Renal Blood Flow and its Renal Blood Flow and its Autoregulation Autoregulation

Overview
Features of Renal Blood Flow
Anatomy Special features

Autoregulation of Renal Blood Flow

Site Mechanisms Dynamics and Efficiency

Techniques to study Renal Blood Flow Applied Aspects

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Renal Blood Flow

Delivery of oxygen and nutrients to nephron

Concentration of Urine

Delivery of substances for excretion in urine

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Blood Flow in the Kidney

Blood flow under resting conditions : 20% of the cardiac output When the mass of kidneys is less than 1% of the body weight!! Flow rate : about 400 mL/100 g of tissue than other well perfused organs

Brenner & Rector, The Kidney, 9th Ed., 2012

Blood Flow in Various Organs

Region Liver Kidneys Brain Skin Skeletal Muscle Mass (kg) Flow (mL/min) 2.6 1500 0.3 1.4 3.6 31.0 1260 750 462 840 Flow/100g (mL/100g/min) 57.7 420.0 54.0 12.8 2.7

Resting Blood Flow in Various Organs in a 63-kg Adult Man

Ganong, Review of Medical Physiology, 23rd ed., 2009 5

Peculiarities of Renal Blood Flow

Extraordinarily large amount of blood flow Distribution of arteries - transmit pressure with minimum energy loss High permeability of glomerular capillary bed Intra renal blood flow - heterogeneous Low and high pressure capillary beds are arranged in series Blood flow determines oxygen demand

Brenner and Rector, The Kidney, 9th ed., 2012

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Renal artery Segmental artery Lobar artery Interlobar artery Arcuate artery Interlobular artery Afferent arteriole Glomerulus Efferent arteriole Peritubular capillaries and Vasa Recta Interlobular vein Arcuate vein Interlobar vein Renal vein
Guyton and Hall, Textbook of Medical Physiology, 12th ed., 2011
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Cortical Blood Flow 85-90% Cortex : filtration and reabsorption Vasoconstrictors (Angiotensin II, Endothelin, Norepinephrine) have greater effect High flow rates

Medullary Blood Flow 10-15% Medulla : urine concentration Vasodilators (Prostaglandins, Kinins, Nitric Oxide, Acetylcholine) have greater effect Lower flow rates

Brenner and Rector, The Kidney, 9th ed., 2012

Total Renal Blood Flow : Calculation

First determine Renal Plasma Flow Substance X -neither metabolized nor synthesized in the kidneys - rate of its appearance in urine equals its rate of extraction from blood Rate of extraction from Blood UxV = (Artx Venx) * RPF RPF = UxV / (Artx Venx) Since Plasma fraction = 1- Hct RBF = RPF / (1 Hct)

Ux : urine conc. of X V : volume of urine Artx and Venx : arterial and venous concentrations of X RPF : Renal Plasma flow Hct : Hematocrit RBF : Renal Blood9Flow

Hydraulic Profile of Renal Circulation

RBF = P / R
Afferent and efferent arterioles are major sites of renal vascular resistance

Brenner and Rector, The Kidney, 9th ed., 2012 10

Vessel Renal Artery Intelobar, Arcuate & Interlobular Artery Afferent arteriole Glomerular capillaries Efferent Arteriole

Pressure in Beginning 100 ~100 85 60 59

Pressure at End 100 85 60 59 18

% of Resistance ~0 ~16 ~26 ~1 ~43

Peritubular capillaries
Intelobar, Arcuate & Interlobular Veins Renal vein

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8 4

8
4 ~4

~10
~4 ~0

Guyton and Hall, Textbook of Medical Physiology, 12th ed., 2011 11

Starling Forces
Constriction of Afferent arteriole decreases GFR while that of efferent arteriole increases GFR

But Effect of afferent and efferent arteriolar resistance change on RBF are the same i.e. decreased blood flow

A : Normal profile B : Following Afferent arteriolar constriction C : Following Efferent arteriolar constriction

Best and Taylor, Physiological Basis of Medical Practice, 13th ed., 2012
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Autoregulation of Renal Blood Flow

The ability to maintain a constant blood flow in face of changes in perfusion pressure
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Decline in perfusion pressure?

Decline in Efferent arteriolar resistance Fall in GFR as well as Glomerular capillary pressure

But both GFR and RBF are autoregulated

So site of principal resistance change is PRE glomerular

Brenner and Rector, The Kidney, 9th ed., 2012 14

Mechanisms of Autoregulation
Myogenic mechanism Tubulo glomerular feedback Third mechanism

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Sir William Maddock Bayliss (1902)

When blood pressure is increased in the blood vessels and the blood vessels distend, they react with a constriction

Bayliss Effect

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Myogenic response
Inherent property of the vascular smooth muscle tendency to contract when stretched Response time in renal vessels (310 s) Considerably faster than that in other vascular beds
skeletal muscle, brain and skin
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Myogenic Mechanism
Renal tissue from newborn hamsters grafted into cheek pouch of adult hamsters Chamber perfused with Ringers Bicarbonate keeping pH, pCO2 and pO2 constant Syringe used to apply positive or negative pressure in pulses of 10 mm Hg ; recorded using transducer Blood vessel diameter measured using microscopy

Gilmore et al., 1980, Circulation Research; 47 : 226- 230

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Perfusion reservoir(R), Pressure reservoir(PR) Chamber (C) Microscope(M) Formica plate(F) Base plate of the chamber(BP) Light rod(LR) Cheek pouch membrane (CPM) Pressure transducer(PT)

Gilmore et al., 1980, Circulation Research; 47 : 226- 230

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Afferent arteriole

Efferent arteriole

Afferent arteriole showed increased arteriole diameter on application of positive pressure and vice versa Efferent arterioles showed a reverse response
Gilmore et al., 1980, Circulation Research; 47 : 226- 230 20

 Preglomerular site of autoregulation But responses were abolished by papaverine

The findings are best explained by a Myogenic mechanism

Gilmore et al., 1980, Circulation Research; 47 : 226- 230

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Mechanosensitive ion channels

Integrin Activation

Phospholipase C Activation

Depolarization of cell membrane

Ca++ influx through Voltage gated Ca++ channels Other mechanisms?? Cyt P450 PKC Myosin Phosphorylase Contraction of Vascular smooth muscle
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Phosphorylation of Calmodulin and Myosin light chain kinase

Tubuloglomerular feedback

MD : Macula densa EGM : Extraglomerular mesangial cells G : Granular cells BM : Basement membrane; BS : Bowman's space; EN : Endothelial cell; FP : Foot processes M : Mesangial cells P : Podocyte PE : Parietal epithelium; PT : Proximal tubule cell
Berne and Levy, Physiology, 6th ed., 2010 23

Increased in delivery of NaCl to the distal tubules

Sensed by Macula Densa cells of JGA

??
Afferent arteriolar constriction and decreased GFR

Berne and Levy, Physiology, 6th ed., 2010

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1. Uptake of Na+K+Cl+ by NKCC2 channel 2. Intra/Extra cellular production of Adenosine 3. Activation of A1 receptors causing increased Ca++ in extra glomerular mesangial cells 4. Coupling between EMC, granular cells and smooth muscle cells 5. Vasoconstriction and inhibition of Renin release

Brenner and Rector, The Kidney, 9th ed., 2012

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Bern and Levy, Physiology ,6th ed., 2012

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3rd Mechanism

Time (sec)

Elimination of TGF on administration of Furosemide

Just A. Am J Physiol Regul Integr Comp Physiol 292:R1-R17, 2007.27

Underlying Mechanism
Not clear Response resistant to inhibition of NOS, ACE Inhibitors and changes in intra renal pressure Cupples et al observed disappearance of the slow response on administration of AT2 receptor inhibitors

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Dynamics of Response
Decreased Perfusion Pressure

Myogenic Response <10 seconds

Tubuloglomerular feedback 3rd Mechanism 30-60 seconds

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TGF shows initial Lag period of 15 s Further delay occurs due to the time needed for the molecular machinery to come into play So total duration needed in 30 - 60 s

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Relative contributions
Under resting conditions Myogenic response 50% Tubulo glomerular feedback 35 - 50% 3rd Mechanism - < 15%

Just A. Am J Physiol Regul Integr Comp Physiol 292:R1-R17, 2007.

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Dehydration Intense fear/Pain Sympathetic Nerves

Increased Blood flow Increased Shear force Nitric Oxide

Nor epinephrine

NSAIDs

PG I2, E1 and E2
Angiotensin II

Hemorrhage
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Techniques to study Renal Microcirculation

Laser Doppler Flowmetery Hydronephrotic Kidney Isolated Renal Micro vessels

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 Laser Doppler Flowmetry

Non invasive, continuous measurement of blood flow on microscopic level Recoding of frequency of oscillation produced by doppler frequency shift of RBCs Signal recorded as intensity oscillation Analyzer calculates flux

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 Hydronephrotic Kidney
Steinhausen and colleagues Germany (1983) Non filtering kidney Integrity of vessels preserved as suggested by histology and electrical studies Visualization of arteries during perfusion

Dr Michael Steinhausen

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 Isolated Renal Microvessels

R M Edwards (1983) Renal microvessels isolated from rabbit kidney Perfused to maintain constant intraluminal pressure

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Applied Aspects
Hemorrhage Diabetes Mellitus
Raised NO, Hyperfiltration and glomerular damage

Hypertension
Raised NO

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NEURAL

HUMORAL

RENAL BLOOD FLOW

UNIQUE

MYOGENIC MECHANISM

3RD MECHANISM

TUBULO GLOMERULAR FEEDBACK

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