Kidney Transplantation

Konvalinka¹,

Tinckam

2015

Journal of the American Society of Nephrology

157

131

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“…[21][22][23][24] Two tests have been developed to directly assess the capacity of anti-HLA antibodies to bind the complement components that initiate the classic pathway. [25][26][27][28] The detection of C4d-and C1q-binding anti-HLA antibodies in renal graft recipients correlated with shorter graft survival in small cohorts, [29][30][31][32][33] a result just confirmed for C1q-binding assay in a large cohort by Loupy et al 34 While these findings are extremely promising, none of these pioneer studies have evaluated the prognostic value of these tests at the diagnosis of AMR, the actual time when the clinician most needs a risk stratification assay that may guide therapeutic decision making.…”

mentioning

confidence: 99%

Detection of C3d-Binding Donor-Specific Anti-HLA Antibodies at Diagnosis of Humoral Rejection Predicts Renal Graft Loss

Sicard

Ducreux

Rabeyrin

et al. 2015

Journal of the American Society of Nephrology

228

105

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Antibody-mediated rejection (AMR) is a major cause of kidney graft loss, yet assessment of individual risk at diagnosis is impeded by the lack of a reliable prognosis assay. Here, we tested whether the capacity of anti-HLA antibodies to bind complement components allows accurate risk stratification at the time of AMR diagnosis. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at the Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of donor-specific anti-HLA antibodies (DSAs) and their ability to bind C1q and C3d using flow bead assays. In contrast with C4d graft deposition, the presence of C3d-binding DSA was associated with a higher risk of graft loss (P,0.001). Despite similar trend, the difference did not reach significance with a C1q-binding assay (P=0.06). The prognostic value of a C3d-binding assay was further confirmed in an independent cohort of 39 patients with AMR (P=0.04). Patients with C3d-binding antibodies had worse eGFR and higher DSA mean fluorescence intensity. In a multivariate analysis, only eGFR,30 ml/min per 1.73 m 2 (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.46 to 8.70; P=0.005) and the presence of circulating C3d-binding DSA (HR, 2.80; 95% CI, 1.12 to 6.95; P=0.03) were independent predictors for allograft loss at AMR diagnosis. We conclude that assessment of the C3d-binding capacity of DSA at the time of AMR diagnosis allows for identification of patients at risk for allograft loss.

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“…[25][26][27] Newer assays are helping to determine which DSAs are more likely to mediate complement activation and induce graft function failure. [28][29][30] We hypothesize that HLA Class II molecules play an important role in affecting the long-term survival of transplanted kidney, since they are mainly expressed on immune cells and involved in the coordination of immune system function. Since low level antibodies do not usually cause immediate damage to the graft, it may be that this antibody mediated damage-repair-damage process requires a few years to mature, before finally leading to irreversible renal graft failure.…”

Section: Discussionmentioning

confidence: 99%

Pre-transplant low level HLA antibody shows a composite poor outcome in long-term outcome of renal transplant recipients

Tian

Alberghini

et al. 2015

Renal Failure

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To determine the significance of low-level DSA (donor specific antibody) in patients transplanted with negative cytotoxicity AHG (antihuman immunoglobulin) crossmatch, data from 279 patients who received a kidney transplant between July 1999 and March 2006 were collected. All kidney recipients received ABO-compatible donors. A poor outcome was defined as any one of the following: death, Cr42.0 mmol/L, occurrence of a rejection episode. Luminex Screening and Single Antigen assays from Tepnel Life Codes were used to detect human leukocyte antigen antibodies on pre-transplant sera retrospectively. Twenty-four out of 279 recipients demonstrated the presence of solid-phase DSA (MFI41000) present pre-transplant. In DSA+ group, the accumulated good versus poor outcome rate was 0.30 versus 0.70, respectively. These rates were 0.49 and 0.51, respectively, in the DSAÀ group. The difference in composite poor outcome between DSA+ versus DSAÀ group was significant (p ¼ 0.030). The DSAÀ group had no difference in patient survival as compared to the DSA+ group (p ¼ 0.061). There is no statistically significant difference for either mortality or outcome results between high MFI (42000) and low MFI ( 2000) groups. Our data suggest that solid-phase antibodies which are not strong enough to elicit a positive T-AHG crossmatch may influence long-term graft outcome.

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Complement‐fixing donor‐specific antibodies identified by a novel C1q assay are associated with allograft loss

Cited by 163 publications

References 24 publications

Utility of HLA Antibody Testing in Kidney Transplantation

Utility of HLA Antibody Testing in Kidney Transplantation

Detection of C3d-Binding Donor-Specific Anti-HLA Antibodies at Diagnosis of Humoral Rejection Predicts Renal Graft Loss

Pre-transplant low level HLA antibody shows a composite poor outcome in long-term outcome of renal transplant recipients

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