Abstract
Renal tubulointerstitial fibrosis caused by congenital ureteropelvic junction obstruction (UPJO) may lead to the development of obstructive nephropathy (ON) and the impairment of kidney function. Hence, the identification of early biomarkers of this condition might be of assistance in therapeutic decisions. This study evaluates serum and urinary metalloproteinases MMP-1, MMP-2, and MMP-9 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 as potential biomarkers of ON in children with congenital unilateral hydronephrosis (HN) caused by UPJO. Forty-five (45) children with congenital HN of different grades of severity and twenty-one (21) healthy controls were enrolled in the study. Urinary and serum concentrations of MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were measured using specific ELISA kits. The urinary excretions were expressed as biomarker/creatinine (Cr) ratios. To evaluate the extracellular matrix remodelling process activity, the serum and urinary MMP-1, -2, -9/TIMP-1, -2 ratios were also calculated. In comparison with the controls, patients with HN, independent of the grade, showed significantly increased median serum MMP-9, TIMP-1, and TIMP-2, median urinary MMP-9/Cr, and TIMP-2/Cr ratios. Lower median values of serum MMP-2/TIMP-1, MMP-9/TIMP-1 in patients with HN were also revealed. Additionally, higher urinary MMP-2/Cr, lower urinary MMP-2/TIMP-2, and lower serum MMP-9/TIMP-2 ratios were observed in patients with HN grades 3 and 4. Patients with ON diagnosed by renal scintigraphy had a significantly higher median serum MMP-9 concentration and lower median serum MMP-9/TIMP-1, -2 ratios in comparison with those without this condition. Patients with nonglomerular proteinuria had a significantly higher median serum TIMP-1 concentration, a higher median urinary TIMP-2/Cr ratio, and a lower serum MMP-9/TIMP-1 ratio compared to those without this symptom. The relationship between the measured biomarkers and the relative function of the obstructed kidney showed no correlations. The ROC curve analysis showed a promising diagnostic profile for the detection of ON for serum MMP-9 and the serum MMP-9/TIMP-1 and MMP-9/TIMP-2 ratios. In conclusion, the results of this study suggest that patients with HN, particularly with grades 3 and 4, are at higher risk of renal tubulointerstitial fibrosis. The noninvasive markers of this condition considered are urinary MMP-2/Cr and MMP-9/Cr, serum MMP-9, serum and urinary MMP-2, MMP-9/TIMP-1, -2. Additionally, serum MMP-9 and MMP-9/TIMP-1, -2 may become promising markers of ON.
Highlights
Obstructive nephropathy (ON) caused by congenital ureteropelvic junction obstruction (UPJO) is progressive tubulointerstitial fibrosis leading to glomerular sclerosis and the impairment of kidney function [1, 2]
Purpose of the Study The purpose of this study is to evaluate the serum and urinary metalloproteinases matrix metalloproteinases (MMPs)-1, MMP-2, and MMP-9 and the tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 as potential biomarkers of ON in children with congenital unilateral hydronephrosis (HN)
Tveitarås et al [34] found that MMP-2 knockout and heterozygote mice are protected from kidney fibrosis despite the presence of coexisting UPJO
Summary
Obstructive nephropathy (ON) caused by congenital ureteropelvic junction obstruction (UPJO) is progressive tubulointerstitial fibrosis leading to glomerular sclerosis and the impairment of kidney function [1, 2]. The final stages of its development are related to an imbalance between the formation and degradation of the extracellular matrix (ECM). Multiple factors such as the grade of hydronephrosis, urinary tract infections, and individual considerations are the sole determinants of the mechanism of renal fibrosis and its initiation and progression. Number of patients Gender (male/female) Age (years) GFR (ml/min/1.73 m2) Number of patients in groups A/B/C Number of patients with obstructive nephropathy Number of patients with proteinuria Protein/creatinine ratio (mg/mg).
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