Mathematical analysis of individual biomarker profiles of kidney damage in children with vesicoureteral reflux
Authors:   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Demidova K.N. , Morozov D.A. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   Academician Yu.E.Veltischev Research Clinical Institute of Pediatrics, Moscow, Russian Federation, Rostovskaya V.V. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Morozova O.L. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Staroverov O.V. ,   G.N.Speransky Children's City Clinical Hospital No 9, Moscow, Russian Federation, Shmyrov O.S. ,   Morozovskaya Children's City Clinical Hospital, Moscow, Russian Federation
Published: April 2022

Objective. To assess the severity of lesions to renal parenchyma in children with grade II–IV vesicoureteral reflux (VUR) using hierarchical clustering based on the analysis of individual profiles of urinary biomarkers. Patients and methods. In this study, we evaluated the excretion of urinary biomarkers of inflammation (IL-8, IL-18, MCP-1), angiogenesis (VEGF), and fibrogenesis (TGF-β1) and compared them with clinical and demographic parameters of 65 patients with grade II–IV VUR aged 1 to 17 years (mean age 4.9 ± 3.1 years) with a normal glomerular filtration rate (GFR). The control group comprised healthy children without kidney diseases (n = 25). We used hierarchical clustering (construction of dendrogram using the Ward's method) for all biomarkers. Results. All patients, regardless of their age, gender, and VUR severity demonstrated a pathological profile of urinary biomarkers excretion, including IL-8, IL-18, MCP-1, VEGF, TGF-β1 (p > 0.05). Using cluster analysis, we divided all patients into three subgroups (clusters) depending on the similarity of their individual biomarker profiles. We identified three main patterns of biomarkers that were associated with different severity of tubulointerstitial nephritis (TIN). The first pattern (I) with low levels of excretion of all biomarkers (p < 0.001) correlated with mild TIN and was observed in 61.5% of children. The second pattern (II) with average excretion of IL-8, IL-18, MCP-1, TGF-β1 (p < 0.01) and high VEGF excretion (p < 0.001) was associated with moderate TIN and was observed in 32.2% of patients. The third pattern (III) with elevated excretion of IL-8, IL-18, MCP-1 and VEGF (by 2.5–17 times compared to patterns I and II) (p < 0.01) correlated with severe TIN and was found in 6.1% of patients. Patients with the same VUR grades demonstrated different biomarker patterns. Conclusion. Hierarchical clustering enables comparison of individual profiles of urinary biomarkers with identified patterns, as well as their stratification into groups according to tubulointerstitial nephritis severity, which often remains undiagnosed with visualization techniques alone. Key words: children, cluster analysis, urinary biomarkers, vesicoureteral reflux, reflux nephropathy, tubulointerstitial nephritis