BackgroundAge- and height-adjusted total kidney volume is currently considered the best prognosticator in patients with autosomal dominant polycystic kidney disease. We tested the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for the prediction of the Mayo Clinic Imaging Classes.MethodsUrinary epidermal growth factor and monocyte chemotactic peptide 1 levels were measured in two independent cohorts (discovery,n= 74 and validation set,n= 177) and healthy controls (n= 59) by immunological assay. Magnetic resonance imaging parameters were used for total kidney volume calculation and the Mayo Clinic Imaging Classification defined slow (1A–1B) and fast progressors (1C–1E). Microarray and quantitative gene expression analysis were used to test epidermal growth factor and monocyte chemotactic peptide 1 gene expression.ResultsBaseline ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 correlated with total kidney volume adjusted for height (r= − 0.6,p< 0.001), estimated glomerular filtration rate (r= 0.69p< 0.001), discriminated between Mayo Clinic Imaging Classes (p< 0.001), and predicted the variation of estimated glomerular filtration rate at 10 years (r= − 0.51,p< 0.001). Conditional Inference Trees identified cut-off levels of the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for slow and fast progressors at > 132 (100% slow) and < 25.76 (89% and 86% fast, according to age), with 94% sensitivity and 66% specificity (p= 6.51E−16). Further, the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 at baseline showed a positive correlation (p= 0.006,r= 0.36) with renal outcome (delta-estimated glomerular filtration rate per year, over a mean follow-up of 4.2 ± 1.2 years). Changes in the urinary epidermal growth factor and monocyte chemotactic peptide 1 were mirrored by gene expression levels in both human kidney cysts (epidermal growth factor: − 5.6-fold, fdr = 0.001; monocyte chemotactic peptide 1: 3.1-fold, fdr = 0.03) andPkd1knock-out mouse kidney (Egf: − 14.8-fold, fdr = 2.37E-20,Mcp1: 2.8-fold, fdr = 6.82E−15).ConclusionThe ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 is a non-invasive pathophysiological biomarker that can be used for clinical risk stratification in autosomal dominant polycystic kidney disease.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40620-022-01468-w.