ABSTRACT
BACKGROUND: Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known. METHODS: In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment. RESULTS: Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir. CONCLUSIONS: Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).
Subject(s)
Antiviral Agents/therapeutic use , Benzimidazoles/therapeutic use , Cytomegalovirus Infections/drug therapy , Cytomegalovirus/physiology , Ribonucleosides/therapeutic use , Valganciclovir/therapeutic use , Viremia/drug therapy , Adult , Aged , Allografts , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Benzimidazoles/adverse effects , Benzimidazoles/pharmacology , Cytomegalovirus/drug effects , Cytomegalovirus Infections/virology , Dysgeusia/chemically induced , Female , Gastrointestinal Diseases/chemically induced , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Intention to Treat Analysis , Male , Middle Aged , Neutropenia/chemically induced , Organ Transplantation/adverse effects , Ribonucleosides/adverse effects , Ribonucleosides/pharmacology , Valganciclovir/adverse effects , Valganciclovir/pharmacology , Virus Activation/drug effectsABSTRACT
BACKGROUND: Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains. METHODS: Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs). RESULTS: From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57-75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses. CONCLUSIONS: Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified. CLINICAL TRIALS REGISTRATION: NCT01611974.
Subject(s)
Antiviral Agents/administration & dosage , Benzimidazoles/administration & dosage , Cytomegalovirus Infections/drug therapy , Immunocompromised Host , Ribonucleosides/administration & dosage , Adolescent , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Drug Resistance, Viral , Female , Hematopoietic Stem Cell Transplantation , Humans , Male , Transplant Recipients , Young AdultABSTRACT
Limited availability of donor organs and risk of ischemia-reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha-1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma-derived AAT has been well tolerated in more than 30 years of use to prevent emphysema in AAT-deficient individuals. Accumulating evidence suggests that AAT has additional anti-inflammatory and tissue-protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro- vs anti-inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune-modulatory effects of AAT and its well-established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation.
Subject(s)
Inflammation/prevention & control , Organ Transplantation , Reperfusion Injury/prevention & control , Serine Proteinase Inhibitors/pharmacology , alpha 1-Antitrypsin/pharmacology , Animals , Apoptosis , Cytokines/metabolism , Humans , NF-kappa B/metabolism , Reperfusion Injury/immunology , Reperfusion Injury/metabolismABSTRACT
OBJECTIVES: To evaluate the use of Cinryze (nanofiltered C1-esterase inhibitor [C1 INH-nf]) for the acute management and prevention of hereditary angioedema attacks in the subgroup of children and adolescents who participated in 2 placebo-controlled and 2 open-label extension studies. STUDY DESIGN: In the acute-attack treatment studies, the efficacy of 1000 U of C1 INH-nf (with an additional 1000 U given 1 hour later if needed) was assessed based on the time to the start of symptomatic relief and the proportion of patients experiencing relief within 4 hours of therapy. In the prophylaxis studies, C1 INH-nf 1000 U was given twice weekly, and efficacy was based on the frequency of attacks. RESULTS: Across 4 studies, 46 children received a total of 2237 C1 INH-nf infusions. The median time to the start of unequivocal relief in the acute-attack treatment study (n = 12) was 30 minutes with C1 INH-nf, compared with 2 hours for placebo. In the open-label extension (n = 22), clinical relief began within 4 hours of therapy in 89% of attacks. In the prophylaxis study (n = 4), the number of attacks was reduced by approximately 2-fold with C1 INH-nf compared with placebo. In the prophylaxis open-label extension (n = 23), the median monthly attack rate decreased from 3.0 before treatment to 0.39 with C1 INH-nf use. CONCLUSION: In children, C1 INH-nf was well tolerated, provided relief from symptoms of hereditary angioedema attacks, and reduced the rate of attacks.
Subject(s)
Angioedemas, Hereditary/drug therapy , Complement C1 Inhibitor Protein/therapeutic use , Hereditary Angioedema Types I and II/drug therapy , Adolescent , Angioedemas, Hereditary/prevention & control , Child , Child, Preschool , Complement C1 Inhibitor Protein/administration & dosage , Complement C1 Inhibitor Protein/adverse effects , Filtration , Hereditary Angioedema Types I and II/complications , Humans , Treatment OutcomeABSTRACT
Data are limited on hereditary angioedema (HAE) in pregnant women and the safety and efficacy of therapies for treatment and prevention of HAE attacks during pregnancy. Prospective studies are unlikely given the rarity of HAE and ethical considerations regarding enrollment of pregnant female subjects in clinical trials. A retrospective analysis of clinical trial and compassionate-use data was conducted to identify subjects who received nanofiltered C1 esterase inhibitor (C1 INH-nf; human) during pregnancy. This study evaluates the efficacy and safety of human C1 INH-nf for treatment and prevention of HAE attacks in pregnant women. Data from pregnant subjects enrolled in either open-label extensions of two randomized, double-blind, placebo-controlled trials of C1 INH-nf or in a compassionate-use program were retrospectively analyzed for efficacy (e.g., total attacks, attack frequency during prophylaxis, and monthly attack rates) and safety (e.g., pregnancy outcomes and adverse events). C1 INH-nf was administered as acute treatment, preprocedural prophylaxis, or routine prophylaxis. C1 INH-nf prophylaxis substantially reduced monthly attack rates. Of 16 subjects, 13 delivered 14 healthy neonates (1 set of twins). Two adverse fetal outcomes were reported; neither was considered by the principal investigator to be related to C1 INH-nf. One subject's pregnancy outcome was unknown. This analysis shows a favorable risk-benefit profile for C1 INH-nf for managing HAE during pregnancy. NCT Identifier: NCT00438815; NCT00462709.
Subject(s)
Angioedemas, Hereditary/prevention & control , Complement C1 Inhibitor Protein/therapeutic use , Complement Inactivating Agents/therapeutic use , Pregnancy Complications/prevention & control , Adult , Female , Humans , Nanotechnology , Pregnancy , Pregnancy OutcomeABSTRACT
Patients with hereditary angioedema (HAE) may have attacks triggered by dental, medical, or surgical procedures. This analysis evaluated the efficacy and safety of preprocedural administration of nanofiltered C1 esterase inhibitor (C1 INH-nf; human) for the prevention of HAE attacks during and after dental, medical, or surgical procedures. Data were reviewed retrospectively from two acute treatment trials in which at least 1000 U of C1 INH-nf was administered i.v. within 24 hours before an emergency or noncosmetic medical, surgical, or dental procedure. Dosing data, HAE attacks reported within 72 hours, and adverse events (AEs) reported within 7 days after a preprocedural dose of C1 INH-nf were analyzed to assess efficacy and safety. Forty-one unique subjects (8 children and 33 adults) received C1 INH-nf for 91 procedures (40 in children and 51 in adults). The majority of procedures (56%) involved dental work and 44% involved a variety of surgical or medical procedures. A single 1000-U dose of C1 INH-nf was administered for 96% of procedures. An HAE attack did not occur within 72 hours after C1 INH-nf dosing for 98% (89/91) of procedures. Two HAE attacks were reported after the procedure, and both were treated with C1 INH-nf and achieved relief. None of the reported AEs were judged to be related to C1 INH-nf or were associated with an HAE attack. This analysis supports the efficacy and safety of preprocedural administration of C1 INH-nf for the prevention of HAE attacks.
Subject(s)
Angioedemas, Hereditary/prevention & control , Complement C1 Inhibitor Protein/therapeutic use , Premedication , Surgical Procedures, Operative/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Angioedemas, Hereditary/drug therapy , Angioedemas, Hereditary/etiology , Child , Complement C1 Inhibitor Protein/administration & dosage , Complement C1 Inhibitor Protein/adverse effects , Female , Filtration/methods , Humans , Male , Middle Aged , Nanotechnology/methods , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: The optimal regimen for prophylaxis of cytomegalovirus (CMV) disease after kidney and/or pancreas transplantation remains unclear. We compared the effectiveness of three months of oral ganciclovir (3 g/day) versus low-dose valganciclovir (450 mg/day) for CMV prophylaxis. METHODS: We performed a retrospective cohort study of patients at our center who received kidney and/or pancreas transplants between January 2000 and April 2003. We used a Cox proportional hazards model to examine the relationship between baseline covariates, including type of CMV prophylaxis, and time to development of CMV disease. RESULTS: Of the 500 patients (295 ganciclovir, 205 valganciclovir), 22 patients (4.4%) developed CMV disease (mean time to CMV disease, 163+/-85 days). Sixteen of the ganciclovir patients (5.4%) and six of the valganciclovir patients (2.9%) developed CMV disease (P=0.18). By CMV serostatus, the incidence of CMV disease during the first posttransplant year was 8.5% among donor-seropositive, recipient-seronegative (D+/R-) patients, 8.6% among D+/R+ patients, 2.9% among D-/R+ patients, 1.0% among D-/R- patients, and 0.9% among patients for whom documentation of CMV serostatus was incomplete. In the unadjusted Cox proportional hazards analysis, race/ethnicity, type of transplant, type of antiviral prophylaxis, CMV serostatus, and use of mycophenolate mofetil were each associated with risk of developing CMV disease. In the adjusted, multivariable model, only CMV serostatus was associated with development of CMV disease. CONCLUSIONS: Three months of low-dose valganciclovir (450 mg/day) was as effective as ganciclovir (3 g/day) for prophylaxis of CMV disease after kidney and/or pancreas transplantation.
Subject(s)
Antiviral Agents/therapeutic use , Cytomegalovirus Infections/prevention & control , Ganciclovir/analogs & derivatives , Ganciclovir/therapeutic use , Kidney Transplantation , Pancreas Transplantation , Administration, Oral , Adult , Antiviral Agents/administration & dosage , Cohort Effect , Female , Ganciclovir/administration & dosage , Humans , Male , Middle Aged , Retrospective Studies , ValganciclovirABSTRACT
PURPOSE: A historical perspective and the epidemiology, pathogenesis, and typical patient presentation of cytomegalovirus (CMV) disease in transplant patients; the implications of clinical trials of prophylactic antiviral drug therapy; and unanswered questions about the optimal duration of prophylaxis and the risk of antiviral drug resistance are discussed. SUMMARY: CMV infection and disease are common in transplant patients. They often are the result of transplantation from a CMV-seropositive donor to a CMV-seronegative recipient or reactivation of latent virus in a CMV-seropositive recipient. Reactivation in transplant recipients may be the result of a blunted cytotoxic T-lymphocyte response and an imbalance in the release of pro-inflammatory and anti-inflammatory cytokines. CMV disease develops in many infected patients and frequently involves the graft. Antiviral drug therapies reduce the risk of and delay the onset of CMV disease in transplant recipients. They also reduce the risk of graft injury. CONCLUSION: The optimal duration of antiviral drug prophylaxis in transplant patients remains to be determined; however, it is clear that antiviral prophylaxis can prevent CMV disease as well as many of the complications associated with CMV disease.
Subject(s)
Antiviral Agents/administration & dosage , Cytomegalovirus Infections/prevention & control , Kidney Transplantation , Clinical Trials as Topic , Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/epidemiology , Cytomegalovirus Infections/pathology , Humans , United States/epidemiologyABSTRACT
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, hematopoietic stem cell disorder that manifests with a complement-mediated hemolytic anemia, bone marrow failure, and a propensity for thrombosis. These patients experience both intra- and extravascular hemolysis in the context of underlying complement activation. Currently eculizumab effectively blocks the intravascular hemolysis PNH. There remains an unmet clinical need for a complement inhibitor with activity early in the complement cascade to block complement at the classical and alternative pathways. C1 esterase inhibitor (C1INH) is an endogenous human plasma protein that has broad inhibitory activity in the complement pathway through inhibition of the classical pathway by binding C1r and C1s and inhibits the mannose-binding lectin-associated serine proteases in the lectin pathway. In this study, we show that commercially available plasma derived C1INH prevents lysis induced by the alternative complement pathway of PNH erythrocytes in human serum. Importantly, C1INH was able to block the accumulation of C3 degradation products on CD55 deficient erythrocytes from PNH patient on eculizumab therapy. This could suggest a role for inhibition of earlier phases of the complement cascade than that currently inhibited by eculizumab for incomplete or nonresponders to that therapy.
Subject(s)
Complement C1 Inhibitor Protein/pharmacology , Complement Pathway, Classical/drug effects , Complement Pathway, Mannose-Binding Lectin/drug effects , Hemoglobinuria, Paroxysmal/drug therapy , Adult , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , CD55 Antigens/blood , CD59 Antigens/blood , Complement C3/metabolism , Complement C5/antagonists & inhibitors , Complement Pathway, Alternative/physiology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Resistance , Erythrocyte Membrane/drug effects , Erythrocyte Membrane/immunology , Erythrocyte Membrane/metabolism , Female , Hemoglobinuria, Paroxysmal/blood , Hemoglobinuria, Paroxysmal/immunology , Humans , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Laryngeal edema is a life-threatening manifestation of hereditary angioedema (HAE), an autosomal-dominant disorder caused by quantitative or functional C1 esterase inhibitor (C1 INH) deficiency. The preparation of nanofiltered C1 INH (C1 INH-nf) used in this study is indicated for routine prophylaxis against angioedema attacks in the United States and for treatment, preprocedure prevention, and routine prevention of HAE in Europe. The objective of this analysis was to evaluate the effectiveness and tolerability of C1 INH-nf when used for the treatment of laryngeal attacks. METHODS: A post hoc analysis of an open-label treatment study evaluated the effectiveness of C1 INH-nf in the treatment of laryngeal attacks in patients with HAE. Outcomes included unequivocal or clinical relief rates and time from treatment to onset of relief. Data were compiled from this and three other studies for post hoc dosing and tolerability analyses. In all studies, C1 INH-nf at 1000 U was administered i.v., with a second 1000-U dose given after 60 minutes if indicated. RESULTS: In the open-label treatment study, 60 (50/84) and 77% (65/84) of attacks achieved unequivocal relief within 1 and 4 hours, respectively, after treatment. Time to unequivocal relief was shorter with prompt treatment. When C1 INH-nf was administered within 4 hours of symptom onset, clinical relief was achieved in 94% (45/48) of attacks within 4 hours after treatment. Of 265 attacks from the four studies, 62% received two 1000-U doses of C1 INH-nf. No serious adverse events occurring within 7 days after treatment were attributed to study drug, and only one patient required intubation after receiving C1 INH-nf (14.5 hours after symptom onset). CONCLUSION: This analysis supports that C1 INH-nf is an effective and well-tolerated therapy for laryngeal angioedema attacks.
Subject(s)
Angioedemas, Hereditary/drug therapy , Complement C1 Inhibitor Protein/therapeutic use , Laryngeal Edema/drug therapy , Complement C1 Inhibitor Protein/administration & dosage , Complement C1 Inhibitor Protein/adverse effects , HumansABSTRACT
We have previously demonstrated that biomarkers of inflammation and immune activity detected within intraoperative renal transplant allograft biopsies are linked to adverse short-term post-transplantation clinical outcomes. Now we provide a post hoc analysis of our earlier data in the light of longer clinical follow-up. A total of 75 consecutively performed renal allografts were analyzed for gene expression of proinflammatory molecules, inflammation-induced adhesion molecules, and antiapoptotic genes expressed 15 minutes after vascular reperfusion to determine whether this analysis can aid in predicting long-term quality of renal function, proteinuria, graft loss, and death-censored graft. We have built predictive models for proteinuria (area under the curve = 0.859, p = 0.0001) and graft loss (area under the curve = 0.724, p = 0.027) 2 years post-transplantation using clinical variables in combination with intragraft gene expression data of tumor necrosis factor-alpha, interleukin-6, CD40, CD3, and tumor necrosis factor-alpha, Bcl-2, and interferon-gamma, respectively. This post hoc analysis demonstrates that hypothesis-driven, targeted polymerase chain reaction profiling of gene expression in the donor kidney at the time of engraftment can predict 2-year post-transplantation clinical outcomes.
Subject(s)
Biomarkers/analysis , Gene Expression Profiling , Graft Survival/genetics , Kidney Transplantation/immunology , Tissue Donors , Area Under Curve , Graft Rejection/genetics , Graft Rejection/immunology , Graft Survival/immunology , Humans , Polymerase Chain Reaction , ROC Curve , Treatment OutcomeABSTRACT
BACKGROUND: The reasons for kidney allograft failure subsequent to pancreas after kidney (PAK) are multifactorial; therefore, we examined these factors to identify a meaningful risk assessment that could assist in patient selection. METHODS: Five transplant centers in New England collaborated for this multiinstitutional retrospective study of 126 PAK transplantation recipients who had a functioning pancreas allograft 7 days after transplantation. Host factors (age at pancreas transplant, gender, body weight, glomerular filtration rate at 3 months pre-PAK and at 3-, 6-, 9-, and 12-month post-PAK, presence of proteinuria, pre- or post-PAK kidney rejection, pancreas rejection, cytomegalovirus disease, and HbA1C at 6-month post-PAK) and transplant factors (time to PAK, use of induction antibody therapy, and combinations of immunosuppressive medications) were assessed in both univariate and multivariate analyses for the primary outcome of kidney allograft failure. RESULTS: Of the variables assessed, factors associated with kidney allograft loss after PAK include impaired renal function in the 3 months before PAK, proteinuria, the occurrence of a post-PAK kidney rejection episode, and interval between kidney and pancreas transplantation more than 1 year. CONCLUSIONS: In our analysis, post-PAK kidney allograft loss was strongly associated with glomerular filtration rate less than 45 mL/min pre-PAK, K to P interval of over 1 year, pre-PAK kidney rejection episode, and pre-PAK proteinuria. Diabetic candidates for PAK with any of these conditions should be counseled regarding the risk of post-PAK renal transplant failure.
Subject(s)
Graft Rejection/epidemiology , Kidney Transplantation/adverse effects , Pancreas Transplantation/physiology , Treatment Failure , Adult , Antilymphocyte Serum/therapeutic use , Body Weight , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/epidemiology , Female , Glomerular Filtration Rate , Glycated Hemoglobin/metabolism , Humans , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/mortality , Kidney Transplantation/physiology , Male , Middle Aged , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/therapeutic use , Predictive Value of Tests , Proteinuria/diagnosis , Proteinuria/epidemiology , Renal Replacement Therapy , Risk Assessment , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Cytomegalovirus (CMV) infection of solid organ transplant (SOT) recipients causes both ''direct'' and ''indirect'' effects including allograft rejection, decreased graft and patient survival, and predisposition to opportunistic infections and malignancies. Options for CMV prevention include pre-emptive therapy, whereby anti-CMV agents are administered based on sensitive viral assays, or universal prophylaxis of all at-risk patients. Each approach has advantages and disadvantages in terms of efficacy, costs, and side effects. Standards of care for prophylaxis have not been established. METHODS: A committee of international experts was convened to review the available data regarding CMV prophylaxis and to compare preventative strategies for CMV after transplantation from seropositive donors or in seropositive recipients. RESULTS: Pre-emptive therapy requires frequent monitoring with subsequent treatment of disease and associated costs, while universal prophylaxis results in greater exposure to potential toxicities and costs of drugs. The advantages of prophylaxis include suppressing asymptomatic viremia and prevention of both direct and indirect effects of CMV infection. Meta analyses reveal decreased in mortality for patients receiving CMV prophylaxis. Costs associated with prophylaxis are less than for routine monitoring and pre-emptive therapy. The optimal duration of antiviral prophylaxis remains undefined. Extended prophylaxis may improve clinical outcomes in the highest-risk patient populations including donor-seropositive/recipient-seronegative renal transplants and in CMV-infected lung and heart transplantation. CONCLUSIONS: Prophylaxis is beneficial in preventing direct and indirect effects of CMV infection in transplant recipients, affecting both allograft and patient survival. More studies are necessary to define optimal prophylaxis regimens.
Subject(s)
Cytomegalovirus Infections/etiology , Organ Transplantation , Postoperative Complications/virology , Antiviral Agents/therapeutic use , Comorbidity , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/prevention & control , Ganciclovir/analogs & derivatives , Ganciclovir/therapeutic use , Graft Rejection , Humans , Liver Transplantation , Neutropenia/epidemiology , Neutropenia/etiology , Valganciclovir , Virus ReplicationABSTRACT
OBJECTIVES: RNA interference as mediated by short-interfering RNA (siRNA) offers a nonviral means to silence genes in tissue; however, few data exist about gene therapy using siRNA in pancreas tissue. To determine if siRNA treatment could silence an endogenous gene in pancreatic islets, we developed a murine model using the endocrine pancreas. METHODS: The insulin 2 (Ins2) gene was targeted with siRNA, and quantitative RT-PCR, fluorescent microscopy, and FACS were used to measure transcript levels and siRNA cellular uptake and transfection efficiency. Isolated pancreatic islets were transfected with siRNA in vitro using a liposomal delivery method in a dose titration (50-400 nM) or pooled from BALB/c mice having received siRNA (100 microg) via hydrodynamic tail vein injection. RESULTS: The Ins2 transcript level was significantly reduced by 55% in vitro with FACS data showing a transfection efficiency over 45% with the 400 nM concentration. In vivo delivery of siRNA to pancreatic islets revealed a 33% reduction in Ins2 mRNA levels, although siRNA was able to be detected in 19% of isolated islet cells. CONCLUSION: We have successfully used RNA interference to silence an endogenous tissue-specific gene (Ins2) in pancreatic islets when transfected in vitro or administered in vivo.
Subject(s)
Gene Silencing , Islets of Langerhans/metabolism , RNA, Small Interfering/pharmacology , Animals , Genetic Therapy , Insulin/genetics , Mice , Mice, Inbred BALB CABSTRACT
Many hypothesize that subtle inflammation and immune activity detected in the intraoperative period are linked to adverse postkidney transplant clinical outcomes. To this end, renal allografts were analyzed for expression of pro-inflammatory, inflammation-induced adhesion molecules, immune activation as well as anti-apoptotic genes expressed 15 min after vascular reperfusion (zero-hour) to determine whether this analysis can aid in predicting the occurrence of delayed graft function (DGF), acute rejection (AR), and the quality of graft function at 6 mo. Intraoperative biopsies were obtained from 75 consecutively performed renal allografts in which consent was obtained 15 min after vascular reperfusion. These biopsies were analyzed by quantitative real-time PCR for transcription of 15 select genes and by standard histopathology. Posttransplant clinical outcomes were also analyzed in respect to intraoperative transcriptional profiles and clinical parameters available at the time of transplantation. This study demonstrates that a limited and hypothesis-driven PCR-based transcriptional profile of the zero-hour kidney biopsy predicts posttransplant clinical outcomes including DGF, early AR, and the quality of renal function 6 mo posttransplantation. For some clinical endpoints, the combined use of molecular analysis and established clinical indicators available at the time of transplantation further enhances the quality of prognosis. The transcriptional profiling data provide absolutely essential data to the predictive models, particularly with respect to AR and renal function 6 mo posttransplantation.
Subject(s)
Graft Survival/genetics , Graft Survival/immunology , Ischemia/genetics , Kidney/immunology , Transplantation, Homologous/immunology , Biomarkers , Graft Rejection/genetics , Graft Rejection/immunology , Humans , Intraoperative Period , Ischemia/immunology , Kidney/blood supply , Kidney Failure, Chronic/surgery , Kidney Transplantation/immunology , Predictive Value of Tests , Reperfusion , Treatment OutcomeABSTRACT
Enteric drainage of exocrine secretions in whole organ pancreas transplantation is generally avoided in patients with pre-existing small bowel disease; however, bladder drainage is associated with a 20% rate of urinary tract-related complications. This is a case report of a type 1 diabetic patient with celiac sprue and renal failure. We performed a simultaneous cadaveric kidney pancreas transplant enterically draining the exocrine pancreas. There were no complications. The patient is now more than 6 months post-transplant with excellent function of both renal and pancreas allografts. We conclude that enteric drainage of pancreas allografts in patients with celiac sprue may be performed safely. Whole organ pancreas transplantation is being performed with greater success than ever before, mostly as a result of lessons learned from past experience (1). Enteric drainage of allograft exocrine secretions is preferred for simultaneous pancreas/kidney (SPK) recipients to avoid urinary tract complications associated with bladder drainage. However, most agree that diabetics with pre-existing bowel disease should have bladder drainage of allograft exocrine secretions, so as to prevent the devastating complication of a bowel leak. We describe here a successful case of enteric drainage of an SPK transplant in a patient with celiac sprue. We believe that, when carefully performed, enteric drainage of pancreas allografts is a safe approach for diabetic patients with celiac sprue, and may avert the serious complications associated with bladder drainage.
Subject(s)
Celiac Disease/complications , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/surgery , Drainage , Kidney Transplantation , Pancreas Transplantation , Adult , Anastomosis, Surgical , Female , Humans , Transplantation, HomologousABSTRACT
CD21 is a multifunctional receptor for Epstein-Barr virus (EBV), for C3dg and for CD23. Upon engagement of immune complexes CD21 modulates immunoreceptor signaling, linking innate and adaptive immune responses. The mechanisms enabling CD21 to independently relay information between the exterior and interior of the cell, however, remain unresolved. We show that formin homologue overexpressed in spleen (FHOS/FHOD1) binds the cytoplasmic domain of human CD21 through its C terminus. When expressed in cells, EGFP-FHOS localizes to the cytoplasm and accumulates with actin in membrane protrusions. Plasma membrane aggregation, redistribution and co-localization of both proteins are stimulated when EBV (ligand) binds CD21. Though widely expressed, FHOS RNA is most abundant in the littoral cell, a major constituent of the red pulp of human spleen believed to function in antigen filtration. Formins are molecular scaffolds that nucleate actin by a pathway distinct from Arp2/3 complex, linking signal transduction to actin reorganization and gene transcription. Thus, ligand stimulation of FHOS-CD21 interaction may transmit signals through promotion of cytoskeletal rearrangement. Moreover, formin recruitment to sites of actin assembly initiated by immunoreceptors could be a general mechanism whereby co-receptors such as CD21 modulate intracellular signaling.