KDIGO Clinical Practice Guideline for Acute Kidney Injury
Recommendations and Rationale

• 3.4.1:We recommend not using diuretics to prevent AKI. (1B)
• 3.4.2:We suggest not using diuretics to treat AKI, except in the management of volume overload. (2C)

Rationale

Loop diuretics have several effects that may protect against AKI. They may decrease oxygen consumption in the loop of Henle by inhibiting sodium transport, thus potentially lessening ischemic injury. Loop diuretics act at the luminal surface of the thick ascending limb of the loop of Henle and inhibit the Na-K-2Cl cotransporter,^184,185 resulting in a loss of the high medullary osmolality and decreased ability to reabsorb water. Inhibition of active sodium transport also reduces renal tubular oxygen consumption, potentially decreasing ischemic damage of the most vulnerable outer medullary tubular segments;¹⁸³ therefore, furosemide might protect kidneys against ischemic injury.¹⁸⁶ Furosemide also might hasten recovery of AKI by washing out necrotic debris blocking tubules, and by inhibiting prostaglandin dehydrogenase, which reduces renovascular resistance and increases renal blood flow.^186,187 Based on these properties, loop diuretics might be expected to prevent or ameliorate AKI. However, there are only minimal data to support this theory, and there is some evidence of harm associated with loop diuretic use to prevent or treat AKI.^188-191 Furosemide is the most commonly prescribed diuretic in the acute-care setting,^183-185 and a number of RCTs have tested whether furosemide is beneficial for prevention or treatment of AKI. Specifically, prophylactic furosemide was found to be ineffective or harmful when used to prevent AKI after cardiac surgery,^189,190 and to increase the risk of AKI when given to prevent CI-AKI.¹⁹¹ Epidemiologic data have suggested that the use of loop diuretics may increase mortality in patients with critical illness and AKI,¹⁸¹ along with conflicting data that suggest no harm in AKI.¹⁸² Finally, furosemide therapy was also ineffective and possibly harmful when used to treat AKI.^188,192

There is no evidence that the use of diuretics reduces the incidence or severity of AKI. Ho et al.^192,193 conducted two comprehensive systematic reviews on the use of the loop diuretic frusemide (furosemide) to prevent or treat AKI. Furosemide had no significant effect on in-hospital mortality, risk for requiring RRT, number of dialysis sessions, or even the proportion of patients with persistent oliguria. Results from the most recent review¹⁹³ are shown in Figure 9 and Figure 10. The primary prevention studies included patients who underwent cardiac surgery,¹⁸⁹ coronary angiography,¹⁹¹ and major general or vascular surgery.¹⁹⁴ In two of these studies, all participants had mild pre-existing renal impairment. Two of the three studies reported mortality in patients randomized to furosemide (n = 103) vs. placebo (n = 99), with a pooled RR of 2.67 (95% CI 0.75–7.25; P = 0.15). All three studies reported RRT incidence in patients randomized to furosemide (n = 128) vs. placebo (n = 127), with a pooled RR of 4.08 (95% CI 0.46–35.96; P = 0.21). Thus, subanalysis to separate primary and secondary prevention trials did not alter the conclusion that, within the sample size limitations of this study, furosemide is not effective for the prevention of AKI.

The systematic review and meta-analysis by Ho and Power¹⁹³ also included six studies that used furosemide to treat AKI, with doses ranging from 600 to 3400 mg/d (Figure 9 and Figure 10).¹⁹² No significant reduction was found for in-hospital mortality or for RRT requirement. The largest single study of furosemide for treating AKI was conducted by Cantarovich et al.,¹⁸⁸ which included 338 patients with AKI requiring dialysis. Patients were randomly assigned to the administration of either furosemide (25 mg/ kg/d i.v. or 35 mg/kg/d orally) or placebo. Although time to reach 2 l/d of diuresis was shorter with furosemide (5.7 days) than placebo (7.8 days, P = 0.004), there was no difference in survival and number of dialysis sessions. At present, the current evidence does not suggest that furosemide can reduce mortality in patients with AKI.

Furosemide may, however, be useful in achieving fluid balance to facilitate mechanical ventilation according to the lung-protective ventilation strategy in hemodynamically

Figure 9 | Effect of furosemide vs. control on all-cause mortality. Reprinted from Ho KM, Power BM. Benefits and risks of furosemide in acute kidney injury. Anaesthesia 2010; 65: 283–293 with permission from John Wiley and Sons¹⁹³; accessed http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2044.2009.06228.x/full

Figure 10 | Effect of furosemide vs. control on need for RRT. Reprinted from Ho KM, Power BM. Benefits and risks of furosemide in acute kidney injury. Anaesthesia 2010; 65: 283–293 with permission from John Wiley and Sons¹⁹³; accessed http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2044.2009.06228.x/full

stable patients with acute lung injury. On the other hand, the literature also suggests that high-dose furosemide ( > 1 g/d) may cause ototoxicity. In the first meta-analysis by Ho and Sheridan,¹⁹² high doses of furosemide (range 1–3.4 g/d) caused deafness or tinnitus more frequently than the control (RR 3.97; 95% CI 1.00–15.78; P = 0.05). When administered as continuous infusion a dose of 0.5 mg/kg/ hour was not associated with ototoxicity.¹⁹⁵ Taken together with several small studies showing that the prophylactic use of diuretics to prevent AKI actually increased AKI incidence, these data raise significant concerns regarding use of loop diuretics to prevent or treat AKI in any setting. We similarly conclude that there is no evidence that the use of loop diuretics reduces the severity of AKI, or improves outcomes in this syndrome. Although the use of loop diuretics in early or established AKI facilitates management of fluid balance, hyperkalemia, and hypercalcemia, and is indicated for these clinical purposes, any putative role in the prevention or amelioration of AKI course is unproven.

Two recent studies have investigated whether the administration of furosemide to patients treated with CVVH could be associated with a more rapid discontinuation of the dialysis therapy. van der Voort et al., observed, as expected, an increased urinary volume and sodium excretion, but this intervention did not lead to a shorter duration of renal failure or more frequent renal recovery.¹⁹⁵ The second study by Uchino et al.,¹⁹⁶ analyzed data from the B.E.S.T. kidney and found that, from a total of 529 critically ill patients who survived during CRRT, 313 patients were removed successfully from CRRT while 216 patients needed ‘‘repeat RRT’’ after temporary discontinuation. Urine output (during the 24 hours before stopping CRRT) was identified as a significant predictor of successful cessation, but the predictive ability of urine output was negatively affected by the use of diuretics. Thus, a beneficial role for loop diuretics in facilitating discontinuation of RRT in AKI is not evident.