REGULATION OF ACIDS, BASES, &

ELECTROLYTES

Key Topics

• Ventilation as an Acid-Base Controller• Renal Anatomy Review• Starling’s Law of the Capillary• Fluid and Electrolyte balance• Renal Physiology• Kidney as an Acid-Base Controller• Diuretics

Ventilation Control & Regulation

• Volatile acids (i.e. Carbonic Acid) are removed via the lungs.

• The volume of gas that is removed is directly related to the alveolar ventilation.

• The amount of alveolar ventilation is determined by the control and regulation of ventilation.

Ventilation Control

• Primary respiratory generator is the inspiratory & expiratory centers in the medulla.• These are in turn regulated by:

• The apneustic center• The pneumotaxic center• The cerebral cortex – voluntary changes in

ventilation

Ventilation Regulation

• Amount of ventilation is also regulated through feedback mechanisms.• Chemoreceptors

• Central and Peripheral• Reflex Mechanisms

• Hering-Breuer• J Receptors

Central Chemoreceptors• Located in the medulla of the CNS

• Not to be confused with the respiratory centers!

• Chemoreceptors are bathed in CSF that respond to the pH of the CSF (H+, ventilation).

• CSF is relatively impermeable to ions (i.e. HCO3-),

only gases (i.e. PaCO2).• Known as the blood-brain barrier.

• Slight changes in PaCO2 will yield a change in ventilation.

• No response to hypoxemia.

Peripheral Chemoreceptors• Located in arterial system

• Carotid Bodies• Aortic Bodies

• They respond to the blood passing by them.• Both respond to:

• PaCO2 /pH: Large increases are needed in PaCO2 or pH before changes in minute ventilation occur.

• PaO2 : Comes into play with chronic pulmonary disease (hypoxic drive)

• Dramatic increase in stimulation when PaO2 < 60 mm Hg.• Baroreceptors: Regulate blood pressure &

2Ventilation.

Regulation of Ventilation and Blood Gases in Progressive Pulmonary Disease

Progressive DiseaseProgressive DiseaseNormalNormal MildMild ModerateModerate SevereSevere

PaO2 (mm Hg) 100 65 55 50

PaCO2

(mm Hg)

40 40 34 50

Central Chemoreceptors

++++ ++++ ++ +

Peripheral Chemoreceptors

+ ++ +++ ++++

Control C C P P

Reflexes• Hering-Breuer

• Stretch reflex• Regulates tidal volume & respiratory rate to minimize work of

breathing.• Active during overinflation and underinflation.

• Inflation reflex • Deflation reflex (rapid-shallow breathing)

• J receptors• Juxtapulmonary capillary receptors• Interstitial tissue of the A-C membrane• Respond to thickening of this membrane (? pressure)

• Pulmonary Edema & Pulmonary Fibrosis• Result in tachypnea & hyperventilation

Renal Anatomy & Physiology

Renal Function

• Three primary functions• Excretion of nonvolatile waste products

(including nonvolatile acids)• Regulation of blood volume.• Regulation of various electrolytes & blood

constituents.

Kidney A & P• Retroperitoneal organ.• Outer cortex; inner medulla.• Ureter transports urine from

kidney to bladder.

Nephron• Functional unit of

the kidney.• 1,300,000 per

kidney• Composed of

• Bowman’s Capsule• Proximal

Convoluted Tubules

• Loop of Henle• Distal Convoluted

Tubules• Collecting Tubule

• EGAN

Fluid Compartments

• Total amount of water in 70 kg man = 40 L• Accounts for 60% of the body’s weight

• Intracellular (within the cells): 25 L• Red Blood Cell volume: 2 L

• Extracellular (outside the cells): 15 L• Interstitial (in the spaces between cells): 12 L• Plasma: 3 L

• 2/3rd of the blood volume is in the cell.

Electrolytes

• Two types of substances found in body water:• Non-Electrolytes: Intact uncharged particles

• Urea, Creatinine, Glucose• Electrolytes: Particles that dissociate and

carry electrical charges• Cations – Positively charged• Anions – Negatively charged

Capillary Structure & Function

• Capillaries allow movement of substances (O2, K+, Glucose) out of the capillary and into the cell through diffusion and movement of water by osmosis.

• Capillaries have (basement) membranes with varying permeability. • Different organs allow substances of various size to

diffuse across. (lung vs. kidney vs. intestine)• Some substances never leave the vascular space

under normal conditions (hemoglobin, albumin)

Capillary Structure & Function

• Capillaries are like a leaky hose; the bulk of the fluid continues along the hose but some fluid leaks out due to pressure within the hose.

Fluid Dynamics in the Capillary

• Five factors regulate fluid movement in and out of the capillary.• 2 Hydrostatic pressures

• One inside & One outside• 2 Osmotic (Oncotic) pressures

• One inside & One outside• The relative permeability of the capillary wall

Hydrostatic Pressure

• HYDROSTATIC PRESSURES PUSH FLUID OUTOUT.

• Increased capillary (arterial side) hydrostatic pressure forces fluids out of the capillary.

• Increased interstitial hydrostatic pressure forces fluid out of the interstitial space (into the alveolus in fulminate pulmonary edema)

Osmotic Pressure

• OSMOTIC PRESSURES PULL FLUID ININ.• Plasma proteins (hemoglobin, albumin)

[aka colloids] that don’t move out of the vascular space and cross the capillary wall exert an osmotic (oncotic) pressure within the vessel and draw fluid (and any associated soluble waste products) back into the capillary at the venous end.• 2 Osmotic pressures (capillary and interstitial)

Starling Forces

• 5th factor is the permeability of the membrane.

• This phenomenon is known as Starling forces.

• This movement of fluid allows for:• Delivery of nutrients to cell• Waste products to be reabsorbed• Fluid and Electrolyte Homeostasis both in

peripheral cells and in the kidney.

Net Effect

• Excess fluid left in the tissues can be caused by:• Increased Capillary Hydrostatic pressure• Decreased Capillary Osmotic pressure• Decreased Interstitial Hydrostatic pressure• Increased Interstitial Osmotic pressure• Increased Permeability of the capillary wall

Nephron

Bowman’s Capsule• Located in cortical portion of kidney.• Beginning of the Proximal Convoluted

Tubule• Blood enters via afferent arteriole• Branches into a tuft of capillaries called

the glomerulus.• The hydrostatic pressure of the capillary

forces fluid out of the capillary and into Bowman’s capsule.• Hydrostatic pressure controlled by

contraction and dilation of the arteriole.

Bowman’s Capsule• 20% of the renal

blood is filtered in the glomerulus.

• Remainder of the blood passes out the glomerulus via the efferent arteriole and eventually branches into the peritubular capillaries (98-99%) and vasa recta (1-2%).

• Fluid from the Bowman’s capsule flow into the Proximal Convoluted Tubule.

Urine Formation

• Three factors are involved in the formation of urine:• Glomerular Filtration

• Volume of renal perfusion• Afferent arteriolar constriction reduces GFR• Efferent arteriolar constriction increases GFR

• Tubular Reabsorption• In the peritubular capillaries & vasa recta

• Tubular Secretion• Exchange of electrolytes as needed

Glomerular Filtration Rate• Fluid which is filtered by the glomerulus into

Bowman’s capsule is called glomerular filtrate. It is made up of same substances as are in plasma with the exception of proteins (albumin, hemoglobin).

• The amount of glomerular filtrate formed each minute is called the Glomerular Filtration Rate.• Average GFR is 125 mL/minute (180 liters/day)

• 15L (entire ECF) every 2 hours!

• 99% of it is reabsorbed; remainder passes out as urine (1 mL/min)

Proximal Convoluted Tubule

• Glomerular filtrate collects from Bowman’s capsule into the proximal convoluted tubule.

• Terminal end near medullary border where it forms the beginning of the Loop of Henle.

• Proximal Convoluted Tubule is surrounded by the peritubular capillaries, which are protein “rich” and have a high osmotic pressure.

Proximal Convoluted Tubule

• Reabsorption of:• Water (65% of glomerular filtrate volume)• Amino Acids & Glucose (unless there is

an increased plasma level)• Urine samples are obtained to look for

“spilled” protein and glucose.• Active reabsorption of Sodium (99% of

Na+ is ultimately reabsorbed.)• This is continued throughout the Loop of

Henle, Distal Convoluted Tubule & Collecting Tubule.

•Active “pumping” of Sodium from tubule to peritubular capillary.

•Chloride diffuses with the Sodium to maintain neutrality.

NaCl Mechanism

Loop of Henle• Three components

• Descending limb• Sharp hairpin turn• Ascending limb

• 70% of glomeruli are in the cortex with short Loops of Henle.

• Other 30% are near medulla (juxtamedullary nephrons) and have long Loops of Henle surrounded by the vasa recta.• Medullary interstitial fluid has a greater osmotic

pressure the “longer” the descending loop.

Descending Loop of Henle• 25% of

glomerular filtrate enters the descending loop.

• High osmotic pressure towards the bottom causes large reabsorption of water (15%)

Ascending Loop of Henle• Flow is back up towards

cortex (countercurrent flow).

• This portion of the loop is impermeable to water (no water excretion)

• Sodium is actively pumped into the interstitial fluid.

• This Sodium is reabsorbed into the Descending Loop which leads to a high level of Sodium near the bottom of the Loop that causes the high osmolarity (Countercurrent multiplier)

Distal Tubules & Collecting Duct• Located in

cortex.• Additional

10% of water is reabsorbed.

• Any additional Sodium is reabsorbed (as NaCl)

• Juxta-glomerular apparatus

Sodium Regulation I & II• NaCl MechanismNaCl Mechanism

• As above.• Primary Active

Transport• Secondary

reabsorption through secondary active secretion of H+ and K+.

• Used when Cl is not available.

• Causes Metabolic Alkalosis• Loss of H+

Na+ Regulation: Active Secretion of Potassium

• Occurs when Hydrogen ions are scarce (alkalemia)

• Can lead to hypokalemia.

Water Reabsorption

• 65% in Proximal Convoluted Tubule• 25% in Descending Loop of Henle• 10% in Distal Tubule

Sodium Reabsorption• As Sodium Chloride via active transport

of Sodium ion (80%).• As Sodium Bicarbonate (20%) in two

forms:• With loss of H+ ion in urine and resulting

alkalosis.• With loss of K+ ion in urine in presence of

existing alkalosis (can’t sacrifice H+)• This mechanism is also the way the body

controls the level of HCO3-

Renal Failure

• Failure of the kidneys to produce urine, filter waste products, and regulate fluid and electrolyte levels.

• Caused by reduced Glomerular Filtration Rate and manifested by a reduction in urine formation and an increase in Blood Urea Nitrogen (BUN) and Creatinine levels.

• Can be acute (over a few days) or chronic in nature.

RIFLE Classification of Renal Failure

• Risk (R) - Increase in serum creatinine level X 1.5 or decrease in GFR by 25%, or UO <0.5 mL/kg/h for 6 hours

• Injury (I) - Increase in serum creatinine level X 2.0 or decrease in GFR by 50%, or UO <0.5 mL/kg/h for 12 hours

• Failure (F) - Increase in serum creatinine level X 3.0, decrease in GFR by 75%, or serum creatinine level >4 mg/dL with acute increase of >0.5 mg/dL; UO <0.3 mL/kg/h for 24 hours, or anuria for 12 hours

• Loss (L) - Persistent ARF, complete loss of kidney function >4 weeks

• End-stage kidney disease (E) - Loss of kidney function >3 months

• Acute Dialysis Quality Initiative (ADQI) group

Causes of Renal Failure

• Pre-renal• Post-renal• Renal

Pre-Renal Failure• Normal tubular or glomerular filtration function.• Reduced GFR is secondary to reduced renal perfusion.• The most common cause is hypotension, often due to

hypovolemia.• Evaluate for hemorrhage, vomiting, diarrhea, or reduced fluid

intake in the elderly.• Less common cause is a pre-renal obstruction (renal

arterial tumor)• No real damage to kidney itself if treated early.• Lab results

• Urine osmolarity > 500 mOsm/kg water• Plasma BUN – creatinine ratio >20• Urine/Plasma Creatinine ratio > 40

Post-Renal Failure• Also known as obstructive renal failure as the

problem is with a downstream obstruction.• Reversible if the source can be identified.• Causes include

• Ureter obstruction due to kidney stone or cancer.• Bladder obstruction due to kidney stone, cancer, and

enlarged prostate (most common cause).• Kidney function returns to normal after correction

of problem.

Renal Failure• Damage to the nephron which limits its ability to filter

and remove waste material, and its ability to regulate fluid and electrolytes.

• Causes include:• Blood vessel disease (e.g. HTN)• Glomerulonephritis• Acute Tubular Necrosis (ATN)• Ischemia from cardiac arrest or a significant reduction in

renal perfusion.• Lab results

• Urine osmolarity < 500 mOsm/kg water• Plasma BUN – creatinine ratio < 10-15 • Urine/Plasma Creatinine ratio < 20

Diuretics

Objectives• After today’s presentation you will:

• Diagram the renin-angiotensin-aldosterone system.

• Explain how diuretics increase urine formation by interfering with the NaCI reabsorption mechanism.

• Explain how diuretics increase urine formation by interfering with the NaHCO3 reabsorption mechanism.

• State the body’s response to hypotension as it relates to aldosterone and ADH

Diuretics

• Used to affect the water (and sodium) level in the body.• Renal Failure• Heart Failure• Hypertension• Glaucoma ( intraocular pressure)• intracranial pressure (cerebral edema)• Edema

Types of Diuretics

• 5 types• Carbonic Anhydrase Inhibitors• Osmotic• Thiazides• Loops• Potassium Sparing Diuretics

Web Site on Diuretics

• http://www.thedrugmonitor.com/diuretics.html

Carbonic Anhydrase Inhibitors

• Prevent the reabsorption of water via the NaHCO3 reaction by inhibiting the conversion of CO2 into carbonic acid.

• Works in Proximal Tubule.• Example: Acetazolamide (Diamox)• Not usually used as a primary diuretic;

used for control of glaucoma.

Osmotic Diuretics• Osmotic Diuretics: Substances that

pass through glomerular membrane into filtrate but are not reabsorbed by peritubular capillaries.• Mannitol: Elevates osmotic concentration

of tubular fluid, thereby keeping water in tubules.

• Works in Proximal Tubule and Descending Loop of Henle.

• Used for Increased Intracranial Pressure.

Thiazide Diuretics• Thiazide diuretics work by interfering with

Sodium (mostly as NaCl) reabsorption in the distal tubule.• Distal tubule accounts for only 10% of the sodium

reabsorption.• Not an extremely potent diuretic.

• Examples: Diuril, Hydrodiuril• Can lead to potassium excretion and

hypokalemia.

Loop Diuretics• Loop Diuretics: Block active Sodium and

Chloride transport out of the ascending loop. Diuresis occurs because Sodium stays in tubule (and water follows) and because medullary interstitial osmotic pressure decreases

• Examples:• Furosemide (Lasix)• Bumetanide (Bumex)• Ethacrynic Acid (Edecrin)

• Because they function in the Loop of Henle, they are more potent diuretics than thiazides.

Potassium Sparing Diuretics

• Prevents sodium reabsorption (via the NaHCO3 mechanism) in the distal tubule where Na+ usually exchanges with K+

• If Na+ reabsorption does not occur, K+ is not excreted into the tubule cells.

• Example: • Spironolactone (Aldactone)• Amiloride (Midamor)• Triamterene (Dyazide, Maxzide)

Fluid Balance

Renin-AngiotensinADH

Aldosterone

Juxtaglomerular apparatus and the Renin-Angiotension-Aldosterone mechanism & Antidiuretic

Hormone (ADH)• Reduced BP• Reduced blood flow

by juxtaglomerular apparatus

• Renin released by kidney

• Renin converted to Angiotension I

• Angiotension I converted to Angiotension II• Vasoconstriction• Release of Aldosterone

• Sodium Reabsorption

ADH (Vasopressin)• If blood osmolarity increases

(say when you are in the desert sweating), ADH is released from the pituitary gland (on orders from the hypothalamus) and water is retained.

• ADH alters the permeability of the walls of the collecting duct, thereby increasing water reabsorption.

• SIADH (low Na)• Diabetes Insipidus

• Pituitary doesn’t secrete ADH