Humoral Alloreactivity in VCA Recipients: Should We Learn From Our Experience?

Initially overlooked in favor of T cell-mediated rejection, the importance of the humoral alloimmune response has progressively emerged. As a result, antibody-mediated rejection is now widely recognized as the main cause of late allograft loss in most (if not all) types of solid-organ transplantation. Over the last 2 decades, vascularized composite allotransplantation (VCA) has appeared for replacing tissue defects in patients for whom no other satisfactory reconstructive options were available. Although it is now clear that VCA recipients can develop donor-specific antibodies, conclusions made in solid organ transplantation regarding antibody-mediated rejection may not systematically apply to VCA. Here, we propose to use the experience gained in organ transplantation to shed light on the path that shall be followed to evaluate and manage humoral alloreactivity in VCA recipients.

Induction of Accommodation by Anti-complement Component 5 Antibody-based Immunosuppression in ABO-incompatible Heart Transplantation.

BACKGROUND: Plasmapheresis in combination with immunoglobulin and rituximab is often used to induce accommodation in ABO-incompatible (ABOi) living-donor transplantation; however, this regimen cannot be applied to cases of ABOi deceased-donor transplantation. Here, we investigated whether an anti-complement component 5 (C5) antibody-based regimen can induce accommodation in ABOi heart transplantation. METHODS: Both IgM and IgG anti-blood type A antibodies were induced in wild-type mice by sensitization using human blood type A antigen. Heterotopic ABOi heart transplantation was performed from human blood type A-transgenic C57BL/6J mice to sensitized wild-type DBA/2 mice. RESULTS: Either anti-C5 antibody or conventional triple immunosuppressants (corticosteroid, tacrolimus, mycophenolate mofetil) alone did not induce accommodation in majority of ABOi heart allografts, whereas their combination induced accommodation in more than 70% of cases despite the presence of anti-A antibodies. The combination therapy markedly suppressed the infiltration of T cells and macrophages into ABOi allografts, despite mild deposition of IgG and C4d. T-cell activation and differentiation into Th1, Th2, and Th17 cells were suppressed along with CD49dCD4 T and follicular helper T cells in the combination treatment group. CD24 B cells, including both CD24CD23 marginal zone B cells and CD24CD23 T2-marginal zone B cells, were increased in the accommodation group. CONCLUSIONS: C5 inhibitor-based immunosuppression induced accommodation in murine ABOi heart transplantation, presenting a promising strategy for ABOi deceased-donor transplantation.

Results of a multicenter prospective clinical study in Japan for evaluating efficacy and safety of desensitization protocol based on rituximab in ABO-incompatible kidney transplantation.

BACKGROUND: Deceased organ donations are rare in Japan, with most kidney transplants performed from a limited number of living donors. Researchers have thus developed highly successful ABO-incompatible transplantation procedures, emphasizing preoperative desensitization and postoperative immunosuppression. A recent open-label, single-arm, multicenter clinical study prospectively examined the efficacy and safety of rituximab/mycophenolate mofetil desensitization in ABO-incompatible kidney transplantation without splenectomy. METHODS: Mycophenolate mofetil and low dose steroid were started 28 days pretransplant, followed by two doses of rituximab 375 mg/m2 at day -14 and day -1, and postoperative immunosuppression with tacrolimus or ciclosporin and basiliximab. The primary endpoint was the non-occurrence rate of acute antibody-mediated rejection. Patient survival and graft survival were monitored for 1 year posttransplant. RESULTS: Eighteen patients received rituximab and underwent ABO-incompatible kidney transplantation. CD19-positive peripheral B cell count decreased rapidly after the first rituximab infusion and recovered gradually after week 36. The desensitization protocol was tolerable, and most rituximab-related infusion reactions were mild. No anti-A/B antibody-mediated rejection occurred with this series. One patient developed anti-HLA antibody-mediated rejection (Banff 07 type II) on day 2, which was successfully managed. Patient and graft survival were both 100 % after 1 year. CONCLUSION: Our desensitization protocol was confirmed to be clinically effective and with acceptable toxicities for ABO-I-KTx (University Hospital Medical Information Network Registration Number: UMIN000006635).

5-Aminolevulinic acid regulates the inflammatory response and alloimmune reaction.

5-Aminolevulinic acid (5-ALA) is a naturally occurring amino acid and precursor of heme and protoporphyrin IX (PpIX). Exogenously administrated 5-ALA increases the accumulation of PpIX in tumor cells specifically due to the compromised metabolism of 5-ALA to heme in mitochondria. PpIX emits red fluorescence by the irradiation of blue light and the formation of reactive oxygen species and singlet oxygen. Thus, performing a photodynamic diagnosis (PDD) and photodynamic therapy (PDT) using 5-ALA have given rise to a new strategy for tumor diagnosis and therapy. In addition to the field of tumor therapy, 5-ALA has been implicated in the treatment of inflammatory disease, autoimmune disease and transplantation due to the anti-inflammation and immunoregulation properties that are elicited with the expression of heme oxygenase (HO)-1, an inducible enzyme that catalyzes the rate-limiting step in the oxidative degradation of heme to free iron, biliverdin and carbon monoxide (CO), in combination with sodium ferrous citrate (SFC), because an inhibitor of HO-1 abolishes the effects of 5-ALA. Furthermore, NF-E2-related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), and heme are involved in the HO-1 expression. Biliverdin and CO are also known to have anti-apoptotic, anti-inflammatory and immunoregulatory functions. We herein review the current use of 5-ALA in inflammatory diseases, transplantation medicine, and tumor therapy.

Preconditioning Therapy in ABO-Incompatible Living Kidney Transplantation: A Systematic Review and Meta-Analysis.

BACKGROUND: ABO-incompatible (ABOi) kidney transplantation is now an established form of renal replacement therapy, but the efficacy and safety of the different types of preconditioning therapies are unclear. We aimed to synthesize the totality of the published evidence about the effects of any form of preconditioning therapies in living donor ABOi kidney transplantation on graft and patient outcomes. METHODS: We searched MEDLINE, Embase, and Clinicaltrial.gov databases (inception through June 2015) to identify all studies that described the outcomes of adult living donor ABOi kidney transplantations using any form of preconditioning therapies. Two independent reviewers identified studies, extracted data, and assessed the risk of bias. Data were summarized using the random effects model, and heterogeneity was explored using subgroup analyses. We assessed confidence in the evidence using the Grading of Recommendations Assessment, Development, and Evaluation framework. RESULTS: Eighty-three studies (54 case reports and case series, 25 cohort, 2 case-control, and 2 registry studies) involving 4810 ABOi transplant recipients were identified. Overall, confidence in the available evidence was low. During a mean follow-up time of 28 (standard deviation [SD], 26.6) months, the overall graft survival for recipients who received immunoadsorption or apheresis was 94.1% (95% confidence interval [95%CI], 88.2%-97.1%) and 88.0% (95% CI, 82.6%-91.8%), respectively. For those who received rituximab or underwent splenectomy, the overall graft survival was 94.5% (95% CI, 91.6%-96.5%) and 79.7% (95% CI, 72.9%-85.1%), respectively. Data on other longer-term outcomes, including malignancy, were sparse. CONCLUSIONS: Rituximab or immunoadsorption appeared to be promising preconditioning strategies before ABOi kidney transplantation. However, the overall quality of evidence and the confidence in the observed treatment effects are low. The increased use of ABOi kidney transplantation needs to be matched with randomized trials of different types, dosing, and frequency of preconditioning therapies so that this scarce resource can be used most effectively and efficiently.

A Phase I/II Trial of the Interleukin-6 Receptor-Specific Humanized Monoclonal (Tocilizumab) + Intravenous Immunoglobulin in Difficult to Desensitize Patients.

BACKGROUND: Current desensitization (DES) methods are not always effective. Thus, novel, more effective approaches are desirable. Interleukin (IL)-6 is an attractive target as it promotes B-cell differentiation to plasma cells, is important for immunoglobulin production, and induces Th17 cells. Here, we undertook a phase I/II pilot study of DES using a novel drug (anti-IL-6 receptor (IL-6R),Tocilizumab [TCZ]) + intravenous Ig (IVIg) to assess safety and limited efficacy. METHODS: From July 2012 to November 2013, 10 patients unresponsive to DES with IVIg + Rituximab were treated with IVIg + TCZ. Patients received IVIg on days 0 and 30 at 2 g/kg and TCZ 8 mg/kg on day 15 then monthly for 6 months. If transplanted, patients received IVIg once and TCZ monthly for 6 months. RESULTS: No differences in baseline characteristics were seen in patients not transplanted versus transplanted. Two patients in each group developed serious adverse events: not transplanted- pulmonary congestion with epilepticus (likely not related) versus transplanted infective colitis with colonic perforation and Bell Palsy (both possibly related). Five of 10 patients were transplanted. Mean time to transplant from first DES was 25 +/- 10.5 months but after TCZ was 8.1 +/- 5.4 months. Six-month protocol biopsies showed no antibody-mediated rejection. Donor-specific antibody strength and number were reduced by TCZ treatment. Renal function at 12 months was 60 +/- 25 mL/min. CONCLUSIONS: Tocilizumab and IVIg appear to be safe. From this pilot trial, we are cautiously optimistic that targeting the IL-6/IL-6R pathway could offer a novel alternative for difficult to desensitize patients. Larger controlled studies are essential to prove efficacy

Panel reactive antibodies in predicting hepatitis C virus treatment outcome in kidney transplant candidates.

OBJECTIVES: Chronic hepatitis C virus infection compromises hemodialysis patients and increases liver-related mortality. Interferon treatment is associated with improved sustained virological response rates and increased risk of graft loss after kidney transplant. This may be related to the development of antihuman leukocyte antigen antibodies, which may be a surrogate marker of potent immune response. We evaluated panel reactive antibody 1 and 2 levels for prediction of sustained viral response in patients with kidney transplant. MATERIALS AND METHODS: In this retrospective cohort study, we reviewed data from hepatitis C virusinfected hemodialysis patients who received interferon treatment before kidney transplant. Panel reactive antibody > 20% was considered positive. Sustained viral response rates for interferon treatment were obtained and compared with panel reactive antibody 1 and 2 values. RESULTS: There were 40 patients (16 female and 24 male patients; mean age, 41.5 y; range, 18-65 y). Sustained viral response rate was 18/40 (45%). Panel reactive antibody 1 was negative in 31 patients and positive in 9 patients. Sustained viral response ratio was not correlated with panel reactive antibody 1 positivity. Panel reactive antibody 2 was negative in 31 patients (sustained viral response: present, 11 patients; absent, 20 patients) and positive in 9 patients (sustained viral response: present, 7 patients; absent, 2 patients). Sustained viral response ratio was significantly correlated with panel reactive antibody 2 positivity. CONCLUSIONS: We showed a correlation between panel reactive antibody 2 positivity and sustained viral response rates that may be a predictive tool for hepatitis C virus treatment response. In patients with other complications that compromise hepatitis C virus treatment, panel reactive antibody 2 may be a surrogate marker for sustained viral response prediction. The induction of cellular immunity may cause clearance of hepatitis C virus infection and formation of high panel reactive antibody 2 levels.

Bortezomib in ABO-incompatible kidney transplant desensitization: a case report.

Positive B cell crossmatch accompanied by high levels of pre-transplant human leukocyte antigen donor-specific antibodies are associated with adverse graft outcomes in kidney transplant recipients. Targeting plasma cells, the main antibody producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We report using a combination of bortezomib and plasmapheresis to desensitize a highly sensitized kidney transplant recipient for an ABO-incompatible living donor kidney transplant. The flow cytometric B cell crossmatch was positive on presentation. After treatment, the anti-A titres fell from 1:64 to 1:4, and a negative B flow cytometric crossmatch was achieved prior to transplantation. The combined approach of bortezomib to abrogate antibody production at the plasma cell level, followed by plasmapheresis and low-dose intravenous immunoglobulin to remove in-circulation alloantibodies, has proven to be effective in our case. Bortezomib may play a role in highly sensitized renal transplants.

Removal of donor human leukocyte antigen class I proteins with papain: translation for possible whole organ practices.

BACKGROUND: Papain is a protease with potential use in transplantation because of its targeted capacity to selectively remove human leukocyte antigen (HLA) class I proteins from donor human cells. However, its proteolytic activity has not been studied under conditions suitable for use in perfusing donor organs, namely, under a temperature of 4°C and dissolution in Belzer-UW solution. METHODS: We test papain's HLA class I removing activity under recognized whole organ transplant conditions of lowered temperature. The activity of papain's substrate selectivity was tested using both a test substrate (casein) and fresh peripheral blood lymphocytes (PBLs). The activity of papain was also tested at 4°C, the temperature of whole organ storage. RESULTS: We found that papain at a range of concentrations is nearly as active in cleaving the test substrate in Belzer-UW solution as in distilled water. In distilled water, papain is as active in cleaving a test substrate at a temperature of 4°C as compared to its optimal temperature of 37°C, if the incubation time is extended from 10 min to 3 hr. This finding also holds true if papain is dissolved in Belzer-UW solution. In peripheral blood lymphocytes, papain cleaved off HLA class I proteins as effectively at 4°C as at 37°C, provided the incubation time was also extended to 3 hr. CONCLUSION: These findings suggest that papain's targeted enzymatic cleavage of donor HLA class I has potential use in the whole organ transplant setting with retained activity at lower temperatures and when activated and dissolved in Belzer-UW solution.

Living-donor kidney transplant in T-cell and B-cell flow cytometry crossmatch-positive patients.

OBJECTIVES: Complement-dependent cytotoxic crossmatch is an important indicator for kidney transplant. However, there is controversy about treatment for flow cytometry crossmatch-positive cases. MATERIALS AND METHODS: This was a retrospective study of 127 living-donor kidney transplant recipients from May 2007 to July 2011. We divided patients into 115 flow cytometry crossmatch T-cell and B-cell-negative cases, and 12 T-cell and B-cell-positive cases. Both groups were given 20 mg basiliximab the day of surgery and 4 days after surgery. Common oral immunosuppressive agents used were tacrolimus, mycophenolate mofetil, and methylprednisolone. Flow cytometry crossmatch T-cell and B-cell-negative recipients started immunosuppression 7 days before surgery, T-cell and B-cell-positive recipients started immunosuppression 14 days before surgery. T-cell and B-cell-positive patients also received 200 mg rituximab 1 week before surgery, had 3 plasma exchange sessions before transplant, and received intravenous immunoglobulin 20 g/day during surgery and after surgery for 5 days. We measured flow-panel reactive antibodies of T-cell and B-cell-positive patients just before surgery to check desensitization efficiency. We evaluated patient survival, graft survival, graft function, and frequency of rejection and infectious diseases. RESULTS: Patient survival and graft survival were 100% in both groups. Flow cytometry crossmatch T-cell and B-cell-positive cases had no rejection events, but T-cell and B-cell-negative groups developed rejection. There was no statistical difference in the incidence of infection and graft function. Flow-panel reactive antibody demonstrated improvement in all T-cell and B-cell-positive cases. CONCLUSIONS: In living-donor kidney transplant, flow cytometry crossmatch T-cell and B-cell-positive patients are still considered to be at high risk. Although this is a short-term outcome, all T-cell and B-cell-positive patients in this study achieved excellent results with appropriate preoperative and postoperative treatment.

Crossmatch-positive liver transplantation in patients receiving thymoglobulin-rituximab induction.

BACKGROUND: Positive crossmatch (CM) in liver transplantation (LT) is associated with worse outcomes. Role of induction immunosuppression in this setting remains to be studied. METHODS: One thousand consecutive LT patients receiving rabbit antithymocyte globulin±rituximab induction were studied. Pretransplantation sera of 55 CM-positive (CM) patients were tested for C1q-fixing donor-specific antibodies (DSA). Diagnosis of antibody-mediated rejection required presence of diffuse vascular C4d expression on liver biopsies. RESULTS: CM was positive in 112 (11%) recipients. Antibody-mediated rejection was observed in 3 (0.03%) patients, whereas acute cellular rejection (ACR) occurred in 31 (3%) patients. CM status was associated with a higher incidence of ACR (9% in CM vs. 2% in CM-negative [CM]; P<0.01) and chronic rejection (4% in CM vs. 1% in CM; P<0.01). Graft survival was slightly lower in CM patients (at 1 year; 85% in CM vs. 89% in CM; P=0.26). Patients with autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis as a group had a tendency toward CM status as well as developing ACR. Upon multivariate analysis, CM status was the strongest predictor of ACR (B=1.14; P=0.02). Only half of CM patients harbored C1q-fixing DSA. Presence of C1q-fixing DSA was not associated with increased incidence of ACR. CONCLUSIONS: In LT, CM status is associated with an increased incidence of acute rejection, chronic rejection, and slightly worse graft survival. With the use of rabbit antithymocyte globulin±rituximab induction, overall low rejection rates can be achieved in CM LT.

Failure of neonatal B-cell tolerance induction by ABO-incompatible kidney grafts in piglets.

BACKGROUND: ABO-incompatible (ABOi) infant heart transplantation results in B-cell tolerance to graft A/B antigens, confirming human susceptibility to acquired immunologic or "neonatal" tolerance as described originally in murine models. Starting with this clinical observation, we sought to model neonatal ABOi organ transplantation to allow mechanistic studies of tolerance. METHODS: Plasma anti-A/B antibodies were measured over time in piglets to establish developmental antibody kinetics. Blood group O piglets received kidney allografts from group A (AO-incompatible) or group O (AO-compatible) donors under cyclosporine immunosuppression. Anti-A antibodies were measured serially after transplantation; A/H antigen expression and allograft rejection were assessed in graft biopsies. RESULTS: Anti-A antibodies developed in naïve piglets in a kinetic pattern analogous to human infants; anti-B remained low. After transplantation, anti-A antibodies developed similarly in AO-incompatible and AO-compatible groups and were not suppressed by cyclosporine. A/H antigen expression was persistent in all graft biopsies; however, A/H antigens were not detected in vascular endothelium. Cellular and antibody-mediated rejection was absent or minimal in early and late biopsies in both groups, with one exception. CONCLUSIONS: Naturally delayed isohemagglutinin production in piglets is analogous to the developmental kinetics in human infants. However, in contrast to deficient anti-A antibody production as seen long-term after "A-into-O" infant heart transplant recipients, normal anti-A antibody production after "A-into-O" piglet kidney transplantation indicates that tolerance did not develop despite graft A antigen persistence. These findings suggest that the impact on the host immune system of exposure to nonself ABH antigens during early life in human heart versus porcine kidney grafts may depend on expression in vascular endothelium.

Increasing relevance of donor-specific antibodies in antibody-mediated rejection.

One of the major concerns in organ transplantation is the early detection of humoral rejection, through improved diagnostic and prognostic biomarkers. Long-term survival of renal allografts is significantly lower in recipients developing donor-specific anti-HLA antibodies (DSAs) either pretransplant or posttransplant. Patients can form antibodies following blood transfusions, pregnancies or previous transplants. DSAs can lead to endothelial damage through complement-dependent or independent pathways. Universal testing of kidney transplant patients and careful monitoring of graft function if DSAs are detected are recommended. Since there are different techniques to detect DSAs presence and serum levels, nephrologists have to face challenges in their interpretation due to variable sensitivity and specificity. Moreover, other biomarkers of rejection (T-cell reactivity, gene expression pattern modulation, early features of immunological damage in protocol renal biopsies) may be adopted together with DSAs detection tools, thus providing a global approach to the issue. To date, however, there are no well-defined strategies of intervention in cases of humoral graft damage. Future resolution of both interpretative and therapeutic concerns will make DSAs monitoring a very effective way to predict incoming immunological events. Therefore, an operative protocol for DSAs detection in renal recipients has been illustrated.

Characteristics and influencing factors of CD19+ B cell reconstitution in patients following haploidentical/mismatched hematopoietic stem cell transplantation.

In patients undergoing hematopoietic stem cell transplantation (HSCT), B cells exert important, prolonged effects that provide protection from infection. In this study, we analyzed characteristics and influencing factors of CD19+ B cell reconstitution in 83 patients who underwent unmanipulated haploidentical/mismatched blood and bone marrow transplantation. Of these patients, 45 % showed a normal CD19+ B cell count at +360 days. Factors associated with lower CD19+ B cell levels were as follows: aGVHD grades II-IV had a trend to affect CD19+ B cell reconstitution at +180 days; clinically extensive cGVHD was significantly associated with CD19+ B cell deficiency at +360 days and serum IgG level at +180 and +360 days; cytomegalovirus (CMV) infection occurred after +38 days was correlated with lower B cell level at both +90 and +360 days, while those occurred before +38 days did not show this effect; glucocorticoids used around +90 and +180 days was associated with lower CD19+ B cell levels at +90 and +360 days, respectively, especially in patients that did not experience extensive cGVHD. In contrast, the number of HLA-mismatched locus positively correlated with CD19+ B cell at +90 days and serum IgG level at +180 days. In conclusion, CD19+ B cell recovery after haploidentical/mismatched HSCT was mainly influenced by GVHD and/or its treatment, CMV infection that occurred later (after +38 days) and use of glucocorticoids. Improvement of B cell recovery is likely to be achieved through effective prophylaxis of GVHD, minimized use of glucocorticoids, and preemptive treatment of CMV infection occurring after +38 days. More HLA-mismatched loci may initiate a stronger humoral response toward alloantigens >180 days after HSCT, which may be beneficial for the eradication of minimal residual disease and protection from infection.

Long-term recurrence-free survival after liver transplantation from an ABO-incompatible living donor for treatment of hepatocellular carcinoma exceeding Milano criteria in a patient with hepatitis B virus cirrhosis: a case report.

The early results of liver transplantations (OLT) in patients with advanced hepatocellular carcinoma (HCC) were poor because of frequent tumor recurrence. However, OLT has significant, theoretical advantage that it removes both the tumor and the organ that is at a risk of malignancy. The Japanese law on organ transplantation limited the availability of cadaveric liver donors until its revision on July 17, 2011. ABO-incompatible OLT was formerly contraindicated because performed anti-A/B antibodies on recipient endothelial cells raised the risk of antibody-mediated humoral graft rejection. We have herein described four successful cases of steroid withdrawal among adult patients who underwent living donor OLT from ABO-incompatible donors. In addition, we transplanted a liver from a living donor into an ABO-incompatible recipient on August 9, 2004. The 55-year-old man with HCC due to hepatitis B virus (HBV) a cirrhosis had a Child-Pugh score of C, and Model for End-stage Liver Disease score of 22. Two tumors greater than 5 cm, exceeded the Milan criteria. His des-gamma-carboxy prothrombin level was 6 mAu/mL, and alpha-fetoprotein, 18.78 ng/mL. Antirejection therapy included multiple perioperative plasmaphereses and splenectomy; with an immunosuppressive regimen consisting of tacrolimus, methylprednisolone, and mycophenolate mofetil. The maintenance dose of immunosuppression did not differ from that of ABO-identical cases. After transplantation, we used intrahepatic arterial infusion therapy with prostaglandin E1 (PG E1). The patient had complications of portal vein thrombosis, hepatic artery thrombosis, and acute myocardial infarction, which were treated by interventional radiology in the posttransplantation period. We controlled the HBsAb titer by administering hepatitis B immunoglobulin and lamivudine (200 IU/L doses) for 1 year after OLT and 100 IU/L doses thereafter. As a result, the patient achieved long-term, disease-free graft survival without steroids. He currently has good liver function and leads a normal lifestyle. Our results suggested the feasibility of controlling antibody-mediated humoral rejection and other complications in living donor liver transplantations into ABO-incompatible adults via intrahepatic arterial PG E1 infusion splenectomy, and plasmapheresis with regular immunosuppression. Withdrawal of steroids, HBV vaccination, and lamivudine, an nucleoside analog reverse transcriptase inhibitor, have achieved long-term (7 years) survival without recurrent HBV infection or tumor.

Phase II prospective study of treosulfan-based reduced-intensity conditioning in allogeneic HSCT for hematological malignancies from 10/10 HLA-identical unrelated donor.

Different RIC regimens were evaluated prior to allo-HSCT in different hematological malignancies. We conducted this prospective study in adult patients with various hematological malignancies in order to evaluate the toxicity and efficacy of treosulfan-based conditioning, followed by allo-HSCT from 10/10 HLA-identical unrelated donors. Conditioning included treosulfan 12 g/m(2)/day i.v. (day -6 to day -4), fludarabine 30 mg/m(2)/day i.v. (day -6 to day -2), and ATG 2.5 mg/kg/day (day -2 to day -1). PBSC were used as HSC source. We included 56 patients (29 AML, 9 MM, 8 MDS, 6 CLL, 3 ALL, and 1 CML) with a median age of 57 years (18-65.5). Fifty-four (96%) patients engrafted; the cumulative incidence of aGVHD grade ≥II at 3 months reached 31%. The cumulative incidence of cGVHD at 18 months was 34% limited and 8% extensive. The median overall survival (OS) was not reached with a 3-year probability of 52%. The cumulative incidence of relapse at 3 years was 25%, and the cumulative incidence of transplant-related mortality (TRM) at 12 and 24 months was 20% and 23%, respectively. Treosulfan appears to be a good alternative for conditioning of MUD transplant patients with promising results in terms of OS, relapse, and TRM.

Desensitizing the broadly human leukocyte antigen-sensitized patient awaiting deceased donor kidney transplantation.

For broadly human leukocyte antigen-sensitized patients (HS; calculated panel-reactive antibody >80%), options for deceased donor (DD) transplantation are extremely limited. Data from United Network for Organ Sharing (2000-2009) indicate that <10% of HS patients are transplanted each year. Immune modulation of HS patients using intravenous immunoglobulin (IVIG) and rituximab has shown promise in reducing donor-specific antibody (DSA) titers and improving the chances for successful transplantation for patients awaiting DD transplants. Critical to the success of desensitization with IVIG + rituximab is a coherent antibody-testing strategy aimed at detection of DSA reductions and identification of crossmatch parameters that are associated with a low likelihood of antibody-mediated rejection posttransplant. Here, we discuss data that examine the efficacy of IVIG + rituximab in reducing DSA levels and improving chances for a successful DD transplantation. Patient and graft survival data are also presented as is an analysis of the safety of IVIG + rituximab in sensitized patients.

Cyclosporine or tacrolimus: which is the better partner for myfortic or cellcept?

BACKGROUND: Mycophenolic acid (MPA) pharmacokinetics using the mycophenolate mofetil (CellCept) formulation are known to differ between patients receiving tacrolimus (FK) or cyclosporine (CyA), but only limited data exist concerning concomitant use of FK or CyA with enteric-coated mycophenolate sodium (EC-MPS; Myfortic). This retrospective study compared the drug interactions with the mycophenolic acid blood levels using different immunosuppressants and their relation to graft survival. PATIENTS AND METHODS: We studied MPA levels in posttransplant sera from 298 renal transplant recipients. RESULTS: Patients receiving immunosuppression with CyA + Myfortic showed 94% at 5- and 10-year graft survivals, which were better than CyA + CellCept (75%, 63%). This combination suppressed posttransplant human leukocyte antigen (HLA) antibody development significantly (P = .03) with higher MPA levels. CONCLUSION: Patients immunosuppressed with CyA + Myfortic showed higher MPA levels and lower posttransplant HLA antibody development as well as the best graft survival. CyA + Myfortic or FK + Cellcept may be better combinations.