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OBJECTIVE: To evaluate the role of urinary epidermal growth factor (EGF) as a biomarker of chronic kidney damage in lupus nephritis (LN). METHODS: A proteomics approach was used to identify urinary EGF as a biomarker of interest in a discovery cohort of patients with LN. The expression of urinary EGF was characterized in 2 large multiethnic LN cohorts, and the association between urinary EGF levels at the time of flare and kidney outcomes was evaluated in a subset of 120 patients with long-term follow-up data. For longitudinal studies, the expression of urinary EGF over time was determined in 2 longitudinal cohorts of patients with LN from whom serial urine samples were collected. RESULTS: Discovery analysis showed the urinary EGF levels as being low in patients with active LN (median peptide count 8.4, interquartile range [IQR] 2.8-12.3 in patients with active LN versus median 48.0, IQR 45.3-64.6 in healthy controls). The peptide sequence was consistent with that of proEGF, and this was confirmed by immunoblotting. The discovery findings were verified by enzyme-linked immunosorbent assay. Patients with active LN had a significantly lower level of urinary EGF compared to that in patients with active nonrenal systemic lupus erythematosus (SLE), patients with inactive SLE, and healthy kidney donors (each P < 0.05). The urinary EGF level was inversely correlated with the chronicity index of histologic features assessed in kidney biopsy tissue (Spearman's r = -0.67, P < 0.001). Multivariate survival analysis showed that the urinary EGF level was associated with time to doubling of the serum creatinine level (DSCr), a marker of future end-stage kidney disease (ESKD) (hazard ratio 0.88, 95% confidence interval 0.77-0.99, P = 0.045). Patients whose LN symptoms progressed to DSCr and those who experienced progression to ESKD had a lower urinary EGF level at the time of flare, and urinary EGF levels decreased over the 12 months following flare. All patients who experienced progression to ESKD were identified based on a urinary EGF cutoff level of <5.3 ng/mg. CONCLUSION: Urinary EGF levels are correlated with histologic kidney damage in patients with LN. Low urinary EGF levels at the time of flare and decreasing urinary EGF levels over time are associated with adverse long-term kidney outcomes.

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ABSTRACT Purpose The aim of this study was to investigate the urinary concentration of epidermal growth factor (EGF) and monocyte chemotactic protein-1 (MCP-1) as reflux nephropathy (RN) biomarkers before and after endoscopic treatment of moderate to severe vesico-ureteral reflux (VUR). Materials and methods A prospective study was carried out on 72 children with moderate to severe VUR. All patients underwent endoscopic treatment using Macroplastique® or Deflux®. Vesico-ureteral reflux resolution was tested by post-operative voiding cystourethrography after 3 months and 2 years. Follow-up urinary samples were collected at that time. Control samples were taken from healthy children with no clinical evidence of renal and bladder disease and no history of UTI. Results In VUR patients, pre-operative urinary EGF levels had a down-regulation when compared to controls. Following successful VUR repair, urinary EGF levels of VUR children progressively increased only at long term follow-up but without returning to normal levels. Urinary MCP-1 levels were highly expressed in pre-operative samples and decreased markedly during early post-operative measurements. Urinary MCP-1 levels did not further decreased in late post-operative follow-up. In fact, these levels remained significantly higher when compared to controls. Conclusions Urinary levels of EGF and MCP-1 may become useful markers for monitoring the response to surgical treatment in VUR patients. Although endoscopic VUR treatment is effective in reducing the inflammatory response, the persistence of significant abnormal levels of inflammatory cytokines (such as urinary MCP-1) at long term follow-up suggests that surgery alone may not completely treat the chronic renal inflammation evidenced in these children.

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PURPOSE: The aim of this study was to investigate the urinary concentration of epidermal growth factor (EGF) and monocyte chemotactic protein-1 (MCP-1) as reflux nephropathy (RN) biomarkers before and after endoscopic treatment of moderate to severe vesico-ureteral reflux (VUR). MATERIALS AND METHODS: A prospective study was carried out on 72 children with moderate to severe VUR. All patients underwent endoscopic treatment using Macroplastique ® or Deflux®. Vesico-ureteral reflux resolution was tested by post-operative voiding cystourethrography after 3 months and 2 years. Follow-up urinary samples were collected at that time. Control samples were taken from healthy children with no clinical evidence of renal and bladder disease and no history of UTI. RESULTS: In VUR patients, pre-operative urinary EGF levels had a down-regulation when compared to controls. Following successful VUR repair, urinary EGF levels of VUR children progressively increased only at long term follow-up but without returning to normal levels. Urinary MCP-1 levels were highly expressed in pre-operative samples and decreased markedly during early post-operative measurements. Urinary MCP-1 levels did not further decreased in late post-operative follow-up. In fact, these levels remained significantly higher when compared to controls. CONCLUSIONS: Urinary levels of EGF and MCP-1 may become useful markers for monitoring the response to surgical treatment in VUR patients. Although endoscopic VUR treatment is effective in reducing the inflammatory response, the persistence of significant abnormal levels of inflammatory cytokines (such as urinary MCP-1) at long term follow-up suggests that surgery alone may not completely treat the chronic renal inflammation evidenced in these children.

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OBJECTIVE: To identify urine biomarkers predictive of acute kidney injury (AKI) in infants admitted to level 2 and 3 neonatal intensive care units with birth weight >2000 g and 5-minute Apgar score ≤ 7. STUDY DESIGN: A nested case-control study was performed comparing 8 candidate urine AKI biomarkers in infants with AKI (defined as a rise in serum creatinine of at least 0.3 mg/dL or a serum creatinine elevation ≥ 1.7 mg/dL persisting for 3 days) and 24 infants from the described cohort without AKI. Urine was analyzed for neutrophil gelatinase-associated lipocalin, osteopontin, cystatin C, albumin, ß(2) microglobulin, epithelial growth factor, uromodulin (UMOD), and kidney injury molecule 1. RESULTS: Compared with the infants without AKI, those with AKI had higher levels of urine cystatin C (1123 pg/mL [95% CI, 272-4635 pg/mL] vs 90 pg/mL [95% CI, 39-205 pg/mL]; P < .004; area under the receiver operating characteristic curve [AUC] = 0.82), lower levels of UMOD (11.0 pg/mL [95% CI, 5.7-21.4 pg/mL] vs 26.2 pg/mL [95% CI, 17.4-39.4 pg/mL]; P < .03; AUC = 0.77), and lower levels of epithelial growth factor (6.7 pg/mL [95% CI, 4.0-11.3 pg/mL] vs 17.4 pg/mL [95% CI, 12.7-23.8 pg/mL; P = .003; AUC = 0.82). Although the differences were not statistically significant, levels of urine neutrophil-associated gelatinase lipocalin, kidney injury molecule 1, and osteopontin trended higher in infants with AKI. CONCLUSION: Urinary biomarkers can predict AKI in neonates admitted to level 2 and 3 neonatal intensive care units.

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Se determinaron los valores urinarios del Factor de Crecimiento Epidérmico (FCE) absolutos y corregidos por la excreción de creatinina en 23 ulcerosos duodenales y se compararon con un grupo control. En los pacientes se dosificaron valores basales de Pepsinógeno I sérico. Los valores absolutos de FCE urinario de los ulcerosos fueron más bajos que los controles, pero tal diferencia ni la de FCE corregido por la excreción urinaria de creatinina fueron estadísticamente significativas (p > 0,05). La excreción absoluta de FCE de los ulcerosos varones fue mayor que en las damas (p<0,05), pero al establecer la relación FCE/Creatinina, la diferencia desapareció. No hubo correlación entre FCE y Pepsinógeno I, fue inversa con la edad y positiva con la excreción de creatinina. Varios mecanismos se plantean para explicar la normalidad urinaria del FCE en estos pacientes. La importancia creciente que se da al FCE en enfermedad ulcerosa y ulteriores investigaciones, son analizadas

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Absolute and corrected by creatinine excretion urinary Epidermal Growth Factor (EGF) values were determined in 23 duodenal ulcer patients and compared to a control group. Basal serum pepsinogen I levels were measured in the patient group. Absolute urinary EGF values in patients were lower than in control group, such difference however, as such of EGF corrected by urinary creatinine excretion were not statistically significant (p > 0.05). Absolute urinary EGF excretion in male patients was higher than in female patients (p < 0.05), but after establishing the ratio EGF/Creatinine, the difference disappeared. There was no correlation between EGF and Pepsinogen I, it was inverse with age and positive with creatinine excretion. Some mechanisms are considered to explain the urinary EGF normality in these patients. The increasing importance given to EGF in ulcerous diseases and further trends in research are analyzed.

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Se desarrolló un radioinmunoensayo homólogo, con anticuerpos policlonales, utilizando un antígeno altamente purificado, obtenido por DNA recombinante. El método permite cantidades del factor de crecimiento epidérmico tan bajas como 20 picogramos/tubo; es altamente específico y confiable. El presente estudio aporta a la literatura la primera evidencia científica de la existencia de niveles inmunoreactivos medibles del Factor de Crecimiento Epidérmico en la primera orina de un grupo de recién nacidos a término. En el líquido amniótico se demuestra que existen niveles medibles de hEGF al igual que lo han demostrado otros autores en dos trabajos anteriores. Estos niveles son relativamente bajos en comparación con los urinarios

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