Renal Handling Of H+/HCO3- Flashcards
What is normal physiological pH?
7.35-7.45
Acidemia = < 7.35
Alkalosis = > 7.45
PH range that is comparable with life = 6.8-8.0
- anything outside of this range for an extended period of time = death
How does the concentration of protons change with respect to shortcut pH values?
Changes in 1.0 pH = 10x fold
- i.e: 7.0 ->6.0 pH =
1 x10^-7 -> 1 x 10^-6 H+ concentrations
Changes in 0.3 pH = 2x fold
- i.e 7.4 -> 7.1 pH = 4 x 10^-8 -> 8 x 10^-6
Changes in concentration fo H+ ions and pH exists on a logarithmic relationship, not linear
The three main mechanisms that contribute to maintaining pH in the normal range
1) buffering of H+ in both ECF/ICF
2) Respiratory compensation
3) Renal compensation
What are the most important extracellular buffers?
Bicarbonate: most important ECF buffer
HA form = CO2
A- form = HCO3-
- is the first line of defense when H+ is added or lost from the body
- normal HC03- concentration = 24 mEq/L
- CO2 form of bicarbonate is volatile and easily expired
- **when a strong acid is added to bicarbonate solutions = becomes carbonic acid and then dissociates into CO2/H20 and excreted via lungs
Phosphate
HA form = H2PO4(-)
A- form = HPO4(2-)
when a strong acid is added to HPO4(2-) it becomes H2PO4(-) which is excreted by the kidneys
Henderson-hasselbach equation purpose
CO2 from atmosphere combines with water to form carbonic acid spontaneously
Carbonic acid will break down into protons and bicarbonate via carbonic anhydrase into H+ and HCO3-
Net reaction: CO2 + H20 -> H+ + HCO3-
Henrys law
A concentration of a dissolved gas is directly related to its partial pressure
Why is bicarbonate buffer system more effective than phosphate buffer?
Bicarbonate (24 mmol/L) is much higher concentration that phosphate (1-2 mmol/L)
The acid form of bicarbonate is CO2 which is volatile and can be excreted via lungs
The base form of bicarbonate is HC03- which can be excreted via kidneys
How does calcium change in acidemia vs alkalemia?
Acidemia = ionized calcium (free)
- albumin proteins release non ionized calcium to bind excess H+ ions
- produces hypercalcemia
Alkalemia = non-ionized calcium (bound)
- albumin proteins bind more calcium due to deficiency of H+ ions in blood
- produces hypocalcemia
Most important intracellular buffers
Includes organic phosphates (ADP/ATP), DPG and proteins (especially hemoglobin which is most significant)
In order to be used, H+ has to get into cells via 1 of 3 ways:
- 1) conditions where there is an excess or deficit of CO2 (respiratory acidosis)
- 2) conditions where there is excess fixed acids in the blood (H+ can attach to lactate for example)
- 3) conditions where there is excess H+ with no organic anion (switch’s with K+ to get into cell)
Reabsorption of filtered bicarbonate
1) bicarbonate binds to H+ ions that are secreted via sodium/H+ exchanger channels on the lumen surface of primarily the PCT (but also DCT and CD).
- forms carbonic acid via carbonic anhydrase
2) carbonic anhydrase cleaves carbonic acid into CO2/H20 which easily diffuse into the PCT cells
3) CO2/H20 then recombine into carbonic acid via carbonic anhydrase and then also break down into H+/HCO3- ions
- essentially step 1 in reverse
4) bicarbonate is then reabsorbed via Na+/bicarbonate cotransporter channels and Cl-/HCO3- exchangers on the basolateral surface
Where does excretion of titratable acid occur?
also one way to create new bicarbonate
In the a-intercalated cells of the collecting duct and very late DCT
1) secretes H+ ions into the lumen and bind to phosphate ions and generate H2PO4- which is excreted
2) a-intercalated cells use carbonic anhydrase to form and break apart carbonic acid into H+/HCO3- ions
- this bicarbonate is reabsorbed via bicarbonate/Cl- exchanges on the basolateral surface
- this is termed “new” bicarbonate
Excretion of NH4+ occurs where?
also the 2nd area to reabsorb new HCO3-
In PCT/TAL/(a)-intercalated cells
- (primarily PCT though)
1) ammonium ions (NH4+) are generated inside PCT cells via break down of glutamine -> glutamate +(NH4+)-> a-ketoglutarate -> HCO3-
- **this generates new HCO3- which is reabsorbed while also generating NH4+
2) these ammonium ions (NH4+) spontaneously break apart into NH3 + H+ so NH3 can leave the cell and go into the lumen
3) ammonia (NH3+) ions that are found in the lumen uptake H+ ions that get into the lumen via Na+/H+ exchanger channels found on lumen and form NH4+
4) NH4+ is readily excretable since it cant be reuptaken unless pathology is present
HCO3- made in step 1 is reabsorbed via Na+/HCO3- cotransporter on basolateral side
Winters formula
Gives the expected PCO2 based on a measured HCO3- concentration
Used to determine respiratory compensation for a metabolic acidosis
PCO2 = [(1.5 x HCO3-) + 8] +/-2
Anion gap
Anion gap = (Na+)-(Cl- + HCO3-)
- normal = 8-12 mEq/L
- high = > 12 mEq/L
Must check this if metabolic acidosis is present in a patient since this tells you possible underlying pathologies
How does intracellular and extracellular pH differ?
Intracellular =7.2
Extracellular = 7.4
Na+/H+ channels = move H+ out of ICF = more alkaline intracellular
Cl-/HCO3- channels = moves HCO3- out of cells = more acidic intracellular
Difference between Volatile and nonvolatile/fixed acids
Volatile acid = CO2
- becomes carbonic acid (weaker acid) when combined with H20
- dissociates into H+/HCO3- and travels through the blood to lungs. Here the reaction reverses and CO2 is expelled (or vise versa and regenerated)
Fixed acids = sulfuric, phosphoric acids, B-hydroxybutyric acid and AOA, lactic acid, formic acid, glycolic acid, oxalic acid (etc).
- cant be expelled by the lungs and instead needs to be buffered by body fluids until excreted by kidneys
How do ATP and ADP work as buffers?
The phosphate groups on these molecules bind to H+ free ions
how does hemoglobin work as a buffer?
As blood flows through capillaries, O2 is released and hemoglobin -> deoxyhemoglobin
Deoxyhemoglobin accepts CO2 which gets converted into carbonic acid and H+/HCO3-. HCO3- leaves the red blood cell but the H+ gets buffered by binding to the hemoglobin
primary reason behind why venous blood is only 0.03 lower in pH, despite having much larger amounts of CO2 than arterial blood
What are the two ways that kidneys excrete fixed H+?
1) excretion of H+ bound to phosphate (H2PO4-)
2) excretion of H+ bound to NH3 (makes NH4+ which cant leave the renal lumen)
- both methods generate new HCO3- which is reabsorbed in the a-intercalated cells*
- this is to replenish the HCO3- that was used to buffer fixed acids
How do you measure the reabsoption rate of HC03-?
Filtered load of HCO3- = (GFR) x ( plasma concentration)
- under normal conditions = (180L/day) x (24mEq/L)= 4320
Excretion rate of HCO3- is almost always 2 mEq/day (except in pathology)
reabsorption rate = (filtered load) - (excretion rate)
- under normal situations = 4318 mEq/day
the majority of this occurs in the PCT
How does ECF expansion and contraction change bicarbonate reabsoption?
ECF volume expansion = inhibits HCO3- reabsorption
ECF volume contraction = promotes HCO3- reabsorption
this and the function of angiotensin-2 on increasing Na/H+ channel activity explains why contraction alkalosis occurs (volume contraction automatically leads to acute metabolic alkalosis)
How does PCO2 levels affect HCO3- levels?
Directly proportional
1) in metabolic acidosis, there is more H+ present in the blood and filtrate, which leads to increased Na+/H+ activity in the PCT cells.
2) this increase in activity causes higher levels of H+ to be in the lumen which promotes more carbonic acid formation and subsequent HCO3- reabsoption
Mechanism of excretion of titratable acid (H+ ions with urinary buffers (H2PO4- is msot common))
Excreted via a-intercalated cells of late DCT/CD
- use H+/ATPase channels (which are stimulated by aldosterone) and H+/K+/ATPase)
H+ that is secreted binds to free HPO3(2-) and forms titratable acid (H2PO4-) which is secreted
what prevents over excretion of H+ ions?
The pH of urine
- once the pH of urine hits 4.4, no more H+ will be secreted (due to acidic gradient preventing H+ from being pushed in)
this is why it is important to have Phosphate, Bicarbonate and ammonium in the urine/filtrate since the presence fo these limits the speed at which the urine decreases form 7.4 -> 4.4
What is the amount of fixed H+ production in the body from protein/phospholipid catabolism?
50 mEq/day
- 20 mEq/day = excreted via phosphate acid/ titratable acid
- 30 mEq/day = excreted via NH4+ ions
How does acidosis and hyperkalemia affect NH3+ generation?
Hyperkalemia
- inhibits NH3 synthesis and reduces ability to excrete H+ as NH4+
Acidosis
- promotes NH3 synthesis and increases ability to excrete H+ as NH4+
How does diabetic ketoacidosis and chronic renal failure change fixed H+ secretion?
Diabetic ketoacidosis
- increases total fixed H+ to 500 mEq/L a day
- causes increase glutamine metabolism and increased synthesis of NH3
- increases NH3 and titratable acid levels
Chronic renal failure
- normal levels of total fixed H+ (50mEq/L)
- decreased levels of phosphate buffer (since GFR is lowered) and impaired NH3 synthesis in PCT cells
- decreases levels of NH3 and titratable acid levels
Causes of increased anion gap metabolic acidosis
MUDPILES
M = methanol U = uremia D = Diabetic ketoacidosis P = Propylene glycol I = Iron tablets L = lactic acidosis (ethanol OD) E = ethylene glycol S= Salicylate OD
Causes of normal anion gap metabolic acidosis
“HARDASS”
H = hyperchloremia A = addisons/adrenal insufficiency R = renal tubular acidosis D = diarrhea A = acetazolamide OD (Carbonic anhydrase Inhibtors) S = Sprionolactone (K+ sparring) S = Saline hyperinfusion
How does vomiting cause metabolic alkalosis
Gastric parietal cells produce H+ and HCO3- from carbonic anhydrase. HCO3- is reabsorbed and H+ is secreted out with Cl- to form HCL
Under normal nonvomoting conditions, normal HCL concentrations reach the small intestine (with food) and stimulate the originally reabsorbed HCO3- to get excreted but he pancreas back into the small intestine to neutralize the HCL
- this does NOT occur in vomiting, which in turn leads to loss of H+ (from vomiting HCL) and increase of HCO3-
How do loop and thiazides diuretics lead to metabolic alkalosis?
Volume contraction/ loss leads to increased angiotensin-2 and aldosterone which icnreases HCO3- absorption
Renal tubular acidosis subtypes
all subtypes lead to hyperchloremic metabolic acidosis
Type 1 (distal)
- caused by inability of a-intercalated cells to secrete H+ which leads to decreased HCO3- generation
- leads to metabolic acidosis and hypokalemia
- causes = autoimmune diseases, amphotericin B use, urinary tract obstruction
Type 2(proximal)
- caused by PCT defects where HCO3- cannot be reabsorb properly
- leads to metabolic acidosis and hypokalemia
- causes = Fanconi syndrome, multiple myeloma, carbonic anhydrase Inhibtors
Type 4 (hyperkalemia)
- caused by hypoaldosteronism or aldosterone resistance which leads to hyponatremia and hyperkalemia (since ENaC channels dont work) this prevents H+ and K+ secretion
- leads to metabolic acidosis and hyperkalemia
