Laboratory Evaluation of Fluid and Electolyte Disturbances

Regulation Hierarcy

Metabolic acid/base disturbances are almost always associated with, or caused by, disturbances in fluid and/or electrolyte balance. Results on serum from venous blood specimens for sodium, potassium, chloride, total CO₂ (~ bicarbonate), urea, creatinine and glucose provide diagnostic information for evaluating metabolic acid/base disturbances and primary disorders of fluid and electolyte balance.
The following is a brief review about the hierarchy and interrelationship of pertinent physiologic control mechanisms.

Physiologic Control Mechanisms

Regulation of fluid volume, electrolyte concentrations and acid/base balance are interrelated in a hierarchical manner. Fluid volume and osmolality are regulated interdependently and with highest priority.
Fluid volume is regulated by way of pituitary sensing of osmolality. Hyperosmolality stimulates thirst and causes pituitary elaboration of ADH which stimulates renal water reabsorption. (Urea reabsorption accompanies ADH stimulated water reabsorption in the distal nephron.) The extent of water reabsorption is limited by the quantity of solutes in tubule fluid, the concentration of which cannot exceed the osmolality of the hypertonic medulla, about 1400 mOsM. Because the daily excrecreted solute load is about 500-700 mOsmoles, minimum urine volume is about 300-500 ml/day.
The kidneys sense hypovolemia as decreased perfusion pressure and respond by elaborating renin with the consequent formation of angiotensin-II causing decreased renal blood flow and, thus, decreased GFR, and also stimulating the adrenal cortex to synthesize and release aldosterone, thereby increasing renal Na⁺ reabsorption.
A hypovolemic state is thus generally revealed by a high urine osmolality (> 900 mOsM), a low urine Na⁺ concentration (generally < 25 mEq/L; a better gauge of the extent of Na⁺ reabsorption is the fraction of filtered sodium excreted which is less than 1 % in hypovolemic cases), increased serum urea and creatinine concentrations, and an increased serum urea/creatinine ratio (the normal ratio is about 15).

Sodium concentration is regulated by way of renal sensing of perfusion pressure which in most cases reflects fluid volume status. Low pressure results in renal renin elaboration with the consequent formation of angiotensin-II and decreased renal blood flow, and thus decreased GFR, and also stimulation of adrenal cortical elaboration of aldosterone thereby increasing renal Na⁺ reabsorption. Renin release, and subsequent effects, is inhibited by elevated renal perfusion pressure. Although angiotensin-II is the major factor stimulating adrenal cortical aldosterone elaboration, hyperkalemia also stimulates, but to a lesser extent.
Aldosterone stimulates Na⁺ reabsorption in the collecting tubules and is accompanied by counter secretion of K⁺ and H⁺, rather than by coreabsorption of anions as in the proximal tubule.
Sodium excess stimulates thirst and water reabsorption resulting in hypervolemia and hypertension rather than in frank hypernatremia. Hypervolemia diminishes Na⁺ reabsorption and the consequent decreased K⁺ and/or H⁺ secretion causes mild hyperkalemia and acidemia.
Sodium deficit results in diminished thirst and water reabsorption and thereby hypovolemia rather than hyponatremia. The consequent aldosterone stimulated renal Na+ reabsorption and increased K⁺ and H⁺ secretion causes hypokalemia and alkalemia. Osmolality (Na⁺) and fluid volume regulation has priority over H⁺ and K⁺ regulation.

Plasma K⁺ and H⁺ regulation are interrelated and are subservient to Na⁺ regulation. Potassium is an abundant nutrient and a mechanism for its regulation (other than intracellular sequestration with the Na⁺ /K⁺ ATPase membrane pump and renal elimination in proportion to intracellular concentration) has not evolved. Aldosterone stimulated Na⁺ reabsorption causes increased K⁺ and H⁺ secretion and consequent hypokalemia and alkalosis. When aldosterone stimulated Na⁺ reabsorption is inhibited, then K⁺ and H⁺ secretion are minimal so that hyperkalemia and acidosis result.
In acidosis, renal H⁺ secretion is increased so that there is a corresponding decrease in K⁺ secretion contributing to hyperkalemia. In alkalosis there is diminished H⁺ secretion and so increased renal K⁺ secretion contributing to hypokalemia. On the other hand, hyperkalemia diminishes H⁺ secretion and contributes to acidemia; and hypokalemia causes increased H⁺ secretion and alkalemia. Another factor contributing to the reciprocal relationship between circulating K⁺ and H⁺ concentrations is the "K⁺/H⁺ shift". K⁺ enters and H⁺ exits cells in hyperkalemia, and vice versa in acidemia. K⁺ exits and H⁺ enters cells in hypokalemia, and vice versa in alkalemia. The acidemia caused by hyperkalemia is anamolous since it is associated with a high intracellular and urinary pH. The alkalemia caused by hypokalemia is similarly anamolous.

Bicarbonate concentration is a reflection of acid/base status.

Cl^- concentration is not directly regulated but changes passively, as demanded for maintenance of electroneutrality, with changes in concentration of other ions.

Anion Gap

Acidosis Normal Alkalosis

The manner in which Cl^- passively changes to maintain electroneutrality in response to changes in concentration of other ions is illustrated in the figures to the right. These figures represent cation/anion balance. There must be equivalent amounts of anions and cations in order for electroneutrality to be attained. The figures show that the major cation, Na⁺ is balanced by equivalent amounts of anions. There isn't quite enough of the major anions, Cl^- and HCO^-₃, to completely balance Na⁺. An additional amount of anions, necessary to balance Na⁺, are, of course, present but are not measured. These unmeasured anions, necessary to balance Na⁺, are referred to as the Anion Gap (AG). Note that:

AG = Na⁺ - ( Cl^- + HCO₃^-)

.
When bicarbonate decreases, as in metabolic acidosis or in compensating for respiratory alkalosis, chloride correspondingly increases.
When bicarbonate increases, as in metabolic alkalosis or in compensating for respiratory acidosis, chloride correspondingly decreases.
The anion gap does not change in most acid/base disturbances.

There are a few notable metabolic acidoses in which the anion gap increases corresponding to the bicarbonate decrease and chloride remains constant, as illustrated in the figure below.

Met. Acidosis
with
normal AG Normal Met. Acidosis
with
increased AG

Metabolic acidoses with an increased anion gap are due to the presence of excess amounts of an organic acid, such as lactic acid, keto-acids, retained metabolic waste products or salicylic acid, occurring in lactic acidosis, diabetic keto-acidosis, uremia, salicylate poisoning, respectively.
The anion gap increases from the presence of the conjugate base of the organic acid, e.g., lactate, acetoacetate, etc.

Last Updated: March 26, 2001