5.4 Glomerular Filtration, Renal Blood Flow and their Control11.pptx

Glomerular Filtration, Renal Blood Flow, and Their Control Lecture Outline I. Glomerular filtration- the first step in urine formation II. Determinants of the glomerular filtration rate III. Renal blood flow IV. Physiological control of glomerular filtration and renal blood flow 1 Glomerular Filt...

Glomerular Filtration, Renal Blood Flow, and Their Control Lecture Outline I. Glomerular filtration- the first step in urine formation II. Determinants of the glomerular filtration rate III. Renal blood flow IV. Physiological control of glomerular filtration and renal blood flow 1 Glomerular Filtration, Renal Blood Flow, and Their Control Objectives 1. Describe how the cardiac output to the kidney is divided into plasma and filtrate 2. Explain why albumin is not filtered through the three layers of the glomerular capillary membrane 3. Identify the blood pressure in renal circulation 4. Identify normal GFR and contribution of Starling forces to net filtration pressure 5. Explain how increases in afferent and efferent arteriolar resistance affect GFR 6. Identify factors that affect the glomerular capillary filtration coefficient (Kf) 7. Explain renal oxygen consumption 8. Identify the effect of the following mechanisms on renal vessels: sympathetic stimulation, norepinephrine, angiotensin II, NO, prostaglandins, the myogenic mechanism, and tubuloglomerular 2 feedback References Assigned reading from your text: Hall Chapter 27 3 lomerular Filtration and Renal Blood Flow  • • • Kidneys receive 20-25% CO Then separates that volume: 20% plasma filtered at the glomerulus- becomes glomerular filtrate 80% of blood not filtered circulates through the peritubular capillaries  • • • • Blood travels through the following structures in order: Afferent arteriole Glomerular capillaries Efferent arteriole Peritubular capillaries  Glomerular filtration is the first step in urine formation • GFR = 125 mL/min = 180 L/day • Most of this filtrate is reabsorbed- only 1 L excreted daily • Per day, the kidneys filter the total plasma volume 60 times • Glomerular capillaries impermeable to large proteins • Filtrate (ultrafiltrate) similar to plasma without proteins Glomerular Capillary Filtration Barrier or Membrane anatomic structures a solute passes through during filtration: 1. Endothelium of capillary • Fenestrated • Fixed negative charges hinder passage of plasma proteins 2. Basement membrane • Collagen and proteoglycan filaments hinders filtration of plasma proteins due to strong negative charges associated with proteoglycans 3. Podocytes-epithelial cells surrounding basement membrane • Not continuous- have long pedicels that encircle the capillaries • Slit pores separate pedicels to filter plasma from blood • Podocytes and their pedicels also have a negative charge to restrict filtration of plasma proteins  Fixed negative charges repel negatively charged macromolecules • Albumin is almost small enough to be filtered- From Slide 18 Lecture 5.1 nical Significance of Proteinuria • Early detection of renal disease in at-risk patients; renal disease can be “silent.” • Hypertension: hypertensive renal disease • Diabetes: diabetic nephropathy • Pregnancy: gestational proteinuric hypertension (pre-eclampsia) • Annual “check-up”: renal disease can be silent. • Assessment and monitoring of known renal disease • Proteinuria/ Albumineria - presence of significant amounts of albumin in urine can be due to loss of negative charges in the glomerular wall (occurs in nephritis)- Renal Plasma Flow, Glomerular Filtration Rate, Tubular Reabsorption and Urine Flow Rate  Filtration volumes and fractions • Average renal plasma flow (no cells) • 900 L/day • 625 ml/min • Normal GFR • 180 L/day • 3 L plasma filtered 60 x/day • 125 ml/min • Filtration fraction = GFR/RPF • ~0.2 • 20% plasma flowing through kidney is filtered through the capillaries Glomerular Filtration Pressure  Blood pressure in renal circulation • Blood flow is inversely proportional to resistance, and a change in resistance is the major mechanism for changing blood flow, particularly in arterioles. • Resistance vessels at each end of glomerular capillaries (in arterioles) maintains high pressure (60 mmHg) that drives filtration • Promotes plasma filtration through glomerulus into Bowman’s space • High resistance to flow in efferent arteriole contributes to low BP in peritubular capillaries to promote erminants of Glomerular Filtration Rate  GFR= net filtration pressure forcing fluid out of the glomerular capillaries and the permeability of the filtration barrier GFR= Net filtration pressure x Kf 1. Starling forces are responsible for the net filtration pressure (bulk flow) across the capillaries: Sum of 2 forces (hydrostatic and osmotic) forces in 2 compartments: • Hydrostatic and osmotic pressure inside glomerular capillaries • Hydrostatic and osmotic pressure inside Bowman’s space 2. Glomerular capillary filtration (or ultrafiltration) coefficient (Kf) • Kf is the permeability of the filtration barrier and is a product of two factors: • Glomerular capillary wall hydraulic conductivity (permeability) • Highly permeable capillaries-50 x more permeable than in muscle • Filterability determined by molecular size and electric charge • Effective filtration surface area GFR Part I- Hydrostatic and Osmotic Press Forces Favoring Filtration  Glomerular Hydrostatic Pressure (PG) = ~ 60 mmHg • • Increased PG increases GFR; Decreased PG decreases GFR Determined by arterial pressure, afferent arteriolar resistance, efferent arteriolar resistance  Bowman’s Capsule Colloid Osmotic Pressure (∏ B) = zero • Normally considered to be zero due to low protein in filtrate Forces Opposing Filtration  Glomerular Capillary Colloid Osmotic Pressure (∏ G) = Averages 32 mmHg • • Increased ∏G decreases glomerular filtration rate Plasma protein concentration increases from afferent to efferent arteriole due to filtered fraction & Donnan effect • eg Severe dehydration from water deprivation, excess sweating, vomiting, and diarrhea  Bowman’s Capsule Hydrostatic Pressure (P B) = ~ 18 mmHg • • • Increased PB decreases GFR Obstruction decreases GFR and can cause hydronephrosis- can damage kidney unless relieved Normally changes as a function of GFR- it is not a regulator of GFR Effect of Afferent and Efferent Arteriolar Constriction on Glomerular Pressure PG determined by arterial pressure, afferent and efferent arteriolar resistance  Afferent arteriolar resistance (R) predictably affects GFR • • Increased RA (Constriction) decreases PG and GFR = Constriction reduces GFR Dilation of RA increases PG and GFR  Efferent arteriolar resistance (R) has a biphasic effect on GFR • • • Constriction of RE increases outflow resistance from glomerular capillaries Increases PG to a point and slightly increases GFR Severe constriction of RE reduces RBF • 3-fold increase in RE will decrease GFR GFR Part II- Glomerular Capillary Filtration Coefficient (Kf) • Kf = hydraulic conductivity (glomerular capillary permeability) × surface area • Normal values: • GFR = 125 mL/min • Net filt. press = 10 mm Hg • Kf = 12.5 mL/min per mm Hg • Normally not highly variable- can change in normal and disease states • Intraglomerular mesangial cells can contract or relax to reduce or increase GFR • Two hormones-Antidiuretic Hormone (ADH) and Angiotensin II -are capable of causing mesangial cells to contract reducing filtration surface area, and GFR Disease that canKf reduce Kf and GFR - chronic hypertension - obesity/diabetes mellitus - glomerulonephritis Renal Blood Flow • High blood flow through both kidneys 1100 ml/min (~22% of CO) • Exceeds metabolic needs • Provides high GFR for ECF regulation of solutes that may be at low % in plasma • Most oxygen consumption is related to active renal tubular sodium reabsorption • RBF = Renal artery pressure – Renal vein pressure Total renal vascular R • An increase in RBF without an increase in BP indicates a decrease in renal vascular resistance • Renal vascular R resides in interlobular arteries, afferent arterioles, and efferent arterioles • Blood flow in vasa recta of renal medulla is Figure 27-8 From Kramer K, Deetjen P: Relation of renal oxygen consumption to blood supply and glomerular filtration during variations of blood pressure. Pflugers Arch Physiol 271:782, 1960 Special Instances of Renal Blood Flow • The renal cortex receives 90% RBF • PO2 in this region is 50 mmHg • The renal medulla and juxtamedullary nephrons receive 10% of RBF • PO2 in this region is 10 mmHg • Lower RBF and PO2 of renal medulla explains sensitivity to ischemia • RBF decreases 10 % per decade of life after age 50 Physiologic Control of Glomerular Hydrostatic Pressure  Glomerular hydrostatic pressure • Is the most variable determinant of GFR subject to physiological control • 70% of vascular resistance to RBF resides in the interlobular arteries, afferent arterioles, and efferent arterioles • This variable (PG) is influenced by the following: • Neurohumoral mechanisms controls resistance to RBF via: • Sympathetic nervous system innervation • Hormones • Autocoids • Autoregulation- maintains a relatively constant GFR to preserve precise control of renal excretion of water and solutes Neurohumoral Mechanisms Control Resistance to RBF - SNS  Resistance to RBF is controlled by: • Sympathetic nervous system • Sympathetic fibers innervate afferent and efferent arterioles • Nociceptive fibers parallel these efferents to convey kidney pain • Innervation from T10-L2 spinal nerves • Release NE on ɑ1 adrenergic receptors of arteriolar smooth muscle cells • Sympathetic outflow causes both afferent and efferent arterioles to vasoconstrict equally • Normal sympathetic input has no significant effect on PGC • Vasoconstriction decreases PGC and RBF; vasodilation increases PGC and RBF • Intense sympathetic stimulation can greatly reduce GFR for minutes to hours Neurohumoral Mechanisms Control Resistance to RBFHormones/Autoicoids  (Continued) Resistance to RBF is controlled by: • Hormones & Autocoids (vasoactive substances released locally) • Norepinephrine, epinephrine, and endothelin • Secreted by the adrenal medulla vasoconstrict afferent and efferent arterioles • Little effect on renal hemodynamics except during severe conditions (hemorrhage) • Endothelin likely responds to vascular injury • Angiotensin II preferentially constricts efferent arterioles • Angiotensin II receptors present in all renal vessels • Endothelial-derived nitric oxide and prostaglandins counteract the vasoconstrictor effect of Angiotensin II in afferent arterioles • ACE Inhibitors and ARBs • Endothelial-derived Nitric Oxide decreases renal vascular resistance and increases GFR • Contributes to basal vasodilation • Damage to endothelium (atherosclerosis) or drugs that inhibit NO formation may increase renal vasoconstriction and elevate blood pressure • Prostaglandins and bradykinin decrease renal vascular resistance and toregulation of Renal Blood Flow Maintains GFR but not Urine F  MAP • Increased MAP increases GFR • Decreased MAP decreases GFR  Autoregulation • Feedback mechanisms intrinsic to the kidneys; Maintains RBF and GFR relatively constant; protects against hypoperfusion and hyperperfusion • Maintained in excised, perfused kidneys • Kidneys autoregulate GFR and RBF over a range of arterial BPs (80-170 mmHg) • Autoregulation does not maintain urine output • Carried out by: 1. Myogenic mechanism 2. Tubuloglomerular feedback from the macula densa - involves the juxtaglomerular apparatus and Autoregulation of Renal Blood Flow- Myogenic Mechanism  Myogenic mechanism controls afferent arteriolar resistance • Renal vascular resistance varies in direct proportion to renal arterial pressure so that RBF remains almost constant • If blood flow increases, the walls of the afferent arteriole distends • Stretching vascular smooth muscle causes movement of Ca+ ions from ECF into the intracellular fluid- causing the smooth muscle to contract which increases vascular resistance and normalizes blood flow • The myogenic mechanism is due to a characteristic of smooth muscle Autoregulation- Tubuloglomerular Feedback and the Macula Densa  Tubuloglomerular feedback also regulates GFR • Macula densa (MD) senses changes in GFR of each nephron- by measuring NaCl in the flow rate • Na+ and Cl- enter the MD cells, increase Na-K-ATPase activity and increase ATP hydrolysis causing more adenosine to be formed • Paracrine signaling molecule that passes from the MD to the afferent arteriole is adenosine or ATP • Juxtaglomerular (JG) cells are granular cells in the smooth muscle of the afferent arteriole • The JG complex includes the MD cells and the afferent arterioles (Hall says efferent- other sources don’t include efferent) • If tubular flow rate increases, MD signals to Juxtaglomerular complex- Hall- the anatomy Tuboglomerular feedback mechanism: physiology Renin, RBF, and GFR  Renin-angiotensin system • Renin is an enzyme secreted from the granular cells of the JG apparatus (complex) • It reacts with plasma protein angiotensinogen produced by liver to produce Angiotensin I • Angiotensin I reacts with angiotensin converting enzyme (ACE) located in pulmonary endothelial cells to produce Angiotensin II • Angiotensin II is a potent vasoconstrictor that increases TPR of both afferent and efferent arterioles to reduce RBF • Decreases GFR • Preferentially constricts efferent arterioles to prevent serious reductions in glomerular hydrostatic pressure and GFR when renal pressure is below normal • Angiotensin II also stimulates secretion of aldosterone from renal cortex to result in increased Na+ reabsorption Macula densa feedback mechanism for autoregulation of glomerular hydrostatic pressure and GFR during decreased renal arterial pressure Tubuloglomerular Feedback and Glomerulotubular Balance  Feedback that ensures a constant delivery of NaCl to the distal tubule for final processing of urine   Tubuloglomerular feedback adjusts GFR • GFR is adjusted to respond to varying tubular loads of NaCl • Signals from the renal tubule in each nephron feed back to affect filtration at its glomerulus Glomerulotubular balance adjusts • Tubules reabsorb a constant fraction of the filtered load of NaCl in response to varying GFRs • Changes in the filtration fraction affect Starling forces in the peritubular capillaries gh Protein Meal Increases GFR  Possible role of MD feedback in increasing GFR after a high protein meal • Amino acids are reabsorbed with sodium by cotransport in the proximal tubules • Increased reabsorption of Na+ decreases Na+ at MD • Decreased afferent arteriolar resistance increases GFR • Increases excretion of the waste products of protein metabolism Other Factors That Influence GFR • Fever, pyrogens: Increase GFR • Glucocorticoids: Increase GFR Aging: Decreases GFR 10%/decade after 40 years yperglycemia: Increases GFR (diabetes mellitus) similarly to increased p • Since glucose reabsorbed with Na+ • Dietary protein: high protein increases GFR; low protein decreases GFR 25