Preformed Donor-specific Antibodies Against HLA Class II and Graft Outcomes in Deceased-donor Kidney Transplantation.

BACKGROUND: Many kidney transplant centers in the United States report both HLA class I and II antibodies detected by sensitive solid-phase assays (SPAs) to United Network for Organ Sharing as unacceptable antigens, significantly reducing the compatible donor organ pool and prolonging waiting time for highly sensitized patients. However, the clinical relevance of all detected donor-specific antibodies (DSAs) by SPA is not unequivocal, because fluorescence intensity does not always accurately reflect antibody pathogenicity. Our center does not exclude patients from transplantation based on DSA class II. METHODS: We performed a retrospective analysis in 179 deceased-donor kidney transplant recipients with solely DSA class II before transplant and patients without DSA and compared graft survival, rejection, and clinical outcomes. Patient survival was also compared with matched controls on the waiting list. RESULTS: Patients transplanted with DSA class II showed a clear survival benefit compared with matched patients who remained on dialysis or were waitlisted on dialysis/transplanted at 5 years (100%, 34%, and 73%, respectively). After a mean follow-up of 5.5 years, there was no significant difference in death-censored graft survival between transplanted patients without DSA and those with preformed DSA class II (adjusted HR 1.10; 95% confidence interval, 0.41-2.97), although the incidence of rejection was higher in recipients with DSA class II (adjusted HR 5.84; 95% confidence interval, 2.58-13.23; P < 0.001). Serum creatinine levels at 1, 3, and 5 years posttransplant did not differ between groups. No predictors of rejection were found, although patients who received basiliximab induction therapy had higher incidence of rejection (100%) compared with those who received antithymocyte globulin (52%). CONCLUSIONS: We conclude that for highly sensitized patients, deceased-donor kidney transplantation with DSA class II yields a survival benefit over prolonged waiting time on dialysis. Instead of listing DSA class II as unacceptable antigens, an individual approach with further immunologic risk assessment is recommended.

Impact of pretransplant anti-HLA antibodies on outcomes in lung transplant candidates.

RATIONALE: The prevalence of anti-HLA antibodies in lung transplant candidates and their impact on waitlist and transplant outcomes is not known. OBJECTIVES: We examined the prevalence of pretransplant anti-HLA antibodies at varying thresholds and evaluated their impact on outcomes before and after lung transplantation. METHODS: We performed a single-center retrospective cohort study including all patients listed for lung transplantation between January 2008 and August 2012. Per protocol, transplant candidates were assessed by solid phase LABscreen mixed Class I and II and LABscreen Single Antigen assays. MEASUREMENTS AND MAIN RESULTS: Among 224 patients, 34% had anti-HLA antibodies at mean fluorescent intensity (MFI) greater than or equal to 3,000 (group III), and 24% had antibodies at MFI 1,000 to 3,000 (group II). Ninety percent of the patients with pretransplant anti-HLA antibodies had class I antibodies, whereas only seven patients developed class II alone. Patients in group III were less likely to receive transplants than patients without any anti-HLA antibodies (group I) (45.5 vs. 67.7%, P = 0.005). Wait time to transplant was longer in group III than group I, although this difference did not meet statistical significance, and waitlist mortality was similar. Among transplant recipients, antibody-mediated rejection (AMR) was more frequent in group III than in group II (20% vs. 0%, P = 0.01) or group I (6.3%, P = 0.05). CONCLUSIONS: The presence of anti-HLA antibodies at the high MFI threshold (>3,000) was associated with lower transplant rate and higher rates of AMR. Screening for anti-HLA antibodies using the 3,000 MFI threshold may be important in managing transplant candidates and recipients.

ATG induction is associated with an increase in anti-HLA antibodies after kidney transplantation.

Anti-human histocompatibility antigen antibodies (HLA-Ab) are deleterious after kidney transplant and may be increased after T-cell depleting agents are given. A retrospective case control study was conducted to evaluate increase in HLA-Ab in 27 kidney transplant recipients who had received antithymocyte globulin (ATG) induction compared with 27 control subjects. A greater than 10% increase in class I or class II HLA-Ab was found in 6 (22.2%) of ATG subjects versus only 1 (3.7%) of non-ATG subjects (p = 0.05). In females, 6/14 ATG subjects developed increased HLA-Ab > or =10% compared with none of the control subjects (p = 0.016). In sensitized subjects, 4/10 in the ATG group developed increased HLA-Ab > or =10% versus none of the controls (p = 0.043). There was no difference in number or severity of acute rejection episodes or estimated glomerular filtration rate 6 months after transplant between the two treatment groups. We conclude that ATG induction may result in increased posttransplant HLA-Ab, particularly in subjects at higher immunologic risk. Further studies are necessary to determine the natural history, clinical consequences, appropriate therapy, and mechanisms responsible for HLA-Ab in this setting.

Investigations into the role of anti-HLA class II antibodies in TRALI.

BACKGROUND: TRALI is thought to be triggered by recipient-specific anti-HLA class I or antibodies against neutrophils in donor plasma. Recently, anti-HLA class II have also been implicated. The prevalence of anti-HLA class II was investigated in normal volunteer platelet donors and in two nonfatal TRALI cases utilizing a flow-based assay. Potential target antigens also were investigated. STUDY DESIGN AND METHODS: Commercial flow cytometry-based assays (FlowPRA, One Lambda, Inc.) for anti-HLA class I and II were compared with standard lymphocytotoxicity tests. Subsequently, 151 volunteer platelet donors and two clinical cases of TRALI were screened with FlowPRA. Immunohistochemical studies were performed on lung tissue from a surgical case, an autopsy case, and a fatal TRALI case. RESULTS: The FlowPRA assays showed moderate concordance for anti-HLA class I (kappa = 0.448) and good concordance for class II antibodies (kappa = 0.801), when compared to standard lymphocytotoxicity assays. Ten and 9 percent of female platelet donors were positive for anti-HLA class I and class II, respectively. Two nonfatal cases of TRALI showed both anti-HLA class I and anti-HLA class II. Immunohistochemical analysis of a TRALI case revealed granulocyte aggregation in alveolar capillaries with activated vascular endothelial cells. HLA class II antigen expression was not present on vascular endothelium or intravascular WBCs; however, strong expression was seen on alveolar macrophages. CONCLUSION: FlowPRA assays often detect anti-HLA class I not detected by conventional lymphocytotoxicity assays. These assays reveal anti-HLA class II in normal female donor plasma and in sera implicated in TRALI. Immunohistochemical studies failed to reveal endothelial or intravascular-WBC HLA class II antigen expression in lung tissue derived from TRALI cases or controls, but demonstrated HLA class II expression on pulmonary macrophages.