Hypokalemia
About 20% of patients are hypokalemic during an inpatient hospitalization. There is a broad differential for hypokalemia, including medical, nutritional, and medication-related causes. Exogenous insulin administration or endogenous production in cases of refeeding syndrome drives potassium intracellularly via the N+/K+ ATPase. Increased sympathetic activity from alcohol withdrawal, acute myocardial infarction, head injury, or thyroid imbalance, as well as iatrogenic causes such as albuterol administration, also drive potassium intracellularly. Diarrhea and nasogastric tube suction lead to gastrointestinal (GI) potassium losses, while antibiotics, chemotherapeutic agents, and diuretics can cause hypokalemia through renal potassium wasting. Hyperaldosteronism and renal tubular acidosis are less common causes.6
The history, review of medications, physical exam, and initial basic laboratory testing (electrolytes, BUN, creatinine, magnesium) should assess for pseudohypokalemia, poor oral intake, diuretic use, acid-base disturbances, or GI losses.
Measuring urine potassium is useful in the work-up of the hypokalemic patient when these conditions are not evident. Urine potassium – either 24-hour or spot urine potassium-to-creatinine ratio – can help determine if urinary potassium wasting is a factor. Potassium is excreted at a near constant rate throughout the day. A urine potassium-to-creatinine ratio corrects for variations in urine volume. When this ratio is greater than 13 mEq/g, renal potassium losses should be suspected. If the ratio is less than 13 mEq/g, hypokalemia is likely due to transcellular potassium shifts, GI losses, diuretics, or poor intake.
The transtubular potassium gradient (TTKG) can also be calculated using the serum and urine potassium and urine osmolality, and reflects the amount of potassium excreted in the tubule (see Table 1).The TTKG should decrease in hypokalemia when urinary potassium excretion is appropriately suppressed. A TTKG greater than 4 is inappropriately high and indicates renal potassium wasting, whereas a TTKG less than 3 suggests extrarenal causes such as cellular shifts.
Hyperkalemia
Several concepts in hypokalemia are relevant to hyperkalemia. Redistribution of potassium into the extracellular fluid can cause hyperkalemia when the body tries to counterbalance low extracellular pH by potassium-hydrogen exchange. Medications may cause an extracellular shift of potassium (e.g. digoxin) or induce diminished potassium excretion (e.g. NSAIDs, spironolactone, ACE/ARBs).
CKD and end-stage kidney disease are common causes of hyperkalemia in the hospitalized patient – as functioning nephrons decrease, poor Na-K exchange ensues. Hypoaldosteronism and type 4 renal tubular acidosis are also on the differential diagnosis. Pseudohyperkalemia secondary to thrombocytosis, erythrocytosis, or activated platelets should be considered and evaluated.
Appropriate renal excretion of potassium is mediated by the connecting segment between the distal tubule and the collecting duct, and the cortical collecting duct itself. There are four major causes of hyperkalemia due to reduced urinary potassium secretion: reduced aldosterone secretion, reduced response to aldosterone, reduced distal sodium and water delivery (often related to low effective arterial blood volume), and kidney injury.6
Measurement of 24-hour urinary potassium excretion is of limited utility in patients with persistent stable hyperkalemia because urinary potassium excretion is related to potassium intake. The TTKG was previously used to assess the degree of aldosterone activity by estimating the potassium concentration in the cortical collecting tubule. However, some assumptions upon which this calculation was based have been considered invalid by the original studies’ authors, and the TTKG to evaluate potassium abnormalities is no longer uniformly recommended.7,8 Ultimately, if patients have persistent hyperkalemia, work-up for hypoaldosteronism should be considered.
Normal anion gap metabolic acidosis
The urine anion gap (UAG) is used to determine the cause of normal anion gap hyperchloremic metabolic acidosis by indirectly measuring urinary excretion of ammonium. To maintain a normal acid/base balance, hydrogen ions are excreted in the urine with simultaneous reabsorption of bicarbonate. Hydrogen ions are bound to ammonia (NH3) to form ammonium (NH4+), which is excreted as NH4Cl in the urine.
The UAG is calculated by adding urine sodium and urine potassium and subtracting urine chloride (see Table 1). In a patient without an acid/base disturbance, the UAG is positive because more Na and K is absorbed in the gastrointestinal system compared to Cl, and thus more Na and K is excreted in the urine. In a normal anion gap metabolic acidosis through an acid load or bicarbonate loss, the normal response of the kidney is to excrete more hydrogen ions, resulting in more chloride excretion as NH4Cl. This leads to a negative urine anion gap, as Cl excretion outweighs Na and K excretion. When NH4+ excretion is impaired, such as in distal renal tubular acidosis (RTA), the urine anion gap will remain positive despite the metabolic acidosis. Thus, a positive UAG points to renal causes of the normal anion gap metabolic acidosis, whereas a negative UAG points to extrarenal causes such as bicarbonate losses in the GI tract.9