Abstract: Objective To investigate the predictive value of preadipocyte factor-1 (Pref-1) for early diabetic nephropathy (DN) and to evaluate the efficacy of the combined therapy with alprostadil and pancreatic kininogenase on DN. Methods A retrospective study was conducted on 104 patients with type 2 diabetes mellitus (T2DM) admitted to Yuncheng Central Hospital, Shanxi Province, between August 2022 and October 2023. Participants were divided into T2DM group and DN group based on their urinary albumin excretion rate (UAER). Pearson correlation and receiver operating characteristic (ROC) curve were used to analyze the relationship between Pref-1 and renal function and its predictive value. The therapeutic effects of alprostatil and pancreatic kininogenase on DN were also evaluated. Results Before treatment, the DN group had significantly higher levels of Pref-1, UAER, blood urea nitrogen (BUN), and serum creatinine (Scr), and a lower estimated glomerular filtration rate (eGFR) than the T2DM group (P＜0.05). Pref-1 was positively correlated with UAER, BUN, and Scr, and negatively correlated with eGFR (P＜0.05). The area under the curve (AUC) of Pref-1 for diagnosing DN was 0.728, which is greater than the corresponding optimal cut-off value (0.352). After treatment, the DN group showed significant reductions in Pref-1, UAER, BUN, and Scr levels, and an increase in eGFR compared to pre-treatment levels (P＜0.05). Conclusion Pref-1 is highly expressed in early DN and demonstrates considerable value in predicting early DN. The combined therapy with alprostadil and pancreatic kininogenase is effective, facilitating the reduction of Pref-1 levels and the improvement of renal function in patients.