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

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.

Association Between Urinary Epidermal Growth Factor and Renal Prognosis in Lupus Nephritis

“…Urinary EGF is not a biomarker of kidney function that is specific for LN. As reported for other kidney diseases (8–18), we found that urinary EGF/Cr levels correlated inversely with the histologic equivalents of chronic renal damage, including glomerular sclerosis, interstitial fibrosis, and tubular atrophy, as well as the combination of these components, also known as the histologic chronicity index. An inverse correlation between the urinary EGF/Cr and chronic kidney damage has also been observed in several other glomerular disease cohorts (the European Renal cDNA Bank [ERCB], Clinical Phenotyping Resource and Biobank Core [C‐PROBE], Nephrotic Syndrome Study Network [NEPTUNE], and Peking University‐IgA Nephropathy [PKU‐IgAN] Consortium), some of which included patients with lupus (6).…”

“…When combined with other biomarkers of kidney function at the time of flare, such as proteinuria, the eGFR, and the histologic chronicity index, the addition of urinary EGF/Cr levels improved the prognostic value of these variables. The association of baseline urinary EGF/Cr levels with adverse kidney outcomes has also been demonstrated in other glomerular disease cohorts (6), patients with Alport syndrome (14), and patients with diabetic kidney disease (11–13).…”

“…Urinary EGF levels have been found to be correlated with intrarenal EGF messenger RNA (mRNA) expression and have been reported to be decreased in several kidney diseases (6). An association between low urinary EGF levels and the degree of interstitial fibrosis and progressive chronic kidney disease was observed in patients with IgA nephropathy (8)(9)(10), diabetic kidney disease (11)(12)(13), Alport syndrome (14) , and other glomerular and nonglomerular diseases (6,(15)(16)(17)(18). Therefore, this study aimed to understand the relationship between urinary EGF levels, histopathologic features of the kidney, and renal outcomes in patients with LN.…”

Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children

“…This adjustment, however, did not abolish the association of uEGF with patient age. A recent study reported that uEGF excretion decreases with age in healthy children, 24 which suggests that higher uEGF levels in younger children may represent a physiological phenomenon.…”

Evolving Clinical Applications of Tissue Transcriptomics in Kidney Disease

“…Betz et al subsequently showed that a lower uEGF/Cr was associated with rapid decline in renal function in a cohort of patients with diabetes with normoalbuminuria and preserved eGFR (19). In a cohort of 117 children with confirmed Alport syndrome, Li et al demonstrated that children with Alport syndrome showed significantly lower uEGF/Cr when compared to 146 age-matched healthy children (20). Again in this population, uEGF/Cr correlated tightly with eGFR ( r = 0.75, p < 0.001), eGFR slope, and “progressors”—those who advanced to a higher CKD stage within the study follow up—were more likely to have low uEGF/Cr.…”