<![CDATA[Diuretics alleviate fluid retention and electrolyte abnormalities; however, comparative preclinical animal studies remain limited. This systematic review evaluated the effects of loop diuretics (furosemide), thiazide diuretics (hydrochlorothiazide), and potassium-sparing agents (amiloride, triamterene) on renal function, electrolyte balance, and survival in rats. PRISMA 2020 guidelines were followed to search PubMed, Web of Science, and Google Scholar for comparative studies published between 2015 and 2025 investigating diuretic effects on glomerular filtration rate, creatinine clearance, urinary sodium/potassium/chloride excretion, plasma electrolytes, kidney injury biomarkers, and survival in rats. Dual screening and data extraction were performed independently by two reviewers, and risk of bias was assessed using the ARRIVE 2.0 checklist. Twelve studies (440 rats) were included. Thiazides (1.3–2.0-fold) and potassium-sparing agents (1.1–1.4-fold) increased urine volume less than loop diuretics (2.8–3.5-fold). Loop diuretics increased urinary potassium excretion and reduced plasma potassium to clinically dangerous levels (2.3–2.5 mmol/L), increasing the risk of hypokalemia by 2.3–3.2-fold. Thiazides showed moderate efficacy but also posed a significant risk of hypokalemia (1.5–1.9-fold K⁺ loss). Combination therapy with loop and potassium-sparing agents increased diuretic efficacy by 30–94% and reduced electrolyte disturbances by 30–50%. Diuretic resistance (approximately a 25% reduction in efficiency) was associated with aldosterone-mediated epithelial sodium channel overexpression during days 5–7 of chronic therapy. Aldosterone-deficient animals responded more favorably to diuretics. In disease models, furosemide promoted medullary damage in acute ischemia–reperfusion injury but improved survival in chronic renal failure (43–82% reduction in kidney injury biomarkers and 75–100% improvement with combination therapy). Metabolomic analyses indicated that outer medullary osmolyte depletion (betaine 89%, glycerophosphocholine 46–63%) contributed to impaired urine concentration. Prolonged furosemide use also resulted in significant micronutrient depletion (magnesium 16–33%, iron 52%, copper 31%). Effective loop diuretic therapy requires careful electrolyte monitoring. Combination therapy, particularly with loop and potassium-sparing diuretics, appears to be the most effective and safest strategy. Diuretic resistance caused by aldosterone-mediated sodium channel activation may be reduced through intermittent dosing, sodium restriction, or renin–angiotensin–aldosterone system antagonism. Future research should investigate long-term treatment protocols, combination regimens, disease-specific responses, and metabolomic standardization to optimize clinical diuretic therapy.]]>
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