Lecture 16: Metabolic Acidosis Flashcards
What is blood pH determined by?
The ratio of HCO3-/pCO2*0.03 (since it is part of Henderson-Hasselbalch)
What does “osis” mean?
It describes a process (how we got to a certain state) but does NOT tell us the pH of the blood
Can be respiratory/metabolic acidosis/alkalosis
Example: a respiratory disorder = one type of process
Kidney dysfunction = another type of process that can lead to acidemia
Describe the underlying cause of the problem
What is a mixed process mean?
When there are multiply underlying disorders, each of which can cause a change in blood pH
Example: body is capable of having a metabolic alkalosis, metabolic acidosis and EITHER, a respiratory acidosis or alkalosis at the SAME time! So three processes in one
Metabolic acidosis = decreased HCO3-
Metabolic alkalosis = increased HCO3-
Respiratory acidosis = increased pCO2
Respiratory alkalosis = decreased pCO2
What does “emia” mean?
Indicated the blood pH
Acidemia pH < 7.35
Alkalemia pH > 7.45
However does not tell us how we got there
What are causes of metabolic metabolic acidosis?
All causes lead to fall in serum bicarb and increased in [H+] accumulation
- Loss of base (bicarb) from body
- due to renal or GI
- Failure of kidneys to generate sufficient new bicarb and excrete endogenous acid
- Increased generation of endogenous organic acids
- Addition of exogenous acid (or something that generates an acid)
What is the anion gap?
The gap between positive and negative ions
Anion gap = unmeasured anions – unmeasured cations
Unmeasured anions = proteins, organic acids and PO4/SO4
Unmeasured cations = K, Ca and Mg
Anion gap = Na – Cl – HCO3-
Thus unmeasured anions – unmeasured cations = Na-Cl-HCO3-
Normal anion gap values: 10-12 mEq/L
What happens when you add HCl or lose HCO3-, two potential processes that lead to metabolic acidosis?
Adding HCl will increase Cl- concentration (teal bar on right will increase)
Losing HCO3- will decreased the blue bar on the right proportional to teal bar change
Anion gap stays the same
Lost bicarb replaced by chloride
Na stays the same
This is an example of normal anion gap metabolic acidosis
What are the characteristics of normal anion gap metabolic acidosis?
When chloride concentration makes up for the loss of bicarb Primary problem is twofold: i. loss of bicarb ii. gain of HCl aka Hyperchloremic metabolic acidosis
What are the causes of normal anion gap metabolic acidosis?
- Renal causes
- GI tract causes
- Addition of HCl and/or NH4Cl (basically anything that can exchange H+ excretion for Cl- accumulation)
What are the renal causes of normal anion gap metabolic acidosis?
Leads to loss of bicarb or abnormal retention of acid
- Renal tubular acidosis (RTA)
- Carbonic anhydrase inhibitors
- Kidney failure (reduced GFR, acute or chronic, mild or moderate)
- Mineralocorticoid deficiency/resistance
- Drugs (cause acidosis by inhibiting effect/synthesis of aldosterone)
What are the drugs that can cause normal anion gap metabolic acidosis?
- Sprionolactone/eplerenone
- NSAIDs
- triamterene
- amiloride
- trimethoprim
- Cyclosporine
- Tacrolimus (calcineurin inhibitors)
What are the GI causes of normal anion gap metabolic acidosis?
- Diarrhea
- Uretero-enterostomy or obstructed ileal conduit
- Drainage of pancreatic or biliary secretions
- Small bowel fistula
How does high anion gap come about?
Not by loss of bicarb or by increase of HCl
Rather this is due to Addition or retention of Organic Acids!
Thus, high anion gap metabolic acidosis is due to addition of non-Cl containing acid to plasma
-this is because adding an organic acid will reduce bicarb (because the two cancel out)
-however, since organic acid wont have Cl- conjugate base, Cl- level does not increase commensurately with bicarb decrease, thereby increasing the anion gap
What makes up the majority of the unmeasured anion value? Significance?
Albumin
In a nutritionally deprived individual, hypoalbuminemia may be present (less albumin than normal)
-this thus lowers the patient’s value for “normal” anion gap to 3 or 4 (instead of 10)
-thus, if a hypoalbuminemia patient has an anion gap of 10, this indicates the presence of additional organic acids (or a high anion gap metabolic acidosis), since the patient should normally have gap of 3-4
Thus, when measuring anion gap of malnourished patient, make sure to use a “corrected” anion gap
What are the causes of high anion gap metabolic acidosis?
- Diabetic ketoacidosis
- Alcoholic ketoacidosis
- Lactic acidosis
- Toxic ingestions
-methanol, ethylene glycol (antifreeze), diethylene glycol - Fasting ketoacidosis
- Pyroglutamic acidosis
- Toluene intoxication (glue sniffing)
- Kidney failure (reduced GFR, acute or chronic, more advanced stages)
Pretty much anything that adds an acid that does not generate Cl- as a conjugate base
What is the significance of determining the anion gap?
Helps determine what type of acidosis patient has
Normal vs high anion gap metabolic acidosis
What are the characteristics of acidosis with reduced GFR?
Characterized by fewer normally functioning nephrons
Leads to reduced GFR
Reduced GFR and less nephrons = less filtration/excretion of organic acids + reduced ammoniagenesis
-reduced ammoniagenesis caused by increased serum potassium concentration
ECF volume expansion (from inability to excrete) will also decrease aldosterone synthesis, thereby reducing distal acidification
-why?
Can lead to BOTH normal and high anion gap metabolic acidosis
How does reduced GFR lead to acidosis?
Mild to moderate kidney failure = retention of acid and failure of bicarb reabsorption/generation
-normal anion gap
Advanced kidney failure = reduced filtration and retention of sulfuric/phosphoric acids
-high anion gap
What decreases as a result of reduced GFR?
- Reduced NH4+ synthesis due to hyperkalemia
- Decreased proximal tubule HCO3 reabsorption due to ECF volume expansion and effects on Na/H exchange
- Decreased distal H secretion due to hypoaldosteronism
What is renal tubular acidosis?
An acidosis that occurs when there is NORMAL kidney function (or kidney function is not so severely impaired as to cause metabolic acidosis)
Composed of 3 different types
1. Proximal (Type II)
-defect in HCO3 reabsorption
2. Distal (Type I)
-defect in acid excretion (HCO3 regeneration)
3. Distal Hyperkalemic (type IV)
-defect in acid excretion (ammoniagenesis, acid excretion)
All RTAs are NORMAL ANION GAP metabolic acidoses
What is the defect in Proximal RTA?
Defect in HCO3 reabsorption
What is the defect in distal RTA?
Defect in acid excretion and thus less HCO3 regeneration
What is the defect in distal hyperakalemic RTA?
Defect in acid excretion due to decrease in ammonia genesis and less responsiveness to aldosterone
Characterized by inability of collecting duct to secrete both H and K
Defined by a high plasma potassium concentration
Distal and proximal RTA have low to normal K concentrations
How does hypoaldosteronism lead to defect in K and H secretion in the principal cells of the collecting ducts?
Aldosterone increases ENaC expression, thereby taking up Na+ into the cell
Since Na leaves the lumen and travels to bloodstream, the luminal fluid becomes more negative
Since luminal fluid becomes more negative, H+ and K+ can travel down its apical gradient (intracellularly to extracellulary) to replace the charge lost by Na
Thus, when you have no aldosterone, Na is secreted and H and K remain inside the cell, since there is no electrogenic gradient
In rodents, it was also observed that aldosterone upregulates apical proton pumps in intercalated cells
-so theoretically, lack of aldosterone means less apical proton pumps
How does hyperkalemia fuck up ammoniagenesis?
Since K travels from ECF to ICF, it will then mean the cell’s H+ will have to go from ICF out to ECF in order to counteract K influx
Thus K influx = increased pH
Increased pH = impairment of enzymes involved in ammoniagenesis (which takes a glutamine and breaks that shit down twice to alphaketoglutarate)
What are the characteristics of Proximal RTA?
Caused by decreased capacity of proximal tubule to reabsorb HCO3
Result = increase in fractional excretion of HCO3
Decreases threshold at which HCO3 reabsorption plateaus
Normally, there is a threshold at which HCO3 reabsorption can no longer increase, despite the plasma HCO3…however normally, this threshold is 25 HCO3 mEq/L…in proximal PTA, the threshold is 19 HCO3 mEq/L…this means less bicarb is reabsorbed
Urine pH is LOW for proximal RTA patients since the ability to acidify urine is determined by distal nephron
-is high at first but will eventually be low pH at steady state
What happens when you have an initial GFR load that is above the threshold of bicarb reabsorption (situation on the right hand side)?
Urine will have so much bicarb, that distal tubule is unable to reabsorb it and the pH will actually start out high
However, since there is less bicarb reabsorption at this point, there will be less bicarb volume filtered over time (which is case C in the figure), thus there will be less bicarb in the urine and closer to the threshold
In case B, body reaches a steady state, and only enough bicarb is secreted such that all of it can be reabsorbed in the distal tubule and the urine pH remains acidic (5.5)
-if you notice in case B, bicarb filtration is 15 mmole/L vs 26 mmole/L of normal patient
What are the mechanisms that lead to deficiency of proximal RTA to reabsorb bicarb?
Giving acetazolamide (carbonic acid anhydrase inhibitor)
Carbonic anhydrase II genetic mutation
Mutation in Na/HCO3 cotransporter gene (isolated proximal RTA)
Fanconi Syndrome
What is Fanconi’s syndrome?
Disease of proximal renal tubules When glucose, amino acids, uric acid, phosphate and bicarb are passed into urine instead of being reabsorbed Caused by a shitload of things such as i. tetracycline ii. tenofovir iii. lead poisoning iv. cystinosis v. Wilson disease vi. Lowe’s syndrome vii. hereditary fructose intolerance viii. multiple myeloma etc. (more causes listed on slide 15) Cystinosis is most common cause in children Multiple myeloma is common in adults of no drugs are present
What is cystinosis?
A lysosomal storage disease characterized by abnormal accumulation of amino acid cysteine
Can effect the transporters in proximal renal tubule thereby impairing reabsorption
Most common cause of Fanconi syndrome in children
