Glomerular Filtration and Renal Blood Flow

Glomerular Filtration and Renal Blood Flow The kidney’s function in waste removal and volume and electrolyte control Excretion of waste products       Urea (aas metabolism) Creatinine (muscle creatine) Uric acid (nucleic acids) Hemoglobin breakdown products (bilirubin) Hormone metabolites Toxins Regulation of water and electrolyte  Excretion must match intake Several control mechanisms Can match 10-1500 mEq/day Na+ intake   Response to Fluid and Electrolyte Load  The renal response to a fluid/salt load is measured in days but balance is completely attained. Regulation of arterial pressure Acid-Base Balance     Along with lungs and buffers Excretion of acids Regulating buffer stores Excretion of sulfuric and phosphoric acid (protein metabolism) Erythropoietin secretion Active form of Vitamin D Gluconeogenesis  Glucose from aas and other precursors during prolonged fasting A look at the kidney structures General Renal Organization  This is basic anatomy necessary to your understanding of basic renal physiology Basic Tubular Segments  Every single name on this diagram is important to your understanding of renal function. Chart the movement of fluid from the blood to the urine Structure of the Bowman’s (glomerular) capsule Parietal layer of glomerular capsule Afferent arteriole Juxtaglomerular cell Capsule space Efferent arteriole Proximal convoluted tubule Endothelium of glomerulus Podocyte Pedicel The nephron The nephron is the functional unit of the kidney Each region is composed of cells that are suited to perform specific transport functions Distal convoluted tubule Proximal convoluted tubule Collecting duct Ascending thin limb of loop of Henlé Ascending thick limb of loop of Henlé  Cortical nephrons have short loops with abundant peritubular capillaries. Juxtamedullary nephrons have long loops and the vasa recta Micturition (The Act…….)  2 step process:  Filling of the bladder and ↑wall tension  Nervous reflex “micturition reflex” that empties the bladder or induces the desire to urinate Reflex from the ANS from the spinal cord Can also be inhibited or facilitated by the cerebral cortex or brain stem   Anatomy of Micturition  The Parasymp. Fibers contain both sensory and excitatory fibers creating a feedback loop. Transport from Kidney to Bladder  Peristaltic action along ureters initiated by stretch of the renal calyces as urine passes out of the collecting ducts. Urine passes down ureter and through bladder wall (detrusor muscle).  In ureters, peristalsis is enhanced by parasymp. stim. and inhibited by symp. stim. Contraction of detrusor muscle is a major step in emptying the bladder.   Muscle cells fused to each other, so action potential can spread along entire bladder.  Vesicoureteral reflux: urine propelled back into the ureter due to incomplete occlusion in bladder wall (kidney damage).  Ureterorenal reflex: blockage of ureters (stones) associated with intense constriction reflex and pain. ↓ Urine output from kidney. Micturition Micturition Reflex  As bladder fills sensory stretch receptors send signals via pelvic nerves to sacral segments of spinal cord. Parasympathetic stimulation of the bladder smooth muscle via the same pelvic nerves occurs. It is “self-regenerative”, subsides, then regenerates again until the external sphincter is relaxed and urination can occur.   Micturition Reflex Cycle        Single and complete cycle Progressive and rapid increase in pressure Period of sustained pressure Return of the pressure to the basal tone of the bladder Once reflex is powerful enough, it will pass via pudendal nerves to the external sphincter to inhibit it If inhibition is more potent in brain than voluntary constrictor signals to external sphincter , urination will occur If not, bladder continues to fill until reflex becomes powerful enough Facilitation and Inhibition by the Brain  Higher centers keep micturition reflex partially inhibited, except when micturition is desired.  Higher centers can prevent micturition by contraction of the external sphincter. When urination is desired, cortical centers can facilitate the sacral micturition centers to help initiate a micturition reflex and inhibit the external sphincter so urination can occur.  Voluntary Urination  Contraction of the abdominal muscles  Increase the pressure in the bladder Extra urine enters bladder neck and posterior urethra leading to wall stretching Stretch receptors activated leading to micturition reflex and inhibition of external urethral sphincter   Micturition Abnormalities    Atonic Bladder - destruction of sensory fibers  Traumatic spinal cord injury  Overflow incontinence Automatic Bladder - spinal cord injury above sacral region  Micturition reflex is intact but uncontrolled Uninhibited Neurogenic Bladder - loss of higher center inhibition  Interruption of inhibitory signals  Frequent urination Urine formation Three step process:  Product of glomerular filtration Tubular reabsorption into the blood Tubular secretion from the blood into renal tubules   Urinary excretion rate =Filtration rate Reabsorption rate + Secretion rate  These are all the possible mechanisms that are involved in the renal handling of fluid, electrolytes, nutrients and waste products. It is also the basis for understanding renal function test. Fundamental Renal Equation   Urine excretion is determined by 3 rates Excretion = Filtration - Reabsorption + Secretion Excretion = amt. of urine lost to outside world  1) Filtration = amt. of plasma filtered at glomerulus into Bowman’s capsule (GFR)  2) Reabsorption = amt. of GFR that filters back into the peritubular capillaries  3) Secretion = amt. of peritubular fluid that is transported into the urinary tubular fluid  Renal Handling of Substances  Four Classes of substances  A - Filtered, not reabsorbed (creatinine, inulin, uric acid)  B - Filtered, partly reabsorbed (Na+, Cl-, bicarbonate)  C - Filtered, totally reabsorbed (amino acids, glucose)  D - Filtered, totally secreted (organic acids and bases) Inulin clearance Advantages of High GFR  High GFR is necessary to remove waste products that are filtered but poorly reabsorbed.  High GFR makes it possible for entire plasma volume to be filtered several times per day. If plasma=3L with GFR 180L/day (60 x/day) Renal Hemodynamics  GFR is determined by:  Hydrostatic and colloid osmostic forces  Capillary filtration coeficient (Kf) Glomerular Capillaries  Higher filtration rate  ↑hydrostatic pressure and large Kf  Renal Hemodynamics  Renal Blood Flow (RBF) is 20% of Cardiac Output (CO)  Glomerular Filtration Rate (GFR) is 20 % of RPF where RPF = Renal Plasma Flow Filtration fraction (FF) = GFR / RPF  FILTRATION FRACTION Filtration fraction is an important expression of the extent of glomerular filtration. Glomerular filtration rate It is the ratio: Filtration fraction = Renal plasma flow Renal blood flow 1250 ml/min glomerulus GFR 150 ml/min tubule ~149 ml/min RPF 750 ml/min Efferent Arteriole 600 ml/min It is the fraction of renal plasma flow that is filtered at the glomerulus renal vein Urine ~1 ml/min FILTRATION FRACTION an example Glomerular filtration rate (GFR) is about: 150 ml/min Renal blood flow is about: 1250 ml/min Renal plasma flow (RPF) is about: 750 ml/min Remember: plasma volume is about 60% of total blood volume Thus, in this example filtration fraction is: 150 ≈ 0.2 750 This means that 20% of the plasma flowing through the kidneys is filtered GFR and RPF can be measured separately using clearance methods Filtration Process  Glomerular membrane is similar to other capillary membranes except for the presence of the Podocytes Effect of charge on filtration Albumin = 6 nanometers vs glomerular membrane = 8 nanometers In some kidney disease negative charges are lost from membrane and albumin appears in urine “Proteinuria” or “Albuminuria” Filtration Process Bowman’s space  pedicel filtration slit capillary Capillary endothelium has fenestra which pass plasma proteins easily. Barrier is associated with (-) charged proteoglycans in the basement membrane. Filterability of the Membrane  Filterability is a term used to describe membrane selectivity based on the molecular size and charge Pore size would favor plasma protein (albumin) passage, but negative charge on protein is repelled by the (-) charged basement membrane (proteoglycan filaments & podocytes) Loss of this (-) charge causes proteinuria condition called minimal change nephropathy   Determinants of GFR GFR=Kf x Net filtration pressure Kf = Capillary filtration coeficient Force Analysis at Glomerular Membrane      Filt. Press. = Kf * (Pg- Pb- pg+ pb) = +10 mmHg Kf is affected by diseases that change membrane thickness or pore area (e.g. diabetes, hypertension) Pb can be increased do to urinary tract obstruction Pg changes with changes in Ra and/or Re pg increases normally from 28 to 36 mm Hg as it passes along capillary due to loss of 1/5 of fluid Forces affecting filtration Favoring Filtration Glomerular hydrostatic pressure 60 mm Hg Bowman’s capsule colloid osmotic pressure 0 mm Hg Opposing Filtration Glomerular capillary colloid osmotic pressure 32 mm Hg Bowman’s capsule hydrostatic pressure 18 mm Hg Net = +10 mm Hg Glomerular capillary filtration coeficient (Kf)  Hydraulic conductivity and surface area of the glomerular capillary  Kf=GFR/Net filtration pressure GFR=125 ml/min and 10 mm Hg filtration pressure Kf=12.5ml/min/mm Hg filtration pressure   Increased Glomerular Capillary Colloid Osmotic Pressure decreases GFR  Note: This is a graphical way of saying that RPF changes can also affect GFR Filtration fraction (FF) = GFR / RPF Glomerular Hydrostatic Pressure Determined by: Arterial Pressure Afferent Arteriolar Resistance Efferent Arteriolar Resistance ↑ Hydrostatic Pressure ↑ GFR, ↓ Hydrostatic Pressure ↓GFR Ra and Re effect on GFR  GFR changes are inversely proportional to Ra changes. Increase in Re causes increase in GFR to a point then GFR decreases to very low value Oxygen consumption vs sodium reabsorption Renal Blood Flow (Renal artery pressure-Renal vein pressure) (Total Renal Vascular Resistance)  Greatest vascular resistance: Interlobular arteries  Afferent arterioles  Efferent arterioles  All controlled by the Sympathetic Nervous System, Hormones and local mechanisms RENAL BLOOD FLOW (RBF) Renal blood flow is about 20% of the cardiac output This is a very large flow relative to the weight of the kidneys (≈350 g)  RBF determines GFR  RBF also modifies solute and water reabsorption and delivers nutrients to nephron cells. Flow, l/min 1.5 1.0 0.5 GFR 0 0 100 200 Arterial blood pressure, mm Hg Renal blood flow  Renal blood flow is autoregulated between 90 and 180 mm Hg by varying renal vascular resistance (RVR) i.e. the resistances of the interlobular artery, afferent arteriole and efferent arteriole Pressure Drops across the Renal Vasculature Autoregulation of RBF & GFR Note: Autoregulation is important to prevent large changes in GFR that would greatly affect urinary output.  Impact of autoregulation  Autoregulation:  GFR=180L/day and tubular reabsorption=178.5L/day  Results in 1.5L/day in urine  Without autoregulation:  Small ↑ in BP 100 to 125mm Hg, ↑GFR by 25% (180 to 225L/day)  If tubular reabsorption constant, urine flow of 46.5 L/day What would happen to plasma volume?  RENAL BLOOD FLOW - AUTOREGULATION Autoregulation effectively uncouples renal function from arterial blood pressure and ensures that fluid and solute excretion is constant. Two hypotheses have been proposed to explain autoregulation 1. Myogenic hypothesis Flow When arterial pressure increases the renal afferent arteriole is stretched increases Increase of arterial pressure Flow increases RENAL BLOOD FLOW - AUTOREGULATION 1. Myogenic hypothesis When arterial pressure increases the renal afferent arteriole is stretched Increase of arterial pressure Vascular smooth muscle responds by contracting thus increasing resistance Increase of vascular tone Flow increases Flow returns to normal RENAL BLOOD FLOW - AUTOREGULATION 2. Tubuloglomerular feedback Alteration of tubular flow (NaCl ) is sensed by the macula densa of the juxtaglomerular apparatus (JGA) and produces a signal (renin) that alters GFR 4. Ra GFR 3.signal from JGA GFR 2. filtrate Juxtaglomerular Apparatus  Each tubular portion of the nephron descends into the medulla and returns to its glomerulus thus providing a direct linkage between tubular processing and glomerular function Feedback mechanism for GFR  Decreased NaCl in macula densa is due to increased reabsorption resulting from the slower tubular flow Regulation of GFR  Sympathetic nerves (↓GFR)  Afferent & efferent arterioles are innervated by α1 adrenoreceptors  A reduction in effective circulating volume or strong emotional stimuli (e.g. fear and pain) usually activates sympathetic nerves Regulation of GFR  Angiotensin II (↑GFR)  Produced systemically (and also by kidneys)  Constricts mainly efferent arterioles  ↑ GFR and ↓ RBF Hemorrhage (↓GFR)  Decreases arterial pressure leading to activation of kidney sympathetic nerves  Regulation of GFR  ANP (↑GFR)  Circulating ANP level rises with hypertension & expansion in effective circulating volume (ECV) dilating afferent arteriole ADH (↓GFR)  High concentration of ADH promotes renal vasoconstriction and contraction of mesangial cells  Regulation of GFR  Glucocorticoids (↑GFR)  Dilation of afferent arterioles which elevates RBF  NO (↑GFR)  Vasorelaxation with increase blood flow  An increase in shear force acting on glomerular endothelial cells increases release of NO and vasodilation via increasing cGMP in mesangial cells Regulation of GFR  Endothelin (↓GFR)  Potent vasoconstrictor secreted by endothelial cells in arterioles in response to vascular damage  Stretch causes increased secretion of endothelin Prostaglandins and Bradykinin (↑GFR)  During pathophysiological conditions (e.g., hemorrhage), PGE2 and PGI2 are produced locally within kidneys and vasodilation of afferent & efferent arterioles 