{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T05:01:27Z","timestamp":1792213287946,"version":"4.4.0"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,1]],"date-time":"2023-04-01T00:00:00Z","timestamp":1680307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The application of pathophysiologic tenets has created significant changes in our approach to hyponatremia and hyponatremia-related conditions. This new approach incorporated the determination of fractional excretion (FE) of urate before and after the correction of hyponatremia and the response to isotonic saline infusion to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from renal salt wasting (RSW). FEurate simplified the identification of the different causes of hyponatremia, especially the diagnosis of a reset osmostat and Addison\u2019s disease. Differentiating SIADH from RSW has been extremely difficult because both syndromes present with identical clinical parameters, which could be overcome by successfully carrying out the difficult protocol of this new approach. A study of 62 hyponatremic patients from the general medical wards of the hospital identified 17 (27%) to have SIADH, 19 (31%) with reset osmostat, and 24 (38%) with RSW with 21 of these RSW patients presenting without clinical evidence of cerebral disease to warrant changing the nomenclature from cerebral to renal salt wasting. The natriuretic activity found in the plasma of 21 and 18 patients with neurosurgical and Alzheimer\u2019s disease, respectively, was later identified as haptoglobin-related protein without signal peptide (HPRWSP). The high prevalence of RSW creates a therapeutic dilemma of deciding whether to water-restrict water-logged patients with SIADH as compared to administering saline to volume-depleted patients with RSW. Future studies will hopefully achieve the following: 1. Abandon the ineffective volume approach; 2. Develop HPRWSP as a biomarker to identify hyponatremic and a projected large number of normonatremic patients at risk of developing RSW, including Alzheimer\u2019s disease; 3. Facilitate differentiating SIADH from RSW on the first encounter and improve clinical outcomes.<\/jats:p>","DOI":"10.3390\/biom13040638","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T03:08:31Z","timestamp":1680491311000},"page":"638","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Haptoglobin-Related Protein without Signal Peptide as Biomarker of Renal Salt Wasting in Hyponatremia, Hyponatremia-Related Diseases and as New Syndrome in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0001-1450","authenticated-orcid":false,"given":"John K.","family":"Maesaka","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Nephrology and Hypertension, NYU Langone Hospital Long Island and NYU Long Island School of Medicines, Mineola, New York, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis J.","family":"Imbriano","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology and Hypertension, NYU Langone Hospital Long Island and NYU Long Island School of Medicines, Mineola, New York, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candace","family":"Grant","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology and Hypertension, NYU Langone Hospital Long Island and NYU Long Island School of Medicines, Mineola, New York, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Miyawaki","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology and Hypertension, NYU Langone Hospital Long Island and NYU Long Island School of Medicines, Mineola, New York, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/0002-9343(87)90649-8","article-title":"Clinical assessment of extracellular fluid volume in hyponatremia","volume":"83","author":"Chung","year":"1987","journal-title":"Am. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"309","DOI":"10.2215\/CJN.02740608","article-title":"More on Renal Salt Wasting Without Cerebral Disease: Response to Saline Infusion","volume":"4","author":"Bitew","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_3","first-page":"174","article-title":"Hyponatremia and hypouricemia: Differentiation from SIADH","volume":"33","author":"Maesaka","year":"1990","journal-title":"Clin. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/sj.ki.5002093","article-title":"Renal salt wasting without cerebral disease: Diagnostic value of urate determinations in hyponatremia","volume":"71","author":"Maesaka","year":"2007","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/ki.2009.263","article-title":"Is it cerebral or renal salt wasting?","volume":"76","author":"Maesaka","year":"2009","journal-title":"Kidney Int."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Maesaka, J.K., Imbriano, L.J., Pinkhasov, A., Muralidharan, R., Song, X., Russo, L.M., and Comper, W.D. (2021). Identification of a Novel Natriuretic Protein in Patients With Cerebral-Renal Salt Wasting\u2014Implications for Enhanced Diagnosis. Am. J. Med. Sci., 361.","DOI":"10.1016\/j.amjms.2020.07.015"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.amjms.2018.03.020","article-title":"High Prevalence of Renal Salt Wasting Without Cerebral Disease as Cause of Hyponatremia in General Medical Wards","volume":"356","author":"Maesaka","year":"2018","journal-title":"Am. J. Med. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1056\/NEJM197909063011005","article-title":"Hypouricemia in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone","volume":"301","author":"Beck","year":"1979","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1203\/00006450-198505000-00003","article-title":"Hypouricemia in Neonates with Syndrome of Inappropriate Secretion of Antidiuretic Hormone","volume":"19","author":"Assadi","year":"1985","journal-title":"Pediatr. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/j.0954-6820.1971.tb04340.x","article-title":"Elevation of uric acid clearance caused by inappropriate antidiuretic hormone secretion","volume":"189","author":"Mees","year":"1971","journal-title":"Acta Med. Scand."},{"key":"ref_11","first-page":"20","article-title":"Increased uric acid clearance in the syndrome of inappropriate secretion of antidiuretic hormone","volume":"24","author":"Sonnenblick","year":"1988","journal-title":"Isr. J. Med Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.amjms.2016.05.035","article-title":"Identifying Different Causes of Hyponatremia With Fractional Excretion of Uric Acid","volume":"352","author":"Imbriano","year":"2016","journal-title":"Am. J. Med Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1152\/ajplegacy.1976.231.2.509","article-title":"Urate reabsorption in proximal convoluted tubule of the rat kidney","volume":"231","author":"Weinman","year":"1976","journal-title":"Am. J. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"482370","DOI":"10.1155\/2013\/482370","article-title":"Delay in Diagnosis of Adrenal Insufficiency Is a Frequent Cause of Adrenal Crisis","volume":"2013","author":"Papierska","year":"2013","journal-title":"Int. J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/joim.12699","article-title":"Clues for early detection of autoimmune Addison\u2019s disease-myths and realities","volume":"283","author":"Saevik","year":"2018","journal-title":"J. Intern. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kim, G.-H. (2022). Pathophysiology of Drug-Induced Hyponatremia. J. Clin. Med., 11.","DOI":"10.3390\/jcm11195810"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/0002-9343(57)90224-3","article-title":"A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone","volume":"23","author":"Schwartz","year":"1957","journal-title":"Am. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/0002-9343(67)90096-4","article-title":"The syndrome of inappropriate secretion of antidiuretic hormone","volume":"42","author":"Bartter","year":"1967","journal-title":"Am. J. Med."},{"key":"ref_19","unstructured":"Squire, L.E., Roberts, J.L., Spitzer, N.C., Zigmond, M.J., McConnell, S.K., and Bloom, F.E. (2003). Fundamental Neuroscience, Elsevier. [2nd ed.]."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sterns, R., and Rondon-Berrios, H. (2022). Cerebral salt wasting is a real cause of hyponatremia: CON. Kidney360.","DOI":"10.34067\/KID.0001412022"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1681\/ASN.2007091042","article-title":"Impact of solute intake on urine flow and water excretion","volume":"19","author":"Berl","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1210\/jc.2013-3032","article-title":"Hyponatremia follow mild\/moderate subarachnoid hemorrhage is due to SIAD and glucocorticoid deficiency and not cerebral salt wasting","volume":"99","author":"Hannon","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1210\/jc.2013-4289","article-title":"Hyponatremia with intracranial disease: Not often cerebral salt wasting","volume":"99","author":"Verbalis","year":"2014","journal-title":"Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.2215\/CJN.00070120","article-title":"The curious story of cerebral salt wasting. Fact of fiction","volume":"15","author":"Verbalis","year":"2020","journal-title":"Clin. J. Amer. Soc. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"833","DOI":"10.5301\/jn.5000074","article-title":"Normal fractional urate excretion identifies hyponatremic patients with reset osmostat","volume":"25","author":"Imbriano","year":"2012","journal-title":"J. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Corona, G., Giuliani, C., Parenti, G., Norello, D., Verbalis, J.G., Forti, G., Maggi, M., and Peri, A. (2013). Moderate Hyponatremia Is Associated with Increased Risk of Mortality: Evidence from a Meta-Analysis. PLoS ONE, 8.","DOI":"10.1530\/endoabs.32.P864"},{"key":"ref_27","first-page":"1056","article-title":"The hyponatremic patient: A systematic approach to laboratory diagnosis","volume":"166","author":"Milionis","year":"2002","journal-title":"Can. Med. Assoc. J."},{"key":"ref_28","first-page":"475","article-title":"Utility of biochemical parameters in the evaluation of hyponatremia in the elderly","volume":"32","author":"Musch","year":"2001","journal-title":"J. Urol. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"938","DOI":"10.3171\/jns.1981.55.6.0938","article-title":"Hyponatremia in intracranial disease: Perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)","volume":"55","author":"Nelson","year":"1981","journal-title":"J. Neurosurg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/ana.410180208","article-title":"Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm","volume":"18","author":"Wijdicks","year":"1985","journal-title":"Ann. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/BF00582152","article-title":"A micropuncture study of the renal handling of lithium","volume":"380","author":"Hayslett","year":"1979","journal-title":"Pflug. Arch."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1016\/0024-3205(93)90008-Q","article-title":"Plasma natriuretic factor(s) in patients with intracranial disease, renal salt wasting and hyperuricosuria","volume":"52","author":"Maesaka","year":"1993","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/j.1532-5415.1993.tb01885.x","article-title":"Hypouricemia, Abnormal Renal Tubular Urate Transport, and Plasma Natriuretic Factor(s) in Patients with Alzheimer\u2019s Disease","volume":"41","author":"Maesaka","year":"1993","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1172\/JCI111759","article-title":"Renl mechanism of action of rat atrial natriuretic factor","volume":"75","author":"Huang","year":"1985","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1097\/00005344-198601000-00031","article-title":"Dose-dependent effect of atrial natriuretic peptide on blood pressure, heart rate, and skin blood flow of normal volunteers","volume":"8","author":"Bussien","year":"1986","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1172\/JCI102805","article-title":"Evidence in man that urinary electrolyte loss induced by pitressin is a function of water retention","volume":"32","author":"Leaf","year":"1953","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1152\/ajplegacy.1959.196.2.451","article-title":"Changes in urine concentration during prolonged administration of vasopressin and water","volume":"196","author":"Levinsky","year":"1959","journal-title":"Am. J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/ana.410170206","article-title":"Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysms: Is fluid restriction harmful?","volume":"17","author":"Wijdicks","year":"1985","journal-title":"Ann. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2846","DOI":"10.1182\/blood-2006-05-022327","article-title":"Haptoglobin-related protein is a high-affinity hemoglobin-binding plasma protein","volume":"108","author":"Nielsen","year":"2006","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.ejcb.2018.06.003","article-title":"A comprehensive review of signal peptides: Structure, roles, and applications","volume":"97","author":"Owji","year":"2018","journal-title":"Eur. J. Cell."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3884","DOI":"10.1074\/jbc.273.7.3884","article-title":"Characterization of the human serum Trypanosome toxin, haptoglobin-related protein","volume":"273","author":"Muranjan","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"30254","DOI":"10.1074\/jbc.M010198200","article-title":"Haptoglobin-related protein mediates trypanosome lytic factor binding to trypanosomes","volume":"276","author":"Drain","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Maesaka, J.K., Imbriano, L.J., Grant, C., and Miyawaki, N. (2022). New approach to Hyponatremia: High Prevalence of Cerebral\/Renal Salt Wasting, Identification of Natriuretic Protein That Causes Renal Salt Wasting. J. Clin. Med., 11.","DOI":"10.3390\/jcm11247445"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/4\/638\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:08:13Z","timestamp":1760123293000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/4\/638"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,1]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["biom13040638"],"URL":"https:\/\/doi.org\/10.3390\/biom13040638","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,1]]}}}