High PRA Research Articles

55-P

With availability of specific and sensitive HLA antibody assays, the importance of donor specific antibodies (DSA) in liver transplant has grown. Patients undergoing 2nd liver transplant are at high risk of DSA. We present contrasting outcomes in 2 patients. We retrospectively reviewed the DSA in 2 liver recipients and compared them to the clinical outcomes. Pt #1: A 28 year old woman with PBC underwent a living donor liver transplant in 2006. In the next 4 years she received her 2nd, 3rd and 4th liver transplants due to graft failures. Plasmapheresis and IVIG were used at the 3rd & 4th transplants due to high PRA. A positive B cell flow crossmatch was noted at the last transplant. DSA monitoring was initiated after the 4th transplant. Elevated levels of class II antibodies to DR4, DR53 and DQ8 persisted. Patient had recurrence of jaundice after 6 months and showed short lived response to thymoglobulin, plasmapheresis, IVIG and Rituximab with rebound of DSA within a month of antibody therapy. Coincidentally, donors 2, 3 and 4 all had DR4, DR53 and DQ8. The patient underwent Bortezomib therapy as liver biopsy continued to show mixed portal infiltrate & bile duct injury. Pt #2: A 25 yr old woman with autoimmune hepatitis underwent liver transplant in 2006. Graft function deteriorated following steroid non-responsive rejection treated with Thymoglobulin & OK T3. Retransplant was done in early 2011. B cell crossmatch was positive and patient received thymoglobulin, plasmapheresis and IVIG. DSA assay showed the presence of anti-A2, -A11, -DR53, and -DQ8. During a follow up of 11 months, graft function was excellent despite the persistence of high titers of Class II antibodies. In contrast, level of class I antibodies remain under cutoff. Sensitization status needs serious consideration in retransplantation of liver. Avoidance of donors with unacceptable antigens may be crucial in some liver retransplant recipients. A positive B cell crossmatch may portend a poor outcome.

Outcomes in pediatric cardiac transplantation with a positive HLA cross‐match

Previous studies have shown poor outcomes in pediatric heart transplant recipients with a high PRA or a positive direct donor-recipient cross-match. This study describes outcomes in patients with a positive cross-match at a large pediatric program. Pediatric heart transplant patients at a large single center between January 1993 and July 2009 were reviewed; those with cross-match data were analyzed. Cross-match data were available in 242/262 (92.4%) patients. Indications for transplant were cardiomyopathy (58%), CHD (32%), and retransplant (7%). PRA was ≥10% in 31/213 (14.6%) patients. A retrospective cross-match was positive in 17/31 (55%) patients with PRA ≥10% and 0/182 with PRA <10%. In positive cross-match patients, rejection frequency in the first year post-transplant was higher than negative cross-match patients (1.69 vs. 0.96 episodes/pt year, p = 0.014). There was no difference in rejection frequency after the first year post-transplant (0.18 vs. 0.12 episodes/pt year, p = 0.14). Overall survival was not significantly different between the groups with a median follow-up time of 4.5 yr. Heart transplantation in patients with a positive cross-match may result in good medium-term survival but a higher frequency of early rejection. Further investigation is warranted to define which patients with a positive cross-match will do poorly.

04 Safety and efficacy of basiliximab vs. anti-thymocyte globulin in living donor high risk renal transplant recipients

04 Safety and efficacy of basiliximab vs. anti-thymocyte globulin in living donor high risk renal transplant recipients

Lessons Learned From 119 Consecutive Cardiac Transplants for Pediatric and Congenital Heart Disease

This manuscript reviews all patients who underwent orthotopic heart transplantations (OHT) at our program (116 patients underwent 119 OHT) to describe their diagnostic characteristics and to assess risk factors for mortality. Median age at OHT was 179 days (mean, 1,446.6 ± 188.9 days [4.0 ± 0.5 years]; range, 5 days to 7,125 days [19.5 years]; 15 neonates, 68 infants). Median weight at OHT was 5.5 kg (mean, 17.2 ± 2.1 kg; range, 2.2 to 113 kg). Diagnoses were cardiomyopathy (n = 37), primary transplantation for hypoplastic left heart syndrome (HLHS) or HLHS-related malformation (n = 29), transplantation after prior cardiac surgery for HLHS or HLHS-related malformation (n = 9), non-HLHS congenital heart disease (n = 39), and retransplant (n = 5). Overall Kaplan-Meier 5-year survival was 72.7%. Operative mortality was 12.6% (15 patients). Late mortality was 13.4% (16 patients). Eighty-five patients survived, with a mean follow-up of 5.76 ± 0.48 years (median, 5.1 years; range, 0.12 to 14.0 years). Total follow-up was 507.0 years. No survival difference was seen among the five diagnostic subgroups (p = 0.20). Univariate association between risk factors and survival was assessed for the following variables: age (p = 0.91), weight (p = 0.86), sex (p = 0.47), race (p = 0.40), insurance classification (p = 0.42), high PRA (p = 0.20), pretransplant mechanical circulatory support (p < 0.001), posttransplant mechanical circulatory support (p < 0.001), redo sternotomy (p = 0.07), heterotaxy (p = 0.02), cardiopulmonary bypass time (p = 0.01), and donor heart cross-clamp time (p = 0.02). Excellent results are expected for children undergoing OHT regardless of diagnostic classification. Pretransplant mechanical circulatory support, posttransplant mechanical circulatory support, cardiopulmonary bypass time, donor heart cross-clamp time, and heterotaxy are risk factors for decreased survival.

Does advanced-stage endometriosis affect the gene expression of estrogen and progesterone receptors in granulosa cells?

To evaluate how endometriosis affects the expression of estrogen and progesterone receptors mRNA in granulosa cells. Prospective study. IVF-ET program at Osaka Medical College. Eighteen patients with revised American Fertility Society stage IV endometriosis and 23 patients with tubal infertility without endometriosis. Granulosa cells obtained from patients with endometriosis were examined for estrogen (ER-β, ER-α) and progesterone (PR-A, PR-B) receptor mRNA expression ratio against GAPDH. Hormonal environment and clinical outcome were investigated. Expression of ER and PR mRNA were evaluated by StepOne real-time polymerase chain reaction (PCR) analysis. Total hMG/FSH levels were statistically higher in patients with endometriosis; however, high-quality embryo rates and pregnancy rates were lower in patients with endometriosis than in patients with tubal infertility. Expression of PR-A and ER-α in patients with endometriosis was statistically higher than in patients with tubal infertility. The expression of PRs and ERs in patients with tubal infertility showed a positive correlation; however, it was not identified in the endometriosis group. The higher PR-A and ER-α gene expression in granulosa cells in patients with endometriosis, compared with patients with tubal infertility, might be a leading cause of ovarian dysfunction due to endometriosis.

175-P: Complete Resolution of False “High PRA” Results

175-P: Complete Resolution of False “High PRA” Results

A comparative study on inter and intralaboratory reproducibility of renin measurement with a conventional enzymatic method and a new chemiluminescent assay of immunoreactive renin

The activity of the renin-angiotensin system is usually evaluated as plasma renin activity (PRA, ngAI/ml per h) but the reproducibility of this enzymatic assay is notoriously scarce. We compared the inter and intralaboratory reproducibilities of PRA with those of a new automated chemiluminescent assay, which allows the direct quantification of immunoreactive renin [chemiluminescent immunoreactive renin (CLIR), microU/ml]. Aliquots from six pool plasmas of patients with very low to very high PRA levels were measured in 12 centres with both the enzymatic and the direct assays. The same methods were applied to three control plasma preparations with known renin content. In pool plasmas, mean PRA values ranged from 0.14 +/- 0.08 to 18.9 +/- 4.1 ngAI/ml per h, whereas those of CLIR ranged from 4.2 +/- 1.7 to 436 +/- 47 microU/ml. In control plasmas, mean values of PRA and of CLIR were always within the expected range. Overall, there was a significant correlation between the two methods (r = 0.73, P < 0.01). Similar correlations were found in plasmas subdivided in those with low, intermediate and high PRA. However, the coefficients of variation among laboratories found for PRA were always higher than those of CLIR, ranging from 59.4 to 17.1% for PRA, and from 41.0 to 10.7% for CLIR (P < 0.01). Also, the mean intralaboratory variability was higher for PRA than for CLIR, being respectively, 8.5 and 4.5% (P < 0.01). The measurement of renin with the chemiluminescent method is a reliable alternative to PRA, having the advantage of a superior inter and intralaboratory reproducibility.

Highly Successful and Low-Cost Desensitization Regime for Sensitized Living Donor Renal Transplant Recipients

10–30% of dialysis population awaiting renal transplantation is sensitized. Present desensitization protocols use intravenous immune globulins, rituximab, and plasmapheresis in various combinations; however, these regimens are unaffordable by many in developing countries. We tried desensitization with mycophenolate mofetil and plasmapheresis. Methods. Patients with high PRA titre (≥50%) or positive crossmatch (>10%) were treated with MMF for a month before proposed transplant and were given five sittings of plasmapheresis. Results. 11 of 12 patients had normalization of PRA/crossmatch with this regimen and were successfully transplanted. One patient lost the graft due to graft vein thrombosis, and two patients died within three months after transplant due to septicemia and pulmonary embolism, respectively, with a functioning graft. No patient, including the two who died, developed clinical rejection over a mean follow-up of 10 months (range 1–16 months). Mean serum creatinine at last follow up was 1.1 mg/dL (range 0.9–1.3 mg/dL). Conclusions. Though the number of patients studied is small, we feel that highly sensitized patients awaiting living donor renal transplant should be tried on this simple and cost-effective regime before transplant. The more aggressive and expensive approaches incorporating IVIg and rituximab should be used only if this relatively low-cost regime is unsuccessful.

Prediction of Early Readmission in Medical Inpatients Using the Probability of Repeated Admission Instrument

In the absence of an instrument to predict risk of early readmission, examination of the well-validated probability of repeated admission (Pra) for this new purpose is indicated. The objective of this study was to examine the use of the Pra in accurately identifying and predicting adult medical inpatients at risk of early readmission. Over 20 months, 1,077 consecutively admitted medical patients were enrolled in this prospective cohort study at a Midwestern tertiary care medical center. Pra score values were calculated within 2 days of discharge. Databases at the index medical center and other institutions were queried to identify readmission within 41 days. Prevalence of readmission was 14% (confidence interval = 12.4%-15.6%). Pra score values ranged from .16 to .75. Indices to identify and predict readmission for a range of cut points were reported to minimize loss of information. The likelihood ratio for patients with a Pra score value > or = .53 was 1.67. Using a Pra cut point of > or = .45, readmission of patients with a high Pra was 2.3 times more likely than that of patients with a low Pra (p < .001, confidence interval = 1.63-3.27). Comparisons between cohorts indicated that differences existed with four of the eight variables used to calculate the Pra score: diabetes (p = .01), self-rated health status (p = .007), and number of doctor visits (p < .001) and hospitalizations (p < .001) in the past year. Within this heterogeneous sample, prediction of readmission using the Pra was better than chance. These findings may facilitate development of a better predictive model by combining select Pra variables with other variables associated with early readmission.

Will Transplant Tourism Erode the Surgical Skills of Transplant Surgeons in Israel?

To the Editor: In the May 2008 issue of AJT, Drs. Budiani-Saberi and Delmonico address the issue of ‘transplant tourism’ (1Budiani-Saberi DA Delmonico FL Organ trafficking and transplant tourism: A commentary on the global realities.Am J Transplant. 2008; 8: 925-929Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). The authors state that because of transplant tourism ‘the expertise in performing organ transplantation within Israel may be lost’, quoting an Internet reference (2Israel Citizens Organ Transplant in Colombia – Medellin. Available at: http://www.happylife.co.il/main_eng.html. Accessed May 27, 2008.Google Scholar). The website quoted belongs to Ventex Management Medical Services LTD. According to the front page of that website, Ventex ‘is specialized in sending Israel citizen for transplant in Colombia’ (2Israel Citizens Organ Transplant in Colombia – Medellin. Available at: http://www.happylife.co.il/main_eng.html. Accessed May 27, 2008.Google Scholar) (quote slightly changed for correct spelling). As such, Ventex has a business interest in convincing the Israeli patients that transplantation abroad is a better alternative to surgery in Israel. As a transplant surgeon, who practiced in Israel between 2004 and 2006, I do not share the beliefs of that specific website and organization. ‘Transplant tourism’ is reserved for the patients who can afford travel costs for themselves and their family. As brokers facilitating this process become experienced, they tend to avoid problem patients. While straightforward cases end up seeking transplantation elsewhere, the transplant surgeon practicing in Israel operates more often than the average on patients with multiple comorbidities, sensitized patients with high PRA, patients with challenging anatomy, while trying to overcome donor shortage by using expanded criteria donor organs and donation after cardiac death. Based on my firsthand experience, I am convinced that the skills of the Israeli transplant surgeons will not suffer due to transplant tourism, in contrast to the concerns voiced in the paper. While publications in peer-reviewed journals are typically trustworthy references, websites can be biased for various reasons. Therefore, I urge the authors and the readers to exercise caution when quoting information from websites.

Do we have a answer for patients with High PRA or Positive cross match ?

Do we have a answer for patients with High PRA or Positive cross match ?

271: Perioperative Alemtuzumab (Campath 1-H) and Plasmapheresis for High-PRA, Positive Lymphocyte-Crossmatch Heart Transplant: A Strategy To Shorten LVAD Support

Patients on a LVAD often have a high PRA. Conventional therapy is to await a heart from a negative prospective-crossmatch donor. We transplanted 3 high-PRA patients with non-crossmatched hearts, using intra- and post-op plasmapheresis and long-term T/B/plasma cell therapy with Alemtuzumab.

205-P: Forteen day desensitization enabled kidney transplantation of patient with high PRA and donor specific antibodies

205-P: Forteen day desensitization enabled kidney transplantation of patient with high PRA and donor specific antibodies

Complex HLA antibody responses: HLA-A2 subtype reactive antibodies in high PRA sera

Complex HLA antibody responses: HLA-A2 subtype reactive antibodies in high PRA sera

Synthesis of New and Memory HLA Antibodies From Acute and Chronic Rejections Versus Pregnancies and Blood Transfusions

Background This study compared HLA antibody (abs) production following acute (AR) and chronic (CR) rejection with HLA abs production following blood transfusions (TF) or pregnancies (P) among kidney and kidney pancreas transplant candidates. Methods Serum samples from 145 patients were screened for anti-HLA abs by flow cytometry using beads coated with purified HLA molecules. Among these patients, nine had lost their graft due to AR; 13, CR; six had been immunized by a single P; 20 by no more than two TF; 28 had no documented immunization; and 69 had multiple immunizations. A Fisher exact test was used for the statistical analysis. Results Neither a single P nor a couple of TF by themselves immunized primary transplant recipients ( P = .17, and P = .42, respectively). However, multiple P and TF together provided a potent immunogenic stimulus ( P = .00001). In contrast, a single allograft loss induced a strong anti-HLA response ( P = 1.03 × 10 −8). Following AR, anti-class I and II abs ( P = .001), and following CR, anti-class II abs developed ( P = .03). Waitlisted female candidates had significantly high PRA values than men ( P = .00005), possibly because women had received significantly more immunizations than men ( P = 4.0 × 10 −10). Summary Patients are likely to produce both class I and II HLA abs following AR and only class II abs following CR. A couple of TF or a P may not be immunogenic; however, together they have great potential to sensitize female candidates. Perhaps that is why waitlisted women are far more immunized than waitlisted men.

The Use of Platelet Antibody Testing at a Tertiary Medical Center.

Detection of platelet antibodies is often helpful in the diagnosis of platelet transfusion refractoriness (PR), neonatal alloimmune thrombocytopenia (NAIT), and post-transfusion purpura (PTP), but is controversial in idopathic thrombocytopenia purpura (ITP). We performed a retrospective chart review to determine the utilization and value of a solid-phase ELISA assay consisting of 6 wells coated with platelet glycoproteins (GP), and one well with HLA class I antigens (GTI PakPlus, Brookfield WI) at our medical center. For a 3 year period between June 2001 and June 2004, 183 tests for 163 patients were ordered for the following diagnostic questions: 151 tests for ITP, 19 for PR, 6 for NAIT, 2 for transfusion-related acute lung injury (TRALI), 5 for unclear reasons, and none for PTP. The mean patient age was 55 (range 12 – 94), 55% were male, 50% were inpatients, and the mean platelet count (excluding mothers with NAIT and a patient with TRALI) was 60x109/l (range 5–215 x 109/l). There were 48 patients who had 51 positive tests (28%), of which 61% were inpatients. The mean platelet count was 47 x 109/l (range 5–115 x 109/l). Only one or more GP wells were positive in 57% of positive tests, only the HLA class I well was positive in 27%, and ≥one GP well plus the HLA well were positive in 16%. To determine how results were used, we reviewed the medical records associated with each positive test. Out of 51 positive tests, no mention was made of the test order or result in 21 (41%). For 6 tests (12%), the order was noted, but no results were mentioned. In the other 24 tests, the result was used to make a diagnosis in 12 cases (3 NAIT, 3 PR, 6 ITP), and in 12 the result was used to confirm an already known diagnosis (1 NAIT, 4 PR, 7 ITP). Therapy was started before the test was completed on 17 occasions (4 PR, 13 ITP). Eighteen patients had repeat testing (38 tests). The interval of time between tests was 112 days on average (range 8–365), including 5 sets within 28 days. The results were unchanged in 11 patients (61%); in 5 patients GP wells changed from positive to negative; and in 2 patients the HLA well changed, including a patient with pre- and post-transfusion samples for evaluation of TRALI, and another in whom the test went from positive to negative. In 3 mothers evaluated for NAIT with positive results (1 HPA-1a, 2 HPA-5b), confirmation was obtained at a reference laboratory (Blood Center for Southeastern Wisconsin). A total of fifteen patients were evaluated for PR with 19 samples. Seventeen samples underwent parallel testing (HLA lymphocytotoxic antibody screen alone, or with platelet antibody detection at the reference laboratory); 13 results (76%) were confirmed. All four mismatches were between the HLA ELISA well and the HLA antibody screen: in 2 samples the PakPlus was positive but the HLA antibody screen was negative; in the other 2 a negative HLA well was accompanied by a high PRA (63%, 80%). These results demonstrated that 1) the ELISA assay was routinely negative in patients with platelet counts >115 x 109/l; 2) 53% of positive results were ignored in the medical records; 3) the test had a moderate reproducibility (61%), but could have been related to clinical changes in the patients; and 4) the yield of clinically useful information for patients with ITP (151 tests, 13 positive results utilized for clinical management) was low. For PR, the PakPlus is reliable but only qualitative, compared to the quantitative HLA antibody screen. The test appears most useful for rapid antibody identification in NAIT and is of limited clinical utility for ITP.

Complex HLA antibody responses: Epitope specificity of HLA-A2 reactive antibodies in high PRA sera

Complex HLA antibody responses: Epitope specificity of HLA-A2 reactive antibodies in high PRA sera

Just how complex are the HLA Class I alloantibodies in patients with extremely high PRA?

Just how complex are the HLA Class I alloantibodies in patients with extremely high PRA?

Predicting crossmatch outcome in high PRA renal transplant patients: Triplet amino acid matching vs. single-antigen antibody screening

Predicting crossmatch outcome in high PRA renal transplant patients: Triplet amino acid matching vs. single-antigen antibody screening

ANTI-THYMOCYTE RABBIT IMMUNOGLOBULIN: POSTOPERATIVE RISK FACTOR FOR SIROLIMUS TREATED RENAL TRANSPLANT PATIENTS

O211 Aims: Improved efficacy of immunosuppression has decreased the length of post renal transplant hospitalization and has facilitated patient return to work. Randomized controlled studies of sirolimus treated renal transplant patients suggested an increased incidence in perioperative wound complications. This study analyzes the effect of Rabbit Anti-Thymocyte Globulin (RATG) on postoperative complications of sirolimus regimens. Methods: 412 renal transplants were performed and managed postoperatively at two university affiliated hospitals between January 1st 2001 and December 31st 2003 receiving corticosteroids and sirolimus, with delay of cyclosporine introduction until serum creatinine levels decreased below 3mg/dL. Patients were induced with Basiliximab 20mg on day 0 and day 4 (n=283) unless they had a high PRA or were retransplant patients; these latter groups received RATG for induction (n=129) until cyclosporine could be started, for a maximum of two weeks postoperatively. Postoperative hernia, wound infections and lymphoceles required drainage were noted for each group, and statistical significance of the differences in occurrence were analyzed by Chi-Square analysis. The incidence of rejection was 14.5% for Basiliximab vs. 8.5% for RATG induced patients. Only non-rejecting patients were included in the statistical analysis, to avoid confounding variable of rejection treatment. Patients with follow-up less than 30 days were also excluded. The study group included 350 patients, 235 with Basiliximab induction (group 1) and 115 with RATG induction (group 2). The mean follow-up was 21.8 months (SD ± 11). Results: The percentage of patients with wound complications was 26.0% vs. 39.1% (p 0.025) for group 1 and group 2 respectively. Incisional hernias occurred in 10.6% vs. 18.3% patients (p 0.05), patients with wound infections were 11.1% vs. 16.5% (p 0.2), while lymphoceles requiring drainage were 10.6% vs. 15.9% (p 1) for both groups respectively. Conclusions: RATG induced renal transplants managed with sirolimus, cyclosporine and steroids have a significant increase in postoperative wound complications. The incidence of incisional hernias was higher in thymoglobulin-induced patients with statistically significant difference. Lymphocele and wound infection complications were also higher but not statistically significant. Avoidance of RATG minimizes postoperative complications in sirolimus treated renal transplant patients.