Association between diuretics and successful discontinuation of continuous renal replacement therapy in critically ill patients with acute kidney injury

Acute kidney injury (AKI) is a major morbidity in critically ill patients and is associated with high mortality [1]. The overall incidence of AKI in critically ill patients is 6–20% and varies depending on the patient’s medical status [2‐4]. Major complications of AKI such as volume overload, severe metabolic acidosis or hyperkalemia, and overt uremic signs are well-known indications for renal replacement therapy (RRT) [5, 6]. Continuous renal replacement therapy (CRRT) is the preferred treatment option for critically ill patients with AKI requiring RRT due to better hemodynamic tolerance and steadier solute control [7‐9].

Despite aggressive application of CRRT in critically-ill patients with AKI over the last decade, evidence-based guidelines for optimal timing and adequate methods for CRRT discontinuation are lacking [10]. Assessment of AKI and predicting the prognosis of renal recovery after discontinuing CRRT remain challenging. Several studies have reported lower sequential organ failure assessment scores, fewer prior CRRT cycles, younger age, and higher urine output (UO) after discontinuing CRRT as predictors of renal recovery after AKI requiring CRRT [11‐13].

UO is partly manageable by appropriate administration of diuretics in patients with AKI with volume overload [14]. A recent study reported that furosemide was not associated with more frequent renal recovery despite increasing urine volume [15], whereas a previous meta-analysis showed that loop diuretics were associated with shorter duration of RRT [16]. Despite great feasibility and possible cost-effectiveness, contradictory studies on the clinical effectiveness of diuretics after CRRT have prevented a consensus on diuretic therapy, even in patients with AKI at risk of volume overload when CRRT is discontinued. We hypothesized that diuretics may facilitate successful discontinuation of CRRT. In this study, the effects of diuretics on the clinical course of critically ill patients with AKI were investigated, focusing on UO and recovery of renal function following CRRT.

In this study, we demonstrated that starting diuretics at the cessation of CRRT contributes to successful discontinuation of CRRT by reducing volume overload risk in critically ill patients with AKI. Patients treated with diuretics following CRRT had a greater increase in UO, with tolerable elevation of sCr not only in the CRRT discontinuation group, but also in other groups. Continuous infusion of furosemide increased UO more effectively compared to other methods. High day − 1 UO, use of diuretics, and short duration of CRRT were predictors of successful discontinuation of CRRT. The cutoff values for day − 1 UO for predicting successful discontinuation of CRRT in all patients and oliguric patients in the diuretics group were 191 mL/day and 125 mL/day, respectively.

Most patients who survive AKI requiring CRRT are reported to recover from oliguria and uremic complications after 12–13 days of RRT [20, 21]. Insufficient urine volume is a common problem in critically ill patients with AKI when discontinuation of CRRT is under consideration. Re-initiation of CRRT is required in a substantial portion of patients with incomplete renal recovery [22]. Previous studies have reported that furosemide does not improve renal outcome after RRT [11, 15]. Uchino et al. reported an association between diuretic therapy within 24 h before stopping CRRT and successful discontinuation of CRRT [12]. However, no previous reports have focused on the clinical impact of diuretic therapy initiated after stopping CRRT on successful discontinuation of CRRT and optimal indications or appropriate administration methods for diuretics following CRRT, even though a positive fluid balance is associated with delayed recovery of kidney function and increased mortality [23, 24]. Our large cohort study demonstrated that diuretics were significantly associated with successful discontinuation of CRRT, and continuous infusion of furosemide was more effective at increasing UO than other methods of administering diuretics. Diuretic therapy was even effective in oliguric patients with UO greater than 125 mL/day before stopping CRRT.

There is still no consensus on the management of patients with AKI discontinuing CRRT. When to discontinue CRRT in patients with AKI depends on various factors [25, 26]. A previous study reported that the possibility of successful CRRT discontinuation is higher in patients with a relatively greater baseline UO or no history of chronic kidney disease [12]. A high 6-h UO immediately before CRRT initiation is associated with lower mortality [27]. Similarly, patients in the CRRT discontinuation group had higher UO compared to patients resuming RRT at both initiation and cessation of CRRT in our study. The HD initiation group had higher sCr and had a greater proportion of hypertensive patients compared with other groups. On the other hand, patients with diuretics in the HD initiation group also had increased UO. Therefore, diuretics may reduce the risk of volume overload regardless of re-initiation of RRT.

In our study, patients treated with diuretics had significantly greater increase in UO, although sCr elevation also occurred. The clinical impact of diuretics on the outcome of AKI has been evaluated in several studies. A previous systematic review reported that furosemide has no significant effect on renal outcome, including RRT and in-hospital mortality [28]. One randomized placebo-controlled study showed that furosemide significantly increased urine volume but did not facilitate post-RRT renal recovery [15]. The best method for evaluation of actual renal function during the peri-RRT period remains unclear [29], although continuous solute clearance by CRRT is known to stabilize sCr after 48 h [30]. Other observational studies have reported UO as the most significant predictor of successful termination of CRRT [11, 12]. Furthermore, UO during the first 2 h after a furosemide stress test shows predictive value for prognosis of AKI [31] and creatinine clearance > 30 mL/h assessed by 6-h urine collection has been suggested as a criterion for discontinuing RRT [32]. Therefore, both our study and several previous reports support the clinical importance of UO as a better indicator of actual renal function than sCr in patients with AKI who discontinued CRRT.

Regarding the methods of administering diuretics, there has been only one study comparing torasemide and furosemide following CRRT in patients with AKI after cardiac surgery. Both loop diuretics were effective for diuresis, while torasemide showed better dose response effects than furosemide [33]. Our study analyzed more diverse administration methods, including combination treatment, and showed that continuous infusion of furosemide was the most effective in increasing UO. These results suggest that continuous infusion of furosemide would be beneficial for patients with AKI discontinuing CRRT, especially those who are at risk of volume overload, because fluid overload is a major complication of AKI [34]. High UO induced by furosemide might protect the injured kidneys from necrotic debris and sludge blocking the tubular lumen through increased tubular flow [35].

Multivariable regression analysis revealed greater UO on day − 1, shorter duration of CRRT, and use of diuretics as predictive factors for successful discontinuation of CRRT. UO before stopping CRRT has previously been reported as a significant predictive factor for successful discontinuation of RRT [11‐13, 27]. The 2-h UO after a furosemide stress test has been suggested as a novel prognostic marker for RRT in AKI compared with several urinary biomarkers [36]. Shorter duration of CRRT has also been reported as a predictive factor for renal recovery in previous studies [11‐13]. Despite the utility of RRT in severe AKI, timely discontinuation of RRT needs to be attempted as RRT itself might delay renal recovery through hemodynamic instability and catheter-related infection [37]. Although diuretics were expected to be beneficial in patients with AKI discontinuing CRRT due to increased UO, the evidence is lacking. Our finding that diuretics are a predictive factor for successful discontinuation of CRRT is clinically meaningful because most previous studies have failed to prove a beneficial effect of diuretics following CRRT, except for one small study by Heise [11‐13, 15]. In addition, 191 mL/day of UO before stopping CRRT was found to be the optimal cutoff value for predicting successful discontinuation of CRRT in our study, while a previous study reported a UO cutoff value of 436 mL/day [12]. Furthermore, we found that 125 mL/day UO on day − 1 was the optimal cutoff value for predicting successful discontinuation of CRRT by diuretic therapy in oliguric patients. The urine volume cutoff for diuretic therapy in the CRRT discontinuation group was smaller in our study compared to the previous report [12]. The difference between their report and our study in the prediction of urine volume for successful discontinuation of CRRT may be attributed to the difference in the study population and the time period of successful discontinuation of CRRT: 7 days in their study versus 3 days in our study. We believe that differences in regional or institutional policies regarding operation protocols, restart indications, or the insurance reimbursement system for CRRT may also contribute to the difference in urine volume cutoff.

Several limitations in our study deserve consideration. First, the study was a retrospective cohort study of both medical and surgical ICU patients. Multivariable analyses adjusted with patient comorbidities were conducted to minimize the impact. In particular, blood pressure and vasopressor requirements were also adjusted. Only a few small studies have investigated the predictive factors for restoration of renal function after discontinuation of CCRT [11‐13]. Our study showed the clinical potential of diuretics in patients with AKI discontinuing CRRT and suggested clinical significance based on a large cohort. However, the degree of diuresis before attempting CRRT discontinuation was still a confounding factor affecting both initiation and maintenance of diuretic therapy in our cohort. To overcome this inevitable critical limitation, we performed a multivariable analysis including UO on the day before CRRT discontinuation, and diuretic therapy was identified as a significant predictor of successful discontinuation of CRRT. A well-designed, randomized, controlled trial is required to further clarify the clinical effectiveness of diuretics. Second, long-term outcome was not analyzed. Since various confounding events can occur in critically ill patients with AKI and the main purpose of this study was to investigate the clinical effectiveness of diuretics for successful discontinuation of CRRT, we focused on the short-term renal outcome up to 3 days after stopping CRRT and briefly investigated short-term overall outcomes. Patients who died within 3 days following discontinuation of CRRT were excluded from the analyses to reduce confounding factors for evaluating the clinical usefulness of diuretics in patients with AKI who are discontinuing CRRT. Third, in previous studies, fractional excretion of urea and furosemide stress test were studied as predictors of AKI prognosis [31, 38] and creatinine clearance assessed by 6-h urine collection was suggested as a predictor of successful CRRT discontinuation [32]. However, these parameters could not be included in our study because of the retrospective study design.

In conclusion, diuretic therapy following CRRT increased UO significantly with tolerable elevation of sCr. Day − 1 UO, use of diuretics, and duration of CRRT were significantly related to successful CRRT discontinuation. Aggressive use of diuretics seemed more helpful in oliguric patients whose UO was ≥ 125 mL/day on the day before stopping CRRT. Our study supports the clinical usefulness of diuretic therapy in critically ill patients with AKI by inducing favorable fluid balance, especially those who are at risk of volume overload after discontinuation of CRRT.