When accounting for demographic and clinical variables, the doses of ≥250 mg of furosemide and ≥ 50 mg of spironolactone received for at least a month, or concomitant use of both diuretics regardless of their dose, were independent predictors of hyponatremia at hospital admission of patients due to HF. In addition, increasing age, diabetes mellitus and alcohol consumption were baseline characteristics independently associated with the occurrence of hyponatremia.
Hyponatremia is a predictor of adverse outcomes, in both short- and long-term prognosis [9, 10, 20,21,22,23,24,25,26], and has been closely associated with increased length of in-hospital stay [23, 24], rate of rehospitalizations, major complications , and risk for in-hospital mortality [24,25,26]. In addition, hyponatremia has been suggested as an important predictor of adverse in-hospital outcomes in all HF patients, regardless of the LVEF . Our univariate analysis showed that hyponatremic patients more often had LVEF ≤45%, but this association disappeared in the multivariate analysis. In HF, hyponatremia is a product of several simultaneous pathophysiological mechanisms, including arterial underfilling, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, enhanced arginine vasopressin secretion, renal impairment and diuretic therapy [2, 6]. Our study suggests that the net-effect of these mechanisms is more important for the occurrence of hyponatremia than isolated effect of LVEF. An inverse association of LVEF and GFR with NT-proBNP levels in our patients is compatible to the basic mechanisms of failing heart within the pathophysiological framework of the cardiorenal syndrome .
In addition to some smaller studies [29,30,31], a large cohort study using data from the Rotterdam study  and a retrospective study by Arampatzis et al.  have reported the association of thiazide use with hyponatremia. In contrast, we did not confirm such an association, regardless of the hydrochlorothiazide dose. However, none of our HF patients took > 25 mg of hydrochlorothiazide. Most recently, the dose of ≥25 mg of hydrochlorothiazide, in addition to advanced age, female sex, use of benzodiazepines or statins and previous cerebrovascular accident, has been suggested as a clinical predictor of hyponatremia among hypertensive patients taking thiazide diuretics . There is a possibility that metabolic and other effects of thiazide diuretics may vary in specific populations which should be accounted for in future studies.
Several studies have linked the use of loop diuretics to hyponatremia [15, 33]. Loop diuretics promote natriuresis and water loss through the inhibition of sodium chloride reabsorption at the ascending limb of Henle’s loop . However, these drugs act at the macula densa, affecting both renal concentrating and diluting mechanisms , and when water loss is insufficiently replaced, hypernatremia may also occur [12, 33]. In contrast to some exceptions , our finding of 60% of HF patients taking furosemide is in agreement with other studies on this topic [15, 34]. We found a strong association of high doses, i.e., 250 to 500 mg of furosemide with hyponatremia, in both univariate and multivariate analysis. In the previous studies, loop diuretics were analyzed as the class, and dosage was not taken into account [9, 12, 14, 15, 33]. This may at least partly explain conflicting results in the association between loop diuretic use and serum sodium levels, including hyponatremia [15, 33], hypernatremia [12, 33] or lack of association [9, 14].
A recent study in stable HF patients, in whom the furosemide dose was reduced by 50%, has shown that this change may cause a 20% increase in GFR among those with GFR lower than 60 ml/min/1.73 m2 . We observed no association of kidney failure with hyponatremia in either univariate or multivariate analysis. This suggests that other significant predictors such as diuretics, increasing age, diabetes mellitus or alcohol consumption play a more important role in the occurrence of hyponatremia. Lowering GFR may be an adverse effect of higher diuretic doses which occasionally may worsen kidney failure.
In this line, a reduction of furosemide dose of ≥120 mg to a third of the baseline dose in patients with HF, has been associated with increased 1- and 2-year survival rates free of hospitalization or cardiac death . Our results extend this knowledge by strongly linking the dose of ≥250 mg to hyponatremia. Therefore, a careful titration and reduction of furosemide dose below 250 mg seems to be an important clinical goal, whenever possible.
Spironolactone, a potassium sparing diuretic, has also been implicated in the development of hyponatremia [10, 12]. A possibility that coadministration of a second diuretic with potassium sparing diuretic can either cause or aggravate hyponatremia has been reported [17, 18]. A fact that every fourth of our patients concomitantly used spironolactone with furosemide, and nearly all of those who took ≥50 mg of spironolactone, supports this possibility. When drug doses were taken into account, we observed an independent association of high spironolactone dose (50 or 100 mg daily) with hyponatremia. By inhibiting aldosterone-induced synthesis of epithelial Na+ channels and consequently, Na+-K+ exchange, spironolactone enhances natriuresis . Our results suggest that dose of 25 mg of spironolactone is relatively safe, while doses of 50 or 100 mg, or concomitant use with furosemide, probably enhance natriuresis to the extent that often cause hyponatremia. As in the case of furosemide, this suggests that a reduction of the spironolactone dose may be a useful clinical approach. The strong positive association between NT-pro BNP levels and spironolactone use, as well as its dose, could be a consequence of more frequent spironolactone prescription in higher dose to patients with most severe clinical HF. Interestingly, the dose of furosemide did not correlate with NT-pro BNP levels. It may be assumed that introduction of spironolactone and increase in its dose is most often gradual and compatible with the severity of HF. In contrast, variations in the dose of furosemide could be more frequent and more subjected to other clinical symptoms associated with electrolyte disbalance, changes in volume status and other pathophysiological consequences of cardiorenal syndrome.
Hyponatremia commonly occurs in elderly patients [4,5,6] which is supported by our results. The underlying pathophysiological mechanisms include age-related impairment in water excretory capacity causing a reduction in GFR , concomitant use of diuretics and central nervous system active drugs [4, 5], the syndrome of inappropriate antidiuretic hormone secretion  and the presence of other comorbidities such as HF [1, 2], diabetes mellitus [7, 8], kidney failure , cirrhosis  and others . Alcohol consumption was also independently associated with hyponatremia. Patients with a chronic alcohol-use disorder commonly exhibit hyponatremia, as a result of increased vasopressin levels which induce an increased urine osmolality and decreased clearance of free water .
Diabetic patients frequently develop a wide array of electrolyte and acid-base disorders [7, 8]. Patients with diabetes mellitus are usually hyponatremic , a finding which is concurred by our results. In the hyperglycemic state, hyponatremia develops as a result of transition of water out of the cells and a reduction in sodium levels through dilution . On the other hand, increased or normal serum sodium levels in diabetic patients may be associated with a significant deficit in total body water . Other important causes and types of sodium disorders in patients with diabetes include osmotic diuresis induced hypovolemic hyponatremia , drug induced hyponatremia (oral hypoglycemics, insulin, tricyclic antidepressants) , pseudohyponatremia induced by hypertriglyceridemia  and pseudohypernatremia due to severe hypoproteinemia .
Cardiac troponin is another biomarker with an important prognostic value in acute HF, which has been consistently shown to correlate with increased morbidity and mortality . A positive association between NT-proBNP and troponin I levels observed in our patients confirms its role as a valuable clinical indicator of HF severity. Calcium antagonist therapy is not recommended in patients with HF and reduced LVEF . Our patients who received calcium antagonists had a significantly higher and on average preserved LVEF which indicates that these medications are predominantly prescribed according to current recommendations.
There are several limitations to our study. Firstly, in addition to serum sodium level, volemic status is a closely interrelated factor which determines the course and prognosis of HF patients. Both factors are significantly dependent on the effects of diuretic therapy. However, we did not have an insight into the patients’ volume status, but evaluation of congestion and clinical euvolaemia remains challenging since no reliable clinical test exists to determine euvolaemia . Secondly, we did not collect data on several medications which may also influence serum sodium level, such as benzodiazepines, antiepileptics, selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs . Thirdly, we did not collect data on the New York Heart Association class, previous HF hospitalizations, duration or worsening of HF symptoms, and mechanisms of death in our patients. Finally, we investigated only patients with HF, and there is a possibility that our findings may not be generalized to other patient subgroups.