Background <p>Osmotic nephropathy is an infrequent drug‑induced complication characterized by vacuolization of renal tubular cells secondary to lysosomal uptake, which increases osmotic pressure within the proximal tubule. This lesion pattern has been linked to administration of intravenous immunoglobulins, iodinated contrast agents, mannitol, dextrans and glucose solutions, and more recently to the use of sodium–glucose cotransporter‑2 (SGLT2) inhibitors.</p> Case presentation <p>A 49‑year‑old man with a history of hypertension, type 2 diabetes mellitus and obesity, chronically treated with empagliflozin, presented with diarrhea, abdominal pain and oliguria. Laboratory tests revealed acute kidney injury with a serum creatinine of 13&#xa0;mg/dL and electrolyte disturbances. In light of a suspected rapidly progressive glomerulonephritis, renal replacement therapy was initiated owing to failure of hydration. Renal biopsy showed diffuse tubular vacuolization compatible with osmotic nephropathy, leading to discontinuation of the SGLT2 inhibitor. The patient’s renal function recovered after two weeks of hemodialysis.</p> Conclusions <p>Osmotic nephropathy is a rare histopathological diagnosis associated with exposure to hyperosmolar agents, as exemplified by this case related to empagliflozin use. The proposed pathophysiological mechanism involves lysosomal uptake secondary to increased intratubular osmotic pressure caused by glucosuria. Predisposing factors include therapy with SGLT2 inhibitors, diabetes mellitus, advanced age and pre-existing mild chronic kidney impairment. The cornerstone of management is discontinuation of the offending agent and supportive measures. It is recommended that SGLT2 inhibitors be withheld during episodes of diarrhea or acute dehydration to prevent further renal impairment.</p>