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

Abstract

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.

Predicting treatment response and clinicopathological findings in lupus nephritis with urine epidermal growth factor, monocyte chemoattractant protein-1 or their ratios

“…As far as we know, there has been only one study evaluating the role of EGF in LN. Mejia-Vilet et al evaluated the relationship of urinary EGF to renal histology and long-term change in GFR in US and Mexican patients with LN [ 35 ]. They found that EGF correlated with chronicity index and predicted long term GFR levels, but did not correlate with activity index.…”

Urinary Biomarkers in Lupus Nephritis: Are We There Yet?

“…The study by Mejia‐Vilet and colleagues (11) is a pilot study that validates the urinary EGF level as a biomarker for kidney reserve in LN. Although the urinary EGF level is not specific for SLE, it may be a surrogate marker for residual nephron mass in patients with kidney diseases.…”

“…In this same issue of Arthritis & Rheumatology , Mejia‐Vilet et al (11) reported on their study of the relationship between the urinary epidermal growth factor (EGF) level and progression of chronic kidney disease in several cohorts of patients with LN. This biomarker was identified by MS‐based proteomics screening in a discovery cohort and validated by immunoblotting and ELISA.…”

Biopsy or Biomarker? Children With Minimal Change Disease Have a Distinct Profile of Urinary Epidermal Growth Factor

“…uEGF levels correlate with intrarenal mRNA expression of EGF on kidney biopsy and inversely correlate with the degree of interstitial fibrosis and tubular atrophy ( 16 , 19 , 20 ). Theoretically, already at an early stage in the disease, a decrease in uEGF could thus precede glomerular deterioration visualized on kidney biopsy ( 15 , 19 , 21 ). Tubular injury is closely linked to progression in glomerular nephropathies ( 22 ).…”

“…Therefore, tubular proteins such as uEGF are potentially better predictive markers for progression of glomerular damage and renal deterioration than proteinuria and albuminuria ( 17 ). Particularly for uEGF, over the last few years, increasing evidence highlights its added value in predicting kidney deterioration in many disease entities such as systemic lupus disease ( 21 ), diabetes mellitus ( 23 ), but also in IgA nephropathy ( 15 , 24 ), and other chronic kidney diseases ( 17 ) in adults. Specifically in children, recent reports illustrated the prognostic capacities of uEGF regarding renal decline in pediatric patients with chronic kidney disease ( 25 ), Alport syndrome ( 20 ), and nephrotic syndrome ( 19 ).…”