Urinary peptidomics in a rodent model of diabetic nephropathy highlights epidermal growth factor as a biomarker for renal deterioration in patients with type 2 diabetes

Abstract

Many diabetic patients suffer from declining renal function without developing albuminuria. To identify alternative biomarkers for diabetic nephropathy (DN) we performed urinary peptidomic analysis in a rodent model in which hyperglycemia and hypertension synergize to promote renal pathologic changes consistent with human DN. We identified 297 increased and 15 decreased peptides in the urine of rats with DN compared with controls, including peptides derived from proteins associated with DN and novel candidate biomarkers. We confirmed by ELISA that one of the parent proteins, urinary epidermal growth factor (uEGF), was more than 2-fold reduced in rats with DN in comparison with controls. To assess the clinical utility of uEGF we examined renal outcomes in 642 participants from the Edinburgh Type 2 Diabetes Study who were normoalbuminuric and had preserved renal function at baseline. After adjustment for established renal risk factors, a lower uEGF to creatinine ratio was associated with new-onset estimated glomerular filtration rate less than 60 ml/min per 1.73m(2) (odds ratio 0.48; 95% confidence interval, 0.26-0.90), rapid (over 5% per annum) decline in renal function (odds ratio 0.44; 95% confidence interval, 0.27-0.72) or the composite of both outcomes (odds ratio 0.38; 95% confidence interval, 0.24-0.62). Thus, the utility of a low uEGF to creatinine ratio as a biomarker of progressive decline in renal function in normoalbuminuric patients should be assessed in additional populations.

Renal disease pathophysiology and treatment: contributions from the rat

“…For example, one downregulated gene in both the rat model and in the kidneys of individuals with DN was epidermal growth factor (EGF). Urinary EGF levels reflect renal EGF expression, and subsequent studies confirmed that low levels of urinary EGF excretion predict a poor renal outcome in individuals with DN and with other CKDs (Betz et al, 2016; Ju et al, 2015). Hence, non-biased transcriptomic approaches could be used to identify as-yet-unknown prognostic biomarkers for therapeutic targets or to recruit high-risk individuals for clinical trials.…”

Epidermal growth factor as a prognostic biomarker in chronic kidney diseases

“…EGF expression was observed in the thick ascending limb of Henle and distal tubules (8), EGF activates tubular cell proliferation in autocrine/paracrine manner. Decreased renal expression and urinary excretion of EGF has been observed in various human kidney diseases, including diabetic nephropathy (14), IgA nephropathy (15), acute kidney injury (16), and lupus nephritis (17). Recently, Betz et al (14) demonstrated that uEGF decreased early in the development of the disease in the Cyp1a1mRen2 model, in which streptozotocin-induced hyperglycemia develops in parallel with renin-dependent hypertension.…”

Urinary epidermal growth factor predicts renal prognosis in antineutrophil cytoplasmic antibody-associated vasculitis

“…Several studies have shown that urinary EGF (uEGF) is decreased in a variety of renal diseases including diabetic nephropathy,4 acute kidney injury,5 IgA nephropathy (IgAN),6 congenital ureteropelvic junction obstruction7 and chronic kidney disease (CKD) in children 8. More importantly, it has been shown that uEGF has the ability to predict the development of diabetic nephropathy9 and IgAN 6. In the present study, we investigated the association between intrarenal EGF mRNA and kidney function, and the association between uEGF and renal outcomes, including the renal response to treatment and renal disease progression in patients with AAV.…”