**2.1 Pathophysiology of RSW**

RSW starts with a disease entity that appears to induce production of a natriuretic factor(s) that inhibits mainly proximal tubule sodium transport and possibly other solutes such as urate. Depending on the balance between the severity of the sodium transport defect and sodium intake, ECV depletion of varying magnitude ensues. The patient will first enter a stage of negative sodium balance, which will stimulate the renin-angiotensin aldosterone system, reduce atrial/brain natriuretic peptide (A/BNP), alter glomerular hemodynamics and possibly activate neural factors that attempt to decrease sodium excretion. (Abuelo, 2007) In some, a combination of inadequate sodium intake and profound inhibition of tubule sodium transport can lead to severe, symptomatic ECV depletion that is manifested as postural hypotension, unsteady gait, and postural somnolence, dizziness and slurred speech. (Gutierrez et al, 2007; Maesaka et al, 1990, 2007; Wijdicks et al, 1985) A more common scenario is a milder defect in sodium transport and mild ECV depletion that cannot be appreciated unless we refine our ability to diagnose RSW accurately. There are, therefore, different degrees of volume depletion that depend on the severity of the inhibition of renal sodium transport and salt and water intake. The true prevalence of RSW, therefore, cannot be appreciated until we refine methods of determining ECV accurately by simple methods or develop other as yet unidentified methods of defining RSW. Moreover, because SIADH and RSW typically present with hyponatremia, high urine osmolality and UNa, these overlapping features of RSW and SIADH and divergent therapeutic goals of each syndrome introduce an urgency to differentiate one syndrome from the other to achieve these opposing therapeutic goals.

The volume-depleted subject must reach an equilibrated state of sodium balance, otherwise a sustained negative sodium balance will result in total loss of body sodium and collapse of the vascular system. Sodium excretion and UNa can thus be low, if sodium intake is low. (Maesaka et al, 2007) A similar sequence of negative sodium balance followed by equilibration has been noted for SIADH. (Jaenike et al, 1961) The increase in water reabsorption maintains ECV at high normal and increases ANP levels, which can cause natriuresis by multiple factors. (de Zeeuw et al, 1992)

Interestingly, plasma renin in RSW can be variable depending on sodium intake, whereas plasma aldosterone tends to be increased irrespective of sodium intake when volume depleted. (Bitew et al, 2009; Maesaka et al, 2007) In this scenario, we noted increased plasma renin in a patient with RSW while on a low sodium intake. The decrease in sodium delivery to the distal tubule stimulated COX2 activity and increased plasma renin. (Traynor et al, 1999) On the other hand, a salt wasting patient on a normal sodium intake had higher sodium delivery to the distal tubule by virtue of an underlying decrease in proximal tubule sodium transport that failed to increase COX2 activity and maintained normal plasma renin, while being volume depleted. (Bitew et al, 2009; Traynor et al, 1999)

In contrast to SIADH, when ADH production fails to respond to conventional volume and osmolar stimuli, there is appropriate stimulation of ADH production in RSW by ECV depletion. The volume stimulus for ADH production is more potent than the osmolar effect

without cerebral disease. Although an increased FEurate has been demonstrated in a number of patients with RSW, we will withhold including FEurate to our definition of RSW

RSW starts with a disease entity that appears to induce production of a natriuretic factor(s) that inhibits mainly proximal tubule sodium transport and possibly other solutes such as urate. Depending on the balance between the severity of the sodium transport defect and sodium intake, ECV depletion of varying magnitude ensues. The patient will first enter a stage of negative sodium balance, which will stimulate the renin-angiotensin aldosterone system, reduce atrial/brain natriuretic peptide (A/BNP), alter glomerular hemodynamics and possibly activate neural factors that attempt to decrease sodium excretion. (Abuelo, 2007) In some, a combination of inadequate sodium intake and profound inhibition of tubule sodium transport can lead to severe, symptomatic ECV depletion that is manifested as postural hypotension, unsteady gait, and postural somnolence, dizziness and slurred speech. (Gutierrez et al, 2007; Maesaka et al, 1990, 2007; Wijdicks et al, 1985) A more common scenario is a milder defect in sodium transport and mild ECV depletion that cannot be appreciated unless we refine our ability to diagnose RSW accurately. There are, therefore, different degrees of volume depletion that depend on the severity of the inhibition of renal sodium transport and salt and water intake. The true prevalence of RSW, therefore, cannot be appreciated until we refine methods of determining ECV accurately by simple methods or develop other as yet unidentified methods of defining RSW. Moreover, because SIADH and RSW typically present with hyponatremia, high urine osmolality and UNa, these overlapping features of RSW and SIADH and divergent therapeutic goals of each syndrome introduce an urgency to differentiate one syndrome from the other to achieve these

The volume-depleted subject must reach an equilibrated state of sodium balance, otherwise a sustained negative sodium balance will result in total loss of body sodium and collapse of the vascular system. Sodium excretion and UNa can thus be low, if sodium intake is low. (Maesaka et al, 2007) A similar sequence of negative sodium balance followed by equilibration has been noted for SIADH. (Jaenike et al, 1961) The increase in water reabsorption maintains ECV at high normal and increases ANP levels, which can cause

Interestingly, plasma renin in RSW can be variable depending on sodium intake, whereas plasma aldosterone tends to be increased irrespective of sodium intake when volume depleted. (Bitew et al, 2009; Maesaka et al, 2007) In this scenario, we noted increased plasma renin in a patient with RSW while on a low sodium intake. The decrease in sodium delivery to the distal tubule stimulated COX2 activity and increased plasma renin. (Traynor et al, 1999) On the other hand, a salt wasting patient on a normal sodium intake had higher sodium delivery to the distal tubule by virtue of an underlying decrease in proximal tubule sodium transport that failed to increase COX2 activity and maintained normal plasma renin,

In contrast to SIADH, when ADH production fails to respond to conventional volume and osmolar stimuli, there is appropriate stimulation of ADH production in RSW by ECV depletion. The volume stimulus for ADH production is more potent than the osmolar effect

until there are more confirmatory data.

**2.1 Pathophysiology of RSW** 

opposing therapeutic goals.

natriuresis by multiple factors. (de Zeeuw et al, 1992)

while being volume depleted. (Bitew et al, 2009; Traynor et al, 1999)

on ADH production, so a volume depleted patient continues to increase ADH production, increase free water reabsorption and decrease serum sodium and osmolality. (Robertson & Ganguly, 1986) Administration of saline in our patient with RSW eliminated the volume stimulus for ADH production to allow the coexisting hypoosmolality of plasma to inhibit ADH production to indeterminate levels, thus decreasing urine osmolality, increase free water excretion and increase serum sodium, figure 1.

Fig. 1. Urine osmolality and serum sodium concentration during saline infusion at 125 ml/hr. over 48 hour period. Note dilution of urine 13 hours after initiation of saline, at which time a previously increased plasma ADH was not detectable, appropriate AD secretion. See text. (reproduced with permission from publisher)

This appropriate increase in plasma ADH in a patient with unequivocal RSW illustrates this important physiologic difference between RSW and SIADH. (Maesaka et al, 2007, 2009) As noted earlier, the task of clinically determining whether the increase in plasma ADH levels are appropriate or inappropriate rests solely on differences in ECV, since both present with hyponatremia, high urine osmolality and UNa. Our reliance on the assessment of ECV becomes critical in differentiating SIADH from RSW. Our inability to assess this critical parameter remains central to the unresolved controversy regarding the prevalence of SIADH and RSW. (Maesaka et al, 2009, 1999; Oh & Carroll, 1999; Singh et al, 2002).

#### **2.2 Natriuretic factor(s) in RSW**

Atrial or brain natriuretic peptide (A/BNP) has been frequently mentioned as a possible cause of the salt wasting in RSW. (Ellison & Berl, 2007; Palmer, 2003*)* A/BNP has been reported to be increased in patients with subarachnoid hemorrhage (SAH), a condition that has been shown to have a high prevalence for RSW, but it has also been reported to be increased in a non salt wasting syndrome such as SIADH and salt-retaining conditions such as congestive heart failure. (Burnett et al, 1986; Fichman et al, 1974; Wijdicks et al, 1991) The low normal ANP level in RSW is consistent with the volume-depleted state and strongly argues against any role of ANP in salt wasting. (Maesaka et al, 2007, Vogel, 1963)

Complexity of Differentiating Cerebral-Renal Salt Wasting

Wijdicks et al, 1985)

on RSW and SIADH.

from SIADH, Emerging Importance of Determining Fractional Urate Excretion 45

studies in neurosurgical and AD, who had increased FEurate with normonatremia, an association that is highly suggestive of RSW. This conclusion is consistent with the frequency with which RSW is seen in neurosurgical diseases, with and without hyponatremia, see below. (Nelson et al, 1981; Sivakumar et al, 1994; Singh et al, 2002;

The consistent view among internists and nephrologists is that RSW is a rare entity as compared to neurosurgeons, who consider RSW to be a common disorder. This important controversy exists because of the difficulty with which one syndrome can be differentiated from the other by usual clinical criteria. Because of overlapping clinical parameters such as hyponatremia, concentrated urines with high UNa, hypouricemia, increased FEurate, associations with intracranial diseases and normal renal, thyroid and adrenal function, there is a diagnostic dilemma that must be resolved in order to arrive at an appropriate therapeutic strategy for both syndromes. The only difference on first exposure with the patient is the volume depletion in RSW and increased volume in SIADH. (Bitew et al, 2009; Schwartz et al, 1957) Unfortunately, the clinical assessment of the volume status of nonedematous patients has been regarded as consistently inaccurate by usual clinical criteria.

We and others have encountered patients with RSW, who became symptomatic while being water-restricted for an erroneous diagnosis of SIADH. (Gutierrez et al ,2007; Maesaka et al, 1990,2007; Wijdicks et al, 1985 ) The common teaching that RSW is a rare clinical entity virtually eliminates its consideration when encountering patients with nonedematous hyponatremia. Because the major diagnostic conundrum rests with the volume status of these patients, we will review volume studies, mainly in neurosurgical patients, and offer strategies by which we can differentiate one syndrome from the other. In our view, the myriad of studies that have been published on cerebral/renal salt wasting, including the original report on cerebral salt wasting, has not adequately supported the diagnosis of RSW and have contributed to misconceptions. We will attempt to identify parameters by which the diagnosis of RSW can be made in order of their priority. We hope this review will provide information that will allow the reader to assess critically the merit of manuscripts

**4. Evolution of the controversy over the existence and prevalence of RSW** 

The derivation of the controversy regarding the existence and relative prevalence of RSW and SIADH can be appreciated by a brief review of salt balance in normal subjects. Studies in Yanomamo Indians, the "no salt society", support the notion that we require virtually no salt in our diet to maintain normal ECV. (Hollenberg, 1980; Oliver et al, 1975) In Yanomamo Indians, the mean sodium excretion is 1 mmol/day, mean serum sodium 140 mmol/L, mean urine volume 1 L/day and mean blood pressure 102/62 mmHg. (Oliver et al, 1975) These studies suggest that we require little or no salt in our diets to maintain normal ECV. Normal kidneys appear to have an innate sense of what is a normal ECV for that individual and adjust to any fluctuations in sodium intake to maintain ECV within narrow limits. (Hollenberg, 1980) The adjustments, however, are not instantaneous as sodium excretion will exceed input for up to 5 days before reaching equilibrium after an acute reduction in

**3. Controversy over the relative prevalence of RSW and SIADH** 

(Chung et al, 1987; Maesaka et al, 1999; Oh & Carroll; 1999; Singh et al, 2002)

ANP increases GFR, decreases renal blood flow and blood pressure and increases sodium excretion by the increase in GFR and inhibition of sodium transport in the proximal and distal tubule. ANP responds to changes in intravascular volume and would be lower in volume depleted states such as RSW. (Maesaka et al, 2007) The contribution of ANP in maintaining sodium homeostasis has not been clearly established, being considered by some to have no role as compared to others who feel ANP does contribute to sodium balance. (de Zeeuw et al, 1992).

The infusion of BNP into normal subjects increased GFR, decreased renal plasma flow, increased urine flow and sodium excretion, and inhibited plasma renin without affecting blood pressure, angiotensin II or aldosterone levels. There was evidence for inhibition of proximal tubule and larger inhibition of distal sodium transport. (Jensen, 1998) There is questionable relevance of these findings to RSW because A/BNP responds to changes in intravascular volume and are, thus, lower in RSW. (Maesaka et al, 2007; Vogel, 1963) We favor a natriuretic factor that does not have characteristics of A/BNP that is evident in plasma and urine of patients with evidence for RSW, see below.

We infused plasma from patients with neurosurgical and Alzheimer's diseases (AD) with increased FEurate and normonatremia into rats, and demonstrated a significant increase in FElithium and FENa, suggesting that a natriuretic factor(s) had a predominant effect on proximal tubule sodium transport. (Maesaka et al, 1993, 1993) Blood pressure and GFR remained unchanged from baseline and from controls throughout the study. Since lithium transport follows sodium transport on a one to one basis in the proximal tubule in the absence of nonelectrolyte solutes such as mannitol, the significant increase in FElithium from 22.3 and 27.2% in control animals to 36.6 and 41.7% in neurosurgical and AD patients, respectively, indicates that the same fraction of filtered sodium escaped reabsorption in the proximal tubule. (Dorhout Mees,1990; Leyssac et al, 1990; Maesaka et al 1993, 1993) This increase in distal delivery of sodium only increased FENa significantly from control values of 0.3 and 0.33% to 0.59 and 0.63% in rats infused with plasma of neurosurgical and AD, respectively, indicating that the distal tubule had actually increased distal sodium reabsorption from control values of 22.0 and 26.87% to 36.01 and 41.07% of the filtered sodium. (Maesaka et al, 1993, 1993) The significant increase in FENa indicated a net sodium loss in animals infused with plasma of neurosurgical and AD. An unresolved question is whether the increase in the distal delivery of sodium exceeded the capacity of the distal tubule to transport sodium or whether the natriuretic factor(s) had an effect on distal sodium transport as well. These data, nevertheless, indicate that the major site of natriuretic activity resides in the proximal tubule and there was a net loss of sodium. In RSW the increase in FEurate, an anion that is exclusively transported in the proximal tubule, supports our proposal that the major site of solute transport abnormality in RSW is in the proximal tubule and introduces the possibility that the natriuretic factor(s) might affect more than one transporter. (Maesaka & Fishbane, 1998) Moreover, these data do not have any similarities to the effects of A/BNP.

More recently, ammonium precipitates of urinary proteins of 5 of 6 neurosurgical patients with increased FEurate and normonatremia inhibited transcellular 22Na transport in a dosedependent manner across cultured pig proximal tubule cells, LLC-PK1, in transwells, as compared to precipitates from urine of neurosurgical patients with normal FEurate and normonatremia, and SIADH. (Youmans & Maesaka, 2011) These data support our previous

ANP increases GFR, decreases renal blood flow and blood pressure and increases sodium excretion by the increase in GFR and inhibition of sodium transport in the proximal and distal tubule. ANP responds to changes in intravascular volume and would be lower in volume depleted states such as RSW. (Maesaka et al, 2007) The contribution of ANP in maintaining sodium homeostasis has not been clearly established, being considered by some to have no role as compared to others who feel ANP does contribute to sodium balance. (de

The infusion of BNP into normal subjects increased GFR, decreased renal plasma flow, increased urine flow and sodium excretion, and inhibited plasma renin without affecting blood pressure, angiotensin II or aldosterone levels. There was evidence for inhibition of proximal tubule and larger inhibition of distal sodium transport. (Jensen, 1998) There is questionable relevance of these findings to RSW because A/BNP responds to changes in intravascular volume and are, thus, lower in RSW. (Maesaka et al, 2007; Vogel, 1963) We favor a natriuretic factor that does not have characteristics of A/BNP that is evident in

We infused plasma from patients with neurosurgical and Alzheimer's diseases (AD) with increased FEurate and normonatremia into rats, and demonstrated a significant increase in FElithium and FENa, suggesting that a natriuretic factor(s) had a predominant effect on proximal tubule sodium transport. (Maesaka et al, 1993, 1993) Blood pressure and GFR remained unchanged from baseline and from controls throughout the study. Since lithium transport follows sodium transport on a one to one basis in the proximal tubule in the absence of nonelectrolyte solutes such as mannitol, the significant increase in FElithium from 22.3 and 27.2% in control animals to 36.6 and 41.7% in neurosurgical and AD patients, respectively, indicates that the same fraction of filtered sodium escaped reabsorption in the proximal tubule. (Dorhout Mees,1990; Leyssac et al, 1990; Maesaka et al 1993, 1993) This increase in distal delivery of sodium only increased FENa significantly from control values of 0.3 and 0.33% to 0.59 and 0.63% in rats infused with plasma of neurosurgical and AD, respectively, indicating that the distal tubule had actually increased distal sodium reabsorption from control values of 22.0 and 26.87% to 36.01 and 41.07% of the filtered sodium. (Maesaka et al, 1993, 1993) The significant increase in FENa indicated a net sodium loss in animals infused with plasma of neurosurgical and AD. An unresolved question is whether the increase in the distal delivery of sodium exceeded the capacity of the distal tubule to transport sodium or whether the natriuretic factor(s) had an effect on distal sodium transport as well. These data, nevertheless, indicate that the major site of natriuretic activity resides in the proximal tubule and there was a net loss of sodium. In RSW the increase in FEurate, an anion that is exclusively transported in the proximal tubule, supports our proposal that the major site of solute transport abnormality in RSW is in the proximal tubule and introduces the possibility that the natriuretic factor(s) might affect more than one transporter. (Maesaka & Fishbane, 1998) Moreover, these data do not have any similarities

More recently, ammonium precipitates of urinary proteins of 5 of 6 neurosurgical patients with increased FEurate and normonatremia inhibited transcellular 22Na transport in a dosedependent manner across cultured pig proximal tubule cells, LLC-PK1, in transwells, as compared to precipitates from urine of neurosurgical patients with normal FEurate and normonatremia, and SIADH. (Youmans & Maesaka, 2011) These data support our previous

plasma and urine of patients with evidence for RSW, see below.

Zeeuw et al, 1992).

to the effects of A/BNP.

studies in neurosurgical and AD, who had increased FEurate with normonatremia, an association that is highly suggestive of RSW. This conclusion is consistent with the frequency with which RSW is seen in neurosurgical diseases, with and without hyponatremia, see below. (Nelson et al, 1981; Sivakumar et al, 1994; Singh et al, 2002; Wijdicks et al, 1985)
