Haptoglobin-related protein without signal peptide induces high prevalence of renal salt wasting and new syndrome of salt wasting in Alzheimer’s disease
Main Article Content
Abstract
Our understanding of hyponatremia, defined as a serum sodium < 135 mmol/L, and hyponatremia-related diseases is in a state of flux. A better understanding is now being established by abandoning the ineffective volume approach that has been in existence for over 50 years. We utilized comprehensive pathophysiologic phenomena that brought greater clarity to understanding and identifying the different causes of hyponatremia. An important message was to emphasize the difficulty in differentiating the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from appropriate antidiuretic hormone secretion in patients with cerebral or renal salt wasting (RSW), a condition that was previously considered to be rare among internists. Both syndromes present with identical clinical parameters that need to be appreciated and emphasized. The new approach demonstrated a high prevalence of RSW in hyponatremic patients from the general medical wards of the hospital to raise the awareness that hyponatremia is not all due to SIADH. We demonstrated natriuretic activity in the plasma of 21 neurosurgical and 17 Alzheimer’s disease patients by performing rat renal clearance studies while infusing plasma from these patients. The natriuretic factor was later identified as haptoglobin related protein without signal peptide in both groups of patients. Interestingly, blood levels of HPRWSP appears to increase progressively as the dementia worsens below a mini mental state examination score of 12 in Alzheimer’s. Additional data suggest that RSW might be present at an early stage of Alzheimer’s and these patients may become more dehydrated as the dementia worsens. Future studies intend to prove the existence and extent of volume depletion in Alzheimer’s and to develop HPRWSP as a biomarker of RSW.
Keywords:
Haptoglobin related protein without signal peptide, renal salt wasting in Alzheimer’s disease, cerebral salt wasting, Haptoglobin related protein, Alzheimer Disease, Hyponatremia, Fractional urate excretion, Dehydration, Natriuretic factor, Renal salt wasting, Syndrome of inappropriate antidiuretic hormone secretion
Article Details
How to Cite
MAESAKA, John K. et al.
Haptoglobin-related protein without signal peptide induces high prevalence of renal salt wasting and new syndrome of salt wasting in Alzheimer’s disease.
Medical Research Archives, [S.l.], v. 13, n. 1, feb. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6287>. Date accessed: 01 may 2025.
doi: https://doi.org/10.18103/mra.v13i1.6287.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Maesaka JK, Imbriano LJ, Miyawaki N. High prevalence of renal salt wasting without cerebral disease as cause of hyponatremia in general medical wards. Am J Med Sci. 2018;356:15–22.
2. Maesaka JK, Venkatesan J, Piccione JM, et al. Plasma natriuretic factor[s] in patients with intracranial disease, renal salt wasting and hyperuricosuria. Life Sci 1993; 52:1875–1882.
3. Maesaka JK, Wolf-Klein G, Piccione JM, et al. Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor[s] in patients with Alzheimer’s disease. J Am Geriatr Soc 1993; 41:501–506.
4. Maesaka JK, Imbriano LJ, Pinkhasov A, et al. Identification of a novel natriuretic protein in patients with cerebral-renal salt wasting- Implications for enhanced diagnosis. Am Jour Med Sci 2021; 361:261-268.
5. Maesaka JK, Batuman V, Yudd M, et al. Hyponatremia and hypouricemia: differentiation from SIADH. Clin Nephrol 1990; 33:174–178.
6. Chung H.-M, Kluge R, Schrier, R.W. Clinical assessment of extracellular fluid volume in hyponatremia. Am. J. Med. 1987, 83, 905–908.
7. Beck LH. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 1979; 301:528–530.
8. Assadi F.K. John E.G. Hypouricemia in Neonates with Syndrome of Inappropriate Secretion of Antidiuretic Hormone. Pediatr. Res. 1985; 19, 424–427.
9. Mee, E.J.D, Van Assendelft P.B, Nieuwenhuis M.G. Elevation of uric acid clearance caused by inappropriate antidiuretic hormone secretion. Acta Med. Scand. 1971; 189, 69–72.
10. Sonnenblick M, Rosin A. Increased uric acid clearance in the syndrome of inappropriate secretion of antidiuretic hormone. Isr. J. Med Sci. 1988; 24, 20–23.
11. Weinman EJ, Steplock D, Suki WN, et al. Urate reabsorption in proximal convoluted tubule of the rat kidney. Am J Physiol 1976; 231:509–515.
12. Maesaka JK, Miyawaki N, Palaia T, et al.. Renal salt wasting without cerebral disease: value of determining urate in hyponatremia. Kidney Int. 2007;71:822–826.
13. Bitew S, Imbriano L, Miyawaki N, et al. More on renal salt wasting without cerebral disease, response to saline infusion. Clin J Amer Soc Nephol. 2009;4:309–315.
14. Maesaka JK, Imbriano LJ, Ali NM, et al. Is it cerebral or renal salt wasting? Kidney Int 2009; 76:934–938.
15. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1967; 42:790–805.
16. Jancic N, Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am 2003; 32:459-481.
17. Stricker E.M, Verbalis J. Water intake and body fluids. In Fundamental Neuroscience, 2nd ed.; Squire, L.E., Roberts, J.L., Spitzer, N.C., Zigmond, M.J., McConnell, S.K., Bloom, F.E., Eds.; Elsevier: La Jolla, CA, USA, 2003; pp. 1011–1029.
18. Sterns RH. Disorder of plasma sodium-causes, consequences and correction. N Engl J Med 2015;372:55–65
19. Imbriano LJ, Ilamathi E, Ali NM, et al. Normal fractional urate excretion identifies hyponatremic patients with reset osmostat. J Nephrol 2012; 25:833–838.
20. Assadi F, Mazaheri M. Differentiating syndrome of inappropriate ADH, reset Osmostat, cerebral/ renal salt wasting using fractional urate excretion. J Pediatr Endocrinol Metab 2020 Nov12;34(1):137-140. Doi:10.1515/jpem-2020-0379. PMID:33180045
21. Jaenike JR, Waterhouse C. The renal response to sustained administration of vasopressin and water in man. J Clin Endocrinol Metab 1961; 21:231–242.
22. Levinsky NG, Davidson DG, Berliner RW. Changes in urine concentration during prolonged administration of vasopressin and water. Am J Physiol 1959; 196:451–456.
23. Steele A, Gowrishankar M, Abrahamson S, et al. Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination. Ann Intern Med 1997; 126:20–25.
24. Maesaka JK, Imbriano L, Miyawaki N. 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. Frontiers in Medicine. November 2018; Volume 5: article 319 000
25. Nelson PB, Seif SM, Maroon JC, et al. Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone [SIADH]. J Neurosurg 1981; 55:938–941.
26. Wijdicks EF, Vermeulen M, ten Haaf JA, et al. Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm. Ann Neurol 1985; 18:211–216.
27. Sivakumar V, Rajshekhar V, Chandy MJ. Management of neurosurgical patients with hyponatremia and natriuresis. Neurosurgery 1994; 34:269–274.
28. Kasa M, Bierma TJ, Waterstraat F Jr, et al. Routine blood chemistry screen: a diagnostic aid for Alzheimer's disease. Neuroepidemiology, 1989 ; 8[5]pp.254-256
29. Hayslett JP, Kashgarian M. A micro puncture study of the renal handling of lithium. Pflug Arch 1979; 380:159–163.
30. Wijdicks EF, Vermeulen M, Hijdra A, et al. Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysm: is fluid restriction harmful. Ann Neurol. 1985;17:137–140.
31. Begg DP. Disturbances of thirst and fluid balance associated with aging. Physiol Behav. 2017 Sep 1;178:28-34. doi: 10.1016/j.physbeh.2017.03. 003. Epub 2017 Mar 4. PMID: 28267585.
32. Arredouani, M.; Matthijs, P.; Van Hoeyveld, E.; Kasran, A.; Baumann, H.; Ceuppens, J.L.; Stevens, E. Haptoglobin directly affects T cells and suppresses T helper cell type 2 cytokine release. Immunology 2003, 108, 144–151.
33. Levy, A.P. Haptoglobin: A major susceptibility gene for diabetic cardiovascular disease. Isr. Med. Assoc. J. IMAJ 2004, 6, 308–310.
34. Quaye, I.K.; Ababio, G.; Amoah, A.G. Haptoglobin 2-2 Phenotype is a Risk Factor for Type 2 Diabetes in Ghana. J. Atheroscler. Thromb. 2006, 13, 90–94.
35. Quaye, I.K. Haptoglobin, inflammation and disease. Trans. R. Soc. Trop. Med. Hyg. 2008, 102, 735–742.
36. Delanghe, J.; Langlois, M.; Duprez, D.; De Buyzere, M.; Clement, D. Haptoglobin polymorphism and peripheral arterial occlusive disease. Atherosclerosis 1999, 145, 287–292.
37. Yildirim, C.; Kekec, Z.; Sozuer, E.M.; Ikizceli, I.; Avsarogullari, L. Blood levels of acute phase reactants with traffic accidents. Soudni Lekarstvi 2004, 49, 25–29
38. Arredouani, M.S.; Kasran, A.; Vanoirbeek, J.A.; Berger, F.G.; Baumann, H.; Ceuppens, J.L. Haptoglobin dampens endotoxininduced inflammatory effects both in vitro and in vivo. Immunology 2005, 114, 263–271.
39. Imrie HJ, Fowkes FJ, Migot-Nabias F, et al. Individual variation in levels of haptoglobin-related protein in children from Gabon. PLoS ONE. 2012;7:e49816.
40. Harrington JM, Nishanova T, Rose Pena S, et al. A retained secretor signal peptide mediates high density lipoprotein [HDL] assembly and function of haptoglobin-related protein. J Biol Chem 2014;289 number 36:24811-24820
41. Owji H, Nezafat N, Negahdaripour M, et al. A comprehensive review of signal peptides: structure, roles, and applications. Euro J Cell. 2018; 97[6]:422–441.
42. Hardwick RJ, Menard A, Sironi M, et al. Haptoglobin [HP] and haptoglobin-related protein [HPR] copy number variation, natural selection, and trypanosomiasis, Hum Genet 2014; 133: 69-83 DOI 10.1007/s00439-013-1352-x
43. Nielsen MJ, Petersen SV, Jacobsen C, et al. Haptoglobin-related protein is a high-affinity hemoglobin-binding plasma protein. Blood. 2006;108:2846–2849.
44. Saraswat M, Joenvaara S, Tohmola T, et al. Label-free plasma proteomics identifies haptoglobin-related protein as candidate marker of idiopathic pulmonary fibrosis and dysregulation of complement and oxidative pathways. Scientific Reports 2020;10:7787 https://doi.org/10.1038/s41598-020-64759-
45. Kuhajda FP, Katumuluwa AI, Pasternak GR. Expression of haptoglobin-related protein and its potential role as a tumor antigen. Proc Natl Acad Sci 1989;86:1188-1192
46. Maesaka JK, Imbriano LJ. Debates in Nephrology. Cerebral salt wasting is a real cause of hyponatremia: PRO. Kidney360. Published ahead of print 2022 DOI: 10.34067/KID.0001422022.
47. Sterns R, Rondon-Berrios H. Debates in Nephrology. Cerebral salt wasting is a real cause of hyponatremia: CON. Kidney360 published ahead of print, 2022; DOI 10.3406/KID.0001412022a
48. Verbalis J.G Hyponatremia with intracranial disease: not often cerebral salt wasting. J Clin Endocrinol Metab 2014;99:59-62 https://doi.org/10.1210/jc.2013-4289
49. Verbalis J.G. The curious story of cerebral salt wasting. Fact or fiction. Clin J Amer Soc Nephrol. 2020;15:1666-1668. DOI:https://doi.org/10.2215/CJN.00070120
50. Hannon MJ, Behan LA, O’Brien MM, et al. Hyponatremia following mild/moderate subarachnoid hemorrhage is due to SIAD and glucocorticoid deficiency and not cerebral salt wasting. J Clin Endocrinol Metab 2014;99:291-298.
51. Schwartz WB, Bennett W, Curelop S. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957;23:529–42.
52. Lacey J, Corbett J, Forni L, et al. A multidisciplinary consensus on dehydration: definitions, diagnostic methods and clinical implications. Annala Med. 2019;51,NOS,3-4,232-251. https://doi.org/10.1080/07853890.2019.1628352l
53. NICE clinical guidelines 174. Intravenous fluid therapy in adults in hospital. London: NICE 2013
54. Skytthe MK, Sørensen AL, Hennig D, et al., Haptoglobin-related protein in human plasma correlates to haptoglobin concentrations and phenotypes. Scand J Clin Lab Invest. 2022 Oct;82 (6):461-466. doi: 10.1080/00365513.2022.212207 6. Epub 2022 Sep 21. PMID: 36129375.
55. Song IU, Kim YD, Chung SW, et al. Association between serum haptoglobin and the pathogenesis of Alzheimer’s disease. Int Med. 2015;54:453–456.
56. Cen-Jing Zhu, Guo-Xin Jiang, Jin-Mei Chen, et al. Serum haptoglobin in Chinese patients with Alzheimer’s disease and mild cognitive impairment: A case-control study. Brain Res Bull. 2018 Mar:13 7:301-305. Doi:10.1016/j.brainresbull.2018.01.005
57. Murthy SB, Caplan J, Levy AP, et al. Haptoglobin 2-2 genotype is associated with cerebral salt wasting syndrome in aneurysmal subarachnoid hemorrhage. Neurosurgery. 2016;78:71–76.
2. Maesaka JK, Venkatesan J, Piccione JM, et al. Plasma natriuretic factor[s] in patients with intracranial disease, renal salt wasting and hyperuricosuria. Life Sci 1993; 52:1875–1882.
3. Maesaka JK, Wolf-Klein G, Piccione JM, et al. Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor[s] in patients with Alzheimer’s disease. J Am Geriatr Soc 1993; 41:501–506.
4. Maesaka JK, Imbriano LJ, Pinkhasov A, et al. Identification of a novel natriuretic protein in patients with cerebral-renal salt wasting- Implications for enhanced diagnosis. Am Jour Med Sci 2021; 361:261-268.
5. Maesaka JK, Batuman V, Yudd M, et al. Hyponatremia and hypouricemia: differentiation from SIADH. Clin Nephrol 1990; 33:174–178.
6. Chung H.-M, Kluge R, Schrier, R.W. Clinical assessment of extracellular fluid volume in hyponatremia. Am. J. Med. 1987, 83, 905–908.
7. Beck LH. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 1979; 301:528–530.
8. Assadi F.K. John E.G. Hypouricemia in Neonates with Syndrome of Inappropriate Secretion of Antidiuretic Hormone. Pediatr. Res. 1985; 19, 424–427.
9. Mee, E.J.D, Van Assendelft P.B, Nieuwenhuis M.G. Elevation of uric acid clearance caused by inappropriate antidiuretic hormone secretion. Acta Med. Scand. 1971; 189, 69–72.
10. Sonnenblick M, Rosin A. Increased uric acid clearance in the syndrome of inappropriate secretion of antidiuretic hormone. Isr. J. Med Sci. 1988; 24, 20–23.
11. Weinman EJ, Steplock D, Suki WN, et al. Urate reabsorption in proximal convoluted tubule of the rat kidney. Am J Physiol 1976; 231:509–515.
12. Maesaka JK, Miyawaki N, Palaia T, et al.. Renal salt wasting without cerebral disease: value of determining urate in hyponatremia. Kidney Int. 2007;71:822–826.
13. Bitew S, Imbriano L, Miyawaki N, et al. More on renal salt wasting without cerebral disease, response to saline infusion. Clin J Amer Soc Nephol. 2009;4:309–315.
14. Maesaka JK, Imbriano LJ, Ali NM, et al. Is it cerebral or renal salt wasting? Kidney Int 2009; 76:934–938.
15. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1967; 42:790–805.
16. Jancic N, Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am 2003; 32:459-481.
17. Stricker E.M, Verbalis J. Water intake and body fluids. In Fundamental Neuroscience, 2nd ed.; Squire, L.E., Roberts, J.L., Spitzer, N.C., Zigmond, M.J., McConnell, S.K., Bloom, F.E., Eds.; Elsevier: La Jolla, CA, USA, 2003; pp. 1011–1029.
18. Sterns RH. Disorder of plasma sodium-causes, consequences and correction. N Engl J Med 2015;372:55–65
19. Imbriano LJ, Ilamathi E, Ali NM, et al. Normal fractional urate excretion identifies hyponatremic patients with reset osmostat. J Nephrol 2012; 25:833–838.
20. Assadi F, Mazaheri M. Differentiating syndrome of inappropriate ADH, reset Osmostat, cerebral/ renal salt wasting using fractional urate excretion. J Pediatr Endocrinol Metab 2020 Nov12;34(1):137-140. Doi:10.1515/jpem-2020-0379. PMID:33180045
21. Jaenike JR, Waterhouse C. The renal response to sustained administration of vasopressin and water in man. J Clin Endocrinol Metab 1961; 21:231–242.
22. Levinsky NG, Davidson DG, Berliner RW. Changes in urine concentration during prolonged administration of vasopressin and water. Am J Physiol 1959; 196:451–456.
23. Steele A, Gowrishankar M, Abrahamson S, et al. Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination. Ann Intern Med 1997; 126:20–25.
24. Maesaka JK, Imbriano L, Miyawaki N. 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. Frontiers in Medicine. November 2018; Volume 5: article 319 000
25. Nelson PB, Seif SM, Maroon JC, et al. Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone [SIADH]. J Neurosurg 1981; 55:938–941.
26. Wijdicks EF, Vermeulen M, ten Haaf JA, et al. Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm. Ann Neurol 1985; 18:211–216.
27. Sivakumar V, Rajshekhar V, Chandy MJ. Management of neurosurgical patients with hyponatremia and natriuresis. Neurosurgery 1994; 34:269–274.
28. Kasa M, Bierma TJ, Waterstraat F Jr, et al. Routine blood chemistry screen: a diagnostic aid for Alzheimer's disease. Neuroepidemiology, 1989 ; 8[5]pp.254-256
29. Hayslett JP, Kashgarian M. A micro puncture study of the renal handling of lithium. Pflug Arch 1979; 380:159–163.
30. Wijdicks EF, Vermeulen M, Hijdra A, et al. Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysm: is fluid restriction harmful. Ann Neurol. 1985;17:137–140.
31. Begg DP. Disturbances of thirst and fluid balance associated with aging. Physiol Behav. 2017 Sep 1;178:28-34. doi: 10.1016/j.physbeh.2017.03. 003. Epub 2017 Mar 4. PMID: 28267585.
32. Arredouani, M.; Matthijs, P.; Van Hoeyveld, E.; Kasran, A.; Baumann, H.; Ceuppens, J.L.; Stevens, E. Haptoglobin directly affects T cells and suppresses T helper cell type 2 cytokine release. Immunology 2003, 108, 144–151.
33. Levy, A.P. Haptoglobin: A major susceptibility gene for diabetic cardiovascular disease. Isr. Med. Assoc. J. IMAJ 2004, 6, 308–310.
34. Quaye, I.K.; Ababio, G.; Amoah, A.G. Haptoglobin 2-2 Phenotype is a Risk Factor for Type 2 Diabetes in Ghana. J. Atheroscler. Thromb. 2006, 13, 90–94.
35. Quaye, I.K. Haptoglobin, inflammation and disease. Trans. R. Soc. Trop. Med. Hyg. 2008, 102, 735–742.
36. Delanghe, J.; Langlois, M.; Duprez, D.; De Buyzere, M.; Clement, D. Haptoglobin polymorphism and peripheral arterial occlusive disease. Atherosclerosis 1999, 145, 287–292.
37. Yildirim, C.; Kekec, Z.; Sozuer, E.M.; Ikizceli, I.; Avsarogullari, L. Blood levels of acute phase reactants with traffic accidents. Soudni Lekarstvi 2004, 49, 25–29
38. Arredouani, M.S.; Kasran, A.; Vanoirbeek, J.A.; Berger, F.G.; Baumann, H.; Ceuppens, J.L. Haptoglobin dampens endotoxininduced inflammatory effects both in vitro and in vivo. Immunology 2005, 114, 263–271.
39. Imrie HJ, Fowkes FJ, Migot-Nabias F, et al. Individual variation in levels of haptoglobin-related protein in children from Gabon. PLoS ONE. 2012;7:e49816.
40. Harrington JM, Nishanova T, Rose Pena S, et al. A retained secretor signal peptide mediates high density lipoprotein [HDL] assembly and function of haptoglobin-related protein. J Biol Chem 2014;289 number 36:24811-24820
41. Owji H, Nezafat N, Negahdaripour M, et al. A comprehensive review of signal peptides: structure, roles, and applications. Euro J Cell. 2018; 97[6]:422–441.
42. Hardwick RJ, Menard A, Sironi M, et al. Haptoglobin [HP] and haptoglobin-related protein [HPR] copy number variation, natural selection, and trypanosomiasis, Hum Genet 2014; 133: 69-83 DOI 10.1007/s00439-013-1352-x
43. Nielsen MJ, Petersen SV, Jacobsen C, et al. Haptoglobin-related protein is a high-affinity hemoglobin-binding plasma protein. Blood. 2006;108:2846–2849.
44. Saraswat M, Joenvaara S, Tohmola T, et al. Label-free plasma proteomics identifies haptoglobin-related protein as candidate marker of idiopathic pulmonary fibrosis and dysregulation of complement and oxidative pathways. Scientific Reports 2020;10:7787 https://doi.org/10.1038/s41598-020-64759-
45. Kuhajda FP, Katumuluwa AI, Pasternak GR. Expression of haptoglobin-related protein and its potential role as a tumor antigen. Proc Natl Acad Sci 1989;86:1188-1192
46. Maesaka JK, Imbriano LJ. Debates in Nephrology. Cerebral salt wasting is a real cause of hyponatremia: PRO. Kidney360. Published ahead of print 2022 DOI: 10.34067/KID.0001422022.
47. Sterns R, Rondon-Berrios H. Debates in Nephrology. Cerebral salt wasting is a real cause of hyponatremia: CON. Kidney360 published ahead of print, 2022; DOI 10.3406/KID.0001412022a
48. Verbalis J.G Hyponatremia with intracranial disease: not often cerebral salt wasting. J Clin Endocrinol Metab 2014;99:59-62 https://doi.org/10.1210/jc.2013-4289
49. Verbalis J.G. The curious story of cerebral salt wasting. Fact or fiction. Clin J Amer Soc Nephrol. 2020;15:1666-1668. DOI:https://doi.org/10.2215/CJN.00070120
50. Hannon MJ, Behan LA, O’Brien MM, et al. Hyponatremia following mild/moderate subarachnoid hemorrhage is due to SIAD and glucocorticoid deficiency and not cerebral salt wasting. J Clin Endocrinol Metab 2014;99:291-298.
51. Schwartz WB, Bennett W, Curelop S. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957;23:529–42.
52. Lacey J, Corbett J, Forni L, et al. A multidisciplinary consensus on dehydration: definitions, diagnostic methods and clinical implications. Annala Med. 2019;51,NOS,3-4,232-251. https://doi.org/10.1080/07853890.2019.1628352l
53. NICE clinical guidelines 174. Intravenous fluid therapy in adults in hospital. London: NICE 2013
54. Skytthe MK, Sørensen AL, Hennig D, et al., Haptoglobin-related protein in human plasma correlates to haptoglobin concentrations and phenotypes. Scand J Clin Lab Invest. 2022 Oct;82 (6):461-466. doi: 10.1080/00365513.2022.212207 6. Epub 2022 Sep 21. PMID: 36129375.
55. Song IU, Kim YD, Chung SW, et al. Association between serum haptoglobin and the pathogenesis of Alzheimer’s disease. Int Med. 2015;54:453–456.
56. Cen-Jing Zhu, Guo-Xin Jiang, Jin-Mei Chen, et al. Serum haptoglobin in Chinese patients with Alzheimer’s disease and mild cognitive impairment: A case-control study. Brain Res Bull. 2018 Mar:13 7:301-305. Doi:10.1016/j.brainresbull.2018.01.005
57. Murthy SB, Caplan J, Levy AP, et al. Haptoglobin 2-2 genotype is associated with cerebral salt wasting syndrome in aneurysmal subarachnoid hemorrhage. Neurosurgery. 2016;78:71–76.