Determining Fractional Urate Excretion Rates in Hyponatremic Conditions and Improved Methods to Distinguish Cerebral/Renal Salt Wasting From the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Abstract

Our evaluation of hyponatremic patients is in a state of confusion because the assessment of the volume status of the patient and determinations of urine sodium concentrations (UNa) >30-40 mEq/L have dominated our approach despite documented evidence of many shortcomings. Central to this confusion is our inability to differentiate cerebral/renal salt wasting (C/RSW) from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), syndromes with diametrically opposing therapeutic goals. The recent proposal to treat most or all hyponatremic patients makes differentiation even more important and reports of C/RSW occurring without cerebral disease leads to a clinically important proposal to change cerebral to renal salt wasting (RSW). Differentiating SIADH from RSW is difficult because of identical clinical parameters that characterize both syndromes. Determination of fractional urate excretion (FEurate) is central to a new algorithm, which has proven to be superior to current methods. We utilized this algorithm and differences in physiologic response to isotonic saline infusions between SIADH and RSW to evaluate hyponatremic patients from the general medical wards of the hospital. In 62 hyponatremic patients, 17 (27%) had SIADH, 19 (31%) had reset osmostat (RO), 24 (38%) had RSW, 1 due to HCTZ and 1 Addison's disease. Interestingly, 21 of 24 with RSW had no evidence of cerebral disease and 10 of 24 with RSW had UNa < 20 mEqL. We conclude that 1. RSW is much more common than is perceived, 2.the term cerebral salt wasting should be changed to RSW 3. RO should be eliminated as a subclass of SIADH, 4. SIADH should be redefined 5. The volume approach is ineffective and 6. There are limitations to determining UNa, plasma renin, aldosterone or atrial/brain natriuretic peptides. We also present data on a natriuretic peptide found in sera of patients with RSW and Alzheimer's disease.

Keywords: SIADH; cerebral/renal salt wasting; fractional urate excretion; hyponatremia; salt balance.

Figure 1

New algorithm based on determinations of fractional excretion of urate in diverse hyponatremic conditions. Assessment of volume status, UNa, plasma renin, aldosterone and atrial/brain natriuretic peptides are not included because of unreliability in the evaluation of hyponatremic patients.

Figure 2

Differentiation of SIADH and RSW based on differences in relationship to serum sodium concentrations and FEurate. There is ample evidence to support this unique relationship between FEurate and serum sodium in SIADH and RSW.

Figure 3

Demonstration of the effect of large volumes of isotonic saline on FEurate in SIADH. Note the gradual normalization of FEurate by correcting hyponatremia after substituting isotonic with hypertonic saline. This graph illustrates the unique relationship between FEurate and serum sodium in SIADH and supports the notion that saline has a meager effect on FEurate. Correction of hyponatremia with hypertonic saline may be one way to differentiate SIADH from RSW as noted in Figure 4.

Figure 4

Figure demonstrating the ineffectiveness of isotonic saline in SIADH on urine dilution to comply with the term inappropriate secretion of ADH. Like the patient noted in Figure 7, this patient had RSW without evidence of cerebral disease.

Figure 5

Graph demonstrating more potent effect of volume depletion on ADH secretion as demonstrated in Figure 7. Volume repletion would eliminate the volume stimulus for ADH and permit the hypo osmolality to inhibit ADH secretion.

Figure 6

Dilution of urine with isotonic saline in hip fracture patient with RSW without cerebral disease.

Figure 7

Case of hyponatremic patient with pneumonia without cerebral disease responding to isotonic saline by diluting his urine that is consistent with an appropriate increase in ADH in RSW.

Figure 8

Figure demonstrating the concept of DOCA escape where normal subjects received daily injection of a salt retaining mineralocorticoid, desoxycorticosterone acetate (DOCA), while on a constant salt intake. Sodium excretion was initially lower than intake to increase sodium retention and weight gain only to escape the sodium retaining properties of DOCA to reach an equilibrated state where sodium input matched sodium excretion but at a higher weight from the initial sodium retention. If there was not “escape” from the sodium retaining properties of DOCA, sodium retention would persist indefinitely, which does not happen.

Figure 9

This graph illustrates the superiority of determining FEurate in hyponatremic conditions in which UNa can vary considerably in different clinical conditions in which the etiology can be diverse.

Figure 10

Graph showing the different subclasses of SIADH. Type C is patients with a reset osmostat who have normal FEurates as compared to being increased in the typical form of SIADH. In addition the predictable response to water loading supports our contention that patients with RO represent different pathophysiologic characteristics than SIADH and should thus be eliminated as a subclass of SIADH.