Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow and Their Control

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow and Their Control

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University of JordanFaculty of Medicine

Department of Physiology and BiochemistryRenal Physiology (Dental) spring 2014

Textbook: Textbook of Medical Physiology By : Arthur C. Guyton and John E. Hall, 12th ed. 2011*****************************************************************Lect. No. Topic 12th Ed.1-2 Glomerular Filtration, Renal 303-307 Blood Flow and their Control 310-321

3-5 Tubular Reabsorption and 323-343 Secretion

6-7 Urine concentration and Dilution 345-360

8 Acid-Base Regulation 379-3929. Micturition 307-310

Faisal I. Mohammed. MD, PhDEmail: [email protected]

Optional Reading:1.Physiology, by: Robert Berne & Matthew Levy, 6th. ed. 20102. Human physiology, by: Lauralee Sherwood, last edition.

Objectives

List the functions of the renal system Describe the processes of urine formation Describe glomerular filtration Explain the control of glomerular filtration Describe renal blood flow and its control Explain the glomerulotubular feedback

mechanism as a way for control of GFR.

Body fluid regulation.Body fluid regulation.

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Summary of Kidney Functions

• Excretion of metabolic waste productsurea,creatinine, bilirubin, hydrogen

• Excretion of foreign chemicals:drugs, toxins, pesticides, food additives

• Secretion, metabolism, and excretion of hormones- renal erythropoetic factor- 1,25 dihydroxycholecalciferol (Vitamin D)- renin

• Regulation of acid-base balance• Gluconeogenesis: glucose synthesis from

amino acids• Control of arterial pressure• Regulation of water & electrolyte excretion

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• Urea (from protein metabolism)

• Uric acid (from nucleic acid metabolism)

• Creatinine (from muscle metabolism)

• Bilirubin (from hemoglobin metabolism)

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• Pesticides

• Food additives

• Toxins

• Drugs

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Secretion, Metabolism, and Excretion of Hormones

• Renal erythropoetic factor• 1,25 dihydroxycholecalciferol (Vitamin D)• Renin

Hormones produced in the kidney

Hormones metabolized and excreted by the kidney

• Most peptide hormones (e.g. insulin, angiotensin II, etc.)

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O2 Delivery Kidney

Erythropoetin

Erythrocyte Production in Bone Marrow

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• Kidney produces active form of vitamin D(1,25 dihydroxy vitamin D3 )

• Vitamin D3 is important in calcium and phosphate metabolism

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• Excrete acids (kidneys are the only means of excreting non-volatile acids)

• Regulate body fluid buffers (e.g. Bicarbonate)

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Gluconeogenesis: kidneys synthesize glucose from precursors (e.g., amino acids) during prolonged fasting

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Endocrine Organ• renin-angiotensin system• prostaglandins• kallikrein-kinin system

Control of Extracellular Fluid Volume

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• Sodium and Water

• Potassium

• Hydrogen Ions

• Calcium, Phosphate, Magnesium

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Organs of the urinary system

University of Jordan


Internal anatomy of the kidneys



Blood supply of the kidneys


Nephron Tubular Segments

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Cortical and juxtamedullary nephrons

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Basic Mechanisms of

Urine Formation

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Structures and functions of a nephron

Renal corpuscle Renal tubule and collecting duct

Peritubular capillaries

Urine(containsexcretedsubstances)

Blood(containsreabsorbedsubstances)

Fluid inrenal tubule

Afferentarteriole

Filtration from bloodplasma into nephron

Efferentarteriole

Glomerularcapsule

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Tubular reabsorptionfrom fluid into blood


Afferentarteriole


Efferentarteriole

Glomerularcapsule

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2





Tubular secretionfrom blood into fluid

Tubular reabsorptionfrom fluid into blood


Afferentarteriole


Efferentarteriole

Glomerularcapsule

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2 3

Excretion = Filtration - Reabsorption + Secretion

Filtration : somewhat variable, not selective (except for proteins), averages 20% of renal plasma flow

Reabsorption : highly variable and selective most electrolytes (e.g. Na+, K+, Cl-) and

nutritional substances (e.g. glucose) are almost completely reabsorbed; most waste products (e.g. urea) poorly reabsorbed

Secretion : highly variable; important for rapidly excreting some waste products (e.g. H+), foreign substances (including drugs), and toxins

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Renal Handling of

Different Substances

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Glucose 180 180(gm/day)

Filtration Reabsorption Excretion

Water 180 179 (liters/day)

Sodium 25,560 25,410 (mmol/day)

Creatinine 1.8 1.8(gm/day)

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0

150

0

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GFR = 125 ml/min = 180 liters/day

• Plasma volume is filtered 60 times per day

• Glomerular filtrate composition is about thesame as plasma, except for large proteins

• Filtration fraction (GFR / Renal Plasma Flow)= 0.2 (i.e. 20% of plasma is filtered)

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Glomerular capillary filtration barrier

Glomerular capillary filtration barrier

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Effects of size and electrical charge of dextran on Effects of size and electrical charge of dextran on filterability by glomerular capillaries. filterability by glomerular capillaries.

Effects of size and electrical charge of dextran on Effects of size and electrical charge of dextran on filterability by glomerular capillaries. filterability by glomerular capillaries.

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Clinical Significance of Proteinuria

Early detection of renal disease in at-risk patients 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

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Microalbuminuria

• Definition: urine excretion of > 30 but < 150mg albumin per day

• Causes: early diabetes, hypertension, glomerular hyperfiltration

• Prognostic Value: diabetic patients withmicroalbuminuria are 10-20 fold morelikely to develop persistent proteinuria

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Determinants of Glomerular Filtration Rate

Normal Values:GFR = 125 ml/minNet Filt. Press = 10 mmHg

Kf = 12.5 ml/min per mmHg, or4.2 ml/min per mmHg/ 100gm(400 x greater than inmany tissues)

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• Kf = hydraulic conductivity x surface area

• Disease that can reduce Kf and GFR- chronic hypertension- obesity / diabetes mellitus- glomerulonephritis

• Normally not highly variable

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Glomerular Injury in Chronic Diabetes

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• Normally changes as a function of GFR, not a physiological regulator of GFR

• Tubular Obstructionkidney stonestubular necrosis

• Urinary tract obstructionProstate hypertrophy/cancer

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• Filtration Fraction (FF) FF G

• Arterial Plasma Oncotic Pressure (A)

A G

FF = GFR / Renal plasma flow = 125 / 650 ~ 0.2 (or 20%)

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Increase in colloid osmotic pressure in plasmaflowing through glomerular capillary

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Net Filtration Pressure

PB = 18

PG = 60G = 28

PG = 60G = 36

Net Filtration Pressure Decreases Along the Glomerulus Because of Increasing Glomerular

Colloid Osmotic Pressure

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Factors Influencing Glomerular Capillary Oncotic Pressure ( G)

• Plasma Protein Concentration Arterial Plasma Oncotic Pressure (A)

A G

• Filtration Fraction (FF) FF G

FF= GFR / Renal plasma flow

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• Is the determinant of GFR most subjectto physiological control

• Factors that influence PG

- arterial pressure (effect is buffered by autoregulation)

- afferent arteriolar resistance- efferent arteriolar resistance

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50 100 150 2000

Arterial Pressure (mmHg)

GlomerularHydrostatic

Pressure(mmHg)

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40

20

80

Autoregulation of Glomerular Hydrostatic Pressure

Normal kidney

Kidney disease

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Autoregulation of renal blood flow and GFR but not

urine flow

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Effect of afferent and efferent arteriolar constriction on glomerular pressure

PG

GFRBloodFlow

Ra

Ra GFR + Renal

Blood Flow

Re

PG

GFR

Blood Flow

Re GFR + Renal

Blood Flow

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Effect of changes in afferent arteriolar

or efferent arteriolar resistance

Effect of changes in afferent arteriolar

or efferent arteriolar resistance

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RE

RBF G

GFR

PG

+

_

G determined by : FF = GFR / RPF

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Kf GFR

PB GFR

G GFR

A G

FF G

PG GFR

RA PG

RE PG

Summary of Determinants of GFR

GFR

GFR

GFR(as long as RE < 3-4 x normal)

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Determinants of Renal Blood Flow (RBF)

RBF = P / R

P = difference between renal artery pressure and renal vein pressure

R = total renal vascular resistance = Ra + Re + Rv = sum of all resistances in kidney

vasculature

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• High blood flow (~22 % of cardiac output)

• High blood flow needed for high GFR

• Oxygen and nutrients delivered to kidneys normally greatly exceeds their metabolic needs

• A large fraction of renal oxygen consumption is related to renal tubular sodium reabsorption

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Renal oxygen consumption

and sodium

reabsorption

Renal oxygen consumption

and sodium

reabsorption

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Control of GFR and renal blood flow

• Neurohumoral

• Local (Intrinsic)

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1. Sympathetic Nervous System /catecholaminesRA + RE GFR + RBF


2. Angiotensin II RE GFR + RBF

(prevents a decrease in GFR)

e.g. severe hemorrhage

e.g. low sodium diet, volume depletion 50


3. Prostaglandins RA + RE GFR + RBF

Blockade of prostaglandin synthesis → ↓ GFR

This is usually important only when there are other disturbances that are already tending tolower GFR

e.g. nonsteroidal antiinflammatory drugs in a volume depleted patient, or a patient with heart failure,cirrhosis, etc

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4. Endothelial-Derived Nitric Oxide (EDRF) RA + RE GFR + RBF

• Protects against excessive vasoconstriction

• Patients with endothelial dysfunction (e.g. atherosclerosis) may have greater risk for excessive decrease in GFR in response to stimuli such as volume depletion


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5. Endothelin RA + RE GFR + RBF

• Hepatorenal syndrome – decreased renal function in cirrhosis or liver disease?

• Acute renal failure (e.g. contrast media nephropathy)?

• Hypertensive patients with chronic renal failure?

Endothelin antagonists may be useful in these conditions


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Summary of neurohumoral control of GFR and renal blood flow

Effect on GFR Effect on RBF

Sympathetic activityCatecholaminesAngiotensin IIEDRF (NO)EndothelinProstaglandins

increase decrease no change

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Local Control of GFR and renal blood flow

7. Autoregulation of GFR and Renal Blood Flow• Myogenic Mechanism• Macula Densa Feedback

(tubuloglomerular feedback) • Angiotensin II ( contributes to GFR but

not RBF autoregulation)

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Renal ArteryPressure (mmHg)

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Renal Blood Flow

Glomerular Filtration Rate

Renal Autoregulation

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Time (min)0 1 2 3 4 5

120

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100 125 124 1.0

120 150 124

Importance of Autoregulation

Arterial GFR Reabsorption Urine Volume Pressure

Poor Autoregulation + no change in tubular reabsorption

Good Autoregulation + no change in tubular reabsorption120 130 124 5.0

26.0

Good Autoregulation+adaptive increase in tubular reabsorption 120 130 128.8 1.2

= 37.4 L/day!

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Arterial Pressure

Blood Flow and GFR

VascularResistance

Intracell. Ca++

Cell Ca++

EntryStretch ofBlood Vessel

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Structure of the

juxtaglomerular apparatus:

macula densa

Structure of the

juxtaglomerular apparatus:

macula densa

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GFR

Distal NaCl Delivery

Macula Densa NaCl Reabsorption

Afferent Arteriolar Resistance(macula densa feedback)

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Macula Densa Feedback

Proximal NaCl Reabsorption

Distal NaCl Delivery

Macula Densa NaCl Reabsorption

Afferent Arteriolar Resistance

GFR

(macula densa feedback)

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Regulation of GFR by Ang II

GFR Renin

AngII

Macula Densa NaCl

Efferent Arteriolar

Resistance

BloodPressure

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50 100 150 2000

Renal Blood Flow ( ml/min)

1600

1200

800

0

400

120

80

0

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Glomerular Filtration Rate (ml/min)

Arterial Pressure (mmHg)

Ang II Blockade Impairs GFR Autoregulation

NormalAng II Blockade

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Macula densa feedback

mechanism for regulating GFR

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Other Factors That Influence GFR

• Fever, pyrogens: increase GFR

• Glucorticoids: increase GFR

• Aging: decreases GFR 10% / decade after 40 yrs

• Hyperglycemia: increases GFR (diabetes mellitus)

• Dietary protein: high protein increases GFR low protein decreases GFR

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Protein Ingestion

Amino Acids

Tubular Amino Acid Reabs.

Proximal Nacl Reabs.

GFR

Macula Densa NaCl

Afferent Arteriolar Resist.

(macula densa feedback)

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Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow and Their Control

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