Eculizumab Therapy for Chronic Antibody-Mediated Injury in Kidney Transplant Recipients: A Pilot Randomized Controlled Trial.

We hypothesized that de novo donor-specific antibody (DSA) causes complement-dependent endothelial cell injury in kidney transplants, as assessed by expression of endothelial cell-associated transcripts (ENDATs), that may be attenuated through complement inhibition. In total, 15 participants (five control, 10 treatment) with DSA and deteriorating renal function were enrolled. The treatment group received 6 mo of eculizumab followed by 6 mo of observation, whereas controls were observed. The primary end point was percentage change in estimated GFR (eGFR) trajectory over the treatment period. The treatment group had an improved eGFR trajectory versus control, based on our predetermined two-sided 0.10 significance level (p = 0.09). Within-subject analysis of treated participants at 6-mo intervals did not show significant change (p = 0.60). Modeling C1q status showed that C1q-positive patients had significantly higher mean eGFR than patients with negative C1q (p = 0.04). Biopsies revealed elevated renal ENDATs in most participants, but ENDATs were not reduced with complement inhibition. Our data suggest that eculizumab treatment may stabilize kidney function in patients with chronic persistent DSA based on our pilot a priori significance threshold. ENDAT expression predicative of acute humoral injury is not reduced with complement inhibition in this chronic setting. Further studies will be necessary to determine which patients may benefit from eculizumab.

Enteric-coated mycophenolate sodium given in combination with tacrolimus has a lower incidence of serious infections in Asian renal-transplant recipients compared with mycophenolate mofetil.

AIMS: To compare the characteristics of the enteric-coated formulation of mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) given in combination with tacrolimus in Asian renal-transplant recipients. METHODS: In a 24-month, single-centre, randomized, open-label, prospective study, 101 live-donor kidney transplant recipients were randomized to the EC-MPS (n = 50) or MMF (n = 51) group. The incidence of infection, therapeutic effect and adverse events were monitored. RESULTS: The incidences of infection were 40% and 49% for the EC-MPS and MMF groups, respectively (p = 0.362). However, serious infection was only observed in the MMF group (11.8%; p = 0.027). The incidences of gastro-intestinal adverse events (GI AEs) were 24% and 41.2% for EC-MPS and MMF, respectively (p = 0.066). However, serious diarrhoea only occurred in the MMF group (9.8%; p = 0.056). The trough level of FK 506 at the time of diarrhoea (13.22 ± 3.66 ng/ml) was significantly higher than the level within 1 month before (9.18 ± 1.12 ng/ml; p < 0.05) and 1 month after diarrhoea (9.13 ± 0.85 ng/ml; p < 0.05). The infection rate of patients with diarrhoea was significantly higher than those without diarrhoea (68%, 39%, p = 0.024). The serum creatinine level was 698 ± 60 µmol/l for EC-MPS and 673 ± 68 µmol/l for MMF from baseline (p > 0.05), and it decreased to 66 ± 6 µmol/l for EC-MPS and 69 ± 8 µmol/l for MMF at 24 months (p > 0.05). The incidences of biopsy proven acute rejection (BPAR) were 20% and 25.5% for EC-MPS and MMF, respectively (p = 0.511). CONCLUSIONS: Enteric-coated formulation of mycophenolate sodium, given in combination with tacrolimus, has a lower incidence of serious infection in Asian renal-transplant recipients compared with MMF, and the therapeutic effect of EC-MPS is similar to MMF. The clinical trial registration number is ChiCTR-IPR-14005509. The registry name is 'Effect of Enteric-coated mycophenolate sodium on posttransplant infection rate after renal transplantation compared with Mycophenolate mofetil'.

A new allocation plan for renal transplantation.

BACKGROUND: A novel plan of renal allograft allocation has been conducted by United Network for Organ Sharing Region 1 transplant centers since September 3, 1996, based upon HLA matching, time waiting, and population distance points. The objectives of this plan were to achieve a balance between increasing the opportunity of renal transplantation for those patients listed with long waiting times and promoting local organ donor availability. METHODS: A single list of candidates was formulated for each cadaver donor, assigning a maximum of 8 points for time waiting, a maximum of 8 points for population distance from the donor hospital, and HLA points based upon the degree of B/DR mismatch. Additional points were awarded to a cross-match-negative patient with a panel-reactive antibody of >80%, and to pediatric patients. RESULTS: The total number of kidneys transplanted to patients who had waited >3 years was 100 (46%), and to patients who had waited >2.5-3 years was 29 (13%). However, the total number of kidneys transplanted to patients with the maximum population distance points was only 72 (33%). Thus, although the plan achieved a favorable distribution of kidneys to patients with longer waiting times (nearly 60%), the other, equally important objective of promoting local donor availability was not initially accomplished. Moreover, minor HLA B/DR differences between the donor and the recipient (i.e., not phenotypically matched) were unexpectedly consequential in determining allocation. As a result of these observations, the following adjustments were made in the plan (as of December 3, 1997): a maximum of 10 points for population distance, a maximum of 8 points for time waiting (both by a linear correlation), and the retention of HLA points for 0 B/DR mismatch only. After these interval changes, the percentage of patients receiving a kidney with some population distance points increased from 85% to 96%. Conclusions. We have shown that a heterogeneous region of multiple transplant centers can devise (and modify) an innovative and balanced plan that provides an equitable system of allocation for an ever-increasing number of patients.

Interferon-gamma effects on activities of gentamicin and vancomycin against Enterococcus faecalis resistant to the drugs: an in vitro study with human neutrophils.

The emergence of multidrug-resistant enterococci presents a major therapeutic challenge since there is currently no clearly effective antimicrobial therapy for these infections. The combinatorial effects of interferon-gamma (IFN-gamma) with gentamicin and/or vancomycin against a clinical isolate of drug-resistant Enterococcus faecalis, were evaluated in an in vitro system with human neutrophils. Following inoculation of cultures of human neutrophils with the organism, treatments were initiated immediately after the infection and the number of viable bacteria was determined at 12, 18 and 24 h. Antibiotics were applied at concentrations close to their clinically achievable serum trough and peak levels. Treatment with IFN-gamma alone induced a maximal growth inhibition of up to 40% at a concentration of 100 U/ml. Addition of the cytokine to either therapeutic trough or peak concentrations of gentamicin and vancomycin, or a combination of both antimicrobials, was associated with a significant (P < 0.01) enhancement of anti-enterococcal activity compared with the effects of the agents alone. Investigation of a potential underlying mechanism of anti-enterococcal action of IFN-gamma reveals that it is, most probably, largely due to an activated secretion of the microbicidal reactive oxygen intermediates by neutrophils. The results of this study show that there is a possibility that IFN-gamma could be a useful adjunct in the treatment of multidrug-resistant E. faecalis.

Influence of adjunctive interferon-gamma on treatment of gentamicin- and vancomycin-resistant Enterococcus faecalis infection in mice.

Increasing antibiotic resistance and the development of multidrug-resistance in the enterococci has complicated the treatment of serious enterococcal infections. It has been demonstrated in vitro that interferon-gamma (IFN-gamma) significantly augments the activities of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The present study was aimed at determining whether this beneficial effect of IFN-gamma on antienterococcal antibiotic activity can be validated in vivo. Following intraperitoneal inoculation in mice with a gentamicin- and vancomycin-resistant E. faecalis clinical isolate, the animals received IFN-gamma, antibiotic or a combination of both agents, subcutaneously, at determined dosing regimens. Treatment with IFN-gamma alone significantly improved survival of infected animals in a dose-dependent manner. High dose IFN-gamma was not beneficial and the level of enterococcal infectious burden influenced the effectiveness of the cytokine. The addition of IFN-gamma to therapy with gentamicin or vancomycin, or a combination of both antibiotics was associated with a marked increase in survival of infected non-neutropenic mice compared to treatments with the agents alone. However, the same treatments made in infected neutropenic mice did not show an enhancement effect by IFN-gamma after a combination therapy with antibiotics. In a study to examine pharmacokinetic interactions, concurrent administration with IFN-gamma significantly modified the disposition of gentamicin but not that of vancomycin. The results of this study suggest that the use of IFN-gamma in combination with vancomycin or gentamicin is a new treatment option that might improve the outcome of therapy of multidrug-resistant E. faecalis infections.

Effectiveness of a writing improvement intervention program on the readability of the research informed consent document.

BACKGROUND: Problems with the comprehensibility of human research informed consent have been documented since the 1970s, and efforts aimed at rewriting consents have not been successful in consistently producing more readable consents. This study employed researched principles of reading comprehension research to create writing intervention program designed to help the research writer produce more comprehensible informed consent documents. The purpose of this study was to determine if this intervention program was effective. METHOD: The key component of the writing improvement intervention packet was a newly formatted consent form that contained annotated instructions for researchers on how to write each section for optimum comprehension. The resulting consent forms were evaluated using a Readability and Processability Form (RPF). The RPF is based on reading research and includes the Fry Scale, which yields an approximate grade reading level. The RPF assigned points to each of the 20 areas of comprehension analysis according to strict scoring criteria, and target scores were established by the authors in consultation with the hospital institutional review board. RESULTS: We evaluated 66 post-intervention informed consents. The mean readability and processability score was 62, resulting in the RPF classification of "good." The established readability and processability target range was good to excellent or 61-100 points; 66% of the forms scored in this range. In our 1995 pre-intervention study, the corresponding score was 12%. The target range for grade reading level was 8th grade: 53% scored in that range as compared with 4% in 1995. A question-by-question analysis of each of the 20 checklist items on the RPF identified important aspects of the consent writing that improved and others that were still weak and needed improvement. CONCLUSIONS: The Hartford Hospital writing improvement intervention program was associated with the production of more comprehensible informed consent documents. Using the intervention materials, investigators from a variety of departments could function independently to produce readable consent forms. This program may help others who wish to assist their research departments in creating consents that are written for optimal reading comprehension.

Neonatal tolerance increases efficacy of antisera production.

In this investigation we demonstrate that neonatal tolerance can be used to increase the specificity of antisera. We have shown that if mice are immunized with a human B cell line then the antisera they produce also reacts strongly with human T cells. However, if the mice are first neonatally tolerized to a human T cell line and then immunized with the B cell line the antisera becomes much more specific for the B cell line. In theory this approach, of initially tolerizing the animal to uninteresting antigens, may also make it possible to produce monoclonal antibodies to rare cellular determinants more efficiently.

Organ transplantation at the Hartford Transplant Center.

Over 1,243 organ transplants have been performed at the Hartford Transplant Center over the past two decades. Survival in kidney, heart, liver, and pancreas patients is at or above the national average. Hartford was one of the first centers to use triple immunosuppression, which significantly improved survival in kidney transplantation. For recipients of kidneys from living related donors and cadaveric kidneys, two-year actuarial graft survival has been 98% and 83%, respectively, over the last five years. For heart and liver transplants, two-year survival has been 79% and 67%, respectively. Despite high success rates at most transplant centers, donor organs remain scarce. This problem needs to be addressed through increased cooperative efforts in the health-care community and the general public.