Accepted Manuscript Urine tests for chronic hypokalemia: When in doubt, check urine sodium to chloride ratio Yeong-Hau H. Lien, MD, PhD PII:

S0002-9343(17)30269-3

DOI:

10.1016/j.amjmed.2017.02.040

Reference:

AJM 13985

To appear in:

The American Journal of Medicine

Received Date: 27 February 2017 Accepted Date: 27 February 2017

Please cite this article as: Lien YHH, Urine tests for chronic hypokalemia: When in doubt, check urine sodium to chloride ratio, The American Journal of Medicine (2017), doi: 10.1016/j.amjmed.2017.02.040. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Urine tests for chronic hypokalemia: When in doubt, check urine sodium to chloride ratio

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Yeong-Hau H. Lien, MD, PhD1,2

Department of Medicine, College of Medicine, University of Arizona, Arizona Kidney Disease and Hypertension Center

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Correspondence: Yeong-Hau H. Lien, M.D., Ph.D.,

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Tucson, Arizona, USA

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Arizona Kidney Disease and Hypertension Center Tucson, AZ 85718

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USA

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Tel: (520) 529-6500

FAX: (520) 209-7337

E-mail: [email protected] CofI: None Funding: None The author is solely responsible for the content of this manuscript.

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Urine tests are very helpful for the diagnosis of renal and electrolyte disorders. However, ordering and interpreting urine tests properly have been an Achilles’ heel for many primary care physicians and residents. It is particularly difficult for chronic hypokalemia because the

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pathophysiological mechanisms behind it can be rather complicated. Traditionally, we use

transtubular K+ gradient (TTKG) or urinary K+/Creatinine ratio (UK/Cr) to identify the source of K+ loss,1,2 thinking that if it is an extra-renal loss, TTKG or UK/Cr would be low, because the K+

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secretion from the collecting duct would be compensatorily diminished. On the other hand, if K+ is lost via the kidney, TTKG or UK/Cr would be high as more K+ is delivered to the collecting

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duct. In this issue, Wu et al,3 reported that TTKG and UK/Cr are not reliable for predicting source of K+ loss based on a cohort of 99 patients with chronic hypokalemia without hypertension, collected over 5 years at a tertiary hospital in Taipei. They came up a rather clever approach for identifying sources of K+ loss.

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In their cohort, 33 patients had gastrointestinal loss of potassium due to chronic vomiting (anorexia/bulimia) or diarrhea (laxative abuse), and 66 patients with renal potassium loss associated with diuretic abuse, hereditary or acquired Batter syndrome, Gitelman syndrome, or

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distal renal tubular acidosis.3 It should be mentioned that most of hereditary renal tubular

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disorders were verified with genetic testing in this study, and that it is the largest series of chronic hypokalemia in the era of molecular diagnosis of renal tubular disorders. In this study, authors confirmed that renal loss is associated with elevated TTKG (>3) and UK/Cr (> 2 mmol/mmol)2 except that 33% of patients with surreptitious diuretic use showed low TTKG and UK/Cr. The absence of elevated K+ excretion is associated with remote diuretic use, therefore, diuretic effects were already washed off. On the other hand, for patients with K+ loss due to anorexia/bulimia nervosa, very low percentage had low TTKG (5%) and UK/Cr (29%).

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For those with laxative abuse, UK/Cr appears better than TTKG for predicting the GI loss, with 91% showing low UK/Cr, and only 36% showing low TTKG.3 Gladziwa et al4 reported similar results with urinary K+ concentration >20 mmol/L in patients with surreptitious vomiting and

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laxative abuse. The elevated urinary K+ excretion in patients with chronic vomiting is probably due to bicarbonaturia, while in patients with chronic diarrhea may be due to hypomagnesemia and hyperaldosteronism.

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The authors proposed to use urine sodium to chloride ratio (UNa/Cl) to predict the source of K+

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loss. The reason is that renal Na+ excretion is always coupled with Cl- excretion in renal tubular disorders as listed above, thus the UNa/Cl is close to one. It is therefore extremely useful for patients with remote diuretic abuse, because their TTKG and UK/Cr may be low, but their urinary Na+ excretion is still coupled to Cl-. For patients with K+ loss due to vomiting, UNa/Cl is high because of Cl- deficiency and bicarbonaturia; while K+ loss due to chronic diarrhea, UNa/Cl

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would be low because of hyperchloremia. Using UNa/Cl >1.6 for anorexia/bulimia nervosa, the sensitivity was 95.2% and specificity 98.7%. Using UNa/Cl < 0.7 for laxative abuse, the sensitivity is 86.5% and specificity 100%.3 The UNa/Cl seems to be a reasonable tool for

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distinguishing extra-renal K loss from renal loss.

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However, we should notice that the study cohort does not include patients with proximal renal tubular acidosis. Those patients have a high UNa/Cl because of bicarbonaturia, particularly during the correction of metabolic acidosis.5 The presence of metabolic acidosis can separate those from patients with anorexia/bulimia nervosa who always have metabolic alkalosis. Another cause for uncoupling urinary Na+ to Cl- excretion associated with renal K+ loss is primary hyperaldosteronism, which was excluded from the study because of hypertension. The UNa/Cl ratio is low in patients with hyperaldosteronism because of excessive renal absorption of Na+ and

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secretion of K+ with relatively unchanged Cl-.6 The low UNa/Cl is similar to patients with laxative abuse who tend to have elevated renin and aldosterone levels due to volume depletion, while patients with primary hyperaldosteronism have hypertension and suppressed plasma renin

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activity.

In conclusion, UNa/Cl, but not TTKG or UK/Cr, is quite useful for predicting the source of K+ loss in patients with chronic hypokalemia: coupling Na+ to Cl- excretion (UNa/Cl is close to 1)

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indicates a renal loss, while uncoupling indicates an extra-renal loss with two exceptions:

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proximal renal tubular acidosis and primary hyperaldosteronism. For difficult cases of chronic

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hypokalemia, ordering urinary Na+ and Cl- levels can tell you how the K+ is lost.

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References: 1.

West ML, Marsden PA, Richardson RM, Zettle RM, Halperin ML. New clinical approach to evaluate disorders of potassium excretion. Miner Electrolyte Metab. 1986;12(4):234-

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Lin SH, Lin YF, Halperin ML. Hypokalaemia and paralysis. QJM. 2001;94(3):133-139.

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Wu K-L, Cheng C-J, Sung C-C, et al. Identification of the Causes for Chronic

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Hypokalemia: Importance of Urinary Sodium and Chloride Excretion. Am J Med. 2017; Gladziwa U, Schwarz R, Gitter AH, et al. Chronic hypokalaemia of adults: Gitelman’s

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syndrome is frequent but classical Bartter’s syndrome is rare. Nephrol Dial Transplant. 1995;10(9):1607-1613. 5.

Sebastian A, McSherry E, Morris RC. On the mechanism of renal potassium wasting in

1971;50(1):231-243.

Carlisle EJ, Donnelly SM, Ethier JH, et al. Modulation of the secretion of potassium by

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accompanying anions in humans. Kidney Int. 1991;39(6):1206-1212.

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renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA). J Clin Invest.