The Kidneys and the Urinary Tract

Urine is a fluid of variable composition that requires specialized structures to remove it from the body safely and efficiently. Blood is filtered, and the filtrate is transformed into urine at a relatively constant rate throughout the day, where it is stored until a convenient time for excretion. All structures involved in the transport and storage of the urine are large enough to be visible to the naked eye. This transport and storage system not only stores the waste, but it protects the tissues from damage due to the wide range of pH and osmolarity of the urine, prevents infection by foreign organisms, and for the male, provides reproductive functions.

Urethra

The urethra transports urine from the bladder to the outside of the body for disposal. The urethra is the only urologic organ that shows any significant anatomic difference between males and females; all other urine transport structures are identical.

Figure 1: The urethra transports urine from the bladder to the outside of the body. This image shows (a) a female urethra and (b) a male urethra.

The urethra in both males and females begins inferior and central to the two ureteral openings forming the three points of a triangular-shaped area at the base of the bladder called the trigone (Greek tri- = “triangle” and the root of the word “trigonometry”). The urethra tracks posterior and inferior to the pubic symphysis. In both males and females, the proximal urethra is lined by transitional epithelium, whereas the terminal portion is a nonkeratinized, stratified squamous epithelium. In the male, pseudostratified columnar epithelium lines the urethra between these two cell types. Voiding is regulated by an involuntary autonomic nervous system-controlled internal urinary sphincter, consisting of smooth muscle and voluntary skeletal muscle that forms the external urinary sphincter below it.

Female Urethra

The external urethral orifice is embedded in the anterior vaginal wall inferior to the clitoris, superior to the vaginal opening (introitus), and medial to the labia minora. Its short length, about 4 cm, is less of a barrier to fecal bacteria than the longer male urethra and the best explanation for the greater incidence of UTI in women. Voluntary control of the external urethral sphincter is a function of the pudendal nerve. It arises in the sacral region of the spinal cord, traveling via the S2–S4 nerves of the sacral plexus.

Male Urethra

The male urethra passes through the prostate gland immediately inferior to the bladder before passing below the pubic symphysis. The length of the male urethra varies between men but averages 20 cm in length. It is divided into four regions: the preprostatic urethra, the prostatic urethra, the membranous urethra, and the spongy or penile urethra. The preprostatic urethra is very short and incorporated into the bladder wall. The prostatic urethra passes through the prostate gland. During sexual intercourse, it receives sperm via the ejaculatory ducts and secretions from the seminal vesicles. Paired Cowper’s glands (bulbourethral glands) produce and secrete mucus into the urethra to buffer urethral pH during sexual stimulation. The mucus neutralizes the usually acidic environment and lubricates the urethra, decreasing the resistance to ejaculation. The membranous urethra passes through the deep muscles of the perineum, where it is invested by the overlying urethral sphincters. The spongy urethra exits at the tip (external urethral orifice) of the penis after passing through the corpus spongiosum. Mucous glands are found along much of the length of the urethra and protect the urethra from extremes of urine pH. Innervation is the same in both males and females.

Bladder

The urinary bladder collects urine from both ureters. The bladder lies anterior to the uterus in females, posterior to the pubic bone and anterior to the rectum. During late pregnancy, its capacity is reduced due to compression by the enlarging uterus, resulting in increased frequency of urination. In males, the anatomy is similar, minus the uterus, and with the addition of the prostate inferior to the bladder. The bladder is partially retroperitoneal (outside the peritoneal cavity) with its peritoneal-covered “dome” projecting into the abdomen when the bladder is distended with urine.

Figure 2: (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)

The bladder is a highly distensible organ comprised of irregular crisscrossing bands of smooth muscle collectively called the detrusor muscle. The interior surface is made of transitional cellular epithelium that is structurally suited for the large volume fluctuations of the bladder. When empty, it resembles columnar epithelia, but when stretched, it “transitions” (hence the name) to a squamous appearance. Volumes in adults can range from nearly zero to 500–600 mL.

The detrusor muscle contracts with significant force in the young. The bladder’s strength diminishes with age, but voluntary contractions of abdominal skeletal muscles can increase intra-abdominal pressure to promote more forceful bladder emptying. Such voluntary contraction is also used in forceful defecation and childbirth.

Micturition Reflex

Micturition is the proper term for urination or voiding. It is controlled through an interplay of involuntary and voluntary actions by the internal and external urethral sphincters. When bladder volume reaches about 150 mL, an urge to void is sensed but is easily overridden. Voluntary control of urination relies on consciously preventing relaxation of the external urethral sphincter to maintain urinary continence. As the bladder fills, subsequent urges become harder to ignore. Ultimately, voluntary constraint fails with resulting incontinence, which will occur as bladder volume approaches 300 to 400 mL.

Normal micturition is a result of stretch receptors in the bladder wall that transmit nerve impulses to the sacral region of the spinal cord to generate a spinal reflex. The resulting parasympathetic neural outflow 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 muscle of the external urethral sphincter. The micturition reflex is active in infants but with maturity, children learn to override the reflex by asserting external sphincter control, thereby delaying voiding (potty training). This reflex may be preserved even in the face of spinal cord injury that results in paraplegia or quadriplegia. However, relaxation of the external sphincter may not be possible in all cases, and therefore, periodic catheterization may be necessary for bladder emptying.

Nerves involved in the control of urination include the hypogastric, pelvic, and pudendal (see figure 3 below). Voluntary micturition requires an intact spinal cord and functional pudendal nerve arising from the sacral micturition center. Since the external urinary sphincter is voluntary skeletal muscle, actions by cholinergic neurons maintain contraction (and thereby continence) during filling of the bladder. At the same time, sympathetic nervous activity via the hypogastric nerves suppresses contraction of the detrusor muscle. With further bladder stretch, afferent signals traveling over sacral pelvic nerves activate parasympathetic neurons. This activates efferent neurons to release acetylcholine at the neuromuscular junctions, producing detrusor contraction and bladder emptying.

Figure 3: Sagittal view of the bladder, pudendal nerve, and urinary tract anatomy is visible

Ureters

The kidneys and ureters are completely retroperitoneal, and the bladder has a peritoneal covering only over the dome. As urine is formed, it drains into the calyces of the kidney, which merge to form the funnel-shaped renal pelvis in the hilum of each kidney. The renal pelvis narrows to become the ureter of each kidney. As urine passes through the ureter, it does not passively drain into the bladder but rather is propelled by waves of peristalsis. As the ureters enter the pelvis, they sweep laterally, hugging the pelvic walls. As they approach the bladder, they turn medially and pierce the bladder wall obliquely. This is important because it creates an one-way valve (a physiological sphincter rather than an anatomical sphincter) that allows urine into the bladder but prevents reflux of urine from the bladder back into the ureter. Children born lacking this oblique course of the ureter through the bladder wall are susceptible to “vesicoureteral reflux,” which dramatically increases their risk of serious UTI. Pregnancy also increases the likelihood of reflux and UTI.

The ureters are approximately 30 cm long. The inner mucosa is lined with transitional epithelium and scattered goblet cells that secrete protective mucus. The muscular layer of the ureter consists of longitudinal and circular smooth muscles that create the peristaltic contractions to move the urine into the bladder without the aid of gravity. Finally, a loose adventitial layer composed of collagen and fat anchors the ureters between the parietal peritoneum and the posterior abdominal wall.

Figure 4: 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)

The Kidneys

The kidneys lie on either side of the spine in the retroperitoneal space between the parietal peritoneum and the posterior abdominal wall, well protected by muscle, fat, and ribs. They are roughly the size of a fist, and the male kidney is typically a bit larger than the female kidney. The kidneys are well vascularized, receiving about 25 percent of the cardiac output at rest.

External Anatomy

The left kidney is located at about the T12 to L3 vertebrae, whereas the right is lower due to slight displacement by the liver. Upper portions of the kidneys are somewhat protected by the eleventh and twelfth ribs. Each kidney weighs about 125–175 g in males and 115–155 g in females. They are about 11–14 cm in length, 6 cm wide, and 4 cm thick, and are directly covered by a fibrous capsule composed of dense, irregular connective tissue that helps to hold their shape and protect them. This capsule is covered by a shock-absorbing layer of adipose tissue called the renal fat pad, which in turn is encompassed by a tough renal fascia. The fascia and, to a lesser extent, the overlying peritoneum serve to firmly anchor the kidneys to the posterior abdominal wall in a retroperitoneal position.

Figure 5: The kidneys are slightly protected by the ribs and are surrounded by fat for protection (not shown).

On the superior aspect of each kidney is the adrenal gland. The adrenal cortex directly influences renal function through the production of the hormone aldosterone to stimulate sodium reabsorption.

Internal Anatomy

A frontal section through the kidney reveals an outer region called the renal cortex and an inner region called the medulla. The renal columns are connective tissue extensions that radiate downward from the cortex through the medulla to separate the most characteristic features of the medulla, the renal pyramids and renal papillae. The papillae are bundles of collecting ducts that transport urine made by nephrons to the calyces of the kidney for excretion. The renal columns also serve to divide the kidney into 6–8 lobes and provide a supportive framework for vessels that enter and exit the cortex. The pyramids and renal columns taken together constitute the kidney lobes.

Figure 6: Note the internal structures of the kidney

Renal Hilum

The renal hilum is the entry and exit site for structures servicing the kidneys: vessels, nerves, lymphatics, and ureters. The medial-facing hila are tucked into the sweeping convex outline of the cortex. Emerging from the hilum is the renal pelvis, which is formed from the major and minor calyxes in the kidney. The smooth muscle in the renal pelvis funnels urine via peristalsis into the ureter. The renal arteries form directly from the descending aorta, whereas the renal veins return cleansed blood directly to the inferior vena cava. The artery, vein, and renal pelvis are arranged in an anterior-to-posterior order.

Nephrons and Vessels

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, in turn, branch into arcuate arteries, cortical radiate arteries, and then into afferent arterioles. The afferent arterioles service about 1.3 million nephrons in each kidney.

Nephrons are the “functional units” of the kidney; they cleanse the blood and balance the constituents of the circulation. The afferent arterioles form a tuft of high-pressure capillaries about 200 µm in diameter, the glomerulus. The rest of the nephron consists of a continuous sophisticated tubule whose proximal end surrounds the glomerulus in an intimate embrace—this is Bowman’s capsule. The glomerulus and Bowman’s capsule together form the renal corpuscle. As mentioned earlier, these glomerular capillaries filter the blood based on particle size. After passing through the renal corpuscle, the capillaries form a second arteriole, the efferent arteriole. These will next form a capillary network around the more distal portions of the nephron tubule, the peritubular capillariesand 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 the circulation. Since a capillary bed (the glomerulus) drains into a vessel that in turn forms a second capillary bed, the definition of a portal system is met. This is the only portal system in which an arteriole is found between the first and second capillary beds. (Portal systems also link the hypothalamus to the anterior pituitary, and the blood vessels of the digestive viscera to the liver.)

Figure 7: The two capillary beds are clearly shown in this figure. The efferent arteriole is the connecting vessel between the glomerulus and the peritubular capillaries and vasa recta.

Cortex

In a dissected kidney, it is easy to identify the cortex; it appears lighter in color compared to the rest of the kidney. All of the renal corpuscles as well as both the proximal convoluted tubules (PCTs) and distal convoluted tubules are found here. Some nephrons have a short loop of Henle that does not dip beyond the cortex. These nephrons are called cortical nephrons. About 15 percent of nephrons have long loops of Henle that extend deep into the medulla and are called juxtamedullary nephrons.

Microscopic Anatomy of the Kidney

The renal structures that conduct the essential work of the kidney cannot be seen by the naked eye. Only a light or electron microscope can reveal these structures. Even then, serial sections and computer reconstruction are necessary to give us a comprehensive view of the functional anatomy of the nephron and its associated blood vessels.

Nephrons: The Functional Unit

Nephrons take a simple filtrate of the blood and modify it into urine. Many changes take place in the different parts of the nephron before urine is created for disposal. The term forming urine will be used hereafter to describe the filtrate as it is modified into true urine. The principle task of the nephron population is to balance the plasma to homeostatic set points and excrete potential toxins in the urine. They do this by accomplishing three principle functions—filtration, reabsorption, and secretion. They also have additional secondary functions that exert control in three areas: blood pressure (via production of renin), red blood cell production (via the hormone EPO), and calcium absorption (via conversion of calcidiol into calcitriol, the active form of vitamin D).

Renal Corpuscle

The renal corpuscle consists of a tuft of capillaries called the glomerulus that is largely surrounded by Bowman’s (glomerular) capsule. The glomerulus is a high-pressure capillary bed between afferent and efferent arterioles. Bowman’s capsule surrounds the glomerulus to form a lumen, and captures and directs this filtrate to the proximal convoluted tubule (PCT). The outermost part of Bowman’s capsule, the parietal layer, is a simple squamous epithelium. It transitions onto the glomerular capillaries in an intimate embrace to form the visceral layer of the capsule. Here, the cells are not squamous, but uniquely shaped cells (podocytes) extending finger-like arms (pedicels) to cover the glomerular capillaries. These projections interdigitate to form filtration slits, leaving small gaps 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 to be captured by Bowman’s capsule and funneled to the PCT. Where the fenestrae (windows) in the glomerular capillaries match the spaces between the podocyte “fingers,” the only thing separating the capillary lumen and the lumen of Bowman’s capsule is their shared basement membrane. These three features comprise what is known as the filtration membrane. This membrane permits very rapid movement of filtrate from capillary to capsule though pores that are only 70 nm in diameter.

Figure 8: Podocytes interdigitate with structures called pedicels and filter substances in a way similar to fenestrations. In (a), the large cell body can be seen at the top right corner, with branches extending from the cell body. The smallest finger-like extensions are the pedicels. Pedicels on one podocyte always interdigitate with the pedicels of another podocyte. (b) This capillary has three podocytes wrapped around it.

Figure 9: Fenestrations allow many substances to diffuse from the blood based primarily on size.

The fenestrations prevent filtration of blood cells or large proteins, but allow most other constituents through. These substances cross readily if they are less than 4 nm in size and most pass freely up to 8 nm in size. An additional factor affecting the ability of substances to cross this barrier is their electric charge. The proteins associated with these 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 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, and the 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.

Lying just outside Bowman’s capsule and the glomerulus is the juxtaglomerular apparatus (JGA). At the juncture where the afferent and efferent arterioles enter and leave Bowman’s capsule, the initial part of the distal convoluted tubule (DCT) comes into direct contact with the arterioles. The wall of the DCT at that point forms a part of the JGA known as the macula densa. This cluster of cuboidal epithelial cells monitors the fluid composition of fluid flowing through the DCT. In response to the concentration of Na⁺ in the fluid flowing past them, these cells release paracrine signals. They also have a single, nonmotile cilium that responds to the rate of fluid movement in the tubule. The paracrine signals released in response to changes in flow rate and Na⁺ concentration are adenosine triphosphate (ATP) and adenosine.

Figure 10: (a) 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 © 2012)

A second cell type in this apparatus is the juxtaglomerular cell. This is a modified, smooth muscle cell lining the afferent arteriole that can contract or relax in response to ATP or adenosine released by the macula densa. Such contraction and relaxation regulate blood flow to the glomerulus. If the osmolarity of the filtrate is too high (hyperosmotic), the juxtaglomerular cells will contract, decreasing the glomerular filtration rate (GFR) so less plasma is filtered, leading to less urine formation and greater retention of fluid. This will ultimately decrease blood osmolarity toward the physiologic norm. If the osmolarity of the filtrate is too low, the juxtaglomerular cells will relax, increasing the GFR and enhancing the loss of water to the urine, causing blood osmolarity to rise. In other words, when osmolarity goes up, filtration and urine formation decrease and water is retained. When osmolarity goes down, filtration and urine formation increase and water is lost by way of the urine. The net result of these opposing actions is to keep the rate of filtration relatively constant. A second function of the macula densa cells is to regulate renin release from the juxtaglomerular cells of the afferent arteriole. Active renin is a protein comprised of 304 amino acids that cleaves several amino acids from angiotensinogen to produce angiotensin I. Angiotensin I is not biologically active until converted to angiotensin II by angiotensin-converting enzyme (ACE) from the lungs. Angiotensin II is a systemic vasoconstrictor that helps to regulate blood pressure by increasing it. Angiotensin II also stimulates the release of the steroid hormone aldosterone from the adrenal cortex. Aldosterone stimulates Na⁺ reabsorption by the kidney, which also results in water retention and increased blood pressure.

Figure 11: The enzyme renin converts the pro-enzyme angiotensin I; the lung-derived enzyme ACE converts angiotensin I into active angiotensin II.

Proximal Convoluted Tubule (PCT)

Filtered fluid collected by Bowman’s capsule enters into the PCT. It is called convoluted due to its tortuous path. Simple cuboidal cells form this tubule with prominent microvilli on the luminal surface, forming a brush border. These microvilli create a large surface area to maximize the absorption and secretion of solutes (Na⁺, Cl^–, glucose, etc.), the most essential function of this portion of the nephron. These cells actively transport ions across their membranes, so they possess a high concentration of mitochondria in order to produce sufficient ATP.

Loop of Henle

The descending and ascending portions of the loop of Henle (sometimes referred to as the nephron loop) are, of course, just continuations of the same tubule. They run adjacent and parallel to each other after having made a hairpin turn at the deepest point of their descent. The descending loop of Henle consists of an initial short, thick portion and long, thin portion, whereas the ascending loop consists of an initial short, thin portion followed by a long, thick portion. The descending thick portion consists of simple cuboidal epithelium similar to that of the PCT. The descending and ascending thin portions consists of simple squamous epithelium. The differences in cell composition indicate the different permeabilities for solutes and water in the respective sections. The ascending thick portion consists of simple cuboidal epithelium similar to the DCT.

Distal Convoluted Tubule (DCT)

The DCT, like the PCT, is very tortuous and formed by simple cuboidal epithelium, but it is shorter than the PCT. These cells are not as active as those in the PCT; thus, there are fewer microvilli on the apical surface. However, these cells must also pump ions against their concentration gradient, thus there are large numbers of mitochondria, although fewer than in the PCT.

Collecting Ducts

The collecting ducts are continuous with the nephron but not technically part of it. In fact, each duct collects filtrate from several nephrons for final modification. Collecting ducts merge as they descend deeper in the medulla to form about 30 terminal ducts, which empty at a papilla. They are lined with simple squamous epithelium with receptors for ADH. When stimulated by ADH, these cells will insert aquaporin channel proteins into their membranes, which as their name suggests, allow water to pass from the duct lumen through the cells and into the interstitial spaces to be recovered by the vasa recta. This process allows for the recovery of large amounts of water from the filtrate back into the blood. In the absence of ADH, these channels are not inserted, resulting in the excretion of water in the form of dilute urine. Most, if not all, cells of the body contain aquaporin molecules, whose channels are so small that only water can pass. At least 10 types of aquaporins are known in humans, and six of those are found in the kidney. The function of all aquaporins is to allow the movement of water across the lipid-rich, hydrophobic cell membrane.

Figure 12: Positive charges inside the channel prevent the leakage of electrolytes across the cell membrane, while allowing water to move due to osmosis.

Physiology of the Kidneys, Urinary Tract, and Urine Formation

The nephron utilizes specific processes to modify the composition of the plasma through filtration, reabsorption, and secretion systems.

Failure of the renal anatomy and/or physiology can lead suddenly or gradually to renal failure. In this event, a number of symptoms, signs, or laboratory findings point to the diagnosis as listed below.

Glomerular Filtration Rate (GFR)

The volume of filtrate formed by both kidneys per minute is termed the glomerular filtration rate (GFR). The heart pumps about 5 L blood per min under resting conditions. Approximately 20 percent or one liter enters the kidneys to be filtered. On average, this liter results in the production of about 125 mL/min filtrate produced in men (range of 90 to 140 mL/min) and 105 mL/min filtrate produced in women (range of 80 to 125 mL/min). This amount equates to a volume of about 180 L/day in men and 150 L/day in women. Ninety-nine percent of this filtrate is returned to the circulation by reabsorption so that only about 1–2 liters of urine are produced per day.

GFR is influenced by the hydrostatic pressure and colloid osmotic pressure on either side of the capillary membrane of the glomerulus. Recall that filtration occurs as pressure forces fluid and solutes through a semipermeable barrier with the solute movement constrained by particle size. Hydrostatic pressure is the pressure produced by a fluid against a surface. For example, if there is fluid on both sides of a barrier, both fluids exert a pressure in opposing directions. Thus, net fluid movement will be in the direction of the lower pressure. Osmosis is the movement of solvent (water) across a membrane that is impermeable to a solute in the solution. This creates a pressure, osmotic pressure, which will exist until the solute concentration is the same on both sides of a semipermeable membrane. As long as the concentration differs, water will move. Glomerular filtration occurs when glomerular hydrostatic pressure exceeds the luminal hydrostatic pressure of Bowman’s capsule. There is also an opposing force, the osmotic pressure, which is typically higher in the glomerular capillary.

This results because of the microenvironment on either side of the filtration membrane, in which the the solutes exert osmotic pressure inside the lumen of the capillary as well as inside of 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 the medium-to-large proteins cannot pass between the podocyte processes or through the fenestrations of the capillary endothelial cells. 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 (fluid) pressure is sufficient to push water through the membrane despite the osmotic pressure working against it. The sum of all of the influences, both osmotic and hydrostatic, results in a net filtration pressure (NFP) of about 10 mm Hg.

Figure 1: The NFP is the sum of osmotic and hydrostatic pressures.

A proper concentration of solutes in the blood is important in maintaining osmotic pressure both in the glomerulus and systemically. There are disorders in which too much protein passes through the filtration slits into the kidney filtrate. This excess protein in the filtrate leads to a deficiency of circulating plasma proteins. In turn, the presence of protein in the urine increases its osmolarity; this holds more water in the filtrate and results in an increase in urine volume. Because there is less circulating protein, principally albumin, the osmotic pressure of the blood falls. Less osmotic pressure pulling water into the capillaries tips the balance towards hydrostatic pressure, which tends to push it out of the capillaries. The net effect is that water is lost from the circulation to interstitial tissues and cells. This “plumps up” the tissues and cells, a condition termed systemic edema.

Net Filtration Pressure (NFP)

NFP determines filtration rates through the kidney. It is determined as follows:

NFP = Glomerular blood hydrostatic pressure (GBHP) – [capsular hydrostatic pressure (CHP) + blood colloid osmotic pressure (BCOP)] = 10 mm Hg

That is:

NFP = GBHP – [CHP + BCOP] = 10 mm Hg

Or:

NFP = 55 – [15 + 30] = 10 mm Hg

There is a low net pressure across the filtration membrane. Minor changes in osmolarity of the blood or changes in capillary blood pressure result in major changes in the amount of filtrate formed at any given point in time. The kidney is able to cope with a wide range of blood pressures. In large part, this is due to the autoregulatory nature of smooth muscle. When stretched it, it contracts. Thus, when blood pressure goes up, smooth muscle in the afferent capillaries contracts to limit any increase in blood flow and filtration rate. When blood pressure drops, the same capillaries relax to maintain blood flow and filtration rate. The net result is a relatively steady flow of blood into the glomerulus and a relatively steady filtration rate in spite of significant systemic blood pressure changes. Mean arterial blood pressure is calculated by adding 1/3 of the difference between the systolic and diastolic pressures to the diastolic pressure. Therefore, if the blood pressure is 110/80, the difference between systolic and diastolic pressure is 30. One third of this is 10, and when added to the diastolic pressure of 80, the calculated mean arterial pressure is 90 mm Hg. Therefore, if mean arterial pressure is used for the GBHP in the formula for calculating NFP, it indicates that as long as mean arterial pressure is above approximately 60 mm Hg, the pressure will be adequate to maintain glomerular filtration. Blood pressures below this level will impair renal function and cause systemic disorders that are severe enough to threaten survival. This condition is called shock.

Determination of the GFR is one of the tools used to assess the kidney’s excretory function. This is more than just an academic exercise. Since many drugs are excreted in the urine, a decline in renal function can lead to toxic accumulations. Additionally, administration of appropriate drug dosages for those drugs primarily excreted by the kidney requires an accurate assessment of GFR. GFR can be estimated closely by intravenous administration of inulin. Inulin is a plant polysaccharide that is neither reabsorbed nor secreted by the kidney. Its appearance in the urine is directly proportional to the rate at which it is filtered by the renal corpuscle. However, since measuring inulin clearance is cumbersome in the clinical setting, most often, the GFR is estimated by measuring naturally occurring creatinine, a protein-derived molecule produced by muscle metabolism that is not reabsorbed and only slightly secreted by the nephron.

Tubular Reabsorption

With up to 180 liters per day passing through the nephrons of the kidney, the vast majority of the contents are reabsorbed. Reabsorption occurs in the PCT, loop of Henle, DCT, and the collecting ducts . Various portions of the nephron differ in their capacity to reabsorb water and specific solutes. 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. This control is exerted directly by ADH and aldosterone, and indirectly by renin. Most water is recovered in the PCT, loop of Henle, and DCT. About 10 percent (about 18 L) reaches the collecting ducts. The collecting ducts, under the influence of ADH, can recover almost all of the water passing through them, in cases of dehydration, or almost none of the water, in cases of over-hydration.

Mechanisms of Recovery

Mechanisms by which substances move across membranes for reabsorption or secretion include active transport, diffusion, facilitated diffusion, secondary active transport, and osmosis.

Active transport utilizes energy, usually the energy found in a phosphate bond of ATP, to move a substance across a membrane from a low to a high concentration. It is very specific and must have an appropriately shaped receptor for the substance to be transported. An example would be the active transport of Na⁺ out of a cell and K⁺ into a cell by the Na⁺/K⁺ pump. Both ions are moved in opposite directions from a lower to a higher concentration.

Simple diffusion moves a substance from a higher to a lower concentration down its concentration gradient. It requires no energy and only needs to be soluble.

Facilitated diffusion is similar to diffusion in that it moves a substance down its concentration gradient. The difference is that it requires specific membrane receptors or channel proteins for movement. The movement of glucose and, in certain situations, Na⁺ ions, is an example of facilitated diffusion. In some cases of mediated transport, two different substances share the same channel protein port; these mechanisms are described by the terms symport and antiport.

Symport mechanisms move two or more substances in the same direction at the same time, whereas antiport mechanisms move two or more substances in opposite directions across the cell membrane. Both mechanisms may utilize concentration gradients maintained by ATP pumps. As described previously, when active transport powers the transport of another substance in this way, it is called “secondary active transport.” Glucose reabsorption in the kidneys is by secondary active transport. Na⁺/K⁺ ATPases on the basal membrane of a tubular cell constantly pump Na⁺ out of the cell, maintaining a strong electrochemical gradient for Na⁺ to move into the cell from the tubular lumen. On the luminal (apical) surface, a Na⁺/glucose symport protein assists both Na+ and glucose movement into the cell. The cotransporter moves glucose into the cell against its concentration gradient as Na⁺ moves down the electrochemical gradient created by the basal membranes Na⁺/K⁺ ATPases. The glucose molecule then diffuses across the basal membrane by facilitated diffusion into the interstitial space and from there into peritubular capillaries.

Most of the Ca⁺⁺, Na⁺, glucose, and amino acids must be reabsorbed by the nephron to maintain homeostatic plasma concentrations. Other substances, such as urea, K⁺, ammonia (NH₃₎, creatinine, and some drugs are secreted into the filtrate as waste products. Acid–base balance is maintained through actions of the lungs and kidneys: The lungs rid the body of H⁺, whereas the kidneys secrete or reabsorb H⁺ and HCO₃^–. In the case of urea, about 50 percent is passively reabsorbed by the PCT. More is recovered by in the collecting ducts as needed. ADH induces the insertion of urea transporters and aquaporin channel proteins.

Reabsorption and Secretion in the PCT

The renal corpuscle filters the blood to create a filtrate that differs from blood mainly in the absence of cells and large proteins. From this point to the ends of the collecting ducts, the filtrate or forming urine is undergoing modification through secretion and reabsorption before true urine is produced. The first point at which the forming urine is modified is in the PCT. Here, some substances are reabsorbed, whereas others are secreted. Note the use of the term “reabsorbed.” All of these substances were “absorbed” in the digestive tract—99 percent of the water and most of the solutes filtered by the nephron must be reabsorbed. Water and substances that are reabsorbed are returned to the circulation by the peritubular and vasa recta capillaries. It is important to understand the difference between the glomerulus and the peritubular and vasa recta capillaries. The glomerulus has a relatively high pressure inside its capillaries and can sustain this by dilating the afferent arteriole while constricting the efferent arteriole. This assures adequate filtration pressure even as the systemic blood pressure varies. Movement of water into the peritubular capillaries and vasa recta will be influenced primarily by osmolarity and concentration gradients. Sodium is actively pumped out of the PCT into the interstitial spaces between cells and diffuses down its concentration gradient into the peritubular capillary. As it does so, water will follow passively to maintain an isotonic fluid environment inside the capillary. This is called obligatory water reabsorption, because water is “obliged” to follow the Na⁺.

Figure 2: Note the paths of salts from the location in the tubules to the interstitial space or blood stream for reabsorbtion.

More substances move across the membranes of the PCT than any other portion of the nephron. Many of these substances (amino acids and glucose) use symport mechanisms for transport along with Na⁺. Antiport, active transport, diffusion, and facilitated diffusion are additional mechanisms by which substances are moved from one side of a membrane to the other. Recall that cells have two surfaces: apical and basal. The apical surface is the one facing the lumen or open space of a cavity or tube, in this case, the inside of the PCT. The basal surface of the cell faces the connective tissue base to which the cell attaches (basement membrane) or the cell membrane closer to the basement membrane if there is a stratified layer of cells. In the PCT, there is a single layer of simple cuboidal endothelial cells against the basement membrane. The numbers and particular types of pumps and channels vary between the apical and basilar surfaces. A few of the substances that are transported with Na⁺ (symport mechanism) on the apical membrane include Cl^–, Ca⁺⁺, amino acids, glucose, and PO₃⁻⁴.

Sodium is actively exchanged for K⁺ using ATP on the basal membrane. Most of the substances transported by a symport mechanism on the apical membrane are transported by facilitated diffusion on the basal membrane. At least three ions, K⁺, Ca⁺⁺, and Mg⁺⁺, diffuse laterally between adjacent cell membranes (transcellular).

About 67 percent of the water, Na⁺, and K⁺ entering the nephron is reabsorbed in the PCT and returned to the circulation. Almost 100 percent of glucose, amino acids, and other organic substances such as vitamins are normally recovered here. Some glucose may appear in the urine if circulating glucose levels are high enough that all the glucose transporters in the PCT are saturated, so that their capacity to move glucose is exceeded (transport maximum, or T_m). In men, the maximum amount of glucose that can be recovered is about 375 mg/min, whereas in women, it is about 300 mg/min. This recovery rate translates to an arterial concentration of about 200 mg/dL. Though an exceptionally high sugar intake might cause sugar to appear briefly in the urine, the appearance of glycosuria usually points to type I or II diabetes mellitus. The transport of glucose from the lumen of the PCT to the interstitial space is similar to the way it is absorbed by the small intestine. Both glucose and Na⁺ bind simultaneously to the same symport proteins on the apical surface of the cell to be transported in the same direction, toward the interstitial space. Sodium moves down its electrochemical and concentration gradient into the cell and takes glucose with it. Na⁺ is then actively pumped out of the cell at the basal surface of the cell into the interstitial space. Glucose leaves the cell to enter the interstitial space by facilitated diffusion. The energy to move glucose comes from the Na⁺/K⁺ ATPase that pumps Na⁺ out of the cell on the basal surface. Fifty percent of Cl^– and variable quantities of Ca⁺⁺, Mg⁺⁺, and HPO_4^2-  are also recovered in the PCT.

Recovery of bicarbonate (HCO₃^–) is vital to the maintenance of acid–base balance, since it is a very powerful and fast-acting buffer. An important enzyme is used to catalyze this mechanism: carbonic anhydrase (CA). This same enzyme and reaction is used in red blood cells in the transportation of CO₂, in the stomach to produce hydrochloric acid, and in the pancreas to produce HCO₃^– to buffer acidic chyme from the stomach. In the kidney, most of the CA is located within the cell, but a small amount is bound to the brush border of the membrane on the apical surface of the cell. In the lumen of the PCT, HCO₃^– combines with hydrogen ions to form carbonic acid (H₂CO₃). This is enzymatically catalyzed into CO₂ and water, which diffuse across the apical membrane into the cell. Water can move osmotically across the lipid bilayer membrane due to the presence of aquaporin water channels. Inside the cell, the reverse reaction occurs to produce bicarbonate ions (HCO₃^–). These bicarbonate ions are cotransported with Na⁺across the basal membrane to the interstitial space around the PCT. At the same time this is occurring, a Na⁺/H⁺ antiporter excretes H⁺ into the lumen, while it recovers Na⁺. Note how the hydrogen ion is recycled so that bicarbonate can be recovered. Also, note that a Na⁺ gradient is created by the Na⁺/K⁺ pump.

Reabsorption and Secretion in the Loop of Henle

The loop of Henle consists of two sections: thick and thin descending and thin and thick ascending sections. The loops of cortical nephrons do not extend into the renal medulla very far, 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 recovery of much of the Na⁺ and water that were filtered by the glomerulus. As the forming urine moves through the loop, the osmolarity will change from isosmotic with blood (about 278–300 mOsmol/kg) to both a very hypertonic solution of about 1200 mOsmol/kg and a very hypotonic solution of about 100 mOsmol/kg. 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 the circulation by way of the vasa recta.

Descending Loop

The majority of the descending loop is comprised of simple squamous epithelial cells; to simplify the function of the loop, this discussion focuses on these cells. These membranes have permanent aquaporin channel proteins that allow unrestricted movement of water from the descending loop into the surrounding interstitium as osmolarity increases from about 300 mOsmol/kg to about 1200 mOsmol/kg. This increase results in reabsorption of up to 15 percent of the water entering the nephron. Modest amounts of urea, Na⁺, and other ions are also recovered here.

Most of the solutes that were filtered in the glomerulus have now been recovered along with a majority of water, about 82 percent. As the forming urine enters the ascending loop, major adjustments will be made to the concentration of solutes to create urine.

Ascending Loop

The ascending loop is made of very short thin and longer thick portions. Once again, to simplify the function, this section only considers the thick portion. The thick portion is lined with simple cuboidal epithelium without a brush border. It is completely impermeable to water due to the absence of aquaporin proteins, but ions, mainly Na⁺ and CL^–, are actively reabsorbed by a cotransport system. This has two significant effects: Removal of NaCl while retaining water leads to a hypoosomotic filtrate by the time it reaches the DCT; pumping NaCl into the interstitial space contributes to the hyperosmotic environment in the kidney medulla.

The Na^+/K⁺ ATPase pumps in the basal membrane create an electrochemical gradient, allowing reabsorption of Cl^– by Na⁺/Cl^– symporters in the apical membrane. At the same time that Na⁺ is actively pumped from the basal side of the cell into the interstitial fluid, Cl^– follows the Na⁺ from the lumen into the interstitial fluid by a paracellular route between cells through leaky tight junctions. These are found between cells of the ascending loop, where they allow certain solutes to move according to their concentration gradient. Most of the K⁺that enters the cell via symporters returns to the lumen (down its concentration gradient) through leaky channels in the apical membrane. Note the environment now created in the interstitial space: With the “back door exiting” K⁺, there is one Na⁺ and two Cl^– ions left in the interstitium surrounding the ascending loop. Therefore, in comparison to the lumen of the loop, the interstitial space is now a negatively charged environment. This negative charge attracts cations (Na⁺, K⁺, Ca⁺⁺, and Mg⁺⁺) from the lumen via a paracellular route to the interstitial space and vasa recta.

Countercurrent Multiplier System

The structure of the loop of Henle and associated vasa recta create a countercurrent multiplier system. The 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 solute pumps that increase (multiply) the concentrations of urea and Na⁺deep in the medulla.

As discussed above, the ascending loop actively reabsorbs NaCl out of the forming urine into the interstitial spaces. In addition, collecting ducts have urea pumps that actively pump urea into the interstitial spaces. This results in the recovery of NaCl to the circulation via the vasa recta and creates a high osmolar environment in the depths of the medulla.

Ammonia (NH₃) is a toxic byproduct of protein metabolism. It is formed as amino acids are deaminated by liver hepatocytes. That means that the amine group, NH₂, is removed from amino acids as they are broken down. Most of the resulting ammonia is converted into urea by liver hepatocytes. Urea is not only less toxic but is utilized to aid in the recovery of water by the loop of Henle and collecting ducts. At the same time that water is freely diffusing out of the descending loop through aquaporin channels into the interstitial spaces of the medulla, urea freely diffuses into the lumen of the descending loop as it descends deeper into the medulla, much of it to be reabsorbed from the forming urine when it reaches the collecting duct. 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.

The amino acid glutamine can be deaminated by the kidney. As NH₂ from the amino acid is converted into NH₃ and pumped into the lumen of the PCT, Na⁺ and HCO₃^– are excreted into the interstitial fluid of the renal pyramid via a symport mechanism. When this process occurs in the cells of the PCT, the added benefit is a net loss of a hydrogen ion (complexed to ammonia to form the weak acid NH₄⁺) in the urine and a gain of a bicarbonate ion (HCO₃^–) in the blood. Ammonia and bicarbonate are exchanged in a one-to-one ratio. This exchange is yet another means by which the body can buffer and excrete acid. The presence of aquaporin channels in the descending loop allows prodigious quantities of water to leave the loop and enter the hyperosmolar interstitium of the pyramid, where it is returned to the circulation by the vasa recta. As the loop turns to become the ascending loop, there is an absence of aquaporin channels, so water cannot leave the loop. However, in the basal membrane of cells of the thick ascending loop, ATPase pumps actively remove Na⁺ from the cell. A Na⁺/K⁺/2Cl^– symporter in the apical membrane passively allows these ions to enter the cell cytoplasm from the lumen of the loop down a concentration gradient created by the pump. This mechanism works to dilute the fluid of the ascending loop ultimately to approximately 50–100 mOsmol/L.

At the transition from the DCT to the collecting duct, about 20 percent of the original water is still present and about 10 percent of the sodium. If no other mechanism for water reabsorption existed, about 20–25 liters of urine would be produced. Now consider what is happening in the adjacent capillaries, the vasa recta. They are recovering both solutes and water at a rate that preserves the countercurrent multiplier system. In general, blood flows slowly in capillaries to allow time for exchange of nutrients and wastes. In the vasa recta particularly, this rate of flow is important for two additional reasons. The flow must be slow to allow blood cells to lose and regain water without either crenating or bursting. Second, a rapid flow would remove too much Na⁺ and urea, destroying the osmolar gradient that is necessary for the recovery of solutes and water. Thus, by flowing slowly to preserve the countercurrent mechanism, as the vasa recta descend, Na⁺and urea are freely able to enter the capillary, while water freely leaves; as they ascend, Na⁺ and urea are secreted into the surrounding medulla, while water reenters and is removed.

Reabsorption and Secretion in the Distal Convoluted Tubule

Approximately 80 percent of filtered water has been recovered by the time the dilute forming urine enters the DCT. The DCT will recover another 10–15 percent before the forming urine enters the collecting ducts. Aldosterone increases the amount of Na⁺/K⁺ ATPase in the basal membrane of the DCT and 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 by a paracellular route across tight junctions. Peritubular capillaries receive the solutes and water, returning them to the circulation.

Cells of the DCT also recover Ca⁺⁺ from the filtrate. Receptors for parathyroid hormone (PTH) are found in DCT cells and when bound to PTH, induce the insertion of calcium channels on their luminal surface. The channels enhance Ca⁺⁺recovery from the forming urine. In addition, as Na⁺ is pumped out of the cell, the resulting electrochemical gradient attracts Ca⁺⁺ into the cell. Finally, calcitriol (1,25 dihydroxyvitamin D, the active form of vitamin D) is very important for calcium recovery. It induces the production of calcium-binding proteins that transport Ca⁺⁺into the cell. These binding proteins are also important for the movement of calcium inside the cell and aid in exocytosis of calcium across the basolateral membrane. Any Ca⁺⁺ not reabsorbed at this point is lost in the urine.

Collecting Ducts and Recovery of Water

Solutes move across the membranes of the collecting ducts, which contain two distinct cell types, principal cells and intercalated cells. A principal cell possesses channels for the recovery or loss of sodium and potassium. An intercalated cell secretes or absorbs acid or bicarbonate. As in other portions of the nephron, there is an array of micromachines (pumps and channels) on display in the membranes of these 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 hyperosmotic, the collecting ducts recover more water to dilute the blood; if the blood becomes hyposmotic, the collecting ducts recover less of the water, leading to concentration of the blood. Another way of saying this is: If plasma osmolarity rises, more water is recovered and urine volume decreases; if plasma osmolarity decreases, less water is recovered and urine volume increases. This function is regulated by the posterior pituitary hormone ADH (vasopressin). 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 apical 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 mechanisms described above). If aquaporin water channels are present, water will be osmotically pulled from the collecting duct into the surrounding interstitial space and into the 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. By altering the number of aquaporin channels, the volume of water recovered or lost is altered. This, in turn, regulates the blood osmolarity, blood pressure, and osmolarity of the urine.

As Na⁺ is pumped from the forming urine, water is passively recaptured for the circulation; this preservation of vascular volume is critically important for the maintenance of a normal blood pressure. Aldosterone is secreted by the adrenal cortex in response to angiotensin II stimulation. As an extremely potent vasoconstrictor, angiotensin II functions immediately to increase blood pressure. By also stimulating aldosterone production, it provides a longer-lasting mechanism to support blood pressure by maintaining vascular volume (water recovery).

In addition to receptors for ADH, principal cells have receptors for the steroid hormone aldosterone. While ADH is primarily involved in the regulation of water recovery, aldosterone regulates Na⁺ recovery. Aldosterone stimulates principal cells to manufacture luminal Na⁺ and K⁺ channels as well as Na⁺/K⁺ ATPase pumps on the basal membrane of the cells. When aldosterone output increases, more Na⁺ is recovered from the forming urine and water follows the Na⁺ passively. As the pump recovers Na⁺ for the body, it is also pumping K⁺ into the forming urine, since the pump moves K⁺ in the opposite direction. When aldosterone decreases, more Na⁺ remains in the forming urine and more K⁺ is recovered in the circulation. Symport channels move Na⁺ and Cl^– together. Still other channels in the principal cells secrete K⁺ into the collecting duct in direct proportion to the recovery of Na⁺.

Intercalated cells 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 the urine.

Regulation of Renal Blood Flow

It is essential that the blood flows through the kidneys at a suitable rate to allow for filtration. This rate determines how much solute is retained or discarded, how much water is retained or discarded, and ultimately, the osmolarity of blood and the blood pressure of the body.

Sympathetic Nerves

The kidneys are innervated by the sympathetic neurons of the autonomic nervous system via the celiac plexus and splanchnic nerves. Reduction of sympathetic stimulation results in vasodilation and increased blood flow through the kidneys during resting conditions. When the frequency of action potentials increases, the arteriolar smooth muscle constricts (vasoconstriction), resulting in diminished glomerular flow, so less filtration occurs. Under conditions of stress, sympathetic nervous activity increases, resulting in the direct vasoconstriction of afferent arterioles (norepinephrine effect) as well as stimulation of the adrenal medulla. The adrenal medulla, in turn, produces a generalized vasoconstriction through the release of epinephrine. This includes vasoconstriction of the afferent arterioles, further reducing the volume of blood flowing through the kidneys. This process redirects blood to other organs with more immediate needs. If blood pressure falls, the sympathetic nerves will also stimulate the release of renin. Additional renin increases production of the powerful vasoconstrictor angiotensin II. Angiotensin II, as discussed above, will also stimulate aldosterone production to augment blood volume through retention of more Na⁺ and water. Only a 10 mm Hg pressure differential across the glomerulus is required for normal GFR, so very small changes in afferent arterial pressure significantly increase or decrease GFR.

Autoregulation

The kidneys are very effective at regulating the rate of blood flow over a wide range of blood pressures. Blood pressure normally decreases during relaxation or sleeping and increases when exercising. Despite fluctuation to blood pressure, the filtration rate through the kidney changes very little due to two internal autoregulatory mechanisms that operate involuntarily: the myogenic mechanism and the tubuloglomerular feedback mechanism.

Arteriole Myogenic Mechanism

The myogenic mechanism regulating blood flow within the kidney depends upon a characteristic shared by most smooth muscle cells of the body. When stretched, a smooth muscle cell contracts; when stopped, it relaxes, restoring its resting length. This mechanism works in the afferent arteriole that supplies the glomerulus. When blood pressure increases, smooth muscle cells in the wall of the arteriole are stretched and respond by contracting to resist the pressure, resulting in little change in flow. When blood pressure drops, the same smooth muscle cells relax to lower resistance, allowing a continued even flow of blood.

Tubuloglomerular Feedback

The tubuloglomerular feedback mechanism involves the JGA and a paracrine signaling mechanism utilizing ATP, adenosine, and nitric oxide (NO). This mechanism stimulates either contraction or relaxation of afferent arteriolar smooth muscle cells. Recall that the DCT is in intimate contact with the afferent and efferent arterioles of the glomerulus. Specialized macula densa cells in this segment of the tubule respond to changes in the fluid flow rate and Na⁺concentration. As GFR increases, there is less time for NaCl to be reabsorbed in the PCT, resulting in higher osmolarity in the filtrate. The increased fluid movement more strongly deflects single nonmotile cilia on macula densa cells. This increased osmolarity of the forming urine, and the greater flow rate within the DCT, activates macula densa cells to respond by releasing ATP and adenosine (a metabolite of ATP). ATP and adenosine act locally as paracrine factors to stimulate the myogenic juxtaglomerular cells of the afferent arteriole to constrict, slowing blood flow and reducing GFR. Conversely, when GFR decreases, less Na⁺ is in the forming urine, and most will be reabsorbed before reaching the macula densa, which will result in decreased ATP and adenosine, allowing the afferent arteriole to dilate and increase GFR. NO has the opposite effect, relaxing the afferent arteriole at the same time ATP and adenosine are stimulating it to contract. Thus, NO fine-tunes the effects of adenosine and ATP on GFR.

Endocrine Regulation of Kidney function

Several hormones have specific, important roles in regulating kidney function. They act to stimulate or inhibit blood flow. Some of these are endocrine, acting from a distance, whereas others are paracrine, acting locally.

Renin–Angiotensin–Aldosterone

Renin is an enzyme that is produced by the granular cells of the afferent arteriole at the JGA. It enzymatically converts angiotensinogen (made by the liver, freely circulating) into angiotensin I. Its release is stimulated by prostaglandins and NO from the JGA in response to decreased extracellular fluid volume.

ACE is not a hormone but it is functionally important in regulating systemic blood pressure and kidney function. It is produced in the lungs but binds to the surfaces of endothelial cells in the afferent arterioles and glomerulus. It enzymatically converts inactive angiotensin I into active angiotensin II. ACE is important in raising blood pressure. People with high blood pressure are sometimes prescribed ACE inhibitors to lower their blood pressure.

Angiotensin II is a potent vasoconstrictor that plays an immediate role in the regulation of blood pressure. It acts systemically to cause vasoconstriction as well as constriction of both the afferent and efferent arterioles of the glomerulus. In instances of blood loss or dehydration, it reduces both GFR and renal blood flow, thereby limiting fluid loss and preserving blood volume. Its release is usually stimulated by decreases in blood pressure, and so the preservation of adequate blood pressure is its primary role.

Aldosterone, often called the “salt-retaining hormone,” is released from the adrenal cortex in response to angiotensin II or directly in response to increased plasma K⁺. It promotes Na⁺ reabsorption by the nephron, promoting the retention of water. It is also important in regulating K⁺, promoting its excretion. (This dual effect on two minerals and its origin in the adrenal cortex explains its designation as a mineralocorticoid.) As a result, renin has an immediate effect on blood pressure due to angiotensin II–stimulated vasoconstriction and a prolonged effect through Na⁺ recovery due to aldosterone. At the same time that aldosterone causes increased recovery of Na⁺, it also causes greater loss of K⁺. Progesterone is a steroid that is structurally similar to aldosterone. It binds to the aldosterone receptor and weakly stimulates Na⁺ reabsorption and increased water recovery. This process is unimportant in men due to low levels of circulating progesterone. It may cause increased retention of water during some periods of the menstrual cycle in women when progesterone levels increase.

Antidiuretic Hormone (ADH)

Diuretics are drugs that can increase water loss by interfering with the recapture of solutes and water from the forming urine. They are often prescribed to lower blood pressure. Coffee, tea, and alcoholic beverages are familiar diuretics. ADH, a 9-amino acid peptide released by the posterior pituitary, works to do the exact opposite. It promotes the recovery of water, decreases urine volume, and maintains plasma osmolarity and blood pressure. It does so by stimulating the movement of aquaporin proteins into the apical cell membrane of principal cells of the collecting ducts to form water channels, allowing the transcellular movement of water from the lumen of the collecting duct into the interstitial space in the medulla of the kidney by osmosis. From there, it enters the vasa recta capillaries to return to the circulation. Water is attracted by the high osmotic environment of the deep kidney medulla.

Endothelin

Endothelins, 21-amino acid peptides, are extremely powerful vasoconstrictors. They are produced by endothelial cells of the renal blood vessels, mesangial cells, and cells of the DCT. Hormones stimulating endothelin release include angiotensin II, bradykinin, and epinephrine. They do not typically influence blood pressure in healthy people. On the other hand, in people with diabetic kidney disease, endothelin is chronically elevated, resulting in sodium retention. They also diminish GFR by damaging the podocytes and by potently vasoconstricting both the afferent and efferent arterioles.

Natriuretic Hormones

Natriuretic hormones are peptides that stimulate the kidneys to excrete sodium—an effect opposite that of aldosterone. Natriuretic hormones act by inhibiting aldosterone release and therefore inhibiting Na⁺ recovery in the collecting ducts. If Na⁺ remains in the forming urine, its osmotic force will cause a concurrent loss of water. Natriuretic hormones also inhibit ADH release, which of course will result in less water recovery. Therefore, natriuretic peptides inhibit both Na⁺ and water recovery. One example from this family of hormones is atrial natriuretic hormone (ANH), a 28-amino acid peptide produced by heart atria in response to over-stretching of the atrial wall. The over-stretching occurs in persons with elevated blood pressure or heart failure. It increases GFR through concurrent vasodilation of the afferent arteriole and vasoconstriction of the efferent arteriole. These events lead to an increased loss of water and sodium in the forming urine. It also decreases sodium reabsorption in the DCT. There is also B-type natriuretic peptide (BNP) of 32 amino acids produced in the ventricles of the heart. It has a 10-fold lower affinity for its receptor, so its effects are less than those of ANH. Its role may be to provide “fine tuning” for the regulation of blood pressure. BNP’s longer biologic half-life makes it a good diagnostic marker of congestive heart failure.

Parathyroid Hormone

Parathyroid hormone (PTH) is an 84-amino acid peptide produced by the parathyroid glands in response to decreased circulating Ca⁺⁺ levels. Among its targets is the PCT, where it stimulates the hydroxylation of calcidiol to calcitriol (1,25-hydroxycholecalciferol, the active form of vitamin D). It also blocks reabsorption of phosphate (PO₃^–), causing its loss in the urine. The retention of phosphate would result in the formation of calcium phosphate in the plasma, reducing circulating Ca⁺⁺ levels. By ridding the blood of phosphate, higher circulating Ca⁺⁺ levels are permitted.

Regulation of fluid volume and composition

The major hormones influencing total body water are ADH, aldosterone, and ANH. Circumstances that lead to fluid depletion in the body include blood loss and dehydration. Homeostasis requires that volume and osmolarity be preserved. Blood volume is important in maintaining sufficient blood pressure, and there are nonrenal mechanisms involved in its preservation, including vasoconstriction, which can act within seconds of a drop in pressure. Thirst mechanisms are also activated to promote the consumption of water lost through respiration, evaporation, or urination. Hormonal mechanisms are activated to recover volume while maintaining a normal osmotic environment. These mechanisms act principally on the kidney.

Volume-sensing Mechanisms

The body cannot directly measure blood volume, but blood pressure can be measured. Blood pressure often reflects blood volume and is measured by baroreceptors in the aorta and carotid sinuses. When blood pressure increases, baroreceptors send more frequent action potentials to the central nervous system, leading to widespread vasodilation. Included in this vasodilation are the afferent arterioles supplying the glomerulus, resulting in increased GFR, and water loss by the kidneys. If pressure decreases, fewer action potentials travel to the central nervous system, resulting in more sympathetic stimulation-producing vasoconstriction, which will result in decreased filtration and GFR, and water loss.

Decreased blood pressure is also sensed by the granular cells in the afferent arteriole of the JGA. In response, the enzyme renin is released, leading to an almost immediate rise in blood pressure as activated angiotensin II that produces vasoconstriction, as discussed earlier. The rise in pressure is sustained by the aldosterone effects initiated by angiotensin II; this includes an increase in Na⁺ retention and water volume. As an aside, late in the menstrual cycle, progesterone has a modest influence on water retention. Due to its structural similarity to aldosterone, progesterone binds to the aldosterone receptor in the collecting duct of the kidney, causing the same, albeit weaker, effect on Na⁺and water retention.

Cardiomyocytes of the atria also respond to greater stretch (as blood pressure rises) by secreting ANH. ANH opposes the action of aldosterone by inhibiting the recovery of Na⁺ by the DCT and collecting ducts. More Na⁺ is lost, and as water follows, total blood volume and pressure decline. In low-pressure states, ANH does not seem to have much effect.

ADH is also called vasopressin. Early researchers found that in cases of unusually high secretion of ADH, the hormone caused vasoconstriction (vasopressor activity, hence the name). Only later were its antidiuretic properties identified. Synthetic ADH is still used occasionally to stem life-threatening esophagus bleeding in alcoholics.

When blood volume drops 5–10 percent, causing a decrease in blood pressure, there is a rapid and significant increase in ADH release from the posterior pituitary. Immediate vasoconstriction to increase blood pressure is the result. ADH also causes activation of aquaporin channels in the collecting ducts to affect the recovery of water to help restore vascular volume.

Diuretics and Fluid Volume

A diuretic is a compound that increases urine volume. Three familiar drinks contain diuretic compounds: coffee, tea, and alcohol. The caffeine in coffee and tea works by promoting vasodilation in the nephron, which increases GFR. Alcohol increases GFR by inhibiting ADH release from the posterior pituitary, resulting in less water recovery by the collecting duct. In cases of high blood pressure, diuretics may be prescribed to reduce blood volume and, thereby, reduce blood pressure. The most frequently prescribed anti-hypertensive diuretic is hydrochlorothiazide. It inhibits the Na⁺/ Cl^– symporter in the DCT and collecting duct. The result is a loss of Na⁺ with water following passively by osmosis.

Osmotic diuretics promote water loss by osmosis. An example is the indigestible sugar mannitol, which is most often administered to reduce brain swelling after head injury. However, it is not the only sugar that can produce a diuretic effect. In cases of poorly controlled diabetes mellitus, glucose levels exceed the capacity of the tubular glucose symporters, resulting in glucose in the urine. The unrecovered glucose becomes a powerful osmotic diuretic. Classically, in the days before glucose could be detected in the blood and urine, clinicians identified diabetes mellitus by the three Ps: polyuria (diuresis), polydipsia (increased thirst), and polyphagia (increased hunger).

Regulation of Extracellular Na⁺

Sodium has a very strong osmotic effect and attracts water. It plays a larger role in the osmolarity of the plasma than any other circulating component of the blood. If there is too much Na⁺ present, either due to poor control or excess dietary consumption, a series of metabolic problems ensue. There is an increase in total volume of water, which leads to hypertension (high blood pressure). Over a long period, this increases the risk of serious complications such as heart attacks, strokes, and aneurysms. It can also contribute to system-wide edema (swelling).

Mechanisms for regulating Na⁺ concentration include the renin–angiotensin–aldosterone system and ADH. Aldosterone stimulates the uptake of Na⁺on the apical cell membrane of cells in the DCT and collecting ducts, whereas ADH helps to regulate Na⁺ concentration indirectly by regulating the reabsorption of water.

Regulation of Extracellular K⁺

Potassium is present in a 30-fold greater concentration inside the cell than outside the cell. A generalization can be made that K⁺ and Na⁺ concentrations will move in opposite directions. When more Na⁺ is reabsorbed, more K⁺ is secreted; when less Na⁺ is reabsorbed (leading to excretion by the kidney), more K⁺ is retained. When aldosterone causes a recovery of Na⁺ in the nephron, a negative electrical gradient is created that promotes the secretion of K⁺ and Cl^– into the lumen.

Regulation of Cl^–

Chloride is important in acid–base balance in the extracellular space and has other functions, such as in the stomach, where it combines with hydrogen ions in the stomach lumen to form hydrochloric acid, aiding digestion. Its close association with Na⁺ in the extracellular environment makes it the dominant anion of this compartment, and its regulation closely mirrors that of Na⁺.

Regulation of Ca⁺⁺ and Phosphate

The parathyroid glands monitor and respond to circulating levels of Ca⁺⁺ in the blood. When levels drop too low, PTH is released to stimulate the DCT to reabsorb Ca⁺⁺ from the forming urine. When levels are adequate or high, less PTH is released and more Ca⁺⁺ remains in the forming urine to be lost. Phosphate levels move in the opposite direction. When Ca⁺⁺ levels are low, PTH inhibits reabsorption of HPO₂^4- so that its blood level drops, allowing Ca⁺⁺ levels to rise. PTH also stimulates the renal conversion of calcidiol into calcitriol, the active form of vitamin D. Calcitriol then stimulates the intestines to absorb more Ca⁺⁺ from the diet.

Regulation of H⁺, Bicarbonate, and pH

The acid–base homeostasis of the body is a function of chemical buffers and physiologic buffering provided by the lungs and kidneys. Buffers, especially proteins, HCO₂^3-, and ammonia have a very large capacity to absorb or release H⁺ as needed to resist a change in pH. They can act within fractions of a second. The lungs can rid the body of excess acid very rapidly (seconds to minutes) through the conversion of HCO₃^– into CO₂, which is then exhaled. It is rapid but has limited capacity in the face of a significant acid challenge. The kidneys can rid the body of both acid and base. The renal capacity is large but slow (minutes to hours). The cells of the PCT actively secrete H⁺ into the forming urine as Na⁺ is reabsorbed. The body rids itself of excess H⁺ and raises blood pH. In the collecting ducts, the apical surfaces of intercalated cells have proton pumps that actively secrete H⁺ into the luminal, forming urine to remove it from the body.

As hydrogen ions are pumped into the forming urine, it is buffered by bicarbonate (HCO₃^–), H₂PO₄^– (dihydrogen phosphate ion), or ammonia (forming NH₄⁺, ammonium ion). Urine pH typically varies in a normal range from 4.5 to 8.0.

Regulation of Nitrogen Wastes

Nitrogen wastes are produced by the breakdown of proteins during normal metabolism. Proteins are broken down into amino acids, which in turn are deaminated by having their nitrogen groups removed. Deamination converts the amino (NH₂) groups into ammonia (NH₃), ammonium ion (NH₄⁺), urea, or uric acid. Ammonia is extremely toxic, so most of it is very rapidly converted into urea in the liver. Human urinary wastes typically contain primarily urea with small amounts of ammonium and very little uric acid.

Elimination of Drugs and Hormones

Water-soluble drugs may be excreted in the urine and are influenced by one or all of the following processes: glomerular filtration, tubular secretion, or tubular reabsorption. Drugs that are structurally small can be filtered by the glomerulus with the filtrate. Large drug molecules such as heparin or those that are bound to plasma proteins cannot be filtered and are not readily eliminated. Some drugs can be eliminated by carrier proteins that enable secretion of the drug into the tubule lumen. There are specific carriers that eliminate basic (such as dopamine or histamine) or acidic drugs (such as penicillin or indomethacin). As is the case with other substances, drugs may be both filtered and reabsorbed passively along a concentration gradient.

Urinary Systems and Homeostasis

Because all systems of the body are interrelated, any change in one system may affect other systems in the body, causing mild to devastating effects. The loss of certain urinary functions may be fatal. A failure to synthesize vitamin D is one such example.

Vitamin D Synthesis

In order for vitamin D to become active, it must undergo a hydroxylation reaction in the kidney, that is, an –OH group must be added to calcidiol to make calcitriol (1,25-dihydroxycholecalciferol). Activated vitamin D is important for absorption of Ca⁺⁺ in the digestive tract, its reabsorption in the kidney, and the maintenance of normal serum concentrations of Ca⁺⁺ and phosphate. Calcium is vitally important in bone health, muscle contraction, hormone secretion, and neurotransmitter release. Inadequate Ca⁺⁺ leads to disorders like osteoporosis and osteomalacia in adults and rickets in children. Deficits may also result in problems with cell proliferation, neuromuscular function, blood clotting, and the inflammatory response. Recent research has confirmed that vitamin D receptors are present in most, if not all, cells of the body, reflecting the systemic importance of vitamin D. Many scientists have suggested it be referred to as a hormone rather than a vitamin.

Erythropoiesis

EPO is a 193-amino acid protein that stimulates the formation of red blood cells in the bone marrow. The kidney produces 85 percent of circulating EPO; the liver, the remainder. At higher altitudes, the partial pressure of oxygen is lower, meaning there is less pressure to push oxygen across the alveolar membrane and into the red blood cell. One way the body compensates is to manufacture more red blood cells by increasing EPO production. Likewise, when engaging in aerobic exercise, the tissues require a higher oxygen supply causing the kidney to send more EPO to the tissues. If erythrocytes are lost due to severe or prolonged bleeding, or under produced due to disease or severe malnutrition, the kidneys come to the rescue by producing more EPO. Renal failure (loss of EPO production) is associated with anemia, which makes it difficult for the body to cope with increased oxygen demands or to supply oxygen adequately even under normal conditions. Anemia diminishes performance and can be life threatening.

Blood Pressure Regulation

Due to osmosis, water follows where Na⁺ leads. Much of the water the kidneys recover from the forming urine follows the reabsorption of Na⁺. ADH stimulation of aquaporin channels allows for regulation of water recovery in the collecting ducts. Normally, all of the glucose is recovered, but loss of glucose control (diabetes mellitus) may result in an osmotic dieresis severe enough to produce severe dehydration and death. A loss of renal function means a loss of effective vascular volume control, leading to hypotension (low blood pressure) or hypertension (high blood pressure), which can lead to stroke, heart attack, and aneurysm formation.

The kidneys cooperate with the lungs, liver, and adrenal cortex through the renin–angiotensin–aldosterone system. The liver synthesizes and secretes the inactive precursor angiotensinogen. When the blood pressure is low, the kidney synthesizes and releases renin. Renin converts angiotensinogen into angiotensin I, and ACE produced in the lung converts angiotensin I into biologically active angiotensin II. The immediate and short-term effect of angiotensin II is to raise blood pressure by causing widespread vasoconstriction. angiotensin II also stimulates the adrenal cortex to release the steroid hormone aldosterone, which results in renal reabsorption of Na⁺ and its associated osmotic recovery of water. The reabsorption of Na⁺ helps to raise and maintain blood pressure over a longer term.

Regulation of Osmolarity

Blood pressure and osmolarity are regulated in a similar fashion. Severe hypo-osmolarity can cause problems like lysis (rupture) of blood cells or widespread edema, which is due to a solute imbalance. Inadequate solute concentration (such as protein) in the plasma results in water moving toward an area of greater solute concentration, in this case, the interstitial space and cell cytoplasm. If the kidney glomeruli are damaged by an autoimmune illness, large quantities of protein may be lost in the urine. The resultant drop in serum osmolarity leads to widespread edema that, if severe, may lead to damaging or fatal brain swelling. Severe hypertonic conditions may arise with severe dehydration from lack of water intake, severe vomiting, or uncontrolled diarrhea. When the kidney is unable to recover sufficient water from the forming urine, the consequences may be severe (lethargy, confusion, muscle cramps, and finally, death) .

Recovery of Electrolytes

Sodium, calcium, and potassium must be closely regulated. The role of Na⁺ and Ca⁺⁺ homeostasis has been discussed at length. Failure of K⁺ regulation can have serious consequences on nerve conduction, skeletal muscle function, and most significantly, on cardiac muscle contraction and rhythm.

pH Regulation

Recall that enzymes lose their three-dimensional conformation and, therefore, their function if the pH is too acidic or basic. This loss of conformation may be a consequence of the breaking of hydrogen bonds. Move the pH away from the optimum for a specific enzyme and its function would be severely hampered throughout the body, including hormone binding, central nervous system signaling, or myocardial contraction. Proper kidney function is essential for pH homeostasis.