physiology of kidney (gfr to counter current)

8/3/2019 Physiology of Kidney (GFR to COUNTER CURRENT)

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KIDNEY

GENERAL FUNCTIONS OF KIDNEY1. HOMEOSTASIS FUNCTION

- maintains the constancy of the internal environment by excretion of urine

- kidneys maintain :

water balance

electrolyte balance blood pH

2. ENDOCRINE FUNCTION

1. Renin Juxta-glomerular

cells

formation of angiotensin II

regulate ABP

2. Erythropoietin stimulate BM RBC

regeneration

3. converts vit D3 to 1,25 DHCC (active form) promotes Ca reabsoprtion

from intestine

4. secretes prostaglandins

*Excreted urine normally contains

1. Surplus water

2. Surplus electrolytes

3. Surplus acids & alkalis

4. Metabolic waste products

1. Urea from amino acids that used for heat & energy

2. Uric acid from nitrogen from nucleic acid/purines

*excessive production gout

3. Creatinine from creatine in the muscle

*presence in urinerepresents loss of nitrogen from body

5. Abnormal constituents (clue for underlying disorder)

1. Glucose (DM)

2. Ketone bodies (ketosis )

3. Albumin(kidney disease )

4. Red blood cells (kidney disease )

5. Galactose (galactoseamia )

6. Phenylketones (phenylketonuria ) 6. Metabolic products of all drug

*hormone chorionic gonadotrophin in urine of pregnant women

RENAL CIRCULATION1. renal artery in the medulla

2. 3-5 interlobar arteries pass between pyramids

3. arcuate branches at bases of pyramids, at cortico-medullary junction

4. inter-lobular arteries ascend through the cortex, between adjacent

medulllary rays to end as capsular capillaries 5. afferent arterioles during the course in cortex

6. glomerular capillaries

[1st

capillary network]

a tuft of coiled capillary network

*glomerular filteration!

7. efferent arterioles

8. [2nd

capillary network]

- peritubular capillaries

- vasa recta

*differs according to position of corpuscles

- subcapsular & intermediate corpuscles

- juxtamedullary corpuscles

9. interlobular veins arcuate veins interlobar veins renal veins *see histo!

Characters of renal circulation

1. Almost, all renal blood has to pass through the glomeruli2. Renal circulation is a portal circulation

- blood circulates into two capillary networks (glomerulus + peritubular capillaries)

- portal renal system has 2 functions :

• Filtration through glomerular capillaries.

• Reabsorption and secretion through peritubular capillaries .

3. High blood flow rate

- 1/4 of COP passes into the kidney (1300 ml blood/ minute)

4-The high renal blood flow is not due to high o2 consumption of kidney

- utilize only 8% of total o2 consumption of body

- ↑ BF is related to homeostatic function of the kidney allowing high GFR

700 ml of plasma passes through glomeruli 120 ml are filtered per minute

180 L/day , 99% of the filtrate is reabsorbed by the renal tubules leaving behind

unwanted substances to be excreted

Pressures in renal circulation

The 2 areas of resistance to blood flow in nephron = afferent & efferent arterioles

in afferent arterioles in efferent arteriole

pressure falls from 100 mmHg at

beginning to 60 mmHg in glomerulus

pressure falls 47 mmHg to be

13 mmHg in peritubular capillaries

leads to filtration leads to reabsorption



Factors affecting Glomerular Filtration Rate (GFR)

1. Renal blood

flow

- ↑ RBF, ↑ GFR

- ↓ RBF, ↓ GFR2. Diameter of

glomerular vessel Afferent arteriole Efferent arteriole

dilatation ↑ BF,

↑ glomerular press,

↑ GFR

↓ glomerular press, ↓ GFR

constriction ↓ BF,

↓ glomerular press,

↓ GFR

- mild constriction, ↑ GFR

- moderate or severe constriction,

↓ glomerular flow rate, ↓ GFR

3. Sympathetic

stimulation

causes constriction of afferent glomerular arterioles decreases renal BF & GFR

*very strong stimulation ↓ glomerular flow & pressure greatly urinary output can fall to

zero

4. Arterial blood

pressure

- autoregulation of GFR occurs between ABP 70 -160 mmHg prevent significant rise in

glomerular pressure corresponding to rise in systemic BP

- ↑ BP automatic afferent arteriolar constriction keep GFR constant

*GFR ↑ only a few percent if ↑ in BP is not severe

- ↓ BP afferent dilatation (↑ BF, ↑ GFR)

5 I t l i ↑ i l l i d t t t ↑i t l & ↓ GFR

1. plasma will remain for a longer time in glomerulus

large amounts of plasma will filter out

2. this increases plasma colloid osmotic pressure paradoxical decrease in GFR

occurs despite the increase in glomerular pressure



THE CONCEPT OF PLASMA CLEARANCE

Plasma clearance = the ability of the kidney to clean or “clear” the plasma of various substance

Measured by measuring “the volume of plasma cleared from this substance per minute”

rate of clearance of a substance from plasma = rate of excretion of this substance in urine

INULIN CLEARANCE- inulin is a polysaccharide having the following characters:

has MW of 5200 freely filtered through the glomeruli

NOT bound to plasma proteinconcentration inglomerular filtrate = concentration in the blood

can be estimated chemically in plasma & urine with high

degree of accuracy

NOT toxic

neither absorbed nor secreted by renal tubules

amount of inulin filtered /min = amount of inulin excreted in

urine

GFR = U x V

P

- inulin clearance = 125 ml/min

used a measure for GFR

behaviour of other substances is compared to it

- clearance < inulin (GFR) = substance is reabsorbed

- clearance > inulin (GFR) = substance is secreted

rate of clearance of a substance from plasma =concentration of substance in x volume of plasma cleared from this

plasma (P) substance per minute (C)

rate of excretion of this substance in urine =

concentration of substance in urine (U) x volume of urine per minute (V)

P x C = U x V

P x plasma clearance of a substance (ml/min) = U x V

plasma clearance of a substance (ml/min) = (U x V)/ P

amount of inulin excreted/min

= inulin concentration in urine

(U) x volume of urine/min (V)

amount of inulin filtered/min =

inulin concentration in filtrate (P) x

vol. of glom filtrate/min(GFR)

CREATININE CLEARANCE (Ccr)- also used to determine GFR

- some are normally secreted by PCT

endogenous creatinine is frequently used tomeasure the GFR

- the values agree quite well with the GFR

measured by inulin

*even the value of urinary creatinine is high

(dt tubular secretion),

value of plasma creatinine is also high

(dt non specific chromogen, present in the

blood, attached to creatinine, cannot be

separated from each other)

high urinary creatinine is abolished

PARA-AMINO HIPPURIC ACID (PAH)CLEARANCE

- renal plasma flow (RPF) is commonly measured by

infusing PAH at low doses (<3mg/100ml)- PAH is cleared from plasma by filtration through

glomeruli & secretion in the PCT

its exctraction ratio ( arterial conc-venous

conc/arterial concentration) is high

- about 90% of PAH in arterial blood is removed in a

single circulation

, only 1/10 remains in venous plasma

when the blood leaves the kidney

- effective RPF is obtained by dividing amount of PAH in

urine by plasma PAH level

ERPF indicates the plasma flowing through

functioning nephrons, so cleared from PAH

*the rest of plasma passes to areas that do not contain

functioning nephrons

(medulla, capsule, perirenal fat)

PAH clearance = Effective Renal Plasma Flow

UPAH

x V = 630 ml/min

PPAH

- ERPF can be converted to actual renal plasma flow

(RPF)

- Average PAH extraction ratio (ER) = 0.9

* Actual RPF = ERPF = 630 =700 ml/min

ER 0.9

*from RPF, renal BF can be calculated;

If hematocrit = 45%,

RBF = RPF 1 = 700 x 1 = 1273ml/min

(1-Ht) 0.9

*Filtration fraction = ratio of GFR to RPF

(125/700) = 0.18%/20%



AUTOREGULATION

Autoregulation of Glomerular Filtration Rate (GFR)

mechanism of autoregulation is uncertain

it is definitely intrinsic to the kidneys , since autoregulation can be demonstrated in

transplanted, denervated kidneys

1. MYOGENIC HYPOTHESIS

increase ABP causes stretch of smooth muscle of afferent glomerular arteriole

this causes reflex constriction of afferent arteriole

decrease ABP decreases stretch on afferent smooth mucsle leads to afferent

dilatation

2. JUXTA-GLOMERULAR / TUBULO-GLOMERULAR HYPOTHESISIn hypotension (means BP decreases below 100mmHg till 70 mmHg ),

2 feedback mechanisms occur :

afferent arteriolar vasodilator feedback efferent arteriolar vasoconstrictor feedback

- ↓ ABP ↓ GFR slow passage of

filtrate in tubules & over reabsorption of

Na+ and Cl- ions in thick ascending limb

in loop of Henle Na+ and Cl- ↓at

macula densa

- ↓ ion concentration causes afferent

dilatation ↑rate of blood flow in

glomerulus ↑glomerular pressure ↑GFR back to normal

- too low GFR causes over reabsorption of

Na+ and Cl- ions from filtrate ↓Na+ and Cl-

at macula densa

-↓ concentration of ions at macula causes

JG cells to secrete renin from their granules

formation of angiotensin II

- angiotensin II constricts the efferent

arterioles ↑ the glomerular pressure ↑ GFR to return back to normal

* in case of ↑ ABP, GFR ↑ ↑Na+ and Cl-

concentration in the macula densa causes

afferent constriction subsequent ↓ in GFR

↓ the concentration of Na+ and Cl-

entering the tubular lumen

Autoregulation of Renal Blood Flow (RBF)

RBF is constant between mean ABP 70-160 mmHg

it is mainly an afferent arteriolar mechanism

- if the mean ABP is ↓, RBF ↓ GP ↓ GFR ↓

- the concentration of Na+ and Cl- ions ↓at macula densa causes afferent

arteriolar dilatation that ↑RBF and GFR back to normal

-however , if mean ABP is ↑ it ↑RBF and GFR

- the concentration of Na+ and Cl- ions at macula densa↑ causes afferent

constriction that decreases the GFR and RBF to normal

* if ABP remains low for 10-20 minutes , RBF autoregulation disappears

= regulation mechanisms are switched!

- efferent arteriolar constriction mechanism becomes more potent RBF ↓ allows GFR to remain constant

- marked decrease in RBF helps ABP to return back to normal



Transport through renal tubules

PRIMARY SECONDARY

PRIMARY ACTIVE REABSOPRTION (PCT) SECONDARY ACTIVE REABSORPTION (Na Co-transporter)

- depends on transport of substances by carrier proteins in

cell membrane

1. Active reabsorption of sodium

- basolateral surface of cell membrane

contains extensive Na-K ATPase that cleaves ATP

highly permeable to potassium

-released energy transport :

sodium ions out of the cell to interstitium (blood)

potassium ions from interstitium to interior cell* K+ diffuses back into the intersti tium (dt hi permeability)

- Na+ transport out of cell ↓ its concentration & ↑ negativity

inside cell to -70 millivolts Na+ diffuses from tubular lumen

to inside of cell by electrochemical gradient,

*but it needs a carrier to facilitate its diffusion through

membrane by a process called “facilitated diffusion “

- glucose & amino acids are transported from tubularlumen through brush border by a process called “sodium

Co-transport “

- glucose or AA binds with same sodium carrier in brush

border

sodium diffuses inward through membrane and

pulls glucose or amino acid along with it

- inside the cell, sodium and glucose or AA split from

carrier

- glucose or AA diffuses through basal membrane of cellinto peritubular capillaries by a carrier down their

concentration gradient “facilitated diffusion”

* glucose or AA diffuse from lumen to inside of cell by

energy of diffusion of sodium against concentration

gradient

PRIMARY ACTIVE SECRETION (late DCT and cortical CD) SECONDARY ACTIVE SECRETION (PCT)

1. Primary active secretion of potassium

- basolateral border of principal cell of CT Na+ ions are pumped to interstitium by Na-K ATPase

K+ ions are transported to interior of cell

* luminal border is very permeable to K+ passes to lumen

2. Primary active secretion of hydrogen

- intercalated cells or dark cells

secretion of hydrogen ions by primary active

secretion in the presence of H+-ATPase

Secondary active secretion of hydrogen ions

- hydrogen ions combine with carrier proteins on cellmembrane which

transports Na+ to inside of cell

hydrogen ions from cell to lumen of tubule

*this is called “Na-H counter-transport”

- give energy to substance to move it against

electrochemical gradient

- have an ATPase activity they cleave ATP to ADP or AMP

and energy



Diffusion means free movement of substance by a concentration gradient as well as chemical, electrical or electrochemical gradient

1-Passive absorption of water by osmosis 2-Passive absorption by diffusion 3-Diffusion caused by electrical difference across tubular

membrane

- when different solutes are transported out of the

tubule their total concentration decreases inside the

tubular lumen, but increases in the renal interstitium

- the concentration difference cause

osmosis of water in the same direction with the

solutes

* different portions of renal tubules have different

permeabilities to water

- when water is reabsorbed by osmosis, the urea

in tubular fluid remains behind

- urea concentration increases in lumen

urea diffuses from lumen to interstitium

*however ,permeability of membrane for urea in

most parts of renal tubule is far less than that of

water

a large proportion of the urea remain in the

tubules and is lost in urine

(usually > 50 % of all that enters the glomerular

filtrate)

Secondary ion reabsorption

- negative ions tend to follow the positive sodium ions by

electrostatic attraction

- when active absorption of sodium takes place chloride ions are

absorbed with it to keep electrical neutrality

Passive secretion :

Ammonia is synthesized inside the tubular cells and diffuses into

the tubular lumen by a concentration gradient

Active transport

1. Reabsorption

- primary Na+

- secondary AA & glucose (Na-Cotransporter)

2. Secretion

- primary K+, H+

- secondary H+ (Na-H counter transport)

H+ secretion

1ry active DCT, CT

(intercalated)

H+ ATPase

2ry active PCT no specific

ATPase

Passive transport

1. osmosis of water (65%)

2. urea (50% reabsorption)

3. passive transport of Cl- & HCO3-

4. passive secretion of ammonia



TUBULAR TRANSPORT MAXIMA

Definition :The maximum amount of a substance in mg. which can be reabsorbed or secreted per minute

* under normal condition, it remains constant for the individual

Glucose tubular maximum (TmG) Para-amino hippuric acid tubular maximum (TmPAH)

definition maximum amount of glucose reabsorbed in mg. per minute in the renal tubules

/ maximum capacity of tubular cells to reabsorb glucose

measures measures the absorbing power of the renal tubules measures the secretory power of the renal tubules

determination 1. increasing the plasma glucose concentration in steps

2. determining the amount of glucose excreted in urine

the difference between the quantities of glucose filtered and those excreted represents =

the amount reabsorbed by the tubules

*the amount of glucose filtered per minute = concentration of glucose per ml plasma x GFR

*the amount of glucose excreted in urine= concentration of glucose per ml urine

x volume of urine per minute

* if PAH is administered intravenously in small amount (to

maintain a low concentration in blood) it is found that that

blood leaving the kidney in renal vein contains 10% of PAH

- the remaining 90% of PAH is removed from the renal blood in

single circulation by filtration and secretion

- if PAH concentration in plasma is increased in steps

the rate of tubular secretion increases until a maximum is

reached & no more increase of secretion occurs denotes

that the tubules have a limit for secretory power

the amount of PAH secreted/min =

(amount of PAH excreted/min) – ( the amount of PAH

filtered/min)

TmPAH=75mg/min

- within the physiological range of BG level (80-180 mg/100ml) all glucose filtered is

reabsorbed by the tubules

- at the threshold level (about 180mg%) glucose starts to be excreted in urine (renal threshold

of glucose) because the absorbing power of some tubules becomes saturated

- with gradual increase of BG level, more renal tubules become saturated until all the tubules

become saturated and no increase in glucose absorption occurs

* excess glucose filteres is excreted in urine because the tubules reach their maximum

absorbing capacity which is about

- 375mg/min for men

- 300mg/min for women



PROXIMAL CONVOLUTED TUBULESLOOP OF HENLE DISTAL

CONVOLUTEDTUBULE

COLLECTING DUCTTHIN DESCENDING THIN ASCENDING THICK ASCENDING

1-Reabsorption of 15-20 % of filtered water

2-Reabsorption of 25 % of filtered Na+

3-Reabsorption of 25 % of filtered K+

4- Reabsorption of chloride

5-Has an important role in concentration and dilution of urine

Reabsorption of about 65% of the GF:

1. 1ry active reabsorption of 65 % of Na+

2. 2ry active reabsorption of glucose & AA

[ Na-Co transport]

3. 2ry active reabsorption of 65% of K+

4. 2y active reabsorption of phosphate

under the control of PTH (inhibition)

5. reabsorption of 65% of water

[OBLIGATORY WATER REABSOPRTION]

* wall is freely permeable to water

not under the control of ADH

6. passive reabsorption of Cl- and HCO3

Secretion of

1. 2ry active secretion of H+

[Na-H counter transport]

2. secretion of diodrast , PAH, and penicillin

1. active reabsorption of 8-10% of filtered Na+

2. active secretion of K+ and H+

controlled by aldosterone

3. reabsorption of up to 15% of filtered water [FACULTATIVE WATER REABSOPRTION]

under effect of ADH

4. Reabsorption of urea

facilitated by ADH

*other parts of tubular epithelium is IMpermeable to urea

- ↑permeability to

water

- ↓ permeability to

solutes

*osmolality of tubular

fluid ↑

- IMpermeable to water

- ↑ permeability to

sodium & chloride

[passive diffusion]

1. active reabsorption of

sodium

2. 2ry active

reabsorption of chloride& potassium

[Na-Co transport]

*osmolality of tubular

fluid ↓ (hypotonic)



osmolality

Definition: measure of total concentration of discrete solute particles in solution

Posm = Osmolality of electrolytes + osmolali ty of glucose + osmolality of urea

Osmolality of electrolytes = osmolality of NaCl

Na+ and Cl- dissociate

• Na+ ions in ECF=140mEqL per litre=140mosm per litre

• Cl- concentration are also140 mEq per litre =140mosm per litre

Osmolarity of Nacl =280 mosm per litre

Glucose and urea will add 20 m0sm to it

so Posm= 300mosm per litre

Normal osmolality of ECF and ICF is about 300 milliosmoles per Kg water

DILUTING MECHANISM OF THE KIDNEY

In case of haemodilution, plasma osmolality decreases and this decreases ADH and absorption of solutes takes place at :

thick portion of the

loop of Henle & first

segment of the DCT

(diluting segment)

- active reabsorption of sodium ions

- secondary active absorption of chloride and potassium ions

osmolality of the fluid in the ascending limb decreases to

about 100 milliosmoles per Kg water

late DCT and CD - active absorption of sodium- passive absorption of chlorides

*IMpermeable to water in the absence of ADH! (facultative)

osmolality decreases to 70-65 mosm /Kg water



Concentrating mechanism of the kidney

In case of inadequate water supply or excess intake of electrolytes (hemoconcentration)

the kidney excretes concentrated urine (excess solutes are excreted with little loss of water)

Kidneys have developed a special mechanism for concentrating urine, called the counter current mechanism of the kidney

• It depends on the special anatomical arrangement of the loops of Henle and the vasa recta in juxtamedullary nephronsin which the loop of Henle dip in the medulla

loops are parallel to vasa recta

counter-current mechanism= a system in which INFLOW runs

(1)PARALLEL,

(2)COUNTER TO &

(3)ADJACENT to the OUTFLOW

1. the first step in the concentration of urine is to create the hyperosmolality of the medullary interstitial fluid (IF)

4 different solute-concentrating mechanisms are responsible for this osmolality :

thick ascending limb of loop of Henle* principal cause

- active reabsorption of sodium ions- secondary active reabsorption of chloride and potassium

increases osmolality of outer medulla interstitial fluid

thin ascending limb of loop of Henle - passive reabsorption of sodium and chloride ions

*depends on prior existence of medullary gradient to reabsorb water from thin descending limb

thereby increasing the concentration of sodium & chloride ions in the tubular fluid delivered to thin ascending limb

inner medullary part of the collecting ducts reabsorption of urea (helped by ADH) increases the inner medullary interstitial fluid osmolality

collecting duct - active reabsorption of sodium

- electrogenic passive absorption of chloride

the net result of these mechanisms = increase in the osmolality of medullary interstitial fluid to 1200-1300 mosm/Kg water in the pelvic tip of medulla

The combination of these mechanisms is called counter-current multiplier mechanism

because it multiplies the osmolality of the renal medullary interstial fluid

*In haemoconcentration,

Concentration of ADH ↑& act on epithelium of late DCT and CD ↑its permeability to waterwater is reabsorbed into the highly concentrated medulla



2 characteristics of medullary blood flow for maintaining the high solute concentration in the medullary IF

1. medullary blood flow is very small in quantity (about only 1-2% of total BF to the kidney)

because of the small and sluggish blood flow, removal of solutesis minimized

2. vasa recta functions as counter current exchanger (prevents washout of solutes from the medulla)

* walls of the vasa recta are highly permeable to NaCl and water

1. as blood flows down the descending limb of the vasa

recta ( which is parallel to the ascending limb of the tubule)

blood osmolality is slightly lower than the

osmolality of medullary IF

Na, Cl & urea diffuse out from the IF into blood

water diffuses out of blood into IF

2. at the tip of vasa recta, the blood osmolality increases to 1200 mosm/Kg water

3. as blood flows up back to the ascending limb blood osmolality is slightly higher than the

osmolality of medullary IF

Na, Cl & urea diffuse back out of the blood into

IF

water diffuses back into the bloodNet result blood of the vasa recta removes a little amount of solutes can maintain high solute concentration in medullary IF

Operation of vasa recta as counter current exchangers in the kidney

1. NaCl & urea diffuse out of ascending limb of vessel into the descending

2. water diffuses out of descending and into the ascending limb of vascular loop

(vasa recta)

physiology of kidney (gfr to counter current)

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