Editorial
Diuretic resistance in heart failure
Resistencia a los diuréticos en la insuficiencia cardiaca
a Servicio de Medicina Interna, Hospital d’Olot i Comarcal de la Garrotxa, Girona, Catalunya, Spain
b Tissue Repair and Regeneration Laboratory (TR2Lab), Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central (IrisCC), Barcelona, Catalunya, Spain
c Grupo de Trabajo de Insuficiencia Cardiaca y Fibrilación Auricular de la Sociedad Española de Medicina Interna, Madrid, Spain
d Servicio de Medicina Interna, Hospital Universitario de Getafe, Madrid, Spain
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class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Jesús" "apellidos" => "Casado" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital d’Olot i Comarcal de la Garrotxa, Girona, Catalunya, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Tissue Repair and Regeneration Laboratory (TR2Lab), Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central (IrisCC), Barcelona, Catalunya, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Grupo de Trabajo de Insuficiencia Cardiaca y Fibrilación Auricular de la Sociedad Española de Medicina Interna, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Universitario de Getafe, Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Resistencia a los diuréticos en la insuficiencia cardiaca" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Heart failure (HF) remains a serious clinical and public health problem today, as the total number of patients living with this syndrome is increasing and is one of the leading causes of hospitalisation in developed countries.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> 70%–80% of patients with acute HF (AHF) present with a clinical-hemodynamic profile of congestion, and it is these congestive symptoms for which these patients seek medical attention and for which they are eventually hospitalised when they decompensate.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> Given the pivotal role of congestion in AHF, diuretics remain the cornerstone of its treatment.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The efficacy of diuretic therapy in HF varies throughout the natural history of HF. In the early stages of HF, patients usually have a good response to loop diuretics, but as the disease progresses, other comorbidities (such as renal failure) develop and patients are chronically exposed to loop diuretics, diuretic efficacy decreases and diuretic resistance develops.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">There is no unanimous definition of the concept of loop diuretic resistance, but it is usually defined as “the inability to achieve decongestion despite the administration of an adequate diuretic regimen”. This conceptual definition has been supplemented by other definitions that allow quantification of diuretic resistance in clinical practice. One of the most widely used (because it is simple and practical) is “persistent congestion despite receiving doses of furosemide equal to or greater than 80 mg per day”.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In our clinical practice, up to 20%–30% of patients with HF will require admission for decompensation, despite receiving treatment with loop diuretics and, in this situation, we should suspect that there is some resistance to diuretics.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Another relevant concept is that of diuretic efficiency, which suggests that the diuretic response should be determined in relation to the dose of diuretic administered. Different metrics have been proposed for this concept focusing on weight loss, diuresis and natriuresis adjusted for the dose of loop diuretic administered. The most commonly used are: weight loss per 40 mg furosemide, diuresis per 40 mg furosemide and urine sodium to furosemide <span class="elsevierStyleItalic">ratio</span>.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,8</span></a> However, there is also no unanimous agreement on the best metrics to quantify diuresis and natriuresis.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">To understand diuretic resistance, it is important to understand four fundamental steps in the pharmacodynamics of diuretics: 1) gastrointestinal intake and absorption (if administered orally); 2) arrival in the kidney; 3) active secretion into the tubular lumen; and 4) binding to transporter proteins. Conditions such as decreased intestinal absorption, decreased renal blood flow, azotaemia, hypoalbuminaemia and proteinuria (resulting in reduced levels of active diuretics in the tubular lumen) can affect diuretic efficacy.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Some of these situations can be resolved by increasing the dose of the loop diuretic without there actually being a “true” resistance to loop diuretics. In clinical practice, under-dosing of loop diuretics due to (sometimes unjustified) fear of impaired renal function (especially in patients with already reduced baseline renal function) is a common cause of deficient congestion resolution.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Physiologically there are a number of adaptive mechanisms that seek to prevent excessive volume depletion secondary to diuretic treatment which, in the context of patients with persistent congestion, contribute to “true” diuretic resistance. These mechanisms are often referred to as the “braking phenomenon” and include activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system, as well as nephron remodeling.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> Chronic treatment with loop diuretics, blocking NaCl reabsorption in proximal segments of the nephron, leads to increased NaCl reaching distal segments, which progressively increase their sodium reabsorption capacity and, finally, result in a reduction in natriuresis. This increase in distal NaCl absorption capacity occurs as a result of nephron remodelling (hypertrophy of the distal convoluted tubule, connecting tubule and collecting duct).<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> These morphological and functional alterations were described almost four decades ago<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a> and are the basis for the lack of diuretic efficacy observed in patients chronically treated with loop diuretics.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,8,9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Similar to the classification of acute renal failure, an anatomical categorisation of the mechanisms of diuretic resistance has been proposed, dividing it into pre-renal and intrarenal. Pre-renal mechanisms appear to be less relevant in patients with HF, where intrarenal mechanisms rule. These are further divided according to the anatomical segments of the nephron in which the resistance mechanism is generated (pre-loop of Henle, loop of Henle and post-loop of Henle). Although most of the filtered sodium is reabsorbed in the proximal tubule and loop of Henle, most data from animal models and the current literature on humans suggest that tubular mechanisms downstream from the loop of Henle (compensatory distal tubular sodium reabsorption described above) are the major contributors to the diuretic resistance that occurs in HF.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,12</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Identifying the anatomical region of the nephron that is contributing most to diuretic resistance in a patient with HF would be of great help to the clinician in choosing the optimal therapeutic strategy to overcome this resistance. Unfortunately, we do not currently have tools in clinical practice that allow us to make this anatomical diagnosis of diuretic resistance in such a precise manner. This fact, together with the absence of clinical trials on diuretic resistance in HF, means that treatment has historically been based on personal experience and expert opinion.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Thus, the expert consensus of the European Society of Cardiology recommends upward titration of loop diuretic doses (up to 400–600 mg per day) before initiating other strategies, such as combined diuretic therapy, with thiazide diuretics being the first choice in this case.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The first large clinical trial of combined diuretic therapy was ATHENA-HF (Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial) which randomised 360 patients with AHF treated with loop diuretics to receive high-dose spironolactone (100 mg per day) or placebo for 96 h. This intervention did not improve any of the study objectives, including symptom improvement and decongestion.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Two clinical trials on combined diuretic therapy have recently been conducted that could change treatment recommendations for congestion in AHF. First, the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) study is a multicentre, double-blind clinical trial that randomised 519 AHF patients to receive early acetazolamide (500 mg intravenously for three days) or placebo, in addition to loop diuretic therapy. Patients treated with acetazolamide had greater decongestion, diuresis and natriuresis than those treated with placebo, with no safety concerns.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Although the study did not include patients with estimated glomerular filtration rate (eGFR) < 20 ml/min/1.73 m<span class="elsevierStyleSup">2</span>, it is important to note that acetazolamide was effective across the entire range of renal function.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> A difficult access to this molecule in its intravenous formulation in our country limits the implementation of this diuretic strategy for the time being.</p><p id="par0060" class="elsevierStylePara elsevierViewall">On the other hand, the CLOROTIC study (Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial) is a multicentre, double-blind clinical trial conducted in Spain that randomised 230 patients hospitalised with AHF despite prior treatment with loop diuretics (doses equal to or greater than 80 mg per day of oral furosemide) to receive oral hydrochlorothiazide (HCTZ) or placebo for five days, in addition to a standardised intravenous furosemide regimen. Patients treated with HCTZ had greater weight loss, higher diuresis and better diuretic response metrics (weight loss per mg of furosemide administered), at the expense of greater renal function impairment and hypokalaemia that did not lead to higher mortality or short-term readmissions.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In the CLOROTIC study, eGFR values at admission were not an exclusion criterion (except if the patient required renal replacement therapy) and the dose of HCTZ was adjusted according to eGFR as follows: >50 ml/min/1.73 m<span class="elsevierStyleSup">2</span>, 25 mg once daily; 20–50 ml/min/1.73 m<span class="elsevierStyleSup">2</span>, 50 mg once daily; and <20 ml/min/1.73 m<span class="elsevierStyleSup">2</span>, 100 mg once daily. The strategy of combining HCTZ with furosemide was shown to be effective across the renal function spectrum, disproving (again) the cliché that thiazides are not useful or potent when eGFR is severely reduced.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Finally, the advent of sodium-glucose cotransporter type 2 inhibitors (SGLT2i) has been a revolution in the treatment of HF, as it is the only pharmacological group with an indication to treat HF across the entire ejection fraction spectrum.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The SGLT2i can be safely initiated during the acute phase of decompensation and even have a diuretic and natriuretic effect to improve congestion, although they have not yet shown sufficient potency to overcome resistance to loop diuretics.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The favourable results of the ADVOR and CLOROTIC clinical trials provide evidence to recommend early initiation of combined diuretic therapy without titrating loop diuretics to high doses. The question is: which diuretic should be the first choice when deciding to combine with loop diuretics: acetazolamide or HCTZ? While thiazides might be particularly useful in patients chronically taking higher doses of loop diuretics (suggesting distal nephron remodelling), acetazolamide might be of choice in patients with metabolic alkalosis and/or treated with lower doses of furosemide at baseline.</p><p id="par0075" class="elsevierStylePara elsevierViewall">To answer these and other questions in an unfortunately somewhat neglected field of research, more studies are needed. On the one hand, studies on the pathophysiology of diuretic resistance that allow us to personalise treatment by adapting it to nephron remodelling and, on the other hand, new clinical trials comparing different diuretic strategies.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0080" class="elsevierStylePara elsevierViewall">No funding was obtained.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0085" class="elsevierStylePara elsevierViewall">None.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology of heart failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. 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