• Alfredo G Casanova, Isabel Fuentes-Calvo, María T Hernández-Sánchez, Miguel Quintero, Paula Toral, María T Caballero, Carlos Martínez-Salgado, Ana I Morales, Anita T Layton, Nélida Eleno, and Francisco J López-Hernández.
• Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Soria, Spain; Department of Physiology and Pharmacology, University of Salamanca (USAL), Salamanca, Spain; Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain, National Network for Kidney Research REDINREN, RD016/0009/0025, Instituto de Salud Carlos III, Madrid, Spain.
• Transl Res. 2021 May 1; 231: 76-91.

AbstractAcute kidney injury (AKI) diagnosis relies on plasma creatinine concentration (Crpl), a relatively insensitive, surrogate biomarker of glomerular filtration rate that increases only after significant damage befalls. However, damage in different renal structures may occur without increments in Crpl, a condition known as subclinical AKI. Thus, detection of alterations in other aspects of renal function different from glomerular filtration rate must be included in an integral diagnosis of AKI. With this aim, we adapted to and validated in rats (for preclinical research) the furosemide stress test (FST), a tubular function test hitherto performed only in humans. We also tested its sensitivity in detecting subclinical tubular alterations. In particular, we predisposed rats to AKI with 3 mg/kg cisplatin and subsequently subjected them to a triggering insult (ie, 50 mg/kg/d gentamicin for 6 days) that had no effect on nonpredisposed animals but caused an overt AKI in predisposed rats. The FST was performed immediately before adding the triggering insult. Predisposed animals showed a reduced response to the FST (namely, reduced furosemide-induced diuresis and K+ excretion), whereas nonpredisposed animals showed no alteration, compared to the controls. Computational modeling of epithelial transport of solutes and water along the nephrons applied to experimental data suggested that proximal tubule transport was only minimally reduced, the sodium-chloride symporter was upregulated by 50%, and the renal outer medullary potassium channel was downregulated by 85% in predisposed animals. In conclusion, serial coupling of the FST and computational modeling may be used to detect and localize subclinical tubular alterations.Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.

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