The term cerebral salt wasting (CSW) was introduced before the syndrome of inappropriate Four years later, Schwartz et al. published their landmark paper on SIADH. . Damaraju SC, Rajshekhar V, Chandy MJ: Validation study of a central. Cerebral salt wasting (CSW) is another potential cause of hyponatremia in those with The causes and diagnosis of hyponatremia, causes and treatment of SIADH, and the general Sivakumar V, Rajshekhar V, Chandy MJ. While fluid restriction is the treatment of choice in SIADH, the treatment .. Differential diagnosis of cerebral salt wasting (CSW) vs syndrome of.

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Hyponatremia is the most common electrolyte abnormality. Its diagnostic and therapeutic approaches are in a state of flux. It is evident that hyponatremic patients are symptomatic with a potential for serious consequences at sodium levels that were once considered trivial. The recommendation to treat virtually all hyponatremics exposes the ssiadh to resolve the diagnostic cerebrla therapeutic dilemma of deciding whether to water restrict a patient with the syndrome of inappropriate antidiuretic hormone secretion SIADH or administer salt and water to a renal salt waster.

In this review, cerebrral briefly discuss the pathophysiology eiadh SIADH and renal salt wasting RSWand the difficulty in differentiating SIADH from RSW, and review the origin of the perceived rarity of RSW, as wasying as the value of determining fractional excretion of urate FEurate in differentiating both syndromes, the high prevalence of RSW which highlights the inadequacy of the volume approach to hyponatremia, the importance of changing cerebral salt wasting to RSW, and the proposal to eliminate reset osmostat as a subtype of SIADH, and finally propose a new algorithm to replace the outmoded volume approach by highlighting FEurate.

Symptoms related to hyponatremia have been traditionally associated with severe hyponatremia and acute reductions in serum sodium, but there is a growing awareness that even mild hyponatremia is associated with mental dysfunction, unsteady gait, osteoporosis, increased falls and bone fractures [ 3456789 ].

Cerebral salt wasting versus SIADH: what difference?

Based on this awareness, there is an evolving tendency to treat every patient with hyponatremia. This recommendation creates an urgent need to assess with assurance the wastjng of the hyponatremia in a group of patients with diverse clinical associations and different therapeutic goals. Unfortunately, the present volume approach to hyponatremia, siqdh has been in existence for decades, has been inadequate and misleading, in part because of misconceptions that are unsubstantiated by supportive data.

Foremost among the misconceptions is the common but unproven perception that cerebral salt wasting CSW is a rare clinical entity.

SIADH versus Cerebral Salt Wasting

Clarification of cerebral, or the more appropriate term, renal salt wasting RSWvide infraand its differentiation from SIADH becomes critical because of opposing therapeutic goals, which are to provide salt and water to a volume depleted patient with RSW and water restriction for a water-loaded patient with SIADH.

The volume stimulus for ADH secretion is common to any state where there is ineffective circulatory volume be it heart failure or true volume aasting. The volume stimulus is more potent than the osmolar stimulus so a volume depleted patient continues to secrete ADH despite becoming progressively hyponatremic as long as the patient continues to take in free water [ 10 ]. Removal of the volume stimulus allows the coexistent hypo-osmolality wastong inhibit ADH secretion, remove water from the body by excreting dilute urines and correcting the hyponatremia to illustrate appropriate ADH secretion in RSW [ 1112 ].

As previously reviewed, the first descriptions of CSW failed to prove with certainty a salt wasting syndrome [ 1314 ]. RSW was possible in one patient who was described as being dehydrated with a urine chloride of Previous studies have demonstrated that a sodium depleted patient will virtually eliminate sodium from urine until the sodium losses have been replaced [ 151617 ].

The high urine chloride and presumably sodium concentration in urine would, thus, have been consistent with RSW and the wastinb CSW was thus derived. SIADH evolved as a clinical entity by the demonstration of a clinical correlate to the seminal work by Leaf et al. The proposal satl an inappropriate secretion of ADH in the absence of methods to determine plasma ADH levels epitomized the application of basic physiologic principles to the bedside [ 19 ]. This hypothesis was later proven by demonstrating inappropriately high ADH levels that did not respond to the usual volume and osmolar stimuli [ 19 ].

An increase in intravascular volume by the gold standard radioisotope dilution method has been demonstrated by others in SIADH [ 122021 ]. The existence of CSW, therefore, was seriously questioned to the point of being considered either nonexistent or certainly rare. Differentiating SIADH from RSW has been extremely difficult to accomplish, in part because of significant overlapping clinical findings between both syndromes.

This diagnostic dilemma needs to cerebgal urgently resolved because of the evolving awareness that even mildly hyponatremic patients are symptomatic and should therefore be treated [ 57 ]. In addition, a fourfold increase in bone fractures in elderly hyponatremic patients and increased osteoporosis with chronic hyponatremia has been reported [ 5722 ].


The urgency in resolving the diagnostic and therapeutic dilemma becomes most evident by the divergence in therapeutic goals of water restricting patients with SIADH and administering salt and water in RSW. There is universal agreement that we cannot assess ECV with any degree of accuracy by usual clinical criteria, yet the approach to hyponatremia starts with an assessment of volume.

The ineffectiveness of this volume approach is becoming even more evident by an objective review of the literature and recent publications of RSW occurring in patients without clinical cerebral disease [ 1112 ]. It is clear from these studies that RSW is much more common than SIADH, yet it is still perceived as a rare clinical entity, which has been propagated for many years without either negating these compelling studies nor by providing evidence to the contrary by suitable methods.

Moreover, water restricting these patients for an erroneous diagnosis of SIADH when in fact they have RSW has been reported to increase morbidity and mortality rates in patients with subarachnoid hemorrhage [ 122425 ]. Summary of volume studies by gold standard radio-isotope dilution methods in hyponatremic neurosurgical patients. Calculation of fractional excretion FE of urate determines the percent excretion of the filtered load of urate at cerebdal glomerulus.

It determines the net transport of urate without distinguishing what xalt secreted or reabsorbed and can be readily determined by collecting blood and spot urine at the same time. FEurate in cerebdal excretion of the filtered load of urate can be wsating by dividing the ratio of urine to plasma urate by the ratio of urine to plasma creatinine and multiplying by FEurate can exceed normal values in patients with reduced GFR, so the algorithm is valid in patients with serum creatinine less than 1.

Shaded areas represent normal ranges. Two unequivocal cases of RSW without clinical evidence of cerebral disease not only verified the persistent increase in FEurate with correction of wasying, but served as the basis for us to make a clinically important proposal to fs CSW to RSW [ 111234 ].

One was a hyponatremic patient with a simple hip fracture with no clinical evidence of cerebral disease who exhibited all of the essential features of RSW. A similar case of RSW was a hyponatremic patient with a pneumonia without cerebral disease, who diluted his urine 20 h after initiating saline therapy [ 11 ].

As in the hip fracture salg, the increased FEurate ceerebral after volume repletion and correction of hyponatremia. A water cerebfal test was normal after volume repletion and correction of his hyponatremia, suggesting that like the patient with a hip fracture, there was an appropriate hypovolemia-induced increase in ADH.

Saline infusions eliminated the volume stimulus szlt ADH secretion to allow the coexistent plasma hypo-osmolality to inhibit ADH secretion, thereby excreting dilute urines and correcting the hyponatremia [ 1112 ]. In two patients with SIADH and increased blood volumes, saline infusion failed to dilute their urine or correct their hyponatremia [ 11 ].

Correction of serum sodium and achievement of dilute urine after saline infusion cerebrap permission, Kidney InternationalMaesaka J.

Cerebral salt wasting versus SIADH: what difference?

As extensively reviewed in our review of renal urate transport, we cite four papers that demonstrate the meager effect of saline infusions on FEurate, Table 3 [ 35363738 ].

The marked reduction in FEurate after the administration of isotonic and hypertonic saline is contradictory to the common belief that saline reduces the net transport of many solutes, cererbal urate. As previously reviewed, the increase in FEurate cannot be explained by the V1 activity of ADH or chronic hyponatremia in SIADH but it is probable that the natriuretic factor demonstrated in RSW might reduce urate transport in the proximal tubule where urate is exclusively transported and is the major site of inhibiting sodium transport by the natriuretic factor [ 394041 ].

Summary of extracellular volume expansion with isotonic, hypotonic and hypertonic saline on fractional excretion of sodium [FEsodium] and urate [FEurate] at control and experimental Exp. The value of determining FEurate in hyponatremic conditions has been further amplified by a normal FEurate being observed in every hyponatremic patient with RO [ 42 ].

The normal FEurate seen in psychogenic polydipsia and possibly in beer potomania can be readily identified by the history of excess intake of water or beer, respectively [ 4243 ]. Based on a large database, we would like to introduce a new, updated algorithm which centers on the determination of FEurate outlined in Figure 3. Each citation can be supported by credible data. This algorithm has been found to be superior to the traditional volume approach, which has been used for decades and is clearly inadequate.

The administration of saline should not affect the FEurate to any significant degree Table 3and drugs such as atorvastatin and losartan which are known to increase urate excretion have not been shown to have a meaningful effect on the results [ 4445 ]. Psychogenic polydipsia can be readily diagnosed by the history of ingesting large volumes of water, having polyuria and excretion of dilute urines, and beer potomania by the history of ingesting large amounts of beer with low solute intake [ 4243 ].


The dotted lines connecting a high FEurate with normonatremia and RSW can be supported by indirect data but it is our belief that this will eventually turn out to be a predictor of RSW without going through a phase of hyponatremia because the patient had very little water intake.

This possibility is evident by the need to ingest water to become hyponatremic, since the insensible water losses are largely hypotonic to induce hypernatremia without sufficient water intake. Developing hyponatremia without water intake is extremely difficult if not impossible to achieve except if UNa exceeds serum sodium concentration in the absence of water intake. In some cases, the reduced salt intake could be iatrogenic.

This has been reported with increased morbidity when the patient with RSW was fluid restricted for an siadb diagnosis of SIADH [ 12242530 ]. The determination of UNa has not been useful in the evaluation of patients with hyponatremia. There is mounting evidence to prove the ineffectiveness of the volume approach to hyponatremia. Surprisingly, about a third of hyponatremic patients outside of the neurosurgical intensive care unit had RSW; the majority demonstrating no clinical evidence of cerebral disease; thus providing additional support for our proposal to change CSW to RSW [ 3449 ].

As discussed, this is an important change, as RSW would otherwise not be siafh in the absence of clinical cerebral disease [ 34 ].

This raises the possibility that the high morbidity and mortality rates associated with hyponatremia may have a significant iatrogenic component secondary to inappropriate water restriction in patients with RSW who were thought to have SIADH. These data provide further evidence for the ineffectiveness of the volume approach to evaluating patients with hyponatremia and support the common notion that we cannot assess the volume status of patients with any degree of accuracy.

To persist in this outmoded approach will lead to misdiagnosis and mistreatment of patients with hyponatremia that will lead to increased morbidity and mortality of a group of patients with what appears to be more serious wastinng conditions.

This differentiation is extremely important because of divergent therapeutic goals of appropriately water restricting those with SIADH and increasing salt and water siad RSW to avoid iatrogenic increases in morbidity and mortality.

The recent recommendations to treat most or all patients with hyponatremia introduce an urgency to resolve this diagnostic and therapeutic dilemma. Changing CSW to RSW is an important modification in nomenclature that will expand our consideration of a large number of RSW patients without evidence of clinical cerebral disease and to avoid mismanagement and possibly reduce morbidity and mortality.

The volume approach to hyponatremia and perception that RSW is a rare clinical entity should be abandoned in favor of a more open-minded approach that will lead to better diagnosis and treatment of hyponatremic conditions.

To this end, we propose a new algorithm that utilizes FEurate as a pivotal determination, Figure 3. Determining FEurate after correcting hyponatremia by cerebbral use of hypertonic saline might be an effective way of differentiating SIADH from RSW Figure 1being mindful of avoiding too rapid correction of hyponatremia to reduce the risk of developing osmotic demyelination, monitor the patient for any evidence of fluid overload such as induction of heart failure and that saline has a meager effect on FEurate.

Portions of the work discussed in this manuscript were supported by a grant from Otsuka America Pharmaceutical, Inc. Maesaka, Louis Imbriano, Joseph Mattana, and Dympna Gallagher have contributed to the design, analysis and interpretation of the results.

Naveen Bade and Sairah Sharif contributed to the analysis and the preparation of this manuscript. National Center for Biotechnology InformationU. Journal List J Clin Med v. Published online Dec 8. Find articles by John K. Find articles by Louis Imbriano. Find articles by Joseph Mattana.

Find sallt by Naveen Bade. Find articles by Sairah Sharif. Author information Article notes Copyright and Ceebral information Disclaimer. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license http: This article has been cited by other articles in PMC. Abstract Hyponatremia is the most common electrolyte abnormality. Open in a separate window.

Table 2 Summary of volume studies by gold standard radio-isotope dilution methods in hyponatremic neurosurgical patients. Table 3 Summary of extracellular volume expansion with isotonic, hypotonic and cerebraal saline on fractional excretion of sodium [FEsodium] and urate [FEurate] at control and experimental Exp. Proposal of New Algorithm Based on a large database, we would like to introduce a new, updated algorithm which centers on the determination of FEurate outlined in Figure 3.

Algorithm for determining cause of cersbral, using FEurate. Acknowledgments Portions of the work discussed in this manuscript were supported by a grant from Otsuka America Ceeebral, Inc. Author Contributions John K. Conflicts of Interest The authors declare no conflict of interest. The syndrome of inappropriate antidiuresis. Moderate hyponatremia is associated with increased risk of mortality: