Renal Physiology

PHYSIO B 1.2 RENAL PHYSIOLOGY PT. 4 [DR. VILA]

FEU-NRMF INSTITUTE OF MEDICINE

11.11.14 [1MD-D]

Disorders of Urinary Concentrating Ability

Impairment in the ability of the kidneys to concentrate or dilute the

urine appropriately can occur with one or more of the following

abnormalities:

1. Inappropriate secretion of ADH

2. Impairment of the countercurrent mechanism. A

hyperosmotic medullary interstitium is required for

maximal urine concentrating ability. No matter how much

ADH is present, maximal urine concentration is limited by

the degree of hyperosmolarity of the medullary

interstitium.

3. Inability of the distal tubule, collecting tubule, and

collecting ducts to respond to ADH

Failure to produce ADH: “Central” Diabetes Insipidus



Also known ad pituitary diabetes insipidus



Hypothalamus or posterior pituitary gland fails to produce

or secrete ADH



Large volumes of dilute urine (can exceed 15L/day)

Inability of the kidneys to respond to ADH: “Nephrogenic” Diabetes

Mellitus”



Normal or elevated levels of ADH are present



But renal tubules cannot respond



Can be caused by:

o

Failure of countercurrent mechanism (Guyton)

o

Failure of distal and collecting ducts to respond to

ADH (Guyton)

o

Absence of V2 receptors for ADH (Accdg. to

Dr.Vila)



Large volumes of dilute urine



Can cause dehydration, unless fluid intake is increased by

the same amount as urine volume is increased

Diabetes: common manifestation is polyuria



Diabetes insipidus: secondary to ADH deficiency



Diabetes mellitus: secondary to glucose

No ADH Secretion / No response to ADH

Decrease reabsorption of water

Increase Urine Volume

Decrease urine tonicity

The Syndrome of Inappropriate ADH Secretion (SIADH)



Plasma ADH elevated (as in sobrang taas, above what

would be expected on the basis of the body fluid osmolality

and, blood volume and pressure, kaya siya “inappropriate”)



Water is retained, hence body fluid becomes hypoosmotic

(more water, less concentrated ang body fluids)



Urine is hyperosmotic



The tonicity of plasma decreases due to dilutional

hyponatremia



However, the amount of sodium still falls within normal

range



It appears to be hyponatremic due to the increase in water

reabsorption (dilution)

Increase ADH

Increase water reabsorption

Decrease urine volume

Increase urine tonicity

Supposedly.

Because of increase water reabsorption:

Increase BV

Increase BF

Increase GFR

Increase urine volume



Initially, there is an increase in water reabsorption



Eventually, the end effect will be an increase in urine

excretion due to increase blood volume

Osmoreceptor-ADH Feedback System



Example: Increase plasma osmolarity due to dehydration

o

Fluid shift from the interstitium into the

intravascular compartment

o

Osmoreceptors are located in the anterior

hypothalamus near the supraoptic nuclei

[Guyton]

o

Osmoreceptors are sensitive to changes in

osmolarity

o

An increase in extracellular osmolarity will cause

the osmoreceptors to shrink

o

Sends signals to the hypothalamus to secrete ADH

o

ADH enters blood stream towards the kidneys to

increase water reabsorption and decrease urine

volume

Edema



Excess fluid within the interstitial compartment producing

visible swelling



Increased capillary hydrostatic pressure



Decreased plasma colloid osmotic pressure

Edema caused by Heart Failure [Guyton, Chp. 25]



One of the most serious and most common causes of

edema



In heart failure, the heart fails to pump blood normally from

veins into the arteries, which raises the venous and capillary

pressures, which eventually increases capillary filtration



Increase capillary filtration  lalabas ang fluid sa

interstitium  edema



Heart failure can also decrease blood flow to the kidneys



Decrease blood flow  decrease Na+ concentration 

detected by macula densa  secrete renin by JG cells 

activate angiotensinogen to angiotensinogen I 

conversion to angiontensin II by ACE in lungs  release

aldosterone  Increase salt and water retention 

Increase BV  Increase capillary hydrostatic pressure



Increase hydrostatic pressure  edema

Edema caused by Decreased Plasma Proteins [Guyton, Chp. 25]



One of the most important causes of decreased plasma

protein concentration is loss of proteins in the urine –

Nephrotic syndrome



The glomerular basement membrane widens, that allows

the filtration of proteins



Protein will therefore appear in the urine – Proteinuria



Therefore, there will be a decrease in plasma proteins



Decrease plasma protein decrease plasma colloid

osmotic pressure  edema

Lymphedema – Failure of the Lymph Vessels to return fluid and

protein to the blood [Guyton, Chp. 25]



Plasma proteins tend to leak into the interstitium, which

can attract water and eventually cause edema



The proteins be removed through the lymphatics



Example of lymph obstructions are infections with filaria

nematodes (Wuchereria bancrofti)

o

Blocks lymph vessels

o

Causes lymphedema and elephantiasis

o

Localized edema (limited to a one area only, [ex.]

Extremities, penis, breast)

Localized Edema

1. Venous obstruction

2. Capillary was damaged due to inflammation

3. Lymphatic obstruction

Generalized Edema

1. Increase capillary hydrostatic pressure

2. Decrease plasma albumin



Clinical Findings:

o

Swelling in most dependent parts of the body due

to effects of gravity and increase hydrostatic

pressure in the capillaries

Edema vs. Effusion



Edema: fluid in interstitum



Effusion: fluid in potential spaces – pleural, peritoneal,

pericardial cavities, joint spaces

Effect of Adding Saline Solution to the ECF [Guyton, Chp. 25]



Principle of osmosis



If a cell is placed in a hypotonic solution, the cell will swell

(movement of water from extracellular to intracellular)



However, the cell will not swell immediately



The cell will try to pump out electrolytes such as Na+, so

that water will follow these electrolytes out of the cell and

reduce swelling



This is called regulatory volume decrease (decrease cell

volume to reduce swelling)



If a cell is placed in a hypertonic solution, the cell will shrink,

but not immediately (movement of water intracellular to

extracellular)



Electrolytes from the solution will move into the cell, and

water will follow, hence reducing the shrinkage of the cell



This is called regulatory volume increase (increase cell

volume to reduce shrinkage)

Fluid INFLUX

ECF Vol. ECF OP H2O Shift ICF Vol. ICF OP Compensatory Mechanism

Isotonic

Influx (2L

NSS)

SA

ME

NONE

SA

ME

SA

ME

NONE

Hypotonic

Influx (Water

loading)

Extra

to

intrace

llular

-Decrease ECF

tonicity

-Activate ADH

-Water

reabsorbed

-Decrease

urine volume

-Increase

urine tonicity

Hypertonic

Influx (Drink

sea water)

Intra

to

extrac

ellular

-Increase ECF

tonicity

-Inhibit ADH

-Increase

urine volume

-Decrease

urine tonicity

Fluid EFFLUX

ECF Vol. ECF OP H2O Shift ICF Vol. ICF OP Compensatory Mechanism

Isotonic

Efflux

(Burns)

SA

ME

NONE

SA

ME

SA

ME

NONE

Hypotonic

Efflux

(Profuse

Sweating)

Intra

to

extrac

ellular

-High ECF

tonicity

-Activate ADH

-Water

reabsorption

-Decrease

urine volume

-Increase

urine tonicity

Hypertonic

Efflux

(SIADH)

Extra

to

intrace

llular

-Low ECF

tonicity

-Inhibit ADH

-Increase

urine volume

-Decrease

urine tonicity

Acid-Base Balance



Acid: a substance that can release or donate hydrogen ion

[H+]



Base: a substance that can combine with or accept

hydrogen ion [H+]



Normal blood pH: 7.35 – 7.45



Normal pCO2: 35 – 45 mmHg



Normal pCO3-: 22 – 26 mmHg



pO2 is less important

*Respi Physio Review*

Oxygen-Hemoglobin Dissociation Curve



Hemoglobin carries oxygen



However, hemoglobin never reaches 100% oxygen

saturation. Why?

o

All the blood that reaches the lungs will be 100%

oxygenated

o

From the lungs, and along with the blood from

different veins, will drain into the heart

o

Veins carry less oxygenated blood

o

Blood that comes out of the aorta will only be

97-98% saturated with oxygen because it will be

mixed with less oxygenated blood from the veins

o

At 60mmHg, the saturation slows down

o

Below 60mmHg, saturation is steep (Hgb unbinds

immediately from oxygen)

o

In real situations, we never go below 60mmHg

o

pCO2: respiratory component

o

Represent acid

o

Excreted by lungs

o

Increase pCO2: Acidic

o

Decrease pCO2: Basic

o

pCO3-: metabolic component

o

Represent base

o

Excreted by kidneys

o

Increase pCO3-: Basic

o

Decrease pCO3: Acidic



Decrease pH: acidosis



Increase pH: alkalosis

Rules:



Always follow the pH



If fully compensated: pH will go back to normal

o

If pH is slightly toward alkaline but within normal

range: alkalosis, fully compensated

o

If pH is slightly toward acidic but within notmal

range: acidosis, fully compensated



If partially compensated: pH of blood is still abnormal

pH

(7.35 – 7.45)

pCO2

(35 – 45 mmHg)

pCO3-

(22 -26mmHg)

Disorder

7.29

Acidic

48

Acidic

24

Normal

Respiratory

Acidosis

7.29

Acidic

37

Normal

19

Acidic

Metabolic

Acidosis

7.47

Basic

32

Basic

24

Normal

Respiratory

Alkalosis

7.47

Basic

37

Normal

29

Basic

Metabolic

Alkalosis

7.29

Acidic

36

Normal

19

Acidic

Metabolic

Acidosis

7.47

Basic

32

Basic

19

Acidic

Respiratory

Alkalosis,

partially

compensated

by the

kidneys

7.47

Basic

48

Acidic

29

Basic

Metabolic

Alkalosis,

partially

compensated

by lungs

7.29

Acidic

30

Basic

28

Basic

Mixed

Acidosis,

partially

compensated

7.47

Basic

30

Basic

19

Acidic

Respiratory

Alkalosis,

partially

compensated

7.44

Normal

48

Acidic

30

Basic

Metabolic

Alkalosis,

fully

compensated

7.38

Normal

48

Acidic

30

Basic

Respiratory

Acidosis, fully

compensated

pH Units



In the events of everyday life, the variation of ECF pH is very

narrow



1nmol of H+/L = 0.01 pH unit

o

If H+ ions increase: pH decrease, pH is acidic

o

If H+ ions decrease: pH increase, pH is basic



In abnormal situations, much wider changes may be seen.



In practice, a pH of 6.8 or 7.8 will only be seen in profound

pathologic situations

Sources of H+ ions in the body



Metabolism of food stuffs

o

Produces 300L of CO2



Incomplete metabolism of CHO and fats

o

Produces nonvolatile acids

o

Lactic acid from glucose, acetoacetic acid and

Beta-hydroxybutyric acid from fatty acid

oxidation



Oxidation of proteins and amino acids

o

Produces strong acids

o

H2SO4, HCl and H3PO4

Body’s defenses against changes in blood pH



Chemical buffers in ECF, ICF and bone

o

First line of defense of blood pH

o

Minimized a change in pH but cannot remove acid

or base from the body



Respiratory system

o

Second line of defense

o

Large loads of acid stimulate breathing which

removes CO2 from the body



Kidneys

o

Third line of defense

o

Remove excess H+ from the body in combination

with urinary buffers

Henderson-Hasselbach Equation



Shows that the pH of a solution is determined by the pKa of

acid and the ratio of the concentration of conjugate base A-

and acid HA

Bicarbonate Buffer System: Kidneys [Berne&Levy Chp. 36]



The most important ECF buffer

In the proximal tubules:



The proximal tubule reabsorbs the largest portion of the

filtered load of HCO3-



H+ secretion across the apical membrane of the cell occurs

by Na+H+ antiporter and H

+

_-ATPase



Carbonic anhydrase are present in the brush borders that

convert H2CO3 to water and carbon dioxide



They enter the cells and combines to produce H+ and HCO3

by carbonic anhydrase



H+ is secreted via apical membrane, HCO3- via basolateral

membrane



HCO3 exit via a symporter: 1Na+ with 3HCO3



Some of the HCO3 may exit in exchange for Cl-



A K+-HCO3- symporter in the basolateral membrane may

also contribute to the exit of HCO3- from the cell

In the collecting ducts



There are 2 types of cells:

o

Principal cells responsible for electrolyte and fluid

absorption

o

Intercalated cells for acid-base balance



There are 2 types of intercalated cells

o

Alpha-intercalated cells: secrete H+ (reabsorbs

HCO3-)

o

Beta-intercalated cells: secrete HCO3-



Within Alpha-intercalated cells:

o

H+ and HCO3- are produced by the hydration of

carbon dioxide, which is catalyzed by carbonic

anhydrase

o

H+ is secreted into the tubular fluid via:



Apical membrane H+-ATPase



H+,K+-ATPase

o

HCO3- exits across the basolateral membrane in

exchange for Cl-, via a Cl-HCO3- antiporter

o

Active during metabolic acidosis



Within Beta-intercalated cells

o

H+-ATPase is located in the basolateral

membrane

o

Cl-HCO3- antiporter is located in the apical

membrane

[Baliktad sila ng alpha-intercalated]

o

Activity of beta-intercalated cells is increased

during metabolic alkalosis, when the kidneys

must excrete HCO3-

Acid-Base Balance via excretion of ammonium



NH4+: ammonium, acidic



NH3: ammonia



NH4+ is produced by the kidneys by the metabolism of

glutamine



The kidneys metabolize glutamine, excrete NH4+, and add

HCO3- to the body



If NH4+ is not excreted in the urine, it is converted into urea

by the kidneys, which produces H+, and eventually buffered

by HCO3-



Production of urea, therefore, consumes HCO3- and inhibits

HCO3- formation through the synthesis and excretion of

NH4+



NH4+ is produced from glutamine via ammoniagenesis



One glutamine molecule produces two NH4+ molecules and

two HCO3- molecules



HCO3- exits the cells across the basolateral membranes and

enters the peritubular blood



NH4+ exits via apical membrane and enters the tubular

fluid, via NA+-H+ antiporter, but NH4+ is substituted for H+



NH3 is freely permeable and can diffuse out of the cell

where it is protonated into NH4+



The thick ascending limb is the primary site of NH4+

reabsorption, with NH4+ substituting for K+ on the

1Na+-K+-2Cl- symporter



The NH4+ that is reabsorbed, accumulates in the medullary

interstitium which is then secreted into the collecting ducts

via:

o

Nonionic diffusion

o

Diffusion trapping



NH3 diffuses from the medullary interstitium into the

collecting ducts (nonionic diffusion)



The presence of Alpha-intercalated cells which secrete H+

ions will protonate the NH3 to become NH4+



Since NH4+ is less permeable in the collecting ducts, it is

trapped in the tubular lumen (diffusion trapping)



It is then eliminated from the body via the urine

Please refer to Guyton for the Phosphate Buffer System and Proteins

as ICF buffers, and Guyton Chp. 36 Acid-Base Balance (Hindi na

diniscuss ni doc, pero kasama daw sa shifting )

Reading assignments:



Renal Failure



Renal Endocrine Function

Sources:

Lecture: Dr. Vila

Berne&Levy, 6

th

_Edition

Guyton and Hall, 12

th

_Edition

Read Berne & Levy or Guyton, guys! Mas specific at complete mga

explanations dun. Good luck and God bless! Labyu all <3