Clearance GFR RBF Med Apr 2011 LO - medscistudentsmedscistudents.webs.com/MDSC...

Dr J. Mohan

April 04 - 07, 2011 1

Renal Physiology

April, 2011

J. Mohan, PhD.Lecturer, Physiology Unit,Faculty of Medical Sciences,U.W.I., St Augustine.

Office : Room 105, Physiology Unit.

References:

� Koeppen B.E. & Stanton B.A. (2010). Berne & Levy Physiology. 6th Edition. Mosby, Elsevier.

� 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.

� Hall, J.E. (2011). Guyton and Hall Textbook of Medical Physiology. 12th Edition, Elsevier, Saunders.

Dr J. Mohan

April 04 - 07, 2011 2

Physiology Objectives

Objectives 1-5, PBL Booklet (See next page)

TopicsBody Fluid Compartments, Osmolarity, Osmolality & Tonicity and

Membrane Transport Mechanisms.

ReviewCh. 1 : Principles of Cell Function – Mechanisms of Membrane

Transport, p 7-19Ch. 2 : Homeostasis of Body Fluids

Physiology Objectives

• Classify body fluid compartments with regard to their volume, relative percentages and percentage of body weight.

• Quantify the ionic components of the major body fluid compartments.

• Define osmolarity, osmolality and tonicity with respect to movement between intracellular and extracellular body fluid compartments.

• Review the various types of membrane transport (active transport, facilitated diffusion etc.)

• Explain the resultant effects on red blood cells which are added to hypotonic and hypertonic solutions.

Dr J. Mohan

April 04 - 07, 2011 3

Physiology Objectivescont’d. . .

Objectives 6-8, PBL Booklet

Ch 32, 558-566.

TopicFunctional Anatomy of the Kidneys,

Physiology Objectivescont’d. . .

• Review the gross and microscopic structure of the kidney and nephrons.

• Describe in detail the vascular arrangement of the kidneys.

• Give a detailed description of the structures encountered during the passage of the ultrafiltrate from the Bowman’s capsule through the tubular segments into the renal pelvis.

Dr J. Mohan

April 04 - 07, 2011 4

Today’s Topics• Overview of ultrastructure of the Nephron, Renal Corpuscle,

& Juxtaglomerular apparatus.

• Renal Clearance.

• Glomerular Filtration (GFR).– Estimation of GFR- creatinine clearance.– Clinical Importance.– Composition of Ultrafiltrate.– Determinants of Ultrafiltration.– Dynamics of Ultrafiltration.

• Renal Blood Flow (RBF).– Renal Autoregulation

• Mechanisms of Autoregulation– Extrinsic Regulation of RBF & GFR (nerves & hormones).

Functions of the Kidneys

Regulatory 1. body fluid osmolality and volumes importance?2. electrolyte balance importance?3. acid-base balance importance?

Excretory1. metabolic products and foreign substances

e.g. urea , uric acid, creatinine, Hb metabolism, hormone metabolites, drugs

Endocrine1. produce and secrete hormones

e.g. renin, calcitriol, erythropoetin

Dr J. Mohan

April 04 - 07, 2011 5

Mechanisms of Urine Formation

• Urine formation and adjustment of blood composition involves three major processes

– Glomerular filtration

– Tubular reabsorption

– Secretion

Figure 25.10; Marieb & Hoehn, 2010

• Nephrons are the structural and functional units that form urine, consisting of:

– Renal Corpuscle– Proximal Convoluted

Tubule– Loop of Henle– Distal Convoluted

Tubule– Collecting Duct

System

The Nephron

Figure 32.3, Koeppen & Stanton, 2010

Dr J. Mohan

April 04 - 07, 2011 6

• Renal Corpuscle :

– Glomerulus – a tuft of capillaries associated with a renal tubule

– Bowman’s capsule – blind, cup-shaped end of a renal tubule that completely surrounds the glomerulus

The Nephron

The NephronUnique cells in each nephron segment

Figure 32.3; Koeppen & Stanton, 2010

Dr J. Mohan

April 04 - 07, 2011 7

The Nephron

• All cells, (except intercalated cells), have in their apical plasma membrane a single nonmotile primary cilium that protrudes into the tubule fluid

– mechanosensors

– chemosensors

– initiate Ca2+-dependent signaling pathways, e.g. those that control kidney cell function, proliferation, differentiation, and apoptosis

Types of Nephrons

• Cortical nephrons

– 85% of nephrons; located superficially in the cortex

– short LoH– efferent arteriole �

peritubular capillaries• nutrients• delivers substances to

the nephron for secretion

• path for return of reabsorbed H20 & solutes to blood


Dr J. Mohan

April 04 - 07, 2011 8

Types of Nephrons

• Juxtamedullary nephrons:

– located at the cortex-medulla junction

– long LoH– efferent arteriole �

series of vascular loops called the vasa recta

– functions of peritubularcapillaries +

– involved in the production of concentrated urine


Ultrastructure of the Renal Corpuscle

• first step in urine formation : passive movement of a plasma ultrafiltrate from glomerular capillaries � Bowman's space

• ultrafiltration : passive movement of an essentially protein-free fluid from the glomerular capillaries � Bowman's space

Dr J. Mohan

April 04 - 07, 2011 9


• the glomerulus : network of capillaries supplied by the afferent arteriole and drained by the efferent arteriole

• capillaries covered by epithelial cells called podocytes (visceral layer of Bowman's capsule)

• visceral cells face outward at the vascular pole to form the parietal layer of Bowman's capsule

• space between the visceral layer and the parietal layer -Bowman's space - � lumen of the PCT




Dr J. Mohan

April 04 - 07, 2011 10

• endothelial cells of glomerular capillaries are covered by a basement membrane that is surrounded by podocytes

• capillary endothelium, basement membrane & foot processes of podocytes form the filtration barrier/membrane

Filtration Membrane


Endothelium

• fenestrated - contains 700 Å holes, where 1 Å = 10-10 m

• freely permeable to H20, small solutes (such as Na+, urea, & glucose) & most proteins

• not permeable to RBC, WBC or platelets

• endothelial cells express negatively charged glycoproteins on their surface � retard filtration of large anionic proteins into Bowman's space

Filtration Membrane


Dr J. Mohan

April 04 - 07, 2011 11

Basement membrane

• porous matrix of negatively charged proteins, ( type IV collagen, laminin, proteoglycans agrin & perlecan, & fibronectin)

• important filtration barrier to plasma proteins

• “charge-selective” filter

Filtration Membrane


Podocytes

• long finger-like processes that completely encircle the outer surface of the capillaries

• processes of the podocytesinterdigitate to cover the basement membrane

• separated by apparent gaps called filtration slits

Filtration Membrane


Dr J. Mohan

April 04 - 07, 2011 12

Filtration Slits

• each filtration slit bridged by a thin diaphragm that contains pores - 40 × 140 Å

• filtration slit diaphragm composed of several proteins nephrin (NPHS1), NEPH-1, podocin (NPHS2), α-actinin 4 (ACTN4) & CD2-AP

• function primarily as a “size-selective” filter

Filtration Membrane



Mesangium

• mesangial cells & matrix

• mesangial cells possess many properties of smooth muscle cells

– surround the glomerularcapillaries

– provide structural support for the glomerular capillaries

– secrete the extracellular matrix


Dr J. Mohan

April 04 - 07, 2011 13


Mesangium cont’d. . .

– exhibit phagocytic activity by removing macromolecules from the mesangium

– secrete prostaglandins & proinflammatory cytokines

– mesangial cells contract & are adjacent to glomerularcapillaries � may influence the GFR by regulating blood flow through the glomerular capillaries or by altering the capillary surface area

– mesangial cells located outside the glomerulus -extraglomerular mesangial cells

Ultrastructure of the JuxtaglomerularApparatus

JGA

• Involved in: tubulo-glomerularfeedback mechanism (autoregulation of RBF and GFR)

• Comprises : 1. macula densa

2. extraglomerular mesangialcells

3. granular cells of the afferent arteriole (renin)


Dr J. Mohan

April 04 - 07, 2011 14


macula densa

• morphologically distinct region of the thick ascending limb (dct?)

• passes through the angle formed by the afferent and efferent arterioles of the same nephron

• cells contact the extraglomerular mesangialcells & granular cells of the afferent arterioles Figure 32.5; Koeppen & Stanton, 2010


Granular cells

• manufacture, store & release renin

• contain smooth muscle myofilaments


Dr J. Mohan

April 04 - 07, 2011 15

Innervation of the Kidneys

• renal nerves regulate RBF, GFR & salt & water reabsorptionby the nephron

• sympathetic nerve fibers; no parasympathetic

• adrenergic fibers release norepinephrine & dopamine

• adrenergic fibers lie adjacent to the smooth muscle cells of the major branches of the renal artery & the afferent & efferent arterioles

• also, sympathetic nerves innervate the renin-producing granular cells of the afferent arterioles � � renin secretion

• nerve fibers also to – PCT, LoH, DCT & collecting duct; � �Na+ reabsorption by these nephron segments

Today’s Topics• Overview of ultrastructure of the Nephron, Renal Corpuscle, &

Juxtaglomerular apparatus.





Dr J. Mohan

April 04 - 07, 2011 16

Assessment of Renal Function

• The coordinated actions of the nephron's various segments determine the amount of a substance that appears in urine

• Depends on 3 processes :

(1) glomerular filtration

(2) reabsorption of the substance from tubular fluid back into blood

(3) (in some cases) secretion of the substance from blood into tubule fluid

Renal Clearance

• Renal clearance : theoretical basis for measurement of GFR & RBF

• based on the Fick principle (i.e., mass balance or conservation of mass) i.e. the amt substance entering organ= amt leaving organ, assuming no synthesis /degradation of substance by organ

• the renal artery is the single input source to the kidney, whereas the renal vein & ureterare the two output routes


Dr J. Mohan

April 04 - 07, 2011 17

Renal Clearance

• P a x & P v x = concentrations of substance x in the renal artery & renal vein plasma, respectively

• RPFa & RPFv = renal plasma flow rates in the artery & vein, respectively

• U x = concentration of substance x in urine

• V (dot) = urine flow rate


Renal Clearance

• For any substance that is neither synthesized nor metabolized, the amount that enters the kidneys is = the amount that leaves the kidneys in urine + the amount that leaves the kidneys in renal venous blood

• allows measurement of the amount of substance x excreted in urine vs the amount returned to the systemic circulation in renal venous blood


Dr J. Mohan

April 04 - 07, 2011 18

Renal Clearance

C x = U x X V_______________ ml/min

P x

• represents a volume of plasma from which all of substance x has been removed and excreted into urine per unit time

• i.e. rate of removal of substance x from plasma by kidneys

• Note : ratio of the amount of x excreted in urine to the amount of x in plasma

Renal Clearance

• C x = U x X V___________ ml/min

Pa x

• E.g. if Ux = 100 mg/ml; V= 1 ml/min

• Then excretion rate of x = 100 mg/ml x 1 ml/min

= 100 mg/min

• If Px = 1 mg.ml , then Cx = 100 mg/min

_________________________

1 mg/ml

= 100 ml/min

Dr J. Mohan

April 04 - 07, 2011 19




• Glomerular Filtration (GFR).– Estimation of GFR- creatinine clearance.

– Clinical Importance.

– Composition of Ultrafiltrate.

– Determinants of Ultrafiltration.

– Dynamics of Ultrafiltration.



Mechanisms of Urine Formation

• Urine formation and adjustment of blood composition involves three major processes

– Glomerular filtration

– Tubular reabsorption

– Secretion


Dr J. Mohan

April 04 - 07, 2011 20

Glomerular Filtration Rate (GFR)

• GFR

– the sum of the filtration rates of all functioning nephrons– index of kidney function

– quantity of glomerular filtrate formed each minute in all nephronsof both kidneys

– in normal adult male : 90 - 140 mL/min – in normal adult female : 80 - 125 mL/min

– So, in 24 hours or 1 day, as much as 180 L of plasma is filtered by the glomeruli

– can be estimated using creatinine clearance test

Estimation of GFR

• Creatinine

– byproduct of skeletal muscle creatine metabolism

– freely filtered across the glomerulus into Bowman's space

– not reabsorbed, secreted, or metabolized by the cells of the nephron

Dr J. Mohan

April 04 - 07, 2011 21

• the amount of creatinineexcreted in urine per minute = the amount of creatininefiltered at the glomeruluseach minute where :

PCr = [plasma] creatinineUCr = [urine] creatinineV = urine flow

Estimation of GFR


• From equation :

GFR = U Cr X V_____________

P Cr

where :PCr = [plasma] creatinineUCr = [urine] creatinineV = urine flow

Estimation of GFR


Dr J. Mohan

April 04 - 07, 2011 22

• NB: this equation is the same form as that for clearance

• So, clearance of creatinineprovides a means for determining the GFR

Estimation of GFR


• Creatinine is not the only substance that can be used to measure GFR

• Any substance that meets the following criteria can serve as an appropriate marker for the measurement of GFR

• The substance must: 1. Be freely filtered across the glomerulus into Bowman's space2. Not be reabsorbed or secreted by the nephron3. Not be metabolized or produced by the kidney4. Not alter the GFR

e.g. Inulin - fructose polymer- its clearance measures GFR

Estimation of GFR

Dr J. Mohan

April 04 - 07, 2011 23

Filtration Fraction

• not all of the plasma coming into the kidneys is filtered

• approximately 10% of plasma that enters the kidneys in the renal artery does not pass through the glomerulus

• the portion of filtered plasma = filtration fraction

• Filtration Fraction = GFR--------------------

RPF~ 0.15 -0.20

Glomerular Filtration Rate

• Clinical Importance of GFR :

– measuring GFR is important when kidney disease is suspected : � GFR may be the first & only clinical sign of kidney disease

– knowledge of the patient's GFR is essential in evaluating the severity and course of kidney disease

• � GFR � kidney disease is progressing• � GFR � recuperation

– a 50% loss of functioning nephrons reduces the GFR only by about 25%; the decline in GFR is not 50% because the remaining nephrons compensate

Dr J. Mohan

April 04 - 07, 2011 24

• Because measurements of GFR are cumbersome, kidney function is usually assessed in the clinical setting by measuring PCr, which is inversely related to GFR

• BUT changes in PCr are small : �GFR from120 -100 mL/min (~ 20%) is accompanied by an increase in PCr from 1.0 to 1.2 mg/dL

Glomerular Filtration Rate


Composition of Glomerular Filtrate

• first step in the formation of urine is ultrafiltration of plasma by the glomerulus

• the plasma ultrafiltrate = glomerular filtrate

• no cellular elements (i.e., RBC, WBC & platelets) no proteins

• [salts & organic molecules], e.g. glucose and amino acids, is similar to plasma

• Starling forces drive ultrafiltration across the glomerularcapillaries and changes in these forces alter the GFR

Dr J. Mohan

April 04 - 07, 2011 25

Determinants of Ultrafiltrate Composition

• the glomerular filtration barrier determines the composition of the plasma ultrafiltrate

• it restricts the filtration of molecules on the basis of both size & electrical charge – neutral molecules with a radius < 20 Å are filtered freely – molecules > 42 Å are not filtered– molecules between 20 - 42 Å are filtered to various degrees,

depending on their electrical charge e.g. cations

• Eg: serum albumin : – an anionic protein – molecular radius of 35.5 Å, (i.e. < 42 Å) BUT is filtered poorly

(because of negative charges on it)


• Clinical importance of the negative charges on the filtration barrier in restricting the filtration of plasma proteins :

– removal of the negative charges from the filtration barrier �proteins filtered solely on the basis of their size

– at sizes between 20 - 42 Å, filtration of polyanionic proteins > the filtration in the normal state

– E.g. glomerular diseases the negative charges on the filtration barrier are reduced because of immunological damage and inflammation �� filtration of proteins �proteins appear in urine (proteinuria)

Dr J. Mohan

April 04 - 07, 2011 26



Dynamics of Ultrafiltration

• Ultrafiltration occurs because the Starling forces (i.e., hydrostatic and oncotic pressure) drive fluid from the lumen of glomerularcapillaries, across the filtration barrier �Bowman's space


Dr J. Mohan

April 04 - 07, 2011 27


• GFR is proportional to the sum of the Starling forces that exist across the capillaries [(PGC - PBS) – σ (πGC - πBS)] multiplied by the ultrafiltration coefficient (Kf)

• GFR = Kf [(PGC - PBS) – σ (πGC - πBS)]

• GFR = Kf x Net Filtration Pressure (NFP)

• Kf = the product of the intrinsic permeability of the glomerular capillary and the glomerular surface area available for filtration

• σ = reflection coefficient for proteins across the glomerularcapillary = 1


• the rate of glomerular filtration is > in glomerular capillaries than in systemic capillaries, mainly because Kf is approximately 100 times > in glomerular capillaries

• Also, PGC is approximately twice as great as the hydrostatic pressure in systemic capillaries

Dr J. Mohan

April 04 - 07, 2011 28


• GFR can be altered by changing Kf or by changing any of the Starling forces (� NFP)

• In normal individuals, the GFR is regulated by alterations in PGC that are mediated mainly by changes in afferent or efferent arteriolar resistance

• PGC is affected in 3 ways:

1. Changes in afferent arteriolar resistance : � resistance increases PGC & GFR (See D)� resistance decreases PGC & GFR (See A)


2. Changes in efferent arteriolar resistance : – � resistance decreases

PGC & GFR (See C)– � resistance increases

PGC & GFR (See B)

3. Changes in renal arteriolar pressure : – � pressure transiently

increases PGC � �GFR– � pressure transiently

decreases PGC � � GFR


Dr J. Mohan

April 04 - 07, 2011 29





• Renal Blood Flow (RBF).

– Renal Autoregulation

• Mechanisms of Autoregulation

– Extrinsic Regulation of RBF & GFR (nerves &

hormones).

Renal Blood Flow

• Blood flow through the kidneys serves several important functions :

1. Indirectly determines the GFR

2. Modifies the rate of solute & H20 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

Dr J. Mohan

April 04 - 07, 2011 30

Renal Blood Flow

• Blood flow through any organ may be represented by :

Q = ∆P______

R

where :

Q = blood flow∆P = mean arterial pressure minus venous pressure for that organR = resistance to flow through that organ

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 = Aortic pressure – renal venous pressure_________________________________

Renal vascular resistance

Dr J. Mohan

April 04 - 07, 2011 31

Renal Blood Flow

RBF = Aortic pressure – Renal venous pressure_________________________________

Renal vascular resistance

afferent arterioleefferent arterioleinterlobular artery

arterial pressure

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 ∆ in vascular resistance (afferent arterioles)


Dr J. Mohan

April 04 - 07, 2011 32

Autoregulation of RBF & GFR

• Two mechanisms :

1. Responds to changes in arterial pressure

2. Responds to changes in [NaCl] in tubular fluid


Pressure mechanism : “Myogenic Mechanism”

• intrinsic property of vascular smooth muscle: the tendency to contract when stretched

• when arterial pressure rises and the renal afferent arteriole is stretched, the smooth muscle contracts Because the increase in resistance of the arteriole offsets the increase in pressure, RBF & therefore GFR remain constant

• (See equation for Renal Blood Flow)

Dr J. Mohan

April 04 - 07, 2011 33


• [NaCl]-dependent mechanism : “TubuloglomerularFeedback”

• [NaCl] in tubular fluid is sensed by the macula densa of the JGA & converted into a signal that affect afferent arteriolar resistance � GFR


� formation & release of ATP & ADO�

vasoconstriction of afferent arteriole � �

GFR to normal levels

� GFR � � [NaCl] � �

NaCl enters the macula densa cells � � ATP & ADO production & release � vasodilation of the afferent arteriole � � GFR


Dr J. Mohan

April 04 - 07, 2011 34



• � GFR � [NaCl] in tubule fluid at the macula densa� � uptake of NaCl across the apical cell membrane of macula

densa cells via the 1Na+-1K+-2Cl- (NKCC2) symporter� � [ATP] & [adenosine] (ADO)

• ATP binds to P2X receptors & ADO binds to adenosine A1 receptors in the plasma membrane of smooth muscle cells in afferent arteriole � � intracellular [Ca2+] � vasoconstriction of the afferent � � GFR

• ATP & ADO also � renin release by granular cells in the afferent arteriole via � intracellular [Ca2+] in vascular smooth muscle (VSM) cells


Dr J. Mohan

April 04 - 07, 2011 35

• �GFR �� [NaCl] in tubule fluid �� uptake of NaCl into macula densa cells � � release of ATP & ADO ��

intracellular [Ca2+] � �GFR

• � release of ATP & ADO � � release of renin by granular cells

• Also, � entry of NaCl into macula densa cells � �

production of PGE2� � renin secretion by granular cells

• NB: although ADO is a vasodilator in most other vascular

beds, it constricts the afferent arteriole in the kidney


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 fluid and 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– ensures that fluid and solute excretion remain constant

Dr J. Mohan

April 04 - 07, 2011 36


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 certain hormones and by changes in sympathetic nerve activity

Regulation of RBF & GFR

Table 32-1; Koeppen & Stanton, 2010

Dr J. Mohan

April 04 - 07, 2011 37

Can you predict the effect of these changes in afferent & efferent arterioles

on PGC, GFR & RBF?



Dilation of the efferent arteriole (C) decreases PGC and thus decreases GFR

Constriction of the efferent arteriole (B) elevates PGC and thus increases GFR

Constriction of the afferent arteriole (A) decreases PGC because less of the arterial pressure is transmitted to the glomerulus, thereby reducing GFR

Dilation of the afferent arteriole (D) increases PGC because more of the arterial pressure is transmitted to the glomerulus, thereby increasing GFR


Dr J. Mohan

April 04 - 07, 2011 38

Sympathetic Nerves

• Dehydration or strong emotional stimuli, such as fear and 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

• Renalase from kidneys � facilitates degradation of catecholamines


Angiotensin II

• Ag II is produced systemically and locally within the kidneys

• constricts the afferent & efferent arterioles and decreases RBF & GFR

• efferent arteriole more sensitive to Ag II than afferent arteriole, so low [Ag II] � constriction of efferent arteriole � � GFR & �RBF

• high [Ag II] � constriction of afferent & efferent arteriole � �

GFR & � RBF


Dr J. Mohan

April 04 - 07, 2011 39


� blood vol

�� ABP



Prostaglandins (PGs) : clinical importance

• PGs do not play a major role in regulating RBF in healthy, resting people

• However, during pathophysiological conditions e.g. hemorrhage , there is � production of PGs (PGI2, PGE1 & PGE2) by kidneys ; PGs � � RBF without changing GFR

• PGs � RBF by dampening the vasoconstrictor effects of sympathetic nerves & Ag II � prevents severe & potentially harmful vasoconstriction & renal ischemia

• dehydration & stress (e.g., surgery, anesthesia), Ag II, & sympathetic nerves � � synthesis of PGs

Dr J. Mohan

April 04 - 07, 2011 40


Prostaglandins (PGs) : clinical importance

• non-steroidal anti-inflammatory drugs (NSAIDs), e.g. aspirin & ibuprofen � �synthesis of PGs

• administration of NSAIDs during renal ischemia and hemorrhagic shock is contraindicated because by blocking the production of prostaglandins, they decrease RBF & increase renal ischemia

• PGs play an increasingly important role in maintaining RBF & GFR as individuals age, so NSAIDs can significantly � RBF & GFR in the elderly


Nitric Oxide

• NO : an endothelium-derived relaxing factor (EDRF)

• important vasodilator under basal conditions

• counteracts vasoconstriction produced by Ag II & catecholamines

• � blood flow increases � � greater shear force on endothelial cells in the arterioles � � production of NO

• ACh, histamine, bradykinin, & ATP � � facilitate release of NO from endothelial cells

• � NO � dilation of the afferent and efferent arterioles in the kidneys

• � NO � � total peripheral resistance (TPR) • � NO � � TPR

Dr J. Mohan

April 04 - 07, 2011 41


Endothelin

• potent vasoconstrictor secreted by endothelial cells of the renal vessels, mesangial cells, and distal tubular cells in response to Ag II, bradykinin, epinephrine, and endothelial shear stress

• � profound vasoconstriction of the afferent & efferent arterioles � � decreases GFR & RBF

• � production of endothelin in a number of glomerular disease states (e.g., renal disease associated with diabetes mellitus)


Bradykinin

• vasodilator that acts by stimulating the release of NO & PGs• increases GFR & RBF• kallikrein = proteolytic enzyme produced in the kidneys• cleaves circulating kininogen to bradykinin

Adenosine (ADO)

• produced within the kidneys • � vasoconstriction of the afferent arteriole � � GFR & RBF• (see tubuloglomerular feedback)

Dr J. Mohan

April 04 - 07, 2011 42


Natriuretic Peptides

• � secretion of ANP by cardiac atria & BNP by cardiac ventricle when ECF �

• ANP & BNP � dilate afferent arteriole & constrict efferent arteriole

• � ANP & BNP produce a modest increase in GFR with little change in RBF


Adenosine Triphosphate

• cells release ATP into the renal interstitial fluid• ATP has dual effects on GFR & RBF• under some conditions, ATP constricts the afferent arteriole,

reduces RBF & GFR (tubuloglomerular feedback)• ATP also may � NO production & � GFR & RBF

Glucocorticoids

• therapeutic doses of glucocorticoids �� GFR & RBF

Dr J. Mohan

April 04 - 07, 2011 43


• Histamine

• local release of histamine modulates RBF during the resting state and during inflammation and injury

• � � resistance of afferent and efferent arterioles � � RBF without elevating GFR

• Dopamine

• produced by PT • � � RBF & � renin secretion


• NB : role of Angiotensin-converting enzyme (ACE) located on the surface of endothelial cells lining the afferent arteriole &glomerular capillaries

• converts Ag I to Ag II �� GFR & RBF• Ag II also produced locally in granular cells in the afferent

arteriole & PT cells


Dr J. Mohan

April 04 - 07, 2011 44

• Clinical Importance of ACE

– ACE degrades & thereby inactivates bradykinin– converts Ag I to Ag II– ACE � � Ag II levels & �bradykinin levels

– Drugs : ACE inhibitors (e.g., enalapril, captopril), � �Ag II levels & � bradykinin levels � � systemic vascular resistance � � BP

– �Ag II levels & � bradykinin levels � � renal vascular resistance � � GFR & RBF

– therefore used to � systemic blood pressure in hypertensive patients


• Clinical Importance of AgII receptor antagonists

– Ag II receptor antagonists (e.g., losartan) are also used to treat high blood pressure

– block the binding of Ag II to the Ag II receptor (AT1)

– block the vasoconstrictor effects of angiotensin II on the afferent arteriole; � � GFR & RBF

– Ag II receptor antagonists do not inhibit kinin metabolism (e.g., bradykinin) as do ACE inhibitors


Clearance GFR RBF Med Apr 2011 LO - medscistudentsmedscistudents.webs.com/MDSC...

Documents

Transcript of Clearance GFR RBF Med Apr 2011 LO - medscistudentsmedscistudents.webs.com/MDSC...