Week 2 Lectures Flashcards
Source of H+ ions in the body
all acids are produced from METABOLISM
carbonic (volatile) acids=H2CO3–produced from metabolism of carbs and fats; oxidized to CO2 and H2O; exhaled by lungs
non-carbonic (non-volatile) acids=HCl, H2SO4–produced by proteins, sulphates and phosphates; comprises the daily acid load that the kidneys excrete
name the volatile acids
carbonic acids
H2CO3
how are volatile acids removed from the body
exhaled by lungs
Name the non-volatile acids
H2SO4, HCl
how are non-volatile acids removed from the body
comprise the daily acid load that the kidneys excrete
What are the three sources of the body’s buffering system?
- extracellular (major source)
- bone
- intracellular
How do extracellular components participate in the buffering system of the body
HCO3-/CO2 system
plasma proteins
inorganic phosphates
How do intracellular components participate in the buffering system of the body
cellular proteins
phosphates
hemoglobin of RBCs
How does bone participate in the buffering system of the body
bone mineral dissolves to release buffer
especially important during ACIDOSIS
What are the two major mechanisms for compensation during acid base disorders?
- respiratory compensation
2. renal compensation
Describe the mechanism of respiratory compensation during acid base disorders
- in metabolic acidosis–>increase alveolar ventilation to blow off more CO2 (Kusmall breathing = fast and deep breathing characteristic of DIABETIC KETOACIDOSIS)
- in metabolic alkalosis–>decrease alveolar ventilation to retain CO2
describe the mechanism of renal compensation during acid base disorders
- in respiratory acidosis–> increases produced of HCO3-
2. in respiratory alkalosis–> decreases production of HCO3-
Which method (renal or respiratory) acts faster? Which method is more effective at restoring normal values?
renal compensation acts SLOWER but is more effective at restoring normal values than respiratory compensation which works faster
What role does plasma buffering play in acid load?
plasma buffering system uses HCO3- to buffer the H+ load, forming H2CO3 which dissociates into CO2 and H2O–>generated CO2 is expired
What equation describes the relationship between pH, H+, bicarb and pCO2?
henderson hasselbach
henderson hasselbach equation
pH = pKa + log([A-]/[HA])
pH = 6.1 + log10 ([HCO3-]/0.03 X PaCO2])
Describe the renal mechanism for H+ secretion
- H+ is not filtered by the kidney as free ions
- secreted into the lumen at the PT and CD (intercalated cells)
- at the PT uses apical Na+/H+ antiporter
- at the CD uses apical H+ ATPase
- secreted H+ combines with filtered HCO3-, titratable acids (Pi), or ammonium (NH4+)
Describe the renal mechanism for HCO3- reabsorption
-kidney filters 4300 mEq/day of HCO3-
-almost all is reabsorbed at three sites: PT (90%), TAL and CD
-All tubular HCO3- reabsorption is the consequence of H+ secretion
HCO3- + H+ –> H2CO3 –> CO2 and H2O which are both passively reabsorbed
Describe the renal mechanism for HCO3- regeneration (new bicarbonate generated)
- titratable acids–> same process as for HCO3- reabsorption, except that secreted H+ combines with a titratable acid such as a phosphate (HPO4-2)–H+ gets thus trapped in the lumen and secreted as H2PO4—net gain of one HCO3- (unfortunately there is a very limited amount of titratable acids in the body)
- NH4+ secretion–> NH4+ production and excretion increases in response to an increased acid load–under normal circumstances, excretion of NH4+ accounts for less than half of the net acid excreted per day–with an acid load, the kidney can increase NH4+ secretion by about 10X normal to 300-350 mmol/day
How does ammonium act as a buffer in the renal mechanism for NCO3- regeneration
Step 1: ammonium formation in the PT–> 2 NH4+ are generated from each molecule of glutamine in the PT; the same Na+/H+ antiporter is involved, except that NH4+ is transported in place of H+; NH3 can freely reenter the cell while NH4+ is trapped in the lumen
Step 2: ammonium reabsorption and recycling in the TAL/LoH–> reabsorption step at the TAL required to prevent NH4+ from being taken up into the blood and metabolized in the liver to form urea at the cost of 2 HCO3-; NH4+ is recycled into NH3+ and moved to the CD, where urine is more acidic, to reformed NH4+; the same Na+/K+/2Cl- co transporter is involved, except NH4+ is transported in place of K+; free H+ is used in the metabolism of glutamate and alpha-ketoglutarate in the Krebs cycle
Step 3: Ammonium finally acts as a buffer in the CT–> H+ secreted from the aldosterone sensitive ATPase in the CD combines with NH3+ to reform NH4+; NH4+ is trapped in lumen and excreted; net gain in one HCO3- per NH4+ excreted
What defines alkalosis and acidoses?
blood pH >7.4 = alkalosis
What pCO2 defines hyperventilation? Hypoventilation?
- Hyperventilation = pCO2 40 mmHG
What use is the amount of HCO3- in the blood?
gives the status of the primary buffering system of the body
Why must some H+ be secreted with urinary buffers in the case of high acid load?
because the kidney cannot excrete urine more acidic than pH 4.0-4.5
What are titratable acids?
urinary buffers used to excrete excess acid load
How do titratable acids help in acid base balance
- the kidney cannot excrete urine more acidic than pH 4-4.5
- thus, in order to excrete sufficient acid, the kidneys excrete H+ with urinary buffers such as phosphate (Pi) (i.e HPO4-2)–>other urine constituents can also act as buffers (creatinine) but are less important than Pi
- collectively, these urinary buffers are called titratable acids
- however, excretion of H+ as a titratable acid is not sufficient to balance the daily non-volatile acid load–a more important contributor to acid base balance is through the synthesis and excretion of ammonium (NH4+)
How do you calculate the anion gap? (A/G)
Anion Gap = [Na+] + [K+] -([Cl-] + [HCO3-]) = 12+/-2 mEq/L (normal)
Why is K+ often omitted from A/G calculations?
because serum concentrations are normally quite low
why is the anion gap calculated?
to identify the presence of significant unmeasured anions (conjugate bases of a given acid)
when is A/G calculated?
whenever there is a case of metabolic acidosis
- the presence of H+ from an acid will be buffered by HCO3- and therefore deplete the concentration of HCO3-
- some of the H+ will also be buffered by bone minerals and therefore [HCO3-] may decrease by an amount less than the increase in A/G
What are the two types of metabolic acidosis?
- A/G metabolic acidosis
2. Normal A/G metabolic acidosis
What is A/G metabolic acidosis? what does it indicate?
Presents with a change in the anion gap from normal, and indicates the presence of acids
6 causes of A/G metabolic acidosis
“REAL MK”
Renal failure Ethylene glycol Aspirin (ASA) Lactic Acid Methanol Ketoacids
What is normal A/G metabolic acidosis? What does it indicate?
Metabolic acidosis with no change in A/G–>indicates loss of HCO3- (Cl- compensates for loss of HCO3-)
Causes of normal A/G metabolic acidosis
- GI loss from diarrhea
- Renal tubular acidosis–> Type I = impaired HCO3- reabsorption at the PT; Type II - defective H+ secretion at the DT; Type IV = aldosterone deficiency/resistance
- dilution acidosis from rapid ECFV expansion
Symptoms of metabolic alkalosis
- may have confusion or altered mental status
- may have seizures
- may have paresthesias
- may have muscle cramps or tetany
- may have symptoms associated with electrolyte abnormalities
- may have symptoms associated related to specific cause of the disorder (ie drug intake or vomiting)
Signs (labs) indicative of metabolic alkalosis
- high arterial pH
- high HCO3- (primary problem)
- high PaCO2 (compensation)
- often accompanied by low serum Cl- and K+
Signs of metabolic alkalosis on physical exam
- hypoventilation (adaptive)
- confusion
- seizures
- tetany
What 3 factors may be involved in the maintenance of a metabolic alkalosis?
- increased reabsorption of HCO3-
- Hypokalemia
- Chloride depletion
Why might there be increased HCO3- reabsorption?
often due to effective circulating volume depletion
- decrease in GFR leads to activation of the RAAS system
- aldosterone activates H+ ATPase in H+ secreting intercalated cells of the collecting tubule–secreted H+ promotes reabsorption/generation of HCO3-
- aldosterone activates ENaC and Na+/K+ ATPase in principal cells of the collecting tubule–>increased intracellular +ve charge decreases H+ movement into cell
- angiotensin II activates Na+/H+ antiporter in the PT–> Cl- ions follow via pericellular route–> decreases delivery of Cl- ions to HCO3- secreting intercalated cells of the collecting tubule–> decrease in Cl-/HCO3- antiporter activity–>HCO3- retained therefore alkalosis–>secreted H+ promotes reabsorption/generation of HCO3-
How might hypokalemia contribute to causing metabolis alkalosis?
increases HCO3- generation/reabsorption
- transcellular cation exchange of K+ (out of cells) for H+ (into cells) in response to hypokalemia
- increased K+ reabsorption by H+ secreting intercalated cells in the collecting tubule via the K+/H+ antiporter–>secreted H+ promotes reabsorption/generation of HCO3-
How might chloride depletion contribute to causing metabolic alkalosis?
luminal hypochloremia leads to increased distal HCO3- reabsorption
same mechanism as for angiotensin II mediated increase in HCO3- –> decreased delivery of Cl- ions to HCO3- secreting intercalated cells of the CT–>decrease in Cl-/HCO3- antiporter activity–> HCO3- retained in body therefore alkalosis
Common causes of decreased ECFV, hypochloremia and hypokalemia related to metabolic alkalosis
vomiting nasogastric suction diuretics hyperaldosteronism Bartter/Gitelman's syndromes
How do diuretics (loop and thiazide) lead to metabolic alkalosis
- increased luminal Na+ causes increased reabsorption of Na+ in exchange for H+ at downstream site at DT–> metabolic alkalosis
- Increased luminal Na+ causes increased reabsorption of Na+ in exchange for K+ at downstream site of nephron–> hypokalemia
- diuretics cause extracellular volume contraction leading to increase in [HCO3-]–>metabolic alkalosis
How does angiotensin II affect acid-base balance?
- alterations in the Na+ balance through changes in ECFV (volume contraction) activates RAAS
- angiotensin II stimulates: apical Na+/H+ antiporter in the PT (plus increase insertion) and basolateral Na+/3HCO3- symporter in int he PT (plus increase insertion)
How does aldosterone affect acid base balance?
- alterations in the Na+ balance through changes in ECFV (volume contraction) activates the RAAS system
- aldosterone stimulates activity of the apical H+ ATPase
How does cortisol affect acid-base balance?
- acidosis stimulates secretion of cortisol from the renal cortex
- acts to increase expression of 1. apical Na+/H+ antiporter in the PT and 2. basolateral Na+/HCO3- symporter in the PT
How does parathyroid hormone affect acid base balance?
- acidosis stimulates secretion of PTH
- PTH acutely inhibits apical Na+/H+ antiporter in the PT (plus receptor endocytosis)
- PTH stimulates (long term) renal acid excretion by acting on the TAL and DT through the increased delivery of Pi buffer to more distal nephron sites
where is the majority of K+ located? what is its concentration in that compartment?
within cells (ICF = approx 159 mEq/L)
it is the most abundant intracellular cation
What is normal serum potassium?
3.5-5 mEq/L
What cells have the highest K+ content? The lowest?
highest K+= skeletal muscle
lowest K+= bone and fat tissue
Describe regulation of K+ in the tissues (non-renal regulation)
- the high ICF concentration and low ECF concentration depends on the Na+/K+ ATPase which causes influx of 2 K+ and efflux of 3 Na+
- insulin and Beta adrenergic catecholamines drive the action of this pump (happens within minutes of ingesting a K+ diet)
describe regulation of K+ at the kidneys
- K+ is freely filtered
- reabsorption of 75% of filtered K+ occures in the PCT and 25% in the TAL
- the main site of excretion occurs at the CCD–>this depends on aldosterone (increases excretion); tubular luminal flow (decreased flow leads to decreased excretion); delivery of luminal Na+ (decreased delivery leads to decreased K+ excretion); acid base (in metabolic acidosis, serum K+ may remain high)
In a healthy individual, how does ingested K+ related to excreted K+?
in a healthy individual, the amount of K+ ingested is equal to the amount of K+ secreted
Define hyperkalemia
> 5 mEq/L of K+ in serum
when does hyperkalemia get potentially dangerous (at what serum concentration)
> 6 mEq/L
when is treatment for hyperkalemia needed in emergency settings?
when serum levels are >6.5 mEq/L
what is hyperkalemia usually due to?
- increased intake/GI load (unusual)
- impaired renal excretion (due to decreased GFR, impaired secretion)
- shift of K+ out of cells (due to insulin deficiency, beta blockers, metabolic acidosis, digoxin toxicity, hyperglycaemia, familial causes)
What are the principles of treatment of hyperkalemia?
- **correct hyperglycaemia first
- give calcium IV to antagonize cardiac effects of hyperkalemia (only if severe)
- shift potassium into ICF
- removing K+ from body
- stop offending medications
how do you shift K+ into ICF to treat for hyperkalemia
- insulin administration (give glucose infusion as well if patient is not diabetic to prevent hypoglycemia)
- Beta 2 agonists
- infusion of bicarbonate
How do you remove K+ from the body in treatment of hyperkalemia?
- GI excretion, exchange resins
- loop diuretics along with normal saline
- hemodialysis (definitive treatment)
what is the major hormone involved in K+ reabsorption in the kidney
aldosterone
how does aldosterone help to manage excretion of K+
occurs within CCD
activates new production of ENaC channels in the apical membrane
also increases the NA+/K+ ATPase activity on the basolateral membrane
net effect of this is a negative membrane potential on the tubular fluid side, which favors K+ secretion–leading to loss of K+
what hormones other than aldosterone play a role in K+ management in the body?
act on extracellular K+
beta adrenergic molecules and insulin (dont work on the kidney)
What factors play a role in the movement of K+ between ICF and ECF?
- insulin deficiency
- beta blockers
- metabolic acidosis
- digoxin toxicity
- hyperglycemia (most of the time only in diabetics)
How does insulin affect K+ movement between ICF and ECF
less insulin means less uptake of K+ into cells causing hyperkalemia
how do beta blockers affect K+ movement between compartments
cause less uptake of K+ into cells and thus hyperkalemia
how does metabolic acidosis affect K+ movement between compartments?
an increase in H+ ions in the ECF will cause a concentration gradient between the ECF and ICF as well as an electrochemical gradient
results in influx of H+ ions into the cells
this causes K+ to be released out into the ECF to compensate for the intracellular charge change
How does digoxin toxicity affect K+ uptake
impairs Na+/K+ pump, leading to more K+ in interstitium
How does hyperglycemia affect K+ uptake
causes a shift of water from the ICF to ECF due to increase ECF osmolality
there is a development of relative decrease in ICF osmolality
this causes some K+ to exit the cells as a compensatory mechanism
What are the 2 mechanisms by which acid-base balance influences K+ regulation
- an increase in H+ ions in the ECF will cause a concentration gradient between the ECF and ICF as well as an electrochemical one–>results in influx of H+ into cells–>causes K+ to be released out into the ECF to compensate for the intracellular charge change (**opposite also true)
- in the CCD, in addition to the Na+/K+ ATPase chanels on the blood side, there are also Na+/H+ ATPase channels–>in acidodic situations, aldosterone may increase the effect of these channels instead of the Na+/K+ ATPase channels, leading to eventual excretion of H+ instead of K+
what drives/determines urine output?
driven by the osmol/solute load needed to be excreted
how is urine volume determined
urine volume = #osmoles/Uosm
therefore the higher the osmoles, the more urine volume u need
the more concentrated you can make your urine, the less volume you need
what is normal urine volume and osmolality per day
Uvol= 1.5 L/day
Uosm = 600 mosmol/L
what is polyuria
too much urine for a given clinical setting
how much is too much urine for a given day
> 3L/day
what urine osmolality indicates osmotic diuresis?
water diuresis?
osmotic diuresis = >250 mosmol/L
water diuresis = less than 250mosmol/L
what is osmotic diuresis
glucose (DM), mannitol, urea, salts, excessive protein intake
solutes drag water into lumen; diuresis washes out the medullary intersitium gradient
–>no driving force for ADH to work–> high urine output (ADH present but not helpful)
what is water diuresis
- appropriate for intake: psychogenic polydipsia, no ADH stimulus
- inappropriate for intake: unable to raise urine osmolality–patient needs to drink alot–ADH is either low or ineffective (therefor cannot concentrate urine)
what determines the osmolality of urine
at the end of the day, urine osmolality is determined by the level of ADH and the health of the medullary interstitium, and whatever the osmolar load/dietary intake is
what is the role of ADH in renal water regulation
stimulated by low effective circulating volume or high osmolality
osmoreceptors are much more sensitive than volume receptors–therefore ADH will be released due to small changes in osmolality
your body tries to restore major volume depletion at all o=costs even if it means sacrificing a normal osmolality
ADH causes aquaporin to be inserted into the lumen side membrane of principal cells, allowing water reabsorption and urine concentration
Principal extracellular effective osmoles
Na+, Cl-
Principal intracellular effective osmoles
K+, organic phosphates
when will water move between the ICF and ECF
only when there are effective osmoles present
Why does ADH regulate water (for what physiological purpose)
to maintain a physiological serum osmolality
what is the pathway/mechanism by which ADH is released
loss of water (or another reason for increased [Na+])–>increase in [Na+]–> increase in Posm–>cell shrinkage in hypothalamus–>release of ADH by posterior pituitary
where is ADH made
in supraoptic and paraventricular nuclei of the hypothalamus
How do you calculate serum osmolality
serum osmolality = (2Na+) + blood glucose + BUN
“two salts and a sugar bun”
what would be a systematic approach to evaluating ECF volume status in a patient
assess:
- signs and symptoms
- skin and mucous membranes
- pulse and arterial BP
- JVP
- lab findings
signs and symptoms of low ECFV
- thirst, salt cravings
- fatigue, muscle cramps, postural dizziness, weakness
- more severe: oliguria, cyanosis and cold/clammy extremities (peripheral vasoconstriction and hypoperfusion), abdominal/chest pain, confusion or obtundation, eventually loss of consciousness, hypovolemic shock
(not from this week but dont want to forget…. from week 4)
if a patient comes in from a stroke and has signs of right sided paralysis, what is most likely to be seen in the bladder
overactive bladder and dysregulation of the sphincter relaxation and bladder contraction timing (neurogenic bladder)–this is because this is from upper motor neuron damage (suprasacral damage)
Lower motor neuron damage would cause flaccid bladder
signs of low ECFV in the skin and mucous membranes
- diminished skin turgor–usefulness in adults is questioned
- dry axillae
- dryness of mucous membranes of mouth and nose and longitudinal furrows on the tongue
signs of low ECFV in the pulse and arterial BP
- low BP, narrow pulse pressure, tachycardia
orthostatic increase in pulse of 15 bpm, or diastolic BP lower by 10mmHG can detect losses of 5% ECF volume
postural increase in pulse (supine to standing) of >30 bpm is 96% specific for clinically significant ECFV depletion
- mild volume depletion–only postural changes in pulse and BP may be evident
how does JVP correlate with ECFV
low JVP (cannot be observed) may be normal, and is consistent with but never diagnostic of hypovolemia
what are lab findings indicative of ECFV depletion?
- constellations of electrolyte abnormalities are not generally used to diagnose disorders of ECFV—serum [Na+] DOES NOT indicate the ECFV!!!!!!
abnormal values of serum Na+ (and K+/Cl-/HCO3-) concentration suggest, but do not diagnose, volume disorders
hypokalemic metabolic alkalosis is most commonly associated with ECFV depletion but may also be associated with hypervolemia
- elevated BUN:creatinine ratio often >20:1 (normal 10:1) often observed
- hemoconcentration, icrease in serum uric acid concentration may be observed
how might imaging be used to assess volume status
can be estimated with US or echocardiography–measure IVC diameter
what is the initial approach to management in mild volume contraction
fluid replacement via roal route–ORS (with glucose, carbs, Na+, K+, Cl-, citrate)
what is the initial approach to management in more severe volume contraction
IV therapy
- if normonatremic, or most of hyponatremic individuals with hypotension or shock: isotonic 0.9% saline
- if hypernatremic: hypotonic solution (i.e 0.45% saline or 5% dextrose in water)
- if significant hemorrhage, anemia, or intravascular volume depletion: may require blood transfusion or colloid containing solutions (albumin, dextran)
- if hypokalemic: add appropriate amounts of KCl
How does volume depletion affect acid base balance
volume depletion increases RAAS and aldosterone
ATII causes more reabsorption of Na+ with concurrent secretion of H+–>add HCO3- back to blood–>alkalosis
aldosterone causes Na+ reabsorption by principal cells, makes lumen more negative, draws H+ into the lumen–> HCO3- back into the blood, alkalosis (also increases K+/K+ activity of alpha intercalated cells, increases H+/K+ and H-ATPase activity, causing H+ secretion–>pumps HCO3 into blood–>alkalosis
What is the relationship between total body Na+ and ECFV
sodium content (not concentration, content) determines ECFV
higher Na+ content = higher ECFV
Effect of hyperglycemia on ECF osmolality, volume and plasma [Na+]
in the presence of hyperglycemia, ECF:
- osmolality increases
- volume increases
- plasma [Na+] decreases
Effect of hyperglycemia on ICF osmolality, volume and plasma [Na+]
in the presence of hyperglycemia, ICF:
- osmolality increases
- volume decreases
- (plasma is ECF)
in cases where a patient presents with acute confusion, should glucose be given?
in the setting of acute confusion presentation, small amounts of glucose should ALWAYS be given since the acute effects of hypoglycemia are much more detrimental than any acute effects of hyperglycemia (both can cause confusion)
possible causes of confusion: critical
- hypoxia/diffuse cerebreal icshemia (respiratory failure, congestive heart failure, myocardial infarction, shock)
- systemic processes–hypoglycemia
- CNS infection
- hypertensive encephalopathy
- elevated intracranial pressure–medical and surgical origin
possible causes of confusion: emergent
- hypoxia/diffuse cerebral ischemia (severe anemia)
- systemic diseases–electrolyte and fluid disturbance, endocrine disease (thyroid, adrenal), hepatic failure, nutrition, Wernicke’s encephalopathy, sepsis from infection
- intoxications and withdrawal–CNS sedatives, ethanol, others meds (especially anticholinergics)
- CNS disease–trauma, infection, stroke, subarachnoid hemorrhage, epilepsy/seizures
in our case, what did we narrow down the cause of confusion to?
patient was a diabetic
- ketoacidosis
- fluid shifting from the ICF to ECF in the brain
- decreased amounts of glucose in the brain
- hyponatremic state
- hyperkalemic state
