More on Renal Salt Wasting Without Cerebral Disease: Response to Saline Infusion

CJASN ePress. Published on February 6, 2009 as doi: 10.2215/CJN.02740608

Solomon Bitew,* Louis Imbriano,*† Nobuyuki Miyawaki,*† Steven Fishbane,*† and John K. Maesaka*† *Division of Nephrology and Hypertension and Department of Medicine, Winthrop-University Hospital, Mineola, New York; and †State University of New York Stony Brook Medical School, Stony Brook, New York

Background and objectives: The existence and prevalence of cerebral salt wasting (CSW) or the preferred term, renal salt wasting (RSW), and its differentiation from syndrome of inappropriate antidiuretic hormone (SIADH) have been controver- sial. This controversy stems from overlapping clinical and laboratory findings and an inability to assess the volume status of these patients. The authors report another case of RSW without clinical cerebral disease and contrast it to SIADH. Design, setting, participants, & measurements: Three patients with hyponatremia, hypouricemia, increased fractional excretion (FE) of urate, urine sodium >20 mmol/L, and concentrated urines were infused with isotonic saline after collection of baseline data. Results: One patient with RSW had pneumonia without cerebral disease and showed increased plasma aldosterone and FEphosphate, and two patients with SIADH had increased blood volume, low plasma renin and aldosterone, and normal FEphosphate. The patient with RSW responded to isotonic saline by excretion of dilute urines, prompt correction of hyponatremia, and normal water loading test after volume repletion. Hypouricemia and increased FEurate persisted after correction of hyponatremia. Two patients with SIADH failed to dilute their urines and remained hyponatremic during 48 and 110 h of saline infusion. Conclusions: The authors demonstrate appropriate stimulation of ADH in RSW. Differences in plasma renin and aldosterone levels and FEphosphate can differentiate RSW from SIADH, as will persistent hypouricemia and increased FEurate after correction of hyponatremia in RSW. FEphosphate was the only contrasting variable at baseline. The authors suggest an approach to treat the hyponatremic patient meeting criteria for SIADH and RSW and changing CSW to the more appropriate term, RSW. Clin J Am Soc Nephrol 4: 309–315, 2009. doi: 10.2215/CJN.02740608

he differentiation of SIADH from cerebral salt wasting best defined as extracellular volume (ECV) depletion caused by syndrome (CSW) or the preferred term, renal salt wast- a tubular defect in sodium transport with or without hypona- T ing (RSW), represents one of the diagnostic conun- tremia or urinary sodium (UNa) Ͼ 20 mmol/L. Unfortunately, drums that includes the fundamental question of the existence the clinical assessment of ECV, the only differentiating variable and prevalence of RSW (1–4). This conundrum exists because on first encounter, is fraught with errors unless invasive proof multiple overlapping clinical associations and laboratory cedures, such as determination of blood volume by radioiso- abnormalities that characterize both syndromes and the dearth tope dilution methodology, pulmonary wedge, or central ve- of specific parameters that distinguish one syndrome from the nous pressures are used (1–4). The determination of ECV by other (1–4). The increasing acceptance of RSW as a clinical tenuous clinical criteria in the original description of RSW may entity among internists and the realization that RSW might be have contributed to the belief that this was a case of SIADH and more common than previously acknowledged collectively in- not RSW (7). On the basis of the definition of RSW and the tensify the need to differentiate one syndrome from the other difficulty of clinically assessing ECV, the best method of esti- (1,3,4–6). The divergent therapeutic goals make this differenti- mating the prevalence of RSW is to determine ECV by invasive ation even more important: to fluid-restrict in SIADH or pro- methods. Only three reports involving more than a single pa- vide salt and water supplementation in RSW. tient meet these criteria, and in these studies, 67% to 100% of In general, neurosurgeons believe RSW to be more common hyponatremic neurosurgical patients were found to be hypo- than SIADH, whereas internists believe RSW to be rare. RSW is volemic with high UNa, suggesting that RSW is not rare but is more common than SIADH in neurosurgical patients (8–10). Received June 5, 2008. Accepted November 17, 2008. Moreover, UNa, plasma renin, aldosterone, and atrial/brain Published online ahead of print. Publication date available at www.cjasn.org. natriuretic peptide; serum and urinary urate excretion rates; determination of hemoglobin, hematocrit, serum total protein, S.B.’s current affiliation is Kaiser Permanente WLA Medical Center, Los Angeles, California. and albumin; and clinical assessment of ECV are inconsistent,

Correspondence: Dr. John K. Maesaka, 200 Old Country Road, Suite 135, Mineola, inaccurate, or not available on first encounter. NY 11501. Phone: 516-663-2169; Fax: 516-663-2179; E-mail: [email protected] To bring clarity to a perplexing clinical controversy, we un-

Copyright © 2009 by the American Society of Nephrology ISSN: 1555-9041/402–0309 310 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 309–315, 2009 equivocally described RSW in a patient without clinical cere- intake. The morning serum cortisol, TSH, and T4 were normal in all bral disease. We demonstrated the value of determining serum three patients. Blood volume was obtained in two subjects at baseline, 125 urate levels in hyponatremia and fortified our contention that using 51Cr-labeled red blood cells and I serum albumin by standard the persistence of hypouricemia and elevated fractional excre- dilution techniques. All three patients received isotonic saline at 50 to 75 ml/h while on unrestricted food and fluid intake. Serum electro- tion (FE) of urate after correction of hyponatremia differentiate lytes, BUN, creatinine, urate, and phosphate were determined concom- RSW from SIADH, since the hypouricemia and elevated itantly with urine osmolality, sodium, potassium, creatinine, urate, and FEurate in SIADH normalize after correction of the hyponatremia phosphate at regular intervals during the study. (1,5,11–18). Differences in urate metabolism, however, are evident only after correction of the hyponatremia and would not con- tribute to differentiating SIADH from RSW on first encounter. Results Patient 1-RSW, An 80-yr-old male, was admitted with a 3-day We describe three patients with hyponatremia with co- history of sore throat, cough productive of white phlegm, mal- existent hypouricemia and increased FEurate, one with RSW aise, fever of 102°F and pneumonia on chest x-ray. On physical without cerebral disease and the other two as SIADH with examination he had a pulse of 100 bpm, temperature 98.9°F, cerebral/neurologic disease. Both groups responded differ- and BP 124/76 mmHg. He had rales in the right lower lung ently to saline infusions and in the case of RSW, there was fields and was cognitively intact, with a normal neurologic persistence of hypouricemia and increased FEurate after cor- examination. The serum creatinine was 1.0 mg/dl, BUN 14 rection of hyponatremia mg/dl, serum sodium 125 mmol/L, potassium 4.3 mmol/L, urate 2.5 mg/dl, phosphate 3.5 mg/dl, osmolality 263 mosm/ Materials and Methods kg, UNa 39 mmol/L, and Uosm 386 mosm/kg (Table 1). The This study was approved by the Institutional Review Board in ac- patient initially received a rapid intravenous infusion of 500 ml cordance with the Declaration of Helsinki. Every patient signed an informed consent. Baseline studies included serum sodium, potassium, isotonic saline followed by a constant infusion at 75 ml/h for chloride, carbon dioxide, blood urea nitrogen (BUN), creatinine, urate, 4.5 h, in addition to 250 ml of saline containing doxycycline phosphate, calcium, glucose and osmolality, plasma renin and aldoste- before being switched to oral Ofloxacin. He received a total of rone, routine urinalysis and urine osmolality (Uosm), creatinine, so- 1340 ml of saline as serum sodium increased from 125 to 132 dium, potassium, urate, and phosphate while on unrestricted food mmol/L and the Uosm decreased from 386 to 284 mosm/kg.

Table 1. Summary of baseline data and after correction of hyponatremia in patient 1 with RSW and baseline data in patients 2 and 3 with SIADH

Serum

Na, K, Cl, CO2, BUN, Creatinine, Uric Acid, Phosphate, mmol/L mmol/L mmol/L mmol/L mg/d mg/d mg/d mg/d

Patient 1 125 4.8 89 22 14 1 2.5 3.4 Correction 138 1.5 Patient 2 126 3.7 97 25 11 0.7 1.6 2.7 Patient 3 131 3.8 97 28 14 0.6 1.8 3.5

Plasma

Renin, ng/ml/h Aldosterone, ng/dl

Patient 1 1.63 26.2 Patient 2 Ͻ0.15 Ͻ1.6 Patient 3 0.3 4.3

Urine

Osmolality, Na, K, FENa, FEK, FEUA, FEPi, mosm/kg mmol/L mmol/L % % % %

Patient 1 386 39 39 0.31 8 37.9 23.1 Correction 24.6 Patient 2 534 161 28 1.85 10.3 21.1 7.4 Patient 3 303 99 30 1.48 15.8 16.7 10.5

Note persistence of hypouricemia and increased FEurate after correction of hyponatremia and elevated plasma renin and aldosterone levels and increased FEphosphate in patient 1 with RSW as compared to low plasma renin and aldosterone levels and normal FEphosphate in patients 2 and 3 with SIADH. Clin J Am Soc Nephrol 4: 309–315, 2009 Renal Salt Wasting Without Cerebral Disease 311

On the basis of pneumonia, hyponatremia, UNa of 39 mmol/L, admission, was readmitted with aphasia and headache. He had and Uosm of 386 mosm/kg, the diagnosis of SIADH was made a recurrence of the glioblastoma, which was surgically resected. by an internist and the patient was fluid restricted to Ͻ750 His baseline serum sodium was 122 mmol/L, potassium 3.8 ml/d for the next 22 h, at the end of which time there was no mmol/L, CO2 25 mmol/L, BUN 11 mg/dl, creatinine 0.7 mg/ evidence of postural hypotension. At the end of the period of dl, urate 1.6 mg/dl, phosphate 2.7 mg/dl, osmolality 251 fluid restriction, the Uosm increased from 284 to 570 mosm/kg mosm/kg, plasma renin Ͻ0.15 ng/ml/h, aldosterone Ͻ1.6 ng/ and UNa to 60 mmol/L. At this time, the supine plasma renin ml, UNa 161 mmol/L, UK 28 mmol/L, Uosm 534 mosm/kg, was 1.63 ng/ml/h (normal, 0.15 to 2.33 ng/ml/h), aldosterone FEurate 21.1%, and FEphosphate 10.4%. The red cell volume 26.2 ng/ml (normal, 1 to 16 ng/ml), FENa 0.30%, FEurate 37.9% was 24 ml/kg (normal 22 to 30 ml/kg), plasma volume was (normal 5 to 10%), and FEphosphate 23.1% (normal Ͻ20%). 55.3 ml/kg (normal 30 to 45 ml/kg), and blood volume was 79.3 ml/kg (normal 52 to 75 ml/kg), consistent with SIADH. Saline Infusion Saline was infused at a rate of 75 ml/h for 110 h. Uosm Isotonic saline was infused at 50 ml/h for 36 h. The creatinine remained hypertonic and FEurate was not determined because clearance was 94 ml/min, and 24 h urate excretion was 664 mg. the hyponatremia never corrected (Figure 2). His medications included Ofloxacin 400 mg orally twice daily Patient 3-SIADH, a 72-yr-old female, presented with a 20-yr and Colace 100 mg. history of hypertension and 3-yr history of weakness and hy- As noted in Figure 1, Uosm gradually decreased to a nadir of ponatremia after a “bad flu.” She had autonomic dysfunction 178 mosm/kg at 25 h and rose overnight to 640 mosm/kg by with a BP of 168/90 mm/Hg lying, and 150/90 and 130/90 midmorning the following day. The serum sodium increased from mmHg standing for 1 and 2 min, respectively, with no change 132 to 138 mmol/L, urate decreased from 2.5 to 1.5 mg/dl, and in pulse rates. Pertinent laboratory data included a serum so- FEurate remained elevated at 24.6% when his serum sodium was dium of 134 mmol/L, osmolality 265 mosm/kg, BUN 6 mg/dl, 138 mmol/L. His weight increased from 164 lb to 168 lbs. creatinine 0.6 mg/dl, urate 1.7 mg/dl and phosphate 3.8 mg/ dl. The Uosm was 303 mosm/kg, UNa 99 mmol/L, FENa Water Loading Test 1.48%, FEurate 16.7%, FEphosphate 10.8%, and FEK 15.8%. The After correction of hyponatremia, a water loading test was supine plasma renin was 0.29 ng/ml/h and aldosterone 4.3 performed. The patient received 20 ml/kg BW or 1500 ml of ng/dl (Table 1). Red cell volume was 23 ml/kg (normal, 22 to water by mouth within 30 min. His baseline Uosm and Posm 30 ml/kg), plasma volume was 54 ml/kg (normal, 30 to 45 were 570 and 272 mosm/kg, respectively. The Uosm reached a ml/kg), and blood volume was 77 ml/kg (normal, 52 to 75 nadir of 131 mosm/kg at 2.5 h, and he excreted 1240 ml or ml/kg), consistent with SIADH. Isotonic saline was infused at 82.7% of the ingested water after 4 h (normal Ͼ80%, Table 2). a rate of 75 ml/h for 48 h. Serum sodium never exceeded 135 The normal water loading test confirms normal ADH response mmol/L and did not correct while the patients was in the after volume repletion. hospital. Patient 2-SIADH, a 76-yr-old male with hypertension, coro- nary artery disease, peripheral vascular disease, and resection Discussion of a glioblastoma followed by radiation therapy 7 mo before The present report illustrates several important differentiating parameters that not only prove the existence of RSW but also emphasize differences between RSW and SIADH with regard to plasma renin and aldosterone levels, FEphosphate, and response to saline infusion (1,6,19,20). The normal renal, thyroid, and adrenal function; elevated plasma aldosterone; increased FEphosphate; persistent hypouricemia; increased FEurate after correction of hyponatremia; generation of dilute urines with prompt correction of hyponatremia in response to saline; and normal water loading test after volume repletion collectively support the diagnosis of RSW in patient 1. Patient 1 has RSW, which is pathophysiologically different from SIADH. In SIADH, ADH levels are autonomously increased with respect to serum osmolality and ECV, hence the term “inappropriate secretion of ADH.” The elevated ADH levels increase water reabsorption, concentrating the urine and preventing excretion of ingested water. This inappropriate water retention leads to increasing hyponatremia. There is an Figure 1. Graph demonstrating serum sodium concentrations in initial salt-wasting phase when sodium excretion exceeds so- mmol/L and urine osmolalities in mosm/kg during infusion of dium intake, which transitions into a steady-state phase when 0.9% saline at 50 ml/h over 36 h. Note dilution of urine at 24 h sodium and water intake match sodium and water excretion, or of the study and prompt correction of hyponatremia 36 h after vasopressin escape that is in part due to a decrease in aqua- initiation of saline therapy. porin 2 and urea transport UT-A3 (21,22). UNa can be Ͻ20 312 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 309–315, 2009

Table 2. Water loading test in patient 1 after ECV repletion

Time, Urine Volume, Uosm, Posm, Cosm, CH2O, TCH2O, min ml mosm/kg water mosm/kg water mosm/kg water ml/min ml/min

0 570 272 45 75 323 1.98 — 0.31 90 350 150 4.29 3.49 150 450 131 3.61 3.89 210 145 179 1.59 0.83 240 75 192 1.78 0.72

The patient ingested 20 ml/kg water, 1500 ml, in 30 min. He excreted 1240 ml of urine in4hor82.7% of the 1500 ml water ingested at time 0, normal Ͼ80%. Note: the lowest Uosm of 131 mosm/kg at 150 min is higher than would be expected in a normal subject and is consistent with a free-water clearing defect that is characteristic of RSW.

dynamic and neural adjustments that create a new steady-state condition for sodium and water balance at a lower ECV. ECV depletion leads to a reduction in effective arterial volume as pressure in the arterial system and contraction of the venous capacitance vessels lead to prerenal azotemia, a condition char- acterized by increased solute reabsorption, including urea, uric acid, and phosphorus, when renal function is intact (25). In RSW, however, the reduction in ECV is a consequence of de- fective sodium transport that is associated with defects in urate; urea; and, in this and some other cases, phosphate transport. Some of the characteristic findings of prerenal azotemia are therefore not applicable in RSW. Renin production in RSW can be variable, depending on salt intake despite ECV depletion, because the major defect in salt transport resides in the proximal tubule (15,26). Thus, the salt supply to the juxtaglomerular Figure 2. Graph demonstrating serum sodium concentrations in apparatus will reflect salt intake as compared with a decreased mmol/L and urine osmolalities in mosm/kg during infusion of supply in a volume-depleted patient with normal kidneys (27). 0.9% saline at 75 ml/h over 110 h. Note failure of urine osmo- Alternatively, UNa can be Ͻ20 mmol/L if sodium intake is low lality to dilute during the course of the study and failure of (6). This was evident in our hip fracture hyponatremic patient serum sodium to correct during the entire study. without cerebral disease (6). She had a UNa of 6 mmol/L that was attributed to anorexia and reduced sodium intake while fluid restricted, resulting in an erroneous diagnosis of SIADH. mmol/L if sodium intake is low (23). Uosm is always increased The coexisting hypouricemia and increased FEurate, however, above plasma osmolality, although2Lofisotonic saline in- were inconsistent with a volume-depleted patient with normal fused at 16 ml/min has been shown to dilute the urine to 151 kidneys, that is, prerenal azotemia, but consistent with SIADH mosm/kg by unknown mechanisms (24). As seen in patients 2 and RSW. The diagnosis of RSW was based on a 7% reduction and 3, the inappropriate water retention increased ECV and in blood volume; increased plasma renin, aldosterone and decreased plasma renin and aldosterone (20). Fluid restriction FEphosphate; undetectable levels of ADH resulting from elim- of 750 to 1000 ml per day is the recommended treatment for ination of the volume stimulus for ADH secretion by saline and SIADH, although Schwartz et al. increased serum sodium from inhibition by the coexisting plasma hypo-osmolality; genera- 109 to 135 mmol/L over an 8-day balance study, with daily tion of free water excretion; and prompt correction of hypona- fluid and sodium intake averaging 2648 ml and 314.5 mmol, tremia (6). respectively (24). Thus, serum sodium can increase at high fluid The extent of the ECV depletion in RSW depends on the intake as long as sodium intake is high and the intake sodium severity of the defect in tubular sodium transport that induces concentration exceeds the excreted sodium concentration (24). mild to severe ECV depletion, which sets off the compensatory In contrast to SIADH, RSW evolves by physiologic mecha- changes noted above. Thus, fluid restriction in patients with nisms that normally occur with ECV depletion, which in the severe RSW to treat an erroneous diagnosis of SIADH has been case of RSW results from a defect in renal sodium transport. At reported to lead to an array of clinical consequences of ECV the onset of RSW, sodium output exceeds sodium intake to depletion that include weakness, loss of appetite, severe pos- reduce ECV, which sets off a series of compensatory changes tural hypotension, disturbances in gait and mentation, slurred that include increased plasma ADH, renin, and aldosterone; speech, somnolence, syncope, and even aggravation of their decreased glomerular filtration rates; and activation of hemo- underlying disease (6,12,28,29). These consequences of fluid Clin J Am Soc Nephrol 4: 309–315, 2009 Renal Salt Wasting Without Cerebral Disease 313 restriction in severe RSW respond to saline infusions that elim- FEurate after correction of the hyponatremia are not available inate the volume stimulus for ADH secretion and allow the at this time. It does, however, strengthen our contention that coexistent hypo-osmolality to inhibit ADH secretion, induce RSW not only exists but occurs in the absence of clinical cere- free water excretion, and correct the hyponatremia. This se- bral disease (1,6,11,12). It is ironic that patient 1 had RSW quence of physiologic events was clearly demonstrated in pa- without cerebral disease and patient 2 had SIADH with cere- tient 1 and our hip fracture patient (Figure 1) (6). bral disease, a diagnosis that would customarily be reversed Treatment of hyponatremic patients, who meet the criteria when applying standard clinical practices. We have encoun- for SIADH and RSW is not well defined, largely because of tered several patients with RSW without clinical cerebral dis- overlapping clinical and laboratory findings and our inability ease, including patient 1 in this report, hip fracture, broncho- to differentiate SIADH from RSW. There is uniform agreement genic carcinoma with normal CT scan of brain, uncomplicated that symptomatic hyponatremia should be treated with hyper- Hodgkin’s disease and metastatic pancreatic carcinoma (6,12). tonic saline, but treatment of the asymptomatic patient poses a These cases led us to advocate replacing the outmoded term, therapeutic dilemma, to restrict water for SIADH or to admin- CSW, with RSW (1,6,12). ister isotonic saline in RSW. Depending on the severity of the The mechanisms by which hypouricemia and elevated defect in renal sodium transport, the patient with RSW can FEurate develop in SIADH and RSW appear to be different and deteriorate clinically if fluid restricted for an erroneous diag- not well defined. In SIADH, the hypouricemia and increased nosis of SIADH. We are encountering with greater frequency FEurate are present only during hyponatremia and normalize clinical deterioration of patients with RSW who are fluid re- after correction of the hyponatremia (16–18). The hypervolemia stricted for an erroneous diagnosis of SIADH with or without in SIADH is an unlikely cause as intense volume expansion cerebral disease (6,12,29). This outcome may be more common with saline failed to attain the high FEurates seen in SIADH and in patients with intracranial diseases such as those with sub- RSW (32–34). This has been reviewed in our in-depth review of arachnoid hemorrhage in whom fluid restriction increased renal urate transport (11). The V1 receptor activity of ADH is morbidity and mortality, because RSW is more common than untenable because ADH levels are still elevated when FEurate SIADH in these patients (28). Of the blood volume studies that normalizes with the correction of hyponatremia (16,17,18,35) have been reported in a group of hyponatremic neurosurgical and induction of SIADH by dDAVP increased FEurate without patients, the UNa reported in two of three studies ranged from V1 activity (36). 23 to 203 mmol/L, and blood volume was decreased in 67% It would appear that multiple transport abnormalities involv- to100%, suggesting that RSW was more common than SIADH ing the proximal tubule in RSW are reminiscent of the Fanconi (8–10). Moreover, 10 patients with AIDS had hyponatremia, syndrome. We have not investigated amino acid excretion hypouricemia, elevated FEurate, elevated plasma renin and rates, and we have never observed glucosuria in any of our aldosterone levels, UNa Ͼ40 mmol/L, central venous pressures patients. None of our patients appear to have acid base abnor- of 0 cmH2O, and postural hypotension that responded to saline malities, but amino acid and glucose transport or acid base (30). On the basis of these reports, the recent proposal to infuse disturbances have not been systematically investigated. Abnor- hypertonic saline to hyponatremic neurosurgical patients has malities in sodium and urate transport appear to be more merit as a therapeutic first option (4). We should include hy- common than that noted for phosphate transport, and azotemia ponatremic patients with coexistent hypouricemia and FEurate is clearly not a feature of RSW. The BUN-to-creatinine ratios of Ͼ10% without cerebral disease to this list. Subsequent decisions 20.0 in our previous case and 14.0 in patient 1 with RSW and to water restrict or administer isotonic saline depend on plasma 15.7 and 23.3, respectively, in patients 2 and 3 with SIADH renin and aldosterone levels and whether FEurate returns to provide evidence against the proposal that an increase in the normal or remains persistently elevated after correction of the BUN-to-creatinine ratio distinguishes RSW from SIADH (3). hyponatremia. However, if the baseline FEphosphate is Ͼ20%, The absence of a disproportionate rise in BUN over the rise in we advocate isotonic saline as the first therapeutic option, creatinine in RSW has been addressed by others (1,6,37). Vol- because increased FEphosphate is a feature of RSW and not ume depletion in the presence of normal kidney function SIADH. Regardless of the type of saline administered, serum would lead to prerenal azotemia with the disproportionate rise sodium concentration should not increase by more than 10 in BUN and urate, and decreased FEurate as part of the increase mmol/L/d in chronic hyponatremia to minimize the develop- in proximal solute and water reabsorption (38). The increase in ment of osmotic demyelination syndrome. Fluid intake should FEurate and hypouricemia in RSW and SIADH indicates an also be monitored to avoid congestive heart failure. In the rare underlying proximal tubular transport defect that also affects patient with SIADH or RSW, the desalinization syndrome can urea reabsorption through an inability to generate a favorable be observed when the administration of isotonic saline exacer- concentration gradient for urea to be reabsorbed passively, bates the hyponatremia (31). This occurs when the total UNa contributing to the absence of azotemia (12). Determination of and UK exceed 150 mmol/L, in which case hypertonic saline FEurate can, therefore, be a useful tool to assess proximal and water restriction should be instituted. tubule function in various disease states, being low in prerenal The present report does not resolve the conundrum of dif- azotemia with normal kidneys (38) and high in those with ferentiating RSW from SIADH on first encounter, because the proximal tubule dysfunction such as RSW, or transiently high response to saline infusion, determination of plasma renin or in SIADH. The administration of plasma from our patients with aldosterone, or persistence of hypouricemia and elevated neurosurgical and Alzheimer’s diseases who had hypourice- 314 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 309–315, 2009 mia, increased FEurate, and normal serum sodium as seen in 7. 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