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Background. Acutely ill older patients frequently suffer not only from their acute disease, but also polymorbidity and frailty. Dehydration is another typical symptom, usually occurring in its both forms: low-intake dehydration and volume depletion. POCUS is goal-directed bedside ultrasound examination and several studies refer to its positive impact on hydration assessment. The aim of our study was to determine whether POCUS might influence (de)hydration diagnostics and/or treatments in older patients with acute illness. Methods. We randomized 120 acutely ill patients, aged ≥65 years, into POCUS and non-POCUS groups. All participants underwent routine laboratory tests, including haematocrit, serum and urine osmolality, blood urea nitrogen (BUN), creatinine, BUN/creatinine ratio, and C-reactive protein (CRP). POCUS was performed twice during the first two days to determine chest and abdominal status, with inferior vena cava (IVC) measurements. Length of hospital stay (HL) and consumption of infused fluids (CIF) was evaluated too. Data were analysed with exploratory methods and appropriate statistics. Results. Among all participants, the serum osmolality significantly correlated with age, BUN, creatinine and CIF. HL correlated with CRP and CIF. No significant correlations between IVC and other followed parameters were found. The POCUS group consumed significantly less infused fluids than the non-POCUS group, what could be influenced by POCUS examination of defined body compartments. Conclusion. Dehydration is a common feature in older individuals and its diagnostics is rather complicated. The role of POCUS in assessing hydration status remains unclear. However, our study showed, that ultrasound assessment provides next important information for comprehensive understanding of clinical status in older patients and can be beneficial for optimizing the treatment strategy, including fluid management decisions.

Background. Acutely ill older patients frequently suffer not only from their acute disease, but also polymorbidity and frailty. Dehydration is another typical symptom, usually occurring in its both forms: low-intake dehydration and volume depletion. POCUS is goal-directed bedside ultrasound examination and several studies refer to its positive impact on hydration assessment. The aim of our study was to determine whether POCUS might influence (de)hydration diagnostics and/or treatments in older patients with acute illness. Methods. We randomized 120 acutely ill patients, aged ≥65 years, into POCUS and non-POCUS groups. All participants underwent routine laboratory tests, including haematocrit, serum and urine osmolality, blood urea nitrogen (BUN), creatinine, BUN/creatinine ratio, and C-reactive protein (CRP). POCUS was performed twice during the first two days to determine chest and abdominal status, with inferior vena cava (IVC) measurements. Length of hospital stay (HL) and consumption of infused fluids (CIF) was evaluated too. Data were analysed with exploratory methods and appropriate statistics. Results. Among all participants, the serum osmolality significantly correlated with age, BUN, creatinine and CIF. HL correlated with CRP and CIF. No significant correlations between IVC and other followed parameters were found. The POCUS group consumed significantly less infused fluids than the non-POCUS group, what could be influenced by POCUS examination of defined body compartments. Conclusion. Dehydration is a common feature in older individuals and its diagnostics is rather complicated. The role of POCUS in assessing hydration status remains unclear. However, our study showed, that ultrasound assessment provides next important information for comprehensive understanding of clinical status in older patients and can be beneficial for optimizing the treatment strategy, including fluid management decisions. [ABSTRACT FROM AUTHOR]

The purpose of this systematic review and meta-analysis was to evaluate the common clinical adverse events associated with sodium/glucose cotransporter-2 inhibitor (SGLT2i) use compared to placebo in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Twelve articles were chosen via a systematic search of the PubMed, Embase, and Cochrane Library databases. We screened for randomised placebo-controlled trials. The main clinical adverse events included diabetes ketoacidosis (DKA), amputation, and volume depletion. We performed heterogeneity testing and assessment of publication bias. In all, 65 600 patients were included in the analysis. Compared to placebo, SGLT2i may increase the risk of DKA and volume depletion in patients with CKD with or without type 2 diabetes. For DKA, compared with placebo, the combined effect of SGLT2i was OR 2.03 (95% CI: 1.28 to 3.23 I2: 2.3%, P: 0.420). For volume depletion, compared with placebo, the combined effect of SGLT2i was OR 1.24 (95% CI: 1.13 to 1.37 I2: 0.0%, P: 0.484). For the risk of amputation, despite low heterogeneity for amputation, the forest plot indicated no statistical significance, and thus it cannot be concluded that SGLT2i increases the risk of amputation. Compared with placebo, the combined effect of SGLT2i was OR 1.10 (95% CI: 0.94 to 1.29 I2: 0.0%, P: 0.642). The use of SGLT2i may increase the risk of DKA and volume depletion in patients with chronic renal insufficiency with or without type 2 diabetes. [ABSTRACT FROM AUTHOR]

Prerenal azotemia (PRA) is a major cause of acute kidney injury and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of glomerular filtration rate (GFR) that returns to baseline with resuscitation. Adult male C57BL/6J wild-type (WT) and IL-6−/− mice were studied. Intraperitoneal furosemide (4 mg) or vehicle was administered at time = 0 and 3 h to induce PRA from volume loss. Resuscitation began at 6 h with 1 mL intraperitoneal saline for four times for 36 h. Six hours after furosemide administration, measured glomerular filtration rate was 25% of baseline and returned to baseline after saline resuscitation at 48 h. After 6 h of PRA, plasma interleukin (IL)-6 was significantly increased, kidney and liver histology were normal, kidney and liver lactate were normal, and kidney injury molecule-1 immunofluorescence was negative. There were 327 differentially regulated genes upregulated in the liver, and the acute phase response was the most significantly upregulated pathway; 84 of the upregulated genes (25%) were suppressed in IL-6−/− mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included serum amyloid A2, serum amyloid A1, lipocalin 2, chemokine (C-X-C motif) ligand 1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in wild-type PRA and were all reduced in IL-6−/− PRA. This work demonstrates previously unknown systemic effects of PRA that includes IL-6-mediated upregulation of the hepatic acute phase response. NEW & NOTEWORTHY Prerenal azotemia (PRA) accounts for a third of acute kidney injury (AKI) cases yet is rarely studied in preclinical models. We developed a clinically defined murine model of prerenal azotemia characterized by a 75% decrease in measured glomerular filtration rate (GFR), return of measured glomerular filtration rate to baseline with resuscitation, and absent tubular injury. Numerous systemic effects were observed, such as increased plasma interleukin-6 (IL-6) and upregulation of the hepatic acute phase response. [ABSTRACT FROM AUTHOR]

This paper presents a Junction-less SOI FET with an embedded p+ layer (EP-JLFET) to obtain extensive volume depletion in 14 nm channel length of the device. The p+ embedded area improves the OFF-state current (IOFF) ~ five orders, while the ON-state current (ION) degrades, slightly. The subthreshold slope (SS) is also reduced. This remarkable improvement in the IOFF shows the feasibility of the proposed device for achieving wide values of the threshold voltage with varying the metal-gate work function, which is not conceivable in conventional silicon junction-less FETs (C-JLFET). Besides, in this work, the effect of ferroelectric oxide on the efficiency of the suggested device has been investigated. IOFF of the negative capacitance device reduces by about three orders, ION increases by about 1 order, and SS decreases from 92.1 mV/dec in EP-JLFET to 32.3 mV/dec in NCEP-JLFET. [ABSTRACT FROM AUTHOR]

Background: Improving health-related quality of life (HRQoL) is essential in treating heart failure (HF). Evidence of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on HRQoL and exercise capacity needs to be systematically analyzed. Aim: This meta-analysis aimed to summarize the effects of SGLT-2 inhibitors on HRQoL, exercise capacity, and volume depletion in patients with HF. Method: Randomized controlled trials were searched from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. The intervention arm was the SGLT-2 inhibitor group, and the control group was the placebo group. HRQoL outcomes were the Kansas City Cardiomyopathy Questionnaires (KCCQ)-OSS (Overall Summary Score), KCCQ-CSS (Clinical Summary Score), and KCCQ-TSS (Total Symptom Score). Exercise capacity was a 6-min walk test distance (6MWTD). The last search was conducted in May 2022. Two researchers independently screened articles, extracted data, and evaluated the quality of included trials. The Cochrane risk-of-bias tool was used to assess the quality of each study. Random or fixed-effect models were used in statistical methods. I2 statistics were used to assess heterogeneity. Results: Eight studies (6,213 patients) were included. Compared to the placebo group, SGLT-2 inhibitors significantly improved HRQoL parameters of the KCCQ-CSS score [mean difference (MD) 5.17, 95% confidence interval (95% CI) 4.61–5.73, P < 0.01] and the KCCQ-OSS score (MD 4.00, 95% CI 3.44–4.56, P < 0.01). SGLT-2 inhibitors also significantly improved exercise capacity 6MWTD (MD 21.90, 95% CI 6.54–37.25, P = 0.005). There were no significant differences in KCCQ-TSS (MD 1.95, 95% CI − 1.10 to 5.01, P = 0.21) and volume depletion [odds ratio (OR) 1.15, 95% CI 0.94–1.42, P = 0.18] between the treatment and placebo groups. Conclusion: SGLT-2 inhibitors could improve HRQoL and exercise capacity in patients with chronic HF. SGLT-2 inhibitors did not have an impact on volume depletion. [ABSTRACT FROM AUTHOR]

Background: Sodium glucose co‐transporter 2 inhibitors (SGLT2is) are used to prevent cardiovascular complications in type 2 diabetes mellitus (T2DM) and newly indicated to treat heart failure (HF). Loop diuretics are commonly prescribed to manage volume overload in HF and may increase the risk of volume depletion in real‐world practice. This study evaluated the risk of volume depletion following concomitant use of SGLT2is and loop diuretics in veterans. Methods: Veterans with T2DM were included if they received concomitant loop diuretics and SGLT2is and experienced at least one volume depletion event between December 2012 and December 2019, utilizing a self‐controlled case series design. Concomitant prescribing periods were divided into focal windows of 1 to 14 days, 14 to 28 days, and greater than 28 days. Incidence rate ratios (IRR) were estimated using multivariable Poisson regressions adjusted for age and renal function. Results: 3352 patients experienced at least one volume depletion event and were concomitantly prescribed SGLT2is and loop diuretics at least once. The risk of volume depletion increased in the treatment versus control windows during the 1 to 14‐day window (IRR = 1.82, 95% CI 1.63–2.02) the 15‐to‐28‐day window (IRR = 1.46, 95% CI 1.28–1.67), and the greater than 28‐day window (IRR = 1.22, 95% CI 1.21–1.34). Conclusions: Concomitant prescribing of SGLT2is and loop diuretics is associated with an increased risk of volume depletion, an effect that attenuates with longer therapy durations. Prescribers need to closely monitor fluid status in patients receiving concomitant therapy, especially those with advancing age or with eGFR below 60. [ABSTRACT FROM AUTHOR]

Background and Hypothesis: Causes and risk factors for community-acquired acute kidney injury (CA-AKI) have not been thoroughly studied. The aim of this study was to examine the risk factors for CA-AKI., Methods: In this prospective study, we examined serum creatinine from all individuals visiting a university hospital's emergency department (ED) over an 11-month period for the presence of AKI defined according to the KDIGO criteria. Patients with AKI were invited to participate. Randomly selected controls (1:2) were paired according to age, sex, and date of admission. Participants answered questions about their medical history and medication use, including over-the-counter (OTC) drugs. Conditional logistic regression was used to identify factors associated with AKI., Results: Of 602 AKI cases identified, 512 participated in the study. AKI cases were significantly more likely than controls to have used nonsteroidal anti-inflammatory drugs (NSAIDs) (26.0 % vs 18.0 %, p = 0,001) in the week preceding the ED visit, particularly OTC NSAIDs (23.3 % vs 15.9 %, p < 0.001). AKI was associated with a recent history of vomiting (OR 2.52 [95 %CI 1.87-3.39]), diarrhea (1.30 [1.00-1.70]) and urinary retention (1.92 [1.36-2.72]), use of non-selective NSAIDs (1.84, [1.37-2.48]), RAAS blockers (1.63 [1.21-2.19]), and diuretics (1.53 [1.13-2.08]), and a history of diabetes (1.42 [1.04-1.94]), CKD (1.36 [1.01-1.83]) and smoking (1.72 [1.24-2.37])., Conclusions: Events in the setting of acute illness and medication use, including OTC NSAIDs, may play a greater role in the development of CA-AKI than comorbid conditions. Frequent use of OTC NSAIDs is a concern and should be addressed in view of serious adverse effects., (Copyright © 2024. Published by Elsevier B.V.)

Aim of the reviewTo assess the risk of hypovolemia for sodium–glucose cotransporter-2 (SGLT2) inhibitors treatment.MethodA systematic literature retrieval was performed in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Scopus from inception up to 4 October 2022, Data for study characteristics and outcomes of interest were extracted from each eligible study. Risk ratios (RRs) with a 95% confidence interval (CI) for hypovolemia were calculated using a random-effect model.ResultsA total of 57 studies (n = 68,622) were included in our meta-analysis, with a result of 1,972 hypovolemia incidents (1,142 in the SGLT2 inhibitors group and 830 in the control group). The pooled RR was 1.12 (95% CI: 1.02–1.22). It is evident that receiving SGLT2 inhibitors increased the risk of hypovolemia. When stratified by category of SGLT2 inhibitors the result was consistent; when the subgroup was analyzed by age, the pooled RR was 1.07 (95% CI: 0.94–1.23) in patients aged ≥65 years and 1.14 (95% CI: 1.02–1.28) in those aged

In this paper, we present a solution for understanding volume depletion and essentially decreasing the leakage current of β-Ga2O3 junctionless FETs (βJL-FETs) by embedding the 4H-SiC layer into the BOX layer (βESJL-FET). Using the silvaco simulator with 2-D simulations, we illustrate that the βESJL-FET with an embedded 4H-SiC layer shows a very high ION/IOFF ratio of ~1012 even for a 40 nm channel length. The main idea of this work focuses on changing the volume depletion for achieving a lower leakage current. Also, the other goal is obtaining the lower self-heating effect provided by replacing 4H-SiC with a higher thermal conductivity into the BOX layer. Although the silicon FETs are more applicable but, due to better performance at the ultra-scaled dimensions, we propose the β-Ga2O3 instead of silicon. Ga2O3 has a higher effective mass and lower bond distance than silicon and is suitable for short-channel devices. [ABSTRACT FROM AUTHOR]

Among the main factors of pathological changes that accompany acute abdominal pathology are the inflammatory process of the peritoneum and fluid deficiency due to its pathological losses. The aim of our study was to analyze the initial state of fluid compartments of the body and hemodynamics in high surgical risk patients with acute surgical abdominal pathology. There were examined 157 patients with acute abdominal pathology who underwent emergency laparotomy. The presence and severity of fluid deficiency were determined clinically by tissue hydrophilicity test by P.I. Shelestiuk, biochemically – by assessing the levels of hematocrit, hemoglobin, erythrocytes, blood electrolytes, vasopressin (ADH) and brain natriuretic propeptide (proBNP), as well as the mean erythrocyte volume and plasma osmolarity. Variables of fluid compartments of the body and central hemodynamics were studied using the non-invasive bioimpedancemetry. Based on the values of oxygen concentration in arterial and venous blood, total oxygen consumption (VO2) and delivery of oxygen (DO2), oxygen extraction ratio (O2ER) were calculated. The detected changes indicate intravascular fluid deficiency and concomitant hemoconcentration with normal electrolytes levels and plasma osmolarity. In patients with high surgical risk and moderate dehydration according to P.I. Shelestiuk, urgent surgical pathology of the abdominal cavity reduces extracellular fluid volume by 19.1% (p=0.019) of the reference by reducing the volume of the interstitium and intravascular fluid respectively by 20.7% (p=0.002) and 16.3% (p=0.001) of regional values, which forms in patients a state of "volume depletion" of moderate severity. This is accompanied by an increase in the ADH concentration by 16.7% (p=0.041) above reference and normal proBNP levels. Stroke volume decreases by 28.8% (p=0.021) against tachycardia (increase in heart rate by 39.7% (p=0.001) above normal) and vascular spasm (increase in systemic vascular resistance by 86.9% (p=0.001) above reference), which supports the normodynamic type of blood circulation (cardiac index – 3.2 (0.4) l/min/m2) with the decrease in stroke index and peripheral perfusion index by 41.3% (p=0.002) and 55.2% (p=0.002) from reference, respectively. DO2 decreases by 11.1% (p=0.011) from reference with VO2 increased by 16.3% (p=0.004) above reference, which leads to a decrease in oxygen utilization by 7.2% (p=0.041) from reference.

The grain size effect is one of the fundamental characteristics of semiconductor gas sensors. However, it has not been fully understood due to the absence of studies on the volume-depleted grains. In this work, the gas-sensitive SnO2 quantum dots (QDs) from partial depletion to volume depletion are prepared to discuss the size effects. A facile aqueous-based method is used to prepare the size-controllable SnO2 QDs of 2.0–12.6 nm. The resistance shows a monotonically negative size effect while the response reaches the optimization when the grain radius is comparable to the depletion layer width. It is suggested that the design of highly sensitive gas sensors should consider the equal importance of the control of grain size and depletion layer width. The computational results illustrate size-dependent energy level of donors and number of quasi-free electrons, which are responsible for the negative size effect of resistivity in the volume-depleted SnO2 crystallites. This work provides a comprehensive understanding of grain size effects from partial depletion to volume depletion in semiconductor gas sensors.

For the pediatric nephrologist, the over-the-counter status for non-steroidal anti-inflammatory drugs (NSAIDs) is surprising due to their possible harmful side effects. These can include acute renal failure due mainly to glomerular hypoperfusion which may lead to acute tubular necrosis; more rarely in children, medullary ischemic injury and cardiovascular diseases; acute or chronic interstitial nephritis which may cause chronic renal failure. All of them may create electrolyte abnormalities: hyponatremia, hyperkaliemia, renal tubular acidosis, fluid retention causing hypertension.

Aims: To evaluate comprehensively the safety of dapagliflozin in patients with type 2 diabetes (T2DM), with emphasis placed on potential safety concerns related to the sodium‐glucose co‐transporter‐2 inhibitor class. Methods: In the Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58 (DECLARE‐TIMI 58) study, 17 160 patients with T2DM were randomized to dapagliflozin or placebo and followed for a median of 4.2 years. Safety was evaluated in 17 143 patients receiving at least one dose of study drug. Results: Acute kidney injury occurred less frequently with dapagliflozin, and adverse events suggestive of volume depletion were balanced between treatment groups, both irrespective of baseline estimated glomerular filtration rate, blood pressure, diuretic or loop diuretic use (interaction P values >0.05). Fractures and malignancies were balanced between the groups, irrespective of sex, diabetes duration or smoking (interaction P values >0.05) and fewer cases of bladder cancer occurred in the dapagliflozin versus the placebo group. Diabetic ketoacidosis was very rare, but more frequent with dapagliflozin versus placebo (27 vs. 12 patients with events; P = 0.02), yet signs, symptoms and contributing factors were similar in the two groups. Major hypoglycaemia occurred less frequently with dapagliflozin versus placebo, regardless of baseline use of either insulin or sulphonylureas (interaction P values >0.05). There were more adverse events of genital infections leading to discontinuation of study drug in the dapagliflozin versus the placebo group, but serious genital infections were few and balanced between treatment groups. Urinary tract infections, acute pyelonephritis and urosepsis were also balanced between treatment groups. Conclusions: Dapagliflozin was well tolerated. The long duration and large number of patient‐years in DECLARE‐TIMI 58 comprehensively addressed previous safety questions, confirming the robust safety profile of dapagliflozin. [ABSTRACT FROM AUTHOR]

Introduction: The sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin is approved for the treatment of adults with type 2 diabetes mellitus (T2DM). This analysis was conducted on safety data pooled from phase 3 studies using ertugliflozin 5 mg or 15 mg versus placebo or an active comparator. Methods: The placebo pool (n = 1544) comprised data from three similarly designed 26-week placebo-controlled studies. The broad pool (n = 4849) comprised these three placebo-controlled studies plus four placebo- or active-controlled studies with treatment durations of up to 104 weeks. Results: In the placebo pool, there were no notable differences across groups in the incidence of adverse events (AEs), serious AEs, or AEs resulting in discontinuation from study medication, while associations were observed with genital mycotic infection in both females (3.0%, 9.1%, and 12.2% in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively) and males (0.4%, 3.7%, 4.2%), thirst (0.2%, 1.3%, 1.0%), and increased urination (1.0%, 2.7%, 2.4%). In the broad pool, volume depletion was increased with ertugliflozin in patients with estimated glomerular filtration rate < 60 ml/min/1.73 m2, aged ≥ 65 years, or who were taking diuretics. Ertugliflozin was not associated with increased urinary tract infection, fracture, hypoglycemia, pancreatitis, renal or hepatic injury, hypersensitivity, malignancy, or venous thromboembolism. Small numbers of patients were reported with lower limb amputation [0.1% (non-ertugliflozin group), 0.2% (ertugliflozin 5 mg), 0.5% (ertugliflozin 15 mg)]. There were three cases of ketoacidosis (all ertugliflozin 15 mg) and no cases of Fournier's gangrene. Conclusion: This pooled analysis showed that ertugliflozin was generally well tolerated in a large population of patients with T2DM with and without moderate renal impairment who were taking a range of background diabetes medications including insulin and insulin secretagogs, with results that are generally consistent with those for other SGLT2 inhibitors. Trial Registration: Clinicaltrials.gov indentifier, NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218. [ABSTRACT FROM AUTHOR]

Chronic adenine feeding is extensively used to develop animal models of chronic renal failure with metabolic features resembling those observed in humans. However, the mechanism by which adenine induces renal failure is poorly understood. In this study, we examined the early effects of adenine on water metabolism and salt balance in rats placed in metabolic cages and fed control or adenine-containing diets for 7 days. Molecular and functional studies demonstrated that adenine-fed rats exhibited a significant reduction in food intake, polyuria, polydipsia, decreased urine osmolality, and increased salt wasting. These effects are independent of changes in food intake and result from a coordinated downregulation of water channel aquaporin-2 (AQP2) and salt transporter (Na+-K+-Cl− cotransporter 2; NKCC2) in the collecting duct and medullary thick ascending limb, respectively. As a result, adenine-fed rats exhibited massive volume depletion, as indicated by a significant body weight loss, increased blood urea nitrogen, and increased hematocrit and hemoglobin levels, all of which were significantly corrected with NaCl replacement. Adenine-induced urinary concentrating defect was not corrected by exogenous arginine vasopressin (AVP), and it correlated with reduced cAMP production in vivo and in vitro. In conclusion, adenine acts on renal tubules as a signaling molecule and causes nephrogenic diabetes insipidus with salt wasting, at least, by directly interfering with AVP V2 receptor signaling with subsequent downregulation of NKCC2 and AQP2 in the kidney. The combination of renal fluid loss and decreased food intake with subsequent massive volume depletion likely plays an important role in the development of early prerenal failure that progresses to chronic kidney disease in long-term adenine feeding. [ABSTRACT FROM AUTHOR]

There are no relevant meta-analyses that have assessed the safety of the sodium-glucose transporter 2 (SGLT2) inhibitors in different chronic diseases. We aimed at evaluating the safety of four SGLT2 inhibitors in three chronic diseases by meta-analysis of the large randomized trials of SGLT2 inhibitors. We performed random-effects meta-analysis and carried out subgroup analysis according to type of underlying diseases and type of SGLT2 inhibitors. SGLT2 inhibitors versus placebo significantly reduced the risk of acute kidney injury (RR 0.75, 95% CI 0.66–0.85), and showed the reduced trend in the risk of severe hypoglycemia (RR 0.86, 95% CI 0.71–1.03). SGLT2 inhibitors significantly increased the risks of diabetic ketoacidosis (RR 2.57), genital infection (RR 3.75), and volume depletion (RR 1.14); and showed the increased trends in the risks of fracture (RR 1.07), amputation (RR 1.21), and urinary tract infection (RR 1.07). These effects exhibited by SGLT2 inhibitors were consistent across three chronic diseases (i.e. type 2 diabetes, chronic heart failure, and chronic kidney disease) and four SGLT2 inhibitors (i.e. dapagliflozin, empagliflozin, ertugliflozin, and canagliflozin) (all P subgroup > 0.05). These findings will guide that specific adverse events are monitored when SGLT2 inhibitors are used in clinical practice. [ABSTRACT FROM AUTHOR]

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new glucose-lowering therapy for T2DM with documented benefits on blood glucose, hypertension, weight reduction and long term cardiovascular benefit. They have an inherent osmotic diuretic effect and lead to some volume loss and possible dehydration. There is some concern about the safety of using SGLT2 inhibitors in Muslim type 2 diabetes mellitus (T2DM) patients during the fast during Ramadan. Currently, there is a dearth of research data to help guide physicians and reassure patients. One study confirmed good glycemic control with less risk of hypoglycemia and no marked volume depletion. Data in the elderly and in combination with diuretics are reassuring of their safe to use in Ramadan in general. SGLT2 inhibitor-related diabetic ketoacidosis has not been reported during Ramadan and is unlikely to be relevant. Survey of physicians revealed that the majority felt that SGLT2 inhibitors are generally safe in T2DM patients during Ramadan fasting but should be discontinued in certain high risk patients. Some professional groups with interest in diabetes and Ramadan fasting included SGLT2 inhibitors in their guidelines on management of diabetes during Ramadan. They acknowledged the lack of trial data, recommended caution in high risk groups, advised regular monitoring and emphasized pre-Ramadan patients’ education. In conclusion, currently, knowledge, data and experience with SGLT2 inhibitors in Ramadan are limited. Nonetheless, stable patients with normal kidney function and low risk of dehydration may safely use the SGLT2 inhibitors therapy. Higher risk patients should be observed carefully and managed on individual basis.

There are no relevant meta-analyses that have assessed the safety of the sodium-glucose transporter 2 (SGLT2) inhibitors in different chronic diseases. We aimed at evaluating the safety of four SGLT2 inhibitors in three chronic diseases by meta-analysis of the large randomized trials of SGLT2 inhibitors. We performed random-effects meta-analysis and carried out subgroup analysis according to type of underlying diseases and type of SGLT2 inhibitors. SGLT2 inhibitors versus placebo significantly reduced the risk of acute kidney injury (RR 0.75, 95% CI 0.66-0.85), and showed the reduced trend in the risk of severe hypoglycemia (RR 0.86, 95% CI 0.71-1.03). SGLT2 inhibitors significantly increased the risks of diabetic ketoacidosis (RR 2.57), genital infection (RR 3.75), and volume depletion (RR 1.14); and showed the increased trends in the risks of fracture (RR 1.07), amputation (RR 1.21), and urinary tract infection (RR 1.07). These effects exhibited by SGLT2 inhibitors were consistent across three chronic diseases (i.e. type 2 diabetes, chronic heart failure, and chronic kidney disease) and four SGLT2 inhibitors (i.e. dapagliflozin, empagliflozin, ertugliflozin, and canagliflozin) (all Psubgroup > 0.05). These findings will guide that specific adverse events are monitored when SGLT2 inhibitors are used in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The efficacy of different commercial beverage compositions for meeting oral rehydration therapy (ORT) goals in the treatment of acute dehydration in healthy humans has not been systematically tested. The objective of the study was to compare fluid retention, plasma volume (PV), and interstitial fluid (ISF) volume restoration when using 1 popular glucose-based and 1 novel amino acid-based (AA) commercial ORT beverage following experimental hypertonic or isotonic dehydration.Methods: Twenty-six healthy adults (21 males, 5 females) underwent either a controlled bout of hypertonic (n = 13) or isotonic (n = 13) dehydration (3%-4% body mass) via eccrine or renal body water and electrolyte losses induced using exercise-heat stress (EHS) or Lasix administration (LAS), respectively. Rehydration was achieved over 90 minutes by matching fluid intake to water losses (1:1) using a sports drink (SP) or AA commercial ORT beverage. Fluid retention (water and electrolytes), PV, and ISF volume changes were tracked for 180 minutes.Results: AA produced significantly (P <0.05) greater fluid retention (75% vs 57%), ISF volume restoration, and tended (P = 0.06) to produce greater PV restoration in trial EHS. In trial LAS, neither beverage exceeded 65% retention, but AA replaced electrolytes and preserved ISF volume better than SP (P <0.05).Conclusion: The results of this study demonstrate superior rehydration when using AA compared with SP for both hypertonic and isotonic dehydration. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) currently is diagnosed by a temporal trend of a single blood analyte: serum creatinine. This measurement is neither sensitive nor specific to kidney injury or its protean forms. Newer biomarkers, neutrophil gelatinase-associated lipocalin (NGAL, Lipocalin 2, Siderocalin), or kidney injury molecule-1 (KIM-1, Hepatitis A Virus Cellular Receptor 1), accelerate the diagnosis of AKI as well as prospectively distinguish rapidly reversible from prolonged causes of serum creatinine increase. Nonetheless, these biomarkers lack the capacity to subfractionate AKI further (eg, sepsis versus ischemia versus nephrotoxicity from medications, enzymes, or metals) or inform us about the primary and secondary sites of injury. It also is unknown whether all nephrons are injured in AKI, whether all cells in a nephron are affected, and whether injury responses can be stimulus-specific or cell type-specific or both. In this review, we summarize fully agnostic tissue interrogation approaches that may help to redefine AKI in cellular and molecular terms, including single-cell and single-nuclei RNA sequencing technology. These approaches will empower a shift in the current paradigm of AKI diagnosis, classification, and staging, and provide the renal community with a significant advance toward precision medicine in the analysis AKI. [ABSTRACT FROM AUTHOR]

Prerenal azotemia (PRA) is a major cause of acute kidney injury and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of glomerular filtration rate (GFR) that returns to baseline with resuscitation. Adult male C57BL/6J wild-type (WT) and IL-6 -/- mice were studied. Intraperitoneal furosemide (4 mg) or vehicle was administered at time = 0 and 3 h to induce PRA from volume loss. Resuscitation began at 6 h with 1 mL intraperitoneal saline for four times for 36 h. Six hours after furosemide administration, measured glomerular filtration rate was 25% of baseline and returned to baseline after saline resuscitation at 48 h. After 6 h of PRA, plasma interleukin (IL)-6 was significantly increased, kidney and liver histology were normal, kidney and liver lactate were normal, and kidney injury molecule-1 immunofluorescence was negative. There were 327 differentially regulated genes upregulated in the liver, and the acute phase response was the most significantly upregulated pathway; 84 of the upregulated genes (25%) were suppressed in IL-6 -/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included serum amyloid A2, serum amyloid A1, lipocalin 2, chemokine (C-X-C motif) ligand 1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in wild-type PRA and were all reduced in IL-6 -/- PRA. This work demonstrates previously unknown systemic effects of PRA that includes IL-6-mediated upregulation of the hepatic acute phase response. NEW & NOTEWORTHY Prerenal azotemia (PRA) accounts for a third of acute kidney injury (AKI) cases yet is rarely studied in preclinical models. We developed a clinically defined murine model of prerenal azotemia characterized by a 75% decrease in measured glomerular filtration rate (GFR), return of measured glomerular filtration rate to baseline with resuscitation, and absent tubular injury. Numerous systemic effects were observed, such as increased plasma interleukin-6 (IL-6) and upregulation of the hepatic acute phase response.

Acute renal failure is a life threatening condition. Nonsteroidal antiinflammatory drugs (NSAIDs) and cephalosporins are widely used postoperative drugs. NSAID-induced acute renal failure has been reported in the past. In this case, drug interaction and decompensated state of the patient precipitate the condition. NSAIDs inhibit prostaglandins synthesis and thus aggravate ischemia to the kidney that is already facing volume crisis due to surgery. Due to renal dysfunction, plasma ceftriaxone level increases due to decrease clearance and it also acts as nephrotoxic by unknown mechanism. On the other hand, ceftriaxone on its interaction with diclofenac for renal tubular clearance also increases the level of diclofenac and thus further aggravate the ischemia. It is a reversible condition with excluding diclofenac from the treatment regimen and giving adequate hydration to the patient. This highlights the importance of hydration and knowledge of drugs interactions in a postsurgical patient.

Rationale & Objective: Sick day medication guidance (SDMG) involves withholding or adjusting specific medications in the setting of acute illnesses that could contribute to complications such as hypotension, acute kidney injury (AKI), or hypoglycemia. We sought to achieve consensus among clinical experts on recommendations for SDMG that could be studied in future intervention studies., Study Design: A modified Delphi process following guidelines for conducting and reporting Delphi studies., Setting & Participants: An international group of clinicians with expertise relevant to SDMG was recruited through purposive and snowball sampling. A scoping review of the literature was presented, followed by 3 sequential rounds of development, refinement, and voting on recommendations. Meetings were held virtually and structured to allow the participants to provide their input and rapidly prioritize and refine ideas., Outcome: Opinions of participants were measured as the percentage who agreed with each recommendation, whereas consensus was defined as >75% agreement., Analytical Approach: Quantitative data were summarized using counts and percentages. A qualitative content analysis was performed to capture the context of the discussion around recommendations and any additional considerations brought forward by participants., Results: The final panel included 26 clinician participants from 4 countries and 10 clinical disciplines. Participants reached a consensus on 42 specific recommendations: 5 regarding the signs and symptoms accompanying volume depletion that should trigger SDMG; 6 regarding signs that should prompt urgent contact with a health care provider (including a reduced level of consciousness, severe vomiting, low blood pressure, presence of ketones, tachycardia, and fever); and 14 related to scenarios and strategies for patient self-management (including frequent glucose monitoring, checking ketones, fluid intake, and consumption of food to prevent hypoglycemia). There was consensus that renin-angiotensin system inhibitors, diuretics, nonsteroidal anti-inflammatory drugs, sodium/glucose cotransporter 2 inhibitors, and metformin should be temporarily stopped. Participants recommended that insulin, sulfonylureas, and meglitinides be held only if blood glucose was low and that basal and bolus insulin be increased by 10%-20% if blood glucose was elevated. There was consensus on 6 recommendations related to the resumption of medications within 24-48 hours of the resolution of symptoms and the presence of normal patterns of eating and drinking., Limitations: Participants were from high-income countries, predominantly Canada. Findings may not be generalizable to implementation in other settings., Conclusions: A multidisciplinary panel of clinicians reached a consensus on recommendations for SDMG in the presence of signs and symptoms of volume depletion, as well as self-management strategies and medication instructions in this setting. These recommendations may inform the design of future trials of SDMG strategies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new glucose-lowering therapy for T2DM with documented benefits on blood glucose, hypertension, weight reduction and long term cardiovascular benefit. They have an inherent osmotic diuretic effect and lead to some volume loss and possible dehydration. There is some concern about the safety of using SGLT2 inhibitors in Muslim type 2 diabetes mellitus (T2DM) patients during the fast during Ramadan. Currently, there is a dearth of research data to help guide physicians and reassure patients. One study confirmed good glycemic control with less risk of hypoglycemia and no marked volume depletion. Data in the elderly and in combination with diuretics are reassuring of their safe to use in Ramadan in general. SGLT2 inhibitor-related diabetic ketoacidosis has not been reported during Ramadan and is unlikely to be relevant. Survey of physicians revealed that the majority felt that SGLT2 inhibitors are generally safe in T2DM patients during Ramadan fasting but should be discontinued in certain high risk patients. Some professional groups with interest in diabetes and Ramadan fasting included SGLT2 inhibitors in their guidelines on management of diabetes during Ramadan. They acknowledged the lack of trial data, recommended caution in high risk groups, advised regular monitoring and emphasized pre-Ramadan patients' education. In conclusion, currently, knowledge, data and experience with SGLT2 inhibitors in Ramadan are limited. Nonetheless, stable patients with normal kidney function and low risk of dehydration may safely use the SGLT2 inhibitors therapy. Higher risk patients should be observed carefully and managed on individual basis. [ABSTRACT FROM AUTHOR]

Background: Few dehydration assessment measures provide accurate information; most are based on reference change values and very few are diagnostically accurate from a single observation or measure. Bioelectrical impedance may lack the precision to detect common forms of dehydration in healthy individuals. Limitations in bioimpedance may be addressed by a unique resistance-reactance (RXc)-score graph method, which transforms vector components into z scores for use with any impedance analyzer in any population. Objective: We tested whether the RXc-score graph method provides accurate single or serial assessments of dehydration when compared with gold-standard measures of total body water by using stable isotope dilution (deuterium oxide) combined with body-weight changes. Design: We retrospectively analyzed data from a previous study in which 9 healthy young men participated in 3 trials: euhydration (EUH), extracellular dehydration (ED; via a diuretic), and intracellular dehydration (ID; via exercise in the heat). Results: Participants lost 4-5% of their body weight during the dehydration trials; volume loss was similar between trials (ID compared with ED group: 3.5 ± 0.8 compared with 3.0 ± 0.6 L; P > 0.05). Despite significant losses of body water, most RXc vector scores for ED and ID groups were classified as "normal" (within the 75% population tolerance ellipse). However, directional displacement of vectors was consistent with loss of volume in both ED and ID conditions compared with the EUH condition and tended to be longer in ED than in ID conditions (P = 0.054). Conclusions: We conclude that, whereas individual RXc-score graph values do not provide accurate detection of dehydration from single measurements, directional changes in vector values from serial measurements are consistent with fluid loss for both ED and ID conditions. The RXc-score graph method may therefore alert clinicians to changes in hydration state, which may bolster the interpretation of other recognized change measures of hydration. Am J Clin Nutr 2016;103:724-9. [ABSTRACT FROM AUTHOR]