buiding 7, rm 219 tel:54237452 luning7@shmu.edu.cn intenet...

Lu Ning 卢宁

Associate professorDepartment of Physiology and

Pathophysiology

Buiding 7, Rm 219 Tel:54237452Luning7@shmu.edu.cn

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Kidney

Urine formation and excretion

Urinary SystemUrinary System

Renal failureRenal failure

Overview Overview –– Functions of the KidneyFunctions of the Kidney

Regulation of body fluid osmolality and volumes

Regulation of electrolyte and water Excretion of waste products Regulation of acid- base balance

filtrationSelective reabsorptionsecretion

Urine formation

Functions of the KidneyFunctions of the KidneyRegulation of body fluid osmolality and volumes

maintain cell volumenormal function of the cardiovascular system

Regulation of electrolyte and water Na+ , K + ,Cl -, HCO3

-, H +, Ca + (excretion=intake)

Excretion of waste products (Urea, Uric acids, creatine)

Regulation of acid- base balance

Functions of the KidneyFunctions of the Kidney

Production of hormoneserythropoietin: stimulate red blood cell

formation by bone marroweg: Anemia

renin: renin-angiotensin-addsterone system

Calcitriol : a metabolite of Vit D3

Renal failureRenal failure

Urine FormationUrine Formation

Structure of the KidneyStructure of the Kidney

一、nephron1～ 1.2 million each

glomerulusBowman’s capsule

Renal corpuscle

Renal tuble

proximal tubule

loop of henle

distal tuble

nephronnephron

Nervous System

Urinary SystemUrinary System

Cortical Cortical nephronnephron and and JuxtamedullaryJuxtamedullarynephronnephron

Cortical Cortical JuxtamedullaryJuxtamedullary

location

sizeA./A.E (efferent)

ratioin diameter

function

Peritubularcapillaries

Filtration and reabsorbtion of salt

Vasa recta, peritubularcapillaries

Concentration and diluting

NephronNephron

Cortical Cortical nephronnephron and and JuxtamedullaryJuxtamedullarynephronnephron

Cortical Cortical JuxtamedullaryJuxtamedullary

location

sizeA./A.E ratioin diameter

function

Peritubularcapillaries

Filtration and reabsorbtion

Vasa recta

Concentration and diluting

球旁器 juxtaglomerularjuxtaglomerular apparatusapparatus

Juxtaglomerular apparatus

1) The juxtaglomerular cells: renin-producing granular

2) Macula densa

3) Extraglomerular mesangial cells (Mesangial cell)

1. juxtaglomerular cell

granular cells:

modified smooth muscle cells

Produce ,store and release renin

juxtaglomerularjuxtaglomerular apparatusapparatus

2. macula densa：

detecting change of NaCl content → send a signal to the renal arterial system

juxtaglomerularjuxtaglomerular apparatusapparatus

3. extraglomerularmesangial cell:

phagocytic

Blood Blood Supply (main filtration: Supply (main filtration: in cortex of in cortex of nephronnephron))

RBF:1200 ml/min, 20-25 % of the cardiac output 94 % through the cortex; 5-6 % through the outer medulla; < 1 % through the inner medulla

nephronnephron

CapillaryCapillary

Regulation of Renal CirculationRegulation of Renal Circulation

1.Autoregulation of Renal CirculationRelatively constant of RBF and GFR,when the range

of arterial blood pressure: 80 to 180mmHg

Mechanisms of autoregulation: 1) Myogenic mechanism 2) Flow dependent mechanism

(tubuloglomerular feedback)

1. Autoregulation1) Myogenic mechanism:

an increased arterial blood pressure →→contraction of the vascular smooth muscle →→constriction of the blood vessel →→ the blood flow is maintained relatively constant

2) Tubuloglomerular feedback:an increased in renal blood flow →→

change in glomerular filtration →→

change in Na+ content in the renal filtrate →→ detected by the macula densa →→send a signal to the renal arterial system →→restore RBF and glomerular filtration rate (GFR) to normal

TubuloglomerularTubuloglomerular feedback:feedback:

2. Neural and Hormonal Regulation2. Neural and Hormonal Regulation

1) Neural Regulationstrong activation of the renal

sympathetic nerves →→ constrict the renal arterioles →→ ↓renal blood flow and GRF

2. Neural and Hormonal Regulation2. Neural and Hormonal Regulation

2) Hormonal RegulationNorepinephrine, Epinephrine, and Endothelinconstrict renal blood vessel and ↓GFRAngiotensin IIconstricts efferent arteriolesNitric Oxide↓renal vascular resistance and ↑GFRProstaglandins and Bradykinintend to increase GRF

GlomerularGlomerular FiltrationFiltration

GlomerularGlomerular Filtration Rate Filtration Rate

Definition:When blood passes through glomerular

capillaries, part of blood plasma free of proteins is filtered into Bowman’s space.

the volume of fluid filtered from the glomeruli into Bowman’s space per unit time is termed the GFR.

substance plasma(g/L)

ultrafiltred(g/L)

Excreted(g/L)

Excreted／plasma

UreaNH3

Glucoseprotein

3.30.23.70.3

0.0011.0

70～90

3.30.23.70.30.001.00.3

3.51.56.0

20.00.400

1.17.51.660.0

400.000

GlomerularGlomerular filtration barrierfiltration barrier

Structure of the filtration membrane:2-4nm1) Capillary endothelium:

fenestration: 70~90 nm2) Basement membrane:

meshwork of collagen and proteoglycan fibrillae: 2~8 nm3) Epithelial cells of the renal capsule: nephrin

slit pore: 4~11 nm

GlomerularGlomerular filtration barrierfiltration barrierthe filtration membranethe filtration membrane

GlomerularGlomerular filtration barrierfiltration barrierinfluence of size and electrical charge of dextran on its filterability

GlycoproteinsImmunolgical

damage and inflammation

dextrandextran

Cationnic molecules are more readily filted than are anionic molecules.The reduced filtration of anionic

molecules is explained by the presence of negively charged glycoprotein on the surface of all component of the glomerular filtration barrier.

AlportAlport syndromsyndrom

Nephrin is a transmembrane protein(slit diaphragm)

Alport syndrom is characterrized by hematuriaand progressive glumerulonephritis and account for 1%-2% of causes of end-stage failure.

NephroticNephrotic syndromesyndrome

An increase in the permeability of the glomerular capilaries to proteins

proteinuria

edema, hypoalbuminemia

1) The Glomerular filtration rate (GFR)Defined as the quantity of the glomerularultrafiltrate formed each minute in all nephrons of the both kidneys The normal value of GFR: 125 ml / min

Department of Physiology, Zhejiang University School of Medicine

Factors Affecting Filtration1) The glomerular hydrostatic pressure 2) The colloid osmotic pressure of plasma3) The Bowman’s capsule pressure4) The renal plasma flow5) Filtration area6) Permeability of the filtration membrane

Factors that alter filtration pressure Factors that alter filtration pressure change GFRchange GFR

1. Glomerular hydrostatic pressure (PGC)systemic blood pressure

afferent and efferent arteriolar diameters

Blood lose, shock→ PGC ↓→NFP ↓→GFR↓

2. 2. Capsular hydrostatic pressureCapsular hydrostatic pressure(P(PBSBS))

Renal calculus, tumor,

→PBS↑→NFP↓→GFR↓

3. The colloid osmotic pressure of plasma (πGC)

Ponderosus transfusion→ πGC ↓→NFP↑→GFR

4. The renal plasma flow

a decrease in the rate of the oncotic pressure

the distance along the capillary in which filtration was taking place

filtration

Factors governing GFRFactors governing GFR

Factors at the capillary bed are:

Total surface area available for filtration

Filtration membrane permeability

Net filtration pressure (NFP)

Consequences of loss of protein in the urine:

decrease in osmotic pressure

low circulatory volume and possibly shock.

Loss of blood clotting proteins ： uncontrolled bleeding.Loss of globulins and complement proteins make the

individual prone to infection.

The Glomerular Capillary Filtration Coefficient, Kf

The product of the hydraulic conductivity and surface area of the glomerular capillaries

Kf = GRF/Net filtration pressure

Filtration fraction :125/660＝19 %

2) Filtration fraction (FF)The percentage of GFR in the renal plasma flow

GlomerularGlomerular filtration rate (GFR)filtration rate (GFR)

Regulation of Regulation of GlomerularGlomerularFiltrationFiltration

If the GFR is too high:

Needed substances cannot be reabsorbed quickly

enough and are lost in the urine

If the GFR is too low:

Everything is reabsorbed, including wastes that

are normally disposed of

GFRGFR is used to evaluate the kidneysis used to evaluate the kidneys’’ ability to ability to remove waste products from the bodyremove waste products from the body

GFR is used to screen for:GFR is used to screen for:

Early signs of kidney damageEarly signs of kidney damage

A coffee maker

Presence of protein in the urine is called proteinuria.

• Presence of blood cells in the urine is called hematuria.

AlbuminuriaThe presence of significant amounts of albumin in the urine.

The The UremicUremic SyndromeSyndrome

Homeostatic Disorder of water，Electrolyte and Acid-alkali Balance：

Volume OverloadMetabolic AcidosisHyperkalemiaHyponatremiaHypocalcemiaHyperphosphatemia

Factors regulated by three mechanisms

renin-angiotensin-aldosterone system

ReabsorptionReabsorption and Secretion by the Renal and Secretion by the Renal Tubules (Tubules (bukubuku yang yang dikshdiksh halhal 643)643)

ReabsorptionReabsorption and Secretion by the and Secretion by the Renal TubulesRenal Tubules

reabsorption (cat, buku yang diksh paragraf pertama hal643)

180L/d 1.5L／d，

Normal urine volume: 1.5 L, >99％ reabsorbed , (<1% excreted)

secretion：Urine volume:

1.5L/d normal(contains no RBC, no glucose bcs 100%glucose are reabsorbed)

> 2.5 L polyuria< 400 ml oliguria< 100 ml anuria

(cannot be 0)

Renal handing of various plasma Renal handing of various plasma constituents in a normal adult humanconstituents in a normal adult human

ReabsorptionReabsorption and Secretion by the Renal and Secretion by the Renal TubulesTubules

Mechanisms of tubular transport

1) Passive transport(down their chemical or electrical gradient)

Simple diffusionosmosisfacilitated diffusionsolvent drag:the solutes dissolved in the water are also carried

along with the water.

Mechanisms of tubular transportMechanisms of tubular transport

2) Active transportPrimary active transport

against an electrochemical gradientdirectly requires metabolic energy (i.e. hydrolysis of ATP)

Examples: Na+-K+ ATPase, H+ ATPase, H+-K+ ATPase Ca+2 ATPase

ReabsorptionReabsorption and Secretion by the Renal and Secretion by the Renal TubulesTubules

Secondary active transport Symport (Co-transport) Transported substances move in the same direction across the membraneNa+-glucose, Na+- amino acid

Antiport (Counter-transport) Transported substances move in opposite directions across the membrane

Na+-H+ antiport

Reapportion and Secretion by the Reapportion and Secretion by the Renal TubulesRenal Tubules

The pathway of reabsorption1) Paracellular transport

5-10% of water transferPassive diffusion onlyRequires favorable electrochemical gradientPassive diffusion of ions and large non-polar solutes

2) Transcellular pathway90-95% of water transferPassive transportAll active transport

the pathway of the pathway of reabsorptionreabsorption

Apical

Basolateralmembrane

Basolateral

Transcelluar pathway

Paracelluar pathway

ReabsorptionReabsorption and Secretion by the and Secretion by the Renal TubulesRenal Tubules

3) endocytosisUptake by cells of particles too large to diffuse through

the cell membraneExample: Reabsorption of filtered proteins in the proximal

tubules

ReabsorptionReabsorption by the Renal Tubulesby the Renal Tubules

(一)Na+、Cl- Reabsorption

1. Proximal tubule 70％

(1) Na+ and Cl-

first half：active mechanisms

Na+: 65 ~ 70% absorbedco-transport: Na+– glucose and amino acids counter-transport: Na+– H+

Cl–: 55% absorbed passively

co-transport: Na+– glucose and amino acids counter-transport: Na+– H+

Proximal tubule first half

Second half：Proximal tubule

Transcellular and paracellularpathway

TranscellularNa+ and Cl- co-transport ，Na+-H+

Cl-／HCO3 counter-transport

Paracellular:NaCl (Cl- by chamical gradient)

Waterhydrostatic pressure

(2)WaterPassive diffusionPassive diffusionosmoticTranscellular and

paracellular

water channels：aquaporin(AQP-1)

（2003 Nobel prize）

Tubular Tubular ReabsorptionReabsorption of Solutes and Waterof Solutes and Water

Cl- goes up because Na+ is reabsorbed with glucose, amino acids, Pi and HCO3

Glucose, amino acids, Pi and HCO3

- go down due to reabsorptionwith Na+

Unchanged due to isosmoticreabsorption

2. Loop of henle

the thick ascending limb: Na+、Cl-：

Na+：2Cl-：K+ co-transportNa+-H+ counter-transport

Na+、 Cl-、 K+：Transcellular and paracellular

the thick ascending limb: N

、Cl-

2、Loop of Loop of henlehenle

Clinic

furosemide （速尿) inhibit cotransporter →NaCl reabsorbtion

osmolarity of the interstitial

water excretion

3、 Distal tubule and collecting ductsDistal tubule and collecting ducts

Distal tubule：Na+-Cl- symporter

Thiazide diuretics

Distal tubule and collecting ductsDistal tubule and collecting ducts

pricipal cell (主细胞)

Na+ and water: amiloride

secretion：K+

intercalated cell (闰细胞)

reabsorbtion：HCO3-

secretion ：H+

Distal tubule Distal tubule and collecting and collecting ductsducts

CA:cabonicCA:cabonic anhydraseanhydrase

amilorideInhibiteInhibite Na+ Channels

Water:1) Isosmotic trasporting mechanism

a small amount in the early distal tubule 2) Counter-current mechanism

in the late distal tubule and collecting ductcontrolled by ADH

Water：AQP－2：apical membrane，VP(ADH)AQP－3

AQP－4Basolateral membrane

Acid-base balance

HCO3- and H+ transport

Acid-base balance

1、HCO3- reabsorbtion and H+ serection

（1）proximal：>80% HCO3- reabsorbtion

HCO3- : by CO2 reabsorbtion

Na+-H+ antiport

proton pump (H+-ATPase)

Na+-HCO3-

Cl--HCO3-

H+分泌

1、HCO3- and H+

（1）proximal tubules：80%（2）loop of henle：15%,（3）distal tuble and collecting tuble：5%

proton pumpH+-K＋–ATP ase

HCO3- CO2+H2O

HPO42- H2PO4-

NH3 NH4+

HCO3- and H+ transport

NHNH33

glutaminase

Glutamine glutamate +NH4+

glutamic dehydrogense

∂-ketoglutarate +NH4+

(2H+, 2HCO3- )

NH4+ NH3 + H+

Acid-base balance

PotasPotasssiumiumthe proximal tubule (65-70%)

Loop of henle(25-30%)(key element)

in the distal tubule tubule and collecting duct. (both secretion and reabsorbtion)

dependent on reabsroption of sodium, under the control of aldosterone. in competition with secretion of H+

PotasPotasssiumium

4. Calcium99% of filtered Ca+2 is reabsorbed

Proximal tubule (60-65%), thick ascending loop of Henle (25-30%):

passive and paracellular (favorable electrochemical gradient)

4. Calcium4. Calcium

Distal tubule & collecting duct (4-9%): active and transcellularCa+2 diffuses down electrochemical gradient at luminal membraneTransported across basolateral membrane by Na+-Ca+2 antiporter and Ca+2 ATPaseRegulation: parathyroid hormone,calcitriol

5. Glucose totally in the proximal

tubule, mainly the early portions

Sodium-dependent glucose transporter

GlucoseGlucose

Tm-G:(the tubular transport maximum for glucose)

Renal threshold for glucosethe critical value of the plasma glucose concentration when the kidney begins to excrete glucose 180 mg/dL

GlucoseGlucose

Renal threshold for glucosethe critical value of the plasma glucose concentration at

which the glucose first appears in the urine180 mg/dL

Maximal rate of transport of glucose (TmG)plasma glucose concentration:300mg/100ml

375 mg/min (men), 300mg/min(women)

GlucoseGlucose

6. Amino acidsIn a similar way as glucose but by different carrier

Urinary Dilution and ConcentrationUrinary Dilution and Concentration

Urine volume: 1.5L/d normal> 2.5 L /d polyuria< 400 ml /d oliguria< 100 ml/d anuria

osmolality : 50-1200 mOsm/(kg.H2O)

> plasma hyperosmolality urine= plasma < plasma hypoosmolality urine

location：Loop of henle

Urinary concentrating mechanismUrinary concentrating mechanism

Corticomedullaryconcentration gradientA gradient of increasing osmolality

The countercurrent exchanger in the kidney

Urinary concentrating mechanism—the countercurrent theory

The countercurrent multiplication

The countercurrent exchanger in the kidney Permeability properties of the tubular system

Portions of the tubular system

Water Sodium Urea

Thick ascending limb of Henle’s loop

impermeable Actively transport impermeable

thin ascending limb of Henle’s loop

impermeable Highly permeable mid permeable

thin descending limb of Henle’s loop

highly permeable impermeable impermeable

the distal tubule highly permeable in the presence of ADH

secretion of H+ in the presence of aldosterone in exchange for Na+

impermeable

the collecting duct in the cortical and outer medulla

highly permeable in the presence of ADH

highly permeable impermeable

the collecting duct in the inner medulla

highly permeable in the presence of ADH

highly permeable highly permeable

The countercurrent exchanger in the kidney

Establishing of osmotic gradient of the renal medulla

Maintenance of the osmotic gradient in the medulla

The countercurrent exchange

Operation of the Operation of the vasavasa recta as recta as countcurrentcountcurrent exchangers in the kidneyexchangers in the kidney

NaCl and urea diffuse out of the ascending limb of the vessel and into the descending limb,whereas water diffuses and into the ascending limb of the vascular loop

Corticomedullaryconcentration gradient

Formation of concentrated or dilute urine

In the presence of ADH, which increases the permeability of the collect duct to water, water is drawn from the lumen into the interstitial fluid, that results in the excretion of a concentrated urine

In the absence of ADH, the dilute renal fluid is excreted

Factors that affect the concentration and dilution of the urine

1) Damage of renal medullaresult in an impairment of the concentrating ability

2) Loop diuretics such as frusemide, inhibit the active transport of NaCl at the thick asending portion of Henle’ loop, interfere with the establishiment of the osmotic gradient in the medulla of the kidney

3) Lack of urea in the body such as malnutrition, reduce the osmotic gradient established in the renal medulla

4) Increased velocity of blood flow in the vasa rectaupset the osmotic gradient in the medulla by carrying away amount of NaCl, thus reducing the osmotic gradient

Control of Renal FControl of Renal Functionsunctions

Autoregulationosmotic diuresisglomerulotubular balance

Nervous Control of Renal Functionsrenal sympathetic Hormonal Control of Renal Functions

Renin-angiotensin systemvasopressin

osmotic diuresisosmotic diuresis

The presence of large quanties of unreabsorbed solutes in the renal tubules causes an increase in urine volume called __Solutes that are not reabsorbed in the proximal tubules exert an appreciable osmotic effect

osmotic diuresisosmotic diuresis

the concentration of unreabsorbed solutes in the tubules↑→isotonic fluid→

water reabsorption ↓→ Na+ reabsorption↓→

urine volume↑，

excretion of NaCl ↑

diabetes（glucose）

mannitol→ isotonic fluid →diuresis

glomerulotubular balance1. Conceptor：GFR ↑→

an increased reabsorption of solutes and water in theproximal tubule

2. Mechanism: in general the percentage of the solutereabsorbed is held constant despite variations in GFR

constant fraction reabsorption （65-70% of GFR ）

glomerulotubular balance

The protein in the glomerular capillary plasamathe oncotic pressure in the peritubular capillaries↑

↓solute and fluid into peritubular capillaries

Na+ reabsorption ↑

GFR↑

GG--T balanceT balance

3. Meaning： the percentage of the solute in urine is held constant

G-T balance is to reduce the impact of GFR changes on the amount of Na+ and water excreted in the urine

Nervous Nervous Control of Renal FControl of Renal Functionsunctions

Renal sympathetic nerve

1. α-R→arterioles contracts→ RBF↓→GFR↓

2. Proximal tubule α-R→Na+、water reabsorption↑

3. juxtaglomerular cellsβ-R→Renin↑→

Na+、water reabsorption↑

Hormonal Control of Renal FHormonal Control of Renal Functionsunctions

vasopressin, VPRenin-angiotensin systematrial natriretic peptide, ANPKallirein and kinin systemendothelin ETnitric oxide

catecholamineProstaglandin E

Antidiuretic hormone (ADH) acts on the kidneys to regulate the volume and

osmolarity of the urine

Peptide hormone, increasing water permeability of collecting duct

ADH diuresisADH antiduresis

Insertion of aquaporins in apical membrane

Antidiuretic hormone (ADH)Antidiuretic hormone (ADH)

Paraventricular

Supraoptic nucleusPosterior pituitury

There are two effective stimuli that change ADH release.

One is plasma osmolalityplasma osmolality↑ →→hypothalamic osmoreceptors →→ production and release of ADH ↑

the other is blood volume

blood volume ↓→→ baroreceptor reflex & atrial

stretch receptors→→ vagus nerve→→ brainstem(NTS)→→ ADH release ↑

Water diuresisWater diuresis

plasma osmolality →→hypothalamic osmoreceptors →→production and release of ADH

Aldosterone

secreted by the glomerulosa of the adrenal cortex Increases the reabsorption sodium in the distal tubule and early collecting duct

Increases number of Na+ channelsIncreases number activity of Na+ pumps

The reabsrption of sodium is coupled to secretion of potassium.

Regulation of Aldosterone secretiona. Renin-angiotensin system b. Plasma concentrations of sodium and potassiumc. Extracellular fluid volumed. Adrenocorticotrophin (ACTH)

ReninRenin--angiotensin systemangiotensin system

Atrial natriuretic peptides (ANP) Atrial natriuretic peptides (ANP)

Involved in control of both salt and water balanceStretch-sensitive cells in wall of atriumStimulated by stretch to secrete ANPANP

Atrial natriuretic peptide (ANP)

•Produces natriuresis and

diuresis

•Decreases renin release

•Reduces total peripheral

resistance via

vasodilatation

•Decreases heart rate,

cardiac output

•Vasodilator factors

PGI2--prostacyclin

EDRF, NO--endothelium-derived

relaxing factor, nitric oxide

EDHF--endothelium-dependent

hyperpolarizing factor

Endothelium-derived vasoactive substances

The 1998 Nobel Prize in Physiology or Medicine

Nitric oxide as a signaling molecule in the cardiovascular system

Louis J Ignarro Ferid Murad Robert F Furchgott

NO, a signaling molecule with potent cardiovascular, immunomodulatory

& neuromediatory activities (Bredt, 1994)

•Vasoconstrictor factors

Endothelin

Kinin & histamine

Bradykinin, Kallidin--PlasmaHistamine--Mast cells in response to injury, inflammation, and allergic responses

Similar effects:causes vasodilatationincreases capillary permeability

Prostaglandins

Hormonal Control of Renal Hormonal Control of Renal FFunctionsunctions

Epinephrine and norepinephrineProstaglandin AdrenomedullinParathyroid hormone, PTH

Renal ClearanceRenal Clearance

Defined as the volume of plasma required to supply the amount of a substance X to be excreted in urine per unit time

PxVUxCx *

VUxCx *=

MicturitionMicturition

Micturition reflexMicturition occurs when the intravesicular pressure reaches 70 cmH2O via a reflex action

Pdet, cm H2O

0 volume 300 ml

detrusor

Higher control of micturition

There are inhibitory and facilitatory centers in the cerebral cortex and pons

Micturition reflex.swf

Micturition mechanism.swf

Abnormality of micturition

Injureaffrent nerve →overflow incontinence

effrent nerve→ urine retention

spinal cord spastic neurogenic bladder

buiding 7, rm 219 tel:54237452 luning7@shmu.edu.cn intenet...

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