Chapter 2 Interpretation of Urine Electrolytes and Osmolality

Chapter 2 Interpretation of Urine Electrolytes and Osmolality Measurement of urine Na, Cl, and K is rather common in hospitalized patients, and these urine electrolytes are useful in the diagnostic evaluation of volume status, hyponatremia, acute kidney injury (AKI), metabolic alkalosis, hypokalemia and urine anion gap (urine net charge). A spot urine sample is generally adequate for determination of these electrolytes. In addition, urine creatinine is determined to calculate the fractional excretion of Na, K, or other electrolytes. Also, urine osmolality is helpful in the differential diagnosis of hyponatremia, polyuria, and AKI. Table 2.1 summarizes the clinical applications of urine electrolytes and osmolality. Certain Pertinent Calculations Fractional Excretion of Na (FE Na ) and Urea Nitrogen (FE Urea ) Urine Na excretion is influenced by a number of hormonal and other factors. Changes in water excretion by the kidney can result in changes in urine Na concentration [Na ]. For example, patients with diabetes insipidus can excrete 10 L of urine per day. Their urine [Na ] may be inappropriately low due to dilution, suggesting the presence of volume depletion. Conversely, increased water reabsorption by the kidney can raise the urine [Na ] and mask the presence of hypovolemia. To correct for water reabsorption, the renal handling of Na can be evaluated directly by calculating the FE Na, which is defined as the ratio of urine to plasma Na divided by the ratio of urine (U Cr ) to plasma creatinine (P Cr ), multiplied by 100. Quantity of Na excreted FE Na ( % ) = Quantity of Na filtered U Na PCr = 100. P U P Na Cr A. S. Reddi, Fluid, Electrolyte and Acid-Base Disorders, DOI 10.1007/978-1-4614-9083-8_2, Springer ScienceBusiness Media New York 2014 13

14 2 Interpretation of Urine Electrolytes and Osmolality Table 2.1 Clinical applications of urine electrolytes and osmolality Electrolyte Use Na To assess volume status Differential diagnosis of hyponatremia Differential diagnosis of AKI To assess salt intake in patients with hypertension To evaluate calcium and uric acid excretion in stone-formers To calculate electrolyte-free-water clearance Cl Differential diagnosis of metabolic alkalosis K Differential diagnosis of hypokalemia To calculate electrolyte-free-water reabsorption To calculate transtubular K gradient Creatinine To calculate fractional excretion of Na and renal failure index To assess the adequacy of 24-h urine collection Urine osmolality Differential diagnosis of hyponatremia Differential diagnosis of polyuria Differential diagnosis of AKI Urine anion gap To distinguish primarily hyperchloremic metabolic acidosis between distal renal tubular acidosis and diarrhea Electrolyte-free-water clearance To assess the amount of water excretion (without solutes) only in the management of hypo- and hypernatremia AKI acute kidney injury The FE Na is the excreted fraction of filtered Na. The major use of FE Na is in patients with AKI. Patients with prerenal azotemia have low (< 1 %) FE Na compared to patients with acute tubular necrosis (ATN), whose FE Na is generally high (> 2 %). When ATN is superimposed on decreased effective arterial blood volume due to hepatic cirrhosis or congestive heart failure, the FE Na is < 2 % because of the intense stimulus to Na reabsorption. Similarly, patients with ATN, due to radiocontrast agents or rhabdomyolysis have low FE Na for unknown reasons. It was shown that FE Na in children with nephrotic syndrome is helpful in the treatment of edema with diuretics. In these patients, FE Na < 0.2 % is indicative of volume contraction, and > 0.2 % is suggestive of volume expansion. Therefore, patients with FE Na > 0.2 % can be treated with diuretics to improve edema. The FE Na is substantially altered in patients on diuretics. In these patients, the FE Na is usually high despite hypoperfusion of the kidneys. In such patients, the FE Urea may be helpful. In euvolemic subjects, the FE Urea ranges between 50 and 65 %. In a hypovolemic individual, the FE Urea is < 35 %. Thus, a low FE Urea seems to identify those individuals with renal hypoperfusion despite the use of a diuretic. Fractional Excretion of Uric Acid (FE UA ) and Phosphate (FE PO4 ) Uric acid excretion is increased in patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone (SIADH) secretion or syndrome of inappropriate antidiuresis and cerebral salt wasting. As a result, serum uric acid level in both

Certain Pertinent Calculations 15 conditions is low ( < 4 mg/dl). Since serum uric acid levels are altered by volume changes, it is better to use FE UA. In both SIADH and cerebral salt wasting, FE UA is > 10 % (normal 5 10 %). In order to distinguish these conditions, FE PO4 is used. In SIADH, the FE PO4 is < 20 % (normal < 20 %), and it is > 20 % in cerebral salt wasting. Transtubular K Gradient Transtubular K gradient (TTKG) is an indirect measure of K secretion in the distal nephron (cortical collecting duct and to some extent late distal convoluted tubule). In a healthy individual, determination of urine [K ] reflects the amount of dietary K because of its secretion in the distal nephron. TTKG reflects the activity of aldosterone, the major hormone that regulates K secretion. In hypokalemic and hyperkalemic conditions, the urinary excretion of K is low and high, respectively. However, water reabsorption in the cortical and medullary collecting ducts is an important determinant of urinary K concentration. For example, an increase in water reabsorption increases and a decrease in water reabsorption decreases urine [K ]. Therefore, an appropriate method to calculate urine [K ] is the transtubular K gradient (TTKG), which is calculated as follows: TTKG U K P = P U P O sm UO sm where UK and P K are urine and plasma K concentrations, respectively, and P Osm and U Osm are plasma and urine osmolalities, respectively. The urine to plasma osmolality ratio is used to correct the [K ] in the urine for the amount of water reabsorbed in the distal nephron. TTKG is mostly useful in the evaluation of patients with hyperkalemia, but it can also be used in the evaluation of hypokalemia. In normal subjects on a regular diet, the TTKG varies between 6 and 8. A TTKG value < 5 7 in a patient with hyperkalemia indicates impaired distal tubular secretion of K due to aldosterone deficiency or resistance. Patients with mineralocorticoid excess should have a TTKG > 10. In a patient with hypokalemia, the distal nephron should decrease the secretion of K, and a TTKG value should be < 2. Two assumptions must be met before using the TTKG formula: (1) there must be adequate ADH activity, which is verified by measuring urine osmolality that should exceed serum osmolality, and (2) there must be adequate delivery of filtrate to the distal nephron for K secretion. This can be verified by determining urine Na, which should be > 25 meq/l. K, Urine Anion Gap Urine anion gap (U AG ) is an indirect measure of NH 4 excretion, which is not routinely determined in the clinical laboratory. However, it is measured by determining

16 2 Interpretation of Urine Electrolytes and Osmolality the urine concentrations of Na, K, and Cl and is calculated as [Na ] [K ] [Cl ]. In general, NH 4 is excreted with Cl. A normal individual has a negative (from 0 to 50) U AG (Cl > Na K ), suggesting adequate excretion of NH 4. On the other hand, a positive (from 0 to 50) U AG (Na K > Cl ) indicates a defect in NH 4 excretion. The U AG is used clinically to distinguish primarily hyperchloremic metabolic acidosis due to distal renal tubular acidosis (RTA) and diarrhea. Both conditions cause normal anion gap metabolic acidosis and hypokalemia. Although the urine ph is always > 6.5 in distal RTA, it is variable in patients with diarrhea because of unpredictable volume changes. The U AG is always positive in patients with distal RTA, indicating reduced NH 4 excretion, whereas, it is negative in patients with diarrhea because these patients can excrete adequate amounts of NH 4. Also, positive U AG is observed in acidoses that are characterized by low NH 4 excretion (type 4 RTA). In situations such as diabetic ketoacidosis, NH 4 is excreted with ketones other than Cl, resulting in decreased urinary [Cl ]. This results in a positive rather than a negative U AG, indicating decreased excretion of NH 4. Thus, the U AG may not be that helpful in situations of ketonuria. Table 2.2 summarizes the interpretation of urinary electrolytes in various pathophysiologic conditions. Electrolyte-Free-Water Clearance Electrolyte-free-water clearance (T e H2O ) is the amount of water present in the urine that is free of solutes, i.e., the amount of water excreted in the urine. Determination of T e H2O is helpful in the assessment of serum [Na ] in hypernatremia and hyponatremia. For example, hypernatremia may not improve despite volume replacement because the exact amount of free water that is reabsorbed or excreted is not known. In order to quantify how much electrolyte-free-water is being reabsorbed or excreted, the following formula can be used: e [ T = U Na UK ] H2O V 1, P [ P Na ] where V is the total urine volume, and P Na is the plasma [Na ]. Te H2O can be positive or negative. Positive T e H2O means that less water was reabsorbed in the nephron segments, resulting in hypernatremia. On the other hand, negative T e H2O indicates that the nephron segments reabsorbed more water with resultant hyponatremia. Urine Specific Gravity Versus Urine Osmolality Clinically, estimation of specific gravity is useful in the evaluation of urine concentration and dilution. It is defined as the ratio of the weight of a solution to the weight of an equal volume of water. The specific gravity of plasma is largely determined by the protein concentration and to a lesser extent by the other solutes. For this reason,

Certain Pertinent Calculations 17 Table 2.2 Interpretations of urine electrolytes Condition Electrolyte (meq/l) Diagnostic possibilities Hypovolemia Na (0 20) Extrarenal loss of Na Na (> 20) Renal salt wasting Adrenal insufficiency Diuretic use or osmotic diuresis Acute kidney injury Na (0 20) Prerenal azotemia Na (> 20) Acute tubular necrosis (ATN) FE Na (< 1 %) Prerenal azotemia FE Na (> 2 %) ATN due to contrast agent Rhabdomyolysis ATN Diuretic use Hyponatremia Na (0 20) Hypovolemia Edematous disorders Water intoxication Na (> 20) SIADH Cerebral salt wasting (CSW) Adrenal insufficiency FE UA (> 10 %) SIADH and CSW FE PO4 (> 20 %) CSW Metabolic alkalosis Cl (0 10) Cl -responsive alkalosis Cl (> 20) Cl -resistant alkalosis Hypokalemia K (0 10) Extrarenal loss of K K (> 20) Renal loss of K TTKG Normal 6 8 Hyperkalemia < 5 Aldosterone deficiency or resistance Hypokalemia < 2 Appropriate distal tubular secretion U AG Positive (from 0 to 50) Distal renal tubular acidosis Negative (from 0 to 50) Diarrhea TTKG transtubular K gradient, SIADH syndrome of inappropriate antidiuretic hormone plasma is about 8 10 % heavier than pure distilled water. Therefore, the specific gravity of plasma varies from 1.008 to 1.010 compared to the specific gravity of distilled water, which is 1.000. Urine specific gravity can range from 1.001 to 1.035. A value of 1.005 or less indicates preservation of normal diluting ability and a value of 1.020 or higher indicates normal concentrating ability of the kidney. Osmolality measures only the number of particles present in a solution. On the other hand, the specific gravity determines not only the number but also weight of the particles in a solution. Urine specific gravity and urine osmolality usually change in parallel. For example, a urine specific gravity of 1.020 1.030 corresponds to a urine osmolality of 800 1,200 mosm/kg H 2 O. Similarly, the specific gravity of 1.005 is generally equated to an osmolality < 100 mosm/kg H 2 O. This relationship between the specific gravity and osmolality is disturbed when the urine contains an abnormal solute, such as glucose or protein. As a result, the specific gravity increases disproportionately to the osmolality. In addition to these substances, radiocontrast material also increases the specific gravity disproportionately.

18 2 Interpretation of Urine Electrolytes and Osmolality Table 2.3 Urine osmolalities in various clinical conditions Condition Approximate osmolality Comment (mosm/kg H 2 O) Normal 50 1200 Normal urine dilution and concentration AKI-Prerenal azotemia > 400 Increased water reabsorption by nephron segments AKI-Acute tubular necrosis < 400 Injured tubules cannot reabsorb all the filtered water SIADH > 200 Excess water reabsorption by distal nephron Hydrochlorothiazide treatment > 200 Inability to dilute urine Furosemide ~ 300 (isosthenuria) Inability to concentrate and dilute urine Osmotic diuresis > 300 (usually urine Excretion of excess osmoles osmolality > plasma osmolality) Central diabetes insipidus (DI) 100 Lack of ADH Nephrogenic DI < 300 ADH resistance Psychogenic polydipsia ~ 50 Decreased medullary hypertonicity ADH Antidiuretic hormone, AKI acute kidney injury, SIADH syndrome of inappropriate antidiuretic hormone Measurement of urine specific gravity or osmolality is useful in the assessment of volume status, in the differential diagnosis of AKI, polyuria (urination of 3 5 L/ day) and hyponatremia. A volume depleted individual with normal renal function is able to concentrate his or her urine, and, therefore, the specific gravity or osmolality will be greater than 1.020 or 800 mosm/kg H 2 O, respectively. Table 2.3 shows approximate urine osmolalities in various clinical situations. Study Questions Case 1 A 60-year-old male patient with congestive heart failure (CHF) is admitted for chest pain. He is on several medications, including a loop diuretic. The patient develops acute kidney injury following cardiac catheterization with creatinine increase from 1.5 to 3.5 mg/dl. His urinalysis shows many renal tubular cells and occasional renal tubular cell casts, suggesting ATN. Question 1 What would his FE Na be? Answer In ATN, the FE Na should be > 2 %. However, in a patient with CHF there is increased Na reabsorption in the proximal tubule. Despite ATN, such a patient excretes less Na in the urine and the FE Na is usually < 1 %. Other conditions of ATN with low FE Na (< 1 %) are contrast agents and rhabdomyolysis.

Suggested Reading 19 Question 2 How does FE urea help in this patient? Answer The patient is on a loop diuretic. In order to know the volume status in a patient on diuretic, FE Na may not be that helpful. Instead, FE urea distinguishes volume contraction from volume expansion. In volume contracted patient due to diuretics, FE urea is < 35 %. Case 2 A 20-year-old female patient is admitted for weakness, dizziness, and fatigue. Her serum K is 2.8 meq/l and HCO 3 is 15 meq/l. An arterial blood gas revealed a nonanion gap metabolic acidosis. Her urine ph is 6.5. Question 1 Discuss the clinical application of U AG? Answer Two major causes of nonanion gap metabolic acidosis with hypokalemia are diarrhea and distal RTA. The urine ph is always > 6.5 in distal RTA and mostly acidic in diarrhea unless the patient is severely volume depleted. In this patient, determination of the U AG will distinguish diarrhea from distal RTA. The U AG is an indirect measure of NH 4 excretion. It is calculated as the sum of urinary [Na ] plus [K ] minus [Cl ]. Normal U AG is zero to negative, suggesting adequate excretion of NH 4. In patients with distal RTA, NH 4 excretion is decreased, and the U AG is always positive. In metabolic acidosis caused by diarrhea, the U AG is negative. Thus, the U AG is helpful in the differential diagnosis of hyperchloremic metabolic acidosis. Upon questioning, the patient admitted to laxative abuse. Case 3 A 32-year-old diabetic male patient presents to his primary care physician with persistent hyperkalemia. His glucose is 100 mg/dl. He is not on any K - sparing diuretic. Electrocardiography (EKG) does not show any changes consistent with hyperkalemia. His TTKG is 6. Question 1 How does TTKG help in the evaluation of hyperkalemia in this patient? Answer In general, hyperkalemia stimulates the release of aldosterone, which in turn promotes the secretion of K in the distal nephron, leading to a TTKG value > 10 in a normal individual. This suggests that the function of aldosterone is intact. In this patient, the TTKG is 6, suggesting that he has either hypoaldosteronism or aldosterone resistance. Suggested Reading 1. Choi MJ, Ziyadeh FN. The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. J Am Soc Nephrol. 2008;19:424 6. 2. Harrington JT, Cohen JJ. Measurement of urinary electrolytes-indications and limitations. N Engl J Med. 1975;293:1241 3. 3. Kamel KS, Ethier JH, Richardson RMA, et al. Urine electrolytes and osmolality: when and how to use them. Am J Nephrol. 1990;10:89 102. 4. Schrier RW. Diagnostic value of urinary sodium, chloride, urea, and flow. J Am Soc Nephrol. 2011;22:1610 13.

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