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Rationale: There is significant variation in approach to pre-lung transplant donor-specific antibodies (DSA), with some centers declining to cross any DSA. We implemented a protocol for transplantation for candidates with pretransplant DSA so long as a prospective complement-dependent cytotoxicity crossmatch was negative, regardless of number, specificity, class, or mean fluorescence intensity.Objectives: To compare post-transplant outcomes including overall survival, chronic lung allograft dysfunction-free survival, antibody-mediated rejection, and acute cellular rejection in lung transplant recipients where pretransplant DSA was and was not present.Methods: This was a single-center retrospective cohort study. For recipients with pretransplant DSA, if the prospective complement-dependent cytotoxicity crossmatch was negative, the donor offer was accepted and plasmapheresis was performed within 24 hours of transplantation and continued until retrospective crossmatch results returned. Immunosuppression and post-transplant management were not otherwise modified.Results: Of the 203 included recipients, 18 (8.9%) had pretransplant DSA. The median DSA mean fluorescence intensity was 4,000 (interquartile range, 2,975-5,625; total range, 2,100-17,000). The median number of DSA present per patient was one (interquartile range, 1-2). The presence of pretransplant DSA was not associated with increased mortality (hazard ratio, 1.2; 95% confidence interval [CI], 0.4-3.4) or decreased chronic lung allograft dysfunction-free survival (hazard ratio, 1.1; 95% CI, 0.6-2.1). Recipients with pretransplant DSA were more likely to require prolonged mechanical ventilation (adjusted odds ratio, 7.0; 95% CI, 2.3-21.6) and to have antibody-mediated rejection requiring treatment (adjusted odds ratio, 7.5; 95% CI, 1.0-55.8).Conclusions: A protocol of accepting donor offers for lung transplant candidates with preformed, complement-dependent cytotoxicity crossmatch-negative DSA is associated with increased need for prolonged mechanical ventilation and antibody-mediated rejection without affecting short-term overall or chronic lung allograft dysfunction-free survival.

Supplemental Digital Content is available in the text., 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.

There is significant variability in lung transplant centers' approach to HLA antibodies, creating heterogeneity regarding their clinical significance. Some institutions use beads coated with multiple HLA to screen candidate sera and then use single antigen bead (SAB) to determine antibody identity if the pre-screen is positive. Other centers do not pre-screen, using SAB alone, which may detect low-level antibodies of unknown significance. The primary objective of this study was to review the current literature to identify sources of heterogeneity in the identification of pre- and post-lung transplant HLA antibodies, particularly regarding antibody-detection methods. A random effects model meta-analysis was used to evaluate the relationship between pre-transplant HLA antibodies and the development of de novo donor-specific antibodies (dnDSA) and dnDSA and chronic lung allograft dysfunction (CLAD). Each outcome was stratified by the method of antibody detection (pre-screen followed by SAB vs SAB alone). We identified 13 cohort studies with a total of 3039 patients. The use of pre-screening followed by SAB testing and the use of induction immunosuppression were associated with lower prevalence of dnDSA. Patients with pre-transplant HLA antibodies were more likely to develop dnDSA (hazard ratio [HR] = 1.49, 95% confidence interval [CI]: 1.19-1.86, P < .001). dnDSA was associated with CLAD (HR = 2.02, 95% CI = 1.37-2.97, P < .001). When considering studies using SAB alone, however, pre-transplant antibody status was no longer associated with dnDSA and dnDSA was no longer associated with CLAD. Based on the current literature, SAB-alone testing may detect less clinically relevant antibodies than pre-screening followed by SAB.

BACKGROUND Development of donor-specific antibodies (DSA) after lung transplantation is associated with antibody mediated rejection, acute cellular rejection, and bronchiolitis obliterans syndrome; however, the significance of circulating antibodies before transplant remains unclear. METHODS We performed a retrospective cohort study including recipients of primary lung transplants between 2008 and 2012. We assessed the impact of circulating HLA and noncytotoxic DSA detected before transplant on development of Chronic Lung Allograft Dysfunction (CLAD) or CLAD-related death. RESULTS 30% of subjects had circulating class I antibodies alone, 4% Class II, and 14.4% class I and class II at mean fluorescent intensity greater than 1000. Nine percent of the subjects had DSA class I, 9% class II, and 2.4% both DSA classes 1 and 2. Neither the presence of circulating antibodies (adjusted hazard ratio, 0.87; 95% confidence interval, 0.50-1.54) nor the presence of DSA (adjusted hazard ratio, 1.56; 95% confidence interval, 0.77-3.18) before transplant at mean fluorescent intensity greater than 1000 was associated with the development of CLAD or CLAD-related death. CONCLUSIONS Although in previous studies we have shown an increased incidence of antibody-mediated rejection in patients with pretransplant DSA, neither the presence of HLA antibodies nor DSA translated to an increased risk of allograft dysfunction or death if prospective crossmatch testing was negative. Prospective studies are needed to define the impact of pretransplant sensitization on lung transplant recipients.

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 (κ = 0.448) and good concordance for class II antibodies (κ = 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.

The prevalence of anti-HLA antibodies in lung transplant candidates and their impact on waitlist and transplant outcomes is not known.We examined the prevalence of pretransplant anti-HLA antibodies at varying thresholds and evaluated their impact on outcomes before and after lung transplantation.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.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).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.

A 56-year-old white female presented for evaluation for kidney transplantation in November 2003. Her end-stage renal disease (ESRD) was presumed due to medullary sponge kidney associated with stones and infection and she had started haemodialysis in April 2003. Other medical history included hypertension and anaemia. She was otherwise well. She had had four pregnancies and had received blood transfusions. Examination was unremarkable. Initial tests showed blood group ABO-O. Her current panel reactive antibody (PRA) was 64% by the complement-dependent cytotoxicity (CDC) method and the peak PRA, 5 months prior to that, was 100%. Flow PRA screening confirmed IgG antibodies against class I and II human leukocyte antigens (HLA). The cause of the sensitization to HLA antigens was presumed to be the pregnancies and transfusions. Her 37-year-old son was the only potential living donor but he was ABO-A1; furthermore, she had a positive CDC crossmatch against his T and B lymphocytes. The patient’s baseline anti-A antibody titre was 1:128 (Figure 1). Because of her high sensitization to HLA antigens, the idea of a transplant across the HLA and ABO barrier was discussed with the patient. She was advised to wait several months to see if her PRA or crossmatch titres fell with rituximab therapy. She was vaccinated against pneumococcus and meningococcus in the event that a splenectomy would be included in her immunosuppressive protocol. She received rituximab 375mg/m in March and April of 2004. However, the crossmatch remained strongly positive and the PRA remained high (Table 1). After detailed discussion of the risks vs benefits, the patient and son gave informed consent to proceed with transplantation of a kidney from the son to the mother. Before 4 weeks of the transplant, she began receiving thrice-weekly plasmapheresis and daily tacrolimus plus mycophenolate mofetil (MMF). She was given 10 g of IgG intravenously after each plasmapheresis session. The anti-microbial prophylaxis was sulfamethoxazole-trimethoprim (SMX-TMP) and acyclovir. On 20 December 2004, the T-cell and B-cell crossmatch against her donor were negative and the anti-A titre (IgG titer by enhanced antiglobulin assay) was 1:2 (Figure 1). A third dose of rituximab was given, and she underwent kidney transplantation the next day. A laparoscopic handassisted splenectomy was also performed. There were no intra-operative complications and the allograft produced urine immediately. She received five more sessions of plasmapheresis in the first 10 post-operative days, to maintain anti-A titres 1 : 4. The patient was discharged 1 week after surgery with a plasma creatinine of 63 mmol/l. Immunosuppression was now tacrolimus, MMF and prednisone. After 2 weeks of the transplant, the creatinine rose to 141 mmol/l, and an urgent allograft biopsy was performed. The anti-A titre was 1 : 4 and the crossmatch was positive against donor Tand B-cells by flow cytometry. The biopsy showed mild focal neutrophil capillaritis, acute tubular injury and intraluminal calcifications. There was diffuse staining for C4d in the peritubular capillaries. Interestingly, she had started p.o. phosphate 1–2 days prior to the elevation in plasma creatinine. The possibility of acute calcium—phosphate precipitation in the allograft [1] was, therefore, entertained and the phosphate was stopped. The presumed acute antibodymediated rejection was treated with four sessions of plasmapheresis over 10 days (followed by 10 g IgG) and pulse IV methylprednisolone. The plasma creatinine fell quickly to 71 mmol/l. A repeat flow cytometry crossmatch against donor Tand B-cells was negative. The patient was continued on immunosuppression with tacrolimus, MMF and prednisone. No further Correspondence and offprint requests to: Colm C. Magee, MD, Renal Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. Email: cmagee@partners.org Nephrol Dial Transplant (2007) 22: 602–604

Patients were entered into a randomized trial of prophylaxis for renal allograft rejection by the administration of an anti-human IL-2 receptor antibody, anti-Tac, during the first ten days posttransplant. Interleukin-2 receptor (IL-2 R) expression was measured using two anti-IL-2 R monoclonal antibodies (moAbs), anti-Tac and 1HT4-4H3. These two antibodies recognize closely spaced epitopes on the 55 kD chain of the IL-2 R. IL-2 R expression was examined on peripheral blood small lymphocytes in three groups of patients who received: (A) cyclosporine CsA and prednisone for baseline immunosuppression (n = 9); (B) anti-Tac with CsA and prednisone as baseline immunosuppression (n = 12); and (C) anti-Tac with azathioprine and prednisone as baseline immunosuppression (n = 5). We found that large numbers of T cells express IL-2 receptors despite the presence of anti-Tac (average of IL-2 R-positive cells at day of peak IL-2 R expression 56.0 +/- 20.8% in group A, 65.2 +/- 26.6% in group B, 21.0 +/- 7.4% in group C). IL-2 R expression did not correlate with clinical activity, and the presence or accessibility of epitopes on the same 55 kD chain varied dramatically from patient to patient.