A practical approach to sequential nephron blockade in acute decompensated heart failure

CA inhibitors are among the first developed diuretics in the modern diuretic treatment, replacing mercurial diuretics in the mid-1950s. Carbonic anhydrase was discovered in the early 1930s. Later on, it was observed that patients treated with sulfanilamide, a new antimicrobial agent, developed metabolic acidosis and changes in urine output or composition (alkaline urine). It was shown that it can inhibit carbonic anhydrase, thus increasing urine output. Sulfanilamide was then used in patients with heart failure and edema, which led to a new drug development with diuretic properties: acetazolamide, a CA inhibitor [13–16]. Acetazolamide, as well as loop and thiazide diuretics, reaches tubular lumen by secretion into the proximal tubule through organic anion transporters in the basolateral membrane (OAT1 and OAT3) of the proximal tubular cells [17]. Approximately 70% of the filtered Na⁺ is reabsorbed in the proximal tubule through a variety of transporters that couple Na⁺ with other substances. The most important transporter with respect to the reabsorbed quantity of sodium is the isoform Na⁺/H⁺ exchanger located at the luminal membrane, NHE3 [15]. Na⁺ is reabsorbed from the lumen with H⁺ excretion by NHE3. H⁺ is produced intracellularly from H2CO3, which is catalyzed by carbonic anhydrase II (CAII) into HCO3^- and H⁺. HCO3^- is reabsorbed back to the bloodstream through the basolateral side of the proximal tubule and H⁺ becomes available for the exchange with Na⁺. H⁺ and HCO3^- form H2CO3 inside the tubular lumen, which then dehydrates to CO2 and H2O by the action of a second carbonic anhydrase, isoform IV (CAIV). Acetazolamide has the capacity to inhibit both CAs, and so with H⁺ no longer available for exchange with Na⁺, acetazolamide leads to enhanced natriuresis and bicarbonaturia [4]. Since almost 70% of sodium is reabsorbed in the proximal tubule, we would expect CA inhibitors to be strong diuretics, but compensatory distal sodium reabsorption and progressive bicarbonate depletion limits the diuretic efficacy with repeated use over days [4]. Additionally, potassium wasting occurs because of the increased reabsorption of sodium downstream and activation of the renin-angiotensin-aldosterone system [18]. Thus, CA inhibitors are considered to be natriuretic, kaliuretic, and bicarbonaturic [19]. This can lead to hypokalemia and hyperchloremic metabolic acidosis, the most frequent adverse events of CA inhibitors. Other potential side effects can be hypocalcemia (as most filtered calcium is reabsorbed in the proximal tubule [60%–70%]), hypomagnesemia (even if only 10%–25% of magnesium is reabsorbed proximally) and hypocitraturia with alkaline urine, which predisposes the patient to calcium phosphate kidney stones [20]. Long-term administration of acetazolamide should not be considered, because of the high risk of metabolic acidosis. However, it can be the perfect candidate in resistant edema with metabolic alkalosis secondary to other classes of diuretics, with strict monitoring for hypokalemia [17]. For many years, acetazolamide was mostly used in glaucoma, intracranial hypertension, or high-altitude disorders, but recent data from ADHF and nephrotic syndrome demonstrates its efficacy in controlling edema in association with other diuretics, especially a loop diuretic [21,22].

SGLT2i specifically block sodium and glucose reabsorption in the S1 and S2 segments of the proximal convoluted tubule, inducing glycosuria and improvement of glycemic control [23]. These agents have rapidly been incorporated into the standard of care for patients with chronic kidney disease and heart failure (with reduced and preserved ejection fraction), with or without diabetes, as they have been shown to significantly improve renal and cardiovascular outcomes [24–30]. Moreover, the most significant cardiovascular impact of SGLT2i was to reduce the hospitalizations for HF [24,26]. They seem to have many pleiotropic physiological benefits, but the mechanisms of their efficacy are incompletely understood [20,31]. As we have mentioned before, Na⁺ reabsorption in the apical membrane of the proximal tubule is coupled with glucose, amongst others. The two cotransporters are SGLT1, located in the apical membrane of the S3 segment and SGLT2, located in the apical membrane of the S1 and S2 segments of the proximal tubule. Na⁺ and glucose enter the cell at a 1:1 ratio, with a glucose concentration gradient causing exit of glucose to plasma via GLUT2 in the basolateral membrane. Also, Na⁺ is reabsorbed back to the plasma via basolateral Na⁺/K⁺ pump [23]. Sodium-glucose co-transporter 2 (SGLT2) is the major cotransporter responsible for reabsorption of 80–90% of filtered glucose, whereas only a small amount of Na⁺ is reabsorbed through SGLT2 as Na⁺ is mostly reabsorbed through NHE3 [31]. SGLT2i reduce glucose reabsorption by 30–50% causing glucosuria with osmotic diuresis. This diuretic effect is presumably responsible for the cardiorenal protective effects. Increased natriuresis was noted with several SGLT2i in both animal and human studies, especially in the first days of treatment [32]. Dapagliflozin also demonstrated increased glucosuria and natriuresis in healthy subjects and a decrease in tissue sodium levels in patients with type 2 diabetes mellitus. These drugs seem to be safer than any other diuretics, with no electrolyte or acid–base disturbances [33]. Taking everything into consideration, SGLT2i are not suitable for monotherapy for their diuretic effect, but they can be an adequate option for diuretic association, especially with loop diuretics, as it can minimize the risk of hyponatremia [34,35].

Loop diuretics are the most prescribed diuretics for management of hypervolemia. For signs and symptoms of congestion in HF, prescribing a loop diuretic is a recommendation of class I, level of evidence B [10]. They inhibit 25%–30% of sodium reabsorption through Na⁺/K⁺/2Cl’ cotransporter (NKCC) in the thick ascending loop of Henle. The intracellular Na⁺ is reclaimed to the bloodstream by the Na⁺/K⁺ ATPase from the basolateral membrane. They also inhibit the same cotransporter at the apical membrane of the macula densa, which causes renin secretion and inhibition of the tubulo-glomerular feedback with impaired concentrating ability of the nephron and significant water excretion. This is the reason why loop diuretics are considered high efficiency diuretics. They are not freely filtered through the glomerulus, because 90% of the diuretic is bound to albumin [36]. Furosemide, torsemide, and bumetanide are examples of loop diuretics. Furosemide is the most accessible and used agent of this class, even though it shows variable bioavailability (between 10%–90%) and has a short half-life compared to the other loop diuretics. It must reach a certain threshold (which varies among patients) to rapidly increase sodium and water excretion. Also increasing doses beyond a “ceiling” does not increase the diuretic efficacy. Regardless of progressive increase in doses of oral furosemide, most frequently patients require intravenous administration. In this manner, the threshold is immediately reached with a prompt diuretic effect. Furosemide has a t1/2 of 2 hours, but its effect lasts for 6 hours, because of the absorption-limited pharmacokinetic feature. This means that furosemide is slowly absorbed from the gastrointestinal tract, thus increasing the duration of furosemide in the plasma. Beyond this period, post-diuretic sodium retention occurs, which is the reason why furosemide should be administered more frequently, at least twice a day; otherwise the sodium retention can reverse the negative sodium balance. About 50% of a dose of furosemide is conjugated to glucuronic acid in the kidneys, thus the plasma half-time is prolonged in patients with renal impairment, while bumetanide and torsemide are largely metabolized by the liver [2,36]. Torsemide also has a longer half-time in patients with heart failure (6 hours) compared to furosemide (2.7 hours), with a reduced post-diuretic Na⁺ retention and a prolonged urine Na⁺ excretion, making it a better treatment option in patients with renal impairment and heart failure. It can also improve the New York Heart Association functional classification and reduce hospitalization and mortality rates [33].

In patients with heart failure, without renal impairment, the pharmacokinetics of loop diuretics are relatively normal, while there is a pharmacodynamic problem. This occurs secondary to a process called diuretic braking phenomenon [2]. As the extracellular fluid decreases, the natriuretic response to every dose of diuretic also decreases due to several counter-regulatory processes like activation of renin-angiotensin-aldosterone system, activation of the sympathetic nervous system and hypertrophy of distal epithelial cells of the nephron, called nephron remodeling. Thus, the dose-response curve is shifted downwards and to the right, which means there is a secretory defect and a reduced maximal response [2,37]. To overcome this diuretic resistance, we need to increase the frequency of the diuretic doses or associate other classes of diuretics. If renal impairment is associated, then both pharmacokinetics and pharmacodynamics are affected, and we should also increase the dose of diuretic [17].

Loop diuretics can cause serious electrolyte and acid-base disturbances, such as hyponatremia, hypokalemia, hyperuricemia, hyperchloremic metabolic alkalosis, and less frequently, hypomagnesemia [36]. They can cause severe hypovolemia and a consequent rise in serum creatinine [38]. Other side effects of loop diuretics are photosensitivity, dermatitis, acute allergic interstitial nephritis, and ototoxicity (especially when associating other ototoxic drugs like aminoglycosides). The last one is dependent on the dose and rate of infusion of the diuretic. Generally, the dose of furosemide should not exceed 4 mg/min and concomitant administration of aminoglycoside should be avoided [39].

From a historical perspective, after the discovery of CA inhibitors it was observed that these drugs were not efficient in monotherapy for decongestion in patients with heart failure. It was thought that for better volume control it was necessary to excrete both Na⁺ and Cl^-, unlike the mechanism of action of CA inhibitors. This led to the development of thiazide diuretics [15,16] by chemical modification of the sulfa nucleus of acetazolamide. Chlorothiazide was the first thiazide diuretic, followed by hydrochlorothiazide and bendroflumethiazide, with different pharmacokinetic characteristics. Other modifications of the sulfa nucleus led to thiazide-like diuretics, which have the same effect, but a different chemical compound (chlorthalidone, indapamide, metolazone) [40]. They inhibit about 5%–10% of Na⁺ reabsorption through Na⁺/Cl^- cotransporter (NCC), at a 1:1 ratio, in the apical membrane of the distal convoluted tubule, both early (DCT1) and distal segment (DCT2) [41]. This intracellular decrease in Na⁺ activates the basolateral Na⁺/Ca²⁺ exchanger (NCX), to maintain an optimal level of intracellular sodium. This leads to increased reabsorption of calcium from the renal tubule through an apical Ca²⁺ channel according to gradient concentration and then from cytoplasm to plasma through NCX. This is the mechanism responsible for hypocalciuria and kidney stone prevention with administration of thiazides, unlike furosemide, which increases calcium excretion. The distal tubule is also impermeable to water, being responsible for urine dilution [15,42]. Inhibition of NCC leads to a greater Na⁺ delivery to collecting duct, where Na⁺ is reabsorbed in exchange for K⁺ and H⁺, leading to hypokalemia and metabolic alkalosis. Hyponatremia and hypokalemia are especially likely to occur in elderly patients. Thiazides can also cause hypomagnesemia, hyperuricemia, hyperglycemia, and severe volume depletion, particularly when used in combination with loop diuretics [40]. Thiazides have a moderate diuretic effect and are mostly used for hypertension, mild congestive heart failure or in combination with loop or other diuretics to overcome diuretic resistance through sequential nephron blockade [43–46]. A major difference from most loop diuretics is the long duration of action of a thiazide diuretic, making once a day administration suitable.

The landmark trials that have proved significant cardiovascular benefits of SGLT2i in patients with HF regardless of the ejection fraction (EF) or diabetes status have placed these agents in the standard of care of HF [24,27]. SGLT2i have a weak diuretic effect in monotherapy as less than 10% of the sodium handled by the proximal tubule is reabsorbed by the sodium-glucose cotransporter 2 [58]. Nonetheless, SGLT2i lead to significant natriuresis when combined with loop diuretics [59], while animal data points toward an additional effect of SGLT2i on NHE3 as well [60].

SGLT2i have been evaluated in several trials as an add-on therapy in ADHF [61]. The EMPA-RESPONSE-AHF trial randomized 80 patients to either empagliflozin 10 mg or placebo for 30 days [62]. Despite not showing a significant difference between the study arms in any of the primary endpoints (dyspnea, diuretic response, length of hospitalization, change in NT- proBNP), empagliflozin significantly increased the urinary output and reduced the risk of a composite endpoint of worsening or rehospitalization for HF or death at 60 days [62]. The EMPAG-HF randomized 60 patients with ADHF within 12h of admission to empagliflozin 25 mg daily or placebo in addition to standard decongestive therapies [63]. Daily addition of empagliflozin resulted in a 25% increase in cumulative urine output over 5 days (median 10.8 L versus 8.7 L in placebo, group difference estimation of 2.2 L [95% CI, 0.84 to 3.6]; p = 0.003). Furthermore, empagliflozin increased diuretic efficiency compared with placebo (14.1 mL urine per milligram furosemide equivalent [95% CI, 0.6–27.7]; p = 0.041) and led to a more pronounced decrease of NT-proBNP [63]. Moreover, the cumulative dose of loop diuretics was lower in the empagliflozin group compared to placebo [63]. Lastly, the EMPULSE trial randomized patients with ADHF after stabilization (24h) to empagliflozin 10 mg daily or placebo for 90 days [64]. Empagliflozin was associated with a benefit on all markers of decongestion, while a greater weight loss at day 15 was associated with a clinical benefit at 90 days (composite of all-cause death, heart failure events, 5-point or greater difference in a total symptom score change from baseline to 90 days) [64]. Moreover, in all trials empagliflozin was safe and well tolerated with no adverse effects on renal function.

While SGLT2i showed a benefit in both the management of ADHF and long-term management of HF, the preference for these agents as add-on therapy might also be derived from the positive influence on several electrolyte abnormalities [61]. In a propensity-matched analysis, both loop and thiazide diuretics were associated with hyponatremia [65]. In addition, dilutional hyponatremia is frequently encountered in ADHF. Due to their osmotic diuretic properties, SGLT2i have been shown, in two RCTs of patients with the syndrome of inappropriate antidiuresis, to significantly increase serum sodium levels [66,67]. In terms of potassium homeostasis, a post-hoc analysis of the CREDENCE trial showed that among patients treated with RAAS inhibitors, canagliflozin reduced the risk of hyperkalemia without increasing the risk of hypokalemia (see also Clinical Scenario 3) [68].

Hypochloremic metabolic alkalosis frequently develops following loop and thiazide diuretic treatment [61]. It is frequently encountered in patients with HF, as a consequence of neurohumoral activation, and is a contributor to diuretic resistance in such circumstances [69]. In a post-hoc analysis of 678 patients from the DOSE-AHF, CARRESS-HF, and ROSE-AHF trials that had a baseline serum bicarbonate assessment, 46.6% of patients had metabolic alkalosis and serum bicarbonate level further increased following decongestive therapies [69]. Contrary to initial beliefs, a change in serum bicarbonate was not associated with significant decongestion, and elevated bicarbonate level at baseline was identified as an independent predictor of later rehospitalizations for HF [69,70]. These observations have led to the reconsideration of CA inhibitors in ADHF [4].

The DIURESIS-CHF trial randomized 34 patients with ADHF to bumetanide and either acetazolamide (250–500 mg daily) or placebo [71]. The primary endpoint (natriuresis after 24 h) was similar in the two treatment arms [71]. However, the loop diuretic efficacy (defined as natriuresis corrected for loop diuretic dose) was significantly higher with acetazolamide add-on [71]. This pilot study led to the larger Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial that randomized 519 patients with ADHF to receive i.v. acetazolamide (500 mg daily) or placebo in addition to loop diuretics [22]. Patients with an acetazolamide add-on achieved more frequently successful decongestion both within 3 days after randomization (42.2% vs. 30.5%, risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; p < 0.001) and at discharge (78.8% vs. 62.5%, risk ratio, 1.27; 95% CI, 1.13 to 1.43). Acetazolamide led to a greater urinary output and natriuresis, without an increased risk of adverse events [22]. Nonetheless, some criticism arose from the definition of decongestion in the ADVOR trial that may have led to a higher incidence of the primary endpoint occurrence compared to previous studies, especially in light of the fact that the difference in urinary output was only approximately 0.5 L and that the clinical findings did not lead to a reduction in deaths or rehospitalizations for HF [4,61]. Nonetheless, acetazolamide remains an adequate add-on option in patients with metabolic alkalosis and significant residual congestion.

RAAS blockade represents the cornerstone for the management of patients with HF, but the widespread implementation of adequate regimens of ACEIs, ARBs, and MRAs is significantly limited in real-world clinical practice by the occurrence of hyperkalemia or worsening of renal function (WRF), especially in those with preexisting chronic kidney disease [72]. The landmark RALES trial demonstrated that the addition of 25 mg of spironolactone in patients with HF and reduced EF led to a 30% reduction in mortality [73]. A subsequent population-based analysis showed that following the publication of the RALES trial, the prescription for spironolactone increased by approximately four-fold [74]. Moreover, even the use of the newer selective nonsteroidal MRA finerenone still leads to a higher risk of hyperkalemia [75]. Nevertheless, this translated into a significantly increased risk of hospitalizations and mortality associated with hyperkalemia [76]. This frequently leads to suboptimal dosing or discontinuation of RAAS blockade, which alters the cardiovascular outcomes [76]. An observational study from the United Kingdom that included RAAS inhibitors prescribed for patients with new-onset CKD or HF showed that those with hyperkalemia had a higher risk of RAAS inhibitors down-titration that led to a seven-fold increase in mortality [76]. In analysis of the ESC-HFA-EORP Heart Failure Long-Term Registry, it was shown that the discontinuation of RAAS inhibitors rather than hyperkalemia was associated with mortality, leading to the hypothesis that hyperkalemia is a marker for RAAS inhibitor discontinuation, but not a risk factor for worse cardiovascular outcomes [77].

Thiazide diuretics might improve the hyperkalemia associated with RAAS blockade in patients with HF in addition to the potential benefit of improving the diuretic efficacy of loop diuretics. A pooled analysis of patients that received a stepwise pharmacological approach from the CARRESS-HF, DOSE-AHF, and ROSE-AHF trials showed that a combination of loop and thiazide diuretics led to more weight loss compared to loop diuretic monotherapy [78]. The CLOROTIC trial randomized 230 patients with ADHF to hydrochlorothiazide (HCTZ) or placebo for 5 days, in addition to loop diuretics. Patients randomized to HCTZ lost more weight at 72 h [−2.3 vs. −1.5 kg; adjusted estimated difference (95% CI) −1.14 (−1.84 to −0.42); P=0.002], but this did not translate into an improvement in patient-reported dyspnea, rehospitalization, or mortality [79]. Nonetheless, the combination therapy led to significantly higher rates of hypokalemia (either potassium level of ≤ 3.5 mmol/L or ≤ 3 mmol/L) [79]. In addition, HCTZ use was associated with a higher risk of WRF. Despite the initial belief that WRF portends a worse outcome, contemporary data points towards an effective decongestion, as WRF in patients with a good diuretic response was not associated with poor outcomes [80]. Moreover, the mean eGFR in this study was approximately 40 ml/min, while about 20% of patients had a baseline eGFR of less than 30 ml/min [79]. While previous concerns that thiazide diuretics are less effective in patients with low eGFR, recent data provides the evidence of their important antihypertensive effects in patients with advanced CKD (eGFR less than 30 ml/min) [81,82]. Given that distal tubular compensatory sodium reabsorption is the mechanism for diuretic resistance in a substantial proportion of patients with HF, the kaliuretic properties of loop-thiazide diuretic combination might be also the appropriate choice to mitigate the hyperkalemia associated with contemporary management of HF.

Both loop and thiazide diuretics can lead to the development of hypokalemia [65]. Moreover, in the CLOROTIC trial, their combination led to significantly higher rates of hypokalemia (either potassium level of ≤ 3.5 mmol/L or ≤ 3 mmol/L) [79]. Despite the fact that higher doses of spironolactone (100 mg) did not lead to an improvement in markers of decongestion or NT-proBNP in the ATHENA-HF trial, MRAs use might be beneficial in counteracting hypokalemia and metabolic alkalosis associated with loop and thiazide diuretics, especially given their benefit for mortality shown in the RALES trial [73,83].