Endothelin-1 levels are decreased in pediatric Type 1 diabetes and negatively correlate with the carotid intima media thickness.

AIMS: Better understanding of the timeline and risk factors for the appearance of complications in pediatric Type-1-diabetes is key for developing prevention strategies. We studied endothelial markers and their determinants in adolescents with Type-1-diabetes at different time points from diagnosis. METHODS: A cross-sectional study of 58 adolescents, mean age 15.0 ± 2.4 years; 20 with recent-onset Type-1-diabetes, 20 with over 7 years of Type-1-diabetes and 18 controls. Clinical and biochemical data were collected. Fingertip arterial reactive hyperemia (EndoPAT) and carotid intima-media-thickness (cIMT) were measured to assess endothelial function and structure. RESULTS: Compared to controls, individuals with prolonged Type-1-diabetes had higher mean cIMT (0.49 ± 0.07 mm vs. 0.43 ± 0.05 mm p = 0.021) and maximal cIMT (0.61 ± 0.08 mm 0.52 ± 0.08 mm, p = 0.025). Endothelin-1 levels were significantly lower in subjects with prolonged Type-1-diabetes (1.2 ± 1.0 pg/ml) compared to controls (3.0 ± 1.7, p = 0.008 pg/ml); they negatively correlated with the mean cIMT (c = - 0.291, p = 0.031) and mean 6 months hemoglobin A1c (c = - 0.301, p = 0.022) and positively correlated with mean c-peptide levels (c = 0.356, p = 0.006) and the weekly exercise time (c = 0.485, p < 0.001). Endothelin-1 levels did not correlate with EndoPAT results. CONCLUSIONS: Our results suggest that the early years after the diagnosis of Type-1-diabetes are an important window for prevention of arterial damage in the pediatric population. The trajectories of relationships of Endothelin-1 with metabolic and vascular measures were opposite from the anticipated, yet consistent. Endothelin-1 related indirectly to adverse measures and directly to favorable measures. Decreased Endothelin-1 levels might reflect early stages in endothelial impairment in Type-1-diabetes, yet its' exact role in the development of complications is yet to be unraveled.

Combination of hyperglycaemia and hyperlipidaemia induces endothelial dysfunction: Role of the endothelin and nitric oxide systems.

Endothelial dysfunction (ED) is a key feature of diabetes and is a major cause of diabetic vasculopathy. Diabetic patients who also exhibit hyperlipidaemia suffer from accelerated vascular complications. While the deleterious effects of high glucose levels (HG) and hyperlipidaemia alone on ED are well established, the effects of combined hyperlipidaemia and HG have not been thoroughly studied. Therefore, the current study examines whether HG and hyperlipidaemia exert synergistic ED, and explores the mechanisms underlying this phenomenon. We applied multi-disciplinary approaches including cultured HUVECs and HMEC-1 as well as knockout mice CByJ.129S7(B6)-Ldlrtm1Her/J (LDLR-/- ) to investigate the mechanisms underlying combined HG and hyperlipidaemia-induced ED. Incremental doses of glucose in the presence or absence of OxLDL were added to HUVECs and HMEC-1. After 5 days, the status of nitric oxide (NO) and endothelin (ET)-1 systems as well as their signal transduction were assessed using Western blot, ELISA and immunoreactive staining. The effects of chronic combination of HG and hyperlipidaemia on endothelial integrity and function as well as alterations in circulatory NO and ET-1 systems were examined in knockout mice LDLR-/- and their wild-type. HUVEC cells exposed to HG and OxLDL displayed enhanced ET-1 production, more than HG or OxLDL when added alone. Overproduction of ET-1 stems from up-regulation of endothelin converting enzyme (ECE)-1 as observed under these conditions. In contrast, combination of HG and OxLDL dramatically decreased both total endothelial NO synthase (eNOS) by 60%, and activated eNOS (peNOS) by 80%. Moreover, NRF2 decreased by 42% and its active form (pNRF2) by 56%, as compared to baseline. Likewise, ETB levels decreased by 64% from baseline on endothelial cells. Furthermore, diabetic LDLR-/- mice displayed a higher blood pressure, plasma triglycerides, cholesterol, ET-1 and NO2/NO3 levels, when compared with normoglycemic LDLR-/- and BALB mice. Combined hyperglycaemia and hyperlipidaemia activates the ET system and attenuates the nitric oxide system with the Nrf2 signalling pathway. These findings suggest that perturbations in these paracrine systems may contribute to ED.

Skin well-being in diabetes: Role of macrophages.

Macrophages are key players in wound healing- along with mediating the acute inflammatory response, macrophages activate cutaneous epithelial cells and promote tissue repair. Diabetes complications, including diabetic chronic wounds, are accompanied by persistent inflammation and macrophage malfunction. Several studies indicate that hyperglycemia induces various alterations that affect macrophage function in wound healing including epigenetic changes, imbalance between pro- and anti-inflammatory modulators, and insensitivity to proliferative stimuli. In this review, we briefly summarize recent studies regarding those alterations and their implications on skin well-being in diabetes.

Biomarker evidence for distal tubular damage but cortical sparing in hospitalized diabetic patients with acute kidney injury (AKI) while on SGLT2 inhibitors.

BACKGROUND: Inhibitors of sodium-glucose co-transporter-2 (SGLT2i) were found to improve renal outcome in diabetic patients in large prospective randomized trials. Yet, SGLT2i may acutely reduce kidney function through volume depletion, altered glomerular hemodynamics or intensified medullary hypoxia leading to acute tubular injury (ATI). The aim or this study was to prospectively assess the pathophysiology of acute kidney injury (AKI) in patients hospitalized while on SGLT2i, differing ATI from pre-renal causes using renal biomarkers. METHODS: Serum and urine Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Ischemia Molecule (KIM)-1, markers of distal and proximal tubular injury, respectively, were determined in 46 diabetic patients who were on SGLT2i upon hospitalization with an acute illness. RESULTS: Serum and urine NGAL, but not KIM-1, were significantly increased in 21 of the patients who presented with AKI upon admission, as compared with 25 patients that maintained kidney function. Both serum and urinary NGAL correlated with the degree of impaired renal function, which in many cases was likely the result of additional acute renal perturbations, such as sepsis. CONCLUSIONS: Increased urinary and serum NGAL indicates that ATI, principally affecting distal tubular segments, may develop in some of the patients hospitalized with an acute illness and AKI while on SGLT2i. It is suggested that intensified medullary hypoxia by SGLT2i might be detrimental in this injury. By contrast, concomitantly unaltered KIM-1 might reflect improved cortical oxygenation by SGLT2i, and may explain an overall reduced risk of AKI with SGLT1i in large series. The independent potential of SGLT2i to inflict medullary hypoxic damage should be explored further.

Galectin-1 Facilitates Macrophage Reprogramming and Resolution of Inflammation Through IFN-ß.

During the resolution of acute inflammation, macrophages undergo reprogramming from pro-inflammatory, to anti-inflammatory/reparative, and eventually to pro-resolving macrophages. Galectin-1 (Gal-1) is a bona fide pro-resolving lectin while interferon ß (IFN-ß) was recently shown to facilitate macrophage reprogramming and resolution of inflammation. In this study, we found Gal-1null mice exhibit a hyperinflammatory phenotype during the resolution of zymosan A-induced peritonitis but not during the early inflammatory response. This phenotype was characterized by reduced macrophage numbers, increased secretion of pro-inflammatory cytokines, such as interleukin-12 (IL-12), and reduced secretion of anti-inflammatory cytokines, such as interleukin-10 (IL-10). In addition, we found a delayed expression of the pro-resolving enzyme 12/15-lipoxygenase in macrophages and heightened levels of the inflammatory protease proteinase-3 (PR3) in peritoneal fluids from Gal-1null mice. Moreover, we observed sex-dependent differences in the inflammatory profile of Gal-1null mice. Notably, we found that IFN-ß levels were reduced in resolution-phase exudates from Gal-1null mice. Administration of IFN-ß in vivo or ex vivo treatment was able to rescue, at least in part, the hyperinflammatory profile of Gal-1null mice. In particular, IFN-ß recovered a subset of F4/80+GR-1+ macrophages, restored IL-12 and IL-10 secretion from macrophages to WT values and diminished abnormal peritoneal PR3 levels in Gal-1null mice. In conclusion, our results revealed a new Gal-1-IFN-ß axis that facilitates the resolution of inflammation and might restrain uncontrolled inflammatory disorders.

Acute Kidney Injury After Radiocontrast-Enhanced Computerized Tomography in Hospitalized Patients With Advanced Renal Failure: A Propensity-Score-Matching Analysis.

BACKGROUND: The overall risk of postcontrast acute kidney injury (PC-AKI) after computerized tomography (CT) is negligible, likely because of the small volume of injected iodinated contrast media required. However, the safety of contrast media-enhanced CT in patients with advanced renal functional impairment, an established major risk factor for PC-AKI, is unknown. MATERIALS AND METHODS: This is a retrospective study using large data analysis of hospitalized patients at a single center. Adults undergoing CT or magnetic resonance imaging were included in the study and were stratified by estimated glomerular filtration rate (eGFR) (≤30 or >30 mL/min/1.73 m) and by either contrast-enhanced or nonenhanced imaging. Only patients with serial determination of creatinine before and after imaging were included. Demographic, clinical, and laboratory data between groups were analyzed and compared using univariate analysis, propensity score matching, and multivariate logistic regression analysis. RESULTS: A total of 22,319 imaging studies were included. Patients with an eGFR of 30 mL/min/1.73 m or lower undergoing contrast-enhanced CT (n = 403) had an increased risk to develop PC-AKI than did similar patients undergoing enhanced or nonenhanced magnetic resonance imaging (n = 96) or nonenhanced CT (n = 1576) or patients undergoing contrast-enhanced CT with a preprocedural eGFR higher than 30 mL/min/1.73 m (n = 9173). These findings remained robust after propensity matching for demographic, procedural, and clinical parameters. Multivariate regression analysis of all patients undergoing CT with preimaging eGFR of 30 mL/min or lower (n = 1979) revealed that iodine-based contrast enhancement increased the likelihood of post-CT AKI by 51% (confidence interval, 1.23-2.05). CONCLUSION: Although radiocontrast-enhanced CT is considered safe in most hospitalized patients and in ambulatory settings, the risk of PC-AKI remains significant among inpatients with substantial preimaging renal functional impairment. Caution is warranted using iodine-based enhanced CT in hospitalized patients with an eGFR of 30 mL/min/1.73 m or lower.

Negligible Risk of Acute Renal Failure Among Hospitalized Patients After Contrast-Enhanced Imaging With Iodinated Versus Gadolinium-Based Agents.

INTRODUCTION: The potential adverse renal outcome among patients undergoing iodine-based contrast-enhanced computerized tomography (CT) has been questioned recently, given the caution undertaken in patients' selection, hydration protocols, and the low radiocontrast volume, used with advanced imaging equipment. MATERIALS AND METHODS: This study is a retrospective assessment of renal outcome in 12,580 hospitalized patients undergoing contrast-enhanced CT, compared with 754 patients subjected to gadolinium-based magnetic resonance imaging, with subsequent propensity matching for clinical characteristics and potential risk factors. RESULTS: The risk of postcontrast acute kidney injury (PC-AKI) was found to be negligible as compared with patients undergoing enhanced magnetic resonance imaging studies, before and after propensity matching (8% vs 7.3% rate of AKI in the nonmatched iodine-based contrast agents [IBCAs] and gadolinium-based contrast agents [GBCAs], respectively, P = 0.3, and 7% in the matched IBCA group, P = 0.9), including comparisons among subgroups with well-defined risk factors such as chronic renal failure, diabetes, older age, and hypertension. However, lower systolic blood pressure before imaging was associated with higher risk to develop PC-AKI after IBCA administration but not with GBCA (for systolic blood pressure lower than 110 mm Hg, odds ratio for AKI after IBCA was 1.49; 95% confidence interval, 1.16-1.88, and after GBCA; odds ratio, 0.12; 95% confidence interval, 0.003-0.73). CONCLUSIONS: With the current precautions undertaken, the real-life risk of PC-AKI among inpatients undergoing CT is insignificant. Possible reasons for the diverse impact of blood pressure on the propensity to develop acute kidney failure after iodine-based but not gadolinium-based enhancement imaging are discussed.

Acute Renal Failure Following Near-Drowning.

INTRODUCTION: Acute kidney injury associated with near-drowning (ND-AKI) has rarely been reported and its incidence among survivors is unknown. A patient with AKI and urine biomarkers indicating tubular injury led us to assess the occurrence and clinical characteristics of ND-AKI and to evaluate possible causative mechanisms. METHODS: We evaluated medical records of patients rescued from near-drowning in the Mediterranean Sea and treated in a tertiary-level medical center during 2000 to 2017. RESULTS: Ninety-five patients with the diagnosis of near-drowning in seawater were treated. Forty-two of these patients (43%) developed ND-AKI and 17 (18%) were classified as AKI Kidney Disease: Improving Global Outcomes stages 2 to 3. ND-AKI was associated with the need for resuscitation and mechanical ventilation, with the calculated seawater volume ingestion (extrapolated from rising plasma sodium) and with the degree of acidemia, lactemia, and ventilatory failure. This series and 28 additional published cases of ND-AKI in the literature showed an overall male predisposition. CONCLUSION: AKI is a common complication of near-drowning and is associated with increased in-hospital mortality. Data analysis suggests a predominant role of hypoxic tubular injury due to systemic hypoxemia in ND-AKI, combined with intense sympathetic activity (reflected by tachyarrhythmias, hyperglycemia, and relative hypokalemia) and increased oxygen expenditure for intensified distal tubular sodium transport. Androgen-related reduced renal vasodilatory capacity may explain male gender predominance.

Galectin-1 induces 12/15-lipoxygenase expression in murine macrophages and favors their conversion toward a pro-resolving phenotype.

During the resolution of inflammation macrophages undergo functional changes upon exposure to pro-resolving agents in their microenvironment. Primarily, engulfment of apoptotic polymorphonuclear (PMN) cells promotes conversion of macrophages toward a pro-resolving phenotype characterized by reduced CD11b expression. These macrophages are not phagocytic, do not respond to TLR ligands, and express relatively high levels of the pro-resolving enzyme 12/15-lipoxygenase (LO). Here, we report that the immuno-regulatory lectin galectin-1 is selectively expressed by CD11b(high), but not CD11b(low) macrophages. Upon exposure in vivo and ex vivo, galectin-1 directly promoted macrophage conversion from a CD11b(high) to a CD11b(low) phenotype and up-regulated the expression and activity of 12/15-LO. Moreover, galectin-1 treatment in vivo promoted the loss of phagocytic capacity (efferocytic satiation) in peritoneal macrophages and down-regulated secretion of TNF-α, IL-1ß, and IL-10 upon LPS exposure. Our results suggest that galectin-1 could be an essential mediator in the control of macrophage function during the resolution of inflammation.