Renal Physiology Part 2.2pptx

3/08/2011

1

Renal PhysiologyPart 2

Dr Bernadette BelletteNational Centre for Adult Stem Cell Research

Griffith UniversityNathan

Ext [email protected]

Utilising Chapters 25 & 26 of your prescribed text you should address each of the following learning objectives:.

• Describe the structure and function of all components of the urinary system.

• Describe the gross anatomy of the kidney.

• Outline the functions of the kidney.

• Describe the anatomy of a nephron.

• Describe the functions of particular regions of the nephron.

• Explain the physiological mechanisms involved in urine production.

• Describe the normal properties of urine as well as the abnormal components.

• Describe the two fluid compartments of the body and their component parts.

• Describe factors that determine fluid shifts in the body.

• Describe the mechanisms involved in water balance

• Explain the physiological importance of the various electrolytes.

• Describe the mechanisms involved in electrolyte balance.

• Describe the chemical buffer systems.

• Explain the role of both the respiratory & urinary systems on acid‐base balance.

Renal Physiology

Today

Revision

3/08/2011

2

Functions of Kidney• Regulation of body fluid osmolarity & volume

• Regulation of water

• Regulation of electrolytes

• Acid‐base regulation.

• Endocrine

• Excretion of metabolic products & foreign substances

• Gluconeogenesis

• Regulation of bone growth through regulation of calcium and phosphate excretion

Nephron

• Functional unit ‐ nephron:– Corpuscle

• Bowman’s capsule• Glomerulus capillaries

– Proximal convoluted tubule (PCT)

– Loop of Henley– Distal convoluted tubule

(DCT)– Collecting duct

3/08/2011

3

Nephron

• Production of filtrate• Reabsorption of organic nutrients

• Reabsorption of water and ions

• Secretion of waste products into tubular fluid

Cortical and Juxtamedullary Nephrons

Blood Supply to the Kidneys

3/08/2011

4

Filtration

Glomerular Filtration

• Glomerular filtrate is produced from blood plasma

• Must pass through:

1. Pores between endothelial cells of the glomerular capillary

2. Basement membrane ‐ acellulargelatinous membrane made of collagen and glycoprotein

3. Filtration slits formed by podocytes

4. Filtrate is similar to plasma in terms of concentrations of salts and of organic molecules (e.g., glucose, amino acids) except it is essentially protein‐free Figure 26.10a, b

Fig. 25.5

Glomerular Filtration• Principles of fluid dynamics that account for tissue fluid in the

capillary beds apply to the glomerulus as well

• Filtration is driven by Starling forces across the glomerularcapillaries

• Starling’s hypothesis states that the fluid movement due to filtration across the wall of a capillary is dependent on the balance between the hydrostatic pressure gradient (pressure that is exerted by a liquid when it is at rest) and the oncotic pressure gradient (capillary barrier is readily permeable to ions, the osmotic pressure within the capillary is principally determined by plasma proteins that are relatively impermeable) across the capillary.

• changes in these forces and in renal plasma flow alter the glomerular filtration rate (GFR)

3/08/2011

5

Glomerular Filtration• The glomerulus is more efficient than other capillary beds

because:

– Its filtration membrane is significantly more permeable

– Glomerular blood pressure is higher

– It has a higher net filtration pressure

• Plasma proteins are not filtered and are used to maintain oncotic (colloid osmotic) pressure of the blood

Forces Involved in Glomerular Filtration

• Net Filtration Pressure (NFP) ‐ pressure responsible for filtrate formation

• NFP equals the glomerularhydrostatic pressure (HPg) minus the oncotic pressure of glomerular blood (OPg) plus capsular hydrostatic pressure (HPc)

• NFP = HPg – (OPg + HPc)

• NFP = 55 – (30 + 15) = 10

Glomerular Filtration Rate (GFR)

• The total amount of filtrate formed per minute by the kidneys

• Filtration rate factors:– Total surface area available for filtration and membrane permeability (filtration coefficient = Kf)

– Net filtration pressure (NFP)– GFR = Kf x NFP

• GFR is directly proportional to the NFP

• Changes in GFR normally result from changes in glomerular capillary blood pressure

3/08/2011

6

Regulation of Glomerular Filtration

• 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

• Control of GFR normally result from adjusting glomerularcapillary blood pressure

• Three mechanisms control the GFR – Renal autoregulation (intrinsic system)– Neural controls– Hormonal mechanism (the renin‐angiotensin system)

Control of renal blood supply: Intrinsic Kidney‐controlled

• Myogenic – contraction or relaxation of smooth muscle surrounding renal arterioles.• Contraction prevents overdistention of vessels, increases resistance and prevents excessive increase in renal blood flow (increases pressure results in constriction)

• Decreased pressure results in vasodilation and relaxation

• Tubuloglomerular – macula densa cells monitor blood flow and blood concentration and change diameter of vessels.

Control of renal blood supply: ExtrinsicOutside the kidney

• Sympathetic nervous system (SNS) – shutting down renal blood supply (adrenaline‐induced vasoconstriction)

• Endocrine – renin‐angiotensin mechanism.

3/08/2011

7

http://en.wikipedia.org/wiki/File:Renin‐angiotensin‐aldosterone_system.png

Extrinsic Controls

• When the sympathetic nervous system is at rest:– Renal blood vessels are maximally dilated– Autoregulation mechanisms prevail

• Under stress:– Norepinephrine is released by the sympathetic nervous system– Epinephrine is released by the adrenal medulla – Afferent arterioles constrict and filtration is inhibited

• The sympathetic nervous system also stimulates the renin‐angiotensin mechanism

• A drop in filtration pressure stimulates the Juxtaglomerularapparatus (JGA) to release renin and erythropoietin

Other Factors Affecting Glomerular Filtration

• Prostaglandins (PGE2 and PGI2)– Vasodilators produced in response to sympathetic stimulation

and angiotensin II – Are thought to prevent renal damage when peripheral

resistance is increased

• Nitric oxide – vasodilator produced by the vascular endothelium

• Adenosine – vasoconstrictor of renal vasculature

• Endothelin – a powerful vasoconstrictor secreted by tubule cells

3/08/2011

8

Response to a Reduction in GFR

What Happens in PCT?Reabsorption (into body)

• Na+ via active transport, which sets up electrochemical gradient for passive diffusion of other solutes

• Virtually all nutrients (i.e. glucose, vitamins), active co transport with Na+

• Cations, driven by electrochemical gradient

• Anions, passive diffusion and co active transport

• Water, osmosis• Urea and fat soluble solutes, diffusion

driven by water movement• Small proteins

Secretion (into urine)

• H+ and ammonium salts

• Bile salts, drugs (egpenicillin)

• Prostaglandins, uric acid

Cells are: cuboid with microvilli – big surface area, and lots of mitochondria – need the energy!Active enzyme production and excretion into lumen

What happens in the Loop of Henle?Reabsorption (into body)

• After the PCT collection of ions the filtrate in the descending loop of Henle has low osmotic pressure so water is sucked into tissue and then into blood

• Little solute moment in descending loop

• In ascending loop lots of Na/K/Cl‐ reasborption via active transport, co transport and diffusion


• Very little

Descending Cells are: simple squamousepithelium – freely permeable to water

Ascending cells are like PCT – so more active absorption

3/08/2011

9

What happens in the distal convoluted tubule (DCT)?

Reabsorption (into body)

• Na+, primary active transport triggered by aldosterone

• Ca2+

• Cl‐, diffusion and cotransport with Na+

• Water, osmosis increased by ADH enhancing permeability


• H+ and K+ (acids)

• Drugs, toxins

Cells are:Cuboid epithelial cells. Thinner & fewer microvilli. Clues for secretion (not reabs.)

What happens in the Collecting Duct

Reabsorption (into body)

• Na+, H+, K+, HCO3‐, Cl‐, aldosterone mediated active transport of Na+, passive diffusion of HCO3‐and CL‐ and co transport of H+, K+, HCO3‐ and Cl‐

• Water, osmosis enhanced by ADH

• Urea, facultative diffusion in response to medullaryconcenration gradient


• Na+, K+, H+ and bicarbonate HCO3

• Cells are:More heterogeneous cells. Intercalated cells; alpha ‐cuboid – abundant microvilli. Principal cells ; beta – lack microvilli

GOOD SUMMARY:Copstead & Banasik, 2005Figure 26‐7

Each segment of the nephron is specialized for certain functions, which is reflected in the type of epithelial cells that make up the tubules.

3/08/2011

10

GOOD SUMMARY:Copstead & Banasik, 2005Figure 26‐16

Summary of nutrient and electrolyte composition of the filtrate in each segment of the nephron. Two thirds of the filtrate is reabsorbed in the proximal

tubule.

Note: increases in some solutes!SECRETION

Some solutes are mostly balanced

Renin‐Angiotensin Mechanism• Renin release is triggered by:

– Reduced stretch of the granular JG cells– Stimulation of the JG cells by activated macula densa cells– Direct stimulation of the JG cells via 1‐adrenergic receptors by renal nerves

• Renin acts on angiotensinogen to release angiotensin I which is converted to angiotensin II

• Angiotensin II: – Causes mean arterial pressure to rise (VIA VASOCONSTRICTION OF

ARTERIOLES)– Stimulates the adrenal cortex to release aldosterone

• As a result, both systemic and glomerular hydrostatic pressure rise

3/08/2011

11

Fig. 25.10

Anti‐Diruetic Hormone Pathway (ADH)

• One of the most important roles is in the body’s retention of water

• Released when body is dehydrated and causes body to conserve water thereby concentrating urine and reducing urine volume

• water permeability of DT and CD, occurs via insertion of water channels (aquaporins) into membrane of DCT and CD

• Release is triggered by increased osmolarity of plasma and to a lesser degree decreased volume of extracellular fluid

http://www.google.com.au/imgres?q=Antidiuretic+hormone+pathway&hl=en&client=firefox‐a&sa=X&rls=org.mozilla:en‐GB:official&biw=1304&bih=780&tbm=isch&tbnid=hp5S6o_8URALmM:&imgrefurl=http://medical‐dictionary.thefreedictionary.com/arginine%252Bvasopressin&docid=jEhaMb8xnm_2JM&w=300&h=176&ei=s9MwTsjGNuLmiAKJ8uCTBg&zoom=1&iact=hc&vpx=843&vpy=511&dur=1159&hovh=140&hovw=240&tx=120&ty=33&page=5&tbnh=111&tbnw=190&start=99&ndsp=24&ved=1t:429,r:10,s:99

Urine• Fresh urine is transparent & yellow’ish (due to urochrome)

• Colour may change

• Cloudy urine – often indicative of UTI

• Little odour

• Sweet smelling urine – indicative of diabetes mellitus

• pH ~6

• should not contain; protein, blood/blood cells, glucose, unmodified bile pigments, bacteria, viral particles, ketone bodies

3/08/2011

12

Ureters + Bladder• Carry urine into bladder

• Internal epithelium surrounded by transverse, circular & transverse smooth muscle (peristaltic urine transport)

• PNS & SNS input

• Very little change to urine content (secretion/reabsorption)

• Bladder is retroperitoneal smooth stretchy muscular sac sitting on pelvic floor

• Inner epithelium, central detrusor muscle (LCL), outer fibrous adventitia – superiorly covered by peritoneum

Fig. 25.18

urethra• Epithelium changes near opening to stratified squamous

epithelium

• Internal bladder‐urethral junction ‘guarded’ by internal urethral sphincter (invol)

• External urethral sphincter (sphincter urethrae) ‘guards’ passage thru urogenital diaphragm – sk. Muscle (vol)

• EUS aided by levator ani muscle of pelvic floor (pudendal motor fibres)

• Females ‐ tightly bound to anterior vaginal wall emptying at external urethral orifice (meatus) between clitoris and vagina– Note ‘bladder’ proximity to urethral & so anal opening

• Males – prostatic (~2.5cm), membranous (~2cm), spongy or penile (~15cm) emptying at external urethral orifice – Double function – carrying semen & urine

3/08/2011

13

Control of micturition

• Voiding/urination• Stimulated by activation

of stretch receptors in bladder walls from ~200mls

• Reflex controlled by dorsolateral pons brain region can be overridden (and thus ignored) initially

• Reflex reactivated on sign. increasing stretch

Significance of medullary transit…

Fig. 25.13

• Change in osmotic gradient in kidney medulla

• Described in mOmols(milliosmoles –thousandths of an Osmol)

• Body fluids ~300mOsmol

Countercurrent Mechanisms

• Occurs when fluid flows in opposite directions in two adjacent segments of the same tube

– Filtrate flow in the loop of Henle (countercurrent multiplier)

– Blood flow in the vasa recta (countercurrent exchanger)

3/08/2011

14

Countercurrent Mechanisms

• Role of countercurrent mechanisms

– Establish and maintain an osmotic gradient (300 mOsm to 1200 mOsm) from renal cortex through the medulla

– Allow the kidneys to vary urine concentration

Counter Current System• The ascending limb of the loop of Henle

transports solutes (NaCl) out of the tubule = high concentration of solutes in ECF

• There are now more solutes outside the tubule than in it so water moves out of the tubule in the descending limb to try and bring things to equilibrium (this is what we want! We want to absorb water!)

• But to continually absorb water we must draw the water away from the interstitial fluid so that the osmotic gradient is maintained. This is achieved by the vasarecta pulling water into the blood

• The osmolarity of the interstitium is therefore maintained and the cycle can keep going

Counter Current System• Enables us to vary the concentration of our urine to match our body’s requirements.

• What if we are dehydrated?– The countercurrent system permits forming a concentrated urine– In the presence of ADH, which increases water permeability, water will move into tissues in the DT and CD.

– So much water is withheld that the concentration of the urine is increased (less solvent!)

• What if our blood volume is too high?– hyposmotic fluid that enters the DT from the loop of Henle, continues to be diluted by transport of NaCl via NaClcotransporters and channels.

– Water reabsorption is limited so that the tubule fluid becomes more and more dilute until it is excreted as a large volume of hyposmotic urine

3/08/2011

15

Today’s Lecture

Fluid Compartments in the Human Body• Extracellular fluid

– Interstitial, surrounds the cells of a given tissue• excessive fluid accumulates in the interstitial space, edema develops• allows for movement of ions, proteins and nutrients across the cell barrier

– Intravascular• complex fluid with elements of a suspension (blood cells), colloid (globulins) and solvent (glucose and ions).

• approximately 3.5 liters

– Other ECF: lymph, CSF, humors of the eye, synovial fluid, serous fluid, and gastrointestinal secretions

• Intracellular fluid– Fluid inside cells– 60‐65% of body water– 28 liters of fluid, remains in osmotic equilibrium with the ECF

Figure 26.1

Total body waterVolume = 40 L60% body weight Extracellular fluid (ECF)

Volume = 15 L20% body weight

Intracellular fluid (ICF)Volume = 25 L40% body weight

Interstitial fluid (IF)Volume = 12 L80% of ECF

3/08/2011

16

Composition of Body Fluids

• Water: the universal solvent

• Solutes: nonelectrolytes and electrolytes– Nonelectrolytes: most are organic

• Do not dissociate in water: e.g., glucose, lipids, creatinine, and urea

• Electrolytes– Dissociate into ions in water; e.g., inorganic salts, all acids and bases, and some proteins

– The most abundant (most numerous) solutes– Have greater osmotic power than nonelectrolytes, so may contribute to fluid shifts

– Determine the chemical and physical reactions of fluids

Intracellular and Extracellular Fluid

• Each fluid compartment has a distinctive pattern of electrolytes

• ECF

– All similar, except higher protein content of plasma

• Major cation: Na+

• Major anion: Cl–

Intracellular and Extracellular Fluid

• ICF:

– Low Na+ and Cl–

– Major cation: K+

– Major anion HPO42–

3/08/2011

17

Figure 26.2

Na+ Sodium

K+ Potassium

Ca2+ Calcium

Mg2+ Magnesium

HCO3– Bicarbonate

Cl– Chloride

HPO42–

SO42–

Hydrogenphosphate

Sulfate

Blood plasma

Interstitial fluid

Intracellular fluid

Body Water Content

• Infants: 73% or more water (low body fat, low bone mass)

• Adult males: ~60% water

• Adult females: ~50% water (higher fat content, less skeletal muscle mass)

• Water content declines to ~45% in old age

Factors that Influence Fluid Shift

• Osmotic and hydrostatic pressures (pull or push)

• Osmolarity of ECF and ICF (concentration of solutes)

• Plasma serves as the communicating medium between external and internal environments

3/08/2011

18

External Influences• External temperature ‐ when it is hot, we sweat more and lose water, thereby making the blood plasma more concentrated.

• Amount of exercise ‐ if we exercise, we get hot and increase our sweating, so we lose more water and the blood plasma becomes more concentrated.

• Fluid intake ‐ the more we drink, the more we dilute the blood plasma. The kidneys respond by producing more dilute urine to get rid of the excess water.

• Salt intake ‐ salt makes the plasma more concentrated. This makes us thirsty, and we drink more water until the excess salt has been excreted by the kidneys.

Figure 26.3

Lungs

Interstitialfluid

Intracellularfluid in tissue cells

Bloodplasma

O2 CO2 H2O,Ions

Nitrogenouswastes

Nutrients

O2 CO2 H2O Ions Nitrogenouswastes

Nutrients

KidneysGastrointestinaltract

H2O,Ions

Water Balance and ECF Osmolality

• Water intake = water output = 2500 ml/day

• Water intake: beverages, food, and metabolic water

• Water output: urine, insensible water loss (skin and lungs), perspiration, and feces

3/08/2011

19

Figure 26.4

Feces 4%

Sweat 8%

Insensible lossesvia skin andlungs 28%

Urine 60%

2500 ml

Average outputper day

Average intakeper day

Beverages 60%

Foods 30%

Metabolism 10%

1500 ml

700 ml

200 ml

100 ml

1500 ml

750 ml

250 ml

Regulation of Water Intake

• Thirst mechanism is the driving force for water intake

• The hypothalamic thirst center osmoreceptors are stimulated by

• Plasma osmolality of 2–3%

• Angiotensin II or baroreceptor input

• Dry mouth

• Substantial decrease in blood volume or pressure

Regulation of Water Intake• Drinking water creates inhibition of the thirst center

• Inhibitory feedback signals include

– Relief of dry mouth

– Activation of stomach and intestinal stretch receptors

3/08/2011

20

Figure 26.5

(*Minor stimulus)

Granular cellsin kidney

Dry mouth

Renin-angiotensinmechanism

Osmoreceptorsin hypothalamus

Hypothalamicthirst center

Sensation of thirst;person takes a

drink

Water absorbedfrom GI tract

Angiotensin II

Plasma osmolality

Blood pressure

Water moistens mouth, throat;

stretches stomach, intestine

Plasmaosmolality

Initial stimulus

Result

Reduces, inhibits

Increases, stimulates

Physiological response

Plasma volume*

Saliva

Regulation of Water Output

• Obligatory water losses

– Insensible water loss: from lungs and skin

– Feces

– Minimum daily sensible water loss of 500 ml in urine to excrete wastes

• Body water and Na+ content are regulated in tandem by mechanisms that maintain cardiovascular function and blood pressure

Regulation of Water Output

• Water reabsorption in collecting ducts is proportional to ADH release

• ADH dilute urine and volume of body fluids

• ADH concentrated urine

3/08/2011

21

Regulation of Water Output: Influence of ADH

• Hypothalamic osmoreceptors trigger or inhibit ADH release

• Other factors may trigger ADH release via large changes in blood volume or pressure, e.g., fever, sweating, vomiting, or diarrhea; blood loss; and traumatic burns

Figure 26.6

OsmolalityNa+ concentration

in plasma

Stimulates

Releases

Osmoreceptorsin hypothalamus

Negativefeedbackinhibits

Posterior pituitary

ADH

Inhibits

Stimulates

Baroreceptorsin atrium andlarge vessels

Stimulates Plasma volumeBP (10–15%)

Antidiuretichormone (ADH)

Targets

Effects

Results in

Collecting ductsof kidneys

OsmolalityPlasma volume

Water reabsorption

Scant urine

Disorders of Water Balance: Dehydration

• Negative fluid balance

• ECF water loss due to: hemorrhage, severe burns, prolonged vomiting or diarrhea, profuse sweating, water deprivation, diuretic abuse

• Signs and symptoms: thirst, dry flushed skin, oliguria

• May lead to weight loss, fever, mental confusion, hypovolemic shock, and loss of electrolytes

3/08/2011

22

Figure 26.7a

1 2 3Excessiveloss of H2Ofrom ECF

ECF osmoticpressure rises

Cells loseH2O to ECFby osmosis;cells shrink

(a) Mechanism of dehydration

Patient Case History 1

• Two 23yr olds bring Patient A, a 21 yr old university student, to emergency presenting with gastrointestinal upset, confusion, extreme lethargy and fatigue. There are no obvious signs of trauma.

• What signs of trauma would you observe?

• You ask the two friends if your friend has attended a party

• She attended a party the night before and their were drugs, including Ecstasy, at the party

HistoryObservation Normal Patient A

Heart rate (beats/minute) 60-100 90

Blood pressure (mmHg) 90/50-140/0 135/87

Temperature (°C) 37 42

Glucose (mg/dl) 60-109 72

Sodium (mM/L) 135-146 115

Potassium (mM/L) 3.5-5.5 2.9

Chloride (mM/L) 95-109 88

Oxygen (mmHg) 80-100 93

Carbon Dioxide (mM/L) 22-32 24

What do you think the test results suggest is wrong with Patient AHigh blood pressure or rapid heart rate?HypoglycemiaHyperthermiaHypothermiaExcessive water retentionDehydration

3/08/2011

23

More…..

• You notice that her electrolyte values are low and query as to whether she had drunk too much last night

• Why do you ask the two friends this question?• The two friends said she only had one beer however she

woke up incredibly thirsty and drank multiple glasses of water

• What does this suggest?• Normally if a patient drinks excess water it is excreted by

the kidney by making a large volume of dilute urine. From your medical training you know that Ecstacy is an anti‐diuretic. This means it forces Patient A’s kidneys to make a very concentrated urine. Does this explain her results?

Diagnosis• Patient A was diagnosed with hyponatremia

– Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. Sodium is the dominant extracellular cation and cannot freely cross the cell membrane. Its homeostasis is vital to the normal physiologic function of cells. Normal serum sodium levels are between 135‐145 mEq/L. Hyponatremia is defined as a serum level of less than 135 mEq/L and is considered severe when the serum level is below 125 mEq/L.

– Hyponatremia is most often a complication of other medical illnesses in which either fluids rich in sodium are lost (for example because of diarrhoea or vomiting) or excess water accumulates in the body at a higher rate than can be excreted (for example in congestive heart failure, syndrome of inappropriate antidiuretic hormone, SIADH, or polydipsia).

– Hyponatremia can also affect athletes who consume too much fluid during endurance events, people who fast on juice or water for extended periods and people whose dietary sodium intake is chronically insufficient.

• Patient A was treated by giving IV fluids with normal or slightly higher sodium concentrations to correct the salt imbalance in her tissues

• A problem associated with acute or sudden hyponatremia, or water intoxication, is swelling of tissue to due osmotic uptake of water by cells

• Fortunately Patient A received treatment in time to reverse the swelling in her brain before her brain stem was damaged

Disorders of Water Balance: Hypotonic Hydration

• Cellular overhydration, or water intoxication

• Occurs with renal insufficiency or rapid excess water ingestion

• ECF is diluted hyponatremia net osmosis into tissue cells swelling of cells severe metabolic disturbances (nausea, vomiting, muscular cramping, cerebral edema) possible death

3/08/2011

24

Patient Case History 2

• Mrs. TB is a 36 year‐old lawyer who presents with ankle oedema.

• Eight year history of systemic lupus erythematosis.

• Originally diagnosed because of joint related symptoms.

• Over the past several weeks has developed a prominent malar rash.

• Has ankle edema.

• Recent serum creatinine was 3.2 mg/dL (normal <1).

• B/P 118/78 T = 37.33

Visual Urine Analysis

Dipstick

3/08/2011

25

What’s going wrong?• Mrs. TB has renal failure and is exhibiting the nephrotic syndrome.• What affect will losing protein in the periphery have?• Edema.

– The most common sign is excess fluid in the body due to the serum hypoalbuminemia. Lower serum oncotic pressure causes fluid to accumulate in the interstitial tissues. Sodium and water retention aggravate the edema

• Lots of protein loss.• Hypoalbuminemia• Broad casts are probably composed of congealed protein lost through the

glomerular basement membrane.• Epithelial cell casts indicate some toxicity to tubular cells.

– This can happen with overwhelming protein loss.

• There is no blood seen.• Urine is relatively dilute.• Her creatinine is pretty bad.• As it turns out, her creatinine clearance is only 12 ml/min.• All indications point to severe glomerular damage.

Disorders of Water Balance: Oedema

• Atypical accumulation of IF fluid tissue swelling

• Due to anything that increases flow of fluid out of the blood or hinders its return– Blood pressure

– Capillary permeability (usually due to inflammatory chemicals)

– Incompetent venous valves, localized blood vessel blockage

– Congestive heart failure, hypertension, blood volume

Oedema

• Hindered fluid return occurs with an imbalance in colloid osmotic pressures, e.g., hypoproteinemia ( plasma proteins)

– Fluids fail to return at the venous ends of capillary beds

– Results from protein malnutrition, liver disease, or glomerulonephritis

3/08/2011

26

What are the important electrolytes in our body?• the primary ions of electrolytes are Na+, K+, Ca2+, Mg2+, Cl−, HPO4

2−, and HCO3

−.

• Gradients affect and regulate the hydration of the body as well as blood pH, and are critical for nerve and muscle function.

• Various mechanisms exist in living species that keep the concentrations of different electrolytes under tight control.

• muscle contraction is dependent upon the presence of Ca2+, Na+, and K+. Without sufficient levels of these key electrolytes, muscle weakness or severe muscle contractions may occur

• electrolyte homeostasis is regulated by hormones such as antidiuretichormone, aldosterone and parathyroid hormone.

• Serious electrolyte disturbances, such as dehydration and overhydration, may lead to cardiac and neurological complications and, unless they are rapidly resolved, will result in a medical emergency

Salts

• Importance of salts

– Controlling fluid movements

– Excitability

– Secretory activity

– Membrane permeability

Central Role of Sodium

• Most abundant cation in the ECF

• Sodium salts in the ECF contribute 280 mOsmof the total 300 mOsm ECF solute concentration

• Na+ leaks into cells and is pumped out against its electrochemical gradient

• Na+ content may change but ECF Na+

concentration remains stable due to osmosis

3/08/2011

27

Central Role of Sodium

• Changes in plasma sodium levels affect

– Plasma volume, blood pressure

– ICF and IF volumes

• Renal acid‐base control mechanisms are coupled to sodium ion transport

Regulation of Sodium Balance

• No receptors are known that monitor Na+

levels in body fluids

• Na+‐water balance is linked to blood pressure and blood volume control mechanisms

Regulation of Sodium Balance: Aldosterone

• Na+ reabsorption

– 65% is reabsorbed in the proximal tubules

– 25% is reclaimed in the loops of Henle

• Aldosterone active reabsorption of remaining Na+

• Water follows Na+ if ADH is present

3/08/2011

28

Figure 26.8

K+ (or Na+) concentrationin blood plasma*

Stimulates

Releases

Targets

Renin-angiotensinmechanism

Negativefeedbackinhibits

Adrenal cortex

Kidney tubules

Aldosterone

Effects

Restores

Homeostatic plasmalevels of Na+ and K+

Na+ reabsorption K+ secretion

Regulation of Sodium Balance: Atrialnatriuretic peptide

• Released by atrial cells in response to stretch ( blood pressure)

• Effects

• Decreases blood pressure and blood volume:– ADH, renin and aldosterone production

– Excretion of Na+ and water

– Promotes vasodilation directly and also by decreasing production of angiotensin II

Figure 26.9

Stretch of atriaof heart due to BP

Atrial natriuretic peptide (ANP)

Adrenal cortexHypothalamusand posterior

pituitary


JG apparatusof the kidney

ADH release Aldosterone release

Na+ and H2O reabsorption

Blood volume

Vasodilation

Renin release*

Blood pressure

Releases

Negativefeedback

Targets

Effects

Effects

Inhibits

Effects

Inhibits

Results in

Results in

Angiotensin II

3/08/2011

29

Influence of Other Hormones

• Estrogens: NaCl reabsorption (like aldosterone)– H2O retention during menstrual cycles and pregnancy – PUFFY eww gross :S

• Progesterone: Na+ reabsorption (blocks aldosterone)– Promotes Na+ and H2O loss

• Glucocorticoids: Na+ reabsorption and promote edema

Cardiovascular System Baroreceptors

• Baroreceptors alert the brain of increases in blood volume and pressure

– Sympathetic nervous system impulses to the kidneys decline

– Afferent arterioles dilate

– GFR increases

– Na+ and water output increase

Figure 26.10

Stretch in afferentarterioles

Angiotensinogen(from liver)

Na+ (and H2O)reabsorption

Granular cells of kidneys

Renin

Posterior pituitary

Systemic arterioles

Angiotensin I

Angiotensin II

Systemic arterioles

Vasoconstriction Aldosterone

Blood volume

Blood pressure

Distal kidney tubules

Adrenal cortex

Vasoconstriction

Peripheral resistance

(+)

(+)

(+)

(+)

Peripheral resistance

H2O reabsorption

Inhibits baroreceptorsin blood vessels

Sympatheticnervous system

ADH (antidiuretichormone)


Filtrate NaCl concentration inascending limb of loop of Henle

Causes

Causes

Causes

Causes

Results in

Secretes

Results in

Targets

Results in

Releases

Release

Catalyzes conversion

Converting enzyme (in lungs)

(+)

(+)(+)

(+)

(+)

(+)

(+) stimulates

Renin-angiotensin system

Neural regulation (sympatheticnervous system effects)

ADH release and effects

Systemicblood pressure/volume

3/08/2011

30

Regulation of Potassium Balance

• Importance of potassium:– Affects RMP in neurons and muscle cells (especially cardiac muscle)

• ECF [K+] RMP depolarization reduced excitability

• ECF [K+] hyperpolarization and nonresponsiveness

• H+ shift in and out of cells– Leads to corresponding shifts in K+ in the opposite direction to maintain cation balance

– Interferes with activity of excitable cells


• K+ balance is controlled in the cortical collecting ducts by changing the amount of potassium secreted into filtrate

• High K+ content of ECF favors principal cell secretion of K+

• When K+ levels are low, type A intercalated cells reabsorb some K+ left in the filtrate


• Influence of aldosterone

– Stimulates K+ secretion (and Na+ reabsorption) by principal cells

– Increased K+ in the adrenal cortex causes

• Release of aldosterone

• Potassium secretion

3/08/2011

31

Regulation of Calcium

• Ca2+ in ECF is important for

– Neuromuscular excitability

– Blood clotting

– Cell membrane permeability

– Secretory activities

Body pH

• pH affects all functional proteins and biochemical reactions

• Normal pH of body fluids– Arterial blood: pH 7.4

– Venous blood and IF fluid: pH 7.35

– ICF: pH 7.0

• Alkalosis or alkalemia: arterial blood pH >7.45

• Acidosis or acidemia: arterial pH < 7.35

Body pH

• Most H+ is produced by metabolism– Phosphoric acid from breakdown of phosphorus‐containing proteins in ECF

– Lactic acid from anaerobic respiration of glucose

– Fatty acids and ketone bodies from fat metabolism

– H+ liberated when dissolved CO2 is converted to HCO3

– in blood

3/08/2011

32

Acid Base Balance

• Concentration of hydrogen ions is regulated sequentially by

– Chemical buffer systems: rapid; first line of defense

– Brain stem respiratory centers: act within 1–3 min

– Renal mechanisms: most potent, but require hours to days to effect pH changes

Acid Base Balance

• Strong acids dissociate completely in water; can dramatically affect pH

• Weak acids dissociate partially in water; are efficient at preventing pH changes

• Strong bases dissociate easily in water; quickly tie up H+

• Weak bases accept H+ more slowly

Figure 26.11

(a) A strong acid such asHCI dissociatescompletely into its ions.

(b) A weak acid such asH2CO3 does notdissociate completely.

H2CO3HCI

3/08/2011

33

Chemical Buffer System

• Chemical buffer: system of one or more compounds that act to resist pH changes when strong acid or base is added

1. Bicarbonate buffer system

2. Phosphate buffer system

3. Protein buffer system

Bicarbonate Buffer System

• Mixture of H2CO3 (weak acid) and salts of HCO3–

• H2CO3 HCO3‐ + H+

• HCO3‐ is the “conjugate base” of H2CO3. It is the

bit left over when H comes off

• Although technically a “weak base” in practice it is what is callled amphoteric. It can act as an acid or a base

• Buffers ICF and ECF

• The only important ECF buffer


• If strong acid is added:

– HCO3– ties up H+ that comes from the acid and

forms H2CO3

• HCl + HCO3– H2CO3 + Cl

– pH decreases only slightly, unless all available HCO3

– (alkaline reserve) is used up

– HCO3– concentration is closely regulated by the

kidneys

3/08/2011

34


• If strong base is added

– It causes H2CO3 to dissociate and donate H+

– H+ ties up the base (e.g. OH–)

– HCO3‐ + OH‐ CO3

2‐ + H2O

– pH rises only slightly

– H2CO3 supply is almost limitless (from CO2

released by respiration) and is subject to respiratory controls

Physiological Buffer Systems

• Respiratory and renal systems

– Act more slowly than chemical buffer systems

– Have more capacity than chemical buffer systems

Respiratory Regulation of H+

• Respiratory system eliminates CO2

• A reversible equilibrium exists in the blood:

– CO2 + H2O H2CO3 H+ + HCO3–

• During CO2 unloading the reaction shifts to the left (and H+ is incorporated into H2O)

• During CO2 loading the reaction shifts to the right (and H+ is buffered by proteins)

3/08/2011

35


• Hypercapnia (too much CO2 blood) activates medullary chemoreceptors

• Rising plasma H+ activates peripheral chemoreceptors

– More CO2 is removed from the blood

– H+ concentration is reduced


• Alkalosis depresses the respiratory center

– Respiratory rate and depth decrease

– H+ concentration increases

• Respiratory system impairment causes acid‐base imbalances

– Hypoventilation respiratory acidosis

– Hyperventilation respiratory alkalosis

Acid Base Balance

• Chemical buffers cannot eliminate excess acids or bases from the body

– Lungs eliminate volatile carbonic acid by eliminating CO2

– Kidneys eliminate other fixed metabolic acids (phosphoric, uric, and lactic acids and ketones) and prevent metabolic acidosis

3/08/2011

36

Renal Mechanisms of Acid Base Balance

• Most important renal mechanisms

– Conserving (reabsorbing) or generating new HCO3–

– Excreting HCO3–

• Generating or reabsorbing one HCO3– is the

same as losing one H+

• Excreting one HCO3– is the same as gaining

one H+

Renal Mechanisms of Acid Base Balance

• Renal regulation of acid‐base balance depends on secretion of H+

• H+ secretion occurs in the PCT and in collecting duct type A intercalated cells:

– The H+ comes from H2CO3 produced in reactions catalyzed by carbonic anhydrase inside the cells

– See Steps 1 and 2 of the following figure

Figure 26.12

1 CO2 combines with water within the tubule cell, forming H2CO3.

2 H2CO3 is quickly split, forming H+ and bicarbonate ion (HCO3

–).

3a H+ is secreted into the filtrate.

3b For each H+ secreted, a HCO3– enters the

peritubular capillary blood either via symport with Na+ or via antiport with CI–.

4 Secreted H+ combines with HCO3– in the

filtrate, forming carbonic acid (H2CO3). HCO3–

disappears from the filtrate at the same rate that HCO3

– (formed within the tubule cell) enters the peritubular capillary blood.

5 The H2CO3formed in the filtrate dissociates to release CO2and H2O.

6 CO2 diffuses into the tubule cell, where it triggers further H+

secretion.

* CA

CO2CO2

+H2O

2K+2K+

*

Na+ Na+

3Na+3Na+

Tight junction

H2CO3H2CO3

PCT cell

NucleusFiltrate intubule lumen

Cl–Cl–HCO3– + Na+

HCO3–

H2O CO2

H+ H+ HCO3–

HCO3–

HCO3–

ATPase

ATPase

Peri-tubular

capillary

1

24

5

6

3a 3b

Primary activetransport

Simple diffusion

Secondary activetransport

Carbonic anhydrase

Transport protein

3/08/2011

37

Reabsorption of Bicarbonate

• Tubule cell luminal membranes are impermeable to HCO3

–

– CO2 combines with water in PCT cells, forming H2CO3

– H2CO3 dissociates

– H+ is secreted, and HCO3– is reabsorbed into capillary blood

– Secreted H+ unites with HCO3– to form H2CO3 in filtrate,

which generates CO2 and H2O

• HCO3– disappears from filtrate at the same rate that it

enters the peritubular capillary blood

Figure 26.12

1 CO2 combines with water within the tubule cell, forming H2CO3.

2 H2CO3 is quickly split, forming H+ and bicarbonate ion (HCO3

–).

3a H+ is secreted into the filtrate.

3b For each H+ secreted, a HCO3– enters the

peritubular capillary blood either via symport with Na+ or via antiport with CI–.

4 Secreted H+ combines with HCO3– in the

filtrate, forming carbonic acid (H2CO3). HCO3–

disappears from the filtrate at the same rate that HCO3

– (formed within the tubule cell) enters the peritubular capillary blood.

5 The H2CO3formed in the filtrate dissociates to release CO2and H2O.

6 CO2 diffuses into the tubule cell, where it triggers further H+

secretion.

* CA

CO2CO2

+H2O

2K+2K+

*

Na+ Na+

3Na+3Na+

Tight junction

H2CO3H2CO3

PCT cell

NucleusFiltrate intubule lumen

Cl–Cl–HCO3– + Na+

HCO3–

H2O CO2

H+ H+ HCO3–

HCO3–

HCO3–

ATPase

ATPase

Peri-tubular

capillary

1

24

5

6

3a 3b

Primary activetransport

Simple diffusion

Secondary activetransport

Carbonic anhydrase

Transport protein

Generating New Bicarbonate Ions

• Two mechanisms in PCT and type A intercalated cells

– Generate new HCO3– to be added to the alkaline

reserve

• Both involve renal excretion of acid (via secretion and excretion of H+ or NH4

+

3/08/2011

38

Excretion of Buffered H+

• Dietary H+ must be balanced by generating new HCO3

–

• Most filtered HCO3– is used up before filtrate

reaches the collecting duct

Excretion of Buffered H+

• Intercalated cells actively secrete H+ into urine, which is buffered by phosphates and excreted

• Generated “new” HCO3– moves into the

interstitial space via a cotransport system and then moves passively into peritubular capillary blood

Respiratory and Renal Compensations

• If acid‐base imbalance is due to malfunction of a physiological buffer system, the other one compensates

– Respiratory system attempts to correct metabolic acid‐base imbalances

– Kidneys attempt to correct respiratory acid‐base imbalances

3/08/2011

39

Respiratory Compensation

• In metabolic acidosis

– High H+ levels stimulate the respiratory centers

– Rate and depth of breathing are elevated

– Blood pH is below 7.35 and HCO3– level is low

– As CO2 is eliminated by the respiratory system, PCO2 falls below normal

Respiratory Compensation

• Respiratory compensation for metabolic alkalosis is revealed by:

– Slow, shallow breathing, allowing CO2

accumulation in the blood

– High pH (over 7.45) and elevated HCO3– levels

Renal Compensation

• Hypoventilation causes elevated PCO2• (respiratory acidosis)

– Renal compensation is indicated by high HCO3–

levels

• Respiratory alkalosis exhibits low PCO2 and high pH

– Renal compensation is indicated by decreasing HCO3

– levels

3/08/2011

40

Important Points

• Describe the factors that determine fluid shifts in the body

• List the routes by which water enters and leaves the body

• What is dehydration, hypotonic hydration and oedema

• What is the importance of sodium, calcium and potassium and how are their levels regulated

Important Points

• What is an acid?

• What is a base?

• Name the 3 buffer systems in the body and describe how they act to resist change in pH

• How is the bicarbonate buffer system amphoteric?

• What is the respiratory and renal control of acid base balance

• What is acidosis and alkalosis?

Documents

Renal Physiology Part 2.2pptx