He noni no Kaualehu, he pūhai aʻa.

It is a noni tree of Kaualehu whose roots are in shallow ground.

Said of a person whose knowledge is shallow. The noni root from shallow ground does not make as good a dye as that from deep ground.

ʻŌlelo Noʻeau, compiled by Mary Kawena Pukui, #845

Introduction

25.1 General Functions of the Urinary System

The urinary system is composed of the kidneys and the organs that make up the urinary tract: ureters, urinary bladder, and urethra (Figure 25.2). The kidneys and ureters are retroperitoneal. The urinary bladder and urethra are located in the pelvic cavity.

Figure 25.2: Structures of the human urinary system (OpenStax Microbiology)

The kidneys are the main organ of the urinary system where blood is filtered, and the filtrate is transformed into urine at a constant rate throughout the day. The organs of the urinary tract transport, store, and eliminate urine from the body. The ureters transport urine from the kidneys to the urinary bladder. The urinary bladder temporarily stores urine until it is ready to be eliminated. The urethra transports urine from the urinary bladder to the outside of the body for disposal.

Functions of the kidneys include:

• Regulating blood pH by controlling the excretion of hydrogen and bicarbonate ions into the urine
• Regulating blood volume and blood pressure by controlling the water concentration in urine
• Regulating plasma concentration of various other ions and solutes
• Removing metabolic wastes and toxins from blood
• Production of the hormones calcitriol, erythropoietin, and renin

25.2 Gross and Microscopic Anatomy of the Kidney

Kidney Structure

The kidneys lie in the retroperitoneal space between the parietal peritoneum and the posterior abdominal wall. Both the right and left kidneys are protected by muscles, fat, and ribs. Kidneys are roughly the size of your fist and are about 11-14 cm in length, 6 cm wide, and 4 cm thick. Kidneys are well vascularized, receiving about 25 percent of the cardiac output at rest.

Figure 25.3: Kidneys (OpenStax)

The kidney surface is a protective fibrous capsule composed of dense, irregular tissue. The capsule is covered by adipose tissue called the renal fat pad that absorbs shock. The renal fat pad is encompassed by a tough renal fascia that helps firmly anchor the kidneys to the posterior abdominal wall. The adrenal glands are located on the superior aspect of the kidney. An in-depth discussion of adrenal glands can be found in the Autonomic Nervous System chapter.

Figure 25.4 Left Kidney (OpenStax)

The internal anatomy of the kidney is divided into two regions. The outer region is called the renal cortex and the inner region is called the medulla. The most characteristic features of the medulla are the renal pyramids and the renal papillae. The pyramids and papillae are separated by the renal columns. The papillae are bundles of collecting ducts that transport urine made by nephrons to the calyces (Figure 25.4). The words major and minor are used to describe the relative size of the calyces. The calyces are like an internal pipe system, functioning to allow the flow of fluid into the renal pelvis and then into the ureter for excretion.

The renal hilum is the entry and exit site for blood vessels, nerves, lymphatics, and the ureters (Figure 25.4).

Renal Blood Flow

Figure 25.5: Blood Flow in the Kidney from OpenStax

The renal artery enters the kidney at the hilum. The renal artery first divides into segmental arteries, followed by further branching to form interlobar arteries that pass through the renal columns to reach the cortex. The interlobar arteries branch into arcuate arteries, then cortical radiate arteries, and finally into afferent arterioles. The afferent arterioles supply blood to about 1.3 million nephrons each in the kidney. The nephron is the “functional unit” of the kidney (Figure 25.5). Blood continues to flow, moving from the afferent arterioles into the glomerulus before entering the efferent arterioles. You may have noticed that the coil-shaped glomerular capillaries are drained by arterioles rather than veins. This is a unique structural modification within the nephron that utilizes the high-resistance arterioles to control blood pressure, and thus filtration within the nephron (Figure 25.6). Veins in the kidney follow the arterial circulation in reverse: Blood draining from the glomerulus progresses through the peritubular capillaries, cortical radiate, arcuate, interlobar, and segmental veins back to renal veins.

Nephrons

Figure 25.6: Blood Flow in the Nephron from OpenStax

Nephrons cleanse the blood and balance the constituents of the circulation. Nephrons consist of five major parts: the glomerulus and glomerular (Bowman’s) capsule, the proximal convoluted tubule (PCT), the nephron loop (formerly known as the loop of Henle), the distal convoluted tubule (DCT), and the collecting duct. There are two types of nephrons, cortical nephrons and juxtamedullary nephrons (Figure 25.7). Cortical nephrons have a short loop of Henle that does not dip beyond the cortex, while juxtamedullary nephrons extend deep into the medulla.

Juxtamedullary Nephron -A. Renal capsule B. Cortex C. Corticomedullary junction D. Medulla E. Minor calyx 1.) Peritubular capillaries 2.) Proximal convoluted tubule 3.) Bowman’s capsule 4.) Glomerulus 5.) Efferent arteriole 6.) Distal convoluted tubule 7.) Afferent arteriole 8.) Interlobular vein 9.) Interlobular artery 10.) Thick descending limb of Loop of Henle 11.) Thick ascending limb of Loop of Henle 12, 13.) Vasae recti 14.) Thin descending limb of Loop of Henle 15.) Thin ascending limb of Loop of Henle 16.) Collecting duct 17.) Arcuate artery 18.) Arcuate vein. (Wiki)

Nephron Types Comparison: Diagram (left) of a long juxtamedullary nephron and (right) of a short cortical nephron. The left nephron is labelled with six named nephron segments. Also labelled is the collecting duct, mislabelled the “collection duct”; it is the last part of the nephron. (Wiki)

Figure 25.7 Cortical and Juxtamedullary Nephrons inside of a kidney.

As mentioned previously, the afferent arterioles form a bunch of high-pressure capillaries known as the glomerulus. The glomerulus is surrounded by the Bowman’s capsule. The glomerulus and Bowman’s capsule together form the renal corpuscle. The glomerular capillaries filter blood based on particle size. After passing the renal corpuscle, the capillaries form a second arteriole called the efferent arteriole. The efferent arteriole will form a capillary network around the more distal portion of the nephron tubules, called the peritubular capillaries, and vasa recta before returning to the venous system. As the glomerular filtrate progresses through the nephron, these capillary networks recover most of the solutes and water, and return them to circulation. This concept is discussed in more detail below.

25.3 Gross and Microscopic Anatomy of the Urinary Tract

Ureters

The renal pelvis of the kidney narrows to become the ureter of each kidney. As urine is formed in the kidney, it drains into the renal pelvis and then into the ureter. The ureters are narrow tubes approximately 30 cm long. The ureters propel urine through waves of peristalsis into the bladder. As the ureters approach the bladder in the pelvis, they turn medially and pierce the posterior wall of the bladder. The oblique orientation of each ureter creates a physiological valve that prevents the backflow of urine from the bladder back into the ureter.

The lumen of the ureters is lined with transitional epithelium. The outer muscular layer consists of two layers of smooth muscles (longitudinal and circular layers) and creates the peristaltic contraction that moves the urine into the bladder. The outermost adventitia layer anchors the ureters between the parietal peritoneum and the posterior abdominal wall.

Figure 25.8 Ureter: Peristaltic contractions help to move urine through the lumen with contributions from fluid pressure and gravity. LM × 128. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012) (OpenStax)

Urinary Bladder

The ureters bring urine to the urinary bladder. The urinary bladder is a highly distensible organ that temporarily stores urine. Volumes in adults can range from nearly zero to 500–600 mL. This is because the bladder is lined with transitional epithelium, which appears columnar when the bladder is empty, but transitions to a more squamous appearance when the organ is full. The wall of the bladder also contains irregular crisscrossing bands of smooth muscle called the detrusor muscle.

Figure 25.9: Bladder (a) Anterior cross section of the bladder. (b) The detrusor muscle of the bladder (source: monkey tissue) LM × 448. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)(OpenStax)

In females, the urinary bladder lies anterior to the rectum and uterus and posterior to the pubic bone. During late pregnancy, the enlarging uterus compresses the bladder, resulting in increased frequency of urination.

At the base of the bladder, a small smooth triangular-shaped area called the trigone is formed by the two ureteral openings on each posterior corner and the opening into the urethra anteriorly.

Urethra

The urethra transports urine from the bladder to the outside of the body for disposal. Just like the rest of the urinary tract organs, much of the urethra is lined by transitional epithelium, except at the end where it is lined by a more protective nonkeratinized stratified squamous epithelium. The internal urethral sphincter is located at the opening into the urethra from the urinary bladder. The internal urinary sphincter consists of smooth muscle that is regulated by an involuntary autonomic nervous system. The external urethral sphincter consists of voluntary skeletal muscle and is located inferior to the internal urinary sphincter.

Figure 25.10: Female and Male Urethras (Openstax)

There are anatomical differences between male and female urethras. The female urethra is short in length, about 4 cm, and the opening of the urethra to the exterior, called the external urethral orifice, is located between the clitoris and the vaginal opening. Women have a higher incidence of urinary tract infection (UTI) because the short length of the urethra is less of a barrier to fecal bacteria than the longer male urethra.

The male urethra passes through the prostate gland immediately inferior to the bladder, before passing below the pubic symphysis. The male urethra can be subdivided into three anatomical regions: prostatic urethra, membranous urethra, and spongy urethra. The prostatic urethra passes through the prostate gland. The membranous urethra passes through the deep muscles of the perineum. The spongy urethra is the longest portion and passes through the penis and exits at the tip of the penis.

Figure 25.11: Male Reproductive System – highlighting segments of the Male Urethra

Micturition (urination)

Micturition is a fancy word for urination or discharge of urine from the urinary bladder. When bladder volume reaches about 150mL, the stretch receptors in the bladder wall transmit nerve impulses to the sacral region of the spinal cord. These impulses trigger a spinal reflex called the micturition reflex that results in parasympathetic impulses to the detrusor muscle and the involuntary internal urethral sphincter. It causes contraction of the detrusor muscle and relaxation of the involuntary internal urethral sphincter. At the same time, the spinal cord inhibits somatic motor neurons, resulting in the relaxation of the skeletal muscles of the external urethral sphincter. When the detrusor muscles contract and the sphincter muscles relax, micturition takes place. Although this is a reflex, in early childhood, we learn to override the reflex by voluntarily controlling the skeletal muscles of the external sphincter and delaying voiding. We commonly call this process “potty training”.

25.4 Functional Process of Urine Formation

Overview of Urine Formation

Nephrons produce urine via three principle actions: filtration, reabsorption, and secretion. The main task of the nephrons is to maintain plasma homeostasis by balancing solutes and excreting potential toxins.

• Glomerular filtration is the first step in the production of urine. Water and solutes in the blood plasma move across the walls of the glomerular capillaries and move into the renal tubules.
• Tubular reabsorption occurs throughout the nephron tubules through to the collecting ducts. Reabsorption is the process where water and solutes return to the blood as it flows through the peritubular capillaries and vasa recta.
• Tubular secretion also occurs throughout the nephron tubules to the collecting ducts. Secretion is the process where materials such as wastes, drugs, and excess ions are released from the blood into the filtrate within the tubules. Nephrons also have secondary functions that exert control in three areas — blood pressure, red blood cell production, and calcium absorption.

Figure 25.12: Physiology of Nephron (Cenveo via CCCOnline)

Glomerular Filtration

The renal corpuscle contains the Bowman’s capsule surrounding the glomerulus. The blood pressure within the glomerulus forces the fluid that enters the capsular space, also known as filtrate, into the surrounding glomerular (Bowman’s) and toward the PCT. The outermost part of the Bowman’s capsule, the parietal layer, is a simple squamous epithelium. It transitions into the glomerular capillaries intimately to form the visceral layer of the capsule. Here there are uniquely shaped cells called podocytes that extend finger-like arms called pedicels to cover the glomerular capillaries.

Each part of the nephron performs a different function in filtering waste and maintaining homeostatic balance. (1) The glomerulus forces small solutes out of the blood by pressure. (2) The proximal convoluted tubule reabsorbs ions, water, and nutrients from the filtrate into the interstitial fluid, and actively transports toxins and drugs from the interstitial fluid into the filtrate. The proximal convoluted tubule also adjusts blood pH by selectively secreting ammonia (NH3) into the filtrate, where it reacts with H+ to form NH4+. The more acidic the filtrate, the more ammonia is secreted. (3) The descending loop of Henle is lined with cells containing aquaporins that allow water to pass from the filtrate into the interstitial fluid. (4) In the thin part of the ascending loop of Henle, Na+ and Cl– ions diffuse into the interstitial fluid. In the thick part, these same ions are actively transported into the interstitial fluid. Because salt but not water is lost, the filtrate becomes more dilute as it travels up the limb. (5) In the distal convoluted tubule, K+ and H+ ions are selectively secreted into the filtrate, while Na+, Cl–, and HCO3– ions are reabsorbed to maintain pH and electrolyte balance in the blood. (6) The collecting duct reabsorbs solutes and water from the filtrate, forming dilute urine. (credit: modification of work by NIDDK) (OpenStax Bio 2e)

The JGA allows specialized cells to monitor the composition of the fluid in the DCT and adjust the glomerular filtration rate. (b) This micrograph shows the glomerulus and surrounding structures. LM × 1540. (Micrograph provided by the Regents of University of Michigan Medical School (OpenStax)

Figure 25.13: Juxtaglomerular Apparatus and Glomerulus 

These projections interdigitate to form filtration slits that leave small gaps in between the digits to form a sieve. As blood passes through the glomerulus, 10 to 20 percent of the plasma filters between these sieve-like fingers will be captured by the Bowman’s capsule and funneled to the PCT. Where the fenestrae (windows) in the glomerular capillaries match the spaces between the podocytes “finger,” the only thing separating the capillary lumen and the lumen of the Bowman’s capsule is their shared basement membrane. These features comprise what is known as the filtration membrane. The filtration membrane permits very rapid movement of filtrate from capillary to capsule through pores. The fenestrations prevent the filtration of blood cells or large proteins but are highly permeable to most other constituents. These substances cross readily if they are less than 4 nm in size and most pass freely up to 8 nm in size. Since glucose is roughly 1 nm in size, it will readily pass through the filtration membrane. An additional factor affecting the ability of substances to cross this barrier is their electrical charge. The proteins associated with the pores are negatively charged so they tend to repel negatively charged substances and allow positively charged substances to pass more readily. The basement membrane prevents the filtration of medium-to-large proteins such as globulins. There are also mesangial cells in the filtration membrane that can contract to help regulate the rate of filtration of the glomerulus.

Overall, filtration is regulated by:

• Fenestrations in capillary endothelial cells
• Podocytes with filtration slits
• Membrane charge
• Basement membrane between capillary cells

The result is the creation of a filtrate that does not contain cells or large proteins and has a slight predominance of positively charged substances.

Figure 25.14 Podocytes (OpenStax)

The glomerular filtration rate (GFR) is defined as the amount of filtrate formed in all renal corpuscles of both kidneys each minute. The GFR is an important readout of kidney function and it is important to maintain a relatively constant GFR. In males, the average GFR is 125 mL/min and in females the average GFR is 105 mL/min. GFR is influenced by the hydrostatic pressure and colloid osmotic pressure on either side of the glomerular capillary membrane. Filtration occurs as pressure forces fluid through a semipermeable barrier with the solute movement constrained by particle size. Hydrostatic pressure is the pressure produced by a fluid against a surface. If you have fluid on both sides of a barrier, both fluids will exert hydrostatic pressure against the barrier. The net fluid movement will be in the direction of the lower pressure. When a solute in a solution is impermeable across a membrane, water will move by osmosis. If a concentration gradient exists across the membrane, water will move. The solute concentration gradient creates a pressure (osmotic pressure) that encourages water to move by osmosis across the membrane from an area of low solute concentration to an area of high solute concentration. Osmosis continues until the solute concentration is the same on both sides of the membrane. Glomerular filtration occurs when the hydrostatic pressure in the glomerulus (glomerular hydrostatic pressure) exceeds the luminal hydrostatic pressure of the Bowman’s capsule. Since the filtration membrane limits the size of particles crossing the membrane, the osmotic pressure inside the glomerular capillary is higher than the osmotic pressure in Bowman’s capsule.

Recall that cells and medium-to-large proteins cannot pass through the filtration membrane. This means that red and white blood cells, platelets, albumins, and other proteins too large to pass through the filter remain in the capillary, creating an average colloid osmotic pressure of 30 mm Hg within the capillary. The absence of proteins in Bowman’s space (the lumen within Bowman’s capsule) results in an osmotic pressure near zero. Thus, the only pressure moving fluid across the capillary wall into the lumen of Bowman’s space is hydrostatic pressure. Hydrostatic pressure is sufficient to push water through the membrane despite the osmotic pressure working against it. The sum of all the influences, both osmotic and hydrostatic, results in a net filtration pressure (NFP) of about 10 mm Hg.

Figure 25.15: Net Filtration Pressure (OpenStax)

GFR is also regulated by the kidneys themselves (autoregulation), signals from the nervous system, and hormones. Regulation of GFR ensures efficient blood flow through the kidney. GFR determines:

• How much solute is retained or discarded
• How much water is reabsorbed or discarded
• The osmolarity of blood
• The blood pressure of the body

Autoregulation of GFR

The kidneys are highly effective at regulating the rate of blood flow over a wide range of blood pressures. Blood pressure decreases while relaxed or sleeping, and increases when exercising. Despite these changes, filtration rates change little. This is due to two autoregulatory mechanisms, meaning that it operates without outside influences. The two mechanisms are called the myogenic mechanism and the tubuloglomerular feedback mechanism.

The myogenic mechanism regulates blood flow through the kidney based on characteristics shared by most smooth muscles within the body. When a smooth muscle is stretched, it will contract. When smooth muscle stops being stretched, it relaxes and returns to resting length. This characteristic of smooth muscle occurs in the afferent arteriole, the mechanism of which is described below. Recall that the afferent arteriole supplies blood to the glomerulus.

• Blood pressure increases → smooth muscle cells of the afferent arteriole stretches → smooth muscle contracts (vasoconstriction) to resist the increased pressure → little change in the blood flow → minimized change in GFR
• Blood pressure decreases → smooth muscle cells relax → vasodilation results in lowers resistance → maintains the blood flow → minimized change in GFR

The tubuloglomerular feedback mechanism involves the juxtaglomerular apparatus (JGA) that lies just outside the Bowman’s capsule (Figure 25.16). At the juncture where the afferent and efferent arterioles enter and leave the Bowman’s capsule, the initial part of the DCT meets with the arterioles. The wall of the DCT at that point forms a part of the JGA known as the macula densa. The cells of the macula densa monitor the flow rate and Na+ concentration of the filtrate flowing through the DCT.

The second type of cell in this apparatus is the juxtaglomerular cell. These cells are modified smooth muscle cells that line the afferent arteriole. Depending on the flow rate and solute concentration of the filtration in the DCT, macula densa cells secrete signals that control the contraction and relaxation of the juxtaglomerular cells. Such contraction and relaxation regulate the blood flow to the glomerulus.

• If the osmolarity of the filtrate is too high (hyperosmotic), the juxtaglomerular cells will contract, decreasing the GFR causing less plasma to be filtered leading to less urine formation and greater fluid retention. This decreases the blood osmolarity back to homeostatic levels.
• If the osmolarity of the filtrate is too low, the juxtaglomerular cells relax, increasing the GFR and therefore enhancing the loss of water to urine and causing blood osmolarity to rise.
• Osmolarity increases → filtration and urine formation decreases → water retained
• Osmolarity decreases → filtration and urine formation increases → water excreted via urine

The result of these opposing actions is to keep the rate of filtration constant.

Figure 25.16 Juxtaglomerular apparatus (OpenStax)

Nervous System Regulation of GFR

The kidneys are innervated by the sympathetic neurons of the autonomic nervous system. We learned in the chapter on the autonomic nervous system that sympathetic stimulation decreases kidney function. Reduction of the sympathetic stimulation results in vasodilation and increased blood flow through the kidneys at rest. Under the sympathetic stimulation, the arteriolar smooth muscle constricts, resulting in decreased flow of blood to the glomerulus and in turn less filtration. Under stressful conditions, sympathetic nervous activity increases resulting in the direct vasoconstriction of the afferent arterioles which reduces the amount of blood flowing through the kidneys.

Hormonal Regulation of GFR

Several hormones play important roles in regulating kidney function. These hormones act to stimulate or inhibit blood flow. Here we discuss angiotensin II and atrial natriuretic peptide (ANP), but note that other hormones play a role in regulating kidney function. Angiotensin II is a vasoconstrictor that narrows both the afferent and efferent arterioles which reduce blood flow and decreases GFR. ANP is secreted by cells within the heart when blood volume increases. ANP will cause relaxation of the glomerular cells and increase GFR by increasing the surface area.

Tubular Reabsorption and Secretion

Approximately 180 liters per day pass through the nephron, therefore, most of the fluid and its contents need to be reabsorbed back into the bloodstream or secreted into the filtrate and expelled as urine. The different portions of the nephron differ in their capacity to reabsorb water and specific solutes. Solutes that are reabsorbed into the bloodstream include glucose, amino acids, urea, and ions, such as sodium (Na+), potassium (K+), calcium (Ca2+), chloride (Cl-), HCO3- (bicarbonate), and HPO24- (phosphate). Secreted substances include hydrogen ions (H+), K+, ammonium ions (NH4+), creatinine, and certain drugs such as penicillin. Tubular secretion is important because the secretion of H+ helps control blood pH. Secretion also helps to eliminate wastes in the body such as urine.

While much of the reabsorption and secretion occur passively based on concentration gradients, the amount of water that is reabsorbed or lost is tightly regulated. Water movement is controlled by antidiuretic hormone (ADH) and aldosterone.

Figure 25.17: Locations of Secretion and Reabsorption in the Nephron (OpenStax)

Proximal Convoluted Tubule

The renal corpuscle filters plasma to create filtrate that differs from the blood by the absence of cells and large proteins. Reabsorption returns 99% of the filtrate volume to the cardiovascular system as plasma. Most of this reabsorption occurs in the PCT.

Sodium-ion (Na+) is actively pumped out of the PCT into the interstitial spaces between cells and diffuses down its concentration gradient into the peritubular capillaries. As it does so, water will follow due to osmotic pressure. This movement is termed obligatory water reabsorption because water is “obliged” to follow the Na+. Generally speaking, ⅔ of all water and sodium reabsorption occurs in the PCT.

Molecules like glucose and amino acids are cotransported with Na+ by symporters, which are membrane proteins that perform secondary active transport. Almost 100 percent of the glucose, amino acids, and other organic substances are reabsorbed. Some glucose may appear in the urine if the circulating glucose levels are high enough that all the glucose transporters in the PCT are saturated. This means that the capacity to reabsorb glucose has been reached (transport maximum). An exceptionally high sugar intake might cause sugar to appear briefly in urine. The appearance of glucose in urine is termed glycosuria and usually indicates diabetes mellitus.

Reabsorption of bicarbonate (HCO3-) is important for the maintenance of acid-base balance within the body. Recall the equation: HCO3− + H+ ↔ H2CO3 ↔ CO2 + H2O. Carbonic anhydrase (CA) is an important enzyme that catalyzes this reaction. As we already learned previously, CA is found in red blood cells, the stomach, and the pancreas. In the kidney, CA is located within the tubular cells and on the luminal membrane (Figure 25.18). In the lumen of the PCT, HCO3- combines with H+ to form carbonic acid (H2CO3). This is enzymatically catalyzed into CO2 and water, which diffuse across the apical membrane into the tubular cell. Water can osmotically move across the lipid bilayer membrane due to the presence of aquaporin channels. Inside the cell, the reverse reaction occurs to produce HCO3-. These HCO3- are cotransported with Na+ across the basal membrane into the interstitial space around the PCT. At the same time this is occurring H+ is excreted into the lumen. These hydrogen ions are recycled so that HCO3- can be reabsorbed and used as a buffer in the body.

Figure 25.18: Reabsorption of Bicarbonate from the PCT (Openstax)

Loop of Henle

The loop of Henle consists of two sections: thick and thin descending and thick and thin ascending sections. Recall that the loops of cortical nephrons do not extend far into the renal medulla, if at all. Juxtamedullary nephrons have loops that extend variable distances, some very deep into the medulla. The descending and ascending portions of the loop are highly specialized to enable the recovery of much of the Na+ and water that were filtered by the glomerulus. As the filtrate moves through the loop, the osmolarity will change from isosmotic with blood to both a very hypertonic solution and a very hypotonic solution. These changes are accomplished by osmosis in the descending limb and active transport in the ascending limb. Solutes and water recovered from these loops are returned to circulation by way of the vasa recta.

The cells of the descending loop have membranes with permanent aquaporin channel proteins that allow unrestricted movement of water from the descending loop into the surrounding interstitium. The osmolarity of the interstitium surrounding the descending loop increases as the loop dips deeper into the renal medulla, and water continues to move out of the descending loop (Figure 25.19). This water movement results in the reabsorption of up to 15 percent of the water entering the nephron. Most of the solutes that were filtered in the glomerulus have now been reabsorbed along with most of the water.

The ascending loop thick portion is completely impermeable to water due to the absence of aquaporin proteins. But, ions such as Na+ and Cl- are actively reabsorbed via a cotransport system. This reabsorption creates a hypoosmotic filtrate by the time it reaches the DCT.

The structure of the loop of Henle and associated vasa recta create a countercurrent multiplier system. The term countercurrent term comes from the fact that the descending and ascending loops are next to each other and their fluid flows in opposite directions (countercurrent). The multiplier term is due to the action of the solute pumps that increase (multiply) the concentrations of urea and Na+ deep in the medulla.

Ammonia (NH3) is a toxic byproduct of protein metabolism. Most of the resulting ammonia is converted into urea by the liver. Urea is utilized to aid in the recovery of water by the loop of Henle and collecting ducts. At the same time, water is freely diffusing out of the descending loop, urea freely diffuses into the lumen of the descending loop as it descends deeper into the medulla. Most urea in the filtrate will be reabsorbed when they reach the collecting duct, and the remaining urea in the filtrate will be eliminated as urine. Thus, the movement of Na+ and urea into the interstitial spaces by these mechanisms creates the hyperosmotic environment of the medulla. The net result of this countercurrent multiplier system is to recover both water and Na+ in the circulation.

Figure 25.19 Countercurrent Multiplier System (OpenStax)

Distal Convoluted Tubule

Approximately 80 percent of filtered water has been recovered by the time the dilute urine enters the DCT. The DCT will recover another 10-15 percent of the filtrate. The hormone aldosterone increases the amount of Na+/K+ ATPase in the basal membrane of the DCT and the collecting duct. The movement of Na+ out of the lumen of the collecting duct creates a negative charge that promotes the movement of Cl- out of the lumen into the interstitial space. Cells within the DCT also recover Ca2+ from the filtrate. The DCT cells have receptors for parathyroid hormone (PTH). When PTH binds to these receptors, calcium channels are inserted into the luminal surface of the tubule. The channels enhance Ca2+ reabsorption. Calcitriol is another hormone that is particularly important for calcium recovery.

Collecting Ducts and Recovery of Water

Two distinct cell types make up the collecting ducts. The principal cells possess channels for the recovery or loss of sodium and potassium. Intercalated cells secrete or absorb acid or bicarbonate and play significant roles in regulating blood pH. Intercalated cells reabsorb K+ and HCO3- while secreting H+. This function lowers the acidity of the plasma while increasing the acidity of urine.

Figure 25.20 Illustration of Principal and Intercalated cells

Regulation of urine volume and osmolarity are major functions of the collecting ducts. By varying the amount of water that is recovered, the collecting ducts play a major role in maintaining the body’s normal osmolarity. If the blood becomes too hyperosmotic, the collecting ducts recover more water to dilute the blood. If the blood becomes hyposmotic, the collecting ducts recover less water, leading to the concentration of the blood.

• Plasma osmolarity increases → more water reabsorbed → urine volume decreases
• Plasma osmolarity decreases → less water reabsorbed → urine volume increases

The amount of water reabsorbed at the collecting ducts is regulated by the posterior pituitary hormone ADH (antidiuretic hormone). With mild dehydration, plasma osmolarity rises slightly. This increase is detected by osmoreceptors in the hypothalamus, which stimulates the release of ADH from the posterior pituitary. If plasma osmolarity decreases slightly, the opposite occurs.

When stimulated by ADH, aquaporin channels are inserted into the membrane of principal cells which line the collecting ducts. As the ducts descend through the medulla, the osmolarity surrounding them increases due to the countercurrent mechanism. If aquaporin channels are present, water will osmotically be pulled from the collecting duct into the surrounding interstitial space and peritubular capillaries. Therefore, the final urine will be more concentrated. If less ADH is secreted, fewer aquaporin channels are inserted and less water is recovered, resulting in dilute urine. Altering the number of aquaporin channels alters the amount of water recovered or lost. This regulates blood osmolarity, blood pressure, and osmolarity of urine.

As Na+ is pumped from the filtrate, water is passively recaptured for circulation. The preservation of vascular volume is important for the maintenance of normal blood pressure. Aldosterone is secreted by the adrenal cortex in response to angiotensin II stimulation. Angiotensin II is a vasoconstrictor that functions to increase blood pressure. It also stimulates aldosterone production and provides a longer-lasting mechanism to support blood pressure by maintaining water recovery (reabsorption). Principal cells of the collecting ducts also have receptors for aldosterone in addition to ADH. Aldosterone causes increased Na+ reabsorption and greater loss of K+.

• Aldosterone increases → more Na+ is reabsorbed (water follows passively) → K+ is secreted into the filtrate
• Aldosterone decreases → Na+ remains in the filtrate → K+ is reabsorbed into circulation

Composition of Normal Urine

The blood entering the glomeruli of the kidneys is filtered according to particle size. Large particles, such as blood cells, platelets, and larger proteins (e.g. antibodies and albumin) are excluded from the filtrate. The urinary system produces about 200 liters (189 quarts) of this filtrate every day.

The nephron is also responsible for reabsorbing most of this volume before the filtrate becomes urine. Typically, less than two liters of urine a day is formed from the filtrate. Water accounts for nearly 95% of urine volume. The remaining 5% consists of electrolytes, nitrogenous wastes such as urea (from protein metabolism), creatinine (from breakdown of creatine phosphates in muscles), uric acid (from nucleic acid metabolism), and other substances secreted by the nephron.

Characteristics of urine vary, depending on fluid and food intake, exercise, and temperature in a healthy individual. They can also provide clues to renal disease and other health conditions. Urinalysis is a test that examines the visual, chemical, and microscopic characteristics of urine. This test can reveal a lot about the state of your body.

The major characteristics of normal urine are summarized in the table below.

Table 25.1 Normal Urine Characteristics

The normal urine volume varies within the range of one to two liters a day, but the kidneys must produce a minimum urine volume of 500 mL per day to rid the body of waste products. Urine output below 500 mL/day is called oliguria and may be caused by severe dehydration or renal disease. The output below 50 mL/day is called anuria (absence of urine production) and is caused by kidney failure or obstruction of the path of urine such as a kidney stone or tumor. Polyuria is excessive urine production and may be due to diabetes mellitus or diabetes insipidus.

The color of urine is determined mostly by the yellow pigment called urochrome. Dehydration produces darker, concentrated urine. Urine color may also be affected by certain foods like beets, berries, and fava beans. Bleeding from a kidney stone, a cancer of the urinary system, or UTIs may result in pink or red urine. Diseases of the liver or obstructions of bile drainage impart a dark “tea” or “cola” hue to the urine.

Figure 25.21: Urine Color (OpenStax)

Most of the ammonia produced from protein breakdown is converted into urea by the liver, so ammonia is rarely detected in fresh urine in a healthy person. The strong ammonia odor you may detect in bathrooms or alleys is due to the breakdown of urea in voided urine into ammonia by bacteria in the environment. Consuming foods such as asparagus can import a distinctive odor in urine in a healthy person, but these food-caused odors are harmless. In diabetes mellitus, the presence of ketone bodies produces a slightly aromatic fruity odor.

The pH (hydrogen ion concentration) of the urine can vary from a normal low of 4.5 to a maximum of 8.0. Diet can influence pH; meats lower the pH, whereas citrus fruits, vegetables, and dairy products raise the pH. Chronically high or low pH can lead to disorders, such as the development of kidney stones (renal calculi) or osteomalacia.

Specific gravity is also called relative density and is the ratio of the density of a substance (in this case, urine) to the density of a reference substance (in this case, pure water). Urine will always have a specific gravity greater than pure water due to the presence of solutes. The higher the concentration of solutes in urine, the higher will be its specific gravity. Laboratories can now measure urine osmolarity directly, which is a more accurate indicator of urinary solutes than specific gravity. Osmolarity, also known as osmotic concentration, is the measure of solute concentration defined as the number of osmoles of solutes per liter of fluid (mOsmol/L). Urine osmolarity ranges from a low of 50–100 mOsmol/L to as high as 1200 mOsmol/L H2O.

Cells are not normally found in urine. The presence of erythrocytes in urine is called hematuria and indicates inflammation from UTIs, tumors, trauma, kidney stones, and kidney diseases. Blood may also appear in the urine as a result of menstruation contamination. As we learned in the immune system chapter, leukocytes (also known as white blood cells) engage in fighting pathogens in the body. The presence of leukocytes may indicate a urinary tract infection. Leukocyte esterase is released by leukocytes; if detected in the urine, it can be taken as indirect evidence of a urinary tract infection (UTI). The presence of leukocytes and other components of pus in the urine is referred to as pyuria.

Protein does not normally leave the glomerular capillaries, so only trace amounts of protein should be found in the urine. Albumin is a plasma protein. If excessive albumin is detected in the urine, it usually means that the glomerulus is damaged and is allowing protein to “leak” into the filtrate. This is called albuminuria.

Bilirubin and urobilinogen are the breakdown products of red blood cell destruction. Recall the chapters on the blood and digestive system [could insert links to those chapters here?], where you learned that in the liver the “heme” of hemoglobin is converted into bilirubin and excreted into bile. In the intestines, bilirubin in bile is converted to urobilinogen. Some urobilinogens are absorbed by the intestinal cells and transported into the kidneys, while the rest are excreted in feces. The urochrome that gives the yellow color of urine is a metabolite of urobilinogen. Urine does not normally contain bilirubin or if it does, only a trace amount is present. The presence of above-normal levels of bilirubin and urobilinogen in urine are called bilirubinuria and urobilinogenuria, respectively, and indicate liver disease.

As you learned earlier, glucose is reabsorbed in the nephron and not present in normal urine. The presence of glucose in urine is called glucosuria and usually indicates diabetes mellitus. High levels of ketone bodies in urine is called ketonuria and is also an indication of diabetes mellitus. Ketone bodies are byproducts of fat metabolism and usually suggest that the body is using fat as an energy source. In diabetes mellitus, the cells cannot take up glucose, either due to the lack of insulin (type 1 diabetes mellitus) or because of insulin resistance (type 2 diabetes mellitus), and are forced to break down fat as their energy source. This results in the presence of high levels of glucose and ketone bodies in plasma, and both end up appearing in the urine. Ketone bodies may also appear because of diets with insufficient proteins or carbohydrates, such as fasting, starvation, or a low-carbohydrate, ketogenic diet.

Nitrates (NO3–) occur normally in the urine. Because nitrate is metabolized into nitrite (NO2–) by some Gram-negative bacteria that commonly cause UTIs, the presence of nitrite in the urine is indirect evidence of infections.

Masses of proteins and cells can build up in the nephron tubules, harden, and be flushed out as cylindrical particles called urinary casts, that are visible under a microscope. Casts are named after their appearance (e.g., waxy cast) or their composition (e.g., white blood cell casts and epithelial cell casts). While some casts are present in normal urine, others indicate kidney disease.

Diabetes is a common disease that can be diagnosed by a urinalysis. If a person has diabetes, what test values of their urinalysis would you expect to be abnormal? Would those values be higher or lower than normal? Why is it higher?

Creatinine Clearance Test

The glomerular filtration rate (GFR) can be determined by the creatinine clearance test. Creatinine is a waste product of muscle metabolism present in plasma. Because it is easily filtered, the levels of creatinine in blood and urine can be used to measure the GFR of the patient’s kidney. Creatinine clearance is the volume of blood plasma cleared of creatinine per unit time which is a reflection of kidney filtration. Other substances can be used to measure GFR. Some of these substances may also be reabsorbed or secreted by the nephron which must be considered when performing calculations.

Renal calculi

Dialysis

25.6 Hormones and the Kidney

All systems of the body are interrelated. The urinary system not only filters blood and regulates what we retain in or eliminate from the body, but it also produces hormones that are important in other functions of the body such as bone metabolism and blood formation.

Vitamin D Synthesis

The kidneys produce calcitriol (an active form of vitamin D known as 1,25-dihydroxycholecalciferol) by chemically modifying a vitamin D molecule. Calcitriol is important for the absorption of calcium ions (Ca2+) and phosphorus in the digestive tract to maintain the levels of plasma Ca2+ and phosphorus. Calcium is not only important for bone health, but also required for muscle contraction, blood clotting, hormone secretion, and neurotransmitter release. Insufficient levels of Ca2+ leads to disorders like osteomalacia and rickets.

Erythropoiesis

The kidneys are the main producer of the hormone erythropoietin (EPO) which stimulates the formation of red blood cells in the bone marrow. Erythropoiesis is a process that produces red blood cells (erythrocytes) from the hematopoietic stem cells in the red bone marrow. EPO increases the number of red blood cell precursors. The kidneys will secrete more EPO when the partial pressure of oxygen is low (e.g. high altitude, exercise) or loss of erythrocytes from severe bleeding. This is why renal failure is associated with anemia which makes it difficult for the body to supply oxygen adequately even under normal conditions and can be life threatening.

Chapter Summary

Citation

1. https://www.cdc.gov/antibiotic-use/uti.html
2. https://medlineplus.gov/urinarytractinfections.html
3. https://www.merckmanuals.com/professional/multimedia/table/urinary-casts
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392553/
5. https://health.hawaii.gov/diabetes/diabetes-prevention-and-control-program/complications/
6. https://www.niddk.nih.gov/health-information/kidney-disease/kidney-failure/hemodialysis
7. https://www.niddk.nih.gov/health-information/urologic-diseases/kidney-stones
8. Woolf AS, Thiruchelvam N. Congenital obstructive uropathy: its origin and contribution to end-stage renal disease in children. Adv Ren Replace Ther. 2001 Jul;8(3):157-63. doi: 10.1053/jarr.2001.26348. PMID: 11533916.

Key Terms

albuminuria  

excessive albumin detected in the urine

afferent arterioles 

division of the adiate arteries that supply blood to about 1.3 million nephrons each in the kidney

angiotensin II

protein produced by the enzymatic action of ACE on inactive angiotensin I; actively causes vasoconstriction and stimulates aldosterone release by the adrenal cortex

anuria

absence of urine produced; production of 50 mL or less per day

arcuate arteries 

division of the interlobar arteries

aquaporin

protein-forming water channels through the lipid bilayer of the cell; allows water to cross; activation in the collecting ducts is under the control of ADH

Bowman’s capsule

cup-shaped sack lined by a simple squamous epithelium (parietal surface) and specialized cells called podocytes (visceral surface) that participate in the filtration process; receives the filtrate which then passes on to the PCTs

calyces

cup-like structures receiving urine from the collecting ducts where it passes on to the renal pelvis and ureter

cortical nephrons

nephrons with loops of Henle that do not extend into the renal medulla

countercurrent multiplier system

involves the descending and ascending loops of Henle directing forming urine in opposing directions to create a concentration gradient when combined with variable permeability and sodium pumping

detrusor muscle

smooth muscle in the bladder wall; fibers run in all directions to reduce the size of the organ when emptying it of urine

dialysis process to artificially filter blood

efferent arteriole

arteriole carrying blood from the glomerulus to the capillary beds around the convoluted tubules and loop of Henle; portion of the portal system

external urethral orifice 

opening of the urethra to the exterior located between the clitoris and the vaginal opening

fenestrations

small windows through a cell, allowing rapid filtration based on size; formed in such a way as to allow substances to cross through a cell without mixing with cell contents

filtration 

the first step in the production of urine. Water and solutes in the blood plasma move across the walls of the glomerular capillaries and move into the renal tubules

filtration slits

formed by pedicels of podocytes; substances filter between the pedicels based on size

glomerular filtration rate (GFR)

rate of renal filtration

glomerulus

tuft of capillaries surrounded by Bowman’s capsule; filters the blood based on size

glycosuria

presence of glucose in the urine; caused by high blood glucose levels that exceed the ability of the kidneys to reabsorb the glucose; usually the result of untreated or poorly controlled diabetes mellitus

Hematuria

presence of erythrocytes in urine

incontinence

loss of ability to control micturition

intercalated cell

specialized cell of the collecting ducts that secrete or absorb acid or bicarbonate; important in acid–base balance

interlobar arteries division of the segmental arteries that pass through the renal columns to reach the cortex

internal urinary sphincter

smooth muscle at the juncture of the bladder and urethra; relaxes as the bladder fills to allow urine into the urethra

juxtaglomerular apparatus (JGA)

located at the juncture of the DCT and the afferent and efferent arterioles of the glomerulus; plays a role in the regulation of renal blood flow and GFR

juxtaglomerular cell

modified smooth muscle cells of the afferent arteriole; secretes renin in response to a drop in blood pressure

juxtamedullary nephrons

nephrons adjacent to the border of the cortex and medulla with loops of Henle that extend into the renal medulla

kidneys 

main organ of the urinary system where blood is filtered, and the filtrate is transformed into urine at a constant rate throughout the day

ketonuria 

high levels of ketone bodies in urine

leukocyte esterase

enzyme produced by leukocytes that can be detected in the urine and that serves as an indirect indicator of urinary tract infection

loop of Henle

descending and ascending portions between the proximal and distal convoluted tubules; those of cortical nephrons do not extend into the medulla, whereas those of juxtamedullary nephrons do extend into the medulla

macula densa

cells found in the part of the DCT forming the JGA; sense Na+ concentration in the forming urine

medulla

inner region of kidney containing the renal pyramids

membranous urethra 

portion of male urethra that passes through the deep muscles of the perineum 

mesangial

contractile cells found in the glomerulus; can contract or relax to regulate filtration rate

micturition

also called urination or voiding

myogenic mechanism

mechanism by which smooth muscle responds to stretch by contracting; an increase in blood pressure causes vasoconstriction and a decrease in blood pressure causes vasodilation so that blood flow downstream remains steady

nephrons

functional units of the kidney that carry out all filtration and modification to produce urine; consist of renal corpuscles, proximal and distal convoluted tubules, and descending and ascending loops of Henle; drain into collecting ducts

net filtration pressure (NFP)

pressure of fluid across the glomerulus; calculated by taking the hydrostatic pressure of the capillary and subtracting the colloid osmotic pressure of the blood and the hydrostatic pressure of Bowman’s capsule

oliguria

below normal urine production of 400–500 mL/day

osteomalacia

softening of bones due to a lack of mineralization with calcium and phosphate; most often due to lack of vitamin D; in children, osteomalacia is termed rickets; not to be confused with osteoporosis

pedicels

finger-like projections of podocytes surrounding glomerular capillaries; interdigitate to form a filtration membrane

peritubular capillaries

second capillary bed of the renal portal system; surround the proximal and distal convoluted tubules; associated with the vasa recta

podocytes

cells forming finger-like processes; form the visceral layer of Bowman’s capsule; pedicels of the podocytes interdigitate to form a filtration membrane

polyuria

urine production in excess of 2.5 L/day; may be caused by diabetes insipidus, diabetes mellitus, or excessive use of diuretics

principal cell

found in collecting ducts and possess channels for the recovery or loss of sodium and potassium; under the control of aldosterone; also have aquaporin channels under ADH control to regulate recovery of water

prostatic urethra 

portion of male urethra that passes through the prostate gland

pyuria 

presence of leukocytes and other components of pus in the urine

Reabsorption 

occurs throughout the nephron tubules through to the collecting ducts. Reabsorption is the process where water and solutes return to the blood as it flows through the peritubular capillaries and vasa recta

Renal artery 

large blood vessel that brings blood into the kidney

renal columns

extensions of the renal cortex into the renal medulla; separates the renal pyramids; contains blood vessels and connective tissues

renal corpuscle

consists of the glomerulus and Bowman’s capsule

renal cortex

outer part of kidney containing all of the nephrons; some nephrons have loops of Henle extending into the medulla

renal fat pad

adipose tissue between the renal fascia and the renal capsule that provides protective cushioning to the kidney

renal hilum

recessed medial area of the kidney through which the renal artery, renal vein, ureters, lymphatics, and nerves pass

renal papillae

medullary area of the renal pyramids where collecting ducts empty urine into the minor calyces

renal pyramids

six to eight cone-shaped tissues in the medulla of the kidney containing collecting ducts and the loops of Henle of juxtamedullary nephrons

renin

enzyme produced by juxtaglomerular cells in response to decreased blood pressure or sympathetic nervous activity; catalyzes the conversion of angiotensinogen into angiotensin I

retroperitoneal

behind the peritoneum; in the case of the kidney and ureters, between the parietal peritoneum and the abdominal wall

secretion 

occurs throughout the nephron tubules to the collecting ducts. Secretion is the process where materials such as wastes, drugs, and excess ions are released from the blood into the filtrate within the tubules

segmental arteries 

division of the renal artery

specific gravity

weight of a liquid compared to pure water, which has a specific gravity of 1.0; any solute added to water will increase its specific gravity

spongy urethra 

longest portion of the male urethra that passes through the penis and exits at the tip of the penis

trigone

area at the base of the bladder marked by the two ureters in the posterior–lateral aspect and the urethral orifice in the anterior aspect oriented like points on a triangle

tubuloglomerular feedback

feedback mechanism involving the JGA; macula densa cells monitor Na+ concentration in the terminal portion of the ascending loop of Henle and act to cause vasoconstriction or vasodilation of afferent and efferent arterioles to alter GFR

Ureters 

transport urine from the kidneys to the urinary bladder

urethra

transports urine from the bladder to the outside environment

urinary bladder 

temporarily stores urine until it is ready to be eliminated

urinary tract

contains the kidneys, ureter, urinary bladder, and urethra. Transport, store, and eliminate urine from the body

urinalysis

analysis of urine to diagnose disease

urochrome

heme-derived pigment that imparts the typical yellow color of urine

vasa recta

branches of the efferent arterioles that parallel the course of the loops of Henle and are continuous with the peritubular capillaries; with the glomerulus, form a portal system