Hyponatremia is the most common electrolyte imbalance encountered in clinical practice. It occurs in 14% to 42% of hospitalized patients and is associated with higher mortality.^1-3 Hypertonic saline is an effective treatment for symptomatic hyponatremia.^4-11 Undercorrection of hyponatremia may be insufficient to prevent life-threatening manifestations of cerebral edema, whereas overcorrection from indiscriminate prolonged use of hypertonic saline may result in permanent neurologic disability from osmotic demyelination syndrome (ODS).^12-19 Owing to this concern, the concept of intermittent use of a bolus of hypertonic saline was introduced in 2005 for the treatment of hyponatremia in marathon runners.^20-22 Recent American and European guidelines have recommended administering hypertonic saline as small, fixed boluses^3,23 based on results of small randomized trials,²⁴ case reports with small numbers of patients,^20,25 and expert opinions.^21,26-28 The appealing aspects of a fixed bolus therapy are²⁹: (1) efficacy: reaches rapid partial correction of serum sodium (sNa); (2) safety: limits risk of overcorrection that occurs commonly with continuous infusion of hypertonic saline³⁰; and (3) user friendly: omits need for calculations. However, few high-quality evidences have clarified whether hypertonic saline is best administered as a slow continuous infusion (SCI) therapy, which is preferred by most, or as a rapid intermittent bolus (RIB) therapy. We compared the efficacy and safety of RIB and SCI with hypertonic saline in patients with moderately severe to severe symptomatic hyponatremia.

Nephrotoxicity is often underestimated because renal clearance in animals is higher compared to in humans. This paper aims to illustrate the potential to fill in such pharmacokinetic gaps between animals and humans using a microfluidic kidney model. As an initial demonstration, we compare nephrotoxicity of a drug, administered at the same total dosage, but using different pharmacokinetic regimens. Kidney epithelial cell, cultured under physiological shear stress conditions, are exposed to gentamicin using regimens that mimic the pharmacokinetics of bolus injection or continuous infusion in humans. The perfusion culture utilized is important both for controlling drug exposure and for providing cells with physiological shear stress (1.0 dyn cm ⁻² ). Compared to static cultures, perfusion culture improves epithelial barrier function. We tested two drug treatment regimens that give the same gentamycin dose over a 24 h period. In one regimen, we mimicked drug clearance profiles for human bolus injection by starting cell exposure at 19.2 mM of gentamicin and reducing the dosage level by half every 2 h over a 24 h period. In the other regimen, we continuously infused gentamicin (3 mM for 24 h). Although junctional protein immunoreactivity was decreased with both regimens, ZO-1 and occludin fluorescence decreased less with the bolus injection mimicking regimen. The bolus injection mimicking regimen also led to less cytotoxicity and allowed the epithelium to maintain low permeability, while continuous infusion led to an increase in cytotoxicity and permeability. These data show that gentamicin disrupts cell–cell junctions, increases membrane permeability, and decreases cell viability particularly with prolonged low-level exposure. Importantly a bolus injection mimicking regimen alleviates much of the nephrotoxicity compared to the continuous infused regimen. In addition to potential relevance to clinical gentamicin administration regimens, the results are important in demonstrating the general potential of using microfluidic cell culture models for pharmacokinetics and toxicity studies.

Traditional approaches to pathophysiology are advancing but still have many limitations that arise from real biologic systems and their associated physiological phenomena being too complicated. Microfluidics is a novel technology in the field of engineering, which provides new options that may overcome these hurdles. Microfluidics handles small volumes of fluids and may apply to various applications such as DNA analysis chips, other lab-on-a-chip analyses, micropropulsion, and microthermal technologies. Among them, organ-on-a-chip applications allow the fabrication of minimal functional units of a single organ or multiple organs. Relevant to the field of nephrology, renal tubular cells have been integrated with microfluidic devices for making kidneys-on-a-chip. Although still early in development, kidneys-on-a-chip are showing potential to provide a better understanding of the kidney to replace some traditional animal and human studies, particularly as more cell types are incorporated toward the development of a complete glomeruli-on-a-chip.

Intestinal microbiota and their metabolites affect systemic inflammation and kidney disease outcomes. Here, we investigated the key metabolites associated with the acute kidney injury (AKI)-to chronic kidney disease (CKD) transition and the effect of antibiotic-induced microbiota depletion (AIMD) on this transition. In 61 patients with AKI, 59 plasma metabolites were assessed to determine the risk of AKI-to-CKD transition. An AKI-to-CKD transition murine model was established four weeks after unilateral ischemia-reperfusion injury (IRI) to determine the effects of AIMD on the gut microbiome, metabolites, and pathological responses related to CKD transition. Human proximal tubular epithelial cells were challenged with CKD transition-related metabolites, and inhibitory effects of NADPH oxidase 2 (NOX2) signals were tested. Based on clinical metabolomics, plasma trimethylamine N-oxide (TMAO) was associated with a significantly increased risk for AKI-to-CKD transition [adjusted odds ratio 4.389 (95% confidence interval 1.106-17.416)]. In vivo, AIMD inhibited a unilateral IRI-induced increase in TMAO, along with a decrease in apoptosis, inflammation, and fibrosis. The expression of NOX2 and oxidative stress decreased after AIMD. In vitro, TMAO induced fibrosis with NOX2 activation and oxidative stress. NOX2 inhibition successfully attenuated apoptosis, inflammation, and fibrosis with suppression of G2/M arrest. NOX2 inhibition (in vivo) showed improvement in pathological changes with a decrease in oxidative stress without changes in TMAO levels. Thus, TMAO is a key metabolite associated with the AKI-to-CKD transition, and NOX2 activation was identified as a key regulator of TMAO-related AKI-to-CKD transition both in vivo and in vitro.

Background: The phospholipase A2 receptor (PLA2R) is a major antigen found in patients with idiopathic membranous nephropathy (MN). The relationship of genetic polymorphisms of PLA2R with the susceptibility and clinical outcomes of this disease is unknown. Methods: We studied 199 patients with idiopathic MN followed up for 3.7 ± 3.2 years. We enrolled 33 patients with secondary MN and 356 subjects with normal blood pressure and no proteinuria. PLA2R single nucleotide polymorphisms (SNPs) were genotyped. Results: The allele frequencies of C in rs35771982 and G in rs3828323 were 73.6 and 73.9%, respectively. Subjects with the CC genotype in rs35771982 had a higher susceptibility to idiopathic MN compared to subjects with other genotypes (odds ratio 2.6; 95% confidence interval 1.8–4.0). Patients with secondary MN were not different from controls with regard to PLA2R genotype. No impact of genetic polymorphisms on renal survival was detected. Conclusion: The findings of this study suggest that PLA2R SNPs might be associated with the risk of developing MN.