Accommodation: does it apply to human leukocyte antigens?

The term "accommodation" was invoked to describe endothelial cell resistance to antibody-mediated rejection after ABO-incompatible kidney or experimental xenograft transplantation. Currently, there is much interest in how to achieve successful human leukocyte antigen (HLA)-incompatible allograft transplantation in HLA-sensitized patients and how to treat antibody-mediated rejection after ABO-compatible HLA-incompatible allotransplantation. The term "accommodation" is often used interchangeably to describe patients who have donor-specific ABO or HLA alloantibodies in the absence of damage to their allograft. Here, we suggest that there are important differences between the immune responses to protein versus carbohydrate antigens and that graft HLA molecules may respond differently to antibodies (and antibody isotypes) than ABO antigens. Neither the mechanisms nor a phenotype of accommodation have been defined fully. Further research is needed to define mechanisms of both resistance and susceptibility to antibody-mediated injury and to predict under which circumstances allograft accommodation may occur.     

β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment

OBJECTIVE

This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.

RESEARCH DESIGN AND METHODS

A group of experts participated in a conference on 14–16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.

RESULTS

The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.

CONCLUSIONS

β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.     

Ability of emergency physicians with advanced echocardiographic experience at a single center to identify complex echocardiographic abnormalities

Objectives

To determine the ability of emergency physicians to detect complex abnormalities on point-of-care (POC) echocardiograms.

Methods

Single-blinded, nonrandomized, cross-sectional study. Twenty-five different emergency medicine clinical scenarios (video clips and digital images) covering a variety of echocardiographic abnormalities were presented to a group of emergency physician sonologists. The echocardiographic abnormalities included right ventricular dysfunction, left ventricular systolic dysfunction, diastolic dysfunction, regional wall motion abnormalities, Doppler abnormalities of pericardial tamponade physiology, left ventricular hypertrophy, hypertrophic cardiomyopathy, and aortic abnormalities. All emergency physician sonologists were blinded to the study hypothesis. They reviewed echocardiography video clips and images individually, and their interpretations were compared with the criterion standard (expert echocardiographer interpretations).

Results

A total of 200 echocardiography studies (video clips and images) were independently reviewed by 8 emergency physician sonologists with varying POC echocardiography experiences. Emergency physicians accurately identified left ventricular systolic dysfunction 94% of the time, diastolic dysfunction (100%), and right ventricular dysfunction 80% of the time. Regional wall motion abnormalities were detected only 50% of the time. Doppler echocardiographic abnormalities of pericardial tamponade physiology were accurately identified 57% of the time. Emergency physicians who performed more than 250 POC echocardiograms were found to be more accurate in identifying complex echocardiographic abnormalities.

Conclusions

Our study results suggest that with increased experience, emergency physicians can accurately identify most of complex echocardiographic abnormalities.     

Factors Associated With Microalbuminuria in 7,549 Children and Adolescents With Type 1 Diabetes in the T1D Exchange Clinic Registry

OBJECTIVE

To examine factors associated with clinical microalbuminuria (MA) diagnosis in children and adolescents in the T1D Exchange clinic registry.

RESEARCH DESIGN AND METHODS

T1D Exchange participants <20 years of age with type 1 diabetes ≥1 year and urinary albumin-to-creatinine ratio (ACR) measured within the prior 2 years were included in the analysis. MA diagnosis required all of the following: 1) a clinical diagnosis of sustained MA or macroalbuminuria, 2) confirmation of MA diagnosis by either the most recent ACR being ≥30 mg/g or current treatment with an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 3) no known cause for nephropathy other than diabetes. Logistic regression was used to assess factors associated with MA.

RESULTS

MA was present in 329 of 7,549 (4.4%) participants, with a higher frequency associated with longer diabetes duration, higher mean glycosylated hemoglobin (HbA_1c) level, older age, female sex, higher diastolic blood pressure (BP), and lower BMI (P ≤ 0.01 for each in multivariate analysis). Older age was most strongly associated with MA among participants with HbA_1c ≥9.5% (≥80 mmol/mol). MA was uncommon (<2%) among participants with HbA_1c <7.5% (<58 mmol/mol). Of those with MA, only 36% were receiving ACEI/ARB treatment.

CONCLUSIONS

Our results emphasize the importance of good glycemic and BP control, particularly as diabetes duration increases, in order to reduce the risk of nephropathy. Since age and diabetes duration are important nonmodifiable factors associated with MA, the importance of routine screening is underscored to ensure early diagnosis and timely treatment of MA.Elevated urinary albumin excretion is an early sign of diabetic kidney disease (DKD). The American Diabetes Association (ADA) recommends screening for microalbuminuria (MA) annually in people with type 1 diabetes after 10 years of age and 5 years of diabetes duration, with a diagnosis of MA requiring two of three tests to be abnormal (1). Early diagnosis of MA is important because effective treatments exist to limit the progression of DKD (1). However, although reduced rates of MA have been reported over the past few decades in some (2–4) but not all (5,6) studies, it has been suggested that the development of proteinuria has not been prevented but, rather, has been delayed by ∼10 years and that further improvements in care are needed (7).Limited data exist on the frequency of a clinical diagnosis of MA in the pediatric population with type 1 diabetes in the U.S. Our aim was to use the data from the T1D Exchange clinic registry to assess factors associated with MA in 7,549 children and adolescents with type 1 diabetes.