Vesicoureteral reflux (VUR) is the most common type of obstructive uropathy in children. Reflux nephropathy (RN) is one of the most common complications of VUR that inevitably leads to chronic kidney disease. Patients with end-stage kidney disease require costly treatment, and the only way to cure them is kidney transplantation. A timely institution of renoprotective therapy is a key factor helping to preserve the function of the native kidneys. Hence, it is necessary to devise new highly sensitive and minimally invasive methods for early diagnosis of RN. The purpose of this article is to review the molecular mechanisms of initiation and progression of kidney fibrosis and the opportunities of instrumental and non-instrumental methods for its diagnosis. Special attention is paid to highly specific and highly sensitive non-invasive methods for the detection of minimal changes in the renal parenchyma. The authors discuss the promising biomarkers for the diagnosis and prediction of RN.