Cancer risk with alemtuzumab following kidney transplantation

Alemtuzumab has been employed for induction therapy in kidney transplantation with low rates of acute rejection and excellent graft and patient survival. Antibody induction therapy has been linked to increased vulnerability to cancer. Data regarding malignancy rates with alemtuzumab are limited. We studied 1350 kidney transplant recipients (between 2001 and 2009) at the University of Pittsburgh Starzl Transplant Institute, for post-transplant de novo and recurrent malignancy, excluding non-melanoma skin cancer, among patients receiving alemtuzumab, thymoglobulin, and no induction therapies. Of the 1350 patients, 1002 (74.2%) received alemtuzumab, 205 (15.2%) received thymoglobulin, and 122 (9%) received no induction therapy. After excluding cancers occurring within 60 d post-transplantation, 43 (3.25%) malignancies were observed during a median follow-up time of 4.0 yr. The incidence of malignancy was 5.4% (1.09 per 100 patient-years [PY]) with thymoglobulin, 2.8% (0.74 per 100 PY) with alemtuzumab, and 3.3% (0.66 per 100 PY) with no induction (across all groups; p = 0.2342, thymoglobulin vs. alemtuzumab; p = 0.008). Thus, with the exception of non-melanoma skin cancer which we did not evaluate, alemtuzumab induction was not associated with increased cancer incidence post-kidney transplantation when compared to no induction therapy and was associated with lower cancer incidence when compared to thymoglobulin (read more)

Center-Level Utilization of Kidney Paired Donation

With many multicenter consortia and a United Network for Organ Sharing program, participation in kidney paired donation (KPD) has become mainstream in the United States and should be feasible for any center that performs live donor kidney transplantation (LDKT). Lack of participation in KPD may significantly disadvantage patients with incompatible donors. To explore utilization of this modality, we analyzed adjusted center-specific KPD rates based on casemix of adult LDKT-eligible patients at 207 centers between 2006 and 2011 using SRTR data. From 2006 to 2008, KPD transplants became more evenly distributed across centers, but from 2008 to 2011 the distribution remained unchanged (Gini coefficient = 0.91 for 2006, 0.76 for 2008 and 0.77 for 2011), showing an unfortunate stall in dissemination. At the 10% of centers with the highest KPD rates, 9.9–38.5% of LDKTs occurred through KPD during 2009–2011; if all centers adopted KPD at rates observed in the very high-KPD centers, the number of KPD transplants per year would increase by a factor of 3.2 (from 494 to 1593). Broader implementation of KPD across a wide number of centers is crucial to properly serve transplant candidates with healthy but incompatible live donors (read more)

Epstein-Barr Virus DNAemia Is an Early Surrogate Marker of the Net State of Immunosuppresion in Solid Organ Transplant Recipients

Background: Epstein-Barr virus (EBV) DNAemia (EBVd) may be a surrogate marker of the net state of immunosuppression after solid organ transplantation (SOT).
Methods: A sample of 81 SOT recipients (53 renal, 21 liver, and 7 cardiac) from our institution (2003–2004) surviving more than 180 days was analyzed. EBVd was monitored in whole blood within the first 6 months using a real-time polymerase chain reaction assay. Using a Cox proportional hazards model, duration and magnitude of EBVd were assessed as potential surrogate markers for the occurrence of late adverse events (>6 months): graft dysfunction, graft loss, death, and immunosuppression-related adverse events (IRAE), defined by the occurrence of solid organ tumor and opportunistic and severe infections.
Results: A median of 10 blood samples per patient was screened. A total of 68 (84%) patients had detectable EBVd. Persistent EBVd (>30 days) was found in 40 (49.4%) and high EBVd (>1500 copies/mL) in 35 (43.3%). Multivariate analyses showed that persistent EVBd and high EBVd levels were independently related to the development of IRAE (hazard ratio, 2.95 and 4.32, respectively), whereas no significant associations were observed with late graft dysfunction or graft loss.
Conclusions: Persistent and high levels of EBVd within the first 6 months after SOT are surrogate markers of increased risk of IRAE (read more)

Systematic Comparison of Four Cell- and Luminex-Based Methods for Assessment of Complement-Activating HLA Antibodies

Background: Efforts to increase the specificity and sensitivity of human leukocyte antigen (HLA) antibody detection assays recently led to the establishment of two novel Luminex bead-based assays to detect complement-activating antibodies by the assessment of complement products C1q or C4d. Here, we present a systematic comparison of the four methods, complement-dependent lymphocytotoxicity (CDC) and C1q-, C4d-, and IgG-Luminex, to assess or predict the complement-binding capability of HLA IgG antibodies.
Methods: Forty-five sera of highly immunized patients have been assessed by in-house modified C1q- and C4d-Luminex assays and compared with standard CDC and IgG-Luminex.
Results: Antibody specificities assigned by the C1q- and C4d-Luminex assay revealed an excellent concordance of 94% and 97% for HLA class I and II, respectively. Complement-fixing HLA class II antibodies were found less frequently among IgG antibodies compared with class I. Both C1q- and C4d-Luminex detected, on average, three times more specificities than CDC. Although we found a high correlation of mean fluorescence intensity values between C1q- and C4d-Luminex assays, IgG mean fluorescence intensity was not a suitable surrogate marker for the prediction of complement binding.
Conclusions: C1q- and C4d-Luminex assays are characterized by an increased sensitivity and specificity compared with CDC, the current standard in detecting complement-fixing HLA antibodies. Pretransplantation risk assessment for transplantation but also posttransplantation monitoring are important applications for both assays to improve overall allograft survival (read more)

Rituximab Prevents an Anamnestic Response in Patients With Cryptic Sensitization to HLA

Background: Some patients sensitized to HLA antigens do not have antibody present in serum specimens that are available before transplantation. However, such patients are at risk for an anamnestic response resulting from a proinflammatory response to the trauma of transplant surgery. Quantifying HLA-specific B cells provides a way to identify these patients and provide treatment to prevent an anamnestic response.
Methods: B cells were isolated before transplantation from 59 patients, 20 of whom were treated with rituximab at the time of transplantation. Ninety-nine tests were performed to quantify HLA-specific B cells by staining with HLA tetramers. Patients were considered sensitized or nonsensitized based on the frequencies of HLA-specific B cells. Pretransplantation and posttransplantation sera were tested for the detection of antibody specific for the tetramer antigen.
Results: Of the 24 cases where patients were considered sensitized to HLA antigens but did not have antibody before transplantation, no posttransplantation antibody to the tetramer antigen was detected in 10 cases when patients were treated with rituximab, but antibody was detected in 13 of 16 cases when there was no rituximab treatment (P=0.00006). The mean frequencies of B cells specific for HLA-B7 were the same in rituximab-treated patients who did not make antibody and in nontreated patients who did make antibody (6.0% vs. 5.7%; P=0.8).
Conclusions: Elimination of peripheral HLA-specific B cells in patients who are sensitized to HLA antigens but lacking detectable antibody abrogates an anamnestic response (read more)

Cotransplantation of Umbilical Cord–Derived Mesenchymal Stem Cells Promote Hematopoietic Engraftment in Cord Blood Transplantation: A Pilot Study

Background: Delayed hematopoietic reconstitution after cord blood transplantation (CBT) may lead to increased risk of complications and longer hospitalization. Bone marrow–derived mesenchymal stem cells (MSCs) have been found to promote engraftment after hematopoietic stem cell transplantation. However, harvesting MSCs from bone marrow involves an invasive procedure. Then again, MSCs can be easily obtained from umbilical cords without harm to the donors.
Methods: Umbilical cord–derived MSCs (UCMSCs) were isolated from Wharton’s jelly and then ex vivo cultured. After showing normal karyotype and negative for infectious contamination, culture-expanded UCMSCs were intravenously infused into the recipients on the day of CBT. The control patients were those receiving CBT alone. Adverse effects and efficacy of intravenous UCMSCs were evaluated.
Results: A total of five patients received cotransplantation of UCMSCs at the time of CBT. No serious adverse events were observed. The time to achieve neutrophil engraftment ranged from 7 to 13 days (median, 11 days) and platelet engraftment ranged from 22 to 41 days (median, 32 days). Compared with the nine patients receiving CBT alone, patients receiving cotransplantation of UCMSCs had significantly faster hematopoietic recovery of neutrophils and platelets (P=0.02 and 0.01, respectively).
Conclusions: This pilot study is the first report of cotransplantation of UCMSCs in CBT. Intravenous infusion of UCMSCs appeared to be a feasible and safe modality to enhance hematopoietic engraftment in patients receiving CBT. Further studies were warranted (read more)

Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients.

In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor-specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean-calculated panel-reactive antibody and MFImax ranged from 10.3-57.2% and 262-1691, respectively, between low- and high-risk protocols. Mean MFImax increased significantly from transplant to 1 week and 1 year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71-6.45) and increased specific antibodies at 1-week post transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients (read more)