Nephrolithiasis associated with metabolic syndrome represents a growing global public health burden with a 5-year recurrence rate of up to 50%. Current first-line preventive strategies, primarily potassium citrate and thiazide diuretics, only correct urinary chemical abnormalities symptomatically, and patient adherence remains below 50% at 1 year. Importantly, these approaches fail to address the core pathological basis of tubular injury driven by metabolic dysregulation. Mitochondrial dysfunction is the central mechanistic hub linking systemic metabolic stress to intrarenal lithogenic susceptibility. In the setting of metabolic syndrome, impaired mitochondrial biogenesis and excessive mitochondrial reactive oxygen species (mtROS) production in renal tubular epithelial cells activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, establishing a self-perpetuating vicious cycle of "metabolic disturbance, mitochondrial damage, inflammatory amplification, calcium oxalate crystal deposition'. This core pathogenic loop has not been targeted by existing therapeutic strategies. Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), exerts pleiotropic renoprotective effects independent of its canonical glucose-lowering actions. It coordinately activates peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) through two complementary pathways: transcriptional upregulation through the PKA/CREB axis, and post-translational deacetylation via the AMPK/SIRT1 pathway. This dual activation restores mitochondrial homeostasis, reprograms tubular lipid metabolism, attenuates oxidative stress, and suppresses inflammatory cascades. This review is the first to systematically integrate the mitochondrial pharmacology of liraglutide with the pathophysiology of nephrolithiasis. It critically appraises the strengths and limitations of preclinical and clinical evidence, identifies key knowledge gaps in the field, and proposes a phased translational research roadmap encompassing mechanistic validation, biomarker development, and clinical trial design. This work provides a solid theoretical foundation for repurposing GLP-1RAs for the prevention of this condition.

Many hypertensive patients require three or more antihypertensive agents to achieve target blood pressure. This randomized, double-blind, multicenter phase 3 trial conducted in South Korea evaluated the efficacy and safety of a single-pill triple combination therapy with valsartan (Val), amlodipine (Aml), and chlorthalidone (CTD) in patients whose blood pressure remained inadequately controlled on Val/Aml dual therapy. Patients uncontrolled after 4 weeks of Val/Aml 80/5 mg were randomized 1:1 to either Val/Aml/CTD 80/5/12.5 mg or Val/Aml 80/5 mg using a double-dummy design. After 2 weeks, doses were escalated to Val/Aml/CTD 160/5/25 mg or Val/Aml 160/5 mg, respectively, for a total treatment duration of 6 weeks. The primary endpoint was the change in mean sitting systolic blood pressure (MSSBP) from baseline to week 8. Of 193 randomized patients, 178 completed the study. The least squares mean ± SE change in MSSBP was -19.70 ± 1.31 mmHg in the Val/Aml/CTD group versus -8.71 ± 1.26 mmHg in the control group, yielding a statistically significant between-group difference of -10.99 ± 1.81 mmHg (95% CI, -14.56 to -7.41; p < 0.0001). No serious adverse events occurred in the Val/Aml/CTD group, compared with an incidence of 1.98% in the control group (p = 0.4985). Triple combination therapy with Val/Aml/CTD demonstrated superior blood pressure reduction and a favorable safety profile in patients with essential hypertension inadequately controlled on Val/Aml dual therapy, supporting its use as an effective treatment option in this population. Trial Registration: This trial was prospectively registered at ClinicalTrials.gov (identifier: NCT06416865).

Primary aldosteronism is the most common cause of secondary hypertension but remains frequently underdiagnosed in primary care. We report a 71-year-old man with resistant hypertension and low-normal serum potassium in whom a minimal increase in hydrochlorothiazide dosage (12.5 to 25 mg) precipitated severe hypokalaemia (1.6 mmol/L), metabolic alkalosis, and rhabdomyolysis. An office electrocardiogram showed hypokalaemia-related changes, prompting urgent referral to the emergency department. Further evaluation revealed an elevated aldosterone-to-renin ratio and a left adrenal nodule, supporting the diagnosis of primary aldosteronism. This case highlights the importance of recognizing a disproportionate hypokalaemic response to thiazide treatment as a potential indicator of underlying primary aldosteronism. It also underscores the role of family physicians in early detection through appropriate screening.

Diuretics remain indispensable for the treatment of congestion in cardiovascular disease, particularly in acute and chronic heart failure. Their principal clinical value is rapid symptom relief, reduction in filling pressures and facilitation of decongestion; however, a mortality benefit has not been consistently demonstrated. This distinction is clinically important because long-term diuretic exposure in patients without objective congestion may promote hypotension, renal dysfunction, electrolyte instability, neurohormonal activation, falls, cognitive impairment and avoidable polypharmacy. The challenge is therefore not whether diuretics should be used, but how intensively, for how long and under which monitoring strategy. In this narrative review, we summarize the pharmacology of major diuretic classes, the mechanisms of diuretic resistance, and the clinical consequences of potassium, sodium and magnesium disorders. We also discuss drug interactions, frailty, chronic kidney disease, pregnancy, heart failure with preserved ejection fraction and the emerging role of sodium-glucose cotransporter 2 inhibitors and adjunctive proximal-tubule strategies. A practical approach is proposed: use loop diuretics promptly when congestion is present, reassess response with symptoms, weight, urine output, renal function, electrolytes and congestion markers, and reduce or discontinue therapy once euvolemia is achieved and maintained. Deprescribing should be individualized, gradual and reversible, with explicit thresholds for restarting treatment. Optimized diuretic care requires the same discipline applied to disease-modifying heart failure therapy: phenotype recognition, dose minimization, close follow-up and avoidance of treatment inertia.

A very sensitive and eco-friendly second-derivative spectrofluorimetric method was developed for simultaneous analysis of hydrochlorothiazide (HCTZ), amlodipine besylate (AML), and telmisartan (TEL) in pharmaceutical products and human plasma. Native fluorescence of HCTZ (λex267/λem295 nm), AML (λex362/λem415 nm), and TEL (λex292/λem369 nm) was used together with fluorescence enhancement achieved through sodium lauryl sulfate micelles at optimum excitation/emission wavelengths for all other analytes being analyzed. Overlap of spectroscopic data was able to be resolved through second-derivative spectrofluorimetry without prior separation. Method validation was performed according to ICH Q2(R1) guidelines; results showed excellent linearity (R[2] > 0.999) across a concentration range of 3-18, 2-10, and 10-50 ng/mL for HCTZ, AML, and TEL, respectively. Accuracy, precision and robustness were demonstrated with %RSD values below two. Application of the method to pharmaceutical product and spiked plasma samples gave satisfactory recoveries with minimal matrix interference. Assessment of method greenness was conducted using AGREE Prep, MoGAPI, AGSA, SAMI, Ma Tool, CACI, and WECA metrics, all of which indicate superior environmental sustainability. The proposed method is simple, fast, low-cost, ultra-sensitive, and suitable for routine quality control and/or bioanalytical analysis.

Diuretics are integral in fluid de-resuscitation of ICU patients following initial stabilization. While loop diuretics are commonly used, sequential nephron blockade (SNB) is an alternative diuretic strategy that combines a loop diuretic with at least one diuretic from another pharmacologic class to increase efficacy and limit adverse effects. The objective of this study was to compare the safety and efficacy of SNB to loop diuretics alone for de-resuscitation of critically ill patients. This retrospective study included adult ICU patients who received either a loop diuretic alone or combined with an aldosterone antagonist, carbonic anhydrase inhibitor, and/or thiazide diuretic on two consecutive days. The primary outcome was comparison of diuretic efficacy, assessed by urine output, on diuresis day 1. Secondary outcomes included comparison of diuretic efficacy on diuresis days 2-5 and incidence of acute kidney injury and electrolyte abnormalities on diuresis day 1. A total of 100 patients were included (SNB = 15, Loop = 85). At baseline, SNB patients had more hypernatremia (20% vs 2.4%, P = 0.023) and hyperchloremia (20% vs 2.4%, P = 0.023). Patients in the SNB group had increased urine output on diuresis day 1 (4725 vs 2215 mL, P = 0.0004). AKI did not occur in SNB patients on diuresis day 1 vs 15.5% of loop patients (P = 0.208). Hypernatremia (26.7% vs 2.4%, P = 0.004) and hyperchloremia (13.3% vs 3.5%, P = 0.161), persisted in the SNB group on diuretic day 2. In conclusion, among ICU patients requiring de-resuscitation, SNB may be associated with improved diuresis and similar safety concerns compared to loop diuretics alone.