# The diagnostic utility of urinary electrolytes

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To present this topic systematically, one can either break it up into indications for urinary electrolyte testing, or into electrolytes tested (and the meaning of abnormal results). Both forms have a relevance. The discussion section for Question 11 from the first paper of 2004 (the only time this has ever come up in the CICM fellowship exam) is laid out according to indications for urinary electrolyte testing, and is reproduced below to simplify revision. It is based on a good article on this topic by A.S.Reddi (2014).  Reddi includes a table (Table 2.1) of urinary electrolyte results, their relevance, and the indications for the tests. A reinterpretation of that table is offered below.

 Indication Electrolyte Meaning of results Oliguria Na+ Na+ < 20mmol/L: appropriate conservation of sodium in the context of hypovolemia Na+ >20mmol/L: renal failure, eg. ATN Hyponatremia Na+ Na+ < 20mmol/L: appropriate conservation of sodium in the context of hyponatremia Na+ >20mmol/L: renal salt wasting or water conservation, eg: - cerebral salt wasting or SIADH - adrenal insufficiency - diuretic use - osmotic diuresis eg. mannitol or glucose Normal anion gap metabolic acidosis Urinary anion gap Positive: renal causes of NAGMA Negative: gastrointestinal causes of NAGMA Urinary osmolal gap In an acidaemic patient with NAGMA: Lower than 150 mOsm/kg = urinary acidification defect (renal tubular acidosis) Higher than 400 mOsm/kg = appropriate renal response to a non-renal cause of acidosis, eg. to diarrhoea. Metabolic alkalosis Cl- 0-10: appropriate renal chloride conservation - gastric chloride losses - diuretic therapy (between doses) - post hypercapnea alkalosis >20: inappropriate renal chloride loss - corticosteroid excess - hypertension - hyperaldosteronism Hypokalemia K+ Low urinary potassium: <5-10mmol/L Diarrhoea Laxative abuse Insulin therapy Bicarbonate therapy Periodic hypokalemic paralysis High urinary potassium: >15mmol/L Renal tubular acidosis (Type 1 or 2) Hyperaldosteronism Upper gastrointestinal losses Corticosteroid excess

## Urinary sodium

### Hyponatremia (it should be low)

Homeostasis of sodium is tightly controlled, as one might expect, given that it is the major determinant of extracellular tonicity and extracellular fluid volume. A normal non-crazed person will consume about 150-200 mmol of sodium every day. The normal urinary concentration of an euvolaemic individual will decrease to about 10mmol/L if the dietary sodium is restricted. Urinary sodium is most useful when one needs to discriminate between SIADH and dehydration (i.e. "appropriate" ADH secretion) - in a hypovolemic state, the urinary sodium should be low, whereas in SIADH it will be over 40mmol/L. In states of abnormal sodium wasting (eg. hypoaldosteronism) urinary sodium will also be high, as the mechanisms of normal sodium conservation are impaired.

### Oliguria due to hypovolemia (it should be low)

Yes, if the oliguria is due to some sort of hypovolemic shock state, the urinary sodium should be low because the nephron is making every effort to retain it. In fact this will happen no matter what sort of shock state uyou are in, and it is the consquence of the stereotypic renin-angiotesin-aldosterone response. However, if there is also acute tubular necrosis, the renal handling of sodium becomes deranged (dead tubules are unresponsive to hormonal signals) and as a consequence urinary sodium ends up being high. Historically, this phenomenon has been used to distinguish between different causes of renal failure (i.e. acute tubular necrosis versus simple hypovolemic dehydration). However, the  urinary sodium value can vary depending on the renal handling of water: excess water reabsorption can result in a high urinary sodium even if some effort is being made to reclaim it (for example, in SIADH the urinary sodium is usually in excess of 40mmol/L). In order to overcome this, one should instead use the fractional excretion of sodium.

### Fractional sodium excretion in distinguishing ATN from pre-renal azotaemia

The fractional excretion of sodium is the percentage of filtered sodium which is excreted. It is calculated using the following formula:

$$FEN (percent) = {U[Na] \times \ S[Cr] \over S[Na] \times \ U[Cr]} \times 100$$

Thus, the product of urinary sodium and serum creatinine is divided by the product of serum sodium and urinary creatinine. With various caveats, the FEN in pre-renal azotaemia should be less than 1%; in ATN it is usually in excess of 2%. The UpToDate article on this topic lists numerous limitations of this variable; suffice to say there are numerous situations where the FEN is less than 1% and the renal failure is not caused by a "pre-renal" hypovolemia.

### Where urinary sodium is falsely deranged

Under certain circumstances the urinary sodium level will either not make any sense or will lead to an incorrect interpretation of the situation. One obvious scenario of this sort would be the recent administration of a loop diuretic (an elevated urinary sodium will be found). Any situation where a substantial amount of bicarbonate is being excreted (eg. after a bicarbonate dose, or with proximal renal tubular acidosis) will lead to an unusually electronegative tubular lumen, which will interefere with sodium reabsorption and lead to an increased urinary sodium. Hyperglycaemia and mannitol therapy will result in an osmotic diuresis, in which case the urinary sodium will be low -  the tubular fluid will be composed of the osmotically active agent and free water, with other electrolytes in the minority (this was demonstrated experimentally by Manninen et al, 1987).

## Urinary chloride

Urinary chloride levels distinguish between renal and extrarenal causes of metabolic alkalosis. Mersin et al (1995) produced a good review of the relevant physiology, confirming this use of urinary  chloride measurements among a case series of alkalotic Swiss children. The measurement can be direct (i.e. in mmol/L) or as a ratio of chloride to creatinine.

### Appropriate chloride conservation

In the presence of a metabolic alkalosis, it is perfectly reasonable to cling to every last shred of chloride. The presence of a low urinary chloride in metabolic alkalosis therefore demonstrates that there is no intrinsic renal problem responsible for the aforementioned alkalosis, and represents a normal compensatory mechanism. This will be the finding in the presence of a post-hypercapneic alkalosis (while the high serum bicarbonate slowly resolves), between doses of loop diuretic and whenever there are excessive gastric chloride losses (eg. by NG drainage). In short, the cause of alkalosis is extrarenal if the urinary chloride is low (<10mmol/L)

### Inappropriate chloride wasting

If the urinary chloride is high in the presence of metabolic alkalosis, one might surmise that the kidneys are either the primary cause of the disorder, or for some reason unable to adapt to it appropriately (i.e. they have been turned off by diuretics). The presence of a high urinary chloride in association with hypokalemia and alkalosis is a characteristic finding of an excessive mineralocorticoid effect, be it from excess corticosteroid use or primary adrenal hyperactivity. Weirder causes include Bartter's syndrome (a mutation of the Na-K-Cl cotransporter from the thick ascending limb). An alternative explanation is a spuriously elevated urinary chloride which occurs with the use of loop diuretics.

## Urinary potassium

The use of urinary potassium (apart from calculating the urinary anion and osmolal gaps) is in the diagnosis of hypokalemia. In short, when the urinary potassium is low the nephron cannot be blamed for wasting the potassium. It must be escaping in some other direction. The normal response to hypokalemia is to excrete less potassium (though the apical potassium channels on the principal cells of the cortical collecting duct) and to increase its reabsorption form the tubular lumen (by the H-K-ATPase exchange pump on the surface of the intercalated cells). Ergo, if the urinary potassium is high in hypokalemia, one expects something in the cortical collectign duct must seriously broken.

### Low urinary potassium in hypokalemia

Less than 2mmol/L of random urinary potassium leads one to conclude that the renal compensaory mechanisms are working, and that the loss of potassium mus have occurred in some other non-renal way. Where did it go?

• It migrated into the cells:
• Under the influence of insulin
• Due to alkalosis, eg. following bicarbonate administration or when the patient is hyperventilating
• It has been excreted in stool:
• Diarrhoea
• Laxative use
• High output ileostomy
• It was being wasted in the urine by means of loop diuretic adminsitration, but the diuretic effect has worn off and you have captured a urine sample which was unaffected.
• It has been washed out by dialysis.

In fact, the range seems to vary between sources. For a canonical reference, UpToDate offers the value of 25-30 mmol/day as the normal response to nonrenal potassium depletion. A random spot urinary potassium consistent with normal conservation would be about 5-10 mmol/L, with anything more than 15mmol/L being consistent with potassium wasting. It is probably impossible to get any lower than 5mmol/L of urinary potassium: Squires and Huth (1959) confirmed this in their series of  cruel potassium restriction experiments. Heroically, along with eleven medical students, Squires and Huth also committed themselves to the potassium-restricted diet (consisting of carefully analysed foodstuffs and  milk which was passed through an ion-exchange resin filter, thereby becoming completely depleted of potassium). The subjects enjoyed a rapid drop in their renal potassium excretion, but at no stage was it reduced to zero- rather, the plateau seemed to be around 5mmol/L.

### High urinary potassium in hypokalemia

This either represents "true" potassium wasting (in which case the kidney is probably to blame for the hypokalemia) or a spuriously elevated urinary potassium in the presence of severely concentrated urine. If you are producing less than 500ml of urine per day, likely your urine has a near-maximal osmolality, and the urinary potassium - though high- is still being conserved appropriately. Under such circumstances, one might feel compelled to order a 24 hour specimen. Even though the urinary potassium concentration might be 50 mmol/L, the total urine volume might only be 400ml, and therefore only 20mmol of potassium was excreted over the whole day, which is a pretty good attempt at potassium conservation.

In the event of "true" potassium wasting, one must ask - why is it wasted so?

• A diuretic effect is the obvious answer.
• Renal tubular acidosis (Type 1 or 2) results in uncontrollable renal loss of potassium
• Hyperaldosteronism results in an excess of sodium reabsorption, with potassium being lost into the tubule to maintain electroneutrality. Corticosteroid excessis functionally the same thing, because of the mineralocorticoid effect of most exogenous steroids. In contrast, dexamethasone would actually produce hyperkalemia and hyponatremia, by suppressing adrenal function.

## Urinary anion gap

This is basically the difference between urinary cations (sodium and potassium) and urinary chloride. Usually, the amount of sodium and potassium being excreted is greater than the amount of excreted chloride, and under these normal circumstances the urinary anion gap is positive. The usual value is about 20-90 mmol/L.

Under conditions of acidosis, the nephron's normal response should be to acidify the urine by excreting ammonium chloride, and the amount of urinary chloride should increase, creating a negative urinary anion gap. The "negativity" of this gap can therefore be used to assess the efficacy of the renal tubular response to systemic acidosis.

The utility of the urinary anion gap in the diagnosis of normal anion gap metabolic acidosis is discussed in greater detail elsewhere. In short, the acidotic patient should have a negative urinary anion gap. And if they do not, then either the kidneys are to blame for the acidosis, or they are not doing their job (and there is a tubular acidification defect).

The urinary anion gap may give spurious results whenever ammonium is being excreted as something other than ammonium chloride. For instance, if the ammonium is being excreted together with hippurate (to use toluene toxicity, that old college favourite) the concentration of chloride may not change - it may remain low-ish,  giving the impression of a positive urinary anion gap (i.e. a distal RTA).  However the total renal excretion of ammonium would still be very high, because there really is no distal renal tubular acidosis.

## Urinary osmolality

### Measures of urinary concentrating capacity

Urinary concentration is interpreted in the context of the clinical need for concentrated urine. If you are volume-depleted or shocked, you want ti have concentrated urine, all the better to retain your precious bodily fluids. In contrast, if you are hyponatremic and volume-overloaded, your urine should be approaching the theoretical limits of maximal dilution.

There are various measures available to assess this variable, and they are the subject of a fascinating article by Chadha et al (2001). In short, the most commonly used is the specific gravity (which is usually measured by means of reagent dipstick). This can be inaccurate in the presence of urea and glucose (which it completely ignores). Another indirect measure is refractometry, but this is also confused by the presence of glucose urea and protein, and really confused by the presence of high-density impurities such as ionic contrast media. Alternatively, specific gravity may be measured directly by old-school analog gravimetry, which compares its density against distilled water (but who has a urinary gravimeter around nowadays).

Or, one can measure the urine osmolality, like a normal person. But before we get to that, let's have another irrelevant tangent.

### Specific gravity, the poor man's osmolality

Given that people rarely order urine osmolality, urine specific gravity is a more common measure, and even that is true only because it comes as a part of the standard battery of tests on the commonly available "dipstick" reagent strip. Otherwise, I don't think anybody would ever order this test intentionally.

The dipstick colour-change strip cheats by measuring urinary sodium and potassium concentration, as these are (usually) the most important contributors to urinary osmolality. The strip is usually composed of a polyelectrolyte, eg. polymethylvinyl ether maleic anhydride (which is colourless) and a pH-sensitive indicator (which changes colour). When the reagents are exposed to urine, the polyelectrolyte (-COOH) groups release a hydrogen ion in return for one of the cations from the urine (either Na+ or K+, the reagent doesn't care).  The resulting increase in the urinary acidity changes the colour of the pH indicator. The more cations there are in solution, the proportionally greater the change in acidity, and therefore the colour change of the indicator can be interpreted as a surrogate for the cation concentration (...which in turn can be interpreted as a surrogate for osmolality).

Ito et al (1983) describe in great detail the limitations of this method.  In short, when you measure only the NaCl contribution to osmolality, you miss out on a whole range of clinically relevant disease states, among them hyperglycaemia and ureaemia. Urea and glucose give rise to elevated urine osmolality, but as long as the sodium and potassium remain the same, the reagent strip will not tell the difference. Don't even get me started on the presence of cationic proteins, or exotic cations (eg. magnesium, contrast media,  Moreover, urinary pH already varies wildly, and is is possible to overestimate the osmolality when the pre-test pH is acidic (or underestimate it if the pre-test pH is already alkaline). In fact it appears that the SG bar on most modern dipstick strips is only accurate within a pH range of 7.0-7.5.

A forceful argument for the ongoing use of these dipstick strips is convenience, cheapness, and workable accuracy in the 99% of the population. Most of the time these strips are used in patients who have reasonably intact physiology. Face it, you're not going to be relying on the dipstick SG to decide on therapy for the patient with a pH of 6.80 and a BSL of 120mmol/L. So, if you're an intensivist, you are rather unlikely to even look at the urinalysis strip, beyond the ketones leukocytes and nitrites. You, as a member of a biochemically advanced elite, will demand accurately  measured variables. Thus, for the purposes of CICM fellowship exam preparation, any further discussion of urinary specific gravity is probably a dangerous waste of time.

### Urinary osmolality and osmolarity

This is the gold standard of urine concentration. The value depends on the number of particles in the solution under study, irrespective of what those particles are. The differences between osmolarity osmolality and tonicity are discussed in greater detail in another chapter; in brief, osmolarity (concentration per liter of solution) differs from osmolality (concentration per kilogram of solution) because osmolarity is affected by temperature and pressure, whereas osmolality is not. Osmolarity of urine is measured by centrifuging out all the particulate muck and then using the freezing point to determine solute concentration (a 1 osmole solution in water freezes at 1.86°C lower than pure water).

The normal osmolality of urine is 300-900 mOsm/kg.  If one has had their water intake restricted, it should trend towards 900. How high can it go?  Curtis and Donovan (1979) recorded a maximum urinary osmolality around 1229 mOsm/kg in a healthy medical technician whom they  poisoned with DDAVP, whereas Kerry Brandis reports a figure of 1400mOsm/Kg. The lowest osmolality is probably around 40 mOsm/kg, as one is physiologically unable to excrete pure water with an osmolality of zero (the nephron is simply unable to reclaim every last bit of excreted solute).

### Urinary osmolal gap

Urinary osmolality can be calculated using roughly the same equation as serum osmolality:

Calculated urine osmolality (mOsm/kg)  =  (2  x  [Na + K])  +  [urea]  +  [glucose]

The difference between measured and calculated osmolality is the osmolal gap. Apart from sodium potassium urea and glucose, the only other important contributor to the osmolality of urine is ammonium salts. The gap therefore represents excretion of ammonium, be it NH4Cl or any other form of NH4.

The normal value for the urinary osmolal gap is about 10-100 mOsm/kg. Of this, exactly half should be ammonium (given that it is excreted alongside some conjugate anion in a 1:1 ratio). Thus, from the urinary osmolal gap one is able to calculate the urinary ammonium excretion. In metabolic acidosis, the excretion of ammonium should escalate to over 75 mOsm/kg, corresponding to a urinary osmolal gap over 150 mSom/kg. Anything less than this suggests that a urinary acidification defect is present. If you are acidotic and your nephrons are making an effort to correct the situation, the urinary NH4 excretion should be massively increased: UpToDate suggests that a urinary osmolal gap of over 400 mOsm/kg should be expected.

The urinary osmolal gap is a superior measure of urinary NH4 excretion, as compared to the urinary anion gap. The reason for this is the tendency of the urinary anion gap to be confused by unmeasured anions, which may be present in large quantities in the urine. Toluene toxicity is a good example of this. Hippurate, the metabolic product of toluene, is excreted renally. When it is excreted along with ammonium the urinary anion gap will remain positive, suggesting a renal acidification defect; however the urinary osmolal gap will increase, revealing a normal urinary NH4 excretion.

In spite of these positive features, the urinary osmolal gap can be misinterpreted in certain circumstances. It is confused by the presence of osmotically active solutes, such as alcohols. For instance, after a big mannitol dose, the urinary osmolal gap will be vastly elevated.  Urease-producing organisms will metabolise urea and water to produce an excess of NH4 and HCO3, creating a spurious elevation of the urinary osmolal gap (i.e. the urinary urea will be decreased).

## References

Reddi, Alluru S. "Interpretation of Urine Electrolytes and Osmolality." Fluid, Electrolyte and Acid-Base Disorders. Springer New York, 2014. 13-19.

Schrier, Robert W. "Diagnostic value of urinary sodium, chloride, urea, and flow." Journal of the American Society of Nephrology 22.9 (2011): 1610-1613.

Harrington, John T., and Jordan J. Cohen. "Measurement of urinary electrolytes-indications and limitations." The New England journal of medicine 293.24 (1975): 1241.

Kamel, K. S., et al. "Urine electrolytes and osmolality: when and how to use them." American journal of nephrology 10.2 (1990): 89-102.

Simerville, Jeff A., William C. Maxted, and John J. Pahira. "Urinalysis: a comprehensive review." Am Fam Physician 71.6 (2005): 1153-62.

Chadha, Vimal, Uttam Garg, and Uri S. Alon. "Measurement of urinary concentration: a critical appraisal of methodologies." Pediatric Nephrology 16.4 (2001): 374-382.

ITO, Kiichi, Masaharu NIWA, and Toshikazu KOBA. "Study of urinary specific gravity by reagent strip method." Tokai journal of experimental and clinical medicine 8.3 (1983): 247-255.

Kirschbaum, Barry, Domenic Sica, and F. Phillip Anderson. "Urine electrolytes and the urine anion and osmolar gaps." Journal of Laboratory and Clinical Medicine 133.6 (1999): 597-604.

Curtis, J. R., and B. A. Donovan. "Assessment of renal concentrating ability." Br Med J 1.6159 (1979): 304-305.

Dyck, R., et al. "A modification of the urine osmolal gap: an improved method for estimating urine ammonium." American journal of nephrology 10.5 (1990): 359-362.

Manninen, Pirjo H., et al. "The effect of high-dose mannitol on serum and urine electrolytes and osmolality in neurosurgical patients." Canadian journal of anaesthesia 34.5 (1987): 442-446.

Mersin, S. S., et al. "Urinary chloride excretion distinguishes between renal and extrarenal metabolic alkalosis." European journal of pediatrics 154.12 (1995): 979-982.

Squires, Russell D., and Edward J. Huth. "Experimental potassium depletion in normal human subjects. I. Relation of ionic intakes to the renal conservation of potassium." Journal of Clinical Investigation 38.7 (1959): 1134.