Post-Transplant Natural Antibodies Associate with Kidney Allograft Injury and Reduced Long-Term Survival.

Background The development of antibodies specific to HLA expressed on donor tissue (donor-specific antibodies [DSAs]) is a prominent risk factor for kidney graft loss. Non-HLA antibodies with pathogenic potential have also been described, including natural antibodies (Nabs). These IgG Nabs bind to immunogenic self-determinants, including oxidation-related antigens.Methods To examine the relationship of Nabs with graft outcomes, we assessed Nabs in blinded serum specimens collected from a retrospective cohort of 635 patients who received a transplant between 2005 and 2010 at Necker Hospital in Paris, France. Serum samples were obtained immediately before transplant and at the time of biopsy-proven rejection within the first year or 1 year after transplant. Nabs were detected by ELISA through reactivity to the generic oxidized epitope malondialdehyde.Results Univariate Cox regression analysis identified the development of post-transplant Nabs (defined as 50% increase in reactivity to malondialdehyde) as a significant risk factor for graft loss (hazard ratio, 2.68; 95% confidence interval, 1.49 to 4.82; P=0.001). Post-transplant Nabs also correlated with increased mean Banff scores for histologic signs of graft injury in post-transplant biopsy specimens. Multivariable Cox analyses confirmed Nabs development as a risk factor independent from anti-HLA DSAs (hazard ratio, 2.07; 95% confidence interval, 1.03 to 4.17; P=0.04). Moreover, patients with Nabs and DSAs had a further increased risk of kidney graft loss.Conclusions These findings reveal an association between Nabs, kidney graft injury, and eventual graft failure, suggesting the involvement of Nabs in immune mechanisms of rejection.

Neighborhood Risk Factors for Pediatric Fall-Related Injuries: A Retrospective Analysis of a Statewide Hospital Network.

BACKGROUND: Falls represent the leading cause of nonfatal unintentional injuries among children in the United States. Although unintentional injury risks have been studied, neighborhood impact on falls remains underexplored. This study examined the association of neighborhood attributes with rates of fall-related injuries. METHODS: This is a retrospective study of children who presented to emergency departments within a statewide hospital network for fall-related injuries between 2005 and 2014. Patients' home addresses were geocoded to identify US Census block groups (BGs). Average annual fall rates were computed for each BG. A neighborhood risk index was constructed using 8 socioeconomic BG measures (education, crowding, vacancy, renter occupancy, poverty, family structure, race/ethnicity, and housing age). Public outdoor recreational facilities in each BG were enumerated. Linear regression analysis was used to assess the association of neighborhood risk and recreational facilities with fall rates. RESULTS: From 2005 to 2014, there were 139,986 unintentional injury emergency department visits; of these, 42,691 (30%) were for falls. The largest proportion of falls were among males (58%), children ages 1 to 4 years (39%), non-Hispanic whites (59%), and children with public health insurance (53%). Higher quintiles of neighborhood risk were associated with higher annual fall rates compared to the lowest quintile of risk: quintile 2, ß = 0.44, 95% confidence interval (CI), 0.20-0.68; quintile 3, ß = 0.85, 95% CI, 0.61-1.10; quintile 4, ß = 1.11, 95% CI, 0.85-1.37; quintile 5, ß = 1.57, 95% CI, 1.29-1.85. The presence of public outdoor recreational facilities was not associated with fall rates (ß = 0.01; 95% CI, -0.14 to 0.15). CONCLUSION: Neighborhood-level socioeconomic characteristics are associated with higher fall-related injuries. Injury prevention programs could be tailored to address these neighborhood risks.

Prevalence of polyreactive innate clones among graft--infiltrating B cells in human cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) has been associated with graft-infiltrating B cells, although their characteristics are still unclear. In this study we examined the frequency, localization and reactivity profile of graft-infiltrating B cells to determine their contribution to the pathophysiology of CAV. METHODS: B cells, plasma cells and macrophages were examined by immunohistochemistry in 56 allografts with CAV, 49 native failed hearts and 25 autopsy specimens. A total of 102 B-cell clones were immortalized directly from the infiltrates of 3 fresh cardiac samples with CAV. Their secreted antibodies were assessed using enzyme-linked immunoassay and flow cytometry. RESULTS: B-cell infiltration was observed around coronary arteries in 93% of allograft explants with CAV. Comparatively, intragraft B cells were less frequent and less dense in the intraventricular myocardium from where routine biopsies are obtained. Plasma cells and macrophages were also detected in 85% and 95% of explants, respectively. Remarkably, B-cell infiltrates were not associated with circulating donor-specific antibodies (DSA) or prior episodes of antibody-mediated rejection (AMR). Among all B-cell clones generated from 3 explants with CAV, a majority secreted natural antibodies reactive to multiple autoantigens and apoptotic cells, a characteristic of innate B cells. CONCLUSIONS: Our study reveals a high frequency of infiltrating B cells around the coronary arteries of allografts with CAV, independent of DSA or AMR. These cells are enriched for innate B cells with a polyreactive profile. The findings shift the focus from conventional DSA-producing B cells to the potentially pathogenic polyreactive B cells in the development of clinical CAV.