Glomerulus

The first structure of each nephron is the glomerulus, a high-pressure capillary bed that serves as the filtering point for the blood. Positive filtration pressure in the glomerulus is achieved as a result of the high arterial pressure as the blood enters the afferent arteriole and the resistance created by the smaller efferent arteriole as the blood exits the glomerulus. As a result of the positive-pressure gradient, fluid and solutes are filtered through the glomerular capillary walls. The glomerulus has three layers: the endothelium, the basement membrane, and the epithelium. The inner endothelial layer lines the glomerulus and contains numerous pores that allow filtration of fluid and small solutes from the blood. The middle basement membrane layer also controls filtration according to the size, electrical charge, protein-binding capability, and shape of the molecules. This complex is also described as the glomerular filtration barrier (GFB). It is freely permeable to water and small or midsized molecules but large molecules such as albumin and red blood cells are prevented from entering the filtrate.³ The presence of large molecules in the urine is a signal that the glomerular membrane is damaged. The outer epithelium layer contains pores that allow the filtered blood, or filtrate, into the Bowman space.

The Bowman Capsule

A filtrate of plasma, usually called the ultrafiltrate, enters the Bowman space, which is surrounded by the Bowman capsule, a tough, membranous layer of epithelial cells that completely surrounds the glomerular capillary bed. The Bowman space is located between the capillary walls of the glomerulus and the inner layer of the Bowman capsule and contains the initial filtrate from the blood. Fluid, solutes, and other substances filtered by the glomerulus collect in the space. The Bowman space is a continuous structure that joins the first portion of the nephron’s tubular system—the proximal tubule.¹

Proximal Tubule

The proximal tubule is located in the cortex of the kidney and has a large surface area available for solute and fluid transportation. The proximal tubule resorbs (takes back) most of the filtered water and sodium and many of the solutes the body does not routinely excrete in the urine. Solutes that are usually resorbed include all of the glucose, some of the water-soluble vitamins, most phosphate and bicarbonate, and much of the potassium, chloride, and calcium that is filtered by the glomerulus. Proteins are resorbed in the proximal tubule by two specialized receptors known as megalin and cubilin that bind albumin and vitamin-binding proteins.¹ Creatinine is minimally resorbed and is excreted in the urine.

In addition to its major role in resorbing water and solutes from the filtrate, the proximal tubule secretes organic anions and cations into the tubular lumen. Ammonia is produced from the metabolism of glutamine in the mitochondria of the proximal tubule cells, where ammonia (NH₃) combines with hydrogen (H⁺) to form ammonium (NH₄⁺), which is secreted into the proximal tubule lumen.¹

Because of the large amount of solutes in the glomerular filtrate, the fluid that enters the proximal tubule is hyperosmotic. When the filtrate leaves the proximal tubule and enters the loop of Henle, it is isosmotic (equivalent to plasma) as a result of the resorption of solutes and water.

Loop of Henle

After selective resorption in the proximal tubule, the isosmotic filtrate enters the loop of Henle. The loop of Henle consists of a thin descending limb, a thin ascending limb, and a thick ascending limb. There are two types of nephrons: the cortical nephrons with short loops of Henle and the juxtamedullary nephrons with long loops of Henle. The nephrons with short loops of Henle do not have a thin ascending limb. As a result, the cortical nephrons perform excretory and regulatory functions but play only a minor role in the concentration or dilution of urine. The juxtamedullary nephrons have glomeruli that are next to (juxtaposed to) the medulla near where the cortex and medulla sections of the kidney join and contain a thin ascending limb. These nephrons with the thin ascending limbs are critical for concentrating and diluting the urine by means of the countercurrent mechanism. The thin descending limb is very permeable to water but fairly impermeable to urea, sodium, and other solutes. As a result, water (but not solute) is resorbed into the general circulation, and a more concentrated filtrate is produced. The filtrate then moves up the thin ascending limb, which is impermeable to water but allows movement of sodium, chloride, and urea back into the filtrate. The thick ascending limb is also impermeable to water but allows resorption of sodium, chloride, potassium, calcium, and bicarbonate. Because of the low water and high solute resorption in the loop of Henle, the filtrate leaves the ascending limb hypo-osmotic (more dilute than plasma).

Distal Tubule

The hypo-osmotic filtrate enters the distal tubule located in the cortex of the kidney. The first portion of the distal tubule contains the cells of the macula densa, which are specialized cells that are a component of the juxtaglomerular apparatus important in blood pressure control. The first section of the distal tubule is impermeable to water and transports solutes such as sodium, bicarbonate, calcium, and potassium. The later section of the distal tubule further regulates sodium, bicarbonate, potassium, and calcium according to hormonal influences and the acid–base and electrolyte balance needs of the body. The permeability of the late distal tubule is influenced by antidiuretic hormone (ADH). In the presence of ADH, the late distal tubule is impermeable to water but resorbs some solutes, and the filtrate remains hypo-osmotic. In the absence of ADH, the late distal tubule is more permeable to water, and the filtrate may become isosmotic.

Collecting Duct

Several distal tubules join to form a collecting duct that begins in the cortex and extends through the medulla to empty into the papilla. The final composition of the urine occurs in the collecting duct, primarily because of the transport of potassium, sodium, and water. Water permeability is determined by the absence or presence of ADH. In the absence of, or with small amounts of ADH, the urine becomes dilute, whereas larger amounts of ADH result in concentrated urine. The filtrate usually is more concentrated when it leaves the collecting duct than it was when it entered. Acidification of the urine is accomplished by the transport of bicarbonate and hydrogen in the collecting duct. Several collecting ducts then combine to form the pyramids. After the urine leaves the collecting ducts, no change in the composition of the filtrate occurs. Box 25-1 summarizes tubular resorption and secretion in the various structures of the nephron.

Glomerular Filtration

The first process in urine formation is glomerular filtration, which depends on glomerular blood flow, pressure in the Bowman space, and plasma oncotic pressure.² Glomerular blood flow is the most important of these three factors and is maintained through an autoregulatory mechanism within the kidneys.² The autoregulatory mechanism maintains consistent kidney blood flow and perfusion at a constant level as long as the mean arterial pressure (MAP) remains between 80 and 180 mm Hg. The afferent and efferent arterioles of the glomeruli have the ability to increase or decrease the glomerular blood flow rate through selective dilation and constriction. When the mean arterial blood pressure is decreased, the afferent arteriole dilates, and the efferent arteriole constricts to maintain a higher pressure in the glomerular capillary bed and maintain the GFR at 125 mL/min. The ability of the kidneys to autoregulate blood flow begins to fail when the mean arterial blood pressure is less than 80 mm Hg or greater than 180 mm Hg.

The second factor that influences the GFR is the pressure in the Bowman space. An increase in pressure in this space decreases filtration because the increased pressure resists the movement of solutes and water from the capillaries into the space. For example, if the tubules of the nephrons are blocked by cellular debris, backward pressure is exerted on the Bowman space, the GFR drops below 125 mL/min, and urine output decreases.

The third factor that influences GFR is plasma oncotic pressure. When the oncotic pressure in the blood is decreased (as in disease states that result in low plasma protein levels), pressure in the glomerular capillary bed is decreased. Although the mean arterial pressure in the glomerulus favors filtration, decreased amounts of fluid and solutes leave the capillaries and enter the Bowman space because the oncotic pressure gradient in the plasma that encourages movement of fluid and solutes out of the plasma is less favorable. Filtration still occurs, but it is decreased from the normal 125 mL/min, resulting in a decrease in the amount of filtrate and therefore urine.

The status of the glomerular filtration system is assessed by measuring the GFR. Creatinine is used as a measure of the GFR because it is a waste product produced at a fairly constant rate by the muscles, is freely filtered by the glomerulus, and is minimally resorbed or secreted by the tubules. Most of the creatinine produced by the body is excreted by the kidneys, making the creatinine clearance a good screening and follow-up test for estimating the GFR. Creatinine clearance usually mirrors the GFR, so that a normal creatinine clearance rate is approximately 125 mL/min. A creatinine clearance rate less than 100 mL/min reflects a GFR of less than 100 mL/min and is a signal of decreased kidney function. A creatinine clearance rate (and GFR) less than 20 mL/min results in symptoms of kidney failure.

Tubular Resorption

The second process in the formation of urine is tubular resorption—the movement of a substance from the tubular lumen (filtrate) into the peritubular capillaries (blood). Tubular resorption allows the 180 L of solutes and water filtered by the glomerulus to be taken back into the circulation, decreasing the 180 L of filtrate to 1 to 2 L of urine per day. Most tubular resorption takes place in the proximal tubule and occurs by passive and active transport processes.

Tubular Secretion

The third process in urine formation is tubular secretion, the transport of substances from the peritubular capillaries into the lumen of the tubules. Tubular secretion allows the body to remove excess substances; it occurs by diffusion and by active transport, and it depends on the needs of the body. For example, potassium, hydrogen, medications, or medication metabolites are secreted into the tubules to decrease their concentration in the body. Tubular secretion plays a lesser role than tubular resorption in changing the filtrate into urine.

Elimination of Metabolic Wastes

Metabolic processes in the body produce waste products that are selectively filtered out of the circulation by the kidneys. Urea, uric acid, and creatinine are byproducts of protein metabolism that the kidneys filter out of the circulation and excrete in the urine. Metabolic acids, bilirubin, and medication metabolites are also eliminated as waste products.

Blood Pressure Regulation

The kidneys regulate arterial blood pressure by maintaining the circulating blood volume by means of fluid balance and by altering peripheral vascular resistance through the renin-angiotensin-aldosterone system (RAAS). Regulation by the RAAS occurs in the juxtaglomerular apparatus (JGA), a group of specialized cells located around the afferent arteriole where the distal tubule and afferent arteriole make contact4,5 (see Fig. 25-3). Another group of specialized cells is located near the distal tubule; known as the macula densa, these cells control a feedback mechanism from the distal tubule to the afferent arteriole to control blood flow through the afferent arteriole.⁴

An increase in tubular filtrate in the macula densa causes the afferent arteriole to constrict and therefore decrease the GFR and the amount of filtrate produced. Conversely, a decrease in the amount of tubular filtrate results in afferent arteriole dilation, an increased GFR, and an increased amount of filtrate.

The JGA synthesizes, stores, and releases renin.⁵ Renin is released in response to reduced pressure in the glomerulus, sympathetic stimulation of the kidneys, and a decrease in the amount of sodium in the distal tubule.⁵ Renin enters the lumen of the afferent arteriole and is released into the general circulation. Renin is then converted to angiotensin I, which is further converted to angiotensin II as the blood circulates through the lungs. Angiotensin II is an active compound that causes afferent and efferent arteriole vasoconstriction, resulting in an increased vascular resistance, and it therefore maintains hydrostatic pressure within the kidneys. A powerful vasoconstrictor, angiotensin II also causes increased systemic vascular resistance and therefore increased arterial blood pressure. Intracellular actions of angiotensin II constitute an emerging area of research.^6,7 Angiotensin II also stimulates the release of aldosterone by the adrenal cortex.

Aldosterone acts on the distal tubule to facilitate sodium and water resorption, resulting in an expanded circulating blood volume and increased blood pressure. When the arterial blood pressure increases, the JGA reduces the release of renin, and the RAAS is less active. Figure 25-4 summarizes the major aspects of the renin-angiotensin-aldosterone mechanism.

Erythrocyte Production

The kidneys secrete erythropoietin, the hormone that controls erythrocyte (red blood cell) production in the bone marrow. Erythropoietin is released in response to a decrease in the amount of oxygen delivered to the kidneys, such as in anemia or prolonged hypoxia.⁸ The hormone remains active for about 24 hours after release and stimulates the bone marrow to increase the production of erythrocytes. The absence of erythropoietin, which occurs in individuals with kidney failure, results in a profound anemia that is treated by administering synthetic erythropoietin or by blood transfusion therapy.^8,9

Vitamin D Activation

The kidneys convert vitamin D from food sources into an active form for use by the body. Active vitamin D stimulates the absorption of calcium by the intestine and resorption of calcium by the tubules so that calcium is available for bone and tooth metabolism and blood clotting functions. When the kidneys fail, the body is unable to convert dietary vitamin D to its active form, calcium is poorly absorbed, and bone disease and other immunologic deficiencies result.¹⁰ Lack of vitamin D may also be responsible for changes in the immune system that increase the risk of infection in patients with chronic kidney disease (CKD).¹¹

Prostaglandin Synthesis

Prostaglandins are vasoactive substances that dilate or constrict the arteries. The kidney produces two vasodilatory prostaglandins (PGs): E and I; they are typically abbreviated PGE₁ and PGI₂.¹² The prostaglandins produced by the kidneys have only local blood flow effects with minimal or no systemic effects. The primary prostaglandins produced by the kidneys are the vasodilators PGE₁ and PGI₂, which act on the afferent arteriole to maintain blood flow and glomerular perfusion and filtration. The vasodilating effects of the prostaglandins also counteract the effects of angiotensin II and the sympathetic nervous system on the kidneys and maintain blood flow to the kidney despite systemic vasoconstriction. Another prostaglandin that may affect kidney function is PGF₂, which contributes to vasoconstriction in times of volume depletion. Box 25-2 lists the effects of prostaglandins.

Acid–Base Balance

The kidneys are actively involved in acid–base regulation by resorbing or excreting acids and bases in the kidney tubules. For example, bicarbonate, the principal blood buffer, is resorbed from the tubules, and hydrogen, a potent organic acid, is secreted into the tubules. However, the tubules do not function as rapidly in altering acid–base concentrations as do the lungs; the kidneys therefore regulate the day-to-day balance rather than coping with emergencies requiring an immediate physiologic response.

Fluid Compartments

The fluid of the body is present in distinct internal spaces or compartments. The compartments are separated from each other by semipermeable membranes with openings (pores) that allow molecules of specific size and molecular weight to pass through while preventing larger, heavier molecules from doing so. As a result of the semipermeable membrane, fluid movement between the compartments is dynamic and constant.

Between 45% and 60% of body weight is made up of water.¹³ The body has two main fluid compartments: intracellular and extracellular. The intracellular compartment is the fluid inside each of the body’s cells, and it accounts for 40% of the total body water content.¹³ The remaining fluid is outside the body’s cells and makes up the extracellular compartment. The extracellular compartment is composed of two distinct subcompartments: intravascular and interstitial. The intravascular compartment, meaning the fluid within the blood vessels, accounts for 5% of the body water. The interstitial compartment corresponds to the fluid in the tissue spaces outside of the body cells and the blood vessels and accounts for 15% of body water. Approximate amounts of fluid contained in each compartment are shown in Figure 25-5A.

With an increase in body fat, the body fluid percentage decreases because fat contains a smaller and less significant amount of water than muscle.

Electrolytes

Electrolytes are elements or compounds that, when dissolved in water, dissociate into ions, electrically charged atomic particles. Ions in solution in the fluid allow the fluid to conduct an electrical current. A balance exists between cations (positively charged ions), anions (negatively charged ions), and other substances in the fluid compartments. Maintaining this balance is important to the normal function of all body systems. Electrolytes exist in differing amounts in each of the fluid compartments. The primary electrolytes and other substances of importance in fluid and electrolyte balance are shown by fluid compartment in Figure 25-5B.

Fluid Physiology

An overall understanding is needed of the structures containing or balancing fluids and electrolytes and the physiologic forces that govern their movement and balance. Knowledge of factors that inhibit or enhance the transfer of fluids and electrolytes is required.

Tonicity

The terms isotonic, hypotonic, and hypertonic all refer to tonicity, or the osmolality of body fluids. Osmolality is a measure of the number of particles (solute) in a solution, and the value is stated in milliosmoles per kilogram (mOsm/kg) of water. The normal osmolality of body fluids is 275 to 295 mOsm/kg of body weight. Different hospital laboratories may use slightly different numbers, such as 280 to 300 mOsm/kg.¹³

Figure 25-6 shows the effects of the tonicity (osmolality) of fluid in the body. An isotonic solution has roughly the same concentration of particles as the blood plasma; cells within an isotonic solution maintain consistency and do not lose or gain fluid to their surroundings. A hypertonic solution contains a greater concentration of particles than that inside the cell and causes fluid to be drawn out of the cells. Used inappropriately, too much fluid may be withdrawn, causing a withering of the cell (crenation). A hypotonic solution contains a lesser concentration of particles than that inside the cell and causes fluid to be drawn into the cells. If used incorrectly, a hypotonic solution can cause too much fluid to enter the cell, causing the cells to swell and burst (hemolysis).

ADH, also known as vasopressin, is secreted by the posterior pituitary gland and functions as the primary controller of ECF volume. Feedback messages for release of ADH are sent by osmoreceptors (water receptors) located in the hypothalamus. As serum osmolality rises above 285 mOsm/kg (normal range, 275 to 295 mOsm/kg), ADH is released and carried through the circulation to the nephrons. The kidney distal tubules, connecting tubules, and the collecting ducts alter their permeability to water by the action of three aquaporins. These are aquaporin-2 (AQP2), aquaporin-3 (AQP3), and aquaporin-4 (AQP4).¹⁴ ADH acts via the aquaporin-2 receptor (AQP2) on the distal tubule and collecting ducts to resorb water.¹⁴ ADH action in the kidney is predominantly mediated through the aquaporins.

The normal range of urinary osmolality is from 500 to 800 mOsm/kg. Box 25-3 identifies several additional mechanisms that stimulate the release of ADH. In addition to the usual stimuli, the presence of severe emotional or physical stress can initiate ADH release through the limbic system that surrounds the hypothalamus.

Sodium

Sodium is the most abundant extracellular electrolyte in the body and is associated with fluid balance and the amount of water retained or excreted by the kidneys.¹³ Along the length of the nephron sodium is resorbed from the filtrate. This is an active metabolic process that is regulated by site-specific sodium transporters.¹⁵ When diuretics are administered, sodium absorption is inhibited and consequently sodium is eliminated in the urine.¹⁵ Sodium plays an essential role in the transmission of nerve impulses through the sodium pump, or active transport mechanism, at the cellular level. Sodium is key to a number of physiologic functions (Box 25-8).

The body contains a complex system of safeguards and feedback mechanisms to protect the level of sodium in the ECF. Sodium balance is regulated by the kidneys, the adrenal glands (aldosterone secretion), and the posterior pituitary gland (ADH secretion). Most sodium resorption occurs in the proximal tubule under the influence of aldosterone. Because of the extremely sensitive mechanism for retaining sodium, ingestion of large amounts of sodium is unnecessary.

Phosphorus

As with calcium and magnesium, the serum values of phosphorus represent a minute portion of the actual body stores. Approximately 80% of the phosphorus is found in the bones.¹⁶ Most of the remaining phosphorus is intracellular, with only a small amount in the ECF. The primary function of phosphorus is the formation of ATP, which provides intracellular energy for active transport mechanisms across the cell membrane. Additional functions of phosphorus include cell membrane structure, acid–base balance, oxygen delivery to the tissues, cellular immunity, and bone strength (Box 25-10).

Absorption of phosphorus takes place in the gastrointestinal tract, and serum phosphorus levels change frequently and dramatically, particularly in response to the ingestion of phosphate-rich foods such as milk, red meats, poultry, and fish. Most excretion occurs in the kidneys. More than 90% of the phosphorus in the plasma is filtered by the glomerulus, and about 80% is resorbed by the proximal tubules. Resorption by the kidneys is increased when body stores are low, and it is combined with sodium and excess hydrogen ions to maintain acid–base balance.

Phosphorus abnormalities are evident early in the course of kidney failure.¹⁷ The Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994, which included 14,722 adults) revealed that people with mild or moderate kidney dysfunction—defined as a urinary creatinine clearance rate (CrCl) between 50 and 60 mL/min—already have elevations of serum phosphorus and potassium levels.^17,18 In contrast, serum ionized calcium remains relatively unchanged until the creatinine clearance rate is extremely low (CrCl less than 20 mL/min) and kidney failure is advanced.

Magnesium

Magnesium is the second most important and abundant intracellular electrolyte; about 60% of it is located in the bone.¹³ The ECF contains only about 1% of the body’s magnesium, and the remaining amount resides in the ICF. The levels of other intracellular electrolytes, such as calcium and potassium, are affected by the level of magnesium. For example, calcium and magnesium compete for absorption in the gastrointestinal tract. If the dietary intake of calcium is higher than that of magnesium, calcium is preferentially resorbed and vice versa. The most important functions of magnesium are ensuring the transport of sodium and potassium across the cell membrane and as a cofactor in many intracellular enzyme reactions. Depletion of magnesium liberates potassium to the ECF, which causes an increase in the excretion of potassium by the kidney and hypokalemia. Magnesium also plays a role in maintaining neuromuscular activity, protein synthesis, and intracellular energy production (Box 25-11).

Chloride

Chloride is predominantly found in the ECF. Changes in serum chloride levels usually indicate changes in the other electrolytes or in acid–base balance. Chloride plays a major role in maintaining serum osmolality, water balance, and acid–base balance. Additional functions of chloride are listed in Box 25-12.

Chloride is usually ingested with sodium in the form of salt and is resorbed or excreted in the proximal tubules of the kidney. Chloride is actively transported out of the tubules into the interstitium with sodium to help maintain the high tubular interstitial osmolality and the mechanism for concentrating the urine.

Bicarbonate

Bicarbonate () is an anion in the ECF, and it performs the essential function of maintaining the acid–base balance.¹³ Although bicarbonate is not solely responsible for the acid–base balance, it is the major ECF buffer. Bicarbonate levels in the body are in balance with carbonic acid (H₂CO₃) levels. The ratio between the two must remain proportional at 1 mEq of carbonic acid to 20 mEq of bicarbonate; otherwise, acid–base disturbances will result. When the carbonic acid level is elevated, acidosis results. When the bicarbonate level is high, alkalosis results.

The kidneys regulate the amount of bicarbonate available in the ECF. Resorption of bicarbonate occurs primarily from the proximal tubule into the peritubular capillaries. Bicarbonate is also produced in the distal tubule and resorbed into the blood in response to acid–base balance and body requirements. The kidneys resorb or excrete bicarbonate in response to the number of hydrogen ions present as part of the body’s buffer system. More bicarbonate is resorbed when a large number of hydrogen ions are present, and more is excreted when few hydrogen ions are present.

Effects of Aging

Kidney function declines gradually with age, but this usually does not affect homeostasis in the healthy older adult unless proteinuria is present.19,20 Proteinuria is associated with complication in both the kidney and cardiovascular systems.¹⁹ With aging, the GFR declines by about 0.75 mL/min/year.¹⁹ However, despite the gradual decrease in the GFR and the associated reduction in clearance of creatinine, serum creatinine levels may not rise. This occurs because the reduced muscle mass associated with aging produces less creatinine to be excreted by the kidneys, essentially masking the overall effects of aging on the kidneys. As a result, relatively low levels of serum creatinine in older adults may be associated with reductions in the GFR and creatinine clearance. The gradual decline in kidney function that occurs with aging usually is not a threat to homeostasis because the remaining GFR is adequate. The Cockcroft-Gault formula is used to estimate GFR and includes age in the formula¹⁹ (see Chapter 26). However, when older adults become ill, the decline in kidney function can be accelerated, making older adults especially susceptible to acute and chronic kidney dysfunction.

The kidneys carry out many functions. Although fluid balance is perhaps the most obvious function, an understanding of the numerous other roles of the kidneys provides crucial information for the care of any critically ill patient.

Physiology