Glomerular filtration, Determinants of GFR and FF Dr. shafali singh

Learning objectives Regional differences in nephron structure: cortical and juxtamedullary nephrons To learn 3 process: Glomerular filtration, Tubular reabsorption and tubular secretion-and how it affects renal excretion To learn about the determinants of GFR To be able to calculate FF, GFR, RBF and RPF

kidneys function As excretory organs, the kidneys ensure that those substances in excess or that are harmful are excreted in urine in appropriate amounts. As regulatory organs, the kidneys maintain a constant volume and composition of the body fluids by varying the excretion of solutes and water. As endocrine organs, the kidneys synthesize and secrete three hormones: renin(enzyme), erythropoietin, and 1,25-dihydroxycholecalciferol

Renal blood flow About 20% of cardiac output(kidneys only 0.4% of BW) Very low oxygen extraction 2 capillary beds arranged in series, separated by efferent arterioles- High hydrostatic pressure in the glomerular capillaries( about 60 mm of Hg) favors filtration; low hydrostatic pressure ( about 13 mm of Hg) in peritubular capillaries favors reabsorption. Blood flow in vasa recta is very low: receives only 1-2%, remainder cortex

Renal artery interlobar artery arcuate artery Interlobular artery afferent arteriole glomerular capillaries efferent arterioles peritubular capillaries

7/8 of all nephrons are cortical nephrons 1/8 of all nephrons are juxtamedullary nephrons

In the cortex, the proximal and distal tubules, as well as the initial segment of the collecting duct, are surrounded by a capillary network, and the interstitium is close to an isotonic environment (300 mOsm). The medullary region instead has capillary loops organized similar to the loops of Henle. The slow flow through these capillary loops preserves the osmolar gradient of the interstitium. However, this slow flow also keeps the PO2 of the medulla lower than that in the cortex. Even though the metabolic rate of the medulla is lower than in the cortex, it is more susceptible to ischemic damage

Glomerular filtration: 1st step in urine formation Structure of the filtering membrane Composition of the glomerular filtrate: ultrafiltrate of plasma devoid of protein and cells The basement membrane has strong negative charge (Proteoglycans) –prevents filtration of Plasma proteins

GLOMERULAR FILTRATION

Filtration membrane

The Filtering Membrane The membrane of the glomerulus consists of 3 main structures: Capillary endothelial wall with fenestrations that have a magnitude greater than proteins. In addition the wall is covered with negatively charged compounds. A glomerular basement membrane made up of a matrix of extracellular negatively charged proteins and other compounds. An epithelial cell layer of podocytes next to Bowman’s space. The podocytes have foot processes bridged by filtration slit diaphragms. Around the capillaries is the mesangium containing mesangial cells, which are similar to monocytes. They can contract and affect GFR and renal blood flow. In addition to the net hydraulic force, GFR depends on both the permeability and the surface area of the filtering membrane. The decrease in GFR in most diseased states is due to a reduction in the membrane surface area. This would also include a decrease in the number of functioning nephrons. The capillary wall with its fenestrated endothelium, the basement membrane with hydrated spaces, and the interdigitating foot processes of the podocytes combined with an overall large surface area, creates a high hydraulic conductivity (permeable to water and dissolved solutes) but restricts the passage of large proteins because of negative charge of the membrane system.

Materials Filtered The following are easily or freely filtered: Major electrolytes: sodium, chloride, potassium, bicarbonate Metabolic waste products: Urea Creatinine Metabolites: glucose, amino acids, organic acids (ketone bodies) Nonnatural substances: inulin, PAH (p-aminohippuric acid) Lower-weight proteins and peptides: insulin, myoglobin The following are not freely filtered: Albumin and other plasma proteins Lipid-soluble substances transported in the plasma attached to proteins such as lipid-soluble bilirubin, T4 (thyroxine), other lipid-soluble hormones

Determinants of GFR GFR=K f X Net filtration pressure Forces favoring Filtration (mm g Hg) Glomerular hydrostatic pressure: 60 Bowmans capsule colloid osmotic pressure:0 Forces opposing filtration Bowmans capsule hydrostatic pressure: 18 Glomerular capillary colloidal osmotic pressue: 32 Net filtration pressure???

GFR = Kf[(Pgc - Pbs) - (Pgc - Pbs)] GFR Formula GFR = Kf[(Pgc - Pbs) - (Pgc - Pbs)] Where Kf = glomerular filtration coefficient (product of glomerular surface times hydraulic conductivity) Pgc = glomerular hydrostatic pressure Pbs = hydrostatic pressure in Bowman’s Space - Pgc = glomerular capillary oncotic pressure - Pbs = Bowman’s Space oncotic pressure (negligible)

Kf is the filtration coefficient of the glomerular capillaries. ■ The glomerular barrier consists of the capillary endothelium, basement membrane,and filtration slits of the podocytes. ■ Normally, anionic glycoproteins line the filtration barrier and restrict the filtration of plasma proteins, which are also negatively charged. ■ In glomerular disease, the anionic charges on the barrier may be removed, resulting in proteinuria.

Effect of size and electrical charge of dextran on its filterability by the glomerular capillaries. A value of 1.0 indicates that the substance is filtered as freely as water, whereas a value of 0 indicates that it is not filtered. Dextrans are polysaccharides that can be manufactured as neutral molecules or with negative or positive charges and with varying molecular weights.

Size of the Capillary Bed Kf can be altered by the mesangial cells, with contraction of these cells producing a decrease in Kf that is largely due to a reduction in the area available for filtration

Increase in colloid osmotic pressure in plasma flowing through the glomerular capillary. Normally, about one fifth of the fluid in the glomerular capillaries filters into Bowman’s capsule, thereby concentrating the plasma proteins that are not filtered. Increases in the filtration fraction (glomerular filtration rate/renal plasma flow) increase the rate at which the plasma colloid osmotic pressure rises along the glomerular capillary; decreases in the filtration fraction have the opposite effect.

Use the values below to answer the following question. Glomerular capillary hydrostatic pressure = 47 mm Hg Bowman’s space hydrostatic pressure = 10 mm Hg Bowman’s space oncotic pressure =0 mm Hg At what value of glomerular capillary oncotic pressure would glomerular filtration stop? (A) 57 mm Hg (B) 47 mm Hg (C) 37 mm Hg (D) 10 mm Hg (E) 0 mm Hg

Q Given the following values, calculate the net filtration pressure: glomerular blood hydrostatic pressure = 40 mmHg, capsular hydrostatic pressure = 10 mmHg, blood colloid osmotic pres-sure =30 mmHg. (a) 20 mmHg (b) 0 mmHg (c) 20 mmHg (d) 60 mmHg (e) 80 mmHg

NEPHRON HEMODYNAMICS The individual nephrons that make up both kidneys are connected in parallel. However, the flow through a single nephron represents2 arterioles and 2 capillary beds connected in series

If Pin and Pout are kept constant, the following will occur if the central resistance,increases: Flow through R1, R2, and R3 will decrease equally. Pb pressure downstream decreases. Pa pressure upstream increases. If Pin and Pout are kept constant, the following will occur if the central resistance decreases: Flow through R1, R2, and R3 will increase equally. Pb pressure downstream increases. Pa pressure upstream decreases.

Connected in series are the high-pressure filtering capillaries of the glomerulus and the low pressure reabsorbing peritubular capillaries.

Determinants of GFR

Consequences of Independent Isolated Constrictions or Dilations of the Afferent and Efferent Arterioles

In adults, the GFR averages 125 mL/min or about 180 L/day The amount of filtrate formed in all the renal corpuscles of both kidneys each minute is the glomerular filtration rate (GFR). In adults, the GFR averages 125 mL/min or about 180 L/day If one kidney is removed (1/2 of the functioning nephrons lost), GFR decreases only about 25% because the other nephrons compensate

Net Filtration pressure

Hydrostatic pressure of the glomerular capillaries PGC: The hydrostatic pressure of the glomerular capillaries is the only force that promotes filtration. Under normal conditions, this is the main factor that determines GFR.

2. Oncotic pressure of the plasma πGC: The oncotic pressure of the plasma varies with the concentration of plasma proteins. Because fluid is filtered but not protein, oncotic pressure, which opposes filtration, will increase from the beginning to the end of the glomerular capillaries The increased concentration of protein will be carried into the peritubular capillaries and will promote a greater net force of reabsorption

3. Hydrostatic pressure in Bowman’s space PBS: The hydrostatic pressure in Bowman’s capsule opposes filtration. Normally, it is low and fairly constant and does not affect the rate of filtration. However, it will increase and reduce filtration whenever there is an obstruction downstream, such as a blocked ureter or urethra (postrenal failure). 4. Protein or oncotic pressure in Bowman’s space πBS: This represents the protein or oncotic pressure in Bowman’s space. Very little if any protein is present, and for all practical purposes this factor can be considered zero

Filtration fraction

Which of the following are features of the renal corpuscle that enhance its filtering capacity? (1) large glomerular capillary surface area, (2) thick, selectively permeable filtration membrane, (3) high capsular hydrostatic pressure, (4) high glomerular capillary pressure, (5) mesangial cells regulating the filtering surface area. (a) 1, 2, and 3 (b) 2, 4, and 5 (c) 1, 4, and 5 (d) 2, 3, and 4 (e) 2, 3, and 5

reduction in renal plasma flow with no initial change in GFR would tend to increase the filtration fraction, which would raise the glomerular capillary colloid osmotic pressure and tend to reduce GFR. For this reason, changes in renal blood flow can influence GFR independently of changes in glomerular hydrostatic pressure. With increasing renal blood flow, a lower fraction of the plasma is initially filtered out of the glomerular capillaries, causing a slower rise in the glomerular capillary colloid osmotic pressure and less inhibitory effect on GFR. Consequently, even with a constant glomerular hydrostatic pressure, a greater rate of blood flow into the glomerulus tends to increase GFR, and a lower rate of blood flow into the glomerulus tends to decrease GFR.

Constriction of the efferent arterioles increases the resistance to outflow from the glomerular capillaries. This raises the glomerular hydrostatic pressure, and as long as the increase in efferent resistance does not reduce renal blood flow too much, GFR increases slightly However, because efferent arteriolar constriction also reduces renal blood flow, the filtration fraction and glomerular colloid osmotic pressure increase as efferent arteriolar resistance increases. Therefore, if the constriction of efferent arterioles is severe (more than about a threefold increase in efferent arteriolar resistance), the rise in colloid osmotic pressure exceeds the increase in glomerular capillary hydrostatic pressure caused by efferent arteriolar constriction.When this occurs, the net force for filtration actually decreases, causing a reduction in GFR.

Three mechanisms control GFR: renal autoregulation- myogenic tubuloglomerular feedback neural regulation hormonal regulation

I. Renal autoregulation consists of two mechanisms— myogenic mechanism tubuloglomerular feedback. Working together, they can maintain nearly constant GFR over a wide range of systemic blood pressures.

Autoregulation of Renal Blood Flow and GFR

1.myogenic mechanism As blood pressure rises, GFR also rises because renal blood flow increases. However, the elevated blood pressure stretches the walls of the afferent arterioles. In response, smooth muscle fibers in the wall of the afferent arteriole contract, which narrows the arteriole’s lumen. As a result, renal blood flow decreases, thus reducing GFR to its previous level. Conversely, when arterial blood pressure drops, the smooth muscle cells are stretched less and thus relax. The afferent arterioles dilate, renal blood flow increases, and GFR increases. The myogenic mechanism normalizes renal blood flow and GFR within seconds after a change in blood pressure.

2. tubuloglomerular feedback.

Low GFR slows the flow rate in the loop of henle, causing increased reabsorption of sodium and chloride ions in the ascending loop of henle

II. Neural Regulation of GFR Kidneys are supplied by sympathetic ANS fibers that release norepinephrine. Norepinephrine causes vasoconstriction through the activation of α 1 receptors, which are particularly plentiful in the smooth muscle fibers of afferent arterioles. At rest, sympathetic stimulation is moderately low, the afferent and efferent arterioles are dilated, and renal autoregulation of GFR prevails.

With moderate sympathetic stimu, both afferent and efferent arterioles constrict to the same degree. Blood flow into and out of the glomerulus is restricted to the same extent, which decreases GFR only slightly. With greater sympathetic stimulation, however, as occurs during exercise or hemorrhage, vasoconstriction of the afferent arterioles predominates. As a result, blood flow into glomerular capillaries is greatly decreased, and GFR drops.

III. Hormonal Regulation of GFR Angiotensin II normalises GFR. Angiotensin constricts the efferent more than the afferent arterioles. 2. Atrial natriuretic peptide (ANP) increases GFR. causes relaxation of the glomerular mesangial cells, and increases the capillary surface area available for filtration. Glomerular filtration rate rises as the surface area increases Cells in the atria of the heart secrete atrial natriuretic peptide (ANP). Stretching of the atria, as occurs when blood volume increases, stimulates secretion of ANP. NE, E, Endothelin constrict renal blood vessels and decrease GFR Nitric oxide causes vasodilation and increase GFR PG, Bradykinin ( cause vasodilation) increase GFR NSAIDs (aspirin) block the vasodilation caused by PGs

Calculate Filtered load of a compound: Plasma concentration of the compound X GFR Excretion load: Urine Concentration X Volume of urine ml/min Filtration fraction (FF= GFR/RPF) RBF and RPF (RBF=Renal Plasma flow/1-Hct)

If plasma concentration of glucose is 100mg/100 ml and GFR is 125ml/min. Calculate Filtered load of glucose? Concentration of calcium in plasma is 5 mmol/l and Bowmans capsule is 3 mmol . How do you explain this? 125mg/min

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