Background: Normal anion gap metabolic acidosis is a common but often misdiagnosed clinical condition associated with diarrhea and renal tubular acidosis (RTA). Early identification of RTA remains challenging for inexperienced physicians, and diagnosis and treatment are often delayed. Summary: The presence of RTA should be considered in any patient with a high chloride level when the CL-/Na+ ratio is above 0.79, if the patient does not have diarrhea. In patients with significant hyperkalemia one should evaluate for RTA type 4, especially in diabetic patients, with a relatively conserved renal function. A still growing list of medications can produce RTA. Key Messages: This review highlights practical aspects concerning normal anion gap metabolic acidosis.

1.
Berend K, de Vries AP, Gans RO: Physiological approach to assessment of acid-base disturbances. N Engl J Med 2015;372:195.
2.
Kraut JA, Madias NE: Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007;2:162-174.
3.
Roberts WL, Johnson RD: Serum anion gap. Has the reference value really fallen? Arch Pathol Lab Med 1997;121:568-572.
4.
Sadjadi SA, Manalo R, Jaipaul N, McMillan J: Ion-selective electrode and anion gap range: What should the anion gap be? Int J Nephrol Renovasc Dis 2013;6:101-105.
5.
Farwell WR, Taylor EN: Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey. CMAJ 2010;182:137-141.
6.
Gamble JL: Extracellular fluid and its maintenance. N Engl J Med 1936;250:1150-1152.
7.
Kelly A, McAlpine R, Elizabeth E: Agreement between bicarbonate measured on arterial and venous blood gases. Emerg Med Australas 2004;16:407-409.
8.
Berend K: Acid-base pathophysiology after 130 years: confusing, irrational and controversial. J Nephrol 2013;26:254-265.
9.
Szerlip HM, Singer I: Hyperchloremic metabolic acidosis after chlorine inhalation. Am J Med 1984;77:581-582.
10.
Durward A, Skellett S, Mayer A, Taylor D, Tibby SM, Murdoch IA: The value of the chloride: sodium ratio in differentiating the aetiology of metabolic acidosis. Intensive Care Med 2001;27:828-835.
11.
Berend K, van Hulsteijn LH, Gans RO: Chloride: the queen of electrolytes? Eur J Intern Med 2012;23:203-211.
12.
Ratnam S, Kaeny W, Shapiro JI: Pathogenesis and management of metabolic acidosis and alkalosis; in Schrier RW (ed): Renal and Electrolyte Disorders, ed 7. Philadelphia, Lippincott, Williams & Wilkins, 2010, pp 86-121.
13.
Hall MC, Koch MO, McDougal WS: Metabolic consequences of urinary diversion through intestinal segments. Urol Clin North Am 1991;18:725-735.
14.
Kamar FB, McQuillan RF: Hyperchloremic metabolic acidosis due to cholestyramine: a case report and literature review. Case Rep Nephrol 2015;309791.
15.
Santos F, Ordóñez FA, Claramunt-Taberner D, Gil-Peña H: Clinical and laboratory approaches in the diagnosis of renal tubular acidosis. Pediatr Nephrol 2015;30:2099-2107.
16.
Aggarwal M, McKenna R: Update on carbonic anhydrase inhibitors: a patent review (2008-2011). Expert Opin Ther Pat 2012;22:903-915.
17.
Supuran CT: How many carbonic anhydrase inhibition mechanisms exist? J Enzyme Inhib Med Chem 2016;31:345-360.
18.
Oosterwijk E: Carbonic anhydrase expression in kidney and renal cancer: implications for diagnosis and treatment. Subcell Biochem 2014;75:181-198.
19.
Curthoys NP, Moe OW: Proximal tubule function and response to acidosis. Clin J Am Soc Nephrol 2014;9:1627-1638.
20.
Rennke H, Denker BM: Renal Pathophysiology, ed 4. Philadelphia, Lippincott Williams & Wilkins, 2014, chapt 6: Metabolic Acidosis, pp 153-173.
21.
Reddy P: Clinical approach to renal tubular acidosis in adult patients. Int J Clin Pract 2011;65:350-360.
22.
Garashi T, Sekine T, Inatomi J, Seki G: Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis. J Am Soc Nephrol 2002;13:2171-2177.
23.
Liamis G, Milionis HJ, Elisaf M: Pharmacologically-induced metabolic acidosis. Drug Saf 2010;33:371-391.
24.
Yaxley J, Pirrone C: Review of the diagnostic evaluation of renal tubular acidosis. Ochsner J 2016;16:525-530.
25.
Taylor D, Durward A, Tibby SM, Thorburn K, Holton F, Johnstone IC, Murdoch IA: The influence of hyperchloraemia on acid base interpretation in diabetic ketoacidosis. Intensive Care Med 2006;32:295-301.
26.
Ritzenthaler T, Grousson S, Dailler F: Hyperchloremic metabolic acidosis following plasma exchange during myasthenia gravis crisis. J Clin Apher 2016;31:479-480.
27.
Bala I, Dwivedi D, Jain D, Mahajan JK: Hyperchloremic metabolic acidosis following total gut irrigation with normal saline in pediatric patients: a rare occurrence. Indian J Crit Care Med 2017;21:55-56.
28.
Thongprayoon C, Cheungpasitporn W, Cheng Z, Qian Q: Chloride alterations in hospitalized patients: prevalence and outcome significance. PLoS One 2017;12:e0174430.
29.
Mahler SA, Conrad SA, Wang H, Arnold TC: Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med 2011;29:670-674.
30.
Reddy P, Mooradian AD: Clinical utility of anion gap in deciphering acid-base disorders. Int J Clin Pract 2009;63:1516-1525.
31.
Rodriguez Soriano J: Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002;13:2160-2170.
32.
Katzir Z, Dinour D, Reznik-Wolf H, Nissenkorn A, Holtzman E: Familial pure proximal renal tubular acidosis - a clinical and genetic study. Nephrol Dial Transplant 2008;23:1211-1215.
33.
Finkel KW, Dubose TF: Metabolic acidosis; in Dubose T Jr, Hamm L (eds): Acid Base and Electrolyte Disorders: A Companion to Brenner & Rector's, The Kidney. Philadelphia, Saunders, 2002, pp 55-66.
34.
Rastegar M, Nagami GT: Non-anion gap metabolic acidosis: a clinical approach to evaluation. Am J Kidney Dis 2017;69:296-301.
35.
Soleimani M, Rastegar A: Pathophysiology of renal tubular acidosis: core curriculum. Am J Kidney Dis 2016;68:488-498.
36.
Cook JD, Strauss KA, Caplan YH, Lodico CP, Bush DM: Urine pH: the effects of time and temperature after collection. J Anal Toxicol 2007;31:486-496.
37.
Kwong T, Robinson C, Spencer D, Wiseman OJ, Karet Frankl FE: Accuracy of urine pH testing in a regional metabolic renal clinic: is the dipstick accurate enough? Urolithiasis 2013;41:129-132.
38.
Delanghe J, Speeckaert M: Preanalytical requirements of urinalysis. Biochem Med (Zagreb) 2014;24:89-104.
39.
Walsh S, Shirley D, Wrong O, Unwin R: Urinary acidification assessed by furosemide and fludrocortisone treatment: an alternative to ammonium chloride. Kidney Int 2007;71:1310-1316.
40.
Wrong O: Distal renal tubular acidosis: the value of urinary pH, PCO2 and NH4+ measurements. Pediatr Nephrol 1991;5:249-255.
41.
Galla JH, Kurtz I, Kraut JA, Lipschik GY, Macrae JP: Acid-base disorders; in Lerma E, Berns J, Nissenson A (eds): Current Essentials of Diagnosis & Treatment in Nephrology & Hypertension, ed 1. New York, McGraw-Hill Education/Medical, 2012, chapt 5, pp 42-59.
42.
Santos F, Ordóñez FA, Claramunt-Taberner D, Gil-Peña H: Clinical and laboratory approaches in the diagnosis of renal tubular acidosis. Pediatr Nephrol 2015;30:2099-2107.
43.
Kim S, Lee JW, Park J, Na KY, Joo KW, Ahn C, Kim S, Lee JS, Kim GH, Kim J, Han JS: The urine-blood PCO gradient as a diagnostic index of H+-ATPase defect distal renal tubular acidosis. Kidney Int 2004;66:761-767.
44.
Emmett M: Approach to the patient with a negative anion gap. Am J Kidney Dis 2016;67:143-150.
45.
Danel VC, Saviuc PF, Hardy GA, Lafond JL, Mallaret MP: Bromide intoxication and pseudohyperchloremia. Ann Pharmacother 2001;35:386-387.
46.
Zimmer BW, Marcus RJ, Sawyer K, Harchelroad F: Salicylate intoxication as a cause of pseudohyperchloremia. Am J Kidney Dis 2008;51:346-347.
47.
Sousa AG, Cabral JV, El-Feghaly WB, de Sousa LS, Nunes AB: Hyporeninemic hypoaldosteronism and diabetes mellitus: pathophysiology assumptions, clinical aspects and implications for management. World J Diabetes 2016;7:101-111.
48.
Haas CS, Pohlenz I, Lindner U, Muck PM, Arand J, Suefke S, Lehnert H: Renal tubular acidosis type IV in hyperkalaemic patients - a fairy tale or reality? Clin Endocrinol (Oxf) 2013;78:706-711.
49.
Rastegar A: Use of the ΔAG/ΔHCO3- ratio in the diagnosis of mixed acid-base disorders. J Am Soc Nephrol 2007;18:2429-2431.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.