New Approach to Hyponatremia: High Prevalence of Cerebral/Renal Salt Wasting, Identification of Natriuretic Protein That Causes Salt Wasting

Abstract

Our understanding of hyponatremic conditions has undergone major alterations. 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. We describe 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. In a study of nonedematous patients with hyponatremia, we utilized FEurate and response to isotonic saline infusions to differentiate SIADH from C/RSW. Twenty-four (38%) of 62 hyponatremic patients had C/RSW with 21 having no clinical evidence of cerebral disease to support our important proposal to change cerebral to renal salt wasting (RSW). Seventeen (27%) had SIADH and 19 (31%) had a reset osmostat. One each from hydrochlorothiazide and Addison's disease. We demonstrated natriuretic activity in the plasma of patients with neurosurgical and Alzheimer diseases (AD) in rat clearance studies and have now identified the natriuretic protein to be haptoglobin related protein without signal peptide (HPRWSP). We introduce a new syndrome of RSW in AD that needs further confirmation. Future studies intend to develop HPRWSP as a biomarker to simplify the diagnosis of RSW in hyponatremic and normonatremic patients and explore other clinical applications that can improve clinical outcomes.

Keywords: cerebral/renal salt wasting; fractional urate excretion; hyponatremia; natriuretic peptide.

Figure 1

Figure depicting the handling of filtered urate, lithium and sodium by different segments of the renal tubule under normal (green) conditions and after infusion of serum from patients with RSW (yellow): one due to a subarachnoid hemorrhage and another due to Alzheimer’s disease. Net proximal reabsorption represents the percent reabsorption of urate, lithium (Li⁺) and sodium (Na⁺) in the proximal tubule. Remaining at the end of proximal tubule (PT) represents the percentage of each solutes filtrate entering the early Loop of Henle. Final urine FE represents the net handling of solute expressed as the fraction of filtered solute excreted in the urine. Yellow boxes indicate the percent of the filtered urate, lithium and sodium remaining at the end of the proximal tubule and in the final urine when rats were injected with serum of a patient with a subarachnoid hemorrhage (SAH) and another with Alzheimer’s disease (AD). Note the identical amount of sodium and lithium leaving the proximal tubule and how sodium is much lower than lithium in the final urine because sodium is reabsorbed by the distal tubule but not lithium.

Figure 2

Algorithm utilizing FEurate to identify the different causes of hyponatremia. FEurate can be used to identify different causes of hyponatremia. Note the increased FEurate in patients with SIADH and RSW who have identical clinical and laboratory parameters when hyponatremic. The response to isotonic saline infusions in patients with increased FEurate >11% can be used to differentiate SIADH from RSW. Note how the changes in FEurate after correction of their hyponatremia with isotonic saline infusions can differentiate SIADH from RSW. See Figure 3.

Figure 3

Effect of isotonic saline on urine osmolality. (A) The effect of isotonic saline infusion on urine osmolality and serum sodium in a volume depleted hip fracture patient without cerebral disease who had increased plasma levels of renin, aldosterone and ADH. Graph. Note progressive dilution of urine with undetectable level of ADH when urine was most dilute. Because water was removed from the body by excretion of dilute urines, serum sodium normalized within 48 h. (B) Graph showing response to isotonic saline infusion in a patient with SIADH who had increased blood volume and decreased plasma renin and aldosterone levels. Note the absence of dilute urines or correction of hyponatremia. This patient failed to inhibit ADH in the absence of volume depletion and presence of hypo-osmolality to meet criteria for SIADH. (C) Algorithm using urine osmolality response to isotonic saline to differentiate SIADH from RSW.

Figure 4

Graph demonstrating the progressive increase in ADH levels with worsening volume depletion despite the coexistence of plasma hypo−osmolality; the volume stimulus is more potent than the osmolar stimulus. This is why a volume depleted patient remains hyponatremic while drinking water. Isotonic saline infusions will eliminate the volume stimulus and allow the hypo−osmolality or hyponatremia to inhibit ADH secretion, get rid of the excess water and correct the hyponatremia.

Figure 5

Graph showing the effect of increasing dose of the natriuretic protein, haptoglobin related protein without signal peptide on fractional excretion of sodium (FENa) and urine flow rates (UFR). Note the robust increase in both with increasing doses of the natriuretic protein.

Figure 6

Graph showing the relationship between fractional excretion of lithium (FElithium) and mini mental state examination (MMSE) scores in patients with Alzheimer’s disease and multi−infarct dementia. Note the increasing FElithium as MMSE is decreasing. Because there is a dose response to the natriuretic factor, blood levels of the natriuretic factor either increased or the patient became more dehydrated as the dementia worsened.