1. Essential Terminologies
Excretion is the elimination / removal from the body of waste metabolic substances, which if permitted to accumulate, would prevent the maintenance of a steady state. Many substances that are not metabolic, that is those which have not been synthesized by the organism, are also removed. It is a homeostatic process. The term excretion is applicable only to substances that have been taken up by cells or have been formed as a result of cell activity. Otherwise, it is called egestion.
Egestion is the elimination of undigested matter in the diet that is discharged from the organism without being taken into the cells and metabolized.
Secretion is the discharge of materials that have been formed by the organism for use inside or outside the body. Examples include the addition of digestive enzymes to food materials; the release of growth regulators or hormones within the plant or animal; the ejection of defective chemicals when under attack; and the pouring of sweat on to the skin as a means of temperature regulation.
Both egested materials and secretions may also contain substances that are being excreted from the body such as salts in sweat and the bile pigments.
Osmoregulation is the mechanism by which the balance of water and dissolved solutes is regulated. An appropriate quantity of water is essential to maintain the volume of cells in organisms within relatively narrow limits. The dissolved solutes, composition of cells and body fluids determine the solute potential and therefore affect the water content. As part of osmoregulation, organisms regulate their content of both non-electrolytes (sugars and amino acids) and electrolytes (inorganic ions).
Osmoregulation and excretion are closely related processes. By excretion, excess water and dissolved solutes are lost from the body.
In humans and other mammals, a number of organs are involved in the excretion of waste products of metabolism mainly the kidneys, lungs, skin and gut.
2. Nitrogenous Excretion
Waste materials are generated by the metabolic activity of cells. If allowed to accumulate, they would reach toxic concentrations and so must be continually removed. Waste products include carbon dioxide and water, and the nitrogenous (nitrogen containing) waste that result from the breakdown of amino acids and nucleic acids.
The simplest breakdown product of nitrogen containing compounds is ammonia, a small molecule that cannot be retained for long in the body because of its high toxicity. Most aquatic animals excrete ammonia immediately into the water.
Other mammals convert the ammonia to a less toxic form that can remain in the body for a short time before being excreted via special excretory organs. The form of the excretory product in terrestrial animals (urea or uric acid) depends on the type of organism and its life history. Terrestrial animals that lay eggs produce uric acid rather than urea, because it is non-toxic and very soluble. It remains as an inert solid mass in the egg until hatching.
3. The Mammalian Urinary System
3.1 Functions of the Kidneys
The kidneys are the primary means for eliminating waste products of metabolism that are no longer needed by the body. These products include urea (from metabolism of amino acids), creatinine (from muscle creatine), uric acid (from nucleic acid), the end products of haemoglobin breakdown such as bilirubin and urobilinogen gives urine its characteristic yellow colour, and various metabolites of various hormones. These waste products must be eliminated from the body as rapidly as they are produced.
The kidneys also eliminate many toxins and other foreign substances that are either produced by the body or ingested such as pesticides, drugs and food additives.
For maintenance of homeostasis, excretion of water and ions (sodium, potassium, chloride and calcium) must precisely match intake. Intakes of water and many electrolytes usually are governed mainly by a person’s eating and drinking habits. This necessitates that the kidney adjust their excretion rates to match intakes of the various substances. This involves regulating the blood volume and blood pressure by adjusting the volume of water lost in the urine. When extracellular fluid volume decreases, blood pressure also decreases. Once these 2 factors fall too low, the body cannot maintain adequate blood flow to the brain and other essential organs.
The kidney contributes to acid-base regulation, along with the lungs and body fluid buffers, by excreting acids and by regulating the body fluid buffer stores. The kidneys are the only means for eliminating from the body certain types of acids generated by metabolism of proteins, such as sulphuric and phosphoric acid.
The kidneys play a dominant role in long-term regulation of arterial pressure by excreting variable amounts of water and sodium. In addition, the kidneys contribute to short-term arterial pressure regulation by secreting vasoactive factors like renin that leads to the formation of vasoactive products like angiotensin II.
They also secrete hormones like erythropoietin which stimulates RBC production and renin which regulates the production of hormones involved in sodium ion balance and blood pressure homeostasis.
Kidneys retain important nutrients such as glucose and amino acids in the blood.
The kidneys synthesize glucose from amino acids and other pre-cursors during prolonged fasting a.k.a. gluconeogenesis. Their capacity to add glucose to the blood during prolonged periods of fasting rivals that of the liver.
3.2 Components of the Urinary System
The urinary system, also called the renal system, consists of the following components. There are 2 kidneys which remove dissolved waste and excess substances form the blood and form urine. There are 2 ureters which transport urine from the kidney to the urinary bladder which acts as a reservoir for urine. Lastly, there is 1 urethra, a duct through which urine from the bladder flows to the outside of the body during urination (micturition).
3.2.1 Location and External Anatomy of Kidneys
The kidney occurs in pairs. The right kidney is covered by the liver and lies slightly lower than the left. Each bean-shaped kidney is about 11 cm long, 6 cm wide, 3 cm thick and weighs about 150g (about the size of a large bar of soap). They take up about 1% of the body weight of humans.
The lateral surface of the kidney is convex. Its medial surface is concave and has a vertical cleft called the renal hilus that leads into a space within the kidney called the renal sinus. The hilus is a small indentation where an artery, vein, nerves and the ureter leave and enter the kidney.
Several structures, including the ureters, the renal blood vessels, lymphatics and nerves, enter or exit the kidney at the hilus and occupy the sinus. Covering and supporting the kidneys are 3 layers of tissue. The innermost layer is a tough, fibrous material called renal capsule. It is continuous with the surface layer of the ureters. The middle layer is the adipose tissue, composed of fat, which gives the kidney a protective cushion against impacts and jolts. The outer layer is called the renal fascia. Surrounding the renal fascia is another layer of fat called pararenal fat. The renal fascia is composed of connective tissue that surrounds the kidney and pararenal fat; it attaches them firmly to the posterior abdominal wall. It has enough flexibility to permit the kidneys to shift slightly as the diaphragm moves during breathing.
3.2.2 Internal Anatomy of Kidneys
3.2.2.1 Renal Cortex
It forms the outermost region and exists as light pink in colour and has a granular appearance.
3.2.2.2 Renal Medulla
It is deep to the cortex and appears as a darker, reddish brown. It exhibits cone-shaped tissue masses called medullary pyramids. The broad base of each pyramid faces towards the cortex whereas its apex (a.k.a. papilla) points towards the inner region of the kidney. The pyramids appear striped because they are formed almost entirely of roughly parallel bundles of microscopic urine-collecting tubules. The renal columns, inward extensions of the cortical tissue, separate the pyramids. Each medullary pyramid and its adjacent “cap” of cortical tissue constitutes a renal lobule (one of approximately 8) of the kidney.
3.2.2.3 Renal Pelvis
It is the innermost region and is a hollow flat, funnel-shaped tube that is continuous with the ureter leaving the hilus. Branching extensions of the pelvis form 2 or 3 major calyces, each of which divides further to form several minor calyces, cup-shaped areas that enclose the papillae of the pyramids. The calyces collect urine, which drains continuously from the papillae, and empty it into the renal pelvis.
Urine then flows through the renal pelvis and into the ureter, which transports it to the bladder to be stored. The walls of the calyces, pelvis and ureter contain smooth muscles, which contracts rhythmically and propels urine along its course by peristalsis.
The urine leaves the bladder during micturition (urination) via the urethra, which leads to the end of the penis in males and into the vulva in the females. The formation of urine is completed as it reaches the pelvic cavity of the kidney. The urine is then carried to the bladder and expelled without further modification.
3.2.3 Vascularization of the Kidneys
The kidneys have a very rich blood supply. Under normal resting conditions, the large renal arteries deliver approximately ¼ of the total systemic cardiac output (about 1200 ml) to the kidneys each minute. As each renal artery approaches the kidney, It divides into 5 segmental arteries that enter the hilus. Within the renal sinus, each segmental artery branches into several lobar arteries. Each lobar artery then divides to form several inter-lobar arteries, which pass between the medullary pyramids to the cortex.
At the medulla-cortex junction, the inter-lobar arteries give off branches, called arcuate arteries that arch over the bases of the medullary pyramids. Small inter-lobular arteries radiate from the arcuate arteries to supply the cortical tissue. More than 90% of the blood entering the kidney perfuses the cortex, which contains the bulk of the nephrons, the structural and functional units of the kidneys.
Veins of the kidneys pretty much trace the pathway of the arterial supply in reverse. Blood leaving the renal cortex drains sequentially into the inter-lobular, arcuate, inter-lobar and finally the renal veins. The renal veins issue from the kidneys and empty into the inferior vena cava.
3.2.4 Nephrons
The nephron is an independent urine-making unit and each kidney contains approximately 1 million nephrons. As a functional unit of the kidney, the nephron accomplishes the initial filtration of blood, the selective reabsorption back into the blood of filtered substances that are useful to the body, and the secretion of unwanted substances for the blood into the filtrate.
3.2.4.1 Different types of Nephrons
Two types of nephrons are recognized: cortical and juxtamedullary.
3.2.4.1.1 Cortical Nephron
They are tubular structures that extend only to the base of the renal pyramid of the medulla. They are 7 times more numerous and represent 85% of the nephrons in the kidney. They perform most of the reabsorptive and secretory functions of the kidney.
3.2.4.1.2 Juxtamedullary Nephron
They are located close to the cortex-medulla junction. The longer loops of the Henle of these nephrons project deeper into the renal pyramid of the medulla and their thin segments are much more extensive than those of the cortical nephrons. They are less numerous than the cortical nephrons and represents the remaining of the 15% of nephrons in the kidneys. They are responsible for the ability to produce concentrated urine.
3.2.4.2 Parts of a Nephron
3.2.4.2.1 Tubular Component
3.2.4.2.1.1 Constituents
They consist of the glomerular (Bowman’s) capsule and the excretory tubules which are the proximal convoluted tubule (PCT), the loop of Henle (which consists of a descending and an ascending limb), and the distal convoluted tubule (DCT).
3.2.4.2.1.2 Structure in Brief
Most tubules of a nephron are coiled and winding; all the tubules from all the nephrons in the body have a combined length of 80km. Each of the excretory tubules leads into a large collecting duct (which is not part of the nephron).
3.2.4.2.1.3 Main Function
It forms and transports the resulting renal filtrate.
3.2.4.2.2 Vascular Component
3.2.4.2.2.1 Constituents
They are made up of blood vessels. These include the afferent and efferent arterioles, the glomerulus and the peritubular capillaries (including the vasa recta), which surround the excretory tubules.
3.2.4.2.2.2 Structure it brief
That of capillaries are discussed in the cardiovascular system of humans and will not be discussed here.
3.2.4.2.2.3 Main Function
It participates in the reabsorption and secretion of substances from the excretory tubules into the blood and this takes place in the peritubular capillaries and vasa recta. The glomerulus form part of the filtration barrier / ultrafilters / filtration membrane of the Bowman’s capsule / renal capsule, allowing for the ultrafiltration to take place. During filtration, blood pressure forces water and small solutes across this membrane and into the capsular space.
3.2.4.3 Structure and Function of Nephrons
3.2.4.3.1 Renal Corpuscle
It is the portion of a nephron than encloses the glomerular capsule like a hand wrapped around a ball. It consists of the glomerular capsule and the glomerulus. It is always located in the cortex of the kidney and is the first part of the nephron. There are 2 layers. The outer (parietal) layer is made up of squamous epithelial cells. The inner (visceral) layer is composed of specialized epithelial cells celled podocytes (foot like cells), closely surrounding the glomerular capillaries. The inner and outer walls form a cavity called the capsular space.
3.2.4.3.1.1 Afferent and Efferent Arterioles
The afferent arterioles are short, straight branches of the inter-lobular arteries with a larger diameter that can transmit relatively high pressure. The efferent arterioles have a smaller diameter and offers considerable resistence and relatively high pressures are needed to force blood into it.
3.2.4.3.1.2 Filtration Barrier
Filtration of the blood occurs in the renal corpuscle. Vascular fluid must cross 3 layers before entering the tubular system.
The first layer is the endothelium of the glomerulus which contains tiny pores called fenestrations. The middle layer is the basement membrane of the glomerulus. The third layer is the visceral layer of the glomerular capsule and the podocytes.
3.2.4.3.1.3 Podocytes
They are relatively large cells with a nucleated cell body from which several thousand cell processes spread. These processes branch to form many smaller, finger-like processes called foot processes or pedicels. These pedicels cover the basement membrane of the glomerulus. The small regions between pedicels where the underlying basement membrane is exposed are called filtration slits. These thin slit membranes extend between the foot processes of adjacent cells; the membrane restricts the passage of certain molecules through the filtration slit but allows the passage of others. This combination of barriers (fenestrated endothelium, basement membrane and the filtration slits) is called the filtration barrier.
3.2.4.3.1.4 Capsular Membrane
The 3 layers of the renal corpuscle (endothelium, basement membrane and the visceral layer) constitute the capsular membrane. The filtration process involves the entire membrane. Although the cellular components of the blood and the large proteins do not normally pass through, water and dissolved solutes (electrolytes, sugars, urea, amino acids and polypeptides) have no trouble passing from the blood into the capsular space of the glomerular capsule. The function of the renal corpuscle is to produce the fluid filtered from the blood and this is called the glomerular filtrate.
3.2.4.3.2 Proximal Convoluted Tubule (PCT)
From the glomerular capsule, the glomerular filtrate drains into the PCT. Interestingly, the name describes its location (it is the portion of the excretory tubule proximal to the glomerular capsule) and its appearance (it is coiled in an irregular, convoluted way).
The epithelial cells that make up the tubule are cuboidal epithelia and the surfaces that face the lumen of the tubule lines with microvilli, forming a brush border. The microvilli enormously increase the epithelial surface area over which transport can occur.
The function of the PCT is as follows. It is the site for the reabsorption of many substances filtered from the blood, including water, electrolytes, glucose and some amino acids and small polypeptides.
3.2.4.3.3 Loop of Henle (LoH)
After passing through the PCT, the remaining glomerular filtrate enters a straight portion of the excretory tubule called the LoH, originally named for the 19th century German anatomist. It is composed of a descending limb and an ascending limb. The descending limb and the first part of the ascending limb (the thin ascending limb) are composed of simple squamous epithelium. The thick ascending limb is composed of cuboidal epithelium. Nephrons in the cortex have a thick ascending limb but no thin ascending limb.
The LoH acts as a countercurrent multiplier to generate a concentration gradient in the interstitial fluid.
3.2.4.3.4 Distal Convoluted Tubule (DCT)
After the glomerular filtrate passes through the LoH, it moves into the DCT in the cortex. As the name suggests, it is an irregularly shaped tubule located far from the glomerular capsule. The cuboidal epithelial cells of the DCT are similar in size to those of the PCT but they have very few microvilli. The cells are abundantly supplied with mitochondria near their basal surfaces to provide energy for the active transport of sodium ions and hydrogen ions.
Through selective reabsorption and secretion, the DCT makes the final adjustments in the solute composition and volume of the tubular fluid.
3.2.4.3.5 Juxtaglomerular Apparatus (JGA)
In the renal cortex, the DCT makes contact with the afferent (and sometimes he efferent) arterioles of the glomerulus. Here, the smooth muscle cells of the tunica media of the arterioles have cytoplasm with rennin-containing granules instead of myofilaments. These specialized smooth muscle cells, known as juxtaglomerular cells, are in contact with a group of epithelial cells of the DCT called the macula densa (dense spot). The cells of the macula densa are longer and narrower than the typical epithelial cells of the DCT.
Together, the juxtaglomerular cells of the afferent arteriole and the macula densa cells of the DCT make up the JGA, which helps regulate systemic blood pressure.
4. Kidney Physiology – Formation of Urine
In the formation of urine, a series of events leads to the following. (a) elimination of metabolic wastes from the body. (b) regulation of total body water balance. (c) control of the chemical composition of the blood and other body fluids. (d) regulation of blood pressure. (e) control of acid-base balance and the regulation of blood pH.
By 3 separate processes, the kidneys produce and modify the glomerular filtrate that is finally excreted from the body as urine.
In glomerular filtration, it occurs in the renal corpuscle (glomerulus and the Bowman ’s capsule). When blood flows from the afferent arteriole into the glomerulus, it is under high pressure (about 75 mmHg). This pressure forces some of the blood plasma into the glomerular capsule, but the blood cells and large proteins remain within the glomerulus, unable to pass through the endothelial capsular membrane. The product is the glomerular filtrate.
In selective reabsorption, it occurs in the PCT, LoH, DCT and the collecting duct. As the glomerular filtrate passes through the length of the nephron tubule, useful substances like water, sodium ions, glucose and amino acids that were initially lost from the blood during ultrafiltration are returned to the blood by active and passive transport. The product is the tubular fluid and urine.
In tubular secretion, it occurs in the PCT, DCT and the collecting duct. Some of the unwanted ions and substances may be transported (secreted) from the blood in the peritubular capillaries into the glomerular filtrate as it passes through the nephron tubules. In this way, products such as potassium ions, hydrogen ions, certain drugs (penicillin) and organic compounds may be excreted. The products are tubular fluid and urine.
In summary, glomerular filtrate flows through a nephron to the inner medulla of the kidney and then back again to the cortex. In the process, essential substances such as water and glucose are reabsorbed into the blood. Finally, the glomerular filtrate moves to the medulla of the kidney again, where it is now called urine and passes to the urinary bladder through the ureter. The filtered blood is returned to the body through the renal vein.
The amount of any substance excreted in the urine reflects how it was handled during the passage through the nephron. The amount excreted is equal to the amount filtered into the tubule minus the amount reabsorbed plus any amount of the substance secreted into the lumen.
4.1 Glomerular Filtration (Ultrafiltration)
Urine formation begins with the filtration of large amounts of fluid through the glomerular capillaries into the renal corpuscles. Like most capillaries, the glomerular capillaries are relatively impermeable to proteins, so that the filtered fluid (called the glomerular filtrate) is essentially protein free and devoid of cellular elements, including red blood cells. The filtration occurs exclusively in the renal corpuscle and is driven by the high capillary hydrostatic pressure (blood pressure) within the glomerulus.
4.1.1 Capsular Membrane (Filtration Barrier)
4.1.1.1 Capillary Endothelium
It is highly perforated with thousands of small holes called fenestrae, similar to the fenestrated capillaries. These fenestrae range from 60 to 100 nm in diameter. Although these pores are relatively large, endothelial cells are richly endowed with fixed negative charges that hinder the passage of plasma proteins.
4.1.1.2 Basement Membrane (Basal Lamina / Lamina Densa)
It is made up of a mesh work of collagen and proteoglycan fibrillae that have large spaces through which it can filter large amounts of water and small solutes. It effectively prevents filtration of plasma proteins, in part because of strong negative electrical charges associated with the proteoglycans
4.1.1.3 Filtration Slits
These slits between the pedicels of the podocytes are only 6 – 9 nm wide, small enough to block the passage of most of the smaller protein molecules. The podocytes and their pedicels also have negative charges to provide additional restriction to filtration of plasma proteins. As a result, under normal circumstances, none of the larger plasma proteins and very few albumin molecules (average diameter of 7 nm) enter the capsular space. The filtrate contains dissolved ions and small organic molecules in roughly the same concentrations as in the plasma.
4.1.2 Filtration Pressures
4.1.2.1 What is Filtration
It is the forcing of a fluid and the substances dissolved in it, through a membrane, by pressure. The resulting fluid is called he filtrate. Ultra filtration occurs in the glomeruli because of blood pressure (glomerular hydrostatic pressure)) forces water and some dissolved solutes in the plasma through the filtration barrier. The resulting fluid is the glomerular filtrate.
The glomerular capillary hydrostatic pressure needs to be determined. We have learnt about afferent and efferent arterioles. The glomeruli send large amounts of glomerular filtrate into the nephron tubules. The blood pressure in the glomerular capillaries is higher than in other capillaries in the body partly because of the following reason. The afferent arterioles are short, straight branches of the inter-lobular arteries that can transmit a relatively high pressure. It is also because the efferent arterioles have a smaller diameter anf offers considerable resistance and relatively high pressures are needed to force blood into it.
4.1.2.2 Net Filtration Pressure (NFP)
Three factors contribute to the determination of NFP, the pressure that promotes glomerular filtration in the kidneys. They are (a) glomerular hydrostatic pressure (GHP) (b) colloidal osmotic pressure and (c) capsular hydrostatic pressure (CHP).
Net hydrostatic pressure (NHP) is made up of 2 opposing forces, GHP and CHP. It tends to drive solutes out of the plasma and into the capsular space. GHP is about 45 – 55 mmHg and is the blood pressure in the glomerular capillaries and is a major force that moves water and solutes across the glomerular membrane. CHP is the hydrostatic pressure of the glomerular filtrate in the capsular space, which is exerted by the fluids in the glomerular capsule. It tends to push water and solutes out of the filtrate and into the plasma. It is a result of the resistance to flow along the nephron and the conducting system and is usually about 15 mmHg.
NHP = GHP – CHP = 50 – 15 = 35 mmHg
The net colloidal osmotic pressure (NCOP) has 2 components. The blood colloidal osmotic pressure (BCOP) is the pressure created by the plasma proteins in the blood within the glomerular capillaries. Over the entire length of the glomerular capillary bed, BCOP is usually about 25 – 30 mmHg. Capsular colloidal osmotic pressure (CCOP) is another factor. Under normal conditions, very few plasma proteins enter the capsular space and CCOP is negligible.
NCOP = BCOP – CCOP = 25 – 0 = 25 mmHg
Thus the NFP for forming the glomerular filtrate is
NFP = NHP – NCOP = 35 – 25 = 10 mmHg
This value represents the average pressure forcing water and dissolved solutes out of the glomerular capillaries and into the capsular spaces. Thus, a NFP of 10 mmHg favours the movement of liquid out of the glomerulus and into the glomerular capsule.
4.2 Tubular Reabsorption (Selective Reabsorption)
As the glomerular filtrate enters the renal tubules, it flows sequentially through the successive parts of the tubule and eventually into the collecting duct before being excreted as urine. Of the filtrate produced each day (180 L), about 99% is reabsorbed from the nephrons into the peritubular capillaries, with the remaining 1% excreted as urine. The reasons are as follows. Many foreign substances are filtered into the nephron and are not reabsorbed. The high daily filtration rate helps to clear such substances from the plasma very rapidly. Filtering ions and water into the tubule simplifies their regulation. If a portion of filtrate that reaches the distal nephron is not needed to maintain homeostasis, it passes into the urine. However, if the ions and water are needed, they are reabsorbed.
Present in the glomerular filtrate as it enters the PCT are water, glucose, amino acids, ions and waste products.
4.2.1 Definition
Tubular reabsorption is the movement of substances from the nephron tubules back into the peritubular capillaries. Reabsorption can be active or passive. For a substance to be reabsorbed, it must first be transported by (a) across the tubular epithelial membranes into the renal interstitial fluid and then (b) through the peritubular capillary membrane back into the blood.
4.2.1.1 Adaptations of Tubular Cells to Reabsorption
Epithelial cells in the tubules of the nephron carry out reabsorption. These tubular epithelial cells have tight junctions at their luminal membrane which limit the movement of substances between cells.
On top of that, the PCT cells are adapted for selective reabsorption as follows. There is a large surface area due to microvilli and basal channels. The PCT is the longest and widest part of the nephron. Outer membrane rests on a basement membrane; invaginated to form a labyrinth of basal channels. There are numerous mitochondria concentrated near the basement membrane to provide ATP for membrane-bound molecules in active transport. There is also the closeness of blood capillaries by surrounding peritubular capillaries.
4.2.1.2 How does fluid get reabsorbed into the peritubular capillary?
Peritubular capillary pressures favour reabsorption. There is low hydrostatic pressure in the entire length of these capillaries. Their average pressure is 10 mmHg as compared to glomerular capillaries which the pressures are on the average 55 mmHg.
4.2.2 Passive Tubular Reabsorption
This encompasses diffusion, facilitated diffusion and osmosis. Substances move along their electrochemical gradient without the use of ATP.
In the renal tubules, the electrochemical gradient that drives most passive transport is established by active reabsorption of sodium ions form the filtrate. As positively charge sodium ions move through the tubule cells into the peritubular capillary blood, they establish an electrical gradient that favours the passive diffusion of anions like chloride ions into the peritubular capillaries to restore electrical neutrality in the filtrate and plasma. Just which anion is absorbed depends on the pH of the blood at that time.
Sodium movement also establishes a string osmotic gradient and water moves by osmosis into peritubular capillaries. Because water is obliged to follow salt, this sodium-linked water flow is referred to as obligatory water reabsorption.
As water leaves the tubules, the relative concentration of substances still present in the filtrate increase dramatically and they too begin to follow their concentration gradients into the tubule cells. This phenomenon of solutes following the movement of solvent is called the solvent drag.
Solvent drag explains the passive reabsorption of some urea as well as that of a number of other lipid soluble substances present in the filtrate, such as fatty acids. Although the gradient provides the driving force, remember that the solute size and lipid solubility may be limiting factors. Solvent drag also explains in part why lipid-soluble drugs and environmental toxins are difficult to excrete.
4.2.3 Active Tubular Reabsorption
Substances reclaimed by active tubular reabsorption are usually moving against electrical and / or chemical gradients and requires the services of an ATP-dependent carrier to eject it across the membrane of the tubule cell into the interstitial space.
From there, it moves passively into the adjacent peritubular capillaries. Movement of absorbed substances into the peritubular capillary blood is rapid because of its low hydrostatic pressure and high osmotic pressure
Substances actively reabsorbed include glucose, amino acids, lactate, vitamins and most ions. Molecules that need to be pushed against their concentration gradients are moved by either primary or secondary active transport. Sodium is directly or indirectly involved in many cases.
4.2.3.1 Active Transport of Sodium
Filtrate entering the PCT is similar in ion concentration to the plasma, with a higher sodium ion concentration than is found within cells. Subsequently, sodium ions in the filtrate moves into the PCT cells through open leak channels, moving down its electrochemical gradient. Once inside the PCT cell, sodium ion is actively transported into the extracellular fluid by the sodium-potassium ATPase on the basolateral membrane. The result is sodium reabsorption across the epithelium.
4.2.3.2 Secondary Active Transport (Symport with Sodium)
Sodium linked secondary active transport in the nephron is responsible for the reabsorption of many substances, including glucose, amino acids, ions and various organic metabolites. The apical membrane contains a sodium-glucose co-transporter that brings glucose into the cytoplasm against its concentration gradient by harnessing the energy of sodium ion moving down its electrochemical gradient.
4.3 Tubular Secretion
Secretion is the transfer of molecules from the extracellular fluid into the lumen of the nephron. Like reabsorption, it depends mostly on membrane transport systems.
The secretion of potassium and hydrogen ions by the nephron is important in the homeostatic regulation of ions. Substances such as creatinine, ammonium ions and certain organic acids move from the blood of the peritubular capillaries through the tubule cells of from the tubule cells themselves into the filtrate. Substances move across epithelial cells using active transport mechanisms but in the opposite direction. Thus, the final composition of the urine excreted from the body depends not only on filtration and reabsorption, but also on tubular secretion of certain substances from the blood into the filtrate.
Tubular secretion occurs in the PCT, DCT and the collecting duct.
The following are the functions of tubular secretion. (1) Disposing of substances not already in the filtrate, (2) elimination of undesirable substances that have been reabsorbed by passive processes, (3) ridding the body of excessive potassium ions and (4) controlling the blood pH.
5. Kidney Physiology – Fluid and Electrolyte Balance
5.1 Introduction
The human body is in a state of constant flux. Over the course of a day, we ingest about 2 L of food and drinks that contains from 6 – 15 g of sodium chloride. In addition, we bring in varying amounts of other electrolytes. The body’s task is to maintain mass balance. What comes in must be excreted if the body does not need it.
The body has several different routes for excreting ions and water. The kidneys are the primary route for water loss and for removal of many ions. Under normal conditions, small amounts of these substances are lost in the faeces as well. In addition, the lungs help remove hydrogen and bicarbonate ions by excretion of carbon dioxide.
Although physiological mechanisms that maintain fluid and electrolyte balance are important, behavioural mechanisms also play an essential role. Thirst is critical because drinking is the only normal way to replace lost water. Salt appetite is a behavior that leads people and animals to seek and ingest salt.
Water and sodium ions are associated with extracellular fluid volume and osmolarity. Disturbances in potassium ion balance can cause serious problems with cardiac and muscle function by disrupting the membrane potential of excitable cells. Calcium ions is involved in a variety of body processes, from exocytosis to muscle contraction to bone formation and blood clotting. Hydrogen ion and bicarbonate ions are the ions whose balance determines blood and body pH.
Why is maintaining osmolarity so important to the body? The answer lies in the fact that water crosses most cell membranes freely. Of osmolarity of the ECF changes, water moves into or out of the cells and changes the intracellular volume. If the ECF osmolarity decreases due to excess water intake, water moves into the cells and they swell. If ECF osmolarity increases due to salt intake, water moves out of cells and they shrink.
Changes in cell volume can impair cell function. When cells swell, ion channels in the membrane open, disrupting membrane potential and cell signaling. The brain is particularly vulnerable to damage from swelling. Maintenance of ECF osmolarity within a normal range is essential to maintain homeostasis.
5.2 Water Balance and the Regulation of Urine Concentration
Urine concentration is determined in the LoH and collecting duct. One of the crucial functions of the kidney is to keep the solute load of body fluids constant at about 300 mosm by regulating urine concentration and volume. Just how the kidneys accomplish this feat is still a matter of controversy, but the most current hypothesis describes this aspect of renal function in terms of the countercurrent mechanism. It is the explanation for the way in which the kidneys form an osmotically concentrated urine.
In the kidneys, the countercurrent mechanism involves the interaction between he flow of filtrate through the LoH and the flow of blood through the limbs of its adjacent vessels, the vasa recta.
5.2.1 Countercurrent Mechanism
To generate osmotically concentrated urine, the following factors must be considered. (1) Permeability of the LoH, vasa recta and the collecting duct. (2) Overall structure of the LoH. (3) Active transport of sodium ions. (4) Concentration gradient of the renal medulla. (5) Fluid flows first in one direction, then in the opposite direction.
Countercurrent mechanism involves 2 phases. They are countercurrent multiplication of the LoH and the countercurrent exchange by the vasa recta.
Countercurrent refers to the fact that the exchange occurs between the fluids moving in opposite directions. The tubular fluid in the descending limb is moving towards the renal pelvis, whereas the tubular fluid in the ascending limb is moving towards the cortex.
Countercurrent exchange systems require arterial and venous blood vessels that pass very close to each other, with fluid flow moving in the opposite direction. This anatomical arrangement allows the transfer of heat or molecules from one vessel to the other.
5.2.1.1 Countercurrent Multiplier – Loop of Henle
5.2.1.1.1 Adaptations of LoH to be a Countercurrent Multiplier
There is a close proximity of the ascending and descending limb (hairpin loop). The thin descending limb is permeable to water but impermeable to solutes. The thick ascending limb, which is relatively impermeable to both water and solutes, contains active transport mechanisms that pump sodium and chloride from the tubular fluid into the interstitial fluid of the medulla.
5.2.1.1.2 Basic Concept involved in Countercurrent Multiplication
Sodium and chloride are pumped out of the thick ascending limb and into the interstitial fluid. This pumping elevates the osmotic concentration in the interstitial fluid around the thin descending limb. This result is an osmotic flow of water out of the thin descending limb and into the interstitial fluid, increasing the solute concentration inside the thin descending limb. The arrival of highly concentrated solution in the thick ascending limb accelerates the transport of sodium and chloride ions into the interstitial fluid of the medulla.
This arrangement is a simple positive feedback loop in whish solute pumping at the ascending limb leads to higher solute concentrations in the descending limb, which then result in accelerated solute pumping in the ascending limb.
The rate of ion transport by the thick ascending limb is proportional to the ion concentration in the tubular fluid. As a result, more sodium and chloride ions are pumped into the medulla at the start of the ascending limb (near the loop) where the solute concentration is higher than near the cortex. This regional difference in the rate of ion transport is the basis of the concentration gradient within the medulla.
In a nut shell, blood plasma = 300 mOsm and human urine = 950 mOsm. Therefore to obtain such concentrated urine, the osmotic concentration of the medulla is about 4 times that of the blood plasma = 1200 mOsm. This helps to maintain the differences in solute concentration from one end of the tubule to the other.
The cells of the ascending limb of the LoH that transports sodium and chloride ions from the filtrate into the interstitial fluid (medulla) are capable of creating a gradient of about 200 mOsm àsingle effect. To generate 1200 mOsm gradient, this single effect is multiplied many times over between the 2 streams of fluid moving in opposite directions in the LoH. This causes more salt in the ascending limb that transports into the interstitial fluid and causes more concentrated fluid in the descending limb.
5.2.1.1.3 Benefits of Countercurrent Multiplication
It is an efficient way to reabsorb solutes and water before the tubular fluid reaches the DCT and collecting system.
It establishes a concentration gradient in the medulla that will permit the passive reabsorption of water from the tubular fluid in the collecting system. This absorption is regulated by circulating levels of antiudiuretic hormone (ADH) a.k.a. vasopressin.
It is highly efficient as only a small numbers of sodium ions that are transported out of the ascending limb are taken away by the vasa recta.
5.2.1.2 Countercurrent Exchanger – vasa recta
It is easy to see how solute from the ascending limb dilutes the fluid in the LoH and helps concentrate fluid in the medulla. Still, why doesn’t the water leaving the descending limb of the LoH dilute the concentrated interstitial fluid of the medulla? The answer lies in the close anatomical association of the LoH and those of the peritubular capillaries known as the vasa recta.
These capillaries, like the LoH, dip down into the medulla and then go back up to the cortex, forming hairpin loops. Although text books traditionally show a single nephron with a single loop of capillary, each kidney has millions of collecting ducts and LoHs packed between millions of vasa recta capillaries. Thus, functionally, blood flow in the limbs of the vasa recta is in opposite direction from fluid flow in the loop.
Water or solutes that leave the tubule move into the vasa recta if a concentration or osmotic gradient exists. Assume that the blood entering the medulla in the vasa recta is 300 mOsm, isosmotic with the cortex. As the blood flows into the medulla, it loses water and picks up solutes transported out of the ascending limb of the LoH, carrying them further into the medulla. By the time the blood reaches the bottom of the vasa recta loop, it has a high osmotic concentration, similar to that of the surrounding interstitial fluid.
Then, as the blood in the vasa recta flows out of the medulla, its high osmolarity attracts the water that is being lost from the tubule. The movement of water into the vasa recta decreases the osmolarity of the blood while simultaneously preventing the water from diluting the concentrated interstitial fluid. As blood in the vasa recta leaves the medulla, it removes water reabsorbed from the LoH. Without the vasa recta, water moving out of the descending LoH would eventually dilute the medullary interstitial fluid. The vasa recta thus are an important part of keeping he medullary concentration high.
5.2.1.2.1 Adaptations of Vasa Recta to be a Countercurrent Exchanger
The vasa recta receives 10% of renal blood supply, thus blood flow through it is sluggish. It is permeable to water and salt, thus it makes passive exchanges with the interstitial fluid.
The descending limb of the vasa recta is called arteria recta. It is located mext to the ascending limb of the LoH i.e. blood flows from the cortex toward the medulla. It passively picks up interstitial sodium chloride in the vasa recta there by facilitating transport of sodium chloride from the ascending limb.
The ascending limb of the vasa recta is called the vena recta. It is located next to the descending limb of the LoH i.e. blood flows for the medulla to the cortex. Excess sodium chloride and urea diffuse back into ICF and water enters the vasa recta.
The vasa recta thus ensures little changes in composition of blood during the circuit through the vasa recta. It also ensures that at the same time, nutrients and oxygen are provided to the cells in the medulla as well as reabsorbed materials are being taken back into the body. Finally, it ensures that it functions as a countercurrent exchanger to maintain the osmotic gradient and minimize the washout of solutes from the medulla.
5.2.1.2.2 Urea increases osmolarity of Medullary Interstitium
The high concentration of the medullary interstitium is only partly due to sodium chloride. Nearly half the solute in the medullary institial fluid is urea. Where does it come from?
The collecting ducts in the deep medullary regions are permeable to urea. In a normally hydrated person, the dilute urine passes through the DCT and the superior portions of the collecting ducts without modifications. The filtrate’s concentration of urea remains high because the tubules in the cortex area are impermeable to it.
However, as urine passes through the deep medullary regions, where the collecting ducts are highly permeable to urea, urea diffuses out of the ducts into the medullary interstitial fluid, where it contributes to the high osmolarity in that region. Urea continues to move passively until its concentrations inside and outside the duct are equal.
Even though the ascending limb of the LoH is poorly permeable to urea, when urea concentrations in the medullary interstitial spaces are very high, some urea does enter the limb. However, it simply gets recycled back to the collecting duct, where it diffuses out again.
For many years, scientists thought urea only crossed cell membranes by passive transport. However, in recent years, we have learnt that there are several different transporters for urea in the collecting duct. (a) A facilitated diffusion carrier and (b) a sodium ion dependent secondary active transporter. The transporters help concentrate urea in the medullary interstitium, where it contributes to the high interstitial osmolarity.
5.3 Hormonal Regulation of Urine Osmolarity (Reabsorption at the DCT and collecting ducts)
Diuresis is the removal of excess water in dilute urine. Antudiuresis is therefore the production of concentrated urine. Drugs that causes dieresis are called diuretics. The normal amount of water and solute loss in the collecting system is regulated in 2 ways. First is by anti-diuretic hormone (ADH) a.k.a. vasopressin which controls the permeability of DCT and collecting ducts to water. Secondly, is by aldosterone which controls the sodium ion pumps along most of the DCT and collecting ducts. Therefore, the body maintains the solute potential of the blood at an approximately steady state by balancing water uptake from the diet with water lost in evaporation, sweating, egestion and urine.
5.3.1 What is ADH?
It is a peptide hormone also known as vasopressin.
It is made in the hypothalamus and is passed to the posterior pituitary gland for storage before release.
ADH has been found to cause the appearance of special water pores (membrane channels) in the luminal surface of epithelial cells in the collecting ducts. Water pores are aquaporins, a family of membrane channels with at least 10 different isoforms that occur in mammalian tissues. The kidney has at least 6 different types of aquaporins, including aquaporin 2, the water pore regulated by vasopressin.
5.3.2 Formation of Diluted Urine
When there is a high intake of water, the solute potential of the blood begins to get less negative. Vasopressin release from the posterior pituitary gland is inhibited.
The tubule cells have fewer water pores in their luminal membranes. These water pores are stored in cytoplasmic vesicles.
Walls of the DCT and collecting duct become impermeable to water. Less water is reabsorbed as the filtrate passes through the medulla. Thus a large volume of dilute urine is excreted.
5.3.3 Formation of Concentrated Urine
This occurs when too little water has been drunk, excessive sweating has occurred or large amount of salt has been taken.
Once any of the above occurs, osmoreceptors in the hypothalamus detect a fall in the blood solute potential. (Osmoreceptors are special receptors that are extremely sensitive to changes in blood concentration.) Nerve impulses will be passed to the posterior pituitary gland where vasopressin is released and travels in the blood to the kidney.
Increased permeability of the DCT and collecting duct to water is the effect of vasopressin on the nephron. AQP2 vesicles move to the luminal surface of the cells of the collecting ducts. Through exocytosis, these water pores will be inserted into the luminal membrane, causing the cells to be permeable to water. The result is 99% of the water in the filtrate is reabsorbed into the cortex and medulla) and returned to the blood. Therefore, only a small amount of highly concentrated urine is excreted.
There will also be an increased permeability of the collecting duct to urea. The result is more urea diffuses out into the medulla. This urea lowers the solute potential of the kidney tissues further. The consequence is more water moves by osmosis from the descending tubule of the LoH and from the collecting duct itself into the medulla. This water will be carried away in the capillary network and vasa recta. Therefore, more water is retained by the body and urine is further concentrated.
5.3.4 Summary of the Main Steps involved in the Excretion of Concentrated Urine
In step 1, the filtrate produced at the renal corpuscle has the same osmolarity as the plasma, about 200 mOsm.
In step 2, in the PCT, selective reabsorption occurs through the active removal of ions and other solutes, produces a continual flow of water out of the filtrate. This reduces the volume of the filtrate, but keeps the solutions inside and outside of the tubule isotonic. Roughly 60% of the volume of filtrate has been reabsorbed before the filtrate reaches the descending limb of the LoH.
In step 3, in the PCT and descending limb of the LoH, water moves into the surrounding interstitial fluids, leaving a small volume (roughly 20% of the original filtrate) of highly concentrated filtrate. To this point, the tubules are freely permeable to water and changes in the internal or external solute concentration results in an immediate osmotic movement of water out of the filtrate. Because this permeability cannot be altered, this process is caller obligatory water reabsorption.
In step 4, the filtrate then enters the ascending limb, where the epithelium is relatively impermeable to water and urea. Although the total osmolarities are equal, the filtrate now contains relatively fewer urea molecules and a higher concentration of sodium and chloride ions than does the surrounding interstitial fluid. Because the thin ascending limb is permeable to sodium and chloride ions, some of the ions diffuse out of the filtrate and into the medulla at this point.
In step 5, the thick ascending limb actively transports sodium and chloride ions out of the filtrate. This transport lowers the osmotic concentration of the filtrate without affecting filtrate volume. The filtrate reaching the DCT is hypotonic relative to the peritubular fluid, with an osmolarity of about 100 mOsm. Because only sodium and chloride ions are removed, urea now accounts for a significantly higher proportion of the total osmotic concentration at the end of the loop than it did at the start.
In step 6, the final composition and concentration of the filtrate will be determined by the events under way in the DCT and the collecting system. Although the DCT, collecting tubule and the collecting duct are generally impermeable to solute molecules, the osmolarity of the filtrate can be adjusted through active transport. One important process is the aldosterone-stimulated reabsorption of sodium ions.
In step 7, the osmotic concentration of urine is controlled by variations in water permeability of the distal portions of the DCT, the collecting tubules and the collecting ducts. These segments are impermeable to water unless exposed to ADH from the posterior pituitary gland. In the absence of ADH, no water reabsorption occurs and the individual excretes virtually all of the filtrate entering the DCT. Sucha person produces relatively large quantities of dilute urine.
At high concentrations of ADH, the distal portions of DCT and the collecting tubules and collecting ducts become freely permeable to water. The filtrate entering the collecting ducts then has an osmolarity of about 300 mOsm, similar to that of the surrounding renal cortex. As the collecting duct descends towards the renal papilla through the medulla, it travels through regions of gradually increasing osmotic concentration. Because the duct now is permeable to water, there is an osmotic flow of water out of the filtrate. Under these conditions, the urine entering the minor calyx has an osmolarity approaching 1200 mOsm.
Because the amount of water reabsorbed in the DCT, collecting tubules and the collecting ducts can be regulated, the process just described is called facultative water reabsorption.
In step 8, as the filtrate becomes increasingly concentrated, the urea concentration rises accordingly. In the final segments of the collecting duct and papillary duct, the urea concentration of the filtrate exceeds that in the surrounding medulla. Because this portion of the collecting system is permeable to urea, the urea molecules diffuse out of the filtrate and into the peritubular fluid.
5.4 Sodium Balance, Regulation of Blood Pressure and Blood Osmolarity
5.4.1 Control of Blood Sodium Levels
The kidneys are the primary means of sodium excretion. Normally, only a small amount leaves the body in feaces and perspiration. However, in situations such as vomiting, through non-renal routes.
5.4.1.1 Aldosterone
It is a steroid hormone synthesized and secreted by the cortex region of the adrenal gland. Like typical steroid hormones, aldosterone is secreted into the blood and transported on a protein carrier to its target. The primary site of its action is the last third of the DCT and the portion of the collecting duct that runs through the kidney cortex. The primary role is the maintenance of a constant level of sodium in the plasma. Its secondary role is to influence water reabsorption.
A decrease in blood sodium level leads to a decrease in blood volume as less water enters the blood by osmosis. This in turn reduces the blood pressure. The decrease in pressure and volume stimulates the juxtaglomerular (JG) complex situated between the DCT and the afferent arterioles, to release an enzyme called renin. Renin activates a protein in the blood plasma, produced by the liver to form the active hormone angiotensin and this releases aldosterone from the adrenal cortex.
Aldosterone travels in the blood to the DCT in the kidney. Here, it stimulates the sodium and potassium pump in the cells of the tubule, resulting in more sodium ions being pumped out of the DCT and into the blood capillaries around the tubules. Potassium moves in the opposite direction. This is an example of active transport. Aldosterone stimulates sodium ion absorption in the gut and decreases loss of sodium ions in sweat. Both these effects tend to raise the blood sodium ion levels. This in turn causes more water to enter the blood by osmosis, raising its volume and hence pressure.
What controls aldosterone secretion? There are 3 primary stimuli. The increased potassium ions, increased blood osmolarity and angiotensin II.
5.4.1.2 Renin – Angiotensin – Aldosterone Pathway
The primary signal for aldosterone release is ANG II. ANG II is one component of the pathway. The pathway is a complex, multistep pathway for maintaining blood pressure. The RAAS pathway begins when the JG cells in the nephrons secrete rennin. Renin converts angiotensin into ANG I. When ANG I in the blood encounters angiotensin converting enzyme, it is the converted to ANG II. This conversion was originally thought to occur only in the lungs, but ACE is now known to occur on the endothelium of blood vessels throughout the body. When ANG II in the blood reaches the adrenal gland, it causes synthesis and release of aldosterone. Finally, at the DCT and collecting ducts, aldosterone initiates a series of intracellular reactions that causes the tubules to reabsorb sodium ions.
The stimuli that begin the RAAS pathway are all related directly or indirectly to low blood pressure. The JG cells are directly sensitive to pressure. They respond to low pressure in renal arterioles by secreting renin. Sympathetic neurons, activated by the cardiovascular control centre when blood pressure decreases, terminate on the JG cells and stimulate renin secretion.
Sodium reabsorption does not directly raise low blood pressure, but retention of sodium ions does help stimulate fluid intake and volume expansion. When blood volume increases, blood pressure also increases. The RAAS pathway does not end here, however. ANG II is a remarkable hormone with additional effects directed at raising blood pressure. These actions make ANG II an important hormone in its own right, not merely an intermediate step in the aldosterone pathway.
5.4.1.3 ANG II influences Blood Pressure
ANG II has significant effects on fluid balance and blood pressure. It increases blood pressure both directly and indirectly through the following pathways.
Activation of ANG II receptors in the brain increases ADH secretion. Fluid retention in the kidney under the influence of ADH helps conserve blood volume.
ANG II stimulates thirst. Fluid ingestion is a behavioral response that expands blood volume and raises blood pressure.
ANG II is one of the most potent vasoconstrictors known in humans. Vasoconstriction causes blood pressure to increase without a change in blood volume.
ANG II receptors are found in the cardiovascular control centre. Their activation increases sympathetic output to the heart and blood vessels, which increases cardiac output and vasoconstriction. These responses both increases blood pressure.
