Effect of 3% saline and furosemide on biomarkers of kidney injury and renal tubular function and GFR in healthy subjects - A randomized controlled trial

Abstract

Background: Chloride is speculated to have nephrotoxic properties. In healthy subjects we tested the hypothesis that acute chloride loading with 3% saline would induce kidney injury, which could be prevented with the loop-diuretic furosemide. Methods: The study was designed as a randomized, placebo-controlled, crossover study. Subjects were given 3% saline accompanied by either placebo or furosemide. Before, during and after infusion of 3% saline we measured glomerular filtration rate (GFR), fractional excretion of sodium (FENa), urinary chloride excretion (u-Cl), urinary excretions of aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaCγ), neutrophil gelatinase-associated lipocalin (u-NGAL) and kidney injury molecule-1 (u-KIM-1) as marker of kidney injury and vasoactive hormones: renin (PRC), angiotensin II (p-AngII), aldosterone (p-Aldo) and arginine vasopressin (p-AVP). Four days prior to each of the two examinations subjects were given a standardized fluid and diet intake. Results: After 3% saline infusion u-NGAL and KIM-1 excretion increased slightly (u-NGAL: 17 ± 24 during placebo vs. -7 ± 23 ng/min during furosemide, p = 0.039, u-KIM-1: 0.21 ± 0.23 vs - 0.06 ± 0.14 ng/ml, p < 0.001). The increase in u-NGAL was absent when furosemide was given simultaneously, and the responses in u-NGAL were not significantly different from placebo control. Furosemide changed responses in u-KIM-1 where a delayed increase was observed. GFR was increased by 3% saline but decreased when furosemide accompanied the infusion. U-Na, FENa, u-Cl, and u-osmolality increased in response to saline, and the increase was markedly pronounced when furosemide was added. FEK decreased slightly during 3% saline infusion, but simultaneously furosemide increased FEK. U-AQP2 increased after 3% saline and placebo, and the response was further increased by furosemide. U-ENaCγ decreased to the same extent after 3% saline infusion in the two groups. 3% saline significantly reduced PRC, p-AngII and p-Aldo, and responses were attenuated by furosemide. p-AVP was increased by 3% saline, with a larger increase during furosemide. Conclusion: This study shows minor increases in markers of kidney injury after 3% saline infusion Furosemide abolished the increase in NGAL and postponed the increase in u-KIM-1. The clinical importance of these findings needs further investigation.