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True volume depletion, or hypovolemia, generally refers to a state of combined salt and water loss, leading to contraction of the ECFV. The loss of salt and water may be renal or nonrenal in origin.

Renal Causes of Hypovolemia

Excessive urinary Na+-Cl and water loss is a feature of several conditions. A high filtered load of endogenous solutes, such as glucose and urea, can impair tubular reabsorption of Na+-Cl and water, leading to an osmotic diuresis. Exogenous mannitol, often used to decrease intracerebral pressure, is filtered by glomeruli but not reabsorbed by the proximal tubule, thus causing an osmotic diuresis. Pharmacologic diuretics selectively impair Na+-Cl reabsorption at specific sites along the nephron, leading to increased urinary Na+-Cl excretion. Other drugs can induce natriuresis as a side effect. For example, acetazolamide can inhibit proximal tubular Na+-Cl absorption via its inhibition of carbonic anhydrase; other drugs, such as the antibiotics trimethoprim (TMP) and pentamidine, inhibit distal tubular Na+ reabsorption through the amiloride-sensitive ENaC channel, leading to urinary Na+-Cl loss. Hereditary defects in renal transport proteins are also associated with reduced reabsorption of filtered Na+-Cl and/or water. Alternatively, mineralocorticoid deficiency, mineralocorticoid resistance, or inhibition of the mineralocorticoid receptor (MLR) can reduce Na+-Cl reabsorption by the aldosterone-sensitive distal nephron. Finally, tubulointerstitial injury, as occurs in interstitial nephritis, acute tubular injury, or obstructive uropathy, can reduce distal tubular Na+-Cl and/or water absorption.

Excessive excretion of free water, i.e., water without electrolytes, can also lead to hypovolemia. However, the effect on ECFV is usually less marked, given that two-thirds of the water volume is lost from the ICF. Excessive renal water excretion occurs in the setting of decreased circulating AVP or renal resistance to AVP (central and nephrogenic DI, respectively).

Extrarenal Causes of Hypovlemia

Nonrenal causes of hypovolemia include fluid loss from the gastrointestinal tract, skin, and respiratory system. Accumulations of fluid within specific tissue compartments, typically the interstitium, peritoneum, or gastrointestinal tract, can also cause hypovolemia.

Approximately 9 L of fluid enter the gastrointestinal tract daily, 2 L by ingestion and 7 L by secretion; almost 98% of this volume is absorbed, such that daily fecal fluid loss is only 100–200 mL. Impaired gastrointestinal reabsorption or enhanced secretion of fluid can cause hypovolemia. Because gastric secretions have a low pH (high H+ concentration), whereas biliary, pancreatic, and intestinal secretions are alkaline (high HCO3 concentration), vomiting and diarrhea are often accompanied by metabolic alkalosis and acidosis, respectively.

Evaporation of water from the skin and respiratory tract (so-called “insensible losses”) constitutes the major route for loss of solute-free water, which is typically 500–650 mL/d in healthy adults. This evaporative loss ...

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