Renal Physiology Does your GI tract absorb into blood all nutrients? ions? water? 1.Now imagine that you drink water: 1 glass, 2, 3, 4, 5 glasses (1L).

Renal Physiology• Does your GI tract absorb into blood all nutrients? ions? water?1. Now imagine that you drink water: 1 glass, 2, 3, 4, 5 glasses (1L). Does the

additional 1 liter of water stay inside the blood vessels (18% increase from 5.5L)?– No. Water will leak into interstitial fluid, so that the load will be redistributed between

the vascular system and the tissues. One becomes 1kg heavier but blood volume is not affected significantly.

2. Now imagine that you drink isosmotic fluid: 300mOsm NaCl (one soup spoon of table salt per liter of water). Does the GI absorb all the ions? water? Does the additional liter of water stay inside the blood vessels?– Yes. Salt will not leave the blood vessels since there is no concentration gradient

between the blood and extracellular fluid. Water will stay with salt, i.e. in blood vessels. One becomes 1kg heavier and blood volume is increased by 18% (assuming no kidney function).

3. Recall that after losing 1L of blood, arterial blood pressure (Pa)is decreased so much that one can collapse (blood donation = 0.5L). Would you collapse if you drink 1L of Gatorade?– No. Because kidneys can transfer extra salt and water into the bladder as fast as we

drink and absorb it.

• Kidney receive 20-25% of cardiac output = 1.25 L/min

• 20% of this volume (i.e. 120 mL/min) is filtered into the internal kidney tubules and, if necessary, kidney would dispose almost all of this amount into the bladder

Homeostasis of ions and water

• Normal plasma sodium levels: 135 to 145 mmol/L.

• Very low Na+ (less than 125 mmol/L) nausea, vomiting, headache, short-term memory loss, confusion, lethargy, fatigue, loss of appetite, irritability, muscle weakness, muscle cramps, seizures, decreased consciousness or coma.

• Very high Na+ (greater than 157 mmol/L) seizures and coma.

• Normal plasma potassium levels: 3.5 to 5.0 mmol/L (98% of K+ is inside cells).

• Very low K+ (less than 3 mmol/L) muscle weakness, muscle pain, tremor, muscle cramps, constipation; flaccid paralysis and hyporeflexia.

• Very high K+ is a medical emergency due to the risk of potentially fatal abnormal heart rhythms.

Kidney processes:1. Filtration

2. Reabsorption3. Secretion

Sensors in kidney and elsewhere

[H+], [Na+], [K+], blood volume, etc. =constcontrolled variables

feedback control

• Kidney is a waterproof bag with one high pressure tube in (=renal artery) and two low pressure tubes out (=renal vein and ureter)

In Out

Out urine

Three processes:1. Filtration: Blood ultrafiltrate is pushed

into renal tubes2. Reabsorption: All glucose, all a.a. and

necessary amount of ions are reabsorbed back into blood. Whatever left is excreted as urine.

3. Secretion: some substances are actively secreted into urine.

urine is ultrafiltrate of blood from which nutrients and necessary ions were removed1 2

3

ultrafiltrate

Starts with renal corpuscle (initial filtering component) = a glomerulus + a Bowman's capsule

Renal tubule

• The building blocks of kidney are called nephrons from G. nephros=kidney

• ~1,000,000 nephrons in each kidney

Ends with collecting

duct

Afferent

arterio

le

Effere

nt ar

terio

le

Glomerular capillaries

• 1. Filtration:• renal artery

subdivides to form afferent arterioles

• Afferent arteriole subdivides into a smaller number of very short capillaries called glomerular capillaries

• The tuft formed of capillary loops is called glomerulus

ultrafiltrate1Renal corpuscle

2

3

43

4

5

5

Afferent

arterio

le

Effere

nt ar

terio

le

Glomerular capillaries

Capillary types

• These glomerular capillaries are very leaky.

• All substances smaller than 40nm can leave these capillaries.

• What substances are smaller than 40nm?

Fenestrations ~ 60 nm wide

Afferent

arterio

le

Effere

nt ar

terio

le

Glomerular capillaries

40nm

= 1mm (millimeter) = 1nm (nanometer)= 1µm (micrometer)

human nail thickness

human hair thickness

(40-140µm)

RBC (7.5µm)

WBC(10-12µm)

Columnar epithelial cell

(40-60µm)

axon diameter

(1µm)

synaptic vesicle diameter(50nm)

ovum(140µm)

Capillary types

• RBC (7.5µm) are not filtered• Everything else: glucose, a.a.,

ions, waste products including urea are filtered into Bowman’s capsule

• What about proteins that are smaller than 40nm? you do not want to loose proteins circulating in blood.

Fenestrations ~ 60 nm wide

Afferent

arterio

le

Effere

nt ar

terio

le

Glomerular capillaries

• Capillaries are covered by podocyte cells.• Podocyte cells have a number of protruding foot processes. • Space between foot processes makes filtration slits.

Efferent arterioleAfferent

arterio

le

Effere

nt ar

terio

le

Glomerular capillaries

Specializations of glomerular capillaries

Podocyte cells with protruding foot processes. Filtration slits make a sieve.

• Filtration slits make a sieve that does not allow proteins to escape blood

• Furthermore podocytes are negatively charges and proteins are also negatively charged so that podocytes repel proteins

width of filtration slits ~ 40 nm

Afferent

arterio

le

Effere

nt ar

terio

le

Glomerular capillaries

- - - - - - - --

-

• C = capillaries. • F = endothelial lining is highly fenestrated (F). • P = podocytes extend primary processes (P1) that give rise to numerous foot

processes (P2)• FS = filtration slits

Afferent

arterio

le

Effere

nt ar

terio

le

Glomerular capillaries

• Filtration summary:• 120 mL/min = 180

L/day is filtered into the internal kidney tubules

• Filtered: glucose, a.a., ions, waste products including urea

• Not filtered: RBC, most proteins, most molecules > 8nm

ultrafiltrate1Renal corpuscle or

2

3

45

180 L/day

Afferent

arterio

le

Effere

nt ar

terio

le

Glomerular capillaries

• 2. Reabsorption:• the renal tubule is

continuous with Bowman’s capsule.

• The epithelial cells of the tubule wall differ in composition and function along the tubule

• Segments:– Proximal convoluted

tubule– Loop of Henle– Distal convoluted tubule – Collecting duct

ultrafiltrate

1

Renal corpuscle or

2

3

4

5

63

45

6

180 L/day

120 L/day in proximal tubule

Amino acids

Amino acids

K+

Amino acids

ultrafiltrate

• a.a. reabsorption cannot be saturated.• normally all glucose is reabsorbed. In

diabetes blood [glucose] is so high that the absorption mechanism is saturated not all glucose is reabsorbed some glucose ends up in urine

• Urea is not reabsorbed at all• Examples of substances NOT regulated by

kidney (absorption is NOT regulated):– a.a. and glucose (reabsorb all)– urea (excrete all)

• Examples of substances regulated by kidney:– Na+ (reabsorb only as much as necessary)– K+ (reabsorb only as much as necessary)– H+ (reabsorb only as much as necessary)– H2O (reabsorb only as much as necessary)

• We will look at regulation of Na+ and H2O

Reabsorption mechanism:1. a.a.: co-transport with

Na+ on luminal side, facilitated diffusion on blood vessel side

2. glucose: same

• 2.1 Regulation of Na+

• Bulk active reabsorption in the proximal convoluted tubule (70%): co-transport with Glucose and a.a.

• Fine Na+ regulation in distal convoluted tubule and collecting duct (30%)

ultrafiltrate1

Renal corpuscle or

2

3

4

1

2

3

180 L/day

120 L/day in proximal tubule

70%

30%Na+

Na+

Na+

• 2.1 Fine tuning of Na+ reabsorption in distal convoluted tubule and collecting duct include regulation of:1. number of Na+-K+ pumps2. number of Na+ channels

on luminal membrane• Both are regulated by

Aldosterone

ultrafiltrate180 L/day

120 L/day in proximal tubule

1

2

Amino acids

Amino acids

K+1

2Na+

Na+ channels

2.1.1 Na+ reabsorption: Aldosterone

Amino acids

Amino acids

K+1

2Na+

Na+ channels

• Aldosterone is a steroid hormone producedby adrenal gland (steroid hormones act on nucleus to promote or inhibit protein production).

• Aldosterone increases synthesis of Na+-K+ pumps and Na+ channels in the cells of distal convoluted tubules and collecting duct.

• Aldosterone absent 2% of filtered Na+ is not reabsorbed but excreted.

• This is equivalent to 35g of NaCl per day

• High Aldosterone almost all Na+ is reabsorbed

• Eat high Na+ diet low Aldosterone • Eat low Na+ diet high Aldosterone • What regulates Aldosterone?

2.1.1 What regulates Aldosterone?• Aldosterone secretion by adrenal gland is directly

stimulated by a hormone Angiotensin II.

Liver secretes Angiotensinogen into blood stream, so that Angiotensinogen is in high and stable concentration

1

2

3

Depending on Na+ needs, Kidney (juxtaglomerular cells) release Renin into blood stream.

Angiotensinogen

Renin is an enzyme

A I

Small polypeptide Angiotensin I (A I) is cleaved by Renin

4 A I is converted into A II by angiotensin converting enzyme (ACE) on the luminal surface of capillaries particularly in the lungs

Angiotensin Converting Enzyme

A II

• ↑Renin ↑A II ↑ Aldosterone ↑ #Na+ channels and ↑ #Na-K pump ↑ Na+ reabsorption

• Thus: ↑Renin ↑ Na+ reabsorption ↑Pa• Renin is released by juxtaglomerular cells:

• How is Renin release regulated?• Three inputs to juxtaglomerular

cells:1. SNS (external regulations): fight-

or-flight ↑SNS ↑Renin ↑ Na+ reabsorption ↑ Pa

2. Juxtaglomerular cells function as baroreceptors: if ↓Pa ↓P in afferent arteriole ↑Renin ↑Na+ reabsorption ↑Pa

3. Osmoreceptors in macula densa located near the start of distal convoluted tubule. Macula densa senses the [Na+] in the tubular fluid flowing past it:↓[Na+] ↑Renin ↑Na+ reabsorption

1

2

3

Kidney internal regulation

2.1.1 Renin / A II / Aldosterone

• In addition. Angiotensin II is a potent constrictor of arterioles all over the body:

• ↓Pa ↑Renin ↑A II constriction of arterioles Pa

↑Aldosterone ↑Na+ Pa• If Angiotensin II levels are continuously elevated, it could

be one cause of hypertension.• What is the first line of defense against high blood

pressure?• ACE inhibitors (angiotensin converting enzyme inhibitors):

lisinopril, benazepril, captopril…

ultrafiltrate

2.1.2 Atrial Natriuretic Factor (ANF)

• ANF (small 28 a.a. peptide) is secreted by the cells of cardiac atria in response to distention which would result from increase of blood volume.

1. ANF is a powerful vasodilator2. ANF acts on renal tubules to inhibit

Na+ reabsorption ↓blood volume3. ANF acts on renal blood vessels to increase

filtration (dilates afferent arterioles and constricts efferent arterioles) more blood plasma is filtered more Na+ can be excreted ↓blood volume

• 2.2 Regulation of water reabsorption

• Bulk water reabsorption in the proximal convoluted tubule.

• Fine water regulation in the distal convoluted tubule and collecting duct

ultrafiltrate1

Renal corpuscle or

2

3

4

1

2

3

180 L/day

120 L/day in proximal tubule

bulk reabsorption

fine tuningNa+

Na+

Na+

Amino acids

Amino acids

K+

Amino acids

H2O

ultrafiltrate

H2O

• 2.2.1 H2O bulk reabsorption• On the peritubular capillary side:

– Na/K pump ↑Na+ – ↑K+ due to leaking back– ↑[glucose] – ↑[a.a.]

• Increased osmolarity on the peritubular capillary side

• Tight junction between cells of proximal tubule are leaky to H2O H2O leaks inside the kidney following osmolarity gradient and then into peritubular capillaries

High osmolarity

ultrafiltrate

• 2.2.2 H2O fine regulation in dist conv. tubule & collecting duct

• Case 1. water needs to be conserved:

• collecting duct becomes very leaky to water water leaks into kidney following osmolarity gradient and then into peritubular capillaries.

• Case 2. drink a lot of water: • distal convoluted tubule and

collecting duct are generally impermeable to water water in not absorbed, but excreted.

• The permeability of collecting duct is regulated by insertion of water channels

Case 2

300 mOsm

300 mOsm

300 mOsm

a lot of water excreted

H2O

H2O

cortex

300 mOsm

600 mOsm

1,200 mOsm

medulla

300 mOsm

600 mOsm

1,200 mOsm

cortexCase 1

medulla

300 mOsm

600 mOsm

1,200 mOsm

very little water excreted

H2O

H2O

H2O

300 mOsm (a lot of water, very little salt)Fluid inside collecting duct:

medulla

cortexKidney

• The permeability of collecting duct is regulated by insertion of water channels

• How water channels are regulated?• By antidiuretic hormone (ADH, also known as vasopressin)

Lum

en o

f the

co

llecti

ng d

uct Peritubular

capillaries

Low osmolarity

High osmolaritytight junctions

• How is ADH regulated?• ADH is produced by a group of hypothalamic neurons and released from posterior

pituitary

ADH

• ADH release is stimulated by:1. ↓of firing of baroreceptors in atria and pulmonary vein2. ↑ of blood osmolarity ↑of firing of hypothalamic

osmoreceptors• Why not position receptors in aorta?• The receptors in aorta would measure Pa which does not change

much; on the contrary blood pressure in atria and pulmonary veins is directly proportional to blood volume.

• Case 1: Hemorrhage ↓ blood volume ↓ firing of baroreceptors ↑ADH ↑water reabsorption ↑ blood volume

• Case 2: Eat salty food ↑osmolarity ↑ADH ↑water reabsorption ↑blood volume ↓ blood osmolarity

ADH

• Let us come back to the example we have started with:• You drink a lot of isosmotic fluid (300mOsl = Gatorade)

GI absorbs all water and all salts

↑ blood volume

↑ atreal baroreceptors firing

↓ SNS activity

↓ Juxtaglomerular cells firing

↓ ADH

↑ ANF

ultrafiltrate

↓ H2O reabsorption

↓ Na+ reabsorption

↑ Na+ and H2O excretion

↑ filtration↓ CO↓ venomotor tone↓ precapillary sphincter tone↓ renin ↓A II

• You eat a lot of salt:

GI absorbs all salts

↑ blood osmolarity

movement of water from ICF ECF blood

↑ hypothalamic osmoreceptors firing

↑ osmoreceptors in macular densa

↑ blood volume

ultrafiltrate

↑ ADH

↑ thirst

↓ renin ↓ Na+ reabsorption

see previous slide

Homeostasis of ions and waterKidney

1. Filtration2. Reabsorption

3. Secretion

I. Sensors:1. SNS activity is function of Pa

2. baroreceptors function of Juxtaglomerular cells

3. osmoreceptors in macular densa4. osmoreceptors in hypothalamus

I. Sensors of blood volume:5. in atria ANF

6. in atria and pulmonary vein ADH

[H+], [Na+], [K+], blood volume =constcontrolled variables

feedback control:regulatory

mechanisms for Na+: renin,

A I, A II, Aldosterone;

ANF, ADH

• 3. Active secretion into renal tubule:– H+

– K+

– Organic anions: choline, creatinine– Foreign chemicals: penicillin

• Properties:– Usually coupled to the reabsorption of Na+

– =active transport– Primarily secretion occurs in the proximal convoluted tubule (except K+)– Secretion improves the efficiency of the kidney to dispose of substances

at a higher rate than the filtered load.

1 23

ultrafiltrate

Summary of kidney function• Major functions:

• regulate water content• Regulate ionic composition: K+, Na+, H+• NB: [H+] (in mM)=24PCO2/[HCO3

-] (in nM); [HCO3

-] is regulated by kidney

• Excretion functions:• urea from proteins (kidney does not regulate urea,

just excrete all urea)• uric acid from nucleic acids• creatinine from muscle creatine• bilirubin from Hb breakdown gives color to urine• drugs, food additives, etc.

• Endocrine functions:• erythropoietin (regulates RBC production)• renin• active form of vitamin D

• During prolonged fasting:• synthesize glucose from a.a. and release it to blood

(gluconeogenesis). Kidney can supply as much glucose as liver at such times (done by cells of renal tubule).

O

ut

urine

Guano

• In the USA about 9% of the population has had a kidney stone • The most common type of kidney stones contains calcium oxalate• At 3 millimeters, stones can cause blockage of the ureter. This leads to pain, nausea, vomiting,

fever, blood in the urine, pus in the urine, and painful urination. • Larger stones can bloc ureter completely and cause dilation of the kidney• Formation: when the urine contains more solutes than it can hold in solution, a seed crystal

may form through the process of nucleation• Prevention: drink lots of fluids so that more than two liters of urine is produced per day, avoid

soft drinks containing phosphoric acid (typically colas)

Renal failure hemodialysis

• What substances will you remove from blood?• What substances you don’t want to remove from blood?

The principle: diffusion of solutes across a semipermeable membrane

• stop here