Renal Physiology Lecture 2 PDF

Renal Physiology March 21, 2024 J. Mohan, PhD., Lecturer, Physiology Unit, Department of Pre-clinical Sciences Faculty of Medical Sciences, U.W.I., St Augustine. Room 104, Physiology Unit, [email protected] References:  Costanzo, L.S. (2022) Physiology. 7th Edition, Elsevier, Saunders.  Ko...

Renal Physiology March 21, 2024 J. Mohan, PhD., Lecturer, Physiology Unit, Department of Pre-clinical Sciences Faculty of Medical Sciences, U.W.I., St Augustine. Room 104, Physiology Unit, [email protected] References:  Costanzo, L.S. (2022) Physiology. 7th Edition, Elsevier, Saunders.  Koeppen B.E. & Stanton B.A. (2010). Berne & Levy Physiology. 6th Edition. Mosby, Elsevier.  Hall, J.E. (2021). Guyton and Hall Textbook of Medical Physiology. 14th Edition, Elsevier, Saunders.  Marieb, E. & Hoehn, K. (2010). Human Anatomy & Physiology. 8th Edition, Pearson, Benjamin Cummings.  Stanfield, C.L. & Germann W.J. (2008). Principles of Human Physiology. 3rd Edition, Pearson, Benjamin Cummings. Today’s Physiology Objectives 1. Describe the regulation of Renal Blood Flow. 2. Define renal plasma flow (RPF) and renal blood flow (RBF) and explain, with the use of equations, the calculation of RPF and RBF. March 21, 2024 Dr. J. Mohan 3 Today’s Topics Renal Blood Flow (RBF). – Autoregulation of RBF. – Extrinsic Regulation of RBF (nerves & hormones). – Measurement of Renal Plasma Flow & Renal Blood Flow. March 21, 2024 Dr. J. Mohan 4 Renal Blood Flow Blood flow through the kidneys in an average 70 kg male is ~ 25% of cardiac output (just > 1 L / min) – relatively high blood flow compared with other organs, considering the small % body weight of the kidneys (~ 0.4% of total body weight) Figure 4-1; Costanzo LS, 2022 March 21, 2024 Dr. J. Mohan 5 Renal Blood Flow It serves several important functions : 1. Indirectly determines the GFR 2. Modifies the rate of solute & H2O reabsorption by the PCT 3. Participates in the concentration and dilution of urine 4. Delivers O2, nutrients, and hormones to the cells of the nephron and returns CO2 and reabsorbed fluid and solutes to the general circulation 5. Delivers substrates for excretion in urine March 21, 2024 Dr. J. Mohan 6 Renal Blood Flow Blood flow through any organ may be represented by : Q = ΔP ______ R where : Q = blood flow ΔP = mean arterial pressure minus venous pressure for that organ R = resistance to flow through that organ March 21, 2024 Dr. J. Mohan 7 Renal Blood Flow Renal Blood Flow (RBF) is equal to the pressure difference between the renal artery and the renal vein divided by renal vascular resistance: RBF = Renal artery pressure – renal venous pressure _________________________________ Renal vascular resistance March 21, 2024 Dr. J. Mohan 8 Renal Blood Flow arterial pressure ~ 3 - 4 mm Hg RBF = Renal artery pressure – Renal venous pressure _________________________________ Renal vascular resistance afferent arteriole efferent arteriole March 21, 2024 Dr. J. Mohan 9 Renal Blood Flow RBF remains relatively constant – ABP = 90 - 180 mm Hg GFR is also regulated over the same range of ABP the phenomenon whereby RBF and GFR are maintained relatively constant = autoregulation achieved by Δ in vascular resistance (afferent arterioles) Figure 32.18; Koeppen & Stanton, 2010 March 21, 2024 Dr. J. Mohan 10 Autoregulation of RBF and GFR Two mechanisms that regulate the tone of the afferent arteriole : 1. Responds to changes in arterial pressure 2. Responds to changes in [NaCl] in tubular fluid March 21, 2024 Dr. J. Mohan 11 Autoregulation of RBF and GFR “Pressure sensitive” mechanism : “Myogenic Mechanism” dependent on the intrinsic property of vascular smooth muscle: the tendency to contract when stretched  ABP  stretching of the renal afferent arteriole  contraction of the smooth muscle in arteriolar walls the resulting increase in resistance of the arteriole almost offsets the increase in pressure, RBF & therefore GFR remain relatively constant (See equation for Renal Blood Flow) March 21, 2024 Dr. J. Mohan 12 Autoregulation of RBF and GFR [NaCl]-dependent mechanism : “Salt Sensitive” “Tubuloglomerular Feedback” [NaCl] in tubular fluid is sensed by the macula densa of the JGA & converted into a signal that affect afferent arteriolar resistance  GFR March 21, 2024 Dr. J. Mohan 13 Autoregulation of RBF and GFR  formation & release of ATP & ADO (adenosine)  vasoconstriction of afferent arteriole   GFR to normal levels Figure 32.19; Koeppen & Stanton, 2010 March 21, 2024 Dr. J. Mohan 14 Autoregulation of RBF and GFR March 21, 2024 Dr. J. Mohan 15 Importance of Autoregulation many activities can change arterial blood pressure, so, we need mechanisms that maintain RBF & GFR relatively constant despite changes in arterial pressure if RBF & GFR  or  suddenly in proportion to changes in blood pressure  urinary excretion of water & solute would also change suddenly; if no corresponding intake  fluid & electrolyte imbalance autoregulation of RBF & GFR : – provides an effective means for uncoupling renal function from arterial pressure; thereby maintaining a relatively constant GFR – ensures that fluid and solute excretion remain fairly constant – protects glomeruli from damage due to high BP March 21, 2024 Dr. J. Mohan 16 Autoregulation of RBF and GFR 3 points concerning autoregulation should be noted : 1. Autoregulation is absent when arterial pressure is < 90 mm Hg 2. Autoregulation is not perfect; RBF & GFR do change slightly as arterial blood pressure varies 3. Despite autoregulation, RBF & GFR can be changed by changes in sympathetic nerve activity and by the levels of certain hormones and autacoids/paracrines (vasoactive substances that are released in the kidneys and act locally) March 21, 2024 Dr. J. Mohan 17 Regulation of Renal Blood Flow & GFR Nerves Sympathetic nerve activity Dehydration/strong emotional stimuli, e.g. fear & pain   sympathetic activity afferent & efferent arterioles innervated by sympathetic neurons sympathetic nerves release NE & dopamine circulating E secreted by adrenal medulla NE & E  vasoconstriction by binding to α1-adrenoceptors mainly on afferent arterioles   GFR & RBF March 21, 2024 Dr. J. Mohan 18 Regulation of Renal Blood Flow & GFR Hormones /Paracrines Angiotensin II Ag II is produced systemically and locally within the kidneys constricts the afferent & efferent arterioles and   RBF efferent arteriole more sensitive to Ag II than afferent arteriole, so low [Ag II]  constriction of efferent arteriole   RBF &  GFR high [Ag II]  constriction of afferent & efferent arteriole   RBF &  GFR March 21, 2024 Dr. J. Mohan 19 Regulation of Renal Blood Flow & GFR Hormones /Paracrines Effect of Ag II Constricts both afferent & efferent arterioles, but preferentially constricts efferent arterioles – (this helps to preserve GFR in circumstances associated with decreased arterial pressure or volume depletion which tend to decrease GFR) Low Ag II – Moderate to large constrictor effect on efferent arterioles – Small constrictor effect on afferent arterioles –  RPF;  PGC;  GFR Very high Ag II e.g. hemorrhage – Very large (severe) constrictor effect on efferent arterioles – Medium constrictor effect on afferent arterioles –  RPF;  PGC; smaller  GFR (than if there was only constriction of afferent arterioles) March 21, 2024 Dr. J. Mohan 20 Regulation of Renal Blood Flow & GFR  blood vol  ABP Figure 32.22; Koeppen & Stanton, 2010 March 21, 2024 Dr. J. Mohan 21 Extrinsic Regulation of Renal Blood Flow Hormones /Paracrines Endothelin Potent vasoconstrictor, secreted by endothelial cells of the renal vessels, mesangial cells and distal tubular cells in response to Ag II, bradykinin, epinephrine, endothelial shear stress constricts the afferent & efferent arterioles and   RBF & GFR production is elevated in a some glomerular disease states March 21, 2024 Dr. J. Mohan 22 Regulation of Renal Blood Flow & GFR Hormones /Paracrines Prostaglandins (PGs) : clinical importance dehydration & stress (e.g., surgery, anesthesia), Ag II, & sympathetic nerves   synthesis of PGs by kidneys PGs   RBF (vasodilation of afferent & efferent arterioles) PGs  RBF by dampening the vasoconstrictor effects of sympathetic nerves & Ag II  prevents severe & potentially harmful vasoconstriction & renal ischemia non-steroidal anti-inflammatory drugs (NSAIDs), e.g. aspirin & ibuprofen   synthesis of PGs March 21, 2024 Dr. J. Mohan 23 Regulation of Renal Blood Flow & GFR Hormones /Paracrines Prostaglandins (PGs) : clinical importance administration of NSAIDs during renal ischemia and hemorrhagic shock is contraindicated because by blocking the production of prostaglandins, they decrease RBF and increase renal ischemia Prostaglandins play an increasingly important role in maintaining RBF and GFR as individuals age so NSAIDs can significantly  RBF and GFR in the elderly March 21, 2024 Dr. J. Mohan 24 Extrinsic Regulation of Renal Blood Flow Hormones /Paracrines Nitric Oxide Shear stress on the blood vessel wall as a consequence of increased blood flow, vasoactive hormones e.g., acetylcholine, histamine, bradykinin & ATP   release of NO from endothelial cells NO   RBF (vasodilation of afferent & efferent arterioles) & GFR Bradykinin A vasodilator (stimulates the release of NO & PG’s)   RBF & GFR March 21, 2024 Dr. J. Mohan 25 Measurement of Renal Plasma Flow and Renal Blood Flow Recall that blood cells are not filtered at the glomerulus, so the flow of plasma that enters the kidney is Renal Plasma Flow Renal Plasma Flow (RPF) can be estimated from the clearance of an organic acid para - aminohippuric acid (PAH) that is both filtered across glomerular capillariies and secreted from the peritubular capillaries into tubular fluid Renal Blood Flow can then be calculated from RPF and the haematocrit March 21, 2024 Dr. J. Mohan 26 Measurement of Renal Plasma Flow and Renal Blood Flow Measuring True Renal Plasma Flow (RPF) by applying the Fick Principle to the kidney : i.e. the amount of substance entering the kidney via the renal artery = amount of substance leaving the kidney via the renal vein + the amount excreted in the urine Figure 6.1 modified; Costanzo, 2022 March 21, 2024 Dr. J. Mohan 27 Measurement of Renal Plasma Flow and Renal Blood Flow For PAH : Amt. of PAH entering kidney= Amt. of PAH leaving kidney Amt. of PAH entering kidney= [RA] PAH x RPF Amt. of PAH leaving kidney = [RV] PAH x RPF + [U] PAH x V Figure 6.8; Costanzo, 2022 March 21, 2024 Dr. J. Mohan 28 Measurement of Renal Plasma Flow and Renal Blood Flow Amt. of PAH entering kidney= Amt. of PAH leaving kidney [RA] PAH x RPF = [RV] PAH x RPF + [U] PAH x V RPF = [U] PAH x V ____________ [RA] PAH - [RV] PAH where RPF = Renal Plasma Flow [U] PAH = [PAH] in urine V = urine flow rate [RA] = [PAH] in renal artery [RV] = [PAH] in renal vein March 21, 2024 Dr. J. Mohan 29 Measurement of Renal Plasma Flow and Renal Blood Flow PAH is ideal for measuring RPF because : 1. PAH is neither used nor produced by the kidney 2. PAH does not alter RPF 3. The kidneys remove most of PAH from renal arterial blood by filtration & secretion leaving very little in renal vein so [RV] is nearly zero 4. No organ apart from the kidney removes PAH from blood so [PAH] in the renal artery = [PAH] in any peripheral vein, which is easier to sample from humans than the renal artery March 21, 2024 Dr. J. Mohan 30 Measurement of Renal Plasma Flow and Renal Blood Flow The measurement of “True Renal Plasma Flow” involves the infusion of PAH into the body, taking urine samples and blood samples Certain simplifications/assumptions can be made which estimate “Effective Renal Plasma Flow” which approximates “true RPF” to 10% 1. [RV] PAH = assumed to be 0 (because 90% of PAH that enters the kidney is excreted in the urine, 10% in the renal vein. The small concentration in the renal vein can be ignored) 2. [RA] PAH = [PAH] in any peripheral vein (since kidneys are the only organs that take up PAH) March 21, 2024 Dr. J. Mohan 31 Measurement of Renal Plasma Flow and Renal Blood Flow This equation : RPF = [U] PAH x V ____________ [RA] PAH - [RV] PAH If [RV] PAH = 0 And [RA] PAH = [RV] PAH = [Plasma] PAH becomes : March 21, 2024 Dr. J. Mohan 32 Measurement of Renal Plasma Flow and Renal Blood Flow Therefore: Effective RPF = [U] PAH x V ____________ [P] PAH = Clearance of PAH where : [U] PAH V [P] March 21, 2024 = [PAH] in urine = urine flow rate = [PAH] in plasma Dr. J. Mohan 33 Measurement of Renal Plasma Flow and Renal Blood Flow Renal Blood Flow can then be calculated from RPF and the haematocrit : RBF = RPF _______ 1 – Hct Where : RBF = Renal Blood Flow (ml/min) RPF = Renal Plasma Flow (ml/min) Hct = haematocrit = fraction of blood volume occupied by red blood cells 1-Hct = fraction of blood volume occupied by plasma March 21, 2024 Dr. J. Mohan 34 Measurement of Renal Plasma Flow and Renal Blood Flow Example : A man with a urine flow rate of 1 ml/min has a plasma concentration of PAH of 1 mg/dl and urine concentration of PAH of 600 mg/dl, and a haematocrit of 0.45. What is his RBF? March 21, 2024 Dr. J. Mohan 35 Measurement of Renal Plasma Flow and Renal Blood Flow Example : A man with a urine flow rate of 1 ml/min has a plasma concentration of PAH of 1 mg/dl and urine concentration of PAH of 600 mg/dl, and a haematocrit of 0.45. What is his RBF? Effective RPF = 600 mg/dl x 1 ml/min ____________ 1 mg/dl = Clearance of PAH = 600 ml/min RBF = 600 ml/min --------------1-0.45 = March 21, 2024 1091 ml/min Dr. J. Mohan 36