Krüppel‑like factor 15 (KLF15), also known as kidney‑enriched transcription factor, is known to participate in podocyte differentiation. However, the role of KLF15 in chronic podocyte injury remains incompletely understood, particularly in proteinuric disease models. In the present study, the 5/6 nephrectomy mouse model was used to induce chronic podocyte injury. Human primary podocytes were isolated by flow cytometry and cultured to emulate the injury process in an in vitro system. Biopsied kidney tissue samples were obtained from patients with primary membranous nephropathy or diabetic nephropathy in order to analyze the relationship between glomerular KLF15 expression and subsequent outcomes. When 5/6 nephrectomy was predisposed to progressive kidney damage, fibrosis markers increased, while podocyte KLF15 expression decreased. In addition, increased fibrosis marker expression in human primary podocytes following treatment with transforming growth factor‑β was aggravated by the knockdown of KLF15. These trends were reversed after cultured podocytes were treated with cyclosporine. When patients were grouped according to KLF15 expression levels in kidney tissue, the low expression groups were demonstrated to have worse renal outcomes, such as non‑remission of disease and end‑stage renal disease. In conclusion, the present findings revealed that low expression of KLF15 was associated with chronic podocyte injury.