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Renal system
- 1. Renal System Themba Hospital FCOG(SA) Part 1 Tutorials By Dr N.E Manana
- 2. THE NEPHRON ⢠Each individual renal tubule and its glomerulus is a unit (nephron) ⢠Each human kidney has approximately 1 million nephrons. ⢠The glomerulus, which is about 200 Îźm in diameter, is formed by the invagination of a tuft of capillaries into the dilated, blind end of the nephron (Bowmanâs capsule) ⢠The capillaries are supplied by an afferent arteriole and drained by the efferent arteriole and it is from the glomerulus that the filtrate is formed ⢠The glomerular membrane permits the free passage of neutral substances up to 4nm in diameter and almost totally excludes those with diameters greater than 8nm.
- 3. ⢠37.1
- 4. ⢠37.2
- 5. ⢠37.3
- 6. RENAL CIRCULATION ⢠In a resting adult, the kidneys receive 1.2â1.3 L of blood per minute, or just under 25% of the cardiac output ⢠Because the kidney filters plasma, any excreted substance can be used if its concentration in arterial and renal venous plasma can be measured and if it is not metabolized, stored, or produced by the kidney and does not itself affect blood flow. ⢠When the mean systemic arterial pressure is 100 mm Hg, the glomerular capillary pressure is about 45 mm Hg
- 7. GLOMERULAR FILTRATION ⢠Glomerular filtration rate (GFR) is the amount of plasma ultrafiltrate formed each minute ⢠A substance to be used to measure GFR must be freely filtered through the glomeruli and must be neither secreted nor reabsorbed by the tubules ⢠Inulin, a polymer of fructose, meets these criteria in humans and most animals and can be used to measure GFR ⢠Clearance of creatinine (CCr ) can also be used to determine GFR, however some creatinine is secreted by the tubules thus the clearance of creatinine will be slightly higher than inulin
- 8. CONTROL OF GFR ⢠The factors governing filtration across the glomerular capillaries are the same as those governing filtration across all other capillaries ⢠The size of the capillary bed ⢠The permeability of the capillaries ⢠And hydrostatic and osmotic pressure gradients across the capillary wall.
- 9. ⢠37.4
- 10. TUBULAR FUNCTION ⢠The amount of the substance excreted per unit of time equals the amount filtered plus the net amount transferred by the tubules ⢠Small proteins and some peptide hormones are reabsorbed in the proximal tubules by endocytosis. ⢠Other substances are secreted or reabsorbed in the tubules by passive diffusion between cells and through cells by facilitated diffusion down chemical or electrical gradients or active transport. ⢠Movement is by way of ion channels, exchangers, cotransporters, and pumps ⢠Renal active transport systems have a maximal rate, or transport maximum
- 11. Na + REABSORPTION ⢠The reabsorption of Na+ and Clâ plays a major role in body electrolyte and water homeostasis ⢠In addition, Na+ transport is coupled to the movement of H+ , glucose, amino acids, organic acids, phosphate, and other electrolytes and substances across the tubule walls ⢠Na+ is actively transported out of all parts of the renal tubule except the thin portions of the loop of Henle ⢠Normally about 60% of the filtered Na+ is reabsorbed in the proximal tubule, primarily by NaâH exchange. ⢠Another 30% is absorbed via the Naâ2ClâK cotransporter in the thick ascending limb of the loop of Henle
- 12. ⢠37.12
- 13. ⢠Table 37.5
- 14. GLUCOSE REABSORPTION ⢠Glucose, amino acids, and bicarbonate are reabsorbed along with Na+ in the early portion of the proximal tubule ⢠Glucose is typical of substances removed from the urine by secondary active transport. ⢠Essentially all of the glucose is reabsorbed, and no more than a few milligrams appear in the urine per 24 h. ⢠When the transport maximum is exceeded, the amount of glucose in the urine rises ⢠Glucose and Na+ bind to the sodium-dependent glucose transporter (SGLT) in the apical membrane, and glucose is carried into the cell as Na+ moves
- 15. ADDITIONAL SECONDARY ACTIVE TRANSPORT ⢠Like glucose reabsorption, amino acid reabsorption is most marked in the early portion of the proximal convoluted tubule ⢠The main carriers in the apical membrane cotransport Na+ , whereas the carriers in the basolateral membranes are not Na+ -dependent ⢠Na+ is pumped out of the cells by Na, K ATPase and the amino acids leave by passive or facilitated diffusion to the interstitial fluid. ⢠Some Clâ is reabsorbed with Na+ and K+ in the thick ascending limb of the loop of Henle.
- 17. WATER TRANSPORT ⢠Normally, 180L of fluid is filtered through the glomeruli each day, while the average daily urine volume is about 1L ⢠At least 87% of the filtered water is reabsorbed ⢠And second, the reabsorption of the remainder of the filtered water can be varied without affecting total solute excretion. ⢠Therefore, when the urine is concentrated, water is retained in excess of solute; and when it is dilute, water is lost from the body in excess of solute ⢠A key regulator of water output is vasopressin acting on the collecting ducts. ⢠The changes in osmolality and volume in the collecting ducts depend on the amount of vasopressin acting on the ducts
- 18. ⢠37.13
- 19. ROLE OF UREA ⢠Urea contributes to the establishment of the osmotic gradient in the medullary pyramids and to the ability to form a concentrated urine in the collecting ducts ⢠Urea transport is mediated by urea transporters, presumably by facilitated diffusion. ⢠During antidiuresis, when vasopressin is high, the amount of urea deposited in the medullary interstitium increases ⢠A high protein diet increases the ability of the kidneys to concentrate the urine
- 20. OSMOTIC DIURESIS ⢠The presence of large quantities of unreabsorbed solutes in the renal tubules causes an increase in urine volume called osmotic diuresis ⢠Solutes that are not reabsorbed in the proximal tubules exert an appreciable osmotic effect ⢠Therefore, they âhold water in the tubules.â ⢠The limiting concentration gradient is reached, and further proximal reabsorption of Na+ is prevented; more Na + remains in the tubule, and water stays with it
- 21. REGULATION OF Na+ EXCRETION MECHANISMS ⢠Variations in Na+ excretion are brought about by changes in GFR and changes in tubular reabsorption, primarily in the 3% of filtered Na+ that reaches the collecting ducts. ⢠The factors affecting GFR, including tubuloglomerular feedback ⢠Factors affecting Na+ reabsorption include the circulating level of aldosterone and other adrenocortical hormones, the circulating level of ANP and other natriuretic hormones, and the rate of tubular secretion of H+ and K + .
- 22. REGULATION OF WATER EXCRETION ⢠The feedback mechanism controlling vasopressin secretion and the way vasopressin secretion is stimulated by a rise and inhibited by a drop in the effective osmotic pressure of the plasma. ⢠The water diuresis produced by drinking large amounts of hypotonic fluid begins about 15 min after ingestion of a water load and reaches its maximum in about 40 min. ⢠The act of drinking produces a small decrease in vasopressin secretion before the water is absorbed, but most of the inhibition is produced by the decrease in plasma osmolality after the water is absorbed.
- 23. REGULATION OF K+ EXCRETION ⢠Much of the filtered K+ is removed from the tubular fluid by active reabsorption in the proximal tubules, and K+ is then secreted into the fluid by the distal tubular cells. ⢠The rate of K+ secretion is proportional to the rate of flow of the tubular fluid through the distal portions of the nephron ⢠In the absence of complicating factors, the amount secreted is approximately equal to the K+ intake, and K+ balance is maintained. ⢠In the collecting ducts, Na+ is generally reabsorbed and K+ is secreted.
- 25. THE BLADDER FILLING ⢠The walls of the ureters contain smooth muscle arranged in spiral, longitudinal, and circular bundles, but distinct layers of muscle are not seen. ⢠Regular peristaltic contractions occurring one to five times per minute move the urine from the renal pelvis to the bladder ⢠The ureters pass obliquely through the bladder wall and, although there are no ureteral sphincters as such, the oblique passage tends to keep the ureters closed except during peristaltic waves,
- 26. THE BLADDER EMPTYING ⢠The smooth muscle of the bladder, like that of the ureters, is arranged in spiral, longitudinal, and circular bundles. ⢠Contraction of the circular muscle, which is called the detrusor muscle, is mainly responsible for emptying the bladder during urination (micturition). ⢠Muscle bundles pass on either side of the urethra, and these fibers are sometimes called the internal urethral sphincter, although they do not encircle the urethra.
- 27. ⢠37.19
- 28. THE BLADDER ⢠During micturition, the perineal muscles and external urethral sphincter are relaxed, the detrusor muscle contracts, and urine passes out through the urethra ⢠One of the initial events is relaxation of the muscles of the pelvic floor, and this may cause a sufficient downward tug on the detrusor muscle to initiate its contraction ⢠The perineal muscles and external sphincter can be contracted voluntarily, preventing urine from passing down the urethra or interrupting the flow once urination has begun ⢠After urination, the female urethra empties by gravity. Urine remaining in the urethra of the male is expelled by several contractions of the bulbocavernosus muscle.
- 29. ⢠38.5
- 30. ⢠38.6
- 31. ⢠Table 38.2 and 38.3
- 33. ERYTHROPOIETIN ⢠When an individual bleeds or becomes hypoxic, hemoglobin synthesis is enhanced, and production and release of red blood cells from the bone marrow (erythropoiesis) are increased ⢠These adjustments are brought about by changes in the circulating level of erythropoietin ⢠Erythropoietin increases the number of erythropoietin sensitive committed stem cells in the bone marrow that are converted to red blood cell precursors and subsequently to mature erythrocytes ⢠In adults, about 85% of the erythropoietin comes from the kidneys and 15% from the liver
- 34. THANK YOU
Editor's Notes
- The diameter of the afferent arteriole is larger than the efferent arteriole Two cellular layers separate the blood from the glomerular filtrate in Bowmanâs capsule: the capillary endothelium and the specialized epithelium of the capsule The endothelium of the glomerular capillaries is fenestrated, with pores that are 70â90 nm in diameter. The endothelium of the glomerular capillaries is completely surrounded by the glomerular basement membrane along with specialized cells called podocytes. Podocytes have numerous pseudopodia that interdigitate to form filtration slits along the capillary wall. The slits are approximately 25 nm wide, and each is closed by a thin membrane. The total area of glomerular capillary endothelium across which filtration occurs in humans is about 0.8 m2 .
- The human proximal convoluted tubule is about 15mm long and 55Îźm in diameter. Its wall is made up of a single layer of cells that interdigitate with one another and are united by apical tight junctions. Between the cells are extensions of the extracellular space called the lateral intercellular spaces The convoluted proximal tubule straightens and the next portion of each nephron is the loop of Henle The descending portion of the loop and the proximal portion of the ascending limb are made up of thin, permeable cells. On the other hand, the thick portion of the ascending limb is made up of thick cells containing many mitochondria The nephrons with glomeruli in the outer portions of the renal cortex have short loops of Henle (cortical nephrons) , whereas those with glomeruli in the juxtamedullary region of the cortex (juxtamedullary nephrons) have long loops extending down into the medullary pyramids. In humans, only 15% of the nephrons have long loops The macula, the neighboring lacis cells , and the renin-secreting granular cells in the afferent arteriole form the juxtaglomerular apparatus The distal convoluted tubule, which starts at the macula densa, is about 5 mm long. Its epithelium is lower than that of the proximal tubule, and although a few microvilli are present, there is no distinct brush border The distal tubules coalesce to form collecting ducts that are about 20 mm long and pass through the renal cortex and medulla to empty into the pelvis of the kidney at the apexes of the medullary pyramids The epithelium of the collecting ducts is made up of principal cells (P cells) and intercalated cells (I cells). Th e P cells, which predominate, are relatively tall and have few organelles. They are involved in Na + reabsorption and vasopressin-stimulated water reabsorption. Th e I cells, which are present in smaller numbers and are also found in the distal tubules, have more microvilli, cytoplasmic vesicles, and mitochondria. They are concerned with acid secretion and HCO 3 â transport. The total length of the nephrons, including the collecting ducts, ranges from 45 to 65mm.
- Cells in the kidneys that appear to have a secretory function include not only the granular cells in the juxtaglomerular apparatus but also some of the cells in the interstitial tissue of the medulla. These cells are called renal medullary interstitial cells (RMICs) and are specialized fibroblast-like cells . They contain lipid droplets and are a major site of cyclooxygenase 2 (COX-2) and prostaglandin synthase (PGES) expression. PGE 2 is the major prostanoid synthesized in the kidney and is an important paracrine regulator of salt and water homeostasis. PGE 2 is secreted by the RMICs, by the macula densa, and by cells in the collecting ducts; prostacyclin (PGI 2 ) and other prostaglandins are secreted by the arterioles and glomeruli.
- The afferent arterioles are short, straight branches of the interlobular arteries. Each divides into multiple capillary branches to form the tuft of vessels in the glomerulus. The capillaries coalesce to form the efferent arteriole, which in turn breaks up into capillaries that supply the tubules (peritubular capillaries) before draining into the interlobular veins. The arterial segments between glomeruli and tubules are thus technically a portal system, and the glomerular capillaries are the only capillaries in the body that drain into arterioles. However, there is relatively little smooth muscle in the efferent arterioles.
- Norepinephrine (noradrenaline) constricts the renal vessels, with the greatest effect of injected norepinephrine being exerted on the interlobular arteries and the afferent arterioles. Dopamine is made in the kidney and causes renal vasodilation and natriuresis. Angiotensin II exerts a constrictor effect on both the afferent and efferent arterioles Renal blood flow can be measured with electromagnetic or other types of flow meters, or it can be determined by applying the Fick principle to the kidney; that is, by measuring the amount of a given substance taken up per unit of time and dividing this value by the arteriovenous difference for the substance across the kidney Because the kidney filters plasma, the renal plasma flow (RPF) equals the amount of a substance excreted per unit of time divided by the renal arteriovenous difference as long as the amount in the red cells is unaltered during passage through the RPF can be measured by infusing p - aminohippuric acid (PAH) and determining its urine and plasma concentrations. Prostaglandins increase blood fl ow in the renal cortex and decrease blood fl ow in the renal medulla. Acetylcholine also produces renal vasodilation. A high-protein diet raises glomerular capillary pressure and increases renal blood fl ow.
- In addition to the requirement that it be freely filtered and neither reabsorbed nor secreted in the tubules, a substance suitable for measuring the GFR should be nontoxic and not metabolized by the body. Renal plasma clearance is the volume of plasma from which a substance is completely removed by the kidney in a given amount of time (usually minutes) . Therefore, if the substance is designated by the letter X, the GFR is equal to the concentration of X in urine (U X ) times the urine fl ow per unit of time (VË ) divided by the arterial plasma level of X (P X ), or UXVË /PX. Th is value is called the clearance of X (C X ).
- It is important to note that the pumps and other transporters in the luminal membrane are different from those in the basolateral membrane As was discussed for the gastrointestinal epithelium, it is this polarized distribution that makes possible net movement of solutes across the epithelia. It should also be noted that the tubular epithelium, like that of the small intestine, is a leaky epithelium in that the tight junctions between cells permit the passage of some water and electrolytes. The degree to which leakage by this paracellular pathway contributes to the net flux of fluid and solute into and out of the tubules is controversial since it is difficult to measure, but current evidence seems to suggest that it is a significant factor in the proximal tubul
- In the distal convoluted tubule 7% of the filtered Na + is absorbed by the NaâCl cotransporter The remainder of the filtered Na + , about 3%, is absorbed via ENaC channels in the collecting ducts In the proximal tubules, the thick portion of the ascending limb of the loop of Henle, the distal tubules, and the collecting ducts, Na + moves by cotransport or exchange from the tubular lumen into the tubular epithelial cells down its concentration and electrical gradients, and is then actively pumped from these cells into the interstitial space. Na + is pumped into the interstitium by Na, K ATPase in the basolateral membrane It extrudes three Na + in exchange for two K + that are pumped into the cell. passive paracellular movement of Na + also contributes to overall Na + reabsorption The remainder of the filtered Na + , about 3%, is absorbed via ENaC channels in the collecting ducts, and this is the portion that is regulated by aldosterone to permit homeostatic adjustments in Na + balance.
- Signals from the renal tubule in each nephron feed back to affect filtration in its glomerulus. As the rate of flow through the ascending limb of the loop of Henle and first part of the distal tubule increases, glomerular filtration in the same nephron decreases, and, conversely, a decrease in flow increases the GFR This process, which is called tubuloglomerular feedback, tends to maintain the constancy of the load delivered to the distal tubule. The sensor for this response is the macula densa. The amount of fluid entering the distal tubule at the end of the thick ascending limb of the loop of Henle depends on the amount of Na + and Cl â in it. Th e Na + and Cl â enter the macula densa cells via the NaâKâ2Cl cotransporter in their apical membranes. The increased Na + causes increased Na, K ATPase activity and the resultant increased ATP hydrolysis causes more adenosine to be formed. Presumably, adenosine is secreted from the basal membrane of the cells. It acts via adenosine A 1 receptors on the macula densa cells to increase their release of Ca 2+ to the vascular smooth muscle in the afferent arterioles. This causes afferent vasoconstriction and a resultant decrease in GFR. Presumably, a similar mechanism generates a signal that decreases renin secretion by the adjacent juxtaglomerular cells in the afferent arteriole but this remains unsettled.
- It is filtered at a rate of approximately 100 mg/min (80 mg/dL of plasma Ă 125 mL/min). The amount reabsorbed is proportional to the amount filtered and hence to the plasma glucose level (P G ) times the GFR up to the transport maximum (Tm G ). The Tm G is about 375 mg/min in men and 300 mg/min in women. One would predict that the renal threshold would be about 300 mg/dL, that is, 375 mg/min (Tm G ) divided by 125 mL/min (GFR). However, the actual renal threshold is about 200 mg/dL of arterial plasma, which corresponds to a venous level of about 180 mg/dL. Glucose reabsorption in the kidneys is similar to glucose reabsorption in the intestine The Na+ is then pumped out of the cell into the interstitium, and the glucose exits by facilitated diffusion via glucose transporter (GLUT) 2 into the interstitial fluid
- Absorption in this location resembles absorption in the intestine In addition, two members of the family of Cl channels have been identifi ed in the kidney. Mutations in the gene for one of the renal channels is associated with Ca 2+ -containing kidney stones and hypercalciuria (Dent disease), but how tubular transport of Ca 2+ and Cl â are linked is still unsettled.
- The same load of solute can be excreted per 24 h in a urine volume of 500 mL with a concentration of 1400 mOsm/kg or in a volume of 23.3 L with a concentration of 30 mOsm/kg Rapid diffusion of water across cell membranes depends on the presence of water channels, integral membrane proteins called aquaporins 13 aquaporins have been cloned; however, only four aquaporins (aquaporin-1, -2, -3, and -4) play a key role in the kidney Aquaporin-1 is localized to both the basolateral and apical membrane of the proximal tubules and its presence allows water to move rapidly out of the tubule along the osmotic gradients set up by active transport of solutes, and isotonicity is maintained. This antidiuretic hormone from the posterior pituitary gland increases the permeability of the collecting ducts to water. Th e key to the action of vasopressin on the collecting ducts is aquaporin-2.
- There are at least four isoforms of the transport protein UT-A in the kidneys (UT-A1 to UT-A4); UT-B is found in erythrocytes and in the descending limbs of the vasa recta. Urea transport in the collecting duct is mediated by UT-A1 and UT-A3, and both are regulated by vasopressin
- Osmotic diuresis is produced by the administration of compounds such as mannitol and related polysaccharides that are fi ltered but not reabsorbed In the loop, reabsorption of water and Na + is decreased because the medullary hypertonicity is decreased. The decrease is due primarily to decreased reabsorption of Na + , K + , and Cl â in the ascending limb of the loop because the limiting concentration gradient for Na + reabsorption is reached. More fluid passes through the distal tubule, and because of the decrease in the osmotic gradient along the medullary pyramids, less water is reabsorbed in the collecting ducts. The result is a marked increase in urine volume and excretion of Na + and other electrolytes. It is also produced by naturally occurring substances when they are present in amounts exceeding the capacity of the tubules to reabsorb them. For example, in diabetes mellitus, if blood glucose is high, glucose in the glomerular filtrate is high, thus the filtered load will exceed the Tm G and glucose will remain in the tubules causing polyuria. Osmotic diuresis can also be produced by the infusion of large amounts of sodium chloride or urea
- There is no rigid one-for-one exchange, and much of the movement of K + is passive.
- Farther along the urethra is a sphincter of skeletal muscle, the sphincter of the membranous urethra (external urethral sphincter). The bladder epithelium is made up of a superficial layer of flat cells and a deep layer of cuboidal cells
- Micturition is fundamentally a spinal reflex facilitated and inhibited by higher brain centers and, like defecation, subject to voluntary facilitation and inhibition A plot of intravesical pressure against the volume of fluid in the bladder is called a cystometrogram . The curve shows an initial slight rise in pressure when the first increments in volume are produced; a long, nearly flat segment as further increments are produced; and a sudden, sharp rise in pressure as the micturition reflex is triggered The first urge to void is felt at a bladder volume of about 150 mL, and a marked sense of fullness at about 400 mL The flatness of segment Ib is a manifestation of the law of Laplace. This law states that the pressure in a spherical viscus is equal to twice the wall tension divided by the radius. In the case of the bladder, the tension increases as the organ fills, but so does the radius. Therefore, the pressure increase is slight until the organ is relatively full
- The bands of smooth muscle on either side of the urethra apparently play no role in micturition, and their main function in males is believed to be the prevention of reflux of semen into the bladder during ejaculation. It is through the learned ability to maintain the external sphincter in a contracted state that adults are able to delay urination until the opportunity to void presents itself The bladder smooth muscle has some inherent contractile activity; however, when its nerve supply is intact, stretch receptors in the bladder wall initiate a reflex contraction that has a lower threshold than the inherent contractile response of the muscle. In the adult, the volume of urine in the bladder that normally initiates a reflex contraction is about 300â400 mL The reason for the difference between the small, hypertrophic bladder seen in this condition and the distended, hypotonic bladder seen when only the afferent nerves are interrupted is not known
- Erythropoietin can also be extracted from the spleen and salivary glands, but these tissues do not contain its mRNA and consequently do not appear to manufacture the hormone. Erythropoietin, a circulating glycoprotein that contains 165 amino acid residues and four oligosaccharide chains that are necessary for its activity in vivo. Its blood level is markedly increased in anemia When renal mass is reduced in adults by renal disease or nephrectomy, the liver cannot compensate and anemia develops. Erythropoietin is produced by interstitial cells in the peritubular capillary bed of the kidneys and by perivenous hepatocytes in the liver. It is also produced in the brain, where it exerts a protective eff ect against excitotoxic damage triggered by hypoxia; and in the uterus and oviducts, where it is induced by estrogen and appears to mediate estrogen-dependent angiogenesis.