The furosemide stress test and computational modeling identify renal damage sites associated with predisposition to acute kidney injury in rats

Transl Res. 2021 May:231:76-91. doi: 10.1016/j.trsl.2020.11.011. Epub 2020 Nov 27.


Acute 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / pathology*
  • Animals
  • Anti-Bacterial Agents / toxicity
  • Antineoplastic Agents / toxicity
  • Cisplatin / toxicity
  • Computer Simulation
  • Furosemide / pharmacology*
  • Gentamicins / toxicity
  • Kidney / drug effects
  • Kidney / pathology
  • Male
  • Rats


  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • Gentamicins
  • Furosemide
  • Cisplatin