Urinary Epidermal Growth Factor Level as a Noninvasive Indicator of Tubular Repair in Patients with Acute Kidney Injury

Abstract

Epidermal growth factor (EGF), an essential factor for the proliferation and survival of renal tubular cells, is expressed by distal tubules and normally excreted via urine. Previous studies in rats demonstrated that acute tubular injury reduces urinary EGF levels. However, it is unclear whether urinary EGF is a suitable monitoring marker of tubular repair status after acute kidney injury (AKI) in humans. To address this question, we measured serum and urinary EGF in patients with AKI (n = 99) using ELISA and investigated whether urinary EGF levels were associated with the severity of tubular injury and renal prognosis. Urinary EGF was abundant in healthy controls but showed a significant decrease in AKI patients (14,522 ± 2190 pg/mL vs. 3201 ± 459.7 pg/mL, p < 0.05). The urinary EGF level in patients with renal AKI was notably lower than that in patients with pre-renal AKI. Furthermore, the urinary EGF level in patients with AKI stage 3 was significantly lower than that in patients with AKI stage 1. Urinary EGF levels were negatively correlated with urinary β-2MG and serum creatinine levels but positively correlated with hemoglobin levels and eGFR. Urinary EGF was not significantly correlated with urinary NAG, α-1MG, L-FABP, NGAL, KIM-1, or urinary protein concentrations. No significant correlation was observed between serum and urinary EGF levels, suggesting that urinary EGF is derived from the renal tubules rather than the blood. In living renal transplantation donors, the urinary EGF/Cr ratio was approximately half the preoperative urinary EGF/Cr ratio after unilateral nephrectomy. Collectively, these data suggest that urinary EGF is a suitable noninvasive indicator of not only the volume of functional normal renal tubules but also the status of tubular repair after AKI.

Keywords: EGF; acute kidney injury; urinary biomarker.

Figure 1

Urinary EGF levels in AKI patients. (A) Urinary EGF levels in the healthy control (HC) (n = 16) and AKI patient (n = 99) groups. (B) Urinary EGF levels in prerenal (n = 16) and renal AKI (n = 83) patients. (C) Urinary EGF levels and severity of AKI according to KDIGO staging criteria (stages 1–3). (D) Urinary EGF level by cause of AKI (sepsis 16, contrast-induced nephropathy 12, hypotension 8, drug-induced 28, miscellaneous 19). (E) Urinary EGF in AKI patients who required RRT and those who did not. * p < 0.05, ** p < 0.01, *** p < 0.001. ns, not significant. Abbreviation: KDIGO, Kidney Disease Improving Global Outcomes.

Figure 2

Correlation of urinary EGF with renal function and tubular damage markers. Correlations between levels of urinary EGF and NAG (A), α1-MG (B), β2-MG (C), urinary protein (D), L-FABP (E), NGAL (F), KIM-1 (G), serum creatinine (H), eGFR (I), hemoglobin (J), and serum EGF (K). Data from patients with renal AKI (n = 83) were used.

Figure 3

Change in urinary EGF over time in AKI patients. (A): Changes in serum creatinine, urinary volume, and NAG in a patient with drug-induced AKI. HD, hemodialysis. (B–E): Changes in serum creatinine and urinary EGF levels in patients with AKI of various causes, including sepsis-associated AKI (B), AKI after cardiac surgery (C), drug-induced nephropathy (D), and drug-induced AKI with progression to ESRD (E). HD, hemodialysis.

Figure 4

Urinary EGF in living-donor kidney transplantation patients. Serum creatinine (A), eGFR (B), serum EGF (C) levels, urinary EGF (D), and the urinary EGF/Cr ratio (E) in living-donor kidney transplantation patients after unilateral nephrectomy.