Renal Function PDF

L3 Objective : 1-Difition of glomerular filtration. 2-Mechanism of glomerular filtration. 3-Struture of glomerular capillary membrane. Glomerular Filtration Urine formation begins with glomerular filtration, the bulk flow of fluid from the glomerular capillaries into Bowman's capsule. The glomerula...

L3 Objective : 1-Difition of glomerular filtration. 2-Mechanism of glomerular filtration. 3-Struture of glomerular capillary membrane. Glomerular Filtration Urine formation begins with glomerular filtration, the bulk flow of fluid from the glomerular capillaries into Bowman's capsule. The glomerular filtrate (ie, the fluid within Bowman's capsule) is very much like blood plasma. However, plasma proteins, blood cells and protein binding substance like fatty acid are virtually excluded from moving through the filtration barrier. The filtrate contains most inorganic ions and low- molecular-weight organic solutes in virtually the same concentrations as in the plasma. Substances that are present in the filtrate at the same concentration as found in the plasma are said to be freely filtered. As glomeular filtrate leaves Bowman's capsule and passes through the renal tubules, its composition is modified by reabsorption of water and specific solutes back into the blood or by secretion of other substances from the peritubular capillaries into the tubules. The volume of filtrate formed per unit time is known as the glomerular filtration rate (GFR). In a normal young adult male, the GFR is an incredible 180 L/day (125 mL/min). When we recall that the average total volume of plasma in humans is approximately 3 L, it follows that the entire plasma volume is filtered by the kidneys some 60 times a day. The opportunity to filter such huge volumes of plasma enables the kidneys to excrete large quantities of waste products and to regulate the constituents of the internal environment very precisely. Urine formation results from glomerular filtration, tubular reabsorption, and tubular secretion The rates at which different substances are excreted in the urine represent the sum of three renal processes: (1) glomerular filtration, (2) reabsorption of substances from the renal tubules into the blood, and (3) secretion of substances from the blood into the renal tubules. Expressed mathematically as follow: Urinary excretion rate = Filtration rate - Reabsorption rate + Secretion rate According to this equation the renal handle different substances in four main pattern : A. some substance is freely filtered by the glomerular capillaries but is neither reabsorbed nor secreted. Therefore, its excretion rate is equal to filtration rate. B. some substance is freely filtered, but partly reabsorbed from the tubules back into the blood. Therefore, the rate of urinary excretion is less than the rate of filtration, like electrolytes (sodium, potassium) C. some substance is freely filtered at the glomerular capillaries but it is totally reabsorbed from the tubules back into the blood. Therefore, the rate of urinary excretion of these substance is zero, like amino acids and glucose. D. some substance is freely filtered at the glomerular capillaries and is not reabsorbed, but additional quantities of this substance are secreted from the blood into the renal tubules. The excretion rate in this case is calculated as filtration rate plus tubular secretion rate, like organic acids and base. Figure9: Urine formation results from glomerular filtration, tubular reabsorption, and tubular secretion. Glomerular Capillary Membrane The filtered substances must pass from blood into bowman capsule through glomerular membrane. The total area of glomerular capillary endothelium across which filtration occurs in humans is about 0.8 m 2. The glomerular capillary membrane has had three major layers: 1.The endothelial cells of the capillaries, is perforated by many large fenestrae ("windows"), like a slice of Swiss cheese. and rich with fixed negative charges. 2.The basement membrane: The thickness of the basement membrane about 50 nm, it consist of glycoproteins and proteoglycans. The proteoglycans have a net negative charge. In minimal change nephropathy the negative charges on the basement membrane are lost , as a result proteins, especially albumin, are filtered and appear in the urine, a condition known as proteinuria or albuminuria. 3.The epithelial cells ( podocytes); the podocytes have an unusual octopus-like structure called pedicels (or foot processes), extend from each arm of the podocyte and are embedded in the basement membrane. Pedicels from adjacent podocytes interdigitate forming slits through which the filtrate enter Bowman's space. Podocyte membranes also have a high density of negative charge. The glomerulus also contain mesangial cells which are interstitial cells ,they act as phagocytes and remove trapped material from the basement membrane. They also contain myofilaments and can contract.Contraction of the mesangial cells could augment the resistance of the arterioles and possibly change the number of open capillary loops in the glomerular tuft.  Figure 10.The glomerular membrane..Size, shape, and electrical charge affect the filterability of molecules The glomerular capillary membrane is thicker than most other capillaries, but it is also much more porous and therefore filters fluid at a high rate. The filtration rate, of any substance depend on: 1.Molecular size; Functionally, the glomerular membrane permits the free passage of neutral substances up to 4 nm in diameter and almost totally excludes those with diameters greater than 8 nm. Most plasma proteins are large molecules, so they are not appreciably filtered. 2.Electrical charge, glomerular endothelial cells, podocytes, and the basement membrane all have a negatively charge. They impede the passage of negatively charged molecules by electrostatic repulsion and favor the passage of positively charged molecules by electrostatic attraction. Filtration fraction(FF) The fraction of the renal plasma flow that is filtered (the filtration fraction) averages about 0.2; this means that about 20 per cent of the plasma flowing through the kidney is filtered through the glomerular capillaries. The filtration fraction is calculated as follows: Determinants of the GFR The pressures that drive fluid movement across the glomerular capillary wall are the Starling forces(pressures). There are four Starling pressures: two hydrostatic pressures (one in glomerular capillary and called Glomerular hydrostatic pressure PG and one in Bowman’s capsul called th Bowman’s capsule hydrostatic pressure PB) and two colloid osmotic pressures (one in glomerular capillary and called Glomerular capillary colloid osmotic pressure πG and one in Bowman's space and called Bowman’s capsule colloid osmotic pressure πB). According to the Starling equation the GFR is the product of Filtration coefficient (K f) and the net ultrafiltration pressure. The net filtration pressure, is the algebraic sum of the four Starling pressures as in the following equation: The net filtration = Forces Favoring Filtration - Forces Opposing Filtration Forces Favoring Filtration (mm Hg) Glomerular hydrostatic pressure 60 Bowman’s capsule colloid osmotic pressure 0 Forces Opposing Filtration (mm Hg) Bowman’s capsule hydrostatic pressure 18 Glomerular capillary colloid osmotic pressure 32 Thus the net filtration = [(60 + 0-(18+32)] = 10 mmHg. According to the Starling equation GFR =Kf x 10 where GFR is the Glomerular filtration rate (mL/min), K f is Filtration coefficient (mL/min. mm Hg) , PG is Hydrostatic pressure in glomerular capillary (mm Hg) , PB is Hydrostatic pressure in Bowman's space (mm Hg), πG is colloid osmotic pressure in glomerular capillary (mm Hg) and πB is colloid osmotic pressure in Bowman's space. Figure9 : The forces causing filtration by the glomerular capillaries. For glomerular capillaries, the net ultrafiltration pressure is 10 mmHg in favors of filtration, so that the direction of fluid movement is always out of the capillaries. The greater the net pressure, the higher the rate of glomerular filtration. Filtration coefficient(Kf )  The Kf is the water permeability or hydraulic conductance of the glomerular capillary wall. The two factors that contribute to K f are the water permeability of glomerular capillary per unit of surface area time the total surface area of the glomerular capillary. K f is calculated from GFR and the net filtration pressure , normally the GFR is about 125 ml/min and the net filtration pressure is 10 mm Hg, Kf = GFR/ net filtration pressure Kf = 125/10 =12.5 ml/min/mm Hg The normal Kf is calculated to be about 12.5 ml/min/mm Hg of filtration pressure for both kidneys. When Kf is expressed per 100 grams of kidney weight, it averages about 4.2 ml/min/mm Hg. The of Kf of renal capillary glomeruli is about 400 times as high as the K f of most other capillary systems of the body; the average Kf of many other tissues in the body is only about 0.01 ml/min/mm Hg per 100 grams. This high Kf for the glomerular capillaries contributes tremendously to their rapid rate of fluid filtration. Factors that decrease GFR 1.decreased Kf lead to decrease GFR, as in uncontrolled hypertension and diabetes mellitus which results in increasing the thickness of the glomerular capillary basement membrane and, eventually, by damaging the capillaries 2. Increased bowman's capsule hydrostatic pressure decreases GFR. This can be produced by obstructing urine flow (e.g., ureteral stone ) 3. Increased glomerular capillary colloid osmotic pressure decreases GFR. 4. constriction of the afferent arteriole, in which afferent arteriolar resistance increases. This will lead to decreases glomerular Hydrostatic Pressure and also decreases GFR. Figure10: decrease GFR due to constriction of the afferent arteriole Factors that increase GFR The main factors that can increase GFR are 1. Increased glomerular capillary hydrostatic pressure increases GFR as in case of increase arterial pressure, or increase efferent arteriolar resistance. 2. decreases in plasma protein concentration (e.g., nephrotic syndrome, in which large amounts of protein are lost in urine) produce decreases in glomerular capillary colloid osmotic pressure (π GC), which increase both net ultrafiltration pressure and GFR. Figure11.increase GFR due to constriction of the efferent arteriole Regulation of renal blood flow (RBF) As with blood flow in any organ, renal blood flow (Q) is directly proportional to the pressure gradient (ΔP) between the renal artery and the renal vein, and it is inversely proportional to the resistance (R) of the renal vasculature: Q = ΔP/R. (Q= renal artery pressure - renal vein pressure/ resistance) the resistance is provided mainly by the arterioles. As described by Poiseiulle's law, resistance of a cylindrical vessel varies inversely with the fourth power of vessel radius. It takes only a 19% decrease or increase in vessel radius to double or halve vessel resistance. The radius of arterioles are regulated by the state of contraction of the arteriolar smooth muscle. The kidneys are unusual, however, in that there are two sets of arterioles, the afferent and the efferent. The major mechanism for changing blood flow is by changing afferent arteriolar resistance and/or efferent arteriolar resistance. The main factors which regulate RBF and in turn GFR are: 1. Sympathetic nervous system and circulating catecholamines Both afferent and efferent arterioles are innervated by sympathetic nerve fibers that produce vasoconstriction by activating α1 receptors. However, because there are far more α1 receptors on afferent arterioles, increased sympathetic nerve activity causes a decrease in both RBF and GFR. The effects of the sympathetic nervous system on renal vascular resistance can be appreciated by considering the responses to hemorrhage. 2.Angiotensin II Angiotensin II is a potent vasoconstrictor, it constricts both sets of arterioles, increases resistance, and decreases blood flow. However, the efferent arteriole is more sensitive to angiotensin II than the afferent arteriole. Thus, low levels of angiotensin II produce more constriction in efferent arterioles leading to increase glomerular hydrostatic pressure and increase in GFR. However, high levels of angiotensin II produce a decrease in GFR by constricting both afferent and efferent arterioles. In hemorrhage, blood loss leads to decreased arterial pressure, which activates the renin-angiotensin-aldosterone system. The high level of angiotensin II, together with increased sympathetic nerve activity, constricts afferent and efferent arterioles and causes a decrease in RBF and GFR.(why ACE inhibitors are contra indicated in hypertensive patients with renal artery stenosis?). 3.Prostaglandins Several prostaglandins (e.g., prostaglandin E2 and prostaglandin I2) are produced locally in the kidneys and cause vasodilation of both afferent and efferent arterioles. The same stimuli that activate the sympathetic nervous system and increase angiotensin II levels in hemorrhage also activate local renal prostaglandin production. Although these actions may seem contradictory, the vasodilatory effects of prostaglandins are clearly protective for RBF. Thus, prostaglandins modulate the vasoconstriction produced by the sympathetic nervous system and angiotensin II. Unopposed, this vasoconstriction can cause a profound reduction in RBF, resulting in renal failure. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit synthesis of prostaglandins and, therefore, interfere with the protective effects of prostaglandins on renal function following a hemorrhage. 4.Dopamine Dopamine, a precursor of norepinephrine, has selective actions on arterioles in several vascular beds. At low levels, dopamine dilates cerebral, cardiac, splanchnic, and renal arterioles, and it constricts skeletal muscle and cutaneous arterioles. Thus, a low dosage of dopamine can be administered in the treatment of hemorrhage because of its protective (vasodilatory) effect on blood flow in several critical organs, including the kidneys. 5.Endothelin The most potent vasoconstrictor of endothelial origin is endothelin. Endothelin actually represents a family of 21-amino-acid peptides that are synthesized by various endothelial cells. Endothelin acts on neighboring vascular smooth muscle cells in arterioles to increase intracellular Ca+2 by releasing it from intracellular stores and thus increasing arteriolar resistance. The production of endothelin has been implicated in the nephrotoxicity of some drugs such as cyclosporine. 6. Nitric oxide (NO), previously referred to as endothelial-derived relaxing factor, is also released by endothelial cells in response to increased shear stress or pressure. NO is a potent vasodilator in most arterioles including the afferent and efferent renal arterioles. The binding of acetylcholine, bradykinin, or histamine to endothelial cells results in the production of NO and decreased arteriolar resistance. Endothelial-derived nitric oxide decreases renal vascular resistance and increases RBF and GFR. Clinical Note Nonsteroidal anti-inflammatory drugs (NSAIDs;e.g., ibuprofen, naproxen, aspirin, and acetaminophen) exert analgesic, antipyretic, and anti- inflammatory effects because they inhibit the enzyme cyclooxygenase, which is necessary for the synthesis of prostaglandins from arachidonic acid. In normal individuals, the use of these drugs has little or no effect on RBF or GFR. However, in patients who have hemorrhaged or who are dehydrated (volume contracted), or who are otherwise physically stressed, these drugs may exacerbate damage to the kidney and increase the likelihood of acute renal failure. In these situations, the pathologic event increases the activity of the renal nerves, which is accompanied by the release of renin and the production of angiotensin II. Both increased renal nerve activity and angiotensin II increase afferent and efferent arteriolar resistance and decrease both RBF and GFR. When severe, these responses can diminish RBF to the point of renal infarction. This extreme situation is normally countered by the release of prostaglandins whose vasodilatory actions oppose the vasoconstrictors. When the patient is being treated with NSAIDs, prostaglandin synthesis is inhibited and, consequently, the likelihood of acute renal failure is increased with hemorrhage, dehydration, or surgical stress. For this reason, NSAIDs are contraindicated before many surgical procedures, or when circulating renin or catecholamine levels, or renal sympathetic nerve activity, are expected to be high. For example, NSAIDs must be used with caution or avoided in patients with chronic renal failure, congestive heart failure, cirrhosis of the liver with ascites, or before surgery. L4 Objective : 1-Mechanism of Autoregulation of renal blood flow and GFR 2- Autocrine function of the kidney Autoregulation of renal blood flow and GFR Despite changes in mean arterial blood pressure (from 80 to 180 mm Hg) , renal blood flow is kept at a relatively constant level, a process known as autoregulation Autoregulation is an intrinsic property of the kidneys and is observed even in an isolated, denervated, perfused kidney. GFR is also autoregulated When the blood pressure is raised or lowered, vessels upstream of the glomerulus (cortical radial arteries and afferent arterioles) constrict or dilate, respectively, maintaining relatively constant glomerular blood flow and capillary pressure. Below or above the autoregulatory range of pressures, blood flow and GFR change appreciably with arterial blood pressure. Renal autoregulation