Monday, December 31, 2012

Please fill the paired kidney exchange questionnaire !!

Dear Colleague,
we are collecting data on paired kidney exchange (PKE) programs worldwide. Please fill the questionnaire that appears in the popup during webpage loading or by clicking this direct link :

Answer statistics will be available after submitting the questionnaire.
Thanks for your help !

Sunday, December 30, 2012

Frequent hepatocyte chimerism in long-term human liver allografts independent of graft outcome.

Microchimerism after liver transplantation is considered to promote graft tolerance or tissue repair, but its significance is controversial. By using multiplex polymerase chain reaction (PCR) of short tandem repeat (STR) loci after laser capture microdissection of hepatocyte nuclei, we compared the proportions of recipient-derived hepatocytes in long-term stable liver allografts and late dysfunctional allografts caused by chronic rejection or idiopathic post-transplantation hepatitis. Through fluorescence in situ hybridization (FISH), we also analyzed the presence of recipient-derived Y-positive hepatocytes in the biopsies of livers transplanted from female donors to male recipients. The study population comprised 24 pediatric liver transplant recipients who survived with the initial graft, whose 10-year protocol biopsy records were available, and who had normal liver function (stable graft, SG; n=13) or a late dysfunctional graft (LDG; n=11) with similar follow-up periods (mean 10.8 years in the SG group and 11.2 years in the LDG group). STR analysis revealed that hepatocyte chimerism occurred in 7 of 13 (54%) SGs and 5 of 11 (45%) LDGs (p=0.68). The proportion of hepatocyte chimerism was low, with a mean of 3% seen in 2 of 3 female-to-male transplanted livers (one each of SG and LDG). In conclusion, hepatocyte chimerism was a constant event. The extent of engraftment of recipient-derived hepatocytes does not seem to correlate with the degree of hepatic injury in long-term liver allografts (read more)

Thursday, December 27, 2012

Comprehensive evaluation of two HLA-B17 monoclonal antibodies for flow cytometry-based HLA-B57/B58 screening prior to abacavir prescription

Hypersensitivity reactions to the drug abacavir, used to treat HIV/AIDS patients, is associated with possession of HLA-B*57:01. We have carefully assessed two commercially available HLA-B57/B58 murine monoclonal antibodies [0196HA and BIH0243 (One Lambda Inc.)] in a simple flow cytometry-based assay. The evaluation involved tests on 228 reference and random samples covering 91% of all WHO recognized HLA-A, B and C specificities. These involved donors with six different HLA-B*57 alleles and included 19 examples of B*57:01. Both antibodies unambiguously detected B57, but there were small difference in their reactivity against B57-positive non-B*57:01 samples. Importantly, there was no reactivity against B57/B58-negative samples. The possible amino acid motifs involved in the reactivity of these antibodies with B57/B58 were delineated. Thus, HLA-B57/B58, normally present in <10% of patients, can be easily recognized using these two antibodies and further tested by a DNA-based typing method to identify B*57:01 (read more)

Saturday, December 22, 2012

16th IHIW: Anti-HLA alloantibodies of the of IgA isotype in re-transplant candidates

In this multicentre study, sera from 803 retransplant candidates, including 775 kidney transplant recipients, were analysed with regard to the presence and specificity of anti-HLA alloantibodies of the IgA isotype using a modified microsphere-based platform. Of the kidney recipients, nearly one-third (n = 237, 31%) had IgA alloantibodies. Mostly, these antibodies were found in sera that also harboured IgG alloantibodies that could be found in a total of 572 (74%) of patients. Interestingly, IgA anti-HLA antibodies were preferentially targeting HLA class I antigens in contrast to those of the IgG isotype, which targeted mostly both HLA class I and II antigens. Donor specificity of the IgA alloantibodies could be established for over half of the 237 patients with IgA alloantibodies (n = 124, 52%). A further 58 patients had specificities against HLA-C or HLA-DP, for which no information regarding donor typing was available. In summary, these data showed in a large cohort of retransplant candidates that IgA alloantibodies occur in about one-third of patients, about half of these antibodies being donor specific (read more)

Friday, December 21, 2012

Cancer Transmission From Organ Donors—Unavoidable But Low Risk

Background: Donor origin cancer (DOC) in transplant recipients may be transmitted with the graft (donor-transmitted cancer [DTC]) or develop subsequently from the graft (donor-derived cancer [DDC]).
Methods: Recipients with DOC between January 1, 2001, and December 31, 2010, were identified from the United Kingdom Transplant Registry and database search at transplantation centers.
Results: Of 30,765 transplants from 14,986 donors, 18 recipients developed DOC from 16 donors (0.06%): 3 were DDC (0.01%) and 15 were DTC (0.05%). Of the 15 DTCs, 6 were renal cell cancer; 5, lung cancer; 2, lymphoma; 1, neuroendocrine cancer; and 1, colon cancer. Recipients with DTC underwent explant/excision (11), chemotherapy (4), and radiotherapy (1). Of 15 recipients, 3 (20%) recipients with DTC died as a direct consequence of cancer. Early DTC (diagnosed ≤6 weeks of transplantation) showed a better outcome (no DTC-related deaths in 11 cases) as opposed to late DTC (DTC-related deaths in 3 of 4 cases). Five-year survival was 83% for kidney recipients with DTC compared with 93% for recipients without DTC (P=0.077). None of the donors resulting in cancer transmission was known to have cancer at donation.
Conclusions: DTC is rare but frequently results in graft loss and death. The risk of cancer transmission cannot be eliminated because, in every case, the presence of cancer was not known at donation. This information will allow informed consent for prospective recipients. Explantation/excision is likely to benefit recipients with localized cancer, but in transplants other than kidney/pancreas, the benefits should be balanced against the risks of retransplantation (read more).

Thursday, December 20, 2012

Impact of donor specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation. A Eurocord, Societe Francophone d'Histocompatibilite et d'Immunogenetique (SFHI) and Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) analysis.

Background. Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. Design and Methods. To analyze the effect of anti-HLA-antibodies on unrelated cord blood transplantation outcomes, we analyzed 294 unrelated cord blood transplant recipients after reduced intensity conditioning regimen. The majority of the patients (82%) were transplanted for malignancies, 60% with double-unrelated cord blood transplant, 63% were HLA mismatched. Retrospectively, pre-unrelated cord blood transplant serum was tested for HLA-Ab using LuminexTM platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. Results. Among 62 recipients (23%) who had anti-HLA- antibodies before unrelated cord blood transplant, 14 patients had donor specific anti-HLA-antibodies (DSA) (7 were donor-specific- anti-HLA-antibodies for single-unrelated cord blood transplant and 7 for double- unrelated cord blood transplant). Donor-specific- anti-HLA-antibodies threshold ranged from 1620-17629 of mean fluorescence intensity (MFI). Cumulative incidence of day-60 neutrophil engraftment was 76%. It was 44% for recipients with donor-specific- anti-HLA-antibodies and 81% in those without donor-specific- anti-HLA-antibodies (p=0.006). The cumulative incidence of 1-year transplant related mortality was 46% in patients with donor-specific- anti-HLA-antibodies and 32% in those without antibodies (p=0.06). The presence of donor-specific-anti-HLA-antibodies was associated with a trend for decreased survival rate (42% vs. 29%, p=0.07). Conclusions. Donor-specific-anti-HLA-antibody in recipients of unrelated cord blood transplant is associated with graft failure and decreased survival. Patient's screening for donor-specific-anti-HLA-antibodies before unrelated cord blood transplantation is recommended before choosing a HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit when the patient has donor-specific-anti-HLA-antibodies against (read more)

Monday, December 17, 2012

Does Rh immune globulin suppress HLA sensitization in pregnancy?

Background : How Rh immune globulin (RhIG) prevents sensitization to D antigen is unclear. If RhIG Fc delivers a nonspecific immunosuppressive signal, then RhIG may inhibit sensitization to antigens other than D. HLA antibody prevalence was compared in previously pregnant D– versus D+ women to investigate whether RhIG suppresses HLA sensitization.
Study Design and Methods : In the Leukocyte Antibody Prevalence Study (LAPS), 7920 volunteer blood donors were screened for anti-HLA and surveyed about prior pregnancies and transfusions. A secondary analysis of the LAPS database was performed.
Results: D– women not more than 40 years old (presumed to have received antenatal with or without postpartum RhIG in all pregnancies) had a significantly lower HLA sensitization rate than D+ women (relative risk, 0.58; 95% confidence interval [CI], 0.40-0.83). When stratified by deliveries (one, two, three, or four or more), D– women not older than 40 were HLA sensitized less often than D+ women in every case. In contrast, a clear relationship between D type and HLA sensitization was not seen in older previously pregnant women whose childbearing years are presumed to have preceded the use of routine RhIG prophylaxis. In a multivariable logistic regression model, D– women not more than 40 years old remained significantly less likely to be HLA sensitized compared with D+ women after adjusting for parity, time from last pregnancy, lost pregnancies, and transfusions (odds ratio [OR], 0.55; 95% CI, 0.34-0.88).
Conclusion : Consistent with a nonspecific immunosuppressive effect of RhIG, younger previously pregnant D– women were less likely than previously pregnant D+ women to be HLA sensitized (read more)

Thursday, December 13, 2012

Cord-Blood Engraftment with Ex Vivo Mesenchymal-Cell Coculture

Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells.We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood. Coculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×107 total nucleated cells per kilogram of body weight and 1.81×106 CD34+ cells per kilogram — doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P<0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P=0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P<0.001).Transplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only (read more)

Saturday, December 8, 2012

Effects of HLA-Matched Blood Transfusion for Patients Awaiting Renal Transplantation

imageBackground: HLA sensitization in potential renal transplant recipients hinders opportunities of receiving suitable organs. To alleviate this, we sought to determine if supplying closely HLA Class I matched leukodepleted blood would minimize sensitization.
Methods: Patients received HLA selected or random units of packed red cells. Selected units were sourced from blood donors included in the British Bone Marrow Registry and had no HLA-A and HLA-B mismatches where available, or alternatively, no HLA antigens with more than five immunogenic triplet mismatches as determined by the HLAMatchmaker algorithm. Posttransfusion antibody screening confirmed development of de novo Class I and Class II HLA-specific IgG antibody(s) or increases in preexisting antibody levels of at least 20%.
Results: Thirty-seven and 31 patients received HLA selected (mean, 2.5 units) and random (mean, 3.4 units) blood, respectively. A total of 20 of 37 (54.1%) patients receiving selected units and 10 of 31 (32.3%) patients receiving random units were previously sensitized. No patient receiving HLA selected units demonstrated any change in antibody levels. In patients who received random units, 7 of 31 demonstrated changes in antibody levels with three developing de novo HLA-specific antibodies and four an increase in panel reactive antibody (PRA) of at least 20% (P=0.002).
Conclusions: The risk of developing HLA-specific antibody is significantly reduced in renal patients awaiting transplantation when transfused with HLA selected units of blood compared with random units. With planning, access to HLA typed blood is achievable as many blood transfusion centers recruit donors for stem cell donor registries (read more and editorial)

Friday, December 7, 2012

Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis

Enhancement of hematopoietic recovery after radiation, chemotherapy, or hematopoietic stem cell (HSC) transplantation is clinically relevant. Dipeptidylpeptidase (DPP4) cleaves a wide variety of substrates, including the chemokine stromal cell-derived factor-1 (SDF-1). In the course of experiments showing that inhibition of DPP4 enhances SDF-1–mediated progenitor cell survival, ex vivo cytokine expansion and replating frequency, we unexpectedly found that DPP4 has a more general role in regulating colony-stimulating factor (CSF) activity. DPP4 cleaved within the N-termini of the CSFs granulocyte-macrophage (GM)-CSF, G-CSF, interleukin-3 (IL-3) and erythropoietin and decreased their activity. Dpp4 knockout or DPP4 inhibition enhanced CSF activities both in vitroand in vivo. The reduced activity of DPP4-truncated versus full-length human GM-CSF was mechanistically linked to effects on receptor-binding affinity, induction of GM-CSF receptor oligomerization and signaling capacity. Hematopoiesis in mice after radiation or chemotherapy was enhanced in Dpp4−/− mice or mice receiving an orally active DPP4 inhibitor. DPP4 inhibition enhanced engraftment in mice without compromising HSC function, suggesting the potential clinical utility of this approach (read more)

Tuesday, December 4, 2012

A Web-Based Application for Initial Screening of Living Kidney Donors: Development, Implementation and Evaluation

Most centers utilize phone or written surveys to screen candidates who self-refer to be living kidney donors. To increase efficiency and reduce resource utilization, we developed a web-based application to screen kidney donor candidates. The aim of this study was to evaluate the use of this web-based application. Method and time of referral were tabulated and descriptive statistics summarized demographic characteristics. Time series analyses evaluated use over time. Between January 1, 2011 and March 31, 2012, 1200 candidates self-referred to be living kidney donors at our center. Eight hundred one candidates (67%) completed the web-based survey and 399 (33%) completed a phone survey. Thirty-nine percent of donors accessed the application on nights and weekends. Postimplementation of the web-based application, there was a statistically significant increase (p < 0.001) in the number of self-referrals via the web-based application as opposed to telephone contact. Also, there was a significant increase (p = 0.025) in the total number of self-referrals post-implementation from 61 to 116 per month. An interactive web-based application is an effective strategy for the initial screening of donor candidates. The web-based application increased the ability to interface with donors, process them efficiently and ultimately increased donor self-referral at our center (read more)

Saturday, December 1, 2012

Donor-Specific Antibodies Adversely Affect Kidney Allograft Outcomes

The effect of low titers of donor-specific antibodies (DSAs) detected only by sensitive solid-phase assays (SPAs) on renal transplant outcomes is unclear. We report the results of a systematic review and meta-analysis of rejection rates and graft outcomes for renal transplant recipients with such preformed DSAs, defined by positive results on SPA but negative complement-dependent cytotoxicity and flow cytometry crossmatch results. Our search identified seven retrospective cohort studies comprising a total of 1119 patients, including 145 with isolated DSA-SPA. Together, these studies suggest that the presence of DSA-SPA, despite a negative flow cytometry crossmatch result, nearly doubles the risk for antibody-mediated rejection (relative risk [RR], 1.98; 95% confidence interval [CI], 1.36–2.89; P<0.001) and increases the risk for graft failure by 76% (RR, 1.76; 95% CI, 1.13–2.74; P=0.01). These results suggest that donor selection should consider the presence of antibodies in the recipient, identified by the SPA, even in the presence of a negative flow cytometry crossmatch result (read more)

Low- versus high-dose rituximab for antibody-mediated rejection after kidney transplantation

The treatment of antibody-mediated rejection (AMR) after kidney transplantation is based on the association of

plasma exchange (PE) with or without rituximab, with or without intravenous immunoglobulins (Iv-Ig). However, if used, the optimal dose of rituximab is still unknown. Furthermore, an increased risk of infection has been reported in kidney-transplant patients receiving rituximab, mainly when combined with polyclonal antibodies. Here, we compared the efficacy and safety of low-dose (375 mg/m²/week for 2 weeks) to high-dose (375 mg/m²/ week for 3–5 weeks, median 4) rituximab given for AMR after kidney transplantation (read more).

Preformed Complement-Activating Low-Level Donor-Specific Antibody Predicts Early Antibody-Mediated Rejection in Renal Allografts.

BACKGROUND: Donor-specific anti-HLA antibodies (DSA) are a major cause of alloimmune injury. Transplant recipients with negative complement-dependent cytotoxic crossmatch (CDC-XM) and donor cell-based flow cytometric crossmatch (flow-XM) but low level DSA (i.e., by Luminex) have worse outcomes compared with nonsensitized patients. The aim of this study was to establish whether complement-activating ability in this low-level DSA, present before transplantation, as determined by this technique is important in dictating pathogenicity.
METHODS: We retrospectively studied 52 patients with preformed DSA detected by single-antigen flow cytometric fluorescent beads (SAFBs). Patients were transplanted using a steroid-sparing regimen consisting of alemtuzumab induction, 1 week of corticosteroids and tacrolimus monotherapy.Fifteen (29%) of 52 patients experienced antibody-mediated rejection (AMR), whereas 37 (71%) patients did not. There were no demographic differences between patients with AMR and those without. Pretransplant sera were retested using a modified (SAFB) assay, which detects the presence of the complement fragment C4d as a result of DSA-induced complement activation.
RESULTS: C4d+DSA were detected in 10 (19%) of 52 patients. Biopsy-proven AMR occurred in 7 (70%) of the 10 patients with C4d+DSA and in 8 (19%) of 42 patients with C4d-DSA. AMR-free survival was worse in patients with C4d+DSA (P<0.001).
CONCLUSIONS: The ability of preformed, low-level, DSA to trigger C4d fixation in vitro in patients with negative conventional crossmatch tests is predictive for AMR. C4d SAFB is potentially a powerful tool for risk stratification prior to transplantation and may allow identification of unacceptable donor antigens, or patients who may require enhanced immunosuppression (read more)