Pre-nephron Diuretic Resistance

Historical literature focusing on pre-nephron and pre-loop of Henle diuretic resistance was performed in healthy subjects or cohorts with hypertension or chronic kidney disease [38–44]. The application of these findings to the AHF patient on modern medical therapies is uncertain. Cardiorenal hemodynamics represent a potential mechanism of pre-nephron diuretic resistance. Poor cardiac output to the kidney was initially believed to be the predominant driver of cardiorenal syndrome and diuretic resistance, but multiple recent analyses have since illustrated that cardiac output is not the primary driver on a population level [13, 14, 45]. Venous congestion, often approximated by elevated right atrial pressure or high intra-abdominal pressure, has been proposed to contribute to diuretic resistance through a reduction in the arterial to venous pressure gradient at the glomerulus. An analysis of the ESCAPE found no difference in baseline right atrial pressure, pulmonary arterial wedge pressure, or cardiac output between patients experiencing high or low diuretic efficiency [20]. Vasodilators such as nesiritide, ularitide, serelaxin, and milrinone failed to augment diuresis by metrics of urine output, IV loop diuretic duration of use, or weight loss in patients with AHF [46–50]. Dopamine at 2 μg/kg/min did not increase urine output compared to placebo in a trial of AHF patients undergoing decongestion with IV loop diuretics [48]. Dopamine trended toward increasing urine volume in those with a baseline systolic blood pressure less than 114 mmHg [48]. Higher diastolic blood pressure predicted greater urine output in the ASCEND-HF trial, although possibly driven by confounding by indication [46]. To the contrary, RAAS antagonism, even in the setting of a blood pressure reduction, may actually improve the natriuretic response to a loop diuretic [51, 52]. Activation of the RAAS varies greatly during decongestion with both diuretics and mechanical volume removal and has unclear associations with diuretic resistance [33, 53]. It remains unclear which patients with lower mean arterial pressures and diuretic resistance should have a temporary cessation in medications that lower blood pressure with initiation of dopamine at 2 μg/kg/min versus those in whom RAAS antagonists should be continued or uptitrated.

Hypoalbuminemia was considered as a pre-nephron diuretic resistance mechanism because all loop diuretics are >90% bound to albumin [54–56]. Hypothesized mechanisms include a reduced intravascular volume available for diuresis and decreased delivery of loop diuretics to the nephron [57]. The majority of literature evaluating the benefit of IV albumin replacement with IV furosemide was performed in nephrotic syndrome or cirrhosis utilizing IV furosemide doses of only 40 mg [41, 58, 59]. A small, retrospective study of patients with a serum albumin <3 g/dL hospitalized for AHF found no difference in net urine output nor diuretic doses needed for diuresis compared to patients with normal serum albumin concentrations [60]. Analysis of the DOSE-AHF and the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-HF) trials found no association between baseline serum albumin concentrations and weight loss (p = 0.43), diuretic efficiency (p = 0.53), or freedom from congestion (p = 0.30) at 72 h [61].

The relationship between sodium and heart failure outcomes is complex [62]. The traditional paradigm teaches that high sodium intake is a driver of pre-nephron diuretic resistance [38, 63]. However, several investigations in AHF populations indicate that a higher sodium intake might be beneficial if a greater net sodium removal is achieved [64]. Hypertonic saline administered with high-dose loop diuretics produced greater urinary sodium excretion, urine volume, and faster achievement of euvolemia than high-dose loop diuretics alone among heart failure patients failing oral combinations of loop and thiazide diuretics [65–67]. However, the quality of data supporting this approach is limited, and it cannot be recommended at this time [68]. Likewise, there is insufficient evidence to recommend any specific dietary sodium limitation for patients with AHF undergoing diuresis [64]. Lastly, non-steroidal anti-inflammatory drugs inhibit renal prostaglandin synthesis leading to a decreased renal blood flow and impaired natriuresis [69, 70].

Pre-loop of Henle Diuretic Resistance

Initially believed to be significant contributors to diuretic resistance from impaired drug delivery to the site of action, renal function and albuminuria are less influential mechanisms of diuretic resistance compared to tubular handling of sodium. In the novel “The House of God”, we see renally-based diuretic adjustments taught with “age + BUN = Lasix dose” [71], which contemporary medical pocket resources continue [72]. Proposed diuretic resistance mechanisms of renal dysfunction are listed in Fig. 11.1. Renal dysfunction is a mechanism of pre-loop of Henle diuretic resistance in chronic kidney disease populations, but is less relevant in the contemporary heart failure patient prescribed an adequate diuretic dose. Estimated glomerular filtration rate (eGFR) poorly correlates with net fluid output (r² = 0.0; p = 0.35) and diuretic efficiency (r² = 0.02; p < 0.001) in the ESCAPE [20]. BUN was significantly associated with low diuretic efficiency (OR 1.19 per 10 g/dL increase in BUN; p = 0.005) in a multivariate model incorporating eGFR, which could be a result of increased neurohumoral activation and/or competition with loop diuretic entry into the nephron. Similarly, elevated BUN but not reduced eGFR predicted urine output in the ASCEND-HF trial [46]. When evaluating the relative importance of diuretic delivery and renal tubular response, eGFR did not predict 6 h net fluid or net sodium output [73]. Patients with a low eGFR had decreased diuretic delivery to the kidney, with eGFR (r = 0.58; p = 0.001) and urea clearance (r = 0.75; p = 0.001) showing strong correlation with urinary diuretic concentration. However, patients with lower eGFR compensated for decreased diuretic concentrations by producing greater fractional excretion of sodium at 6 h. Renal function in heart failure has no impact on the individual nephron’s filtrate, but does influence total natriuresis, although at a less significant degree than loop of Henle and post-loop of Henle diuretic resistance. In summary, renal dysfunction is much less of an important mediator of diuretic resistance in AHF than traditional teaching implies.

Albuminuria might contribute to diuretic resistance by binding loop diuretics in the urine as they do in the serum, decreasing the quantity of free drug able to bind to the Na⁺/K⁺/2Cl⁻ symporter [72]. Literature supporting this hypothesis was performed in animal models of nephrotic syndrome [74–76], raising questions of its relevance in AHF. Patients with AHF and either normal albuminuria (45%), microalbuminura (42%), or macroalbuminuria (13%) exhibit very weak correlation between diuretic efficiency and urinary albumin concentrations [77]. Recent analyses in humans with nephrotic syndrome also refute albuminuria as a primary mechanism of diuretic resistance, making it implausible that albuminuria is a significant mechanism of diuretic resistance in AHF patients [78].

Loop of Henle Diuretic Resistance

Loop of Henle diuretic resistance mechanisms are listed in Fig. 11.1. Diuretic resistance from inadequate dose or frequency could be considered pseudo-diuretic resistance, failing the adequate diuretic regimen portion of the diuretic resistance definition. However, 40 mg of furosemide in a normal volunteer will elicit a maximal natriuretic response, providing a low bar for an adequate dose. The loop diuretic’s dose-response curve exhibits a sigmoidal pattern along a logarithmic relationship, with a threshold and a ceiling dose. The diuretic dose and infusion rate primarily determine the concentration in the lumen of the loop of Henle relative to the diuretic threshold. This relationship determines (1) the peak rate of diuresis and (2) the duration of diuresis as time above the threshold (Fig. 11.2a). A dose exceeding the ceiling can still cause a greater diuretic response by maintaining a concentration above the threshold for a longer time (Fig. 11.2b). The ceiling and non-maladaptive adaptation shield against diuretic concentration-related harm, with the exception of potential ototoxicity at infusion rates >4 mg/min or furosemide equivalent bolus doses >500 mg [79, 80]. The scenario depicted in Fig. 11.2b can be advantageous if achieved with low diuretic doses. Diuretic thresholds and therefore the dose needed for diuresis display interpatient and intra-patient variability. When evaluating for loop of Henle diuretic resistance, the natriuretic response to the dose should first be considered. A low or moderate IV bolus dose of loop diuretic that produces less than 500 mL of urine or a spot urine sodium concentration <70 mmol/L at 2 h may result from the situation pictured in Fig. 11.2c. The primary limitation in this scenario is the time above the renal threshold and the dose should be increased to attempt a profile depicted in Fig. 11.2d.

Diuretic dose and frequency are interdependent in loop of Henle diuretic resistance and both must be considered. If a 240 mg furosemide bolus produces 1500 mL of urine over 6 h, euvolemia would doubtfully be achieved if this dose was given once daily despite overcoming the dose-mediated diuretic resistance. Because the half-life of IV loop diuretics is short (~1–2 h), urinary concentrations fall below the diuretic threshold quickly with a duration of action that rarely exceeds 6 h [55, 56]. Typical twice daily dosing may provide diuretic concentration below the diuretic threshold for the majority of the day, allowing compensatory sodium reabsorbtion [37, 81]. Continuous infusions of loop diuretics that maintain the diuretic concentration above the diuretic threshold should be advantageous [82]. The DOSE-AHF trial hypothesized that continuous infusion dosing would be superior to dosing every 12 h [36, 82]. However, no difference was found in symptom improvement, urine output, or weight loss, although the population studied had an unknown prevalence of diuretic resistance. It is unknown why the pharmacokinetic advantage of continuous infusions has not translated into clinical benefits. In patients exhibiting diuretic resistance but with adequate natriuretic response to an IV bolus dose, consideration can be given to the use of IV loop diuretics at greater frequencies to overcome frequency-mediated diuretic resistance, although data proving this theoretical approach is lacking. The major difference between this strategy and the null findings in the DOSE-AHF trial is that more frequent dosing also represents an uptitration of the total diuretic dose given in addition to increased frequency (Fig. 11.3).

Post-loop of Henle Diuretic Resistance

The few contemporary studies in AHF patients indicate that the majority of diuretic resistance is primarily mediated by post-loop of Henle diuretic resistance. Compared to a pre-diuretic baseline, a median dose of IV furosemide 160 mg (40–270 mg) increased the amount of sodium estimated to be leaving the loop of Henle by 12.6 ± 10.8% (p < 0.001) [83]. Yet, the fractional excretion of sodium only increased 4.8 ± 3.3%, indicating 66% (25–85%) of the sodium leaving the loop of Henle underwent distal tubular reabsorption. After controlling for loop of Henle diuretic resistance by using urine diuretic concentration, the increase in sodium leaving the loop of Henle only accounted for 6.4% of the increase in net fractional excretion of sodium. These findings were substantiated in a study administering IV bumetanide to 50 AHF patients which reported that in the majority (71%) diuretic response was related to intra-renal diuretic resistance via renal tubular changes [73]. Continuous loop diuretic exposure results in rapid distal tubular hypertrophy and hyperfunction in animal models [84–86]. Thus, a focus of restoring diuretic efficacy should be on blocking reabsorption in the distal tubules.

Thiazide(-like) Diuretics

Thiazide (and thiazide-like) medications are the most commonly utilized medications to overcome loop diuretic resistance [88–90]. Thiazides should be the first option to add to loop diuretics, as they inhibit sodium reabsorption in the distal convoluted tubules where the majority of remaining sodium reabsorption occurs after the loop of Henle. Despite experience spanning 50 years, common misconceptions regarding combining thiazides and loop diuretics persist [89]. Metolazone is often referred to as superior to other thiazide agents, but no solid evidence supports the use of metolazone over other thiazides, even in patients with low eGFR [89, 91–93]. Administration of thiazides 30 min prior to loop diuretics is not evidence-based, as most studies administered both simultaneously [89]. Furthermore, the erratic and delayed absorption profile of metolazone makes this practice irrelevant clinically and unnecessarily increases complexity [94, 95]. IV chlorothiazide has only been compared to oral thiazides in small retrospective studies limiting definitive conclusions on efficacy differences [96]. Any thiazide at equipotent dose [97] in daily or divided doses is appropriate to add to loop diuretic therapy. Careful monitoring for hyponatremia, hypokalemia, and volume status is warranted with combination diuretic therapy to avoid adverse events [89].

Mineralocorticoid Receptor Antagonists

Mineralocorticoid receptor antagonists at diuretic doses are employed with loop diuretics in cirrhotic ascites as the primary combination nephron blockade strategy [98, 99]. In AHF, non-diuretic doses (<50 mg/day) of mineralocorticoid receptor antagonists reduce morbidity and mortality [100], but investigations into larger, diuretic doses have been limited until the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy—Heart Failure (ATHENA-HF) trial [101, 102]. The ATHENA-HF trial compared spironolactone 100 mg/day to placebo or continued non-diuretic dose spironolactone in patients with hypervolemic AHF treated with IV loop diuretics [103]. No difference in the primary endpoint of natriuretic peptide change or secondary outcomes such as net urine output, weight change, or titration of IV loop diuretic doses were found [103]. However, ATHENA-HF did not study a population with diuretic resistance and may have utilized insufficient spironolactone doses to achieve therapeutic concentrations of canrenone (active metabolite). Serum potassium levels were no different between spironolactone and placebo, supporting this possibility. Until future studies of diuretic doses of mineralocorticoid receptor antagonists in patients with diuretic resistance are conducted, this class should not be employed over thiazides in combination nephron blockade. Similarly, amiloride cannot be recommended over thiazides in combination nephron blockage because of the reduced capacity for sodium reabsorption in the collecting ducts relative to the distal convoluted tubules.

Vasopressin Antagonists

Vasopressin-2 receptor antagonists have been extensively investigated in AHF, with recent investigations focusing on the diuretic prowess [104]. Three trials comparing tolvaptan to placebo in patients with hypervolemic AHF without diuretic resistance treated with only modest IV loop diuretics found increases in weight loss and urine output [105–107]. However, clinical endpoints such as improvement in dyspnea were not improved, possibly because sodium-free water excretion will have less impact on filling pressures than sodium-rich fluid excretion. Tolvaptan, which acts in the collecting duct, cannot be recommended over thiazides in combination nephron blockage at this time given the limited study in loop diuretic resistance.

Diuretics in the Proximal Tubules of the Nephron

Medications acting in the proximal convoluted tubules such as acetazolamide have shown promise in preliminary investigation of combination nephron blockade and are undergoing further investigation in the Acetazolamide in Decompensated heart failure with Volume Overload (ADVOR) trial [108, 109]. Acetazolamide may be a promising diuretic to add when diuretic resistance persists despite combination nephron blockade with loop diuretics and thiazides but there is no conclusive evidence up to date.

In conclusion, diuretic resistance is problematic to universally define but prevalent in AHF. The mechanisms driving diuretic resistance are diverse and the subsequent strategies should be specific to the mechanism. Optimization of loop diuretic regimens should be the primary strategy followed by combination nephron blockage with thiazides. Several additional strategies are promising but require further investigation before they can be recommended.