Society of Diabetic Nephropathy Prevention Journal of Nephropharmacology 2345-4202 16 1 2027 01 01 The clinical paradox of SGLT2 inhibition in patients with chronic kidney disease; evaluating the spectrum of toxicity and the dangers of overzealous therapeutic use e12899 e12899 10.34172/npj.12899 EN Sepideh Hajian https://orcid.org/0000-0002-3368-0036 Azadeh Zahedi Far https://orcid.org/0009-0009-4054-5199 Journal Article 10.34172/npj.12899 2026 07 26 2026 09 14 Sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized the management of chronic kidney disease (CKD), offering unprecedented renoprotective and cardiometabolic benefits. However, a clinical paradox has emerged wherein the very agents designed to preserve renal function can precipitate significant toxicity when deployed overzealously or without meticulous patient selection. This overview considers the spectrum of adverse effects associated with SGLT2 inhibition in the CKD population, emphasizing the fine line between therapeutic efficacy and iatrogenic harm. Though robust clinical trials demonstrate profound long-term benefits, real-world application reveals distinct vulnerabilities, particularly concerning volume depletion-induced acute kidney injury, euglycemic diabetic ketoacidosis, and severe, recurrent genitourinary infections. The dangers of overzealous therapeutic use are magnified in patients with advanced CKD, those on concurrent high-dose diuretics or renin-angiotensin-aldosterone system inhibitors, and individuals failing to adhere to essential sick day protocols during acute illness. Furthermore, the aggressive continuation of SGLT2 inhibitors below established estimated glomerular filtration rate thresholds risks exacerbating hemodynamic instability and electrolyte derangements without conferring additional renoprotective advantages. By synthesizing recent pharmacovigilance data, case reports, and clinical trial subgroup analyses, this paper underscores the absolute necessity of individualized risk stratification. Clinicians should know this paradox by balancing the undeniable long-term organ-preserving potential of SGLT2 inhibitors with vigilant, proactive monitoring for acute toxicities. Finally, optimizing outcomes in CKD requires a paradigm shift from blanket, protocol-driven prescribing to precision nephrology, ensuring that the well-intentioned pursuit of renal preservation does not inadvertently accelerate clinical decline through unchecked therapeutic enthusiasm and inadequate physiological surveillance.