Urinary epidermal growth factor as a prognostic marker for the progression of Alport syndrome in children

Abstract

Background: Alport 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.

Methods: One 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.

Results: We 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).

Conclusions: Our 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.

Keywords: Alport syndrome; Prognostic marker; Progression; Urinary epidermal growth factor (uEGF).

Fig. 1

Urinary epidermal growth factor/creatinine (uEGF/Cr) levels in different age group of healthy children. uEGF/Cr of healthy children at 3–6 years (54.17 ± 22.84; N = 50) decreased 43% at 7–12 years (30.87 ± 9.37; N = 47) and 59% at 13–18 years (22.06 ± 5.78; N = 49).Triple asterisks denote p < 0.0001

Fig. 2

Urinary epidermal growth factor/creatinine (uEGF/Cr) level in different age groups of healthy children and children with Alport syndrome (mean ± SD). a uEGF/Cr levels were lower in children with Alport syndrome (red column) in comparison with healthy children (blue column) overall and in each individual age group. Double asterisks represent p < 0.01; triple asterisks represent p < 0.0001. b uEGF/Cr levels decrease with age in healthy children (blue dots, N = 146) and children with Alport syndrome (red square, N = 117)

Fig. 3

Correlation of one urinary epidermal growth factor/creatinine (uEGF/Cr) with kidney impairment, evaluated by estimated glomerular filtration rate (eGFR) and 24-h UP. a uEGF/Cr is significantly (p < 0.001) positively correlated with eGFR at the time of urine collection (N = 117). b uEGF/Cr showed a negative correlation with 24-h UP (N = 117), however, did not reach statistical significance

Fig. 4

The urinary epidermal growth factor/creatinine (uEGF/Cr) levels (mean ± SD) in children with Alport syndrome. Children were grouped based on their proteinuria levels and estimated glomerular filtration rate (eGFR). Patients with microalbuminuria (N = 10), proteinuria (N = 61), and renal dysfunction (N = 43) were included in this analysis. uEGF/Cr is 36 or 78% less in patients with proteinuria or renal dysfunction in comparison with patients with microalbuminuria, respectively. Double asterisks represent p = 0.008; triple asterisks represent p < 0.0001

Fig. 5

The level of one urinary epidermal growth factor/creatinine (uEGF/Cr) and kidney disease progression in patients with Alport syndrome. a uEGF/Cr is significantly and positively correlated with estimated glomerular filtration rate (eGFR) slope (r = 0.58, p < 0.001). The majority of progressors (red dots) had lower uEGF/Cr and steeper eGFR slope than non-progressors (black dots). b Thirty five children with Alport syndrome and eGFR above 60 were divided into “lower uEGF/Cr than healthy” (N = 27) and “normal range uEGF/Cr” (N = 8) groups based on cutoff values defined based on healthy children of the same age group, as described in the methods section. In patients with eGFR ≥ 60 but lower uEGF/Cr, 70% had progressed to more advanced chronic kidney disease (CKD) stages during follow-up, whereas in patients with normal range uEGF/Cr, none had progressed