The Proximal Convoluted Loop Biology Essay

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Kidneys are vital organs of body concerned mainly with the maintenance of internal environment of body. They are concerned with excretion of end products of metabolism and excess water from the body. This is necessary to control fluid and electrolyte balance in body. The kidneys also have endocrine functions producing and releasing erythropoietin which affects red blood cell formation, renin which influences blood pressure, 1,25-hydroxycholecalciferol, which is involved in the control of calcium metabolism and is a derivative of vitamin D, and perhaps modifies the action of the parathyroid hormone, and various other soluble factors with metabolic actions(1). Bachmann et al have demonstrated that peritubular fibroblasts are cellular sites for production of erythropoietin in kidneys(2).

A typical adult kidney is a bean shaped structure, about 10 cm (4 in.) in length, 5.5 cm (2.2 in.) in width, and 3 cm (1.2 in.) in thickness. Each kidney weighs about 120-150 g.(3) The kidneys lie retroperitoneally on the posterior abdominal wall, one on each side of the vertebral column at the level of T12-L3 vertebrae. The right kidney usually lies slightly inferior to the left kidney, probably due to its relationship to the liver. Superiorly, the diaphragm separates the kidneys from pleural cavities and the pair of twelfth ribs. The long axis of each kidney is directed inferolaterally and the transverse axis posteromedially. Hence the anterior and posterior aspects usually described are in fact anterolateral and posteromedial. The transpyloric plane passes through the superior part of the right renal hilum and the inferior part of the left(1). Inferiorly, the posterior surfaces of the kidney are related to the quadratus lumborum muscle. The subcostal nerve and vessels and the iliohypogastric and ilioinguinal nerves descend diagonally across the posterior surfaces of the kidneys. The liver, duodenum, and ascending colon are anterior to the right kidney. The right kidney is separated from the liver by the hepatorenal recess. The left kidney is related to the stomach, spleen, pancreas, jejunum, and descending colon(3).

The kidney possesses a capsule which gives the fresh organ a glistening appearance. All surfaces are usually smooth and convex, but traces of lobulation, normal in the fetus, are often seen(4). Thick rounded lips of kidney substance bound the hilum, from which the pelvis emerges behind the vessels to pass down into the ureter(4). The renal hilum is the entrance to a space within the kidney, the renal sinus, which is occupied by the renal pelvis, calices, vessels, and nerves and a variable amount of fat.(3)

The outer margin of kidney is convex, while the inner margin, where hilum and renal sinus is present, is concave, giving it a bean like appearance. Because of the protrusion of the lumbar vertebral column into the abdominal cavity, the kidneys are obliquely placed, lying at an angle to each other. Consequently, the transverse diameter of the kidneys is foreshortened in anteroposterior (AP) radiographs(3).

The inverted cone shaped perinephric fat, which lies outside the renal capsule and fills the funnel-shaped hollow of the suprailiac part of the paravertebral gutter, is more solid at body temperature. This explains the development of nephroptosis ('floating kidney') after severe loss of weight(4).

The renal fascia is little more than a vague condensation of the areolar tissue between the parietal peritoneum and the posterior abdominal wall. It surrounds the perinephric fat and separates the kidneys from the suprarenal gland. At the hilum of the kidney, the fascia is firmly attached to the renal vessels and the ureter. This is a further stabilizing factor for the kidney, and prevents spread of pus across the midline(4).

The kidneys of albino rat are almost similar to the human beings except that they are quite small in size. They are two bean shaped structures having a firm fibrous capsule around. Suprarenal glands are present on their cephalic ends. The right kidney is present at a higher level than the left and is overlapped by the liver anteriorly. Both the kidneys are retroperitoneal and lie on a bed of perinephric fat. The cut sections of the rat kidney reveal an outer dark color cortex and an inner pale medulla. The pelvis of the kidney drains into ureter which in turn burrows into the urinary bladder(5). The archetypal kidney of lower mammals consists of a single lobe made up of a medullary pyramid (actually cone-shaped), the base of which is enveloped by the cortex containing the renal corpuscles and the proximal and distal parts of the tubules(6).

The renal cortex is the outer layer of the kidney in contact with the capsule. The cortex is reddish brown and granular in texture. The renal medulla consists of 6 to 18 distinct conical or triangular structures called renal pyramids. The base of each pyramid faces the cortex, and the tip of each pyramid, a region known as the renal papilla, projects into the renal sinus. Each pyramid has a series of fine grooves that converge at the papilla. Adjacent renal pyramids are separated by bands of cortical tissue called renal columns, which extend into the medulla. The columns have a distinctly granular texture, similar to that of the cortex. A renal lobe consists of a renal pyramid, the overlying area of renal cortex, and adjacent tissues of the renal columns(7).

Urine production occurs in the renal lobes. Ducts within each renal papilla discharge urine into a cup-shaped drain called a minor calyx. Four or five minor calyces merge to form a major calyx, and two or three major calyces combine to form the renal pelvis, a large, funnel-shaped chamber. The renal pelvis, which fills most of the renal sinus, is connected to the ureter at the hilus of the kidney.

HISTOLOGY

Urine production begins in microscopic structures called nephrons in the cortex of each renal lobe. There are one to two million renal corpuscles in each kidney, decreasing with age(8), with a combined length of about 145 km (85 miles)(7).

The nephron is the functional unit of the kidney. Each nephron consists of a dilated portion, the renal corpuscle; the proximal convoluted tubule; the thin and thick limbs of Henle's loop; the distal convoluted tubule; and the collecting tubules and ducts. Some investigators do not consider the collecting tubules and ducts to be part of the nephron.(9)

Each renal corpuscle is about 200 µm in diameter and consists of a tuft of capillaries, the glomerulus, surrounded by a double-walled epithelial capsule called glomerular (Bowman's) capsule.(9) Bowman's capsule consists of a single layer of flattened cells resting on a basement membrane; it is derived from the distended, blind end of the renal tubule.(6) The capillary loops of the glomerulus are invested by the visceral layer of Bowman's capsule: a highly specialized layer of epithelial cells called podocytes(6, 10). The visceral layer is reflected around the vascular stalk of the glomerulus to become continuous with the parietal layer that constitutes Bowman's capsule proper. Between the two layers of Bowman's capsule is the urinary space, which receives the fluid filtered through the capillary wall and the visceral layer. Each renal corpuscle has a vascular pole, where the afferent arteriole enters and the efferent arteriole leaves, and a urinary pole, where the proximal convoluted tubule begins. After entering the renal corpuscle, the afferent arteriole usually divides into two to five primary branches, each subdividing into capillaries and forming the renal glomerulus(9). The parietal layer of Bowman's capsule consists of flat epithelial cells resting on a basal lamina and a delicate layer of reticular fibers. At the urinary pole, this parietal layer becomes cuboidal or low columner, consistent with the epithelium of the proximal convoluted tubule(9).

During embryonic life, cells of parietal layer of Bowman's capsule change little as compared to the cells of visceral layer, the podocytes, which change remarkably. The podocytes have cell bodies from which primary processes arise. Each primary process gives rise to several secondary processes, which embrace the glomerular capillaries(9). The podocytes are metabolically very active cells, a fact which is shown by the presence of many mitochondria, filaments and vesicles in their cell bodies(1). At a periodic distance of 25 nm, the secondary processes are in direct contact with the basal lamina. However, the cell bodies of podocytes and their primary processes do not touch the basement membrane(9). Pedicels of one cell alternate with those of an adjacent cell and interdigitate tightly with each other. Pedicels are separated by narrow (25 nm) gaps, the filtration slits. The latter are covered by a dense, membranous slit diaphragm, through which filtrate must pass to enter the urinary space(1).The slit diaphragm is composed of a single layer of transmembrane protein, nephrin, whose extracellular domains from adjacent foot processes link together rather in the manner of a zip. A layer of negatively charged podocalyxin covers the urinary surface of the podocytes including the slit diaphragms(6). The intracellular component of nephrin is bound to the actin cytoskeleton of the podocyte, and it has been suggested that the slit diaphragm is in fact a modified tight junction(6, 11).

The filtration barrier between the capillary lumen and Bowman's space consists of the capillary endothelium, the podocyte layer and their common basement membrane known as the glomerular basement membrane. The capillary endothelium contains numerous large round fenestrations (70-100 nm in diameter). In adults the fenestrations do not exhibit diaphragms as in fenestrated capillaries elsewhere in the body. The luminal surface of the endothelium is negatively charged due to a surface layer of a glycoprotein called podocalyxin(6).

The glomerular basement membrane is about 350 nm thick in adults and consists of a feltwork of type IV collagen, structural glycoproteins (fibronectin and laminin) and proteoglycans rich in heparan sulphate, the interstices of this highly cross-linked structure being occupied by water molecules(6). Elcectron microscope shows it to consist of three layers; a central dense layer, lamina densa, and two inner and outer layers which are electron-lucent and are called lamina rara interna and lamina rara externa respectively. Both these layers are negatively charged(6). Thus, the glomerular basement membrane is a selective macromolecular filter in which the lamina densa acts as a physical filter, whereas the anionic sites in the laminae rarae act as a charge barrier. Particles greater than 10 nm in diameter do not readily cross the basal lamina, and negatively charged proteins with a molecular mass greater than that of albumin (69 kDa) pass across only sparingly(9).

Irregular mesangial cells, with phagocytic and contractile properties, lie within the delicate supportive mesangial matrix (mesangium) of the glomerulus, which they secrete. The mesangium is a specialized connective tissue which binds the loop of glomerular capillaries and fills the spaces between endothelial surfaces that are not invested by podocytes(1). The mesangeal cells have receptors for angiotensin II. When these receptors are activated, the glomerular flow is reduced. Mesangial cells also have receptors for the natriuretic factor produced by cardiac atria cells. This factor is a vasodilator and relaxes the mesangial cells, probably increasing the blood flow and the effective surface area available for filtration(9). Mesangial cells are also concerned with the turnover of glomerular basal lamina(1). They clear the glomerular filter of, e.g. immune complexes and cellular debris, and their contractile properties help to regulate blood flow(1). However, the effect of such a contraction on capillary diameter and, consequently, on filtration area is relatively small(12). Similar cells, the extraglomerular mesangial (lacis) cells, lie outside the glomerulus at the vascular pole and form part of the juxtaglomerular apparatus(1, 6, 9).

The proximal convoluted loop starts at the urinary pole of the glomerulus, and here the epithelium becomes cuboidal and low columner. It shows many microvilli, about 1 µm in length, which form a brush border and increase the surface area of the cell. The cytoplasm is acidophilic because of the abundance of elongated mitochondria(9).

The apical cytoplasm of these cells has numerous canaliculi between the bases of the microvilli; these canaliculi further increase the capacity of the proximal tubule cells to absorb macromolecules. Pinocytotic vesicles are formed by evaginations of the apical membranes and contain macromolecules (mainly proteins with a molecular mass less than 70 kDa) that have passed across the glomerular filter. The pinocytotic vesicles fuse with lysosomes, where macromolecules are degraded, and monomers are returned to the circulation(9). The epithelial cells of the proximal convoluted tubule form multiple lateral processes which interdigitate with each other to form a complex lateral intercellular space, with a plasma membrane area equivalent to the luminal plasma membrane(6). The lateral intercellular space is separated from the lumen of the PCT by a ring of junctional complexes near the luminal surface. The mitochondria are elongated and arranged at right angles to the basement membrane. These mitochondria supply ATP for the active transport of Na+ by the Na+-K+ ATPase (sodium pump) located in the basolateral plasma membrane. This active transport of Na+ out of the cell is accompanied by facilitated transport into the cells of Na+, glucose and amino acids by means of transport proteins found in the membrane of the brush border. Almost 100% of the filtered glucose and amino acids is reabsorbed by the proximal convoluted tubules(6). Water diffuses passively following the osmotic gradient. When the amount of glucose in the filtrate exceeds the absorbing capacity of the proximal tubule, urine becomes more abundant and contains glucose(9).

Approximately one-seventh of all nephrons are the juxtamedullary nephrons which are located near the corticomedullary junction. The other nephrons are called cortical nephrons. Juxtamedullary nephrons are of prime importance in establishing the gradient of hypertonicity in the medullary interstitium that forms the basis of the kidneys' ability to produce hypertonic urine. Juxtamedullary nephrons have very long Henle's loops, extending deep into the medulla. These loops consist of a short thick descending limb, long thin descending and ascending limbs, and a thick ascending limb. Cortical nephrons, on the other hand, have very short thin descending limbs and no thin ascending limbs(9). The thin limbs have flat squamous epithelium with very few organelles indicating there relative passive role in absorption and secretion. The thick limbs on the other hand are similar in structure to the distal convoluted tubules, and are lined by simple cuboidal epithelium(1). The function of the loop of Henle is to produce an increasing osmotic gradient from the cortex to the tip of the renal papilla by the 'counter-current multiplier mechanism'(6). Although the thin descending limb of the loop is freely permeable to water, the entire ascending limb is impermeable to water. In the thick ascending limb, sodium chloride is actively transported out of the tubule to establish the gradient of hypertonicity in the medullary interstitium that is necessary for urine concentration. The osmolarity of the interstitium at the tips of the medullary pyramids is about four times that of blood(9).

The thick ascending limb after entering the cortex becomes continuous with the distal convoluted tubule. This part of nephron is also lined by simple cuboidal epithelium. The cells differ from those of the proximal convoluted tubules in that they are smaller and flatter, they do not have a brush border because few microvilli are present, and apical canaliculi are absent. Basal infoldings with numerous mitochondria are elaborate indicating their active role in ion transportation(9). Near the vascular pole of its parent glomerulus, the distal convoluted tubule shows certain modifications along with the afferent arteriole to constitute the juxtaglomerular apparatus.

The juxtaglomerular apparatus (JGA) is a specialization of the glomerular afferent arteriole and the distal convoluted tubule of the same nephron and is involved in the regulation of systemic blood pressure via the renin-angiotensin-aldosterone mechanism. The juxtaglomerular apparatus is made up of three components: the macula densa of the distal convoluted tubule, renin-secreting juxtaglomerular cells of the afferent arteriole and extraglomerular mesangial cells(6).

The macula densa is an area of closely packed, specialised epithelial cells of the distal convoluted tubule, where the the tubule abuts the vascular pole of the glomerulus. These cells are taller and have larger more prominent nuclei situated towards the luminal surface. Mitochondria are scattered throughout the cytoplasm and Na+ pump activity is absent. The basement membrane between the macula and underlying cells is extremely thin The cells of the macula densa are thought to be sensitive to the concentration of sodium ions in the fluid within the distal convoluted tubule(6).

Juxtaglomerular cells are modified smooth muscle cells of the wall of the afferent arteriole. Their cytoplasm contains immature and mature membrane-bound granules of the enzyme renin(6). The internal elastic membrane of the afferent arteriole disappears in the area of the juxtaglomerular cells(9).

Extraglomerular mesangial cells are also called Goormaghtigh cells or lacis cells. These cells form a conical mass, bounded by the afferent and efferent arterioles and macula densa. The lacis cells are flat and elongated with extensive fine cytoplasmic processes extending from their ends and surrounded by a network ('lacis') of mesangial material. The function of the extraglomerular mesangial cells is not yet clear. They may participate in the tubuloglomerular feedback mechanism by which changes in Na+ concentration at the macula densa give rise to signals that directly control glomerular blood flow(6).

Juxtaglomerular apparatus acts both as a baroreceptor and a chemoreceptor. Low blood pressure results in decreased glomerular filtration, and low sodium concentration in the distal convoluted tubules. Macula densa cells are thought to respond to high salt concentration in the distal tubule by releasing nitric oxide, which inhibits the tubuloglomerular feedback response and reduces filtration rate(1). The role of macula densa cells in the stimulation of renin release to increase filtration rate is less well understood. Renin acting as an enzyme converts angiotensinogen, an alph-2 globulin synthesized in liver, into the decapeptide angiotensin I. Angiotensin I is acted upon by angiotensin converting enzyme (ACE) released by pulmonary vascular endothelium, and is converted into angiotensin II. Angiotensin II is a potent vasoconstrictor which increases blood pressure and volume by producing peripheral vasoconstriction, releasing aldosterone by the adrenal cortex, and by a direct action on the distal renal tubules to increase sodium and water reabsorption, thereby increasing blood volume(6).

The collecting tubule, or connecting segment, joins the distal convoluted tubule to the collecting duct. Several collecting tubules merge to form each collecting duct. The collecting tubules and ducts descend in the medullary rays towards the renal medulla where they progressively merge to form the large ducts of Bellini which drain urine from the tip of the renal papilla into the pelvicalyceal system(6). The collecting tubules and ducts concentrate urine by passive reabsorption of water into the medullary interstitium following the osmotic gradient created by the counter-current multiplier system of the loops of Henle. The smaller collecting tubules are lined with cuboidal epithelium and have a have a diameter of approximately 40 µm. As they penetrate deeper into the medulla, their cells increase in height until they become columnar. The diameter of the collecting duct reaches 200 m near the tips of the medullary pyramids(9).

VASCULAR SUPPLY AND DRAINAGE

Each kidney receives from its renal artery which usually divides within the renal sinus into anterior and posterior divisions. Based on its blood supply, each kidney is described to possess five vascular segments(4). The posterior division supplies the posterior segment while the anterior division supplies the apical, upper, middle and lower segments. There are always five segments with no collateral circulation between them irrespective of the arterial variations found in different individuals(4). Within the renal sinus, the arteries give rise to interlobar branches which run between the renal pyramids. At the corticomedullary junction, these arteries form the arcuate arteries which run parallel to the renal capsule. Interlobular arteries arise from the arcuate arteries at a right angle and run towards the capsule radially (cortical radial arteries)(6). Afferent arterioles arise from the interlobular arteries and after giving rise to the glomerular capillaries, again unite to form the efferent arterioles. The efferent arterioles of the cortical glomeruli at once divide to form peritubular capillary network that nourishes the renal cortex. The vasa recta form a continuation of the efferent arterioles of juxtamedullary glomeruli and form the microcirculation of the renal medulla. The cortical and medullary capillaries drain via cortical radial (interlobular) veins to arcuate veins at the cortico-medullary junction and thence to the renal vein(6).

EMBRYOLOGY

Although functionally the urinary and genital systems are quite different, embryologically and anatomically both are closely related. Both develop from intermediate mesoderm along the posterior abdominal wall, and initially the excretory ducts of both the systems open into a common cavity, the cloaca.

Three slightly overlapping kidney systems are formed in a cranial to caudal sequence during intrauterine life in humans: the pronephros, mesonephros, and metanephros. The first of these systems is rudimentary and nonfunctional; the second may function for a short time during the early fetal period; the third forms the permanent kidney(13).

Pronephroi

At the beginning of fourth week, 4-7 solid cell groups are formed in the cervical region which represents the pronephros. These groups form vestigial excretory units, nephrotomes that regress before more caudal ones are formed. The pronephric ducts run caudally and open into the cloaca. The pronephroi soon degenerate; however, most of the length of the pronephric ducts persists and is used by the next set of kidneys. By the end of the fourth week, all indications of the pronephric system have disappeared(13).

Mesonephroi

These large, elongated excretory organs appear late in the fourth week, caudal to the rudimentary pronephroi. The mesonephroi are well developed and function as interim kidneys for approximately four weeks, until the permanent kidneys develop. Early in the fourth week of development, during regression of the pronephric system, the first excretory tubules of the mesonephros appear. They lengthen rapidly, form an S-shaped loop, and acquire a tuft of capillaries that will form a glomerulus at their medial extremity. Around the glomerulus the tubules form Bowman's capsule, and together these structures constitute a renal corpuscle. Laterally, the tubule enters the longitudinal collecting duct known as the mesonephric or wolffian duct(13). Urogenital ridge is formed in the middle of second month. While the caudal tubules are still differentiating, the cranial tubules and corpuscles undergo degeneration, and by the end of second month the majority have disappeared(13). In the male, a few of the caudal tubules and the mesonephric duct persist and participate in formation of the genital system, but they disappear in the female.

Metanephroi

The permanent kidneys develop from two sources:

The metanephric diverticulum (ureteric bud)

The metanephrogenic blastema or metanephric mass of mesenchyme

The metanephric diverticulum is an outgrowth from the mesonephric duct near the point where it enters the cloaca. The metanephrogenic blastema is derived from caudal part of the nephrogenic cord(14). As it elongates, the metanephric diverticulum penetrates the metanephrogenic blastema. The stalk of the metanephric diverticulum becomes the ureter, and the cranial portion of the diverticulum undergoes repetitive branching events, forming the branches which differentiate into the collecting tubules of the metanephros. First four generations coalesce to form the major calyces and the next four generations coalesce to form the minor calyces(14). During further development, collecting tubules of successive generations elongate considerably and converge on the minor calyx, forming the renal pyramid. The ureteric bud gives rise to the ureter, the renal pelvis, the major and minor calyces, and approximately 1 to 3 million collecting tubules(13).

Each newly formed collecting tubule is covered at its distal end by a metanephric tissue cap. Under the inductive influence of the tubule, cells of the tissue cap form small vesicles, the renal vesicles, which in turn give rise to small S-shaped tubules. Capillaries grow into the pocket at one end of the S and differentiate into glomeruli. These tubules, together with their glomeruli, form nephrons, or excretory units. The proximal end of each nephron forms Bowman's capsule, which is deeply indented by a glomerulus. The distal end forms an open connection with one of the collecting tubules, establishing a passageway from Bowman's capsule to the collecting unit. Continuous lengthening of the excretory tubule results in formation of the proximal convoluted tubule, loop of Henle, and distal convoluted tubule(13, 14).

Lead:

Lead ranks as one of the most serious environmental threats to human health, especially in developing countries. In 200 BCE, the Greek poet and philosopher Nikander was the first to note the clinical syndrome of lead poisoning. The downfall of Roman Empire is also considered to be the result of high lead concentration in Roman wine.(15)

Lead is a heavy metal, with low melting point and bluish-grey color, and occurs naturally in the Earth's crust. Much of it comes from human activities including burning fossil fuels, mining, and manufacturing. It is usually found combined with two or more other elements to form lead compounds. Lead has been mined and used in industry and in household products for centuries. The dangers of lead toxicity, the clinical manifestations of which are termed plumbism, have been known since ancient times.(16, 17)

Sorurces of lead:

Lead is the heaviest of the non-radioactive metals that occurs substantially in earth's surface.(18)

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