Beyond histology: lowering human leukocyte antigen antibody to improve renal allograft survival in acute rejection.
ABSTRACT The common endpoint in the treatment of antibody-mediated rejection (AMR) is functional reversal (creatinine levels). Reduction of human leukocyte antigen (HLA) antibody strength is not commonly considered as an essential endpoint for AMR resolution. The purpose of this study was to determine whether reduction in HLA antibody intensity in patients with histologic AMR reversal influences long-term renal allograft survival.
Renal allograft recipients were included if he or she had a biopsy diagnosis of AMR (between August 2000 and October 2008) and serial evaluation for HLA antibodies prebiopsy and postbiopsy. Antibody reduction was defined as mean fluorescence intensity decrease more than 50% in highest intensity antibody after AMR therapy and the absence of new antibody formation. Patients were treated with plasmapheresis, thymoglobulin/OKT3, and corticosteroids. Survival analysis was performed using STATA/MP v10 (College Station, TX).
Twenty-eight patients were analyzed. Antibody reduction failed to occur in 22 of 28 cases. Baseline characteristics were similar between groups. Antibody nonresponders had significantly shorter allograft survival time (61.4 months) compared with antibody responders (no failures) (P=0.04, log-rank test).
In conclusion, failure to significantly reduce antibody levels and prevent new formation was strongly predictive of allograft loss. This observation suggests that the therapeutic intervention that reduces antibody production may prolong graft survival in transplantation.
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ABSTRACT: BACKGROUND: Identification of risk factors for renal allograft failure after an episode of acute antibody-mediated rejection (AMR) may help the outcome of this difficult-to-treat complication. METHODS: During December 2003 to February 2011, 833 kidney graft recipients underwent 1120 clinically indicated biopsies at our center. We reviewed the biopsy results and identified 87 biopsy specimens from 87 patients positive for the degradation product of complement component 4 (C4d) and acute AMR. We generated Kaplan-Meier survival curves and performed a multivariable analysis using the Cox proportional hazards regression model to identify risk factors for allograft failure after C4d+ acute AMR. RESULTS: Among the 87 patients, 26 had a diagnosis of acute AMR according to the Banff '09 classification schema, 29 had acute AMR and chronic active AMR, 18 had acute AMR and acute T-cell mediated rejection (TCMR), and 14 had acute AMR, chronic active AMR, and acute TCMR. Kaplan-Meier survival estimates showed that concurrent acute TCMR (P=0.001, Mantel-Cox log-rank test), concurrent chronic active AMR (P=0.03), and time to biopsy (P=0.04) are associated with graft survival. The Cox proportional hazards regression analysis identified that concurrent acute TCMR (hazard ratio, 2.59 [95% confidence interval, 1.21-5.55]; P=0.01) and estimated glomerular filtration rate (hazard ratio, 0.65 [95% confidence interval, 0.48-0.88]; P=0.01) are independent risk factors for allograft loss. Concurrent chronic active AMR or time to biopsy was not associated with graft failure by the multivariable Cox analysis. CONCLUSIONS: Our single-center study has elucidated that concurrent acute TCMR in kidney transplant recipients with C4d+ acute AMR is an independent risk factor for graft failure. Level of allograft function at the time of diagnosis was also an independent predictor of graft loss.Transplantation 08/2012; 94(6):603-611. · 3.78 Impact Factor
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ABSTRACT: Approximately 7% to 9% of patients with donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) fail within 1 year post-DSA onset. However, little is known as to how this DSA-associated failure temporally progresses. This longitudinal study investigates DSA's temporal relationship to allograft dysfunction and identifies predictors of allograft function's progressive deterioration post-DSA. A cohort of 175 non-HLA identical patients receiving their first transplant between March 1999 and March 2006 were analyzed. Protocol testing for DSA via single antigen beads was done before transplantation and at 1, 3, 6, 9, and 12 months after transplantation then annually. Estimated glomerular filtration rate (eGFR) was analyzed before and after DSA onset. Forty-two patients developed DSA and had adequate eGFR information for analysis. Before DSA onset, the 42 patients had stable eGFR. By 1 year post-DSA, the cohort's eGFR was significantly lower (P<0.001); however, 30 of 42 had stable function. Twelve patients had failure or early allograft dysfunction (eGFR decline >25% from DSA onset). Those who failed early (by 1 year post-DSA) had more antibody-mediated rejection than stable patients (P=0.03). Late failures (after 1 year post-DSA) were predictable with evidence of early allograft dysfunction (eGFR decline >25% by 1 year post-DSA; P<0.001). Early allograft dysfunction preceded late failure by nearly 1 year. DSA is temporally related to allograft function deterioration. However, in many cases, late allograft failures are preceded by early allograft dysfunction. Therefore, monitoring for early allograft dysfunction provides treating physicians with a window of opportunity for treatment or continued monitoring.Transplantation 08/2013; · 3.78 Impact Factor
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ABSTRACT: The aim of this study was to evaluate the utility of donor-specific antibodies (DSA) and flow cytometry crossmatch (FCCM) as tools for predicting antibody-mediated rejection (AMR) in desensitized kidney recipients. Sera from 44 patients with DSA at the time of transplant were reviewed. Strength of DSA was determined by single antigen Luminex bead assay and expressed as mean fluorescence intensity (MFI). T- and B-cell FCCM results were expressed as mean channel shift (MCS). AMR was diagnosed by C4d deposition on biopsy. Incidence of early AMR was 31%. Significant differences in the number of DSAs (p = 0.0002), cumulative median MFI in DSA class I (p = 0.0004), and total (class I + class II) DSA (p < 0.0001) were found in patients with and without AMR. No significant difference was seen in MCS of T and B FCCM (p = 0.095 and p = 0.307, respectively). The three-yr graft survival in desensitized patients with DSA having total MFI < 9500 was 100% compared to 76% with those having total MFI > 9500 (p = 0.022). Desensitized kidney transplant recipients having higher levels of class I and total DSA MFI are at high risk for AMR and poor graft survival. Recipient DSA MFI appears to be a more reliable predictor of AMR than MCS of FCCM.Clinical Transplantation 10/2010; 25(1):E96-102. · 1.63 Impact Factor