Treatment of hyperkalemia with intravenous insulin-dextrose is associated with a risk of hypoglycemia. We aimed to determine the factors associated with hypoglycemia (glucose < 3.9 mmol/L, or < 70 mg/dL) and the critical time window with the highest incidence. In a retrospective cohort study in a tertiary hospital network, we included 421 adult patients with a serum potassium ≥ 6.0 mmol/L who received insulin-dextrose treatment. The mean age was 70 years with 62% male predominance. The prevalence of diabetes was 60%, and 70% had chronic kidney disease (eGFR < 60 ml/min/1.73 m2). The incidence of hypoglycemia was 21%. In a multivariable logistic regression model, the factors independently associated with hypoglycemia were: body mass index (per 5 kg/m2, OR 0.85, 95% CI: 0.69-0.99, P = 0.04), eGFR < 60 mL/min/1.73 m2 (OR 2.47, 95% CI: 1.32-4.63, P = 0.005), diabetes (OR 0.57, 95% CI 0.33-0.98, P = 0.043), pre-treatment blood glucose (OR 0.84, 95% CI: 0.77-0.91, P < 0.001), and treatment in the emergency department compared to other locations (OR 2.53, 95% CI: 1.49-4.31, P = 0.001). Hypoglycemia occurred most frequently between 60 and 150 min, with a peak at 90 min. Understanding the factors associated with hypoglycemia and the critical window of risk is essential for the development of preventive strategies.

The aim of this study was to develop a model for early prediction of adverse events and treatment effectiveness in patients with hyperkalemia. We collected clinical data from patients with hyperkalemia in the First Hospital of Zhejiang University School of Medicine between 2015 and 2021. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to analyze the predictors on the full dataset. We randomly divided the data into a training group and a validation group, and used LASSO to filter variables in the training set. Six machine learning methods were used to develop the models. The best model was selected based on the area under the curve (AUC). Shapley additive exPlanations (SHAP) values were used to explain the best model. A total of 1074 patients with hyperkalemia were finally enrolled. Diastolic blood pressure (DBP), breathing, oxygen saturation (SPO2), Glasgow coma score (GCS), liver disease, oliguria, blood sodium, international standardized ratio (ISR), and initial blood potassium were the predictors of the occurrence of adverse events; peripheral edema, estimated glomerular filtration rate (eGFR), blood sodium, actual base residual, and initial blood potassium were the predictors of therapeutic effect. Extreme gradient boosting (XGBoost) model achieved the best performance (adverse events: AUC = 0.87; therapeutic effect: AUC = 0.75). A model based on clinical characteristics was developed and validated with good performance.

Hyperkalemia is frequently observed in patients at the end-stage of chronic kidney disease (CKD), and has possible harmful consequences on cardiac function. Many strategies are currently used to manage hyperkalemia, one consisting of increasing fecal K+ excretion through the administration of cation-exchange resins. In this study, we explored another more specific method of increasing intestinal K+ secretion by inhibiting the H,K-ATPase type 2 (HKA2), which is the main colonic K+ reabsorptive pathway. We hypothetised that the absence of this pump could impede the increase of plasma K+ levels following nephronic reduction (N5/6) by favoring fecal K+ secretion. In N5/6 WT and HKA2KO mice under normal K+ intake, the plasma K+ level remained within the normal range, however, a load of K+ induced strong hyperkalemia in N5/6 WT mice (9.1 ± 0.5 mM), which was significantly less pronounced in N5/6 HKA2KO mice (7.9 ± 0.4 mM, p < 0.01). This was correlated to a higher capacity of HKA2KO mice to excrete K+ in their feces. The absence of HKA2 also increased fecal Na+ excretion by inhibiting its colonic ENaC-dependent absorption. We also showed that angiotensin-converting-enzyme inhibitor like enalapril, used to treat hypertension during CKD, induced a less severe hyperkalemia in N5/6 HKA2KO than in N5/6 WT mice. This study therefore provides the proof of concept that the targeted inhibition of HKA2 could be a specific therapeutic maneuver to reduce plasma K+ levels in CKD patients.

Aldosterone antagonists slow the progression of chronic kidney disease (CKD), but their use is limited by hyperkalemia, especially when associated with RAS inhibitors. We examined the renoprotective effects of Ly, a novel non-steroidal mineralocorticoid receptor (MR) blocker, through two experimental protocols: In Protocol 1, male Munich-Wistar rats underwent 5/6 renal ablation (Nx), being divided into: Nx+V, receiving vehicle, Nx+Eple, given eplerenone, 150 mg/kg/day, and Nx+Ly, given Ly, 20 mg/kg/day. A group of untreated sham-operated rats was also studied. Ly markedly raised plasma renin activity (PRA) and aldosterone, and exerted more effective anti-albuminuric and renoprotective action than eplerenone. In Protocol 2, Nx rats remained untreated until Day 60, when they were divided into: Nx+V receiving vehicle; Nx+L treated with losartan, 50 mg/kg/day; Nx+L+Eple, given losartan and eplerenone, and Nx+L+Ly, given losartan and Ly. Treatments lasted for 90 days. As an add-on to losartan, Ly normalized blood pressure and albuminuria, and prevented CKD progression more effectively than eplerenone. This effect was associated with strong stimulation of PRA and aldosterone. Despite exhibiting higher affinity for the MR than either eplerenone or spironolactone, Ly caused no hyperkalemia. Ly may become a novel asset in the effort to detain the progression of CKD.

Chill susceptible insects suffer tissue damage and die at low temperatures. The mechanisms that cause chilling injury are not well understood but a growing body of evidence suggests that a cold-induced loss of ion and water homeostasis leads to hemolymph hyperkalemia that depolarizes cells, leading to cell death. The apparent root of this cascade is the net leak of osmolytes down their concentration gradients in the cold. Many insects, however, are capable of adjusting their thermal physiology, and cold-acclimated Drosophila can maintain homeostasis and avoid injury better than warm-acclimated flies. Here, we test whether chilling causes a loss of epithelial barrier function in female adult Drosophila, and provide the first evidence of cold-induced epithelial barrier failure in an invertebrate. Flies had increased rates of paracellular leak through the gut epithelia at 0 °C, but cold acclimation reduced paracellular permeability and improved cold tolerance. Improved barrier function was associated with changes in the abundance of select septate junction proteins and the appearance of a tortuous ultrastructure in subapical intercellular regions of contact between adjacent midgut epithelial cells. Thus, cold causes paracellular leak in a chill susceptible insect and cold acclimation can mitigate this effect through changes in the composition and structure of transepithelial barriers.

In maintenance hemodialysis (MHD) patients, low protein intake is associated with protein-energy wasting, a risk factor that affects outcome. However, increased protein intake may lead to hyperphosphatemia and hyperkalemia, which are also mortality risk factors. Here, we evaluated the safety and effects of purified rice endosperm protein (REP), which contains less phosphorus and potassium than soy and casein proteins, as a supplemental protein source for MHD patients. This randomized, double-blind, placebo-controlled, crossover pilot study of REP supplementation (5 g/day × 4 weeks) was carried out in 50 Japanese adult MHD patients (1 dropped out); the primary outcome was the change in the urea kinetic-based normalized protein catabolic rate (nPCR), an indicator of protein intake in MHD patients. Intention-to-treat analyses of 24 patients in the REP-first group and 25 in the placebo-first group showed that REP supplementation increased nPCR significantly by 0.07 g/kg/day (95% confidence interval, 0.03-0.11), whereas changes in serum phosphorus and potassium concentrations were not different from the placebo. REP supplementation did not show a significant effect on other nutritional or metabolic parameters and no specific complications. In conclusion, purified REP with efficient bioavailability may be safe and useful for dietary supplementation in MHD patients.

This study comprehensively investigated clinical outcomes associated with renin angiotensin system inhibitor-based dual antihypertensive regimens in non-dialysis chronic kidney disease (CKD) patients. Keyword searches of databases were performed per PRISMA-NMA guidelines. Frequentist network meta-analysis were conducted with 16 head-to-head randomized controlled trials. The effect sizes of dichotomous and continuous variables were estimated with odds ratio (OR) and standard mean differences (SMD), respectively. The protocol is registered in PROSPERO (CRD42022365927). Dual antihypertensive regimens with combination of angiotensin receptor blockers (ARB) and calcium channel blockers (CCB) demonstrated substantially reduced odd of major cardiovascular disease (CVD) events over other regimens including angiotensin converting enzyme inhibitor (ACEI) monotherapy (OR 3.19) and ARB monotherapy (OR 2.64). Most significant reductions in systolic (SBP) and diastolic blood pressure (DBP) were observed with ARB-based CCB dual regimen over ACEI monotherapy (SMD 17.60 SBP and 9.40 for DBP), ACEI-based CCB regimen (SMD 12.90 for SBP and 9.90 for DBP), and ARB monotherapy (SMD 13.20 for SBP and 5.00 for DBP). However, insignificant differences were noticed for the odds of hyperkalemia, end stage renal disease progression, and all-cause mortality. ARB-based CCB regimen has the greatest benefits on BP reduction as well as major CVD risks in non-dialysis CKD patients.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, hyperkalemia and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca2+ release from myotubes via the ryanodine receptor type 1 (RYR1) and the voltage-dependent L-type calcium channel (CACNA1S). As more than 300 variants of unknown significance have been detected to date, we examined whether freely available pathogenicity prediction tools are able to detect relevant MH causing variants. In this diagnostic accuracy study, blood samples from 235 individuals with a history of a clinical malignant hyperthermia or their close relatives were genetically screened for RYR1 variants of all 106 RYR1 exons and additionally for known variants of CACNA1S. In vitro contracture tests were conducted on muscle biopsies obtained from all individuals, independently of whether a pathogenic variant, a variant of unknown significance or no variant was detected. Comparisons were made to three established bioinformatic pathogenicity detection tools to identify the clinical impact of the variants of unknown significance. All detected genetic variants were tested for pathogenicity by three in silico approaches and compared to the in vitro contracture test. Sensitivity and specificity of exon screening of all individuals listed in our MH database was analyzed. Exon screening identified 97 (41%) of the 235 individuals as carriers of pathogenic variants. Variants of unknown significance were detected in 21 individuals. Variants of unknown significance were subdivided into 19 malignant-hyperthermia-susceptible individuals and 2 non-malignant-hyperthermia-susceptible individuals. All pathogenic variants as well as the malignant-hyperthermia-suspectible variants were correctly identified by the bioinformatic prediction tools. Sensitivity of in silico approaches ranged between 0.71 and 0.98 (Polyphen 0.94 [CI 95% 0.75; 0.99]; Sift 0.98 [CI 95% 0.81; 0.99]; MutationTaster 0.92 [CI 95% 0.75; 0.99]). Specificity differed depending on the used tool (Polphen 0.98 [CI 95% 0.32; 0.99]; Sift 0.98 [CI 95% 0.32; 0.99]; MutationTaster 0.00 [CI 95% 0.00; 0.60]). All pathogenic variants and variants of unknown significance were scored as probably damaging in individuals, demonstrating a high sensitivity. Specificity was very low in one of the three tested programs. However, due to potential genotype-phenotype discordance, bioinformatic prediction tools are currently of limited value in diagnosing pathogenicity of MH-susceptible variants.