The furosemide stress test: current use and future potential

Figures & data

Figure 1. Schematic diagram showing the 12 transmembrane domain Na-K-2Cl (NKCC) transporter in the thick ascending limb of the loop of Henle. Loop diuretics bind to the chloride-binding site (portions of the transmembrane domains 11 and 12) resulting in obstruction and subsequent inhibition of the NKCC-2 transporter domains 2, 4, and 7 transport Na, K, and/or Cl.

Table 1. Altered bioactions of furosemide in critically ill patients with acute kidney injury.

Target abnormality	Mechanism	References
Hypoalbuminemia	Impaired furosemide delivery to nephron	23,24
Loss of epithelial cell polarity	Redistribution of Na/K + ATPase, impairing secondary active transport of organic acid.	25
Oliguria	Toxic plasma levels of furosemide	26
Uremic organic acids accumulation	Competiton with furosemide at the OAT1/OAT3 transporter site	27,28
Severe metabolic acidosis	Competiton with furosemide at the OAT1/OAT3 transporter site	27,28
Elevated OAT1/OAT3 (+/−OAT4) transporter secretion in urine	Tubular damage and destruction	29
Vasopressin administration	Increase expression of NKCC2 transporter and promote insertion into TAL of loop of Henle	18,30
Cephalosporin administration	Competition with furosemide at the OAT1/OAT3 transporter site	27,28

Table 2. Summary of furosemide challenge tests.

Study population	Study type	N,	Definition of FST used	Clinical Outcome	Ref
Adult patients with early AKI (stage I)	Prospective	54 92	IV furosemide 1 mg/kg in diuretic naïve patients and 1.5 mg/kg in non-naïve patients.	UOP <200 ml 2 h post furosemide predicts severe stage 3 AKI	6,31
Patients without AKI, FWC between +15 and −15 ml/h, falling UOP, fluid excess	Prospective	21	IV furosemide 80–160mg	UOP >200/h, Urine Osm from 600 mOsm/l–400 mOsm/l, no change in FWC and subsequent development of AKI	32
Pediatric cardiac surgery patients without AKI	Retrospective	568	Postoperative IV furosemide (0.8–1.2 mg/kg per dose between 8 and 24 h after cardiac surgery	Lack of furosemide responsiveness defined a priori as UOP < 1 mL/kg/h after furosemide predicted subsequent development of AKI	33
Pediatric cardiac surgery patients without AKI	Retrospective	166	IV furosemide (median dose of 0.9 mg/kg) administered 14 hours post cardiac surgery	The 2- and 6-hour urine flow rates were significantly lower in patients in whom AKI developed	34
Pediatric cardiac surgery patients without AKI	Retrospective	99	Postoperative IV furosemide (mean dose 1.1 +/− 0.3 mg/kg) with median of 7.7 hours after cardiac surgery	Lack of furosemide responsiveness defined a priori as 6-h UOP less than or equal to 5.6mL/kg predicted fluid overload and prolonged peritoneal dialysis	35
Non AKI and early AKI patients	Subanalysis of Prospective Observational study	95	Variable furosemide dose used. Furosemide responsiveness (FR) was defined as total UOP in 2 h (mL) divided by the dose of bolus furosemide (mg) administered.	FR could predict AKI progression in patients with high plasma NGAL levels (>142 ng/mL), while few patients with low plasma NGAL levels exhibited AKI progression	36
All stages of AKI	Prospective multicenter pilot study	162	Intravenous furosemide (1 mg/kg in furosemide-naive patients or 1.5 mg/kg in previous furosemide users). FST-nonresponsive patients (urine output less than 200 mL in 2 h) were randomized to early (initiation within 6 h) or standard (initiation by urgent indication) RRT.	AKI: timing of RRT initiation. Only 6/44 (13.6%) FST-responsive patients ultimately received RRT while 47/60 (78.3%) nonresponders randomized to standard RRT either received RRT or died (p < 0.001).	37
Patients with severe AKI on CVVH	Prospective single center randomized placebo-controlled study	71	After cessation of CVVH the first 4 h of urine was collected for measuring creatinine clearance. Patients were subsequently randomized to furosemide (0.5 mg/kg/h) or placebo by continuous infusion.	Furosemide by continuous infusion in the recovery phase of hemofiltration-dependent AKI did increase urinary volume and sodium excretion but did not lead to a shorter duration of renal failure or more frequent renal recovery.	38
Patients undergoing DDKT	Retrospective	200	Furosemide (one time intraoperative dose of 100mg) can predict delayed graft function post deceased donor kidney transplantation (DDKT). Furosemide can predict delayed graft function post DDKT transplantation	The FST predicted DGF with an area-under-the curve of 0.85 at an optimal urinary output cutoff of <600 mL at 6 h.	39
Patients undergoing DDKT	Prospective	59	Single dose of intravenous furosemide, 1.5 mg/kg at 3 h after allograft reperfusion. Urine volume recorded hourly after FST until 6 h. FST was compared to urine NGAL.	The 4-h urine volume less than 350 mL (FST non-responsive) was the best cutoff value in predicting DGF with 87.5% sensitivity, 82.9% specificity, and 82.5% accuracy. The FST is a more accurate biomarker than urine NGAL	40

FST: furosemide Stress test; KT: kidney transplantion; DDKT: deceased donor kidney transplantation; AKI: acute kidney inury; RRT: renal replacement therapy; DGF: delayed graft function; UOP: urinary output; FWC: free water clearance.

Figure 2. Testing of renal tubular integrity with the furosemide stress test in early AKI. In order for a brisk urinary response to furosemide there are four components that must be achieved. 1. Furosemide enters the blood stream and then must bind to albumin. 2. Active secretion by proximal tubular from the basolateral membrane to the lumen by the hOAT system. 3.Transport of the furosemide in the lumen dissolved in the glomerular filtrate transported to the TAL and binding to the Na- K-2Cl apical transporter. 4. Resultant diuresis.

Table 3. Proposed utilization of urinary furosemide and urinary sodium with decreased urine response to FST.

	Urinary furosemide (FEM2)
	FEM high	FEM low
Urine Sodium
High Sodium	Physiology: Consistent preserved proximal tubular function and distal injury preventing sodium reabsorption Syndrome: This profile would be consistent with kidney injury that has a TAL or distal injury profile	Physiology: Consistent with tubular injury resulting inability to reabsorb sodium or to secrete furosemide Syndrome: This profile would be consistent with acute tubular injury and acute tubular necrosis
Low Sodium	Physiology: Demonstrates sufficient oxygen transport to the kidney to enable effective bi-directional proximal tubular function as evidenced by sodium reabsorption and furosemide secretion Syndromes that would show this pathophysiology: decreased effective circulating volume, congestive heart failure, cardiorenal syndrome, central venous congestion	Physiology: Demonstrates sufficient oxygen transport to the kidney to maintain sodium reabsorption but inability to secrete furosemide. Syndrome: This physiology would be consistent with a profound hypo-albuminemia state and may be indicative of the threshold wherein albumin replacement therapy is indicated

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