Real-time urinary electrolyte monitoring after furosemide administration in surgical ICU patients with normal renal function

Our study shows that intravenous administration of furosemide, even at low doses, in patients with relatively normal renal function, induces an immediate subverting of both normal urinary excretion rate and concentration of main electrolytes, which commences very rapidly, and may have subsequent long-term effects as an additive result of sequential administrations.

As a first alteration, in parallel with the rapid increase in urinary output, urinary [Na⁺] constantly increased up to a value close to plasma [Na⁺] (about 142 mEq/L, as average). Notably, such increase did not appear related to baseline urinary [Na⁺] before administration (ranging from 5.0 to 166 mEq/L). Few studies have previously analyzed the time course of urinary [Na⁺] after furosemide administration, being limited to the cumulative natriuresis (over a 24-h period), or the average urinary [Na⁺] over a longer time [2, 19, 20]. In these investigations, urinary [Na⁺] appeared lower than that observed in our study (120–125 mEq/L), but similar, as average, to that measured over the 8-h period, as the possible dilution of the early peaked urinary [Na⁺] with its following reduction. Overall, the urinary [Na⁺] time profile highlights the action of loop-diuretics within the nephron. By inhibiting the cotransport NKCC2 of the Henle’s loop, which generates the hyperosmolar gradient of medullary interstitium [21], furosemide switches off acutely such generation, equilibrating the interstitial osmolality with that of plasma of the peri-tubular capillaries. Therefore, pre-urine arriving to the distal tubules after Henle’s loop inhibition equilibrates with the medullary interstitial space, appearing similar to that of plasma.

Patients with higher values of CVP or FeNa⁺ showed a greater increment in FeNa⁺ after furosemide as compared to those with lower values. Moreover, CVP was higher in patients presenting a slower decrease in urinary [Na⁺] over time (longer \( \tau {\text{Na}}^{ + }_{\text{U}} \)), as compared to patients with a shorter \( \tau {\text{Na}}^{ + }_{\text{U}} \). Expansion of intravascular and right atrial volume have been consistently associated with the release into circulation of both atrial (ANP) and brain natriuretic (BNP) peptides, as a consequence of myocardial stretch [22]. ANP/BNP are thought to promote natriuresis by inhibiting Na⁺ reabsorption in the medullary collecting tubules [23], as well as in the proximal tubule [24, 25]. Although we did not directly measure serum ANP/BNP, we may speculate that the acute resetting of the cotransport NKCC2-dependent hyperosmolality of the Henle’s loop unveils the Na⁺-excretive ANP/BNP-related state characterizing both the proximal and the medullary collecting tubules, especially in patients with greater blood volume expansion.

In parallel with the slow decrease in urinary [Cl⁻] and the urinary [Na⁺]–[Cl⁻] dissociation, we observed a late progressive increase in urinary [NH₄ ⁺]. Renal ammonia production predominantly derives from glutamine metabolism in proximal tubular cells [26, 27]. Moreover, pre-urinary NH₄ ⁺ competes with K⁺ for the cotransport NKCC2, which is responsible for NH₄ ⁺ reabsorption, and NH₃/NH₄ ⁺ recycling within the interstitial medulla [28]. It is conceivable that the late increase in urinary [NH₄ ⁺] may be related to an increased aldosterone synthesis and release, enhancing the activity of the luminal H⁺-ATPase of type A intercalated cells [29], thus increasing the acidification of urine and the amount of NH₃ transformed into NH₄ ⁺ and trapped into the lumen [28, 30].

In the subgroup of patients receiving multiple administrations, we observed the development, in about 22 h, of mild metabolic alkalosis. Several studies have investigated loop-diuretics-induced metabolic alkalosis, focusing on its maintenance and recovery [31, 32], whereas few have investigated its generation. Traditionally, the generation of diuretic-induced metabolic alkalosis is considered as related to the contraction of extracellular fluid volume and the consequent increase in HCO₃ ⁻ concentration [33]. In contrast, recent studies have clearly pointed out the crucial role of Cl⁻ depletion, as opposed to volume depletion, as the main mechanism maintaining diuretic-induced metabolic alkalosis [32]. According to the Stewart’s approach to acid–base equilibrium, metabolic alkalosis is determined either by a reduced plasma concentration of non-volatile weak acids or by an increased plasma SID [34]. In our study, this alteration appeared associated with an increased plasma SID, due to a reduction in plasma [Cl⁻] [35]. During the 8-h period, median urinary [Cl⁻] significantly increased as compared to baseline, and as compared to baseline plasma [Cl⁻], mainly due to the first 3-h period, in which we observed an early peaked urinary [Cl⁻], and a slower decrement, as compared to urinary [Na⁺] time course. Similarly, in patients receiving multiple doses, median urinary [Cl⁻] tended to be higher than baseline plasma [Cl⁻], likely resulting from the cumulative effect of repetitive administrations, which rapidly increase urinary [Cl⁻].

Which are the mechanisms underlying the higher urinary [Cl⁻] excretion rate, as dissociated from [Na⁺], as the key factor generating hypochloremic metabolic alkalosis? First, the acute “switching-off” of the Henle’s loop unveils the quality of the pre-urine originating at the end of the proximal tubule, which may acutely reach the end of the nephron as unmodified. Along the proximal tubule, luminal [Cl⁻] increases to levels higher than plasma [Cl⁻] because of a different Cl⁻ permeability of the luminal membrane, whereas [Na⁺] remains constant [36]. Second, the slow decrement in urinary [Cl⁻], resulting in an increased urinary [Na⁺]–[Cl⁻] difference, may be due to both a secondary increased activity of aldosterone, promoting a Cl⁻-independent cortical Na⁺ reabsorption, and a reduced activity of the luminal Cl⁻/HCO₃ ⁻ exchanger pendrin, mediating Cl⁻ reabsorption and HCO₃ ⁻ secretion in type B cortical intercalated cells [37, 38]. We may hypothesize that the long-term effects of furosemide depend on its acute and immediate inhibition on Henle’s loop, unveiling the activity of nephron proximal tubules, which, as an additive effect of sequential administrations, is responsible of the long-term effects observed.

Our study has certain limitations. First, the sample size included is limited, thereby preventing us to fully investigate the possible pathophysiologic mechanisms underlying the urinary electrolyte alterations observed. Second, due to the retrospective and observational nature of the study, we cannot exclude the effects of possible confounding factors, which we were not able to control. Nonetheless, the consistency of the urinary data observed supports the solidity and the biological plausibility of the findings observed. Third, since plasma creatinine is clinically assessed once daily, GFR was estimated, and not directly calculated, therefore partially limiting the accuracy of electrolyte Fe calculations. Finally, no direct data were obtained on the activation of either ANP/BNP or the renin–angiotensin–aldosterone system in parallel with furosemide administration.

Our findings may have also some clinical implications, which warrant further verifications. First, the renal response to furosemide observed in patients with normal renal function provides a pathophysiological rationale for the furosemide stress test to early detect AKI [5], especially when the injury deemed responsible for renal failure is located at the proximal tubular level [39]. Similarly, the acute response observed after furosemide may unveil patient Na⁺-retaining or Na⁺-excretive state independent of Henle’s loop activity, thereby helping in tailoring patient hemodynamic management. The late increase in urinary NH₄ ⁺ potentially associated with an aldosterone-induced increase in H⁺-ATPase activity may suggest an increased renal O₂ consumption following furosemide, in contrast to previous findings [14, 40], which may warn about the use of furosemide in clinical condition at risk of AKI. Finally, our findings highlight the importance of the increased urinary [Cl⁻] excretion rate as the key mechanism generating diuretic-induced metabolic alkalosis. A real-time urinary electrolyte monitoring may represent a potential novel tool to elucidate the specific effects of loop-diuretics in ICU patients, while clarifying its variable efficacy and helping in better tailoring patient hemodynamics therapy.