**6. Renal salt wasting without clinical evidence of cerebral disease**

To add further confusion to the dilemma of differentiating SIADH from RSW, we recently published 2 cases of unequivocal RSW without cerebral disease. (Bitew et al, 2009; Maesaka et al, 2007) One very instructive case was a hyponatremic patient with a hip fracture, who was initially water-restricted for 7 days for an erroneous diagnosis of SIADH by an internist. While being water-restricted, her Uosm was 362 mosm/kg and UNa only 6 mmol/L, which was initially construed as being consistent with hypovolemic hyponatremia of the prerenal type when UNa is typically low. A serum urate of 3.4 mg/dL, however, was not consistent with prerenal azotemia and more consistent with SIADH and RSW. A volume-depleted patient with normal kidney function would have higher serum urate with a FEurate below 3%. (Steele, 1969) Based on this reasoning, we performed a blood volume determination by gold standard radioisotope dilution methods and started saline infusion after baseline studies were collected. As expected the FEurate was markedly elevated at 29.6%, which was consistent with both SIADH and RSW, but a 7.1% reduction in blood volume was consistent with RSW. Increased baseline plasma renin and aldosterone and low normal ANP strongly supported the diagnosis of RSW. The low UNa of 6 mmol/L was attributed to a loss of appetite and reduced salt intake while being fluid-restricted to 750 ml/day for 7 days prior to our studies. She was feeling weak and anorectic while being fluid-restricted and felt stronger with increased appetite approximately 18 hours after initiating saline infusion. The baseline Uosm of 362 mosm/kg was attributed to a low medullary solute concentration resulting from low salt intake. A Uosm of 587 mosm/kg in the first urine passed after initiation of saline infusion supports our contention that the low salt intake decreased medullary solute concentration and decreased concentrating ability of the kidney, figure 1. The UNa of 6 mmol/L reflects her low sodium intake and reduction of renal medullary solute content. Moreover, saline infusion progressively diluted the urine to a Uosm of 152 mosm/kg 13 hours after initiating saline therapy, at which time plasma ADH decreased from a baseline of 1.9 pg/mL to indeterminate levels. The elimination of the volume stimulus for ADH production by saline allowed the coexisting hypo-osmolality to inhibit ADH production and induce excretion of dilute urines as serum sodium increased from a baseline 120 to 138 mmol/L in the next 48 hours, figure 1. (Maesaka et al, 2007)

In a retrospective study of 319 patients with SAH, 179 were hyponatremic and met criteria for SIADH and CSW. They found that 69.2% had SIADH, 6.5% CSW and 4.8% a combination of SIADH and CSW. The volume status was determined by CVP measurements, presence of hypotension and undefined parameters. This report suffers by its retrospective design, paucity of data to support their diagnoses and reliance on CVP measurements that have little value in assessing ECV. (Sherlock et al, 2006) In a similar retrospective study that included a variety of intracranial diseases, they found 62% of patients to have SIADH, 26.7% hypovolemic, 16.6% drug-related, 4.8% CSW, 3.7% related to IV fluids and 2.7% a combination of CSW and SIADH. In both studies, the combination of SIADH and CSW in 4.8% and 2.7% of patients lacked supportive data to justify such a difficult and improbable diagnostic combination, especially in a retrospective study.

**6. Renal salt wasting without clinical evidence of cerebral disease** 

baseline 120 to 138 mmol/L in the next 48 hours, figure 1. (Maesaka et al, 2007)

To add further confusion to the dilemma of differentiating SIADH from RSW, we recently published 2 cases of unequivocal RSW without cerebral disease. (Bitew et al, 2009; Maesaka et al, 2007) One very instructive case was a hyponatremic patient with a hip fracture, who was initially water-restricted for 7 days for an erroneous diagnosis of SIADH by an internist. While being water-restricted, her Uosm was 362 mosm/kg and UNa only 6 mmol/L, which was initially construed as being consistent with hypovolemic hyponatremia of the prerenal type when UNa is typically low. A serum urate of 3.4 mg/dL, however, was not consistent with prerenal azotemia and more consistent with SIADH and RSW. A volume-depleted patient with normal kidney function would have higher serum urate with a FEurate below 3%. (Steele, 1969) Based on this reasoning, we performed a blood volume determination by gold standard radioisotope dilution methods and started saline infusion after baseline studies were collected. As expected the FEurate was markedly elevated at 29.6%, which was consistent with both SIADH and RSW, but a 7.1% reduction in blood volume was consistent with RSW. Increased baseline plasma renin and aldosterone and low normal ANP strongly supported the diagnosis of RSW. The low UNa of 6 mmol/L was attributed to a loss of appetite and reduced salt intake while being fluid-restricted to 750 ml/day for 7 days prior to our studies. She was feeling weak and anorectic while being fluid-restricted and felt stronger with increased appetite approximately 18 hours after initiating saline infusion. The baseline Uosm of 362 mosm/kg was attributed to a low medullary solute concentration resulting from low salt intake. A Uosm of 587 mosm/kg in the first urine passed after initiation of saline infusion supports our contention that the low salt intake decreased medullary solute concentration and decreased concentrating ability of the kidney, figure 1. The UNa of 6 mmol/L reflects her low sodium intake and reduction of renal medullary solute content. Moreover, saline infusion progressively diluted the urine to a Uosm of 152 mosm/kg 13 hours after initiating saline therapy, at which time plasma ADH decreased from a baseline of 1.9 pg/mL to indeterminate levels. The elimination of the volume stimulus for ADH production by saline allowed the coexisting hypo-osmolality to inhibit ADH production and induce excretion of dilute urines as serum sodium increased from a

**5.2 Other pertinent studies** 

(Sherlock et al, 2006, 2009)

Interestingly, the baseline FEurate of 29.6% increased further to a peak of 63% and 48% at the time of correction of the hyponatremia at 138 mmol/L, figure 2. The effect of saline on FEurate has been amply shown to be minimal. This persistently increased FEurate after correction of hyponatremia is consistent with RSW and not SIADH, to be discussed later. (Maesaka et al, 2007).

Fig. 2. Relationship between serum urate, serum sodium and FEurate during volume repletion with saline for 48 hours. Note that persistence of increased FEurate after correction of hyponatremia contrasts this to SIADH. Saline has been amply shown to have a meager effect on FEurate. (reproduced with permission from publisher)

In our view, this very instructive case followed predicted physiologic parameters for RSW and proved unequivocally the existence of RSW by collectively demonstrating the critical decrease in blood volume, increased plasma renin and aldosterone, low normal plasma ANP, appropriately increased plasma ADH, which was inhibited by the combination of volume repletion and hypo-osmolality, increased free water excretion, and timely correction of hyponatremia. These compelling data proved that RSW can occur without evidence of clinical cerebral disease and that a low sodium intake will be associated with a low UNa in a patient with RSW. (Maesaka et al, 2007)
