Abstract
BackgroundAlport syndrome is a rare hereditary kidney disease manifested with progressive renal failure. Considerable variation exists in terms of disease progression among patients with Alport syndrome. Identification of patients at high risk of rapid progression remains an unmet need. Urinary epidermal growth factor (uEGF) has been shown to be independently associated with risk of progression to adverse kidney outcome in multiple independent adult chronic kidney disease (CKD) cohorts. In this study, we aim to assess if uEGF is associated with kidney impairment and its prognostic value for children with Alport syndrome.MethodsOne hundred and seventeen pediatric patients with Alport syndrome and 146 healthy children (3–18 years old) were included in this study. uEGF was measured in duplicates in baseline urine samples using ELISA (R&D) and concentration was normalized by urine creatinine (uEGF/Cr). In patients with longitudinal follow-up data (n = 38), progression was defined as deteriorated kidney function (CKD stage increase) during follow-up period (follow-up length is about 31 months in average). The association of baseline uEGF/Cr level with estimated glomerular filtration rate (eGFR) slope and Alport syndrome patients’ progression to a more advanced CKD stage during the follow-up period was used to evaluate the prognostic value of the marker.ResultsWe found that uEGF/creatinine (uEGF/Cr) decreases with age in pediatric patients with Alport syndrome with a significantly faster rate than in healthy children of the same age group. uEGF/Cr is significantly correlated with eGFR (r = 0.75, p < 0.001), after adjustment for age. In 38 patients with longitudinal follow-up, we observed a significant correlation between uEGF/Cr and eGFR slope (r = 0.58, p < 0.001). Patients with lower uEGF/Cr level were at increased risk of progression to a higher CKD stage. uEGF/Cr was able to distinguish progressors from non-progressors with an AUC of 0.88, versus 0.77 by eGFR and 0.81 by 24-h urinary protein (24-h UP).ConclusionsOur study suggests that uEGF/Cr is a promising biomarker for accelerated kidney function decline in pediatric patients with Alport syndrome. It may help to identify patients at high risk of progression for targeted clinical care and improve the patients’ stratification in interventional trials.
Highlights
Alport syndrome is a hereditary kidney disease which manifests with hematuria, proteinuria, progressive renal failure, sensorineural deafness, or typical ocular changes, which are caused by mutations in the COL4A5, COL4A3, or COL4A4 genes [1]
Alport syndrome children in respective age groups was separated into patients with Blower Urinary epidermal growth factor (uEGF)/Cr than healthy^ and with Bnormal range uEGF to creatinine ratio (uEGF/Cr)^ based on the cutoff value
Alport syndrome children whose uEGF/Cr were less than the cutoff value for the corresponding age group was defined as Blower uEGF/Cr than healthy,^ whereas Alport syndrome children with Bnormal range uEGF/Cr^ referred to those children whose uEGF/Cr concentration is higher than the cutoff value of the corresponding age group
Summary
Alport syndrome is a hereditary kidney disease which manifests with hematuria, proteinuria, progressive renal failure, sensorineural deafness, or typical ocular changes, which are caused by mutations in the COL4A5, COL4A3, or COL4A4 genes [1]. The progression of Alport syndrome is determined by regular measurements of proteinuria and renal function. These parameters are not sensitive enough to predict the progression of Alport syndrome. In 2016, Betz et al demonstrated that the lower uEGF/Cr at baseline dramatically increased the risk of rapid decline of renal function [14]. These studies further reinforce uEGF/Cr as a potential predictive marker for progressive renal diseases. We aim to assess if uEGF is associated with kidney impairment and its prognostic value for children with Alport syndrome
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