Cerebral/Renal Salt Wasting in Hyponatremia: History
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Contributor:
John K. Maesaka
,
Louis J. Imbriano
,
Candace Grant
,
Nobuyuki Miyawaki

There is a tendency to treat all patients with hyponatremia because of common subtle symptoms that include unsteady gait that lead to increased falls and bone fractures and can progress to mental confusion, irritability, seizures, coma and even death. There is a new approach that is superior to the ineffectual volume approach. Determination of fractional excretion (FE) of urate has simplified the diagnosis of a reset osmostat, Addison’s disease, edematous causes such as congestive heart failure, cirrhosis and nephrosis, volume depletion from extrarenal salt losses with normal renal tubular function and the difficult task of differentiating the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C/RSW). SIADH and C/RSW have identical clinical and laboratory parameters but have diametrically opposite therapeutic goals of water-restricting water-loaded patients with SIADH or administering salt water to dehydrated patients with C/RSW.

  • cerebral/renal salt wasting
  • natriuretic peptide
  • hyponatremia

1. It Is Time to Abandon the Outmoded Volume Approach

The diagnostic approach to hyponatremia has traditionally started with an assessment of the state of extracellular volume, designated as being euvolemic, hypervolemic or hypovolemic, despite a general acceptance that researchers cannot accurately assess the volume status of patients by usual clinical criteria [1].
Foremost among the limitations is to resolve the conundrum of differentiating “euvolemic” patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from hypovolemic patients with cerebral/renal salt wasting (C/RSW) by this ineffectual and technically inaccurate volume approach, as all credible volume determinations in SIADH have shown them to be hypervolemic and not euvolemic [2][3][4][5]. Moreover, this diagnostic dilemma is compounded by having identical clinical and laboratory characteristics that are shared by both SIADH and C/RSW. Both present with normal renal, adrenal and thyroid function, hyponatremia, hypouricemia, concentrated urine with urine sodium concentration (UNa) usually >30 mmol/L and increased fractional excretion (FE) of urate >11%. Studies which utilize these criteria to confirm the diagnosis of SIADH without going through the rigors of differentiating SIADH from C/RSW, should, therefore, be met with legitimate skepticism. It might, however, be an impractical effort to resolve this diagnostic dilemma when C/RSW is considered to be a very rare or non-existent syndrome [6][7][8]. As discussed in previous publications, the perception of the rarity or non-existence of C/RSW is understandable because the original paper on salt wasting failed to prove such a syndrome existed [9][10]. It would be a wasted effort to go through the difficult process of differentiating SIADH from C/RSW if C/RSW is indeed a rare or non-existent syndrome. This diagnostic dilemma, however, needs to be resolved because researchers developed a more pathophysiologic approach over the past 30 years and found C/RSW to occur in 38% of hyponatremic patients in the general medical wards of the hospital [11]. The high prevalence of C/RSW, thus, creates an important therapeutic dilemma of deciding whether to water-restrict or administer the inhibitor of the V2 pitressin receptor to water-loaded hypervolemic patients with SIADH or administer salt and water to volume-depleted patients with C/RSW [11]. Application of this new pathophysiologic approach has improved identification of the different causes of hyponatremia with greater clarity. Moreover, the recent identification of haptoglobin related protein without signal peptide (HPRWSP) as the probable cause of C/RSW can serve as a biomarker to simplify the diagnosis of C/RSW on first encounter when initiation of saline infusions to these dehydrated patients will improve clinical outcomes [12].

2. Utilization of FEurate and Response to Isotonic Saline in Evaluation of Hyponatremic Patients

Researchers decided to determine whether hyponatremic patients with increased FEurate >11% diluted their urine and corrected their hyponatremia with infusions of isotonic saline and determined FEurate before and after correction of their hyponatremia in 62 hyponatremic patients recruited from the general medical wards of the hospital [11]. According to the algorithm presented 17 (27%) had SIADH based on normalization of a previously increased FEurate after correcting their hyponatremia in 5 and 17 failing to dilute their urine or correct their hyponatremia after receiving ample volumes of isotonic saline. Twenty four (38%) had C/RSW. Twelve had persistently increased FEurate after correcting their hyponatremia, 19 had isotonic saline-induced dilute urines with 10 requiring infusions of D5W to prevent too rapid correction of their hyponatremia and osmotic demyelination syndrome [13]. Six of the 19 patients who had isotonic saline-induced dilute urines also had persistently increased FEurate after correction of their hyponatremia. Twenty one of the 24 patients did not have clinical evidence of cerebral disease to support the proposal to change cerebral to renal salt wasting (RSW) [14]. This change in nomenclature is extremely important because many C/RSW patients would otherwise not consider renal salt wasting in the absence of cerebral disease. Researchers will thus use the more appropriate term, RSW, instead of C/RSW for the rest of this entry. Textbooks and many review articles on hyponatremia consider CSW, or more appropriately RSW, to be a rare clinical entity, so the majority of these patients are being fluid-restricted for an erroneous diagnosis of SIADH. This mistreatment of patients with RSW could in part account for the increased morbidity and mortality associated with hyponatremia. Nineteen (31%) had RO based on a normal FEurate in all patients and 8 had confirmatory spontaneously excreted dilute urines. It is interesting to note that baseline UNa <20 mmol/L was found in 10 patients with RSW as compared to 5 with a reset osmostat and 2 with SIADH, suggesting that patients with RSW had lost their appetite and consumed less sodium, probably because of the severity of their comorbid conditions. These patients would not have been considered to have RSW or SIADH by utilizing algorithms which state that UNa is >30 or >40 mmol/L [15][16]. Determining UNa is, therefore, less reliable when evaluating patients with hyponatremia. One each had hyponatremia due to hydrochlorothiazide and Addison’s disease [11].
It should be pointed out that it is extremely difficult to differentiate SIADH from RSW by the methods described above. FEurates must be determined after correction of the hyponatremia or isotonic saline infusions initiated with frequent urine osmolality determinations to see if isotonic saline infusions diluted or failed to dilute the urine when there are length of stay concerns. Successful execution of this difficult protocol was possible by a funded study, which provided the necessary personnel to perform these studies on a timely basis, especially the unexpected high prevalence of RSW in the general medical wards of the hospital. Challenges continue to confront people as researchers attempt to simplify methods to identify the different causes of hyponatremia, especially to differentiate RSW from SIADH.

3. Pathophysiology of RSW

RSW of the type does not include other causes of salt wasting such as chronic kidney disease, Addison’s disease, Bartter’s or Gitelman’s syndromes. It occurs in patients with normal kidney function with creatinine not exceeding 1.3 mg/dL and normal thyroid function. It goes through two important physiologic phases that start with the upregulation of a natriuretic protein such as the recently identified HPRWSP by a multitude of cerebral and many non-cerebral conditions with or without hyponatremia [12].

3.1. Initiation of Nonequilibrated Phase

The natriuretic factor, HPRWSP, has its major effect on proximal tubule sodium transport to increase sodium and water excretion, which exceeds sodium and water intake to decrease extracellular volume. The extent of the volume depletion depends on the balance between the potency of the natriuretic factor in increasing salt and water excretion and salt and water intake. The deficits in sodium and water can be significant enough to cause hemodynamic instability with lower blood pressure and even postural hypotension with reflex tachycardia. This non equilibrated state is difficult to document in the majority of cases because of its short duration. This phase was documented in a 74 year old female hypertensive who sustained a subarachnoid hemorrhage. Her admission systolic blood pressure of 166 mmHg decreased to 98 and 93 mmHg when saline infusions lagged behind an increasing urine output between days 2 and 5. She received four 250 mL IV boluses of isotonic saline to maintain hemodynamic stability untilthe saline infusion matched the urine output of 4–5 L/day [12]. She was not hyponatremic at any time because infusion of isotonic saline has become a standard of care for SAH after reports of fluid restriction increasing morbidity and mortality [17]. The volume depletion appropriately increases the production of renin, aldosterone and ADH and reducing blood pressure and glomerular filtration rates as part of the activating humoral, hemodynamic and neural factors that attempt to reduce sodium and water excretion.

3.2. Equilibrated State

The patients eventually escape the effects of the salt wasting natriuretic protein by undergoing humoral, hemodynamic and neuronal compensations and enter an equilibrated state where sodium and water intake matches sodium and water output but at lower total body salt and water volumes. In this volume-depleted state sodium excretion and even serum sodium concentration will depend on the intake of sodium and water. As noted in 62 hyponatremic patients, 10 of the 24 patients with RSW had UNa <20 mmol/L at a time when they were in the equilibrated phase when sodium input equals output and in a state where their comorbid conditions were severe enough to reduce appetite and sodium intake [11]. An unappreciated aspect of hyponatremic conditions is the need to have sufficient water intake to induce hyponatremia. This is examplified by the inability to induce hyponatremia in healthy humans and dogs given daily injections of pitressin without increasing water intake [18][19]. Since humans lose approximately 500 mL of pure water as insensible water losses each day, Researchers will all become hypernatremic without sufficient water intake. Hyponatremia can only occur when water intake exceeds insensible water losses. Infusions of isotonic saline appears to correct the volume depletion partially as a large part of the infused saline will significantly increase urine output along with very troublesome nocturia. Fortunately, the duration of RSW appears to be of short duration as the comorbid condition subsides. The most effective treatment is to develop an inhibitor to the natriuretic protein, HPRWSP, which would eliminate the distressing urinary frequency and nocturia.

4. Identification of Haptoglobin Related Protein without Signal Peptide as Natriuretic Factor in RSW

Researchers previously injected the plasma of 21 patients with neurosurgical diseases and 18 AD patients into rats and demonstrated significant increases in FENa, FElithium and urine flow rates without changing blood pressure or glomerular filtration rates as compared to normal and gender-matched controls in both studies and vascular dementia in the AD study [20][21]. Because urate is exclusively transported in the proximal tubule, Researchers decided to investigate lithium transport because lithium is transported mainly in the proximal tubule on a one to one basis with sodium [22]. LIthium can thus be a reliable marker of sodium transport in the proximal tubule. Significant advancements in protein analysis over the ensuing 25 years allowed people to identify the natriuretic protein that was present in the serum of a salt wasting patient due to a subarachnoid hemorrhage (SAH) and another due to AD. Researchers accomplished this by performing rat renal clearance studies after injecting the rats with natriuretic activity in their sera [12]. In these studies, FENa increased from 0.2 to 0.5 and 0.69% and FELi increased from 23.9 to 46.1% and 24.4 to 52.2% in the SAH and AD patients, respectively [12]. Since lithium is transported one to one in the proximal tubule with sodium, the 46.1 and 52.2% FELi estimates the amount of sodium being delivered to the distal tubule. The FENa of 0.5 and 0.69% in the final urine suggests that 45.6 of the 46.1 and 51.51 of the 52.2% of the filtered sodium was reabsorbed by the distal nephron in the SAH and AD studies, respectively [12]. These data suggest that the natriuretic protein has a profound effect on proximal tubular sodium transport as well as demonstrating the robust capacity of the distal nephron to transport sodium.
Utilization of the sophisticated protein analysis revealed levels of haptoglobin related protein to be highest as compared to control sera. Haptoglobin related protein with signal peptide did not have natriuretic activity but HPRWSP was the only protein with natriuretic activity in SAH and AD sera. HPRWSP had a dose response with significant increases in FENa and urine flow rate [12]. Because FENa and urine flow rates increased as the dose of HPRWSP was increased, the progressive increase in FElithium with worsening dementia in AD suggests that blood levels of HPRWSP were also increasing progressively [21]. These data suggest that all AD patients with mini-mental state examination (MMSE) of less than 12 are not only dehydrated but become progressively more dehydrated as their dementia worsens. These data suggest that a new syndrome of RSW not only exists in moderately demented patients with AD but also worsens as they become more demented. Future studies must estimate the existence and prevalence of RSW at different stages of their dementia and determine whether HPRWSP can serve as a biomarker to identify patients with RSW. It will be interesting to determine the effect of inhibiting HPRWSP on mental and physical function in AD.

5. RSW Occurring without Hyponatremia, Especially Alzheimer’s Disease and Subarachnoid Hemorrhage

Blood volume studies in patients with subarachnoid hemorrhage revealed 8 of 9 hyponatremic and 8 of 12 normonatremic patients to be volume depleted, suggesting that RSW occurs commonly in hyponatremic and normonatremic patients with SAH [5]. Water restricting hyponatremic patients with SAH has been shown to increase morbidity and mortality by increasing vascular spasm to increase ischemia and infarction of the brain. [17] It is now standard practice to administer isotonic saline to these and possibly other patients with neurosurgical diseases to reduce the likelihood of developing hyponatremia. RSW is probably present in many normonatremic patients.
Hyponatremia in AD is also an unusual occurrence because these patients limit their water intake by the natural reduction in thirst with aging in addition to the dementia that reduces water intake for multiple reasons. As stated above, RSW is not only present but appears to worsen as the MMSE levels decrease below 12 and future studies must determine the prevalence of RSW at all stages of dementia and whether HPRWSP can serve as a biomarker of RSW in AD. It should be noted that the identification of HPRWSP as the natriuretic factor in RSW was accomplished in normonatremic SAH and AD patients. The essential development of HPRWSP as a biomarker for RSW will give people the opportunity to identify RSW in hyponatremic and a potentially large group of normonatremic patients.
HPRWSP is the first legitimate inhibitor of proximal tubular sodium transport and can significantly mobilize fluid overload in patients with congestive heart failure when combined with a distal diuretic such as furosemide. Congestive heart failure induces pre renal azotemia by increasing the reabsorption of sodium and other solutes in the proximal tubule, which reduces the effectiveness of distal diuretics. As noted, the significant increases in FElithium quantitates the profound effect on proximal tubular sodium transport so its combination with the traditional distal diuretics will significantly increase sodium and water excretion with removal of the excess fluid in heart failure. The benefit of combining acetazolamide, a weak proximal diuretic, with furosemide in patients with acute heart failure improved outcomes and decreased length of stay [23]. Combining HPRWSP with a distal diuretic in patients with acute decompensated CHF and even CHF in an outpatient setting has the potential of improving outcome in CHF.

This entry is adapted from the peer-reviewed paper 10.3390/jcm11247445

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