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• W2000567929 abstract "A 76-year-old woman, who sustained an accidental fracture of the femoral neck, developed hyponatremia after admission. The diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was made by the consulting internist and fluid restriction of 700 cc/day was instituted. Her serum sodium (Na) fluctuated between 122 and 129 mmol/l and a renal consultation was requested on the eighth day after undergoing a hemiarthroplasty of the hip when she was ambulating and on no pain medication. Her blood pressure was 100/60 mm Hg, pulse 92 beats/min and there was poor tissue turgor, flat jugular veins, and dry mucous membranes. There was no edema, third spacing, postural hypotension or neurological abnormalities. Her medications included docusate sodium, milk of magnesia, simvastatin, and warfarin. She was not on drugs such as atorvastatin, fenofibrate, or losartan which reduce serum urate by increasing renal urate excretion.1.Milionis H.J. Kakafika A.I. Tsouli S.G. et al.Effects of statin treatment on uric acid homeostasis in patients with primary hyperlipidemia.Am Heart J. 2004; 148: 635-640Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 2.Daskalopoulou S.S. Tzovaras V. Mikhailidis D.P. Elisaf M. Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia.Curr Pharm Des. 2005; 11: 4161-4175Crossref PubMed Scopus (101) Google Scholar, 3.Burnier M. Waeber B. Brunner H.R. Clinical pharmacology of the angiotensin II receptor antagonist losartan potassium in healthy subjects.J Hypertens. 1995; 13: S23-S28Crossref Scopus (36) Google Scholar A low baseline urine Na (UNa) concentration of 6 mmol/l suggested a hypovolemic condition with normal renal function4.Maesaka J.K. An expanded view of SIADH, hyponatremia, and hypouricemia.Editorial Clin Neph. 1996; 46: 79-83PubMed Google Scholar that should result in a prerenal state characterized by low UNa, azotemia, and hyperuricemia. The baseline serum urate of 3.4 mg/dl, however, was inconsistent with prerenal azotemia and its coexistence with hyponatremia was suggestive of SIADH or renal salt wasting.4.Maesaka J.K. An expanded view of SIADH, hyponatremia, and hypouricemia.Editorial Clin Neph. 1996; 46: 79-83PubMed Google Scholar, 5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar, 6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar The patient was, therefore, included in an IRB-approved protocol to differentiate SIADH from renal salt wasting. After obtaining an informed consent, a blood volume study was performed, using a radioisotope dilution technique.7.International Committee for Standardization in Haematology Recommended methods for measurement of red-cell and plasma volume.J Nucl Med. 1980; 21: 793-800PubMed Google Scholar With a hematocrit of 31%, the red cell volume was decreased by 28% and the plasma volume increased by 4.7%, resulting in a net blood volume reduction of 7.1%. The pertinent baseline laboratory data are summarized in Table 1. The baseline plasma renin, aldosterone, antidiuretic hormone (ADH), and fractional urate excretion were elevated at 8.63 ng/ml/h, 16.5 ng/dl, 2.5 pg/ml, and 29.6% (normal 5–10%), respectively. Plasma osmolality was decreased at 260 mosM/kgH2O, atrial natriuretic peptide was in the low normal range at 35 pg/ml, serum phosphorus and urate were decreased at 2.4 and 3.4 mg/dl, respectively. Renal, adrenal, and thyroid functions were normal. The chest X-ray and urinalysis were normal.Table 1Summary of pertinent baseline dataSerum/blood NaKClCO2BUNCrUric acidPO4CaOsmHgHct (mmol/l)(mmol/l)(mmol/l)(mmol/l)(mg/dl)(mg/dl)(mg/dl)(mg/dl)(mg/dl)(mosm/kg)(g/dl)(%) 1293.810623160.83.42.48.526010.631Hormones ADHReninAldoANPCortisolTSHT4 (pg/ml)(ng/ml/h)(ng/dl)(pg/ml)(μg/dl)mIU/l(μg/dl) 2.58.6316.53526.95.047.31Urine UosmUNaFEUAFENaFEKFEPO4 (mos m/kg)(mmol/l)(%)(%)(%)(%) 321629.60.1113.212.7ADH, antidiuretic hormone; ANP, atrial natriuretic peptide; BUN, blood urea nitrogen; FEK, fractional K excretion; FENa, fractional Na excretion; FEPO4, fractional phosphate excretion; FEUA, fractional excretion of uric acid; Osm, osmolality; TSH, thyroid stimulating hormone; UNa, urine Na; Uosm, Urine osmolality. Open table in a new tab ADH, antidiuretic hormone; ANP, atrial natriuretic peptide; BUN, blood urea nitrogen; FEK, fractional K excretion; FENa, fractional Na excretion; FEPO4, fractional phosphate excretion; FEUA, fractional excretion of uric acid; Osm, osmolality; TSH, thyroid stimulating hormone; UNa, urine Na; Uosm, Urine osmolality. Saline was then infused at 125 ml/h for 48 h. Urine osmolality of all spontaneously voided urine was immediately determined and when her urine osmolality decreased to 152 mosM/kgH2O at 13.3 h, a repeat plasma ADH was undetectable when the serum osmolality was 268 mosM/kgH2O. At this time, she had received 1660 ml of saline overnight and excreted 955 ml of urine. The plasma renin and aldosterone decreased to 2.95 ng/ml/h and 7.6 ng/dl, respectively, and plasma atrial natriuretic peptide increased to a high normal 65 pg/ml. The serum Na remained unchanged at 129 mmol/l but the serum urate decreased from 3.4 to 1.7 mg/dl. It should be noted that the baseline urine osmolality of 321 mosM/kgH2O increased to 587 mosM/kgH2O and the UNa only increased from a baseline of 6 to 18 mmol/l in the first urine passed 4 h after initiation of saline infusion (Figure 1, Table 2 ). The serum Na gradually increased from 129 to 138 mmol/l at 45.8 h (Figure 2), as serum urate decreased to 1.0 mg/dl and fractional urate excretion remained elevated (Figure 2). Her UNa increased to a peak of 82 mmol/l at 8.1 h (Table 2). At 16 h, she awoke refreshed and hungry, suggesting that the fluid restriction for treatment of SIADH exacerbated her volume depletion, induced weakness, lethargy, and anorexia, which accounted for the low baseline UNa of 6 mmol/l. Fractional Na excretion gradually increased from 0.11 to 2.86% (Table 2), serum creatinine decreased from a baseline of 0.8 to 0.5 mg/dl at 13.3 h and creatinine clearance increased from 38.2 to 74.6 ml/min over the same period. Fractional potassium (K) excretion was 13.2% at baseline, decreased to 7.9% at 4 h and fluctuated between 2.7 and 4.5% as did serum K between 4.5 and 4.7 mmol/l (Table 2). The baseline fractional phosphate excretion of 12.7% increased to 72.9% at 6.1 h (Table 2).Table 2Summary of time (h), UNa (mmol/l), FENa (%), FEK (%), serum K (mmol/l), FEPO4 (%), and serum phosphorus (mg/dl) at baseline and during 125 ml/h saline infusionHoursUNaFENaFEKSerum KFEPO4Serum PO4(mmol/l)(%)(%)(mmol/l)(%)(mg/dl)060.1113.23.812.72.44180.687.94.7——6.1550.654.5—62.9—8.1820.783.2—59.12.310.8630.792.7—50.9—12.3420.824.0—58.5—13.1270.693.54.669.62.213.3—1.11————14.3461.593.5—76.0—15.6721.53.5——2.117.662—————19.6901.353.1———27.8—1.805.3———40.8872.864.44.5——45.871—————FEK, fractional K excretion; FENa, fractional Na excretion; FEPO4, fractional phosphate excretion; UNa, urine Na. Open table in a new tab Figure 2Persistence of hypouricemia and increased fractional urate excretion after correction of hyponatremia during saline infusion at 125 ml/h.View Large Image Figure ViewerDownload (PPT) FEK, fractional K excretion; FENa, fractional Na excretion; FEPO4, fractional phosphate excretion; UNa, urine Na. The patient was discharged 2 days after completion of the renal studies and was lost to follow-up. We present compelling evidence of renal salt wasting in a hyponatremic patient with a hip fracture, persistent hypouricemia, and elevated fractional urate excretion after correction of hyponatremia, and no clinical evidence of cerebral disease, where a serum urate determination was pivotal in the clinical assessment of the patient. Without the 7.1% reduction in blood volume determination, a test not routinely used in this clinical setting, the initial UNa of 6 mmol/l was more consistent with a hypovolemic prerenal state that is characterized by avid renal conservation of Na, urea, urate, and other solutes, leading to hyperuricemia and azotemia.4.Maesaka J.K. An expanded view of SIADH, hyponatremia, and hypouricemia.Editorial Clin Neph. 1996; 46: 79-83PubMed Google Scholar The hypouricemia and elevated fractional urate excretion indicated a reduction in tubular urate transport that was not consistent with prerenal azotemia and their coexistence with hyponatremia was more consistent with SIADH and renal salt wasting.4.Maesaka J.K. An expanded view of SIADH, hyponatremia, and hypouricemia.Editorial Clin Neph. 1996; 46: 79-83PubMed Google Scholar, 5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar, 6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 8.Steele T.H. Oppenheimer S. Factors affecting urate excretion following diuretic administration in man.Am J Med. 1969; 47: 564-574Abstract Full Text PDF PubMed Scopus (131) Google Scholar Without an appreciation of this coexistence of hyponatremia and hypouricemia, the low UNa of 6 mmol/l could have led to a diagnosis of prerenal azotemia.4.Maesaka J.K. An expanded view of SIADH, hyponatremia, and hypouricemia.Editorial Clin Neph. 1996; 46: 79-83PubMed Google Scholar The elevated plasma renin, aldosterone and ADH and low normal atrial natriuretic peptide levels are all physiologic consequences of the decrease in blood volume resulting from renal salt wasting, but these determinations were not available on first encounter to be of diagnostic value (Figure 3). Finally, to add to the dilemma and instructive value of this case, the clinical absence of cerebral disease probably eliminated renal salt wasting from the differential by the consulting internist, who erroneously diagnosed SIADH, instituted fluid restriction, exacerbated the volume depletion and induced lethargy, anorexia, low sodium intake, and low UNa. It should be noted that UNa in SIADH and renal salt wasting reflects Na intake and can be low if Na intake is low. The initiation of saline infusion supports the diagnosis of renal salt wasting and provides insights into the handling of Na, urate, K, and phosphate in renal salt wasting. The most compelling consequence of the saline infusion other than the dramatic clinical improvement was the illustration of the physiologic consequences of renal salt wasting. Because the hypovolemic stimulus for ADH secretion over rides the inhibition by the coexistent hypoosmolality of plasma, the increased ADH levels produced a defect in free water excretion or inability to extract pure water from the blood and tendency to develop hyponatremia. The saline infusion eliminated the volume stimulus for ADH secretion and permitted the coexistent hypoosmolality to inhibit ADH secretion, leading to undetectable plasma ADH levels, generation of dilute urines, and prompt correction of the hyponatremia (Figure 1). Additionally, the persistence of hypouricemia and increased fractional urate excretion after correction of the hyponatremia provided additional evidence for renal salt wasting and not SIADH (Figure 2), vide infra.4.Maesaka J.K. An expanded view of SIADH, hyponatremia, and hypouricemia.Editorial Clin Neph. 1996; 46: 79-83PubMed Google Scholar, 5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar, 6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar It might be argued that saline increased fractional urate excretion. The fractional urate excretion of 29.6% at baseline is significantly higher than the 4% that is observed in volume depleted subjects with normal renal function.8.Steele T.H. Oppenheimer S. Factors affecting urate excretion following diuretic administration in man.Am J Med. 1969; 47: 564-574Abstract Full Text PDF PubMed Scopus (131) Google Scholar As noted in our review of urate transport, normal, hypotonic, and hypertonic saline increased fractional Na excretion to as high as 18.5% but fractional urate excretion only increased to 12.1%.6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar The fractional urate excretion of 63.1% at 19.6 h when fractional Na excretion was only 1.35% suggests that saline had a minor effect on fractional urate excretion and negate the notion that volume expansion induces the increase in fractional urate excretion in SIADH.9.Decaux G. Schlesser M. Coffernils M. et al.Urate, anion gap and urea concentration in the diagnostic approach to hyponatremia.Clin Nephrol. 1994; 42: 102-108PubMed Google Scholar Finally, this case supports our previous recommendation to eliminate ‘cerebral’ in favor of ‘renal’ in salt wasting syndromes, as the absence of clinical cerebral disease would eliminate renal salt wasting from the differential when evaluating hyponatremic patients.5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar,6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar Cerebral salt wasting has been considered a rare clinical entity and even a misnomer of SIADH,2.Daskalopoulou S.S. Tzovaras V. Mikhailidis D.P. Elisaf M. Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia.Curr Pharm Des. 2005; 11: 4161-4175Crossref PubMed Scopus (101) Google Scholar, 8.Steele T.H. Oppenheimer S. Factors affecting urate excretion following diuretic administration in man.Am J Med. 1969; 47: 564-574Abstract Full Text PDF PubMed Scopus (131) Google Scholar, 10.Beck L.H. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone.N Engl J Med. 1979; 301: 528-530Crossref PubMed Scopus (155) Google Scholar especially among internists and nephrologists. Neurosurgeons, however, consider cerebral salt wasting to be common.11.Nelson P.B. Seif S.M. Maroon J.C. et al.Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).J Neurosurg. 1981; 55: 938-941Crossref PubMed Scopus (198) Google Scholar, 12.Wijdick E.F.M. Vermeulen M. Ten Haaf J.A. et al.Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm.Ann Neurol. 1985; 18: 211-216Crossref PubMed Scopus (207) Google Scholar, 13.Sivakumar V. Rajshekhar V. Chandy M.J. Management of neurosurgical patient with hyponatremia and natriuresis.Neurosurgery. 1994; 43: 269-274Crossref Scopus (122) Google Scholar The major reason for this discrepancy lies in our inability to assess accurately the volume status of a patient on the basis of clinical criteria and many overlapping clinical and laboratory findings in both diseases.4.Maesaka J.K. An expanded view of SIADH, hyponatremia, and hypouricemia.Editorial Clin Neph. 1996; 46: 79-83PubMed Google Scholar, 5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar, 14.Oh M.S. Carroll H.S. Cerebral salt-wasting syndrome, we need better proof of its existence.Nephron. 1999; 82: 110-114Crossref PubMed Scopus (61) Google Scholar Both are characterized by hyponatremia, hypouricemia, concentrated urine, UNa usually exceeding 20 mmol/l, and clinical associations that include intrathoracic disease, intracranial disease, and malignancies.4.Maesaka J.K. An expanded view of SIADH, hyponatremia, and hypouricemia.Editorial Clin Neph. 1996; 46: 79-83PubMed Google Scholar, 5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar, 6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 15.Schwartz W.B. Bennett W. Curelop S. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone.Am J Med. 1957; 23: 529-542Abstract Full Text PDF PubMed Scopus (699) Google Scholar, 16.Peters J.P. Welt L.G. Sims E.A.H. et al.A salt-wasting syndrome associated with cerebral disease.Trans Assoc Am Physicians. 1950; 63: 57-64PubMed Google Scholar As noted in Figure 3, extracellular volume is high normal or increased in SIADH and decreased in renal salt wasting. ADH levels are elevated in both conditions but are inappropriate in SIADH and appropriate in renal salt wasting. As noted in Figure 3, hormonal adjustments such as renin, aldosterone, and atrial or brain natriuretic peptides can collectively differentiate SIADH from renal salt wasting, but the only difference on first encounter is the status of their extracellular volume, which is fraught with errors without edema, third spacing, or invasive procedures.5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar,14.Oh M.S. Carroll H.S. Cerebral salt-wasting syndrome, we need better proof of its existence.Nephron. 1999; 82: 110-114Crossref PubMed Scopus (61) Google Scholar The differentiation of one group from the other is important because patients with SIADH are water-restricted as compared to salt and water supplementation in renal salt wasting. Selecting the wrong mode of therapy can lead to significant clinical consequences.17.Maesaka J.K. Batuman V. Yudd M. et al.Hyponatremia and hypouricemia: differentiation from the syndrome of inappropriate secretion of antidiuretic hormone.Clin Nephrol. 1990; 33: 174-178PubMed Google Scholar,18.Wijdick E.F.M. Vermeulen M. Hijdra A. et al.Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysm: Is fluid restriction harmful.Ann Neurol. 1985; 17: 137-140Crossref PubMed Scopus (274) Google Scholar The clinical improvement noted after initiation of saline infusion illustrates the deleterious effects of fluid restriction in our patient.17.Maesaka J.K. Batuman V. Yudd M. et al.Hyponatremia and hypouricemia: differentiation from the syndrome of inappropriate secretion of antidiuretic hormone.Clin Nephrol. 1990; 33: 174-178PubMed Google Scholar,18.Wijdick E.F.M. Vermeulen M. Hijdra A. et al.Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysm: Is fluid restriction harmful.Ann Neurol. 1985; 17: 137-140Crossref PubMed Scopus (274) Google Scholar To illustrate the clinical consequences of fluid restriction in salt wasting patients, Wijdick et al.12.Wijdick E.F.M. Vermeulen M. Ten Haaf J.A. et al.Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm.Ann Neurol. 1985; 18: 211-216Crossref PubMed Scopus (207) Google Scholar noted increased morbidity and mortality when hyponatremic patients with subarachnoid hemorrhage were fluid restricted for what was assumed to be SIADH. Reduced blood volume determinations consistent with renal salt wasting were noted in eight of nine hyponatremic patients with subarachnoid hemorrhage.12.Wijdick E.F.M. Vermeulen M. Ten Haaf J.A. et al.Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm.Ann Neurol. 1985; 18: 211-216Crossref PubMed Scopus (207) Google Scholar The frequency of salt wasting noted by Wijdick et al.12.Wijdick E.F.M. Vermeulen M. Ten Haaf J.A. et al.Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm.Ann Neurol. 1985; 18: 211-216Crossref PubMed Scopus (207) Google Scholar supported the earlier work by Nelson et al.,11.Nelson P.B. Seif S.M. Maroon J.C. et al.Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).J Neurosurg. 1981; 55: 938-941Crossref PubMed Scopus (198) Google Scholar who demonstrated a reduction in blood volume in eight of nine hyponatremic neurosurgical patients with UNa ranging between 41 and 203 mmol/l11.Nelson P.B. Seif S.M. Maroon J.C. et al.Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).J Neurosurg. 1981; 55: 938-941Crossref PubMed Scopus (198) Google Scholar and later by Sivakumar et al.13.Sivakumar V. Rajshekhar V. Chandy M.J. Management of neurosurgical patient with hyponatremia and natriuresis.Neurosurgery. 1994; 43: 269-274Crossref Scopus (122) Google Scholar who reported decreased blood volumes in 17 of 18 patients and central venous pressures to be reduced in all 18 hyponatremic neurosurgical patients with UNa of 24–203 mmol/l. These neurosurgical studies provide the essential data to support the diagnosis of renal salt wasting.11.Nelson P.B. Seif S.M. Maroon J.C. et al.Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).J Neurosurg. 1981; 55: 938-941Crossref PubMed Scopus (198) Google Scholar, 12.Wijdick E.F.M. Vermeulen M. Ten Haaf J.A. et al.Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm.Ann Neurol. 1985; 18: 211-216Crossref PubMed Scopus (207) Google Scholar, 13.Sivakumar V. Rajshekhar V. Chandy M.J. Management of neurosurgical patient with hyponatremia and natriuresis.Neurosurgery. 1994; 43: 269-274Crossref Scopus (122) Google Scholar It is understandable why the first report of cerebral salt wasting by Peters et al.16.Peters J.P. Welt L.G. Sims E.A.H. et al.A salt-wasting syndrome associated with cerebral disease.Trans Assoc Am Physicians. 1950; 63: 57-64PubMed Google Scholar could be considered a misnomer of SIADH because the diagnosis of dehydration with high UNa was based on weak clinical criteria. The first blood volume determination by Cort19.Cort J.H. Cerebral salt wasting.Lancet. 1954; 1: 752-754Abstract Scopus (94) Google Scholar proved the existence of renal salt wasting but blood volume determinations in subsequent reports other than measurements of central venous pressures or postural hypotension4.Maesaka J.K. An expanded view of SIADH, hyponatremia, and hypouricemia.Editorial Clin Neph. 1996; 46: 79-83PubMed Google Scholar, 6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 13.Sivakumar V. Rajshekhar V. Chandy M.J. Management of neurosurgical patient with hyponatremia and natriuresis.Neurosurgery. 1994; 43: 269-274Crossref Scopus (122) Google Scholar, 18.Wijdick E.F.M. Vermeulen M. Hijdra A. et al.Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysm: Is fluid restriction harmful.Ann Neurol. 1985; 17: 137-140Crossref PubMed Scopus (274) Google Scholar, 19.Cort J.H. Cerebral salt wasting.Lancet. 1954; 1: 752-754Abstract Scopus (94) Google Scholar, 20.Palmer B.F. Hyponatremia in a neurosurgical patient: syndrome of inappropriate antidiuretic hormone secretion versus cerebral salt wasting.Nephrol Dial Transplant. 2000; 15: 262-268Crossref PubMed Scopus (97) Google Scholar have been lacking, thus perpetuating the skepticism of the existence of salt wasting.14.Oh M.S. Carroll H.S. Cerebral salt-wasting syndrome, we need better proof of its existence.Nephron. 1999; 82: 110-114Crossref PubMed Scopus (61) Google Scholar,21.Singh S. Bohn D. Ana P.C.P. et al.Cerebral salt wasting: truths, fallacies, theories, and challenges.Crit Care Med. 2002; 30: 2575-2579Crossref PubMed Scopus (142) Google Scholar Hypouricemia and increased fractional urate excretion have been associated with hyponatremia in SIADH and normalize after correction of the hyponatremia.9.Decaux G. Schlesser M. Coffernils M. et al.Urate, anion gap and urea concentration in the diagnostic approach to hyponatremia.Clin Nephrol. 1994; 42: 102-108PubMed Google Scholar,10.Beck L.H. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone.N Engl J Med. 1979; 301: 528-530Crossref PubMed Scopus (155) Google Scholar This relationship between serum Na, serum urate and fractional urate excretion has been reported both clinically and experimentally.9.Decaux G. Schlesser M. Coffernils M. et al.Urate, anion gap and urea concentration in the diagnostic approach to hyponatremia.Clin Nephrol. 1994; 42: 102-108PubMed Google Scholar, 10.Beck L.H. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone.N Engl J Med. 1979; 301: 528-530Crossref PubMed Scopus (155) Google Scholar, 22.Boer W.H. Koomans H.A. Dorhout Mees E.J. Lithium clearance during the paradoxical natriuresis of hypotonic expansion in man.Kidney Int. 1987; 32: 376-381Abstract Full Text PDF PubMed Scopus (37) Google Scholar We dissociated serum Na from serum urate and fractional urate excretion by demonstrating persistence of hypouricemia and elevated fractional urate excretion after correction of hyponatremia in patients with concentrated urine and UNa >20 mmol/l.13.Sivakumar V. Rajshekhar V. Chandy M.J. Management of neurosurgical patient with hyponatremia and natriuresis.Neurosurgery. 1994; 43: 269-274Crossref Scopus (122) Google Scholar One patient with postural hypotension responded to volume repletion by inhibiting ADH secretion and eight hyponatremic patients with AIDS had central venous pressures of 0 cm H2O, UNa >20 mmol/l, hypouricemia, increased fractional urate excretion and elevated plasma rennin, and aldosterone that responded to saline infusions.6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 13.Sivakumar V. Rajshekhar V. Chandy M.J. Management of neurosurgical patient with hyponatremia and natriuresis.Neurosurgery. 1994; 43: 269-274Crossref Scopus (122) Google Scholar, 23.Maesaka J.K. Cusano A.J. Thies H.L. et al.Hypouricemia in acquired immunodeficiency syndrome.Am J Kidney Dis. 1990; 15: 252-257Abstract Full Text PDF PubMed Scopus (33) Google Scholar The high UNa and volume depletion were consistent with renal salt wasting. We proposed that the persistent hypouricemia and elevated fractional urate excretion after correction of hyponatremia identified a group of patients that was clearly different from SIADH and was most consistent with renal salt wasting.5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar, 6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 13.Sivakumar V. Rajshekhar V. Chandy M.J. Management of neurosurgical patient with hyponatremia and natriuresis.Neurosurgery. 1994; 43: 269-274Crossref Scopus (122) Google Scholar The present case report provides indisputable evidence that hypouricemia and increased fractional urate excretion persist after correction of the hyponatremia in renal salt wasting (Figure 2). The relationship between serum urate, fractional urate excretion, and hyponatremia has yet to be clarified. Hypouricemia has been arbitrarily defined as 1–4 mg/dl as compared to the more physiologically derived fractional urate excretion.6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar We reported elevations in fractional urate excretion with serum urate >4 mg/dl in AIDS, and patients with neurosurgical and Alzheimer diseases.23.Maesaka J.K. Cusano A.J. Thies H.L. et al.Hypouricemia in acquired immunodeficiency syndrome.Am J Kidney Dis. 1990; 15: 252-257Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 24.Maesaka J.K. Venkatesan J. Piccione J.M. et al.Abnormal renal urate transport in patients with intracranial disease.Am J Kidney Dis. 1992; 19: 10-15Abstract Full Text PDF PubMed Scopus (28) Google Scholar, 25.Maesaka J.K. Wolf-Klein G. Piccione J.M. et al.Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer's disease.J Am Geriatr Soc. 1993; 41: 501-506Crossref PubMed Scopus (44) Google Scholar The increased fractional urate excretion with or without hypouricemia in the absence of hyponatremia in the neurosurgical and Alzheimer patients would be consistent with our proposal that fractional urate excretion remains elevated without hyponatremia in renal salt wasting.5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar, 6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 13.Sivakumar V. Rajshekhar V. Chandy M.J. Management of neurosurgical patient with hyponatremia and natriuresis.Neurosurgery. 1994; 43: 269-274Crossref Scopus (122) Google Scholar Alzheimer patients are not typically hyponatremic, possibly because of reduced water intake resulting from a defective thirst mechanism of aging and dementia. We are in agreement with Singh et al.21.Singh S. Bohn D. Ana P.C.P. et al.Cerebral salt wasting: truths, fallacies, theories, and challenges.Crit Care Med. 2002; 30: 2575-2579Crossref PubMed Scopus (142) Google Scholar that hyponatremia is not a prerequisite for making the diagnosis of renal salt wasting. Demonstration of natriuretic activity in the plasma of our neurosurgical and Alzheimer patients further suggests that increased fractional urate excretion without hyponatremia might be a feature of renal salt wasting.25.Maesaka J.K. Wolf-Klein G. Piccione J.M. et al.Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer's disease.J Am Geriatr Soc. 1993; 41: 501-506Crossref PubMed Scopus (44) Google Scholar,26.Maesaka J.K. Venkatesan J. Piccione J.M. et al.Plasma natriuretic factor(s) in patients with intracranial disease, renal salt wasting and hyperuricosuria.Life Sci. 1993; 52: 1875-1882Crossref PubMed Scopus (26) Google Scholar The increase in fractional Na and lithium excretion rates noted in rats infused with plasma of our neurosurgical and Alzheimer patients raises an interesting speculation that a circulating plasma protein might affect Na, urate, phosphorus, and even urea transport in renal salt wasting25.Maesaka J.K. Wolf-Klein G. Piccione J.M. et al.Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer's disease.J Am Geriatr Soc. 1993; 41: 501-506Crossref PubMed Scopus (44) Google Scholar,26.Maesaka J.K. Venkatesan J. Piccione J.M. et al.Plasma natriuretic factor(s) in patients with intracranial disease, renal salt wasting and hyperuricosuria.Life Sci. 1993; 52: 1875-1882Crossref PubMed Scopus (26) Google Scholar Previous studies in renal salt wasting have not addressed the renal handling of Na, K, phosphorus, and urate at baseline and during volume repletion. It is interesting to note that fractional potassium excretion decreased during saline infusion, possibly reflecting the decrease in plasma aldosterone levels despite providing a favorable environment for potassium secretion by increasing Na and flow to the distal nephron. The increase in fractional phosphate excretion is not a feature of SIADH and its coexistence with increased fractional Na and urate excretions is suggestive of a partial Fanconi syndrome with absence of glucosuria and acidosis. Fractional phosphate excretion has not been systematically studied in patients with renal salt wasting for it to be regarded as a consistent abnormality, but its presence would be more suggestive of renal salt wasting than SIADH. Fractional phosphate excretion should, therefore, be determined when evaluating patients with hyponatremia and hypouricemia. In summary, the present case probably represents the tip of the iceberg in estimating the prevalence of renal salt wasting and illustrates the need to eliminate the restrictive and inappropriate term, ‘cerebral’ from salt wasting to expand our consideration of renal salt wasting beyond the cerebrum. The coexistent hypouricemia was consistent with renal salt wasting or SIADH but the decreased blood volume, generation of a dilute urine after appropriate inhibition of ADH secretion with saline, and persistent hypouricemia and increased fractional urate excretion after correction of the hyponatremia are consistent with renal salt wasting.5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar, 6.Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 9.Decaux G. Schlesser M. Coffernils M. et al.Urate, anion gap and urea concentration in the diagnostic approach to hyponatremia.Clin Nephrol. 1994; 42: 102-108PubMed Google Scholar This case, however, does not solve the conundrum of differentiating SIADH from renal salt wasting on first encounter, because difference in volume status is the only variable that differentiates SIADH from renal salt wasting.5.Maesaka J.K. Gupta S. Fishbane S. Cerebral salt wasting syndrome: does it exist?.Nephron. 1999; 82: 100-109Crossref PubMed Scopus (111) Google Scholar,14.Oh M.S. Carroll H.S. Cerebral salt-wasting syndrome, we need better proof of its existence.Nephron. 1999; 82: 110-114Crossref PubMed Scopus (61) Google Scholar Clinical assessment of extracellular volume is, however, inaccurate. While renal salt wasting is a definite clinical entity that deserves serious consideration in any non-edematous hyponatremic patient with or without cerebral disease, the contrasting therapeutic goals make it imperative to develop more effective guidelines to differentiate renal salt wasting from SIADH on first encounter (Figure 3). This study was supported by the Winthrop-University Hospital Biomedical Research Fund." @default.
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• W2000567929 title "Renal salt wasting without cerebral disease: Diagnostic value of urate determinations in hyponatremia" @default.
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