Publications by authors named "Victor Dong"

28 Publications

  • Page 1 of 1

Post-Liver Transplant Acute Kidney Injury.

Liver Transpl 2021 May 8. Epub 2021 May 8.

Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada.

Acute kidney injury (AKI) is a common condition following liver transplantation (LT). It negatively impacts patient outcomes by increasing the chances of developing chronic kidney disease (CKD) and reducing graft and patient survival. Multiple definitions of AKI have been proposed and utilized throughout the years with the International Club of Ascites (ICA) definition being the most widely used now for cirrhosis patients. Multiple factors are associated with development of post-LT AKI and can be categorized into pre-LT comorbidities, donor and recipient characteristics, operative factors, and post-LT factors. Many of these factors can be optimized in an attempt to minimize the risk of AKI occurring and to improve renal function if AKI is already present. A special consideration during the post-LT phase is need for immunosuppression as certain immunosuppressive medications can be nephrotoxic. The calcineurin inhibitor (CNI) tacrolimus is the mainstay of immunosuppression but can result in AKI. Several strategies including use of the monoclonoal antibody basilixamab to allow for delayed tacrolimus start and minimization or elimination of tacrolimus through combination with mycophenolate mofetil (MMF) or mammalian target of rapamycin (mTOR) inhibitors have been implemented to reverse and avoid AKI in the post-LT setting. Renal replacement therapy may ultimately be required to support patients until recovery of AKI post-LT. Overall by improving renal function in post-LT patients with AKI, outcomes can be improved.
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http://dx.doi.org/10.1002/lt.26094DOI Listing
May 2021

Trimethoprim-induced drug reaction with eosinophilia and systemic symptoms (DRESS) associated with reactivation of human herpes virus-6 (HHV-6) leading to acute liver failure.

Clin Case Rep 2020 Dec 9;8(12):2568-2573. Epub 2020 Aug 9.

Liver Intensive Therapy Unit (LITU) King's College Hospital London UK.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome can have insidious symptoms which may lead to acute liver failure and death. Prompt recognition, stopping offending drug, and initiating corticosteroid are the mainstay of treatment. Early involvement of a specialist liver unit is vital.
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http://dx.doi.org/10.1002/ccr3.3218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752394PMC
December 2020

Using technology to assess nutritional status and optimize nutrition therapy in critically ill patients.

Curr Opin Clin Nutr Metab Care 2021 Mar;24(2):189-194

Division of Gastroenterology (Liver Unit).

Purpose Of Review: Malnutrition is prevalent in critically ill patients and is linked to worse outcomes such as prolonged mechanical ventilation, length of intensive care unit (ICU) stay, and increased mortality. Therefore, nutritional therapy is important. However, it is often difficult to accurately identify those at high malnutrition risk and to optimize nutritional support. Different technological modalities have therefore been developed to identify patients at high nutritional risk and to guide nutritional support in an attempt to optimize outcomes.

Recent Findings: Computed tomography (CT), ultrasound (US), and bioelectrical impedance analysis are tools that allow assessment of lean body mass and detection of sarcopenia, which is a significant marker of poor nutrition. The use of indirect calorimetry allows the determination of resting energy expenditure to serve as a guide to providing optimal nutrition intake in ICU patients.

Summary: By using CT, US, or bioelectrical impedance analysis, detection of sarcopenia can be undertaken in patients admitted to the ICU. This allows for an accurate picture of underlying nutritional status to help clinicians focus on nutritional support for these patients. Subsequently, indirect calorimetry can be used to guide optimal nutrition therapy and caloric intake in critically ill patients. However, whether these methods result in improved outcomes in critically ill patients remains to be validated.
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http://dx.doi.org/10.1097/MCO.0000000000000721DOI Listing
March 2021

Identifying Modifiable Predictors of Long-Term Survival in Liver Transplant Recipients With Diabetes Mellitus Using Machine Learning.

Liver Transpl 2021 04 2;27(4):536-547. Epub 2021 Feb 2.

Multi Organ Transplant Program and Division of Gastroenterology, University Health Network, Toronto, Ontario, Canada.

Diabetes mellitus (DM) significantly impacts long-term survival after liver transplantation (LT). We identified survival factors for LT recipients who had DM to inform preventive care using machine-learning analysis. We analyzed risk factors for mortality in patients from across the United States using the Scientific Registry of Transplant Recipients (SRTR). Patients had undergone LT from 1987 to 2019, with a follow-up of 6.47 years (standard deviation [SD] 5.95). Findings were validated on a cohort from the University Health Network (UHN) from 1989 to 2014 (follow-up 8.15 years [SD 5.67]). Analysis was conducted with Cox proportional hazards and gradient boosting survival. The training set included 84.67% SRTR data (n = 15,289 patients), and the test set included 15.33% SRTR patients (n = 2769) and data from UHN patients (n = 1290). We included 18,058 adults (12,108 [67.05%] men, average age 54.21 years [SD 9.98]) from the SRTR who had undergone LT and had complete data for investigated features. A total of 4634 patients had preexisting DM, and 3158 had post-LT DM. The UHN data consisted of 1290 LT recipients (910 [70.5%] men, average age 54.0 years [SD 10.4]). Increased serum creatinine and hypertension significantly impacted mortality with preexisting DM 1.36 (95% confidence interval [CI], 1.21-1.54) and 1.20 (95% CI, 1.06-1.35) times, respectively. Sirolimus use increased mortality 1.36 times (95% CI, 1.18-1.58) in nondiabetics and 1.33 times (95% CI, 1.09-1.63) in patients with preexisting DM. A similar effect was found in post-LT DM, although it was not statistically significant (1.38 times; 95% CI, 1.07-1.77; P = 0.07). Survival predictors generally achieved a 0.60 to 0.70 area under the receiver operating characteristic for 5-year mortality. LT recipients who have DM have a higher mortality risk than those without DM. Hypertension, decreased renal function, and sirolimus for maintenance immunosuppression compound this mortality risk. These predisposing factors must be intensively treated and modified to optimize long-term survival after transplant.
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http://dx.doi.org/10.1002/lt.25930DOI Listing
April 2021

Acute-on-chronic liver failure: Objective admission and support criteria in the intensive care unit.

JHEP Rep 2019 May 18;1(1):44-52. Epub 2019 Mar 18.

Division of Gastroenterology, University of Alberta, Edmonton, Canada.

Cirrhosis is a leading cause of morbidity and mortality throughout the world. Significant complications include variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, and infection. When these complications are severe, admission to the intensive care unit (ICU) is often required for organ support and management. Intensive care therapy can also serve as a bridge to liver transplantation. Along with decompensation of cirrhosis, the concept of acute-on-chronic liver failure (ACLF) has emerged. This involves an acute precipitating event, such as the development of infection in a patient with cirrhosis, which leads to acute deterioration of hepatic function and extrahepatic organ failure. Extrahepatic complications often include renal, cardiovascular, and respiratory failures. Patients with significant extrahepatic and hepatic failures need ICU admission for organ support. Again, in patients who are deemed suitable liver transplant candidates, intensive care management may allow bridging to liver transplantation. However, patients with a Chronic Liver Failure Consortium ACLF score greater than 70 at 48 to 72 hours post-ICU admission do not seem to benefit from ongoing intensive support and a palliative approach may be more appropriate.
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http://dx.doi.org/10.1016/j.jhepr.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001553PMC
May 2019

Pathophysiology of Acute Liver Failure.

Nutr Clin Pract 2020 Feb 15;35(1):24-29. Epub 2019 Dec 15.

Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada.

Acute liver failure (ALF) is a rare syndrome resulting from an acute insult to the liver in patients without known underlying chronic liver disease. It is characterized by loss of synthetic function in the form of jaundice and coagulopathy and development of hepatic encephalopathy. Multiorgan failure (MOF) eventually develops, leading to death. Many different etiologies have been identified, with acetaminophen (APAP) overdose and viral hepatitis being the most common causes worldwide. The pathophysiology of ALF can be divided into cause-specific liver injury pathophysiologies and pathophysiology related to occurrence of secondary MOF. In terms of liver injury pathophysiology, APAP toxicity is the most well known. Secondary MOF is often a result of the initial massive proinflammatory response generating a systemic inflammatory response syndrome followed by a compensatory anti-inflammatory response leading to immune cell dysfunction and sepsis. As the liver is a tremendously important metabolic organ involved in energy metabolism, protein synthesis, fat metabolism, and glycemic control, multiple aspects of nutrition also need to be considered as part of the overall pathophysiology of ALF.
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http://dx.doi.org/10.1002/ncp.10459DOI Listing
February 2020

Significant lung injury and its prognostic significance in acute liver failure: A cohort analysis.

Liver Int 2020 03 13;40(3):654-663. Epub 2019 Oct 13.

Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada.

Background And Aims: Respiratory failure complicating acute liver failure (ALF) may preclude liver transplantation (LT). We evaluated the association between significant lung injury (SLI) and important clinical outcomes.

Methods: Retrospective cohort study of 947 ALF patients with chest radiograph (CXR) and arterial blood gas (ABG) data enrolled in the US Acute Liver Failure Study Group (US-ALFSG) from January 1998 to December 2016. SLI was defined by moderate hypoxaemia (Berlin classification; PaO /FiO  < 200 mm Hg) and abnormalities on CXR. Primary outcomes were 21-day transplant-free survival (TFS) and overall survival.

Results: Of 947 ALF patients, 370 (39%) had evidence of SLI. ALF patients with SLI (ALF-SLI) had significantly worse oxygenation than controls on admission (median PF ratio 120 vs 300 mm Hg, P < .0001) and higher lactate (6.1 vs 4.6 mmol/l, P = .0008). ALF-SLI patients had higher rates of tracheal (19% vs 14%) and bloodstream (17% vs 11%, P < .005 for both) infections and were more likely to receive transfusions (red cells 55% vs 43%; FFP 74% vs 66%; P < .009 for both). ALF-SLI patients were less likely to receive LT (18% vs 25%, P = .02) and had significantly decreased 21-day TFS (34% vs 42%) and overall survival (49% vs 64%, P < .007 for both). After adjusting for significant covariates (INR, bilirubin, acetaminophen aetiology), the development of SLI was independently associated with decreased 21-day TFS (OR 0.71, P = .03) in ALF patients (C-index 0.78). The incorporation of SLI improved discriminatory ability of the King's College Criteria (P = .0061) but not the ALFSG prognostic index (P = .34).

Conclusion: Significant lung injury is a common complication in ALF patients that adversely affects patient outcomes.
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http://dx.doi.org/10.1111/liv.14268DOI Listing
March 2020

The impact of delayed source control and antimicrobial therapy in 196 patients with cholecystitis-associated septic shock: a cohort analysis

Can J Surg 2019 06;62(3):189-198

From the Division of Critical Care Medicine and Gastroenterology/Hepatology, University of Alberta, Edmonton, Alta. (Karvellas); the Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alta. (Karvellas, Dong, Abraldes); the Division of General Surgery, University of Alberta, Edmonton, Alta. (Lester); the Section of Critical Care Medicine, University of Manitoba, Winnipeg, Man. (Kumar); and the Section of Infectious Diseases, University of Manitoba, Winnipeg, Man. (Kumar).

Background: Cholecystitis-associated septic shock carries a significant mortality. Our aim was to determine whether timing of source control affects survival in cholecystitis patients with septic shock.

Methods: We conducted a nested cohort study of all patients with cholecystitis-associated septic shock from an international, multicentre database (1996–2015). Multivariable logistic regression was performed to determine associations between clinical factors and in-hospital mortality. The results were used to inform a classification and regression tree (CART) analysis that modelled the association between disease severity (APACHE II), time to source control and survival.

Results: Among 196 patients with cholecystitis-associated septic shock, overall mortality was 37%. Compared with nonsurvivors (n = 72), survivors (n = 124) had lower mean admission APACHE II scores (21 v. 27, p < 0.001) and lower median admission serum lactate (2.4 v. 6.8 μmol/L, p < 0.001). Survivors were more likely to receive appropriate antimicrobial therapy earlier (median 2.8 v. 6.1 h from shock, p = 0.012). Survivors were also more likely to undergo successful source control earlier (median 9.8 v. 24.7 h from shock, p < 0.001). Adjusting for covariates, APACHE II (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.06–1.21 per increment) and delayed source control > 16 h (OR 4.45, 95% CI 1.88–10.70) were independently associated with increased mortality (all p < 0.001). The CART analysis showed that patients with APACHE II scores of 15–26 benefitted most from source control within 16 h (p < 0.0001).

Conclusion: In patients with cholecystitis-associated septic shock, admission APACHE II score and delay in source control (cholecystectomy or percutaneous cholecystostomy drainage) significantly affected hospital outcomes.
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http://dx.doi.org/10.1503/cjs.009418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738502PMC
June 2019

Graft Dysfunction and Management in Liver Transplantation.

Crit Care Clin 2019 Jan 25;35(1):117-133. Epub 2018 Oct 25.

Division of Gastroenterology (Liver Unit), Department of Critical Care Medicine, University of Alberta, 1-40 Zeidler Ledcor Building, Edmonton, Alberta T6G-2X8, Canada. Electronic address:

Graft dysfunction of the liver allograft manifests across a spectrum in both timing posttransplantation and clinical presentation. This can range from mild transient abnormalities of liver tests to acute liver failure potentially leading to graft failure. The causes of graft dysfunction can be divided into those resulting in early and late graft dysfunction. Although nonspecific, liver biochemistry abnormalities are still the mainstay investigation used in monitoring for dysfunction. This article provides a summary of the main causes and management strategies for liver graft dysfunction in the early through late posttransplant stages.
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http://dx.doi.org/10.1016/j.ccc.2018.08.002DOI Listing
January 2019

Progressive multifocal leukoencephalopathy after fingolimod treatment.

Neurology 2018 05 18;90(20):e1815-e1821. Epub 2018 Apr 18.

From the Department of Neurology (J.R.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Multiple Sclerosis Centre (B.A.C.), University of California, San Francisco; University of Texas Southwestern Medical Center (B.G.), Multiple Sclerosis Program, Dallas, TX; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Infectious Diseases Division (B.J.W.), Research Institute of the McGill University Health Centre, Montreal, Canada; Novartis Pharmaceuticals Corporation (V.M.D.), East Hanover, NJ; and Novartis Pharma AG (M.M.), Basel, Switzerland.

Objective: We describe the characteristics of the 15 patients with fingolimod-associated progressive multifocal leukoencephalopathy (PML) identified from the Novartis data safety base and provide risk estimates for the disorder.

Methods: The Novartis safety database was searched for PML cases with a data lock point of August 31, 2017. PML classification was based on previously published criteria. The risk and incidence were estimated using the 15 patients with confirmed PML and the overall population of patients treated with fingolimod.

Results: As of August 31, 2017, 15 fingolimod-treated patients had developed PML in the absence of natalizumab treatment in the preceding 6 months. Eleven (73%) were women and the mean age was 53 years (median: 53 years). Fourteen of the 15 patients were treated with fingolimod for >2 years. Two patients had confounding medical conditions. Two patients had natalizumab treatment. This included one patient whose last dose of natalizumab was 3 years and 9 months before the diagnosis of PML. The second patient was receiving fingolimod for 4 years and 6 months, which was discontinued to start natalizumab and was diagnosed with PML 3 months after starting natalizumab. Absolute lymphocyte counts were available for 14 of the 15 patients and none exhibited a sustained grade 4 lymphopenia (≤200 cells/μL).

Conclusions: The risk of PML with fingolimod in the absence of prior natalizumab treatment is low. The estimated risk was 0.069 per 1,000 patients (95% confidence interval: 0.039-0.114), and the estimated incidence rate was 3.12 per 100,000 patient-years (95% confidence interval: 1.75-5.15). Neither clinical manifestations nor radiographic features suggested any unique features of fingolimod-associated PML.
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http://dx.doi.org/10.1212/WNL.0000000000005529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957303PMC
May 2018

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up.

Blood 2011 Jul 31;118(4):884-93. Epub 2011 May 31.

Universitá di Milano, Ca Granda Foundation Istituto di Ricovero e Cura a Carattere Scientifico [corrected] (IRCCS), Milan, Italy.

Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.
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http://dx.doi.org/10.1182/blood-2010-11-316646DOI Listing
July 2011

Dual effects of the alloresponse by Th1 and Th2 cells on acute and chronic rejection of allotransplants.

Eur J Immunol 2009 Nov;39(11):3000-9

Cellular and Molecular Immunology Laboratory, Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114, USA.

The contribution of direct and indirect alloresponses by CD4(+) Th1 and Th2 cells in acute and chronic rejection of allogeneic transplants remains unclear. In the present study, we addressed this question using a transplant model in a single MHC class I-disparate donor-recipient mouse combination. BALB/c-dm2 (dm2) mutant mice do not express MHC class I L(d) molecules and reject acutely L(d+) skin grafts from BALB/c mice. In contrast, BALB/c hearts placed in dm2 mice are permanently accepted in the absence of chronic allograft vasculopathy. In this model, CD4(+) T cells are activated following recognition of a donor MHC class I determinant, L(d) 61-80, presented by MHC Class II A(d) molecules on donor and recipient APC. Pre-transplantation of recipients with L(d) 61-80 peptide emulsified in complete Freund's adjuvant induced a Th1 response, which accelerated the rejection of skin allografts, but it had no effect on cardiac transplants. In contrast, induction of a Th2 response to the same peptide abrogated the CD8(+) cytotoxic T cells response and markedly delayed the rejection of skin allografts while it induced de novo chronic rejection of heart transplants. This shows that Th2 cells activated via indirect allorecognition can exert dual effects on acute and chronic rejection of allogeneic transplants.
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http://dx.doi.org/10.1002/eji.200838980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911804PMC
November 2009

Clinical experience with perindopril in patients nonresponsive to previous antihypertensive therapy: a large US community trial.

Am J Ther 2004 May-Jun;11(3):199-205

Clinical Operations and Medical Affairs, Solvay Pharmaceuticals Inc., Marietta, Georgia 30062, USA.

A subgroup analysis of a large US community trial was conducted to evaluate the antihypertensive efficacy and safety of perindopril, an angiotensin-converting enzyme inhibitor (ACEI), in 3159 patients who lacked blood pressure (BP) control at entry with previous antihypertensive therapy. Patients received 4 mg perindopril daily for 6 weeks. Based on physicians' assessment of BP response, the patients were then either maintained on 4 mg daily (group 1) or the dose was increased to 8 mg daily (group 2) for an additional 6 weeks. The mean baseline sitting BP was 158.2/92.9 mm Hg. Perindopril monotherapy produced a significant BP decrease from baseline of 11.6/6.5 mm Hg and 14.9/8.4 mm Hg at weeks 6 and 12, respectively. In group 1 patients, the majority of BP decrease occurred at week 6 (17.3/9.5 mm Hg) and was maintained until the end of week 12 (18.2/10.1 mm Hg). In group 2 patients, the BP decrease on the 4-mg dose was modest at week 6 by 5.2/3.1 mm Hg. However, further dose up-titration of perindopril to 8 mg resulted in a clinically significant BP decrease of 11.9/6.8 mm Hg from baseline to week 12. Significant antihypertensive effects of perindopril were also demonstrated in the special patient populations of elderly (>or=65 years), black, isolated systolic hypertension, patients with concomitant cardiovascular diseases, and patients nonresponsive to other ACEI therapy. Overall, BP control (<140/<90 mm Hg) was achieved in 40.0% of patients at week 12. Perindopril was well tolerated with cough and angioedema reported in 8.5% and 0.4% patients, respectively. Physicians assessed therapeutic response to perindopril as satisfactory in 73.8% patients who were nonresponsive to previous antihypertensive therapy. These results suggest that, in a community-based practice, perindopril monotherapy (4-8 mg/d) is an effective and safe therapeutic option in patients nonresponsive to previous antihypertensive therapy.
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http://dx.doi.org/10.1097/00045391-200405000-00008DOI Listing
August 2004

Depleting anti-CD4 monoclonal antibody cures new-onset diabetes, prevents recurrent autoimmune diabetes, and delays allograft rejection in nonobese diabetic mice.

Transplantation 2004 Apr;77(7):990-7

Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

Background: The prevention of recurrent autoimmunity is a prerequisite for successful islet transplantation in patients with type I diabetes. Therapies effective in preserving pancreatic beta-cell mass in patients with newly diagnosed diabetes are good candidates for achieving this goal. Anti-CD3 monoclonal antibody (mAb) and antilymphocyte antisera are the only therapies to date that have cured early diabetic disease in the nonobese diabetic (NOD) mouse. We investigated whether other immunosuppressive therapies, including short-term depleting anti-CD4 mAb or costimulation blockade, would affect the disease progression in recently diabetic NOD mice. We also evaluated the effect of the anti-CD4 mAb on syngeneic and allogeneic graft survival in diabetic NOD recipients.

Methods And Results: We demonstrate that a short course of anti-CD4 mAb early after hyperglycemia onset cured diabetes. Normal islets and islets with CD4+ and CD8+ T-cell peri-insulitic infiltrate were found in the pancreata of cured NOD mice. A similar regimen prevented the recurrence of autoimmune diabetes in NOD/severe combined immunodeficient disease (SCID) islet isografts and delayed the rejection of allogeneic C57BL/6 islet allografts in diabetic female NOD mice. The co-transfer of diabetogenic splenocytes with splenocytes from anti-CD4 mAb-treated and cured NOD mice into 7-week-old, irradiated, NOD male mice was not able to protect from diabetes occurrence. This indicates that an anti-CD4-mediated cure of diabetes is independent of the induction of immunoregulatory T cells. Anti-CD154 mAb and cytotoxic T-lymphocyte antigen 4 immunoglobulin were ineffective in early-onset diabetes.

Conclusion: Our results provide the first evidence that newly established autoimmune islet destruction in NOD mice responds to a short course of anti-CD4 mAb. In contrast, costimulation blockade is ineffective in this clinically relevant model.
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http://dx.doi.org/10.1097/01.tp.0000118410.61419.59DOI Listing
April 2004

Clinical experience with perindopril in African-American hypertensive patients: a large United States community trial.

Am J Hypertens 2004 Feb;17(2):134-8

Cardiovascular Division, University of Minnesota Medical School, Box 508, 420 Delaware Street SE, Minneapolis, MN 55455, USA.

Background: The prevalence of hypertension is greater in African Americans, and management of this condition presents challenges for practicing physicians.

Methods: The effectiveness and safety of perindopril was evaluated in hypertensive African-American patients (n = 1412) and hypertensive white patients (n = 7745) who had participated in a large United States community trial. Patients received perindopril 4 mg once daily for 6 weeks. Based on physicians' clinical judgment at week 6, the dose was either maintained or increased to 8 mg for an additional 6 weeks.

Results: Reduction of blood pressure (BP) was significant with perindopril monotherapy (4 to 8 mg once daily) in African Americans and whites (P <.001). The magnitude of BP reduction was significantly more in whites (P <.001). Up-titration of perindopril achieved additional BP reduction in both ethnic groups (P <.001). Control of BP (<140/90 mm Hg) in elderly (>65 years of age) and diabetic African-Americans subgroups was achieved in 32.1% and 31.6%, respectively. Perindopril was safe and well tolerated.

Conclusions: Perindopril monotherapy is effective and is a viable initial therapeutic option as an antihypertensive agent in African-American individuals with hypertension.
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http://dx.doi.org/10.1016/j.amjhyper.2003.09.017DOI Listing
February 2004

Antihypertensive utility of perindopril in a large, general practice-based clinical trial.

J Clin Hypertens (Greenwich) 2004 Jan;6(1):10-7

Division of Hypertension, University of Michigan, Ann Arbor, MI 48109, USA.

The authors evaluated, in a community-based open-label trial, the effectiveness and safety of perindopril in 13,220 US hypertensive patients and studied how physicians adhere to hypertension treatment guidelines. Patients received perindopril 4 mg q.d. for 6 weeks. Based on physicians perception of blood pressure response, the patient was either maintained on 4 mg or the dose was increased to 8 mg for an additional 6 weeks. From baseline to week 12, the mean sitting blood pressure significantly declined from 156.9/94.5 mm Hg to 139.2/84.0 mm Hg. Further dose titration resulted in a clinically significant reduction in blood pressure in all patients with inadequate response on 4 mg at week 6. Blood pressure control (<140/<90 mm Hg) was achieved at 12 weeks in 48.8% patients. The subpopulation analyses demonstrated that perindopril monotherapy was effective in both men and women, in patients of all ethnicities, and in patients <65 and > or =65 years of age. Perindopril was safe and well tolerated in all hypertensive subgroups including high-risk patients. Physicians were more attuned to controlling diastolic than systolic blood pressure, and their adherence to the treatment guidelines was found to be not optimal.
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http://dx.doi.org/10.1111/j.1524-6175.2004.02440.xDOI Listing
January 2004

Chemokines and diseases.

Eur J Dermatol 2003 May-Jun;13(3):224-30

Clinical Operations and Medical Affairs, Solvay Pharmaceuticals, Inc., 901 Sawyer Road, Marietta, GA 30062, USA.

Chemokines are a group of small, pro-inflammatory molecules first described for their pivotal role in the mobilization of specific leukocyte subsets towards sites of inflammation and their activation once they arrive. They have now emerged as key regulators in the development, differentiation and anatomic distribution of inflammatory cells. Chemokines also orchestrate both the innate immune response and antigen specific immunity through their coordination of dendritic cells and lymphocytes. Due to their vast functional responsibilities, they are linked to the pathogenesis of many seemingly unrelated diseases that include HIV infection, cancer, atherosclerosis, autoimmune diseases, graft rejection and dermatological disorders. This review focuses on the physiology of chemokines and their significant roles in the pathogenesis and progression of major diseases.
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September 2003

Correlation between glomerular size and long-term renal function in patients with substantial loss of renal mass.

J Urol 2003 Jul;170(1):42-4

Renal Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

Purpose: Focal segmental glomerulosclerosis and progressive renal failure have been reported in reduced renal mass models. However, these findings are not consistent across all species. Increased intracapillary pressure and chronic glomerular hyperfiltration have been shown to contribute to this progression. Studies also have shown that a strong correlation exists between higher glomerular size and the degree of glomerular sclerosis that develops following loss of functioning nephrons.

Materials And Methods: To evaluate the relationship between glomerular size and long-term renal function following massive renal mass removal we describe 9 patients with less than 50% renal mass. All patients had undergone initial nephrectomy followed by partial second nephrectomy, with 30% to 50% of the second kidney excised for localized tumor.

Results: In 3 patients moderate to severe renal failure developed. Mean planar glomerular area (MPA) was 29.45 +/- 2.2 mm3 for all patients. Multivariate linear regression analysis demonstrated a significant association between MPA 30 mm3 or greater and increased serum creatinine. For patients with MPA 30 mm3 or greater the predicted delta creatinine was 2.43 mg/dl higher than that in patients with MPA less than 30 mm3 (p = 0.0028). Age was the only other covariate significantly associated with outcome in multivariate analysis.

Conclusions: Our data indicate an individual susceptibility toward developing renal failure after significant renal mass reduction. We suggest that patients with less than 50% renal mass and higher MPA are at greater risk for progressive renal failure. MPA may be used as a marker in high risk patients with substantial loss of renal mass to predict long-term renal function.
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http://dx.doi.org/10.1097/01.ju.0000069821.97385.6bDOI Listing
July 2003

The role of the CD134-CD134 ligand costimulatory pathway in alloimmune responses in vivo.

J Immunol 2003 Mar;170(6):2949-55

Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

The CD134-CD134 ligand (CD134L) costimulatory pathway has been shown to be critical for both T and B cell activation; however, its role in regulating the alloimmune response remains unexplored. Furthermore, its interactions with other costimulatory pathways and immunosuppressive agents are unclear. We investigated the effect of CD134-CD134L pathway blockade on allograft rejection in fully MHC-mismatched rat cardiac and skin transplantation models. CD134L blockade alone did not prolong graft survival compared with that of untreated recipients, and in combination with donor-specific transfusion, cyclosporine, or rapamycin, was less effective than B7 blockade in prolonging allograft survival. However, in combination with B7 blockade, long-term allograft survival was achieved in all recipients (>200 days). Moreover, this was synergistic in reducing the frequency of IFN-gamma-producing alloreactive lymphocytes and inhibiting the generation of activated/effector lymphocytes. Most impressively, this combination prevented rejection in a presensitized model using adoptive transfer of primed lymphocytes into athymic heart transplant recipients. In comparison to untreated recipients (mean survival time (MST): 5.3 +/- 0.5 days), anti-CD134L mAb alone modestly prolonged allograft survival (MST: 14 +/- 2.8 days) as did CTLA4Ig (MST: 21.5 +/- 1.7 days), but all grafts were rejected within 24 days. Importantly, combined blockade further and significantly prolonged allograft survival (MST: 75.3 +/- 12.7 days) and prevented the expansion and/or persistence of primed/effector alloreactive T cells. Our data suggest that CD134-CD134L is a critical pathway in alloimmune responses, especially recall/primed responses, and is synergistic with CD28-B7 in mediating T cell effector responses during allograft rejection. Understanding the mechanisms of collaboration between these different pathways is important for the development of novel strategies to promote long-term allograft survival.
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http://dx.doi.org/10.4049/jimmunol.170.6.2949DOI Listing
March 2003

New insights into the interactions between T-cell costimulatory blockade and conventional immunosuppressive drugs.

Ann Surg 2002 Nov;236(5):667-75

Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Objective: To determine the precise in vivo interaction between T-cell costimulatory blockade and conventional immunosuppression in transplantation.

Summary Background Data: Blocking B7 or CD154 T-cell costimulatory activation pathways prevents allograft rejection in small and large animal transplant models and is considered a promising strategy for clinical organ transplantation.

Methods: A fully MHC-mismatched vascularized mouse cardiac allograft model was used to test the interactions between anti-CD154 or CTLA4Ig monotherapy and conventional immunosuppressive drugs in promoting long-term graft acceptance. The frequency of alloreactive T cell was measured by ELISPOT. Chronic rejection was examined by histology.

Results: Cyclosporine, tacrolimus, and anti-IL-2R monoclonal antibody therapy abrogated the effect of a single-dose protocol of anti-CD154 therapy. In contrast, rapamycin acted synergistically with anti-CD154 therapy in promoting long-term allograft survival. The addition of calcineurin inhibitors did not abolish this synergistic effect. Intense CD154-CD40 blockade by a multiple-dose schedule of anti-CD154 resulted in long-term graft survival and profound alloreactive T-cell unresponsiveness and overcame the opposite effects of calcineurin inhibitors. CTLA4Ig induced long-term graft survival, and the effect was not affected by the concomitant use of any immunosuppressive drugs.

Conclusions: The widespread view that calcineurin inhibitors abrogate the effects of T-cell costimulatory blockade should be revisited. Sufficient costimulatory blockade and synergy induced by CD154 blockade and rapamycin promote allograft tolerance and prevent chronic rejection.
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http://dx.doi.org/10.1097/00000658-200211000-00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1422626PMC
November 2002

T-cell response to cardiac myosin persists in the absence of an alloimmune response in recipients with chronic cardiac allograft rejection.

Transplantation 2002 Oct;74(7):1053-7

Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA 02114-2500, USA.

Background: Immune-mediated injury to the graft has been implicated in the pathogenesis of chronic rejection. However, little is known regarding the nature of the antigen(s) involved in this immune process. We demonstrated that cardiac transplantation in mice induces an autoimmune T-cell response to a heart tissue-specific protein, cardiac myosin (CM). This response contributes to transplant rejection in that its modulation affects cardiac graft survival. This study investigates whether anti-CM T cells undergo activation and expansion in mice with chronic cardiac allograft rejection.

Methods: The frequency of CM- and donor major histocompatibility complex (MHC)-specific interferon (IFN)-gamma-producing T cells were assessed by ELISPOT in BALB/c mice, which were injected with anti-CD40L (MR1) mAb (chronic rejection group) or CTLA4Ig fusion protein (tolerant group) and transplanted with C57BL/6 cardiac allografts.

Results And Conclusions: MR1-treated BALB/c recipients of C57BL/6 hearts with chronic rejection displayed a high frequency of activated CM-specific T cells, whereas the frequency of activated alloreactive T cells were similar to naïve, nontransplanted mice. In contrast, no activation of CM-reactive T cells was detected in tolerant recipients after CTLA4Ig treatment. Therefore, in the absence of alloimmunity, chronic rejection is associated with persistence of a T-cell response against CM. Our data indicate that anti-CM autoimmunity may be involved in the immune mechanisms of chronic rejection and suggest that tolerance strategies should target both allo- and autoimmune responses to prevent this process.
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http://dx.doi.org/10.1097/00007890-200210150-00028DOI Listing
October 2002

Angiotensin II receptor blocker-associated angioedema: on the heels of ACE inhibitor angioedema.

Pharmacotherapy 2002 Sep;22(9):1173-5

Renal Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

Angioedema and cough are known side effects of angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme is a potent inhibitor of kinase II, which facilitates the breakdown of bradykinin. An increase in bradykinin levels results in continued prostaglandin E2 synthesis, vasodilation, increased vascular permeability, and increased interstitial fluid. In contrast, the angiotensin II receptor blockers (ARBs) do not increase bradykinin levels. Angioedema as a complication of ACE inhibitor therapy is not widely recognized; this complication is even less recognized with second-line ARBs. We report angioedema associated with losartan (an ARB) in a patient who had experienced angioedema secondary to enalapril (an ACE inhibitor). Almost half of patients with ARB-associated angioedema also had developed angioedema while receiving ACE inhibitor therapy. Clinicians should exercise caution when using ARBs in patients with a history of angioedema secondary to ACE inhibitors.
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http://dx.doi.org/10.1592/phco.22.13.1173.33517DOI Listing
September 2002

Modulation of tissue-specific immune response to cardiac myosin can prolong survival of allogeneic heart transplants.

J Immunol 2002 Aug;169(3):1168-74

Cellular and Molecular Immunology Laboratory, Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.

The role of immune response to tissue-specific Ags in transplant rejection is poorly defined. We have previously reported that transplantation of cardiac allografts triggers a CD4(+) Th1 cell response to cardiac myosin (CM), a major contractile protein of the heart, and that pretransplant activation of proinflammatory CM-specific T cells accelerates rejection. In this study, we show that administration of CM together with IFA (CM/IFA) can prevent acute rejection of an allogeneic heart transplant. Prolongation of cardiac graft survival is associated with activation of CM- and allo-specific T cells secreting type 2 cytokines (IL-4, IL-5) and reduction of the frequency of proinflammatory IFN-gamma-secreting (type 1) alloreactive T cells. Blocking of IL-4 cytokine with Abs abrogates the prolongation. CM/IFA treatment prevents acute rejection of MHC class I-mismatched, but not fully mismatched grafts. However, if donor heart is devoid of MHC class II expression, CM-IFA administration delays rejection of fully allogeneic cardiac transplants. This finding suggests that the effect of CM modulation depends on the type (direct vs indirect) and strength of recipient's CD4(+) T cell alloresponse. Our results underscore the important role of host immunity to tissue-specific Ags in the rejection of an allograft. This study demonstrates that modulation of the immune response to a tissue-specific Ag can significantly prolong cardiac allograft survival, an observation that may have important implications for the development of novel selective immune therapies in transplantation.
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http://dx.doi.org/10.4049/jimmunol.169.3.1168DOI Listing
August 2002

Regulatory functions of alloreactive Th2 clones in human renal transplant recipients.

Kidney Int 2002 Aug;62(2):627-31

Division of Nephrology, Children's Hospital, and Renal Division, Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Background: Chronic allograft rejection is the major clinical problem in organ transplantation. There is evidence that indirect T cell recognition of donor-specific HLA peptides may play an important role in the immunopathogenesis of chronic allograft rejection. We have recently shown that HLA allopeptide-specific T cell clones generated from renal transplant recipients with chronic allograft nephropathy are of the Th1 phenotype, while those from stable patients are Th2. There is evidence in experimental animal models of autoimmunity and transplantation that Th2 cells may function to regulate immune responses, but the biological relevance of these observations in humans has not been reported.

Methods: The purpose of this study was to investigate the putative regulatory functions of alloreactive human Th2 clones. HLA-DR allopeptide-specific Th1 and Th2 cell clones were generated from peripheral blood lymphocytes of human renal allograft recipients with chronic allograft nephropathy (CAN) or with stable renal function (SRF), respectively.

Results: An in vitro co-culture system showed that the proliferative responses of Th1 clones from patients with CAN were significantly inhibited by the Th2 clones in response to the donor-derived HLA allopeptides. In addition, co-culture of the Th2 clones inhibited cytokine production (IFN-gamma) by the Th1 clones in response to the donor-specific peptides. The regulatory functions of Th2 clones were antigen-specific since they only occurred when both the Th1 and Th2 clones were reactive to the same HLA-DR allopeptide, and were mediated by IL-4 and IL-10.

Conclusions: This is the first demonstration, to our knowledge, indicating that Th2 cells may function to regulate indirect Th1 alloimmune responses that are critical for the progression of CAN in humans.
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http://dx.doi.org/10.1046/j.1523-1755.2002.00469.xDOI Listing
August 2002

A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection.

Transplantation 2002 Jun;73(11):1736-42

Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, U.S.A.

Background: The CD40-CD154 interaction is critically important in the cell-mediated immune responses. Blockade of this costimulatory pathway has been shown to prevent acute allograft rejection in murine, as well as nonhuman primate models. However, the role of the CD40-CD154 pathway in the development of chronic rejection and the effects of CD154 targeting on progression of chronic rejection have not been evaluated.

Methods: We examined the effect of AH.F5, a new hamster anti-rat CD154 monoclonal antibody, in a fully allogeneic acute(u) into Lewis [LEW] (RT11) and chronic [WF.1L (RT1l) into LEW (RT1l)] vascularized cardiac allograft rejection model. In the chronic model, the antibody was evaluated for prevention (starting day of transplant) and interruption of progression (starting day 30 or 60 after transplant) of chronic vasculopathy. Graft survival, morphology, and immunohistology were evaluated.

Results: In the acute rejection model, anti-CD154 therapy alone prevented acute allograft rejection and resulted in 50% long-term allograft survival (>200 days) and donor-specific tolerance. In recipients treated with anti-CD154 monoclonal antibody in combination with a short course of cyclosporine, 100% of allografts survived long-term and all recipients achieved donor-specific tolerance. In the chronic rejection model, allografts from animals treated with the anti-CD154 antibody had a statistically significant lower score of graft arteriosclerosis and fibrosis in both the prevention and 30-day interruption groups when compared with control allografts. In addition, immunohistochemistry showed a decrease in intragraft mononuclear cell infiltration and activation.

Conclusion: A new anti-CD154 antibody not only prevents acute allograft rejection, but also inhibits and interrupts the development of chronic rejection. In the acute rejection model cyclosporine acts synergistically with anti-CD154 therapy to prolong allograft survival and induce tolerance. In the chronic rejection model relatively early initiation of therapy is essential to prevent progression of chronic allograft vasculopathy and fibrosis.
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http://dx.doi.org/10.1097/00007890-200206150-00008DOI Listing
June 2002

Mechanisms of targeting CD28 by a signaling monoclonal antibody in acute and chronic allograft rejection.

Transplantation 2002 Apr;73(8):1310-7

Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

There is increasing evidence that ongoing T-cell recognition of alloantigen and activation are key mediators of chronic allograft rejection. The CD28-B7 pathway is unique among costimulatory pathways in that two alternate ligands for B7 exist: CD28 and CTLA4. Recently, it has been suggested that CTLA4 negative signaling may be required for induction of acquired tolerance in vivo. A strategy by which the T cell is targeted at the CD28 receptor rather than its ligands would theoretically allow the inhibitory functions of the CTLA4-B7-1/2 axis to remain intact. Using a rat-specific monoclonal antibody, we investigated the effect of targeting CD28 in a model of chronic rejection without the confounding variable of immunosuppression. We also used an acute cardiac allograft rejection model to investigate CD28 stimulation-based strategies to induce donor-specific tolerance. We demonstrated that anti-CD28 monoclonal antibody was as effective as CTLA4 immunoglobulin in protecting against chronic allograft vasculopathy. In addition, a short course of cyclosporine therapy synergized with either anti-CD28 monoclonal antibody or CTLA4 immunoglobulin, suggesting that it may be clinically relevant to combine low-dose calcineurin inhibitors with CTLA4 immunoglobulin or anti-B7 antibodies. Finally, we report on the potential mechanisms of action of targeting CD28 in vivo.
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http://dx.doi.org/10.1097/00007890-200204270-00021DOI Listing
April 2002

Anti-CD28 monoclonal antibody therapy prevents chronic rejection of renal allografts in rats.

J Am Soc Nephrol 2002 Feb;13(2):519-527

*Surgical Research Laboratory, Harvard Medical School Cambridge, Massachusetts; Departments of Surgery and Medicine, Renal Division, Brigham & Women's Hospital, Boston, Massachusetts; Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts.

The effects of a signaling anti-CD28 mAb (JJ319), which interferes with the CD28-B7 T cell costimulation pathway thought to be involved in the development of chronic rejection of organ transplants, was investigated. Functional, morphologic, and molecular changes in rat renal allografts were examined up to 24 wk after placement. Control Lewis rats, recipients of F344 kidneys, received a single dose of a nonspecific mouse mAb intravenously on the day of transplantation (group 1). Group 2 animals were given anti-CD28 mAb in similar fashion. Group 3 animals were treated with a short course of cyclosporin A (CsA), and group 4 received both anti-CD 28 mAb and CsA. The majority (>95%) of animals in groups 2, 3, and 4 survived throughout the follow-up, compared with 28% in group 1 (P < 0.001). Group 2 and 4 recipients produced negligible proteinuria, whereas group 1 controls developed progressively increasing proteinuria after 4 wk and group 3 animals developed proteinuria by 24 wk. Allografts in groups 2 and 4 were morphologically unremarkable at 24 wk. Kidneys of group 1 animals rapidly developed changes of acute rejection, and those that survived long-term showed extensive glomerulosclerosis and interstitial fibrosis. Changes of early chronic rejection were noted in group 3 grafts. By reverse transcriptase-PCR, expression of representative inflammatory factors interferon-gamma and interleukin-10 were significantly elevated at 24 wk only in the surviving group 1 animals. A single dose of a signaling anti-CD28 mAb administered at transplantation or in combination with a short course of CsA significantly prolonged recipient survival, normalized function, and preserved the morphology of renal allografts in an established model of chronic rejection. These data support an important role for T cell costimulation in the evolution of the chronic process.
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http://dx.doi.org/10.1681/ASN.V132519DOI Listing
February 2002