Osmotic nephrosis, a disease caused by intravenous infusion of various fluids such as hypertonic sucrose and isotonic polysaccharide-based plasma volume expanders, exhibits specific histopathological features, including vacuolated and swollen proximal tubules, ie, "clear tubules". Pre-existing kidney injury exacerbates this condition, resulting in major clinical problems. However, the underlying mechanisms are unclear. Animal models often yield results that are directly translatable to humans. Therefore, in this study, we performed detailed histopathological analyses of the formation of clear tubules in rats treated with gentamicin or ischemia/reperfusion (IR) operation followed by dextran administration. The results showed that clear tubules may originate from regenerative tubules. Additionally, we classified regenerative tubules into 3 categories based on their development, with a particular focus on the middle and late stages. Comprehensive microarray and real-time polymerase chain reaction analyses of mRNA extracted from regenerative tubules at each stage using laser microdissection revealed that regenerative tubules in the middle stage showed an imbalance between dextran absorption and metabolism, resulting in accumulation of dextran, particularly in the cytoplasm of the tubules. Overall, our findings demonstrated that clear tubules originated from regenerated tubules and that tubules at the middle stage became clear tubules because of an imbalance during their development. This could explain why osmotic nephrosis is exacerbated in the presence of kidney lesions.