Urinary Epidermal Growth Factor Reflects Distal Tubular Mass and is Associated with Hypertension, Serum Magnesium, and Kidney Outcomes.

Abstract

Background: Epidermal growth factor is expressed in the distal tubule and secreted in urine (uEGF) after cleavage of membrane-bound pro-EGF. Lower uEGF is associated with kidney disease progression. EGF also plays a role in the regulation of serum magnesium and blood pressure, but whether uEGF is associated with these parameters is unknown. We hypothesized that uEGF is a distal tubule marker associated with serum magnesium, blood pressure, and kidney outcomes.

Methods: We first used a cohort of kidney donors (n = 20) and measured uEGF to analyze the association with tubular mass and pro-EGF in urinary extracellular vesicles as proxy for tubular expression. Next, we measured uEGF in a population-based cohort (n = 2382) to investigate the associations with serum magnesium, hypertension, and kidney outcomes (incident eGFR < 60 or < 45 ml/min/1.73 m2, 40% loss of eGFR or kidney failure).

Results: Kidney donation decreased eGFR from 86 to 54 ml/min/1.73 m2 (36% reduction, 95%CI 31-42%), uEGF from 28 to 14 µg/24h (49% reduction, 95%CI 42-55%) and pro-EFG by 29% (95%CI 12-45%). The decrease in uEGF correlated with the decrease in kidney volume. In the population cohort, lower uEGF was significantly associated with hypertension and lower serum magnesium. The association between uEGF and serum magnesium was stronger in participants with lower eGFR, hypertension and diuretic use. Lower uEGF at baseline was also associated with worse kidney outcomes and this association was stronger for normotensive participants.

Conclusions: uEGF is a marker of distal tubular mass that is not only associated with kidney disease progression, but also with serum magnesium and blood pressure. Future studies should address if normotensive people with low urinary EGF excretion represent a group that may benefit from kidney-protective treatment.