Background The level of urinary cluster of differentiation 80 (uCD80) is elevated in most children with minimal change disease (MCD) as opposed to focal segmental glomerulosclerosis (FSGS) during the acute phase. The objective of this follow-up study was to evaluate whether uCD80 elevation is actually associated with MCD and whether it signals better prognosis. Methods We evaluated uCD80 levels and a series of putative progression factors in a cohort of 64 patients with nephrotic syndrome (NS) seen between 2011 and 2016. We monitored progression of chronic kidney disease (CKD), assessed as a glomerular filtration rate of < 90 ml/min/1.73 m(2) for at least 3 months. Patients were classified according to uCD80 level and to the progression rate as calculated by Kaplan-Meier survival analysis and Cox's regression analysis. Results During a mean follow-up period of 4.8 +/- 0.6 (range 3.5-6.0) years, 13 children (20%) evolved to at least CKD stage 2. The 64 patients with NS and normal baseline renal function were divided into two groups based on uCD80 excretion, i. e. below or above a defined cutoff (< or > 328.98 ng/g creatinine). The predicted response to immunosuppression therapy was 34.5 and 100% in the low-and high-uCD80 excretion, respectively (p < 0.001). Progression to CKD was 41.4 vs. 2.9% in NS patients (p < 0.001). Using the Cox model, only uCD80 excretion (p = 0.013, relative risk 6.171) predicted progression to CKD. Conclusions Urinary CD80 predicts progression and remission in children with NS. The use of uCD80 as a prognostic marker facilitates the identification of high-risk patients at an early stage and may lead to better treatment selection.