Abstract: TH-PO282

A Furosemide Excretion Stress Test (FEST) Predicts AKI Progression and Mortality after Sepsis

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Street, Jonathan, NIDDK, Bethesda, Maryland, United States
  • Bellomo, Tiffany Rose, NIDDK, Bethesda, Maryland, United States
  • Koritzinsky, Erik H., NIDDK, Bethesda, Maryland, United States
  • Kojima, Hiroshi, NIDDK, Bethesda, Maryland, United States
  • Chawla, Lakhmir S., George Washington University, San Diego, California, United States
  • Yuen, Peter S.T., NIDDK, Bethesda, Maryland, United States
  • Star, Robert A., NIDDK, Bethesda, Maryland, United States
Background

The furosemide stress test (FST) measures urine production (diuresis) after a furosemide bolus. FST is a sensitive and specific predictor of a need for renal replacement therapy and mortality in the ICU. Furosemide causes a diuresis via 2 steps: 1) active secretion into the proximal tubule lumen, then 2) inhibition of thick ascending limb NKCC2. We hypothesize that tubule damage should reduce furosemide excretion (FEST) and prevent a subsequent increase in urine volume (FST). We developed FST and FEST protocols for a septic mouse model in which mortality is poorly predicted by filtration markers, and also tested the predictive performance of FEST in a human cohort.

Methods

We developed a sensitive reverse phase HPLC assay for urine furosemide. Male CD-1 mice underwent cecal ligation and puncture (CLP) to induce sepsis. 42 hrs post-CLP 1 mg/kg furosemide was given s.c. and urine was collected for the next 12 hrs to allow for intermittent urination. The mice were monitored every 8 hrs and euthanized if their clinical score exceeded the protocol threshold. Furosemide concentration was also measured in the post-furosemide challenge samples of 49 patients from the PASSKI cohort.

Results

A moderate severity of CLP injury was used; 32 mice survived to 42 hr and underwent FST/FEST, 19 mice survived 7 d. Urine production during 12 hr varied from 0.08 to 2.62 ml. Both urine production and the fraction of furosemide recovered in the urine predicted mortality [AUC ROC values of 0.92 (p<0.0001) for FST and 0.87 (p<0.001) for FEST]. In the human cohort, the fraction of furosemide recovered predicted progression to AKIN stage III and was comparable to FST [AUC ROC values of 0.864 for FST and 0.848 for FEST].

Conclusion

The furosemide excretion stress test and furosemide stress test strongly predict post-sepsis mortality in mice, allowing for early stratification by severity in future drug studies of late treatment or enhancing recovery. FEST performs comparably to FST in the human PASSKI cohort.

Funding

  • NIDDK Support