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Background: Acute kidney injury (AKI) is a multifaceted disease characterized by diverse clinical presentations and mechanisms. Advances in artificial intelligence have propelled the identification of AKI subphenotypes, enhancing our capacity to customize treatments and predict disease trajectories., Methods: We conducted a systematic review of the literature from 2017 to 2022, focusing on studies that utilized machine learning techniques to identify AKI subphenotypes in adult patients. Data were extracted regarding patient demographics, clustering methodologies, discriminators, and validation efforts from selected studies., Results: The review highlights significant variability in subphenotype identification across different populations. All studies utilized clinical data such as comorbidities and laboratory variables to group patients. Two studies incorporated biomarkers of endothelial activation and inflammation into the clinical data to identify subphenotypes. The primary discriminators were comorbidities and laboratory trajectories. The association of AKI subphenotypes with mortality, renal recovery and treatment response was heterogeneous across studies. The use of diverse clustering techniques contributed to variability, complicating the application of findings across different patient populations., Conclusions: Identifying AKI subphenotypes enables clinicians to better understand and manage individual patient trajectories. Future research should focus on validating these phenotypes in larger, more diverse cohorts to enhance their clinical applicability and support personalized medicine in AKI management., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background: Sickle cell disease (SCD) is a diverse group of blood disorders with significant global disease burden. Contemporary interest in the underlying inflammatory paradigm of SCD has emphasized the role of the neutrophil-lymphocyte ratio (NLR) as a prognostic inflammatory marker., Methods: We retrospectively reviewed 268 hospitalized patients with SCDs of different genotypes (HbSS, HbSβ 0 thalassemia, HbSβ + thalassemia, and HbSC), totaling 3329 hospital admissions over a 10-year period. Patients were stratified into SS/Sβ 0 and Sβ + /SC groups for statistical analysis of parameters collected at steady state and at hospital admission., Results: At steady state, per unit increase of hemoglobin values was associated with reduced odds of ≥ 2 hospital admissions per year in SS/Sβ 0 and Sβ + /SC groups; per unit increase in platelet count and white blood cell count was associated with increased odds only in the SS/Sβ 0 group. The NLR had no association in either group. During admission, a cutoff of NLR = 3.5 discerned infection with a sensitivity of 60% and specificity of 57%. Performance improved when excluding patients on outpatient hydroxyurea therapy (cutoff of NLR = 3.5; sensitivity of 68% and specificity of 64%)., Conclusion: This study supports the utility of NLR as an accessible adjunctive clinical tool in SCD prognostication.

In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. Under conditions of insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production. In contrast, during euglycemia, insulin potently inhibits glucagon's effect on the liver. The first aim of the present study was to determine whether low blood sugar augments glucagon's ability to increase glucose production. Using a conscious catheterized dog model, we found that hypoglycemia increased glucagon's ability to overcome the inhibitory effect of insulin on hepatic glucose production by almost 3-fold, an effect exclusively attributable to marked enhancement of the effect of glucagon on net glycogen breakdown. To investigate the molecular mechanism by which this effect comes about, we analyzed hepatic biopsies from the same animals, and found that hypoglycemia resulted in a decrease in insulin signaling. Furthermore, hypoglycemia and glucagon had an additive effect on the activation of AMPK, which was associated with altered activity of the enzymes of glycogen metabolism.

Portal glucose delivery enhances net hepatic glucose uptake (NHGU) relative to peripheral glucose delivery. We hypothesize that the sympathetic nervous system normally restrains NHGU, and portal glucose delivery relieves the inhibition. Two groups of 42-h-fasted conscious dogs were studied using arteriovenous difference techniques. Denervated dogs (DEN; n=10) underwent selective sympathetic denervation by cutting the nerves at the celiac nerve bundle near the common hepatic artery; control dogs (CON; n=10) underwent a sham procedure. After a 140-min basal period, somatostatin was given along with basal intraportal infusions of insulin and glucagon. Glucose was infused peripherally to double the hepatic glucose load (HGL) for 90 min (P1). In P2, glucose was infused intraportally (3-4 mg.kg(-1).min(-1)), and the peripheral glucose infusion was reduced to maintain the HGL for 90 min. This was followed by 90 min (P3) in which portal glucose infusion was terminated and peripheral glucose infusion was increased to maintain the HGL. P1 and P3 were averaged as the peripheral glucose infusion period (PE). The average HGLs (mg.kg(-1).min(-1)) in CON and DEN were 55+/-3 and 54+/-4 in the peripheral periods and 55+/-3 and 55+/-4 in P2, respectively. The arterial insulin and glucagon levels remained basal in both groups. NHGU (mg.kg(-1).min(-1)) in CON averaged 1.7+/-0.3 during PE and increased to 2.9+/-0.3 during P2. NHGU (mg.kg(-1).min(-1)) was greater in DEN than CON (P<0.05) during PE (2.9+/-0.4) and failed to increase significantly (3.2+/-0.2) during P2 (not significant vs. CON). Selective sympathetic denervation increased NHGU during hyperglycemia but significantly blunted the response to portal glucose delivery.

Whether glucagon-like peptide (GLP)-1 requires the hepatic portal vein to elicit its insulin secretion-independent effects on glucose disposal in vivo was assessed in conscious dogs using tracer and arteriovenous difference techniques. In study 1, six conscious overnight-fasted dogs underwent oral glucose tolerance testing (OGTT) to determine target GLP-1 concentrations during clamp studies. Peak arterial and portal values during OGTT ranged from 23 to 65 pM and from 46 to 113 pM, respectively. In study 2, we conducted hyperinsulinemic-hyperglycemic clamp experiments consisting of three periods (P1, P2, and P3) during which somatostatin, glucagon, insulin and glucose were infused. The control group received saline, the PePe group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally, the PePo group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then intraportally (P3), and the PeHa group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then through the hepatic artery (P3) to increase the hepatic GLP-1 load to the same extent as in P3 in the PePo group (n = 8 dogs/group). Arterial GLP-1 levels increased similarly in all groups during P2 ( approximately 50 pM), whereas portal GLP-1 levels were significantly increased (2-fold) in the PePo vs. PePe and PeHa groups during P3. During P2, net hepatic glucose uptake (NHGU) increased slightly but not significantly (vs. P1) in all groups. During P3, GLP-1 increased NHGU in the PePo and PeHa groups more than in the control and PePe groups (change of 10.8 +/- 1.3 and 10.6 +/- 1.0 vs. 5.7 +/- 1.0 and 5.4 +/- 0.8 micromol.kg(-1).min(-1), respectively, P < 0.05). In conclusion, physiological GLP-1 levels increase glucose disposal in the liver, and this effect does not involve GLP-1 receptors located in the portal vein.

The infusion of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) causes a rise in tissue concentrations of the AMP analog 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranotide (ZMP), which mimics an elevation of cellular AMP levels. The purpose of this work was to determine the effect of raising hepatic ZMP levels on hepatic insulin action in vivo. Dogs had sampling and infusion catheters as well as flow probes implanted 16 days before an experiment. After an 18-h fast, blood glucose was 82 +/- 1 mg/dl and basal net hepatic glucose output 1.5 +/- 0.2 mg . kg(-1) . min(-1). Dogs received portal venous glucose (3.2 mg . kg(-1) . min(-1)), peripheral venous somatostatin, and basal portal venous glucagon infusions from -90 to 60 min. Physiological hyperinsulinemia was established with a portal insulin infusion (1.2 mU . kg(-1) . min(-1)). Peripheral venous glucose infusion was used to clamp arterial blood glucose at 150 mg/dl. Starting at t = 0 min, dogs received portal venous AICAR infusions of 0, 1, or 2 mg . kg(-1) . min(-1). Net hepatic glucose uptake was 2.4 +/- 0.5 mg . kg(-1) . min(-1) (mean of all groups) before t = 0 min. In the absence of AICAR, net hepatic glucose uptake was 1.9 +/- 0.4 mg . kg(-1) . min(-1) at t = 60 min. The lower-dose AICAR infusion caused a complete suppression of net hepatic glucose uptake (-1.0 +/- 1.7 mg . kg(-1) . min(-1) at t = 60 min). The higher AICAR dose resulted in a profound shift in hepatic glucose balance from net uptake to a marked net output (-6.1 +/- 1.9 mg . kg(-1) . min(-1) at t = 60 min), even in the face of hyperglycemia and hyperinsulinemia. These data show that elevations in hepatic ZMP concentrations, induced by portal venous AICAR infusion, cause acute hepatic insulin resistance. These findings have important implications for the targeting of AMP kinase for the treatment of insulin resistance, using AMP analogs.

Unlabelled: Whether glucagon-like peptide-1 (GLP-1) has insulin-independent effects on glucose disposal in vivo was assessed in conscious dogs by use of tracer and arteriovenous difference techniques. After a basal period, each experiment consisted of three periods (P1, P2, P3) during which somatostatin, glucagon, insulin, and glucose were infused. The control group (C) received saline in P1, P2, and P3, the PePe group received saline in P1 and GLP-1 (7.5 pmol.kg(-1).min(-1)) peripherally (Pe; iv) in P2 and P3, and the PePo group received saline in P1 and GLP-1 peripherally (iv) (P2) and then into the portal vein (Po; P3). Glucose and insulin concentrations increased to two- and fourfold basal, respectively, and glucagon remained basal. GLP-1 levels increased similarly in the PePe and PePo groups during P2 ( approximately 200 pM), whereas portal GLP-1 levels were significantly increased (3-fold) in PePo vs. PePe during P3. In all groups, net hepatic glucose uptake (NHGU) occurred during P1. During P2, NHGU increased slightly but not significantly in all groups. During P3, NHGU increased in PePe and PePo groups to a greater extent than in C, but no significant effect of the route of infusion of GLP-1 was demonstrated (16.61 +/- 2.91 and 14.67 +/- 2.09 vs. 4.22 +/- 1.57 micromol.kg(-1).min(-1), respectively)., In Conclusion: GLP-1 increased glucose disposal in the liver independently of insulin secretion; its full action required long-term infusion. The route of infusion did not modify the hepatic response.

Our aim was to determine whether complete hepatic denervation would affect the hormonal response to insulin-induced hypoglycemia in dogs. Two weeks before study, dogs underwent either hepatic denervation (DN) or sham denervation (CONT). In addition, all dogs had hollow steel coils placed around their vagus nerves. The CONT dogs were used for a single study in which their coils were perfused with 37 degrees C ethanol. The DN dogs were used for two studies in a random manner, one in which their coils were perfused with -20 degrees C ethanol (DN + COOL) and one in which they were perfused with 37 degrees C ethanol (DN). Insulin was infused to create hypoglycemia (51 +/- 3 mg/dl). In response to hypoglycemia in CONT, glucagon, cortisol, epinephrine, norepinephrine, pancreatic polypeptide, glycerol, and hepatic glucose production increased significantly. DN alone had no inhibitory effect on any hormonal or metabolic counterregulatory response to hypoglycemia. Likewise, DN in combination with vagal cooling also had no inhibitory effect on any counterregulatory response except to reduce the arterial plasma pancreatic polypeptide response. These data suggest that afferent signaling from the liver is not required for the normal counterregulatory response to insulin-induced hypoglycemia.

It has been demonstrated in the conscious dog that portal glucose infusion creates a signal that increases net hepatic glucose uptake and hepatic glycogen deposition. Experiments leading to an understanding of the mechanism by which this change occurs will be facilitated if this finding can be reproduced in the rat. Rats weighing 275-300 g were implanted with four indwelling catheters (one in the portal vein, one in the left carotid artery, and two in the right jugular vein) that were externalized between the scapulae. The rats were studied in a conscious, unrestrained condition 7 days after surgery, following a 24-h fast. Each experiment consisted of a 30- to 60-min equilibration, a 30-min baseline, and a 120-min test period. In the test period, a pancreatic clamp was performed by using somatostatin, insulin, and glucagon. Glucose was given simultaneously either through the jugular vein to clamp the arterial blood level at 220 mg/dl (Pe low group) or at 250 mg/dl (Pe high group), or via the hepatic portal vein (Po group; 6 mg. kg(-1). min(-1)) and the jugular vein to clamp the arterial blood glucose level to 220 mg/dl. In the test period, the arterial plasma glucagon and insulin levels were not significantly different in the three groups (36 +/- 2, 33 +/- 2, and 30 +/- 2 pg/ml and 1.34 +/- 0.08, 1. 37 +/- 0.18, and 1.66 +/- 0.11 ng/ml in Po, Pe low, and Pe high groups, respectively). The arterial blood glucose levels during the test period were 224 +/- 4 mg/dl for Po, 220 +/- 3 for Pe low, and 255 +/- 2 for Pe high group. The liver glycogen content (micromol glucose/g liver) in the two Pe groups was not statistically different (51 +/- 7 and 65 +/- 8, respectively), whereas the glycogen level in the Po group was significantly greater (93 +/- 9, P < 0.05). Because portal glucose delivery also augments hepatic glycogen deposition in the rat, as it does in the dogs, mechanistic studies relating to its function can now be undertaken in this species.

Background: Weight gain is a frequent consequence of smoking cessation. Leptin, the protein product of the obese gene, seems to regulate appetite and body fat stores. The purpose of this study was to assess changes in circulating leptin levels and lipid metabolism during nicotine abstinence (NA) and their role in postcessation weight gain., Methods: Six sedentary, weight-stable, nonobese adult smokers were studied before and after 7 days of NA while following a weight-maintenance diet of standard composition. All subjects refrained from smoking overnight (as assessed by breath CO) and were instructed to chew nicotine polacrilex gum (4 mg) hourly from 7:00 AM to 8:00 PM [nicotine intake (NI) day]. Venous blood samples were collected at 7:00 AM (after an overnight fast) and 5:00 PM (pre-supper) on NI day and again after 7 days of NA., Results: Body weight did not change after 7 days of NA (72.0 +/- 2.8 versus 71.8 +/- 2.7 kg). Serum cotinine levels declined from 207 +/- 40 ng/mL during NI to undetectable levels during NA (P < 0.01). Fasting plasma leptin was similar during NI and NA (5.7 +/- 1.4 versus 6.4 +/- 1.9 ng/mL; P = NS). Moreover, plasma concentrations of glucose, insulin, and free fatty acids were unaffected by 7 days of NA. Although plasma triglycerides, total cholesterol, and low-density lipoprotein cholesterol were similar during NI and NA, high-density lipoprotein cholesterol increased by 15% after 7 days of NA (P < 0.05)., Conclusions: In this group of nonobese, adult smokers consuming an isocaloric diet, NA for 7 days did not affect body weight or circulating concentrations of leptin, glucose, insulin, or free fatty acids. In contrast, HDL cholesterol increased significantly after NA. These results indicate that under controlled dietary conditions, changes in leptin expression do not contribute to the weight gain that commonly accompanies smoking cessation.

Immunoassays for circulating leptin are important research tools for examining the role and regulation of leptin expression in human obesity. However, uncertainty exists regarding the comparability between studies of reported plasma or serum leptin concentrations. The purpose of the present study was to directly compare plasma leptin concentrations by using two of the most widely reported immunoassay methods-namely, a commercially available radioimmunoassay (RIA) and a proprietary enzyme-linked immunosorbent assay (ELISA). Plasma leptin concentrations were measured in healthy lean and obese volunteers and in patients with Prader-Willi syndrome (PWS). Over a wide range of plasma concentrations (2 to 70 ng/mL), leptin measurements obtained with the RIA and ELISA methods were highly correlated (r = 0.957, P<.0001) and were essentially indistinguishable. Leptin levels measured by RIA and ELISA were highly correlated with body mass index (BMI) overall (r = 0.784, P<.0001 and r = 0.732, P<.0001, respectively) and in the lean and obese subgroups. When compared with the results in the lean individuals (mean +/- SEM, 11.6+/-3.2 ng/mL), plasma leptin was significantly higher in both the obese (35.5+/-4.0 ng/mL, P<.0001) and the PWS subjects (30.7+/-6.9 ng/mL, P<.05). However, after we controlled for differences in BMI, the leptin levels were similar in all three groups. In conclusion, we found that the RIA and ELISA used in the present study yield plasma leptin concentrations that are essentially indistinguishable. Our findings should facilitate comparisons of leptin levels measured by these two widely used immunoassays in previous and future studies that examine the role of leptin in body weight regulation.

Fuel and energy homeostasis was examined in six male volunteers during a 60-h fast by using a combination of isotopic tracer techniques ([3-3H]glucose, [2H5]glycerol, [1-14C]palmitate, and L-[1-13C]leucine) and indirect calorimetry. Plasma glucose concentration and hepatic glucose production decreased by 30% with fasting (5.2 +/- 0.1 to 3.8 +/- 0.2 mmol/L and 11.8 +/- 0.5 to 8.2 +/- 0.6 mumol.kg-1.min-1, respectively, both P < 0.001) and glucose oxidation declined approximately 85% (P < 0.01). Lipolysis and primary (intraadipocyte) free fatty acid (FFA) reesterification increased 2.5-fold (1.7 +/- 0.2 to 4.2 +/- 0.2 mumol.kg-1.min-1 and 1.5 +/- 0.4 to 4.2 +/- 0.8 mumol.kg-1.min-1, respectively, both P < 0.05). This provided substrate for the increase in fat oxidation (from 2.7 +/- 0.3 to 4.3 +/- 0.1 mumol.kg-1.min-1, P < 0.01), which contributed approximately 75% of resting energy requirements after the 60-h fast and increased the supply of glycerol for gluconeogenesis. Proteolysis and protein oxidation increased approximately 50% during fasting (P < 0.01 and P < 0.05, respectively). We conclude that the increase in FFA reesterification with fasting modulates FFA availability for oxidation and maximizes release of glycerol from triglyceride for gluconeogenesis.

Glucagon may regulate FFA metabolism in vivo. To test this hypothesis, six healthy male volunteers were infused with somatostatin, to inhibit endogenous hormone secretion, and insulin, glucagon, and GH to replace endogenous secretion of these hormones. In the hypoglucagonemia experiments, the glucagon infusion was omitted, and in the hyperglucagonemic experiments glucagon was infused at 1.3 ng/kg.min, to produce physiological hyperglucagonemia. In two sets of control experiments, glucagon was infused at 0.65 ng/kg.min, in order to maintain peripheral euglucagonemia, and the plasma glucose concentrations were clamped at the levels observed in either the hypo- or hyperglucagonemic experiments. Rates of FFA and glycerol (an index of lipolysis) appearance (Ra) were estimated with the isotope dilution method using [1-14C]palmitate and [2H5] glycerol. Plasma glucagon concentrations decreased during the hypoglucagonemic experiments (85 +/- 12 vs. 123 +/- 22 ng/L, P < 0.05) and increased during the hyperglucagonemic experiments (186 +/- 20 vs. 125 +/- 15 ng/L, P < 0.05), whereas other hormone concentrations remained the same. Hypoglucagonemia resulted in equivalent suppression of FFA Ra (3.7 +/- 0.2 vs. 5.9 vs. 0.3 mumol/kg.min, P < 0.01) and glycerol Ra (1.2 +/- 0.2 vs. 2.2 +/- 0.5 mumol/kg.min, P < 0.05). Similarly, hyperglucagonemia resulted in equivalent stimulation of FFA Ra (5.2 +/- 0.4 vs. 3.7 +/- 0.3 mumol/kg.min, P < 0.05) and glycerol Ra (1.5 +/- 0.3 vs. 1.1 +/- 0.1 mumol/kg.min, P < 0.05). These results indicate that glucagon has a physiological role in the regulation of FFA metabolism in vivo.

The role of plasma glucose in the regulation of lipid metabolism in humans, independent of associated changes in hormone concentrations, is controversial. Therefore we examined the role of glucose in the regulation of lipolysis and free fatty acid (FFA) reesterification in six healthy lean male volunteers. Blood glucose concentration was clamped at either 5 or 10 mM during 2-h pancreatic-pituitary clamps. Glycerol and palmitate turnover were measured by isotope dilution ([1-14C]palmitate and [2H5]-glycerol). All hormone concentrations were the same during the euglycemic and hyperglycemic studies. FFA turnover, which represents the difference between lipolysis and FFA reesterification, was reduced 30% by hyperglycemia (29 +/- 2 vs. 20 +/- 3 mumol.kg fat mass-1.min-1, P less than 0.05). Glycerol turnover, which represents lipolysis only, was reduced to a similar extent (9.4 +/- 0.9 vs. 6.2 +/- 0.7 mumol.kg fat mass-1.min-1, P less than 0.05). We conclude that glucose regulates lipid metabolism, independently of changes in hormone concentrations. The equivalent suppression of glycerol and FFA turnover indicates that the effect is mediated by suppression of lipolysis and not by stimulation of FFA reesterification.