Clinical Pharmacology in Diuretic Use

DIURETICS

It is particularly crucial to comprehend and value the pharmacokinetics and pharmacodynamics of diuretics, which are among the most frequently prescribed medications. Despite their effectiveness, diuretics are frequently used to treat patients who are at significant risk for complications (see recent review by Keller and Hann [1]

Despite the fact that the available diuretic drugs have distinct pharmacokinetic and pharmacodynamic properties that influence both response and potential for adverse effects, many clinicians use them in a stereotyped manner, which reduces effectiveness and may increase side effects (Table 1 lists common diuretic side effects). Although there are many applications for diuretics, this review will concentrate on using them to treat edema and extracellular fluid (ECF) volume expansion. Diuretics are also discussed elsewhere for the treatment of kidney stones, hypertension, and other disorders.

CATEGORIZATION AND MECHANISM OF ACTION

Typically, diuretic medications are categorized based on their primary location of action throughout the nephron, followed by the mechanism by which they block transport (Figure 1A). Furosemide, bumetanide, and torsemide are loop diuretics that block the Na-K-2Cl cotransporter (NKCC2, encoded by SLC12A1) along the thick ascending limb and macula densa from the lumen. They interact with the chloride-binding site (2) in the transport protein's translocation pocket as organic anions (Figure 1B, see below for clinical implications). They block the transporter because they are bigger than chloride and cannot pass through the pocket. Thiazides and thiazide-like medications, which work similarly to distal convoluted tubule diuretics, are organic anions that attach to the thiazide-sensitive NaCl cotransporter (NCC, encoded by SLC12A3) along the distal convoluted tubule (Figure 1A). A significant component of loop and distal convoluted tubule diuretic activity is accounted for by this mode of action; both medications work from the luminal side of the tubule. Medications that block apical sodium channels (amiloride and triamterene) and those that antagonistically interact with mineralocorticoid receptors (spironolactone and eplerenone) are examples of potassium-sparing diuretics. Finerenone, a novel nonsteroidal mineralocorticoid blocker, is presently undergoing phase 3 clinical studies. The more toxic loop diuretic ethacrynic acid and the mineralocorticoid blockers work inside cells and don't need to be secreted into the tubule lumen.

Absorption of Diuretics in the Digestive System

Figure 2A depicts the typical metabolism of loop diuretics. When given orally, furosemide, bumetanide, and torsemide are absorbed somewhat fast (see Figure 2B), reaching peak concentrations in 0.5–2 hours (3,4); when given intravenously, their effects are almost immediate. Bumetanide and torsemide usually have oral bioavailability of about 80%, while furosemide has a much lower oral bioavailability of about 50% (see Table 2) (5). Furosemide has a short half-life, but when taken orally, its duration of action is greater since its gastrointestinal absorption may be slower than its elimination half-life.

This feature, known as "absorption-limited kinetics" (3), might account for the drug's "lasts 6 hours" (6) mnemonic. Torsemide and bumetanide, on the other hand, have quick oral absorption (7). When a patient is switched from intravenous to oral loop diuretics, the dose of bumetanide or torsemide should be maintained based on oral bioavailability, while the dose of furosemide should be doubled (7). However, in reality, as will be covered in more detail below, other factors affect diuretic efficacy, and a fixed intravenous/oral conversion cannot be given (8).

The dose-response curves of loop diuretics are steep. Although this feature is usually taught to residents and students, it is sometimes overlooked in clinical practice despite being essential for effective utilization. A typical natriuretic response is displayed against the logarithm of the plasma diuretic concentration in Figure 2C. Examination shows that below a certain plasma concentration (referred to as the "threshold"), there is minimal diuretic or natriuretic impact; above that, the response develops quickly.

Clinicians seldom "think" in logarithmic terms, despite the fact that such relationships are usually represented as the logarithm of the diuretic concentration or dosage. This is the rationale behind the standard advice to "double the dose" in the event that no response is shown. A plateau or "ceiling" is attained at greater doses, and ever higher plasma concentrations are unable to cause additional natriuresis.We shall contend that raising a diuretic dose over this ceiling frequently causes additional natriuresis due to pharmacokinetic factors, despite the fact that this fact has been used to invoke the idea of ceiling doses of loop diuretics (see below).

A diuretic dose must be higher than the threshold in order to be successful, as Figure 2C should make clear. However, people with a range of edematous illnesses may not get a dose that is higher than the threshold. However, following algorithms might result in diuretic failure.Rather, it is frequently preferable to treat a patient as a "n of one trial," which means that the dose should be started in accordance with clinical criteria (more aggressive for acute edema, more conservative for more chronic processes) and then adjusted based on the response.

Furosemide's poor bioavailability is a worry, but its unpredictable bioavailability could be a worse issue. The absorption of furosemide varies both within and across persons on a daily basis (9, 10). Unlike torsemide or bumetanide, absorption is also influenced by meal consumption (11, 12), however the therapeutic importance of this effect has been questioned (3). Two small clinical trials have indicated that torsemide may be a better loop diuretic due to its more consistent bioavailability when compared to furosemide and its comparatively longer t1/2 (13–16). Patients with heart failure who are released on torsemide may have a decreased death rate, according to a new post hoc analysis of the big Effect of Nesiritide in Patients with Acute Decompen-sated Heart Failure research (17). However, none of these investigations are rigorous or adequately powered to be deemed conclusive, and several additional research do not support this advantage (18).

Figure 1: Sites of sodium reabsorption and diuretic action along the nephron.

Figure 2: (A) Features of absorption, distribution, metabolism, and excretion (so-called ADME) of drugs. (B) Comparing the plasma diuretic concentration as a function of time after oral or intravenous diuretic administration.

Relatively short t1/2 is a characteristic of loop diuretics (see Table 2). As a result, the acute natriuresis usually subsides in 3–6 hours, giving the kidneys 16–21 hours to make up for lost water and salt from a single daily dose. The phenomenon known as "post diuretic NaCl retention" describes the fact that as the diuretic effect wears off, urine NaCl excretion falls below the baseline for those in steady state. Until another diuretic dose is given, this is usually the case (45).It should be noted, however, that this relationship is different in patients with decompensated oedema, who may present during a period of positive NaCl balance with urinary [NaCl] very low, even without diuretic administration, even though it applies to patients who are at steady state (and thus excreting their daily intake of salt). Any increase in the excretion of NaCl in the urine will be advantageous in this situation. Despite these variations, a brief time of natriuresis and a prolonged duration of antinatriuresis are usually responsible for the net NaCl loss from a diuretic. This explains the standard advice to take loop diuretics twice a day; it is evident from examining the t1/2 that this requirement is most crucial when using bumetanide and least crucial when using torsemide. As previously mentioned, furosemide's apparent relative potency over bumetanide increases as CKD advances because its t1/2 is prolonged. Long internatriuretic periods, however, reduce medication efficacy even when administered twice daily; this is particularly significant when dietary NaCl intake is high because the kidneys' retention of NaCl will result in a greater positive NaCl balance. Continuous infusion of loop diuretics is one way to manage t1/2 problems, at least for hospitalised patients. While the benefits of this strategy over high-dose bolus therapy are yet mainly theoretical (46), this strategy has an attractive physiological foundation, and current tiered care guidelines (see below) suggest ongoing infusions (47). Accordingly, it has recently been reported that an investigational prolonged release formulation of torsemide, which distributes the medication to the circulation over 8–12 hours, doubles salt and water losses in normal volunteers following a single dosage without affecting potassium excretion (48).If patients with heart failure or nephrotic syndrome respond favourably to such a formulation, which should circumvent some of the clear pharmacokinetic drawbacks of short-acting loop diuretics, the conventional course of treatment may be altered. Patients with cirrhotic ascites require somewhat different considerations. Relative gastrointestinal absorption is typically maintained in this situation (49). It is generally advised to avoid intravenous diuretics if at all possible due to the tendency for relative under filling in this situation (50).In this case, most patients are advised to take a combination of furosemide and spironolactone in a ratio of 40 mg furosemide to 100 mg spironolactone in order to balance safety and efficacy. However, in patients with concurrent kidney disease, this ratio may need to be modified in order to maintain normokalemia (51).

USING DIURETICS EFFECTIVELY TO TREAT ECF VOLUME EXPANSION

When starting diuretics to manage edemaregardless of whether the patient has normal or impaired kidney function it is crucial to ensure the dose achieves a tubular concentration above the threshold (Figure 1B). Moss ambulatory patients can detect that this threshold has been reached by noticing an increase in urine volume within 24 hours after taking an oral dose. A mismatch between diuresis and weight loss in outpatients may indicate that high NaCl intake is reducing treatment efficacy; in such cases, measuring 24-hour urine sodium excretion verified by creatinine to ensure proper collection can help confirm elevated NaCl consumption, though single urine [Na1] samples may not yield fully accurate results (52). In hospitalized patients, achieving the target dose should result in a rise in urine output within the six hours after administration. Based on the relationship between plasma diuretic concentration and time illustrated in Figure 2B, diuresis should begin more quickly following an intravenous administration. This discrepancy may be particularly noticeable if furosemide is the diuretic selected. If no effect is seen during this time, it is standard practice to double the dose for instance, from 20 to 40 mg of furosemide or from 80 to 160 mg of furosemide based on the dose-response curve illustrated in Figure 2C. The dose is then increased to the highest safe level, as explained below. Although loop diuretics are usually given twice a day, there’s no need to add a second daily dose if the first one doesn’t surpass the threshold. However, once a threshold is reached, most patients will need to take two doses per day.

Although dose guidelines for loop diuretics have been established, either through pharmacokinetic and pharmacodynamic reasoning (24) or expert consensus (53), additional, more specific dose ranges have been evaluated in clinical trials. In their study on acute decompensated heart failure, Felker and colleagues compared administering intravenous doses that were 2.5 times the patient’s usual daily dose with doses equal to the usual daily amount. Although no differences in the primary outcome were seen with the higher dose in this trial, the pre-specified secondary outcomes were promising, and no adverse effects were noted. Importantly, this and other recent trials including those for patients with cardio renal syndrome aimed for 35 liters of diuresis per day as an initial treatment (47), a target more aggressive than commonly pursued. These studies highlight that, for hospitalized patients, an aggressive diuresis strategy is frequently both safe and effective. Previous worries that diuretics could harm the kidneys or the body as a whole probably stemmed from confounding by indication in observational studies (54). In fact, post hoc analyses of large trials indicate that individuals who experience a moderate rise in creatinine suggesting worsening kidney function may actually have a better prognosis than those who do not (55,56).

The net or therapeutic natriuretic effect of a diuretic is calculated as the difference between the sodium excreted in the urine and the sodium ingested. Although raising a diuretic dose beyond the ceiling does not enhance the maximal minute-natriuresis ( the highest rate of NaCl excretion per unit time, see Figure 2C), it frequently boosts net natriuresis by extending the duration during which the diuretic concentration remains above the threshold (see Figure 2A). One reason current heart failure guidelines may suggest doses higher than ceiling limits often multiples of previous or home doses (see below and Ellison and Felker [45]) is this.

In both healthy individuals and patients with extracellular fluid (ECF) volume expansion, a linear relationship exists between ECF volume and sodium excretion (UNaV), as clearly demonstrated by Walser (57). This is similar to but distinct from pressure natriuresis, which describes the relationship between mean arterial pressure and UNaV. Diuretics are generally recommended for treating symptomatic ECF volume expansion, with rare exceptions, and therapeutic success is defined as a reduction in ECF volume. This invariably involves initial losses of sodium and water, triggered by diuretic doses surpassing the threshold (Figure 4). However, the situation evolves as initial treatment transitions into effective long-term management. At any dose with therapeutic effect, natriuresis diminishes as extracellular fluid volume decreases, an effect commonly referred to as the “braking phenomenon” (58). This indicates that, at steady state, the individual resumes NaCl balance, with urinary NaCl excretion matching dietary NaCl intake once more. This happens, however, at a lower ECF volume than prior to treatment. Functionally, chronic diuretic treatment shifts the relationship between ECF volume and UNaV to the left (see Figure 4), allowing NaCl excretion rates to once more match intake, even though ECF volume is reduced. It should be noted, however, that while daily NaCl excretion returns to normal, the pattern of salt and water loss remains more episodic, meaning a patient may still report that the diuretic regimen is increasing urine output.

Although the braking phenomenon becomes adaptive once ECF volume has been successfully reduced, it is maladaptive when it arises in the context of ongoing ECF volume expansion. Many factors, chiefly stemming from changes in ECF volume including stimulation of nerves supplying the kidney and activation of the renin-angiotensin system are thought to contribute to braking ( 59,60); however, it is now acknowledged that adaptive modifications in segments beyond the thick ascending limb also play a significant role ( 61,62). Remodelling of the distal nephron takes place (63), resulting in hypertrophy and hyperplasia, particularly in the distal segments. This is due to higher salt delivery (64), elevated levels of angiotensin II (65) and aldosterone (66), and alterations in potassium balance. Remodelling leads to an increase in the transport capacity of distal tubules, matching that of thick ascending limbs; as a result, more NaCl that escapes the loop of Henle is reabsorbed distally, thereby reducing net natriuresis.

Diuretics shift this curve upward (blue line), but can also make it less steep. The dashed line represents the baseline sodium excretion rate, which matches intake. Once a diuretic is initiated, urinary sodium excretion increases as the system shifts to a new curve (from point 1 to point 2). Gradually, through the braking phenomenon, urinary sodium excretion returns to baseline, but at a new, lower ECF volume (from point 2 to point 3).

Adding a thiazide or thiazide-like drug can help treat and possibly prevent this kind of adaptation, thereby restoring diuretic effectiveness. Most frequently, particularly in patients with CKD, metolazone is selected as the second agent, though other thiazides may also be equally effective (67). Interestingly, at least three factors could be responsible for these beneficial effects. First, by inhibiting transport in the distal tubule segment known for transport activation the effectiveness of these typically weak diuretics will be enhanced (68). Second, when oral metolazone or chlorthalidone is used in this context, their longer half-lives (approximately 14 and 50 hours [69]) may help reduce post diuretic sodium chloride retention. Third, these drugs may help reduce distal nephron remodelling and the activation of the thiazide-sensitive NCC (70). Nevertheless, a major risk of this approach is the significant potential for hypokalaemia (71). Since hypokalaemia is now acknowledged as the primary driver activating NCC (72), these secondary effects work against the objective of introducing a second class of diuretic. In this case, lower or less frequent doses may offer similar benefits while also reducing potential risks.

EVIDENCE - BASED DIURETIC DOSING FOR ECF VOLUME EXPANSION

Although loop diuretic dosing recommendations have historically been based on pharmacological properties, more recent studies of acute decompensated heart failure have shifted focus toward patient-centred outcomes. The Diuretic Strategies in Patients with Acute Decompensated Heart Failure trial compared high and low doses of loop diuretics in patients with acute decompensated heart failure and found that the higher dose2.5 times the usual daily doses well tolerated and effective. One concern regarding aggressive diuretic approaches in this situation is the potential for worsening kidney function, which served as a harm signal in this study. Yet, in this trial, worsening kidney function evidenced by an increase in creatinine is actually linked to a better, not worse, prognosis (55). When sufficient diuresis fails to occur, a stepped care approach detailed in Table 3has been recommended (47). Though not directly compared with other methods, this algorithm was successfully applied in randomized trials and demonstrated at least equal effectiveness to invasive techniques like ultrafiltration (73).

More restricted but persuasive data indicate that patients with cirrhotic ascites respond best to a combination of furosemide and spironolactone, administered in a 40:100 mg ratio (74). This generally maintains plasma potassium levels in most patients, though adjustments may be necessary if abnormalities arise. For patients with nephrotic syndrome, diuretic binding was once thought to play a role in resistance. However, a study comparing the natriuretic effect of loop diuretics with and without protein displacement clearly showed that this factor was not playing a role (75). Another factor in this scenario is the cleavage of the epithelial sodium channel by filtered proteases (76); recent animal studies indicate that this process may be a viable target for intervention, using either protease inhibitors or amiloride (77).

DIURETICS FOR AKI

Opinions on whether to use diuretics in AKI have differed significantly. At the close of the 20th century very high doses of diuretics were frequently administered, which can Table 3. Stepwise pharmacologic care algorithm for heart. The complete algorithm described in the references incorporates further factors for vasodilator, inotropic, or mechanical therapy in patients who do not respond within 48 hours, converting oliguria to nonoliguric AKI, yet these interventions were found in controlled trials to be linked with deafness and no effect on mortality ( 78). A subsequent retrospective trial indicated that diuretic use in patients with AKI is linked to higher mortality and recommended that “the widespread use of diuretics in critically ill patients with acute renal failure should be discouraged” (79). Yet, statistical approaches cannot overcome the fundamental limitations of such retrospective studies. To address this concern and minimize confounding by indication, Grams et al.

Conducted a post hoc analysis of data for patients with AKI from the Fluid and Catheter Treatment Trial (80). In this trial, patients with adult respiratory distress syndrome were randomly assigned to either a liberal or restrictive fluid management strategy; those in the restricted group received aggressive diuretic therapy. The trial results indicated that patients who developed AKI and were assigned to a strategy with increased diuretic use had a lower adjusted odds ratio for death (80). Although this trial is not definitive, it indicated that previously reported negative outcomes from diuretic use in AKI probably stemmed from confounding by indication. At this stage, it appears reasonable to use diuretics as an adjunct in AKI to maintain euvolemia. However, it is generally advisable to steer clear of very high doses and to refrain from using diuretics to postpone more definitive treatments, like dialysis.

CONCLUSION

Diuretic drugs, which act on solute transport throughout the nephron, are frequently used in people with normal or impaired kidney function. Each diuretic drug has a distinct pharmacokinetic profile, yet these differences may not be given adequate attention when the drugs are used therapeutically. Recent large clinical trials now offer an evidence base supporting the use of diuretics in treating heart failure. Yet, even when such evidence is available, a thorough grasp of diuretic pharmacokinetics and pharmacodynamics improves the clinical approach to diuresis. Because these drugs significantly help reduce breathlessness and edema, maximizing their use should lead to better patient-centred clinical outcomes. The creation of diuretic drugs stands as one of the most significant achievements in scientific medicine; since disorders of extracellular fluid volume persist into the 21st century, these drugs will remain vital to medical practice for the foreseeable future.

REFERENCES

1. Keller F, Hann A. Clinical pharmacodynamics: Principles of drug response and alterations in kidney disease. Clin J Am Soc Nephrol. 2018;13:1413–1420.
2. Somasekharan S, Tanis J, Forbush B. Loop diuretic and ion-binding residues revealed by scanning mutagenesis of transmembrane helix 3 (TM3) of Na-K-Cl cotransporter (NKCC1). J Biol Chem. 2012;287:17308–17317.
3. Hammarlund MM, Paalzow LK, Odlind B. Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis. Eur J Clin Pharmacol. 1984;26:197–207.
4. Brater DC, Day B, Burdette A, Anderson S. Bumetanide and furosemide in heart failure. Kidney Int. 1984;26:183–189.
5. Shankar SS, Brater DC. Loop diuretics: From the Na-K-2Cl transporter to clinical use. Am J Physiol Renal Physiol. 2003;284:F11–F21.
6. Huang X, Dorhout Mees E, Vos P, Hamza S, Braam B. Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Renal Physiol. 2016;310:F958–F971.
7. Brater DC. Diuretic pharmacokinetics and pharmacodynamics. In: Seldin DW, Giebisch G, editors. Diuretic Agents: Clinical Physiology and Pharmacology. San Diego: Academic Press; 1997. p. 189–208.
8. Brater DC. Pharmacodynamic considerations in the use of diuretics. Annu Rev Pharmacol Toxicol. 1983;23:45–62.
9. Murray MD, Haag KM, Black PK, Hall SD, Brater DC. Variable furosemide absorption and poor predictability of response in elderly patients. Pharmacotherapy. 1997;17:98–106.
10. Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin Pharmacol Ther. 1995;57:601–609.
11. McCrindle JL, Li Kam Wa TC, Barron W, Prescott LF. Effect of food on the absorption of frusemide and bumetanide in man. Br J Clin Pharmacol. 1996;42:743–746.
12. Kramer WG. Effect of food on the pharmacokinetics and pharmacodynamics of torsemide. Am J Ther. 1995;2:499–503.
13. Murray MD, Ferguson JA, Bennett SJ, Adams LD, Forrhofer MM, Minick SM, Tierney WM, Brater DC. Fewer hospitalizations for heart failure by using a completely and predictably absorbed loop diuretic. J Gen Intern Med. 1998;16:45–52.
14. Murray MD, Deer MM, Ferguson JA, Dexter PR, Bennett SJ, Perkins SM, Smith FE, Lane KA, Adams LD, Tierney WM, Brater DC. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513–520.
15. Bikdeli B, Strait KM, Dharmarajan K, Partovian C, Coca SG, Kim N, Li SX, Testani JM, Khan U, Krumholz HM. Dominance of furosemide for loop diuretic therapy in heart failure: Time to revisit the alternatives? J Am Coll Cardiol. 2013;61:1549–1550.
16. DiNicolantonio JJ. Should torsemide be the loop diuretic of choice in systolic heart failure? Future Cardiol. 2012;8:707–728.
17. Mentz RJ, Hasselblad V, DeVore AD, Metra M, Voors AA, Armstrong PW, Ezekowitz JA, Tang WH, Schulte PJ, Anstrom KJ, Hernandez AF, Velazquez EJ, O’Connor CM. Torsemide versus furosemide in patients with acute heart failure (from the ASCEND-HF trial). Am J Cardiol. 2016;117:404–411.
18. Vasavada N, Saha C, Agarwal R. A double-blind randomized crossover trial of two loop diuretics in chronic kidney disease. Kidney Int. 2003;64:632–640.
19. Vasko MR, Cartwright DB, Knochel JP, Nixon JV, Brater DC. Furosemide absorption altered in decompensated congestive heart failure. Ann Intern Med. 1985;102:314–318.
20. Inoue M, Okajima K, Itoh K, Ando Y, Watanabe N, Yasaka T, Nagase S, Morino Y. Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int. 1987;32:198–203.
21. Kitsios GD, Mascari P, Ettunsi R, Gray AW. Co-administration of furosemide with albumin for overcoming diuretic resistance in patients with hypoalbuminemia: A meta-analysis. J Crit Care. 2014;29:253–259.
22. KDIGO practice guideline on glomerulonephritis: Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: Reading between the (guide)lines—application to the individual patient. Kidney Int. 2012;82:840–856.
23. Pasini A, Benetti E, Conti G, Ghio L, Lepore M, Massella L, Molino D, Peruzzi L, Emma F, Fede C, Trivelli A, Maringhini S, Materassi M, Messina G, Montini G, Murer L, Pecoraro C, Pennesi M. The Italian Society for Pediatric Nephrology (SINePe) consensus document on the management of nephrotic syndrome in children: Part I—diagnosis and treatment of the first episode and the first relapse. Ital J Pediatr. 2017;43:41.
24. Brater DC. Diuretic therapy. N Engl J Med. 1998;339:387–395.
25. Brater DC. Disposition and response to bumetanide and furosemide. Am J Cardiol. 1986;57:20A–25A.
26. Voelker JR, Cartwright-Brown D, Anderson S, Leinfelder J, Sica DA, Kokko JP, Brater DC. Comparison of loop diuretics in patients with chronic renal insufficiency. Kidney Int. 1987;32:572–578.
27. Delpire E, Lu J, England R, Dull C, Thorne T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl cotransporter. Nat Genet. 1999;22:192–195.
28. Flagella M, Clarke LL, Miller ML, Erway LC, Giannella RA, Andringa A, Gawenis LR, Kramer J, Duffy JJ, Doetschman T, Lorenz JN, Yamoah EN, Cardell EL, Shull GE. Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem. 1999;274:26946–26955.
29. Dormans TP, van Meyel JJ, Gerlag PG, Tan Y, Russel FG, Smits P. Diuretic efficacy of high-dose furosemide in severe heart failure: Bolus injection versus continuous infusion. J Am Coll Cardiol. 1996;28:376–382.
30. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ. 2006;333:420.
31. Nigam SK, Wu W, Bush KT, Hoenig MP, Blantz RC, Bhatnagar V. Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters. Clin J Am Soc Nephrol. 2015;10:2039–2049.
32. Lau HS, Shih LJ, Smith DE. Effect of probenecid on the dose-response relationship of bumetanide at steady state. J Pharmacol Exp Ther. 1983;227:51–54.
33. Vallon V, Rieg T, Ahn SY, Wu W, Eraly SA, Nigam SK. Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol. 2008;294:F867–F873.
34. Heerdink ER, Leufkens HG, Herings RM, Ottervanger JP, Stricker BHC, Bakker A. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med. 1998;158:1108–1112.
35. Burckhardt G. Drug transport by Organic Anion Transporters (OATs). Pharmacol Ther. 2012;136:106–130.
36. Wu W, Bush KT, Nigam SK. Key role for the organic anion transporters, OAT1 and OAT3, in the in vivo handling of uremic toxins and solutes. Sci Rep. 2017;7:4939.
37. Cemerikic D, Wilcox CS, Giebisch G. Intracellular potential and K⁺ activity in rat kidney proximal tubular cells in acidosis and K⁺ depletion. J Membr Biol. 1982;69:159–165.
38. Loon NR, Wilcox CS. Mild metabolic alkalosis impairs the natriuretic response to bumetanide in normal human subjects. Clin Sci (Lond). 1998;94:287–292.
39. Mann B, Hartner A, Jensen BL, Kammerl M, Krämer BK, Kurtz A. Furosemide stimulates macula densa cyclooxygenase-2 expression in rats. Kidney Int. 2001;59:62–68.
40. Stokes JB. Effect of prostaglandin E2 on chloride transport across the rabbit thick ascending limb of Henle. Selective inhibition of the medullary portion. J Clin Invest. 1979;64:495–502.
41. Hébert RL, Jacobson HR, Breyer MD. Prostaglandin E2 inhibits sodium transport in rabbit cortical collecting duct by increasing intracellular calcium. J Clin Invest. 1991;87:1992–1998.
42. Fernández-Llama P, Ecelbarger CA, Ware JA, Andrews P, Lee AJ, Turner R, Nielsen S, Knepper MA. Cyclooxygenase inhibitors increase Na-K-2Cl cotransporter abundance in thick ascending limb of Henle’s loop. Am J Physiol. 1999;277:F219–F226.
43. Oppermann M, Hansen PB, Castrop H, Schnermann J. Vasodilation of afferent arterioles and paradoxical increase of renal vascular resistance by furosemide in mice. Am J Physiol Renal Physiol. 2007;293:F279–F287.
44. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: Nested case-control study. BMJ. 2013;346:e8525.
45. Ellison DH, Felker GM. Diuretic treatment in heart failure. N Engl J Med. 2017;377:1964–1975.
46. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev. 2005;(3):CD003178.
47. Grodin JL, Stevens SR, de Las Fuentes L, Kiernan M, Birati EY, Gupta D, Bart BA, Felker GM, Chen HH, Butler J, Dávila-Román VG, Margulies KB, Hernandez AF, Anstrom KJ, Tang WH. Intensification of medication therapy for cardio renal syndrome in acute decompensated heart failure. J Card Fail. 2016;22:26–32.
48. Shah S, Pitt B, Brater DC, Feig PU, Shen W, Khwaja FS, Wilcox CS. Sodium and fluid excretion with torsemide in healthy subjects is limited by the short duration of diuretic action. J Am Heart Assoc. 2017;6:e006135.
49. Sawhney VK, Gregory PB, Swezey SE, Blaschke TF. Furosemide disposition in cirrhotic patients. Gastroenterology. 1981;81:1012–1016.
50. Daskalopoulos G, Laffi G, Morgan T, Pinzani M, Harley H, Reynolds T, Zipser RD. Immediate effects of furosemide on renal hemodynamics in chronic liver disease with ascites. Gastroenterology. 1987;92:1859–1863.
51. Runyon BA; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of adult patients with ascites due to cirrhosis. Hepatology. 2004;39:841–856.
52. Titze J. Estimating salt intake in humans: Not so easy! Am J Clin Nutr. 2017;105:1253–1254.
53. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, et al. 2013 ACCF/AHA guideline for the management of heart failure: Executive summary. Circulation. 2013;128:1810–1852.
54. Butler J, Forman DE, Abraham WT, Gottlieb SS, Loh E, Massie BM, O’Connor CM, Rich MW, Stevenson LW, Wang Y, Young JB, Krumholz HM. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J. 2004;147:331–338.
55. Brisco MA, Zile MR, Hanberg JS, Wilson FP, Parikh CR, Coca SG, Tang WH, Testani JM. Relevance of changes in serum creatinine during a heart failure trial of decongestive strategies: Insights from the DOSE trial. J Card Fail. 2016;22:753–760.
56. Ahmad T, Jackson K, Rao VS, Tang WHW, Brisco-Bacik MA, Chen HH, Felker GM, Hernandez AF, O’Connor CM, Sabbisetti VS, Bonventre JV, Wilson FP, Coca SG, Testani JM. Worsening renal function in patients with acute heart failure undergoing aggressive diuresis is not associated with tubular injury. Circulation. 2018;137:2016–2028.
57. Walser M. Phenomenological analysis of renal regulation of sodium and potassium balance. Kidney Int. 1985;27:837–841.
58. Wilcox CS, Mitch WE, Kelly RA, Skorecki K, Meyer TW, Friedman PA, Souney PF. Response of the kidney to furosemide. I. Effects of salt intake and renal compensation. J Lab Clin Med. 1983;102:450–458.
59. Wilcox CS, Guzman NJ, Mitch WE, Kelly RA, Maroni BJ, Souney PF, Rayment CM, Braun L, Colucci R, Loon NR. Na⁺, K⁺, and BP homeostasis in man during furosemide: Effects of prazosin and captopril. Kidney Int. 1987;31:135–141.
60. Kelly RA, Wilcox CS, Mitch WE, Meyer TW, Souney PF, Rayment CM, Friedman PA, Swartz SL. Response of the kidney to furosemide. II. Effect of captopril on sodium balance. Kidney Int. 1983;24:233–239.
61. Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int. 1989;36:682–689.
62. Rao VS, Planavsky N, Hanberg JS, Ahmad T, Brisco-Bacik MA, Wilson FP, Jacoby D, Chen M, Tang WHW, Cherney DZI, Ellison DH, Testani JM. Compensatory distal reabsorption drives diuretic resistance in human heart failure. J Am Soc Nephrol. 2017;28:3414–3424.
63. Subramanya AR, Ellison DH. Distal convoluted tubule. Clin J Am Soc Nephrol. 2014;9:2147–2163.
64. Yang YS, Xie J, Yang SS, Lin SH, Huang CL. Differential roles of WNK4 in regulation of NCC in vivo. Am J Physiol Renal Physiol. 2018;314:F999–F1007.
65. Castañeda-Bueno M, Gamba G. Mechanisms of sodium-chloride cotransporter modulation by angiotensin II. Curr Opin Nephrol Hypertens. 2012;21:516–522.
66. Abdallah JG, Schrier RW, Edelstein C, Jennings SD, Wyse B, Ellison DH. Loop diuretic infusion increases thiazide-sensitive Na⁺/Cl⁻ cotransporter abundance: Role of aldosterone. J Am Soc Nephrol. 2001;12:1335–1341.
67. Fliser D, Schröter M, Neubeck M, Ritz E. Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure. Kidney Int. 1994;46:482–488.
68. Ellison DH. The physiologic basis of diuretic synergism: Its role in treating diuretic resistance. Ann Intern Med. 1991;114:886–894.
69. Kountz DS, Goldman A, Mikhail J, Ezer M. Chlorthalidone: The forgotten diuretic. Postgrad Med. 2012;124:60–66.
70. Grimm PR, Taneja TK, Liu J, Coleman R, Chen YY, Delpire E, Wade JB, Welling PA. SPAK isoforms and OSR1 regulate sodium chloride cotransporters in a nephron-specific manner. J Biol Chem. 2012;287:37673–37690.
71. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010;56:1527–1534.
72. Terker AS, Zhang C, McCormick JA, Lazelle RA, Zhang C, Meermeier NP, Siler DA, Park HJ, Fu Y, Cohen DM, Weinstein AM, Wang WH, Yang CL, Ellison DH. Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab. 2015;21:39–50.
73. Bart BA, Goldsmith SR, Lee KL, Givertz MM, O’Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, LeWinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E; Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardio renal syndrome. N Engl J Med. 2012;367:2296–2304.
74. Runyon BA; AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: An update. Hepatology. 2009;49:2087–2107.
75. Agarwal R, Gorski JC, Sundblad K, Brater DC. Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome. J Am Soc Nephrol. 2000;11:1100–1105.
76. Svenningsen P, Bistrup C, Friis UG, Bertog M, Haerteis S, Krueger B, Stubbe J, Jensen ON, Thiesson HC, Uhrenholt TR, Jespersen B, Jensen BL, Korbmacher C, Skøtt O. Plasmin in nephrotic urine activates the epithelial sodium channel. J Am Soc Nephrol. 2009;20:299–310.
77. Bohnert BN, Menacher M, Janessa A, Wörn M, Schork A, Daiminger S, Kalbacher H, Häring HU, Daniel C, Amann K, Sure F, Bertog M, Haerteis S, Korbmacher C, Artunc F. Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome. Kidney Int. 2018;93:159–172.
78. Brown CB, Ogg CS, Cameron JS. High-dose frusemide in acute renal failure: A controlled trial. Clin Nephrol. 1981;15:90–96.
79. Mehta RL, Pascual MT, Soroko S, Chertow GM; PICARD Study Group. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA. 2002;288:2547–2553.
80. Grams ME, Estrella MM, Coresh J, Brower RG, Liu KD; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network. Fluid balance, diuretic use, and mortality in acute kidney injury. Clin J Am Soc Nephrol. 2011;6:966–973.
81. Milionis HJ, Alexandrides GE, Liberopoulos EN, Bairaktari ET, Goudevenos J, Elisaf MS. Hypomagnesemia and concurrent acid-base and electrolyte abnormalities in patients with congestive heart failure. Eur J Heart Fail. 2002;4:167–173.
82. Karim A. Spironolactone: Disposition, metabolism, pharmacodynamics, and bioavailability. Drug Metab Rev. 1978;8:151–188.