Study Patient population Results Other findings Wald et al. Hypernatremia also associated with higher mortality Equal incidence of community and hospital-acquired hyponatremia Most hyponatremic patients had hypovolemia Mohammed et al. Open in new tab. Open in new tab Download slide. Google Scholar Crossref. Search ADS. Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people.
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Mortality associated with low serum sodium concentration in maintenance hemodialysis. All rights reserved. For Permissions, please e-mail: journals. Issue Section:. Download all slides. Comments 0. Add comment Close comment form modal. I agree to the terms and conditions. Urine volume is a surrogate for renal free water excretion. The maximum urine volume can be calculated using the urine osmolality UOsm formula. UOsm can be conceptualized as the ratio between the daily urine solute load USL and the daily urine volume V expressed as:.
Under solute balance conditions, USL is equal to the daily solute intake. The average daily solute intake is to mOsm. Salt and protein are considered solutes. Carbohydrates do not produce any meaningful solutes, as they are not excreted under normal conditions. This means that ingesting over 18 L of water per day i. Hypotonic hyponatremia can also be due to decreased renal free water excretion and this can occur by three mechanisms:.
Vasopressin binds to the V2 receptor located in the basolateral membrane of principal cells in the collecting duct, which signals through cyclic-AMP and regulates the insertion of the water channel aquaporin-2 into the luminal membrane thereby rendering this epithelium water permeable.
The presence of vasopressin and the activation of this pathway in conjunction with persistent water intake underlies the mechanism of hyponatremia. EABV is conceptualized as the volume of arterial blood that perfuses tissues. EABV depends not only on volume but also on the function of the heart pump and the vascular tone. Therefore, decreased EABV can be caused by hypovolemia, heart failure, or systemic vasodilation.
SIADH is a condition where vasopressin is released in the absence of a physiological stimulus autonomous vasopressin release. However, hyponatremia in SIADH is not purely dilutional, as there is also a component of negative sodium balance.
Following initial water retention which causes mild ECF volume expansion ; there is a compensatory natriuresis that serves to regulate ECF volume towards normal. Cortisol exerts an inhibitory effect in vasopressin gene synthesis effectively inhibiting vasopressin release.
Cortisol also increases the sensitivity of vascular smooth muscle to the actions of catecholamines. Cortisol deficiency therefore causes the opposite effects: decrease negative feedback inhibition of vasopressin synthesis and vasodilation, both of which will stimulate vasopressin release causing hypotonic hyponatremia.
Low dietary solute intake can also result in decreased renal free water excretion. From this, we can infer that USL determines the maximal urine volume, and therefore the maximal renal water excretory capacity. Patients on a low solute diet have a limited ability to excrete free water. Finally, the first step in renal water excretion is glomerular filtration. In conditions associated with reduced glomerular filtration rate GFR , renal water excretion will be compromised. After confirmation that the patient has hypotonic hyponatremia, the next step is to measure the UOsm which can be done on a spot urine collection.
UOsm Figure 2 assesses whether the patient is capable of diluting the urine. Vasopressin limits the diluting ability of the kidney thereby limiting renal water excretion. Obtain a spot urine sodium concentration UNa to determine if vasopressin-dependent hypotonic hyponatremia is appropriate or inappropriate Figure 2. Low UNa in this setting results from renal sodium retention due to renin-angiotensin-aldosterone system RAAS activation. A caveat to this is that hypotonic hyponatremia due to renal sodium loss e.
Hypovolemic hyponatremia is a result of hypovolemia causing decreased EABV that stimulates the non-osmotic release of vasopressin. This leads to free water reabsorption in the kidney and hyponatremia. The classical physical exam findings of hypovolemia are weight loss, dry mucous membranes, sunken eyes, poor skin turgor, dry axilla, orthostatic hypotension, orthostatic tachycardia, frank hypotension, frank tachycardia, and oliguria.
However, multiple studies have shown that the sensitivity and specificity of the clinical evaluation of volume status in the setting of hyponatremia are very poor. Heart failure and cirrhosis. Early in the disease process, reduced EABV from heart failure and splanchnic vasodilation from cirrhosis lead to activation of neurohormonal pathways including the sympathetic nervous system and RAAS which lead to sodium retention and ECF volume expansion.
Late in the course of these conditions, the EABV decreases even further, and now non-osmotic release of vasopressin occurs causing also water retention and the development of hyponatremia.
Hyponatremia in heart failure and cirrhosis reflects the severity of the disease and its onset is associated with increased mortality. Lower extremity edema, ascites, pulmonary edema, pleural effusions, or elevated jugular venous pressure. Patients with decompensated heart failure or cirrhosis may have hypotension in the setting of hypervolemia due to poor cardiac output and splanchnic vasodilatation, respectively.
Hypovolemia from renal sodium losses e. SIADH is a condition characterized by inappropriate vasopressin secretion in the absence of a physiologic stimulus for its release. SIADH is a diagnosis of exclusion. Clinical euvolemia. Patients with SIADH are actually mildly volume expanded from water retention but this is not perceived at the bedside. This is caused by compensatory natriuresis caused by inactivation of the RAAS system from mild volume expansion.
Normal thyroid, kidney and adrenal function. Normal kidney function is suggested by normal BUN and serum creatinine. Mild volume expansion in SIADH decreases the proximal tubular reabsorption of uric acid increasing the fractional excretion of uric acid and decreasing the plasma uric acid concentration. Pulmonary disorders: pneumonia, pleural effusion, pneumothorax, etc. Increased intrathoracic pressure caused by pulmonary problems activate the baroreceptor causing non-osmotic release of vasopressin.
In the case of secondary and tertiary adrenal insufficiency, hyponatremia is a result of selective cortisol deficiency. However, in primary adrenal insufficiency, there is both cortisol and aldosterone deficiency which are responsible for vasopressin release.
Aldosterone deficiency is associated with renal sodium loss and hypovolemia. Symptoms of hyponatremia can be classified as asymptomatic, mild symptoms i. Besides, thiazide diuretics, which inhibit sodium transport in the distal tubule, could prevent the maximal dilution of urine But we found no association between hyponatremia and thiazide diuretics in diuretic users.
These data suggest that impaired renal dilution capability could not explain the prognostic effect of hyponatremia in diuretic users. Hyponatremia may also reflect concurrent heart failure, which may impose additive deleterious effects on poor renal outcomes. Fluid overload as indicated by hyponatremia could cause cardiomyocyte elongation and dysfunction during the left ventricle remodeling Our data demonstrated that hyponatremia was associated with cardiovascular disease in patients with CKD.
Hoorn et al. The concourse of hyponatremia and renal dysfunction has been shown to be associated with heart and liver failure Thus, cardiorenal syndrome can cause a vicious cycle in which deteriorating heart function accelerates the reduction in kidney function via the neurohormonal pathways Hyponatremia is an independent prognostic factor for morbidity and mortality in heart failure 19 , 49 and maintenance hemodialysis 17 , Kovesdy et al.
In our CKD cohort, the lack of association between hyponatremia and mortality could be attributed to the fact that renal replacement therapy could resolve the fluid overload eventually in patients with advanced CKD Our data also reconfirmed the association between hypernatremia and mortality in CKD patients.
Patients with hypernatremia could be associated with acute complications and death, rather than RRT. Our study had several limitations. First, as an observational cohort, our ability to elucidate definite causal links was limited. Second, total body water measured by bioelectrical impedance analysis was not equal to extracellular fluid, though we had found a good correlation.
Third, CV events were recorded in only one hospital, which might have caused an underestimation. Fourth, variations in serum sodium levels caused by daily intake, nutritional status, and medication use during the follow-up period could have confounded the results. However, our purpose was to apply serum sodium as a prognostic factor, not a causal factor. Fifth, the smaller sample size of the 2 extreme serum sodium levels and relatively short follow-up duration could have resulted in lower statistical power, which might account for the weak association with mortality and CV events and the inability to differentiate the effects of loop and thiazide diuretics.
In conclusion, diuretic users have adverse clinical outcomes in CKD population. Hyponatremia is associated with imbalanced TBW and is a prognostic indicator for RRT in diuretic users, but not in diuretic non-users. Hyponatremia was not associated with all- cause mortality or cardiovascular event whereas hypernatremia was associated with an increased risk for all-cause mortality. Therefore, the serum sodium levels of patients with CKD who are being treated with diuretics should be routinely evaluated.
Additionally, interventions other than diuretics aimed at achieving optimal fluid status should be considered. Whether the mechanism behind hyponatremia is diuretic-induced direct renal injury or neuro-hormonal activation requires further study.
Between November 11, , and June 30, , 5, patients who were screened through an integrated CKD care program at 2 affiliated hospitals of Kaohsiung Medical University in Southern Taiwan were included in the CKD cohort and followed until July 31, A total of patients who were lost to follow-up within 3 months and patients with incomplete medication information were excluded.
Of the patients included, 3, were treated as part of the integrated care program and 1, received regular care. A total of 4, patients with CKD between stages 1 and 5 were eligible for this study. Written informed consent was obtained from patients and all clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. Baseline variables included demographic features, medical history, examination findings, laboratory data, and medication history.
The demographic features were the baseline records when patients enrolled in the CKD care program. The medical history was obtained by reviewing doctor charts.
DM and hypertension were defined according to clinical diagnoses and prescribed medications. CVD was defined as a clinical diagnosis of heart failure, acute or chronic ischemic heart disease, or cerebrovascular disease.
Diuretic use was defined as loop diuretics exceeding equivalent furosemide 39 mg per day or thiazide diuretics exceeding equivalent trichlormethiazide 3. Other medication use was also defined as treatment for more than half of the observation period. To prevent variability, electrolytes including serum sodium were collected 3 months before and after enrollment and were averaged. We also examined serum sodium as a continuous predictor using restricted cubic spline analysis Bioelectrical impedance analysis measures the change in impedance of electrical signals, which travel more rapidly through water and lean body mass than through fat body mass.
Three outcomes were assessed: all-cause mortality, renal replacement therapy RRT , and cardiovascular events. Survival status and cause of death were ascertained in a death certificate review by using charts and the National Death Index.
Cardiovascular events were defined as the development of acute coronary syndrome or acute stroke, hospitalization for peripheral arterial occlusion disease or congestive heart failure, and death by these causes.
The development of cardiovascular events was ascertained by reviewing charts. RRT was defined as the initiation of hemodialysis, peritoneal dialysis, or renal transplantation and was ascertained by reviewing charts and catastrophic illness certificate.
Competing risk Cox proportional hazard analysis was used to assess the relationship between serum sodium and clinical outcomes. The covariates were selected according to previous studies and our past publications, and the continuous variables with skewed distributions were log-transformed to obtain normal distributions.
Serum sodium was treated as a continuous variable with 5 knots at , , , , and the 5 th , Association between serum sodium and cardiovascular event by restricted cubic spline model in diuretic users.
How to cite this article : Lim, L. Kumar, S. Atlas of Diseases of the Kidney ed. Schrier, R. Mitch, W. Disorders of body fluids, sodium and potassium in chronic renal failure. Am J Med 72, — Hung, S. Volume overload and adverse outcomes in chronic kidney disease: clinical observational and animal studies. J Am Heart Assoc 4, doi: Taler, S.
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Crit Care Resusc 9, 60—68 Gottlieb, S. Diuretics: are our ideas based on knowledge? J Am Coll Cardiol 57, —, doi: Article PubMed Google Scholar. Eshaghian, S. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol 97, —, doi: Damman, K. Volume status and diuretic therapy in systolic heart failure and the detection of early abnormalities in renal and tubular function.
Chiong, J. Loop diuretic therapy in heart failure: the need for solid evidence on a fluid issue. Clin Cardiol 33, —, doi: Keywords: Hyponatremia; chronic kidney disease; end-stage renal disease; epidemiology; mortality; treatment.
Abstract Hyponatremia is a common condition encountered in clinical practice.
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