Introduction

As living organisms, the maintenance of fluid balance is critical to sustaining many bodily functions, including metabolic and biochemical reactions, transport of nutrients and thermoregulation. The average adult has roughly 65% fluid mass, with this value being slightly lower in females than males. Our body fluids may subcategorize into intracellular and extracellular fluid compartments.[1][2][3]

Intracellular fluid, also considered as the cytosol, is all the fluid contained within cells. The intracellular fluid makes up roughly two-thirds of the total body volume.

Extracellular fluid constitutes the remaining one-third of fluid volume in the body and may further divide into its interstitial, intravascular and transcellular compartments.[1][2][3]

The maintenance of fluid homeostasis in each of these compartments is dependent on the excretion of fluids and the concentration of electrolytes that generate osmotic pressure. This process of passive regulation of osmotic pressure is known as osmoregulation.[1][2][3]

This article will provide an overview of osmoregulation and excretion, focusing on a discussion of the renal system involved in maintaining this intimate balance between fluid retention and excretion.

Cellular Level

Osmosis occurs when two solutions containing different concentrations of solute are divided by a selectively permeable membrane. In the human body, this selectively permeable membrane may be the cellular membrane (in the case of intracellular fluid) or maybe a membrane lining your body cavity composed of cells (in the case of extravascular fluid). The solute concentration difference across the membrane gives rise to a gradient that facilitates the movement of a solvent (usually water in our body) until attaining equilibrium. The tendency of a solution to draw water in through the semipermeable membrane is the osmotic pressure.[1][2][3][4]

The unit of osmoles is used to express the number of particles. One osmole refers to one mole of osmotically active solute particles. Though similar to molarity, osmolarity refers to the total number of active particles. For instance, one mole of glucose dissolved in one liter of solution would have molarity and osmolarity of 1 osm/L (or 1 mol/L). However, if a molecule dissociates into two ions (yielding two particles)—for instance, sodium chloride, then the 1 mol/L solution will yield an osmolarity of 2 osm/L.[5][6]

 It is also noteworthy that there is a distinction between the terms osmolarity and osmolality. While osmolarity is the number of osmoles per liter, osmolality is the number of osmoles per kilogram. In terms of volume status, we are concerned more so with the plasma osmolality, since it is independent of temperature and pressure. However, clinically, it is much easier to express body fluid quantities in liters rather than kilograms. At low concentrations (as in the human body), these two terms are almost synonymous with each other.[5][6]

The total osmolarity for each of the three fluid compartments (intracellular, interstitial, intravascular) is around 280 mOsm/L, with intravascular being slightly greater due to the osmotic effects of plasma proteins. The composition of the interstitial and intravascular fluid is similar, with sodium and chloride being the primary contributors to the osmolarity. For intracellular fluid, almost half the osmolarity is due to potassium ions, with the other half composed of various other substances (e.g., phosphate, phosphocreatine, magnesium ions).[1][6]

Organ Systems Involved

To maintain homeostasis, the excretion of water and electrolytes must match an individual’s intake. The kidneys play a substantial role in osmoregulation by controlling the quantity of fluid reabsorbed from the glomerular filtrate. This fluid is reabsorbed in the renal tubes and may be modulated by hormones such as antidiuretic hormone (ADH), aldosterone, as well as angiotensin II. The capacity of the kidneys to alter fluid excretion, as well as electrolyte excretion (e.g., sodium), is enormous. Studies have shown that sodium intake of 10 times the normal amount has relatively small changes in extracellular fluid volume and plasma sodium concentration as a result of renal compensation.[1][3][6][7]

The glomerular filtration rate (GFR) of an average human is 180L/day. Given that the plasma volume of a person is only 3L, large amounts of body fluid and solutes are processed by the kidney each day. The advantage of this high GFR in terms of osmoregulation is that it enables the kidneys to rapidly and precisely regulate the volume and composition of body fluids.[8]

At the level of the hypothalamus, osmoreceptor response to extracellular fluid hypertonicity (increased osmolarity), will elicit ADH release from axons down to the posterior pituitary into the circulation. ADH serves a primary function to increase solute-free water reabsorption in the nephrons (less water excretion) to bring down body fluid hypertonicity.[9][10]

Function

Osmoregulation and the maintenance of body fluid levels are critical to our metabolic activities as organisms. As mentioned earlier, this is the result of ensuring adequate organ perfusion, proper thermoregulation, excretion of toxic waste and electrolyte balance.[1]

On a cellular level, the osmolarity of the extracellular fluid impacts the passage of water in and out of a cell. Isotonic fluids contain the same concentration as the intracellular milieu, whereas hypertonic fluids (higher concentration than inside the cell) lead to cell shrinkage and hypotonic fluids lead to cell swelling (lower concentration than inside the cell). Exaggerated amounts of solute changes result in osmotic stress, which is damaging to cells.[1][2][3][4]

Mechanism

Several key mechanisms contributing to osmoregulation appear below:

Sympathetic regulation: Strong activation of the renal sympathetic nerves can constrict the renal arterioles and decrease renal blood flow and GFR, leading to increased fluid retention.[11]

Autoregulation: Renal autoregulation helps maintain a relatively consistent GFR and establish delicate control of the excretion of water and solutes. In particular, the tubuloglomerular feedback mechanism of the macula densa serves to ensure steady delivery of sodium chloride to the distal tubule, consequently reducing spurious fluctuations in renal salt excretion.[12][13]

Hormonal regulation:

• Angiotensin II has numerous direct effects on tubular function, including decreased medullary blood flow in the vasa recta, tubule hypertrophy, relative efferent arteriolar constriction leading to the maintenance (or rise) in GFR, and compensatory sodium absorption to maintain fluid balance. Angiotensin II also stimulates the production and release of aldosterone and ADH, both important hormonal contributors to electrolyte and fluid balance.[14]
• Atrial natriuretic peptide gets released in response to elevated atrial pressure. It acts to increase GFR and sodium filtration as well as inhibit sodium uptake, leading to volume loss at the distal convoluted tubule.[15]
• Aldosterone has effects on the distal tubule and collecting duct by increasing sodium uptake and potassium excretion into the urine; this is mediated via upregulation of basolateral Na+/K+ pumps, epithelial sodium channels, amongst other mechanisms, resulting in net fluid retention.[14]
• ADH serves a primary function to increase solute-free water reabsorption in the nephrons (less water excretion) to bring down body fluid hypertonicity; this is induced by the insertion of water channels (aquaporin-2) on the apical membrane of the collecting duct.[9][10]

Pathophysiology

Fluid and electrolyte imbalance may manifest from numerous conditions or maybe the underlying etiology for some disease states.

Syndrome of inappropriate ADH secretion (SIADH) involves the excessive release of antidiuretic hormone. This excessive ADH release may stem from hypothalamic hyperactivity, or ectopic sources (e.g., small-cell carcinoma). Increased ADH promotes free-water reabsorption from the filtrate, leading to an inappropriately elevated urine osmolality (greater than 100 mOsmol/L) compared to blood plasma and by consequence, hyponatremia.[16]

Kidney disease, in both acute and chronic contexts, impairs glomerular function, thereby reducing the production of the filtrate. Typically, this translates to increased water retention, increased potassium retention and dilution of plasma sodium concentrations due to reduced water excretion.[17][18]

Edema is the presence of excess fluid in either the intracellular fluid compartment or the extracellular fluid compartment. In the case of extracellular edema, more commonly considered clinically, osmotic causes may include acute or chronic kidney failure, mineralocorticoid excess, decreased plasma proteins (e.g., nephrotic syndrome) or decreased hepatic synthesis of proteins. Symptomatically, this may present as either generalized edema, also known as anasarca; or it may be more localized, as seen in sacral, pretibial, pulmonary edema.[19]

Clinical Significance

Fluid maintenance in patients: When administering fluids to patients, an important consideration is the osmotic content of the solution. In the case that the patient does not have any underlying electrolyte abnormalities,  normal saline (0.9% NaCl) is a common choice for maintenance (particularly in pediatric populations) as it mimics the tonicity of blood. In cases of hypovolemic shock, hypertonic solutions are increasingly recognized as an alternative resuscitation fluid, albeit insufficient evidence, since they promote fluid movement into the intravascular space (by creating a high osmotic gradient across cellular membranes).[19][20]

Osmolar gap: The osmolar gap is the difference between the measured osmolality and the calculated osmolarity. The calculated osmolarity is given as: 2[Na] + [Glucose] + [Urea] ( all in mmol/L). Clinically, the osmolar gap may be used to detect the presence of an osmotically active particle that is not normally present in plasma. Common examples include toxic alcohol such as methanol or butanol.[21]

Diuretics: The principles of osmoregulation apply nicely to explain the physiological effects of many diuretics. For instance, loop diuretics operate mechanistically by blocking the sodium potassium chloride pump (NKCC) in the ascending loop of Henle. This blockade prevents reabsorption of sodium back into the blood, and by osmotic pressure leads to increased water loss through the urine as well.[22] Another example is with osmotic diuretics, such as mannitol. Mannitol gets filtered through the glomerulus but cannot be reabsorbed in the nephron. Thus, increased osmotic pressure is exerted in the filtrate, causing water to be retained in the tubules to ensure urine osmolality. The result is increased water expulsion in the urine.[23]