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Renal physiologyRenal physiologyDr. Ramadan Mohamed Ahmed.Dr. Ramadan Mohamed Ahmed.Eslam.anes@yahoo.comEslam.anes@yahoo.com

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Chief Functions of Renal System

Chief Functions of Renal System1.Regulation of water & electrolyte balance

2.Regulation of acid & base balance3.Excretion of waste products of protein metabolism, e.g.,

U

rea from protein breakdown U ric acid from nucleic acid breakdown Creatinine from muscle creatine breakdown

End products of hemoglobin breakdown4.Excretion of foreign chemicals, e.g., drugs, food additives,

pesticides, etc.5.Endocrine function: erythropoietin, renin, 1,25-dihydoxy-vitamiD.

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3

FUNCTION AL AN ATO MYO F KIDN EYS &FUNCTION AL AN ATO MYO F KIDN EYS &U

RIN

ARYT

RACT U

RIN

ARYT

RACT

T he kidneys lie high on the posterior abdominal wall below thediaphragm & on either side of the vertebral column.

I n adults each kidney is the size of a clenched fist & weighs ~150U

rine produced by the kidneys is delivered to the urinary bladderby 2 ureters.

T he bladder continuouslyaccumulates urine and periodically

empties its contents via urethraunder the control of an externalurethral sphincter a processknown as micturition.

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FUNCTION

AL AN

ATO

MY: kidneyFUNCTION

AL AN

ATO

MY: kidneyEach kidney is formed of 2 distinctparts:

An outer cortex An inner medulla.

T he nephronis the functional unitof the kidney. Each kidney contains~ 1 million nephrons.

T he nephron is composed of 2 maincomponents: A.T he renal corpuscleB.T he renal tubule

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TH EN EPH RONTH EN EPH RON

A. RenalCorpuscle:(Site of filtration of blood)1.T he Glomerulus:- I t is present in the cortex.- Each glomerulus is formed of a tuft of capillaries thatare invaginated into the Bowmans capsule.- Blood enters the capillaries through theafferentarterioleand leaves through the slightly narrowerefferent arteriole.- Glomerular capillaries are unique in that they areinterposed between 2 arterioles.T his arrangement serves to maintain a high hydrostatic pressure in the capillar

which is necessary for filtration.

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7

TH

EN

EPH

RON

TH

EN

EPH

RON

A. RenalCorpuscle:2. T he BowmansCapsule:I t is the proximal expanded portion of the renal tubule forming adouble-walled cup

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TH

EN

EPH

RON

TH

EN

EPH

RON

B. RenalT ubule:1. Proximal convoluted tubule (PCT )2. Loop of H enle:I t is further subdivided into:

T hin descending limbT hin ascending limbT hick ascending limb

3. Distal convoluted tubule (DCT )- Many DCT s open into acollecting duct (CD). CDs pass from thecortex (corticalCD) to the medulla (medullaryCD) and finally drainurine into the renal pelvis.

- PCT & DCT are present in the cortex, while the descending limb oloop of H enle dips into the medulla, forming a hairpin turn & then

returns back to the cortex.

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TH EN EPH RON TH EN EPH RON

Juxtaglomerular Apparatus: Each DCT passes between the afferent & efferent arterioles of its

own nephron. At this point there is a patch of cells with crowdenuclei in the wall of the DCT called themacula densa.T hey sense the concentration of N aC l in this portion of the tubule.

T he wall of the afferent arteriole opposite the macula densacontains specialized cells known as thejuxtaglomerular cells (JGcells).T hey secrete renin.

T ogether, the macula densa & JG cells are called the juxtaglomerularapparatus (JGA).

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T heT he JuxtaJuxta--glomerularglomerular Apparatus Apparatus

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TH EN EPH RON (cont.)TH EN EPH RON (cont.)T here are 2 types of nephrons in the kidney:

1.CorticalN ephrons:(80% of nephrons) T heir glomeruli lie in the outer layers of the cortex. T heir tubular system is relatively short. T heir loops of H enle penetrate only for a short distance into the

outer portion of renal medulla.

2. JuxtamedullaryN ephrons:(20% of nephrons) T heir glomeruli lie at the boundary between cortex & medull T hey have long loops of H enle, which dip deeply down into the

medulla toward the tips of the pyramids. T hey play a major role in the process of urine concentration.

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T ypes of nephrons Items Cortical nephrons Juxtamedullary nephrons

% Of total 85 % 15%

Glomeruli Out part of cortex Inner part of cortex .

Loop of Henle Short i.e. dips to the junction between

inner and outermedulla.

Long i.e. dips deeplyinto the medullary

pyramids to theinner medulla

Blood supply Peritubular capillariesNo Vasa Recta

Vasa recta andperitubularcapillaries

Specialfunction

Na reabsorption Urine concentration

JG apparatus Present AbsentAutoregulation Present Absent

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Juxtamedullary Nephron Cortical Nephron

The efferent vessels of juxtamedullary glomeruli form long looped vessels,called vasa recta which is important for urine concentration.

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So,why is the loop of H

enle useful? T he longer the loop, the

more concentrated the

filtrate and the medullaryI

Fbecome

I mportance: the collecting tubule runs through thehyperosmotic medullamore ability to reabsorbH 2O Desert animals have long nephronLoop More H 2O is reabsorbed

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BLOO D VESSELS in theN EPH RON SBLOO D VESSELS in theN EPH RON SEach kidney receives its blood supply from arenal artery, which arisesdirectly from theabdominal aorta.

I n the kidney, the renal artery progressively subdivides into smabranches until they formafferent arterioles, which break up into a tuft of capillaries, the glomerulus. T hen the capillaries form theefferent arteriole. T he efferent arteriole again subdivides to formperitubular capillaries,which surround the various segments of the renal tubules.N .B.T here are2 sets of capillaries & 2 sets of arterioles!!

T

he efferent arterioles of juxtamedullary nephrons form a specia type of peritubular capillaries calledvasa recta. T hey are straight & long capillaries that form hairpin loops a

side the loops of H enle. T hey play an important role in the process of urine

concentration.

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Blood supply of the kidney

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Major renal capillariesG lomerular capillary

bed Peritubular capillary

bed

1. Receives bl from afferentart.

Receives bl from efferentart.

2. High presure bed 55 mmHg

Low pressure bed 13 mmHg

3.Represents arterial end of cap.

Represents venous end of cap.

4. allows fluid filtration. Allows fluid reabsorption.

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Blood Supply of Blood Supply of Cortical &Cortical &JuxtamedullaryJuxtamedullaryN ephronsN ephrons

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RENAL BLOOD FLOW (RBF)

R enal blood flow is about 20% of the cardiac outputThis is a very large flow relative to the weight of the kidneys(350 g)

RBF determines G FR

RBF also modifies solute and water reabsorption and deliversnutrients to nephron cells.

R enal blood flow is autoregulated between 70 and 170 mmHg by varying renal vascular resistance ( RVR ).

i.e. the resistances of the interlobular artery, afferent arterioleand efferent arteriole

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Factors affecting RBF1) Autoregulation:

RBF is kept relatively constant between ABP; 70mmH g, I t is present in denervated, isolated kidn this proving that this property is intrinsic property.

2) Sympathetic stimulation: V C of afferent arteriole of cortical nephronsp

decreased cortical blood flow.

Less effect on juxtamedullary nephronsp

remainswell perfused. V C of vasa rectap decrease medullary blood flowp

more urine concentration.

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Autoregulation of RBF & GFR N ote: Autoregulation isimportant toprevent largechanges in GFR thatwould greatly affecturinary output.

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4 0 80 120 160 200 2 4 0

0.5

1.0

1.5

R B F ( L / m i n )

BP (mmHg)

AUTO RE GULATO RYR ANG E

AUTO RE GULATION

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50 100 150 200

50

100

150

R B F o r

G R F ( %

o f n o r m a l

)

Arterial P ressure (mmHg)

Urine Output

GFR

RBF

EFFE CT O F AR TER IAL PRESS URE CHANG ESON G FR , RBF AND U R INE OUT P UT

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I

mpact of autoregulation Autoregulation: GFR=180L/day and tubular reabsorption=178.5L/d Results in 1.5L/day in urine

W ithout autoregulation: Small in BP 100 to 125mmH g, GFR by 25% (180

to 225L/day) If tubular reabsorption constant, urine flow of 46.5

L/day W hat would happen to plasma volume?

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MEASU REMENT O F REN AL BLOO D FLOW MEASU REMENT O F REN AL BLOO D FLOW I f we applyFicks principle, we can calculate RPF:

Amount of PAH filtered & secreted = P x ERPF Amount of PAH excreted in urine/min. =U x V

where, P = conc. of PAH in plasmaERPF = effective RPF (90% of plasma only, i.e., taking into

account that 10% bypasses the nephrons).U = conc. of PAH in urineV = volume of urine/min.

P x ERPF =U x V U x V

ERPF =P

Amount of PAH Amount of PAH=

filtered & secreted/min excreted in urine/min

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U rine formation

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U rine FormationGlomerular Filtration

substances move from blood to glomerular capsule

Tubular Reabsorptionsubstances move from renal tubules into blood of

peritubular capillariesglucose, water, urea, proteins, creatineamino, lactic, citric, and uric acidsphosphate, sulfate, calcium, potassium, and sodium ions

Tubular Secretionsubstances move from blood of peritubular capillaries into renal

tubulesdrugs and ions

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O verall fluid movement in the kidneys

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GlomerularGlomerular filtrationfiltration

It takes place betweenIt takes place between glomerularglomerular capillaries endothelium (characterizedcapillaries endothelium (characterizedby the presence of numerous small poresby the presence of numerous small pores (fenestrations)(fenestrations) and Bowmanand Bowman sscapsule (characterized by the presence of capsule (characterized by the presence of podocytespodocytes).).

PodocytesPodocytes are modifiedare modified squamoussquamous epithelial cells with numerousepithelial cells with numerouselongated branches called foot processes which are separated by narrowelongated branches called foot processes which are separated by narrow

gaps called filtration slits (slit pores).gaps called filtration slits (slit pores).

Fluid and small solutes dissolved in the plasma such as glucose, aminoFluid and small solutes dissolved in the plasma such as glucose, aminoacids, Na, K,acids, Na, K, ClCl, HCO, HCO 33-- , other salts, and urea pass through the, other salts, and urea pass through themembrane and become part of the filtrate.membrane and become part of the filtrate.

TheThe glomerularglomerular membrane hold back blood cells, platelets and mostmembrane hold back blood cells, platelets and mostplasma proteins.plasma proteins.

The filtrate is aboutThe filtrate is about 10 10% of the plasma.% of the plasma.

The volume of fluid filtered per unite time is called theThe volume of fluid filtered per unite time is called the glomerularglomerularfiltration rate (GFR). The GFR is about 180 L/day (=125 ml/min.).filtration rate (GFR). The GFR is about 180 L/day (=125 ml/min.).

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a- Contents:- water- ions:N a+, K+,C l-

- freely filtered substances e.g. glucose, aminoacids.- 0.03% albumin (molecular weight 6900).b- O smolality:300 mosmol/L, isotonic (same

osmolality as plasma).C- Specific gravity:1010D- pH : drops to 6 in urine due to acidification by

the kidney.

CO

MPO

SITION

O

F GFR

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In an average man:125 ml/minute. Inwomen : 10% less. H igh renal blood flow (20-25% of cardiacoutput) needed for high GFR.GFR equals about 180 L/dayso plasma volume(3L) filtered about 60 times daily, More than

99% of GFR is normally reabsorbed. N ormalvolume of urineis about1.5 litre/day.

Glomerular Filtration Rate (GFR)

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Glomerular membraneC apillary endothelium;It has small holes ( 70-90 nm ). It does notact as a barrier against plasma proteinfiltration.

Basement membrane;( BM)filamentous layer attached to glomerular endothelium & podocytes, carry strong-ve charges which prevent the filtration of

plasma proteins, but filters large amountof H2O and solutes.

Podocytes;E pithelial cells that line the outer surfaceof the glomeruli.They have numerous foot processes thatattach to the BM , forming filtration slits(25 nm wide ).

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Filterability of the MembraneFilterabilityis a term used to describemembrane selectivity based on the moleculsize and charge

Pore size would favor plasma protei(albumin) passage, but negative charge oprotein is repelled by the (-) charged basemenmembrane (proteoglycan filaments &podocytes)

Loss of this (-) charge causes proteinuria.

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Forces affecting filtrationFavoring Filtration Favoring Filtration Opposing Filtration Opposing Filtration

Glomerular hyd rostatic

p ressure60 mm Hg

Bowmans ca p sule hyd rostatic p ressure

18 mm Hg

Bowmans ca p sule colloi dosmotic p ressure

0 mm

Hg

Glomerular ca p illar y colloi d osmotic

p ressure32 mm Hg

Ne t = +10 mm Hg

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FO RCES of GFR

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Regulation of Filtration(1)Changes in glomerular hydrostatic pressure.(1) Diameter of the afferent arterioles.

VD of afferent arteriolesp ++H ydrostatic pr. in glomerularcapillaryp ++ GFR.

V C of afferent arterioles e.g ++ sympathetic activityp --H ydrostatic pr. in glomerular capillary (H PGC) p -- GFR.

(2) Diameter of the efferent arterioles.

Moderate V C p

++H

ydrostatic pr. in glomerularcapillaryp slight ++ of GFR.

(3) Arterial Blood Pressure:Between 70 & 170 mmH g: GFR and RBF are kept relatively

constant byautoregulatory mechanisms.

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4 3

Changes in GFR by constriction or dilation of Changes in GFR by constriction or dilation of afferent (AA) or efferent (EA) arteriolesafferent (AA) or efferent (EA) arterioles

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Regulation of Filtration(2) Changes in BowmansCapsule hydrostatic pressure

++H ydrostatic pr in Bowmans capsule e.g. stone inureterp -- GFR .

(3) Change in glomerular colloidal osmotic pressureIncreasedColloidal osmotic pressure in glomerularcapillary

e.g in dehydrationp decreased GFR.DecreasedColloidal osmotic pressure in glomerular

capillarye.g in hypoproteinemiap increased GFR.(4) Functioning kidney mass

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Measurement of GFR:(1)Inulin clearance;Inulin has the following characteristicsFreely filtered i.e. plasma conc.= filtrate concentratio

not reabsorbed or secreted by renal tubules i.e. amount filtered permin.= amount excreted in urine/min.

N

ot metabolized. N ot stored in the kidney. Does not affect filtration rate & its conc. is easily measured.

(2) Creatinine clearanceFreely filtered

N ot reabsorbedpartially secreted by renal tubules.Endogenous so used easily but inaccurate.

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RenalC

learanceDefinition:Volume of the plasma cleared from the substance per minute.

RC

=U

V/PRC = renal clearance rate

U = concentration (mg/ml) of the substance in

urineV = flow rate of urine formation (ml/min)P = concentration of the same substance in plasm

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Inulin clearance

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TU BU LAR FUNCTIONTU BU LAR FUNCTIONT he glomerular filtrateis formed at a rate of 125 ml/min. or 180L/day. I t passes to therenal tubules.

I n the tubules, the tubular fluid issubjected to the 2 main tubular functions,reabsorption &secretion.

I t is finally excreted asurine at a rate of about1-2 ml/min.or ca. 1.5L/day.

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T ubular Reabsorption is a Function of the

EpithelialCells Making up theT ubuleLumen

P lasma

Cells

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ProximalConvolutedT ubule

65% of the nephronfunction occurs in PCT .

T he PCT has a single layerof cuboidal cells withmillions of microvilli.

Increased surface area forreabsorption.PCT' s main function isreabsorption.

T he PCT is full of mitochondria

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Reabsorption in ProximalT ubule

100% Glucose, protein and Amino Acid

60% Sodium,C

l, andH

2O

.80% PH , HCO 3, K.60%Ca.

50% of FilteredU

rea.

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N a reabsorptionN a reabsorption

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Water Reabsorption

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Glucose reabsorption T he transporter for glucose on the basolateral membra

has a limited capacity to carry glucose back into theblood. If blood glucose rises above 180 mg/dl, some o the glucose fails to be reabsorbed and remains in theurine glucosuria.

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Glucose reabsorption

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T ubular maximum for glucose (T mG): T he maximum amount of glucose (in mg ) that can be

reabsorbed per min. I t equals the sum of T mG of all nephrons.

Value; 300 mg/min in , 375 mg/ min in.

RenalT hreshold for Glucose I

s approximately 180 mg/dl I f plasma glucose is greater than 180 mg/dl: T m of tubular cells is exceeded glucose appears in urine

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GLUCO SE REABSO RPTION H AS ATU BU LARMAXIMU M

P lasma Concentration of Glucose

GlucoseR eabsorbed

mg/min

F iltered E xcreted

R eabsorbed

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Glucosuriapresence of glucose in urine

1. Diabetes mellitusblood glucose level > renal threshold.2. Renal glucosuria I t is caused by the defect in the glucose transpomechanism.

3. PhlorhizinA plant glucoside which competes with glucofor the carrier and results in glucosuria (phloriddiabetes).

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Bicarbonate reabsorption

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Secretion in ProximalT ubule H ydrogen secretion for acid/base

regulation.

Ammonia secretion for acid/baseregulation.PAH .

C reatinine. U ric acid.Penicillin.

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Reabsorption: Loop of H enle

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SPECI FIC FUNCTION SO F DIFFERENT TU BU LARSPECI FIC FUNCTION SO F DIFFERENT TU BU LARSEGMENT S (cont.)SEGMENT S (cont.)

II. Loop of H enle: T he loop of H enle with its 3 segments (that differ structurally & functionally

contributes to creating a gradually increasing hyperosmolality (300p 1200mosmol/L) in the renal medullary interstitium.

A.T hin descending limb:

- highly permeable to water. 20% of H 2O is reabsorbed here.- only moderately permeable to solutes.O smolality of tubular fluido gradually as loop dips deep into the medullarypyramid (reaches 1200 mosmol).

B.T hin ascending limb:- impermeable to water- low absorptive power for solutes.

C . T hick ascending limb:- impermeable to water- high reabsorptive power for solutes:I t actively reabsorbs 25% of filtered

N a+, K+, &C l- (by1N a+, 2C l-, 1 K+cotransport) to medullary interstitium.O smolality of tubular fluidq gradually as it reaches DCT (becomeshypoosmotic).I t is called thediluting segment.

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DCT

andC

D

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MedullaryCollecting Ductreabsorbs < 10% of filteredN a+and waterfinal site for processing of urine

functional characteristics:

1. permeability to water is controlled by ADH level- o ADH o water reabsorption

2. permeable to urea- urea is reabsorbed into the medullaryinterstitium where it help increase theosmolality of the interstitium and therefore he to concentrate urine.

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Summary ForT ubular Functions

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Summary of changes in osmolality of tubular fluid invarious parts of the nephron

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HO

RMON

ALCONT

RO

LO

FHO

RMON

ALCONT

RO

LO

FTU BU LAR FUNCTIONTU BU LAR FUNCTION

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H ormones acting on the kidneyH ormones acting on the kidney1. Aldosterone:

Stimulus for its secretion:q Blood volume (via renin-angiotentin system). Actions & their site:I t stimulatesN a+reabsorption in DCT & corticalCD through:1)In principal cells:o N a+reabsorption in exchange with K+.2) In E-intercalated cells:o N a+reabsorption in exchange withH +.

2. AngiotensinII: I t is the most powerfulN a+retaining hormone.Stimulus for its secretion:

q arterial bl. pressure & blood volume, e.g., hemorrhage (via renin). Actions & their site:

1.I t

o Na

+reabsorption by several mechanisms:a. By stimulating aldosterone secretion.

b. In PCT : - By directly stimulatingN a+-K+ AT Pase at basolateral border.- By directly stimulatingN a+-H +countertransp. at luminal

border.2. I t constricts efferent arterioles.

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80

H ormones acting on the kidneyH ormones acting on the kidney3. AtrialN atriuretic Peptide (AN P):I t facilitatesN aC l &H 2O excretion.

Stimulus for its secretion:o Atrial pressure (released from specific atrial fibers when blood volumeo ) Actions & their site:

1.I t o GFR by VD of afferent & V C of efferent arteriole.2. I t q N a+reabsorption from DCT & corticalCD .

4. ADH :Stimulus for its secretion:o Plasma osmolarity &q blood volume. Actions & their site:o water reabsorption in late DCT , cortical & medullaryCD: by inserting

aquaporin water channels into their luminal membranes.5. Parathormone (PTH ):Stimulus for its secretion:q PlasmaCa2+concentration. Actions & their site:

1.o C

a2+

reabsorption from DCT

. 2.q

Phosphate reabsorption from PCT

.

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U reaH andling(1) PCT

About 50% of the filtered urea is passively reabsorbedT he wall of PCT is partially permeable to urea but highly permeable to water so water reabsorpt

from PCT increases urea concentration in tubular lumen.T his creates concentration gradientU rea reabsorption.

(2) T hick ascending limb of loop of H enle, DCT and cortical collecting tubules All are relatively impermeable to urea.

H 2O reabsorbed in DCT and cortical collecting tubule (in presenceof ADH ) p increased urea concentration in tubular fluid.

(3) Inner medullary portion of the collecting ductU rea diffuses into the medullary interstitium to increase its osmolality.

Diffusion of urea is facilitated by ADH .

40 - 60% of the tubular load of urea is excreted in urine.U rea cycle

U rea moves from the medullary interstitium into the thin loop of theH enle and back down into the medullary collecting

duct and again to medullary interstitiumseveral times before urea is excreted.

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U rea recycling

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H andling of H ydrogen1. PCT 85%

2. T hick ascending loop of H enle 10%3. DCT and collecting tubule 5%.

Mechanism of H + secretion

A)I

n PCT

, LH

and initial part of DCT

:Most of H + is secreted bysecondary active transport.I t isN a dependent.

Antiport carrier at luminal border bindN a andH .

B)In late part of DCT andCD:H ydrogen is secreted byprimary active transportByIntercalated cells,

hydrogen secretion is stimulated by aldosterone and bothhydrogen and potassium compete for secretion.

Subs Description Proximal tubule Loop of Henle Distal tubule Collecting duct

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glucose

If glucose is not reabsorbed bythe kidney, it appears in the

urine, in a condition known asglucosuria . This is associated

with diabetes mellitus ..

reabsorption (almost100%) viasodium-glucose transportproteins (apical)

and GLUT(basolateral ).

- - -

aminoacids Almost completely conserved. Reabsorption (active) - - -urea Regulation of osmolality. VarieswithADH

reabsorption (50%) viapassive transport secretion -

reabsorption inmedullary ducts

sodium Uses Na-H antiport, Na-glucosesymport , sodium ion channelsreabsorption (65%,

isosmotic )

reabsorption(25%, thick

ascending, Na-K-2Cl symporter )

reabsorption(5%,sodium-

chloridesymporter )

reabsorption(5%, principal

cells), stimulatedby aldosterone

chlorideUsually follows sodium . Active

(transcellular) and passive

(paracellular )

reabsorptionreabsorption

(thin ascending,thick ascending,

Na-K-2Cl

reabsorption(sodium-

chlorid symp

-

water Uses aquaporin . - reabsorption(descending) -reabsorption(with ADH, viavasopressinrecept or 2)

HCO3 Helps maintain acid-basebalance. [8]reabsorption (80-90%)

[9]reabsorption

(thick ascending)[10]

-reabsorption(intercalated

cells,

H Uses [[vacuolar H+ATPase]] - - -secretion

(intercalatedcells)

K Varies upon dietary needs. reabsorption (80%)reabsorption(20%, thick

ascending, Na-K-2Cl symporter )

secretion increased byaldosterone )

calcium reabsorptionreabsorption (thick

ascending) viapassive transport

reabsorptionstimulated

by PTH-

phosp Excreted as titratable acid .reabsorption (80%)

Inhibited by parathyroid

hormone.

- - -

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U RIN ECONC ENT RATION

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86

PRO DUCTION PRO DUCTION O FCONC ENT RAT EDU RIN EO FCONC ENT RAT EDU RIN E

C oncentrated urine is also calledhyperosmotic urine(urineosmolarity > blood osmolarity). T he kidney excretes excess solutes, but does not excrete exc

amounts of water. T he basic requirements for forming a concentrated urine are:

1. a high level of ADH , e.g., in water deprivation or hemorrhagep o permeability of late DCT & CDs to water, allowing thesesegments

to reabsorb a large amount of water.2. a high osmolarity of the renal medullary interstitial fluid

p provides the osmotic gradient necessary for water reabsorptionoccur in the presence of high levels of ADH .

After passing to the interstitium, water is carried by the vasa rback into the blood.

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PRO DUCTION PRO DUCTION O FCONC ENT RAT EDU RIN EO FCONC ENT RAT EDU RIN EReabsorption of W ater in Presence of ADH :In PCT , loop of H enle & early DCT :

- Same as in formation of dilute urine (see before).- T he tubular fluid reaching the late DCT is hyposmotic (100mO sm/L).

Late DCT :- ADH o the water permeability of the principal cells of the late DCT .

W ater is reabsorbed until the osmolarity of the DCT equals that of surrounding interstitial fluid in renal cortex (300 mO sm/L).

CDs:- ADH o the water permeability of principal cells of CDs.- As the tubular fluid flows through theCDs, it passes through regionsof increasing hyperosmolarity toward the inner medulla.

- W ater is reabsorbed from theCDs until the osmolarity of the tubularfluid equals that of the surrounding interstitial fluid.

T

he osmolarity of the final urine reaches 1200 mO

sm/L.

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II . PRO DUCTION O FCONC ENT RAT EDU RIN E (cont.)II . PRO DUCTION O FCONC ENT RAT EDU RIN E (cont.)

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II . PRO DUCTION O FCONC ENT RAT EDU RIN E (cont.)II . PRO DUCTION O FCONC ENT RAT EDU RIN E (cont.)

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T heCountercurrent SystemT heCountercurrent System T he countercurrent system is responsible for the creation &maintenance of a gradually increasing hyperosmolarity in the ren

medullary interstitium, which is essential for enabling the kidneyconcentrate urine in the presence of enough circulating ADH .

T his osmotic gradient is due to accumulation of solutes (primarilyN

aC

l & urea) in great excess of water in the medullary interstitium O nce the high solute concentration in medulla has been achievedmaintained by a balanced outflow of solutes & water in the medu

T his osmotic gradient is1. established by the loop of H enle, which acts as a countercurrent

multiplier.2. potentiated by the collecting duct, which allows urea recyclinoccur.

3. maintained by the vasa recta, which act as countercurrentexchangers.

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E ER RREE ER RRE SYSEMSYSEM

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TH ECOUNT ERCU RRENT TH ECOUNT ERCU RRENT SYST EMSYST EMLoop of Loop of H enleH enle Acting asCounterCurrent Multiplier Acting asCounterCurrent Multiplier5. MoreN aC l is pumped from thick ascending limb into interstitium

but water remains in tubule.T his continues until a 200 mO sm/Losmotic gradient is established.N ow osmolarity in medullaryinterstitium has risen further to 500 mO sm/L.

6. O nce again the fluid in descending limb equilibrates whyperosmotic medullary interstitial fluid, now reaching 500 mO sm/Lat the tip.7.T hese steps are repeated over & over, adding more & more solut

the medulla in excess of water.T his process gradually traps solutes in the medulla, eventually raising the interstitial osmolarity to 12mO sm/L.

O verall, the progressive transport of N aC l from the tubular fluid into the interstitium results in the establishment of a longitudinal osmgradient in the medulla.

T hus, the countercurrent arrangement of the loop of H enle multiplies arelatively small transepithelial osmotic gradient into a large longitugradient.

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COUNT ERCU RRENT MU LTIPLIER SYST EMIN COUNT ERCU RRENT MU LTIPLIER SYST EMIN LOO PO FH EN LELOO PO FH EN LE

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RoleRole of DCT &CDs inU rineConcentrationof DCT &CDs inU rineConcentration T ubular fluid flowing from loop of H enle into DCT is dilute. T he early DCT further dilutes the fluid, because this segment, like th

ascending limb of loop of H enle, actively transportsN aC l out of tubule, but is impermeable to water.

W ith high ADH concentrations, late DCT & corticalCD becomehighly permeable to waterp large amounts of water are reabsorbedfrom the tubule into the cortical interstitium, where it is swept awby the peritubular capillaries. W ith high ADH levels, there is further water reabsorption frommedullaryCDs to interstitium.H owever, the amount of water isrelatively small compared with that added to the cortical interstitiReabsorbed water is quickly carried away by vasa recta into venoblood.

N

.B.T

he fact that large amounts of water are reabsorbed into thecortex, rather than into the medulla, helps to preserve the highmedullary interstitial fluid osmolarity. T hus, in the presence of ADH , the fluid at the end of CDs has the

same osmolarity as the medullary interstitium (1200 mO sm/L).By reabsorbing as much water as possible, the kidneys form a hconcentrated urine while adding water back to ECF & compensatingfor deficit of body water.

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U reaU rea RecyclingRecycling I n the presence of ADH , urea contibutes 40% to the medullary

interstitial osmolarity (= 500 mO sm/L) by passive urea reabsorptionfrom the inner medullaryCDs into the interstitium.Mechanism:

- Ascending limb of loop of H enle, DCT , corticalCDs & outermedullaryCDs are impermeable to urea.

- As water is reabsorbed from late DCT

, cortical & outer medullaryCDs, urea concentrationo rapidly.- In inner medullaryCDs, further water reabsorption takes place, so that urea concentration rises even more.T hus, urea diffuses out of the tubule into renal interstitium because this segment is highlypermeable to urea, and ADH increases this permeability even more.

- A moderate share of the urea that moves into medullaryinterstitium diffuses into thin descending limb of loop of H enle, so that it passes again in tubular fluid.I t recirculates several timesbefore it is excreted. Each time around it contributes to a higherconcentration of urea in interstitium.U rea recirculation provides an additional mechanism for forminghyperosmotic medulla.

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U REA RECYCLIN GU REA RECYCLIN G

TH ECOUNT ERCU RRENT SYSTEMTH ECOUNT ERCU RRENT SYSTEM

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TH ECOUNT ERCU RRENT SYST EMTH ECOUNT ERCU RRENT SYST EMVasaVasa Recta asCountercurrent ExchangerRecta asCountercurrent Exchanger

Blood must be provided to renal medulla to supply its metabolic nebut without a special blood flow system, solutes pumped into the medby countercurrent multiplier would rapidly get lost.

T here are 2 special features in medullary blood flow that contribute topreservation of the high solute concentrations:

1.T he medullary blood flow is low(only 1-2% of total RBF)p sufficientfor metabolic needs of tissues, but minimizes solute loss.

2. T he vasa recta serve as countercurrent exchangers.Countercurrent Exchange Mechanism: As blood descends into medulla, it becomes more & more concentraby gaining salt & losing water. At the tips of vasa recta blood hconcentration of 1200 mO sm/L. As blood ascends back toward cortex, the reverse sequence occurs, andblood leaving vasa recta is only slightlyhyperosmotic to normal plasma.During its passage through medulla, blood has removed the excess swater that have been added by the transport processes occurring indeeper regions of the medulla.

T hus, theU -shape of vasa recta maintains the concentration of solutestablished by countercurrent system.

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Vasa Recta asCountercurrent ExchangerVasa Recta asCountercurrent Exchanger

Diuresis and diuretics

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Diuresis and diureticsDiuresis is an increase in the rate of urine output.

(A) H 2O diuresisIncreaseH 2O intakep decreaseO smotic. Prp decrease ADH p decreasefacultativeH 2O reabsorption i.e.U rine large volume and hypotonic.

(B)O smotic diuresisU nreabsorbable solute in PCT p decrease obligatoryH 2O reabsorptionpdecreaseN a+ concentration in tubular fluidp decrease osmolarity of medullaryinterstitiump decrease facultativeH 2O reabsorption.-U rine: large volume and isotonic or hypertonic.

(C) Pressure diuresisI

ncrease in arterial blood pressure leads to:GFR.I nhibition of rennin angiotensin system renin and angiotensinII production.

H ydrostatic pressure in peritubular capillaries whichincreaseN a+ &H 2O excretion.

(4) Diuretic drugs

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(4) Diuretic drugs(A)T hiazides: inhibitN a reabsorption in DCT .

(B) Aldosterone inhibitors: (Potassium-sparing diuretice.g. alldactone:

inhibitN a-K exchange in DCT and collecting tubulesp decrease serumN a and increase serum K+.

(C) Carbonic anhydrase inhibitors e.g. acetazolamide(Diamox).I t inhibits carbonic anhydrase enzymedecreaseH secretion

decreaseN aandHCO 3- reabsorption in PCT and increase K secretion in DCT

increaseN a,HCO3& K excretion in urine.

May lead to acidosis.

(D) Loop diuretics e.g. frusemide (lasix):inhibitN a-K-2C l cotransporters in the thick ascending limb

of loop of H enle.

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T

he act of Micturition

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Micturition Reflex As bladder fills sensory stretch receptors sendsignals via pelvic nerves to sacral segments ospinal cord.

Parasympathetic stimulation of the bladdersmooth muscle via the same pelvic nerves occ

I t is self-regenerative, subsides, then re-generates again until the external sphincter isrelaxed and urination can occur.

Innervation

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InnervationParasympathetic

P re-glanglionic S 2, S 3, S 4 unite to form P elvic nervesP ost-ganglionic onto detrusor muscle & internal sphincter

SympatheticP re-ganglionic L1, L2, L3P ost-ganglionic onto trigone, neck, & internal sphincter

Little to do with bladder contractiono--------- o------------------------------------------

Ach N E

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A f i i i

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Anatomy of Micturition

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B ladder Filling and Micturition B ladder Filling:

1. Empty bladder: 0 pressure2. 30 - 50 mls of urine 5 - 10 cm H 2O3. 50 - 300 ml little pressure change4. With filling, increased

activity of external sphincter(maintains continence, or control of

excretory functions)

5. > 300 - 400 ml discomfort;leads to urgency

S tart of Micturition:1. As bladder fills, micturition (bladder)contractions begin to appear

a. Last from a few seconds to more thana minute b. Pressure peaks (micturition waves)may rise a few cm H 2O to more than 100cm H 2Oc. Caused by micturition reflex

Micturition Cont

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Micturition Cont

2. Micturition reflex (does not need the brain)a. Filling stimulates sensory stretchreceptors b. Afferent impulses in Pelvic nervec. Signal reflexively sent back to bladder via efferent parasympatheticfibers in the Pelvic nerved. Detrusor muscle contracts, thenrelaxes

2. M icturition reflex - continuede. As bladder fills, micturition reflex occurs

more frequently, with greater contractionof bladder wall (positive feedback loo p)

f. M icturition powerful enough thenanother signal is sent through P udendal

nerve to inhibit external s phincter (internal relaxes passively when

pressure is 20 - 4 0 cm H 2O)g. Voluntary relaxation of external

s phincter allows for urinationh. F low thru urethra stimulates

parasympathic system, sustaining bladder contraction

Micturition Reflex

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Micturition Reflexstretch reflex initiated by filling of the bladder withurine which results in bladder wall contractionmediated by sensory stretch receptors in the bladderwall,specially by receptors in the posterior urethra

B LADD ER

SP INAL CO R D(sacral segments)

S ensory stretch receptor Detrusor muscle

PE LV IC N ERVE(S ensory F ibers)

PE LV IC N ERVE(P arasympathetic

M otor F ibers)

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V oluntary Control of Micturition

1.M

icturition reflex can be inhibited by:a. P ons b. Cerebral cortex

2. Voluntary contraction of external bladder s phincter means emptying can be delayed even if a micturition reflex occurs (can go and stop voluntarily)

3. Voluntary emptying:a. Contraction of abdominal muscles causes pressure in bladder

micturition reflex and inhibition of external sphincter b. Voluntary relaxation of external sphincter

Problems:

Atonic Bladder- destruction of sensory fibers

Traumatic spinal cord injuryOverflow incontinence.

Automatic Bladder- spinal cord injury above sacral region

Micturition reflex is intact but uncontrolled

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Micturition Abnormalities Atonic Bladder- destruction of sensoryfibers T raumatic spinal cord injury O verflow incontinence.

Automatic Bladder- spinal cord injuryabove sacral regionMicturition reflex is intact but

uncontrolled

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