nephrology is the art of homeostasis
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Nephrology is the art of homeostasis. Its one thing balancing atoms in millimolar quantities. Its another balancing protons at nanomolar quantities. Introduction to acid-base physiology. Joel Topf, M.D. Assistant Professor of Medicine - PowerPoint PPT PresentationTRANSCRIPT
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Nephrology is the art of homeostasis
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Its one thing balancing atoms in millimolar quantities
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Its another balancing protons at nanomolar quantities
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Introduction to acid-base physiology
Joel Topf, M.D.Assistant Professor of Medicine
Oakland University William Beaumont School of Medicine
http://www.pbfluids.com
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Getting acid-base
• Acid base physiology is the regulation of hydrogen ion concentration
• A normal hydrogen concentration is 40 nmol/L
• This is .00004 mmol/L So
• It is measured on a negative log scale called pH, normal is 7.4
40 nanomol/L = 0.00004 milimol/L
Every change of 0.3 pH units represents a change in H+ by a factor of 2
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pH only measures free hydrogen
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Hydrogen regulation is aided by buffers
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bicarbonatehemoglobin
bone
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Bicarbonate is the primary buffer in the body
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Acid base disorders are disturbances to the mantra.
pH ∝HCO3
–
CO2
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There are two independent variables, HCO3 and CO2 and one dependent variable
pH ∝HCO3
–
CO2
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Each independent variable can go up or down
pH ∝HCO3
–
CO2
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That makes 4 possible disturbances
pH ∝HCO3
–
CO2
pH ∝HCO3
–
CO2
pH ∝HCO3
–
CO2
pH ∝HCO3
–
CO2
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Each one gets a name
pH ∝HCO3
–
CO2
pH ∝HCO3
–
CO2
pH ∝HCO3
–
CO2
pH ∝HCO3
–
CO2
Metabolic alkalosis
Metabolic acidosis
Respiratory alkalosis
Respiratory acidosis
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In respiratory disorders, the kidney modifies the HCO3
Patients with primary acid-base disorders compensate to restore normal pH.
In metabolic disorders, the lungs modify the pCO2
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Compensation minimizes changes in the fraction, to minimize changes in the pH
pH ∝HCO3
–
CO2
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Compensation is always in the same direction as the primary disorder.
pCO2HCO3Metabolic acidosis
pCO2HCO3Metabolic alkalosis
HCO3pCO2Respiratory acidosis
HCO3pCO2Respiratory alkalosis
Primary Compensation
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Compensation is always in the same direction as the primary disorder.
pCO2HCO3Metabolic acidosis
pCO2HCO3Metabolic alkalosis
HCO3pCO2Respiratory acidosis
HCO3pCO2Respiratory alkalosis
Primary Compensation
pH
pH
pH
pH
If they move in discordant directions it is respiratory
If all three variables move in the same direction the disorder is metabolic.
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Determine the primary disorder
1. Acidosis or alkalosis– If the pH is less than 7.4 it is acidosis– If the pH is greater than 7.4 it is alkalosis
2. Determine if it is respiratory or metabolic– If the pH, bicarbonate and pCO2 all move in the same
direction (up or down) it is metabolic
– If the pH, bicarbonate and pCO2 move in discordant directions (up and down) it is respiratory
pH / pO2 / pCO2 / HCO3
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Determine the primary disorder
1. Acidosis or alkalosis– If the pH is less than 7.4 it is acidosis– If the pH is greater than 7.4 it is alkalosis
2. Determine if it is respiratory or metabolic– If the pH, bicarbonate and pCO2 all move in the same
direction (up or down) it is metabolic
– If the pH, bicarbonate and pCO2 move in discordant directions (up and down) it is respiratory
7.2 / 78 / 25 / 16pH / pO2 / pCO2 / HCO3
1. Acidosis or alkalosis– If the pH is less than 7.4 it is acidosis– If the pH is greater than 7.4 it is alkalosis
7.2 / 78 / 25 / 16pH / pO2 / pCO2 / HCO3
2. Determine if it is respiratory or metabolic– If the pH, bicarbonate and pCO2 all move in the
same direction (up or down) it is metabolic
– If the pH, bicarbonate and pCO2 move in discordant directions (up and down) it is respiratory
Metabolic Acidosis
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1. Respiratory acidosis2. Metabolic acidosis3. Respiratory alkalosis4. Respiratory alkalosis
7.5 / 55 / 24 / 22pH / pO2 / pCO2 / HCO3
1. Respiratory acidosis2. Metabolic acidosis3. Respiratory alkalosis4. Metabolic alkalosis
1. Respiratory acidosis2. Metabolic acidosis3. Respiratory alkalosis4. Metabolic alkalosis
Respiratory alkalosisDetermine the primary disorder
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The direction of compensation is determined by the direction of the primary disorder
The magnitude of the compensation is determined by
the magnitude of the primary disorder
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Empiric data
pH = 7.3HCO3 = 15 CO2 = 30-26pH = 7.37pH = 7.32-7.38
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Vary the bicarboinate, and map all of the CO2 responses
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Rinse wash repeat for respiratory disorders
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Why do we care?
HCO3 = 9 CO2 = 28pH = 7.12
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Why do we care?We care in order to uncover multiple diseases
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Determine the primary Acid-Base disorder
Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis
Winter’s formula
⅓ the Δ HCO3 1:10 acute3:10 chronic
2:10 acute4:10 chronic
Determine if the compensation is appropriate
To look for a second disease calculate what the compensation should be.
If they overlap, one disease, if they don’t 2 diseases
Compare it to the actual compensation
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• Metabolic acidosis: Winter’s Formula
• 1.5 × HCO3 + 8 ± 2
• Metabolic alkalosis:
• pCO2 rises 0.7 per mmol rise in HCO3
• Respiratory acidosis:
• 1 or 3 mmol rise in HCO3 for 10 rise in pCO2
• Respiratory alkalosis:
• 2 or 4 mmol fall in HCO3 for 10 fall in pCO2
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Predicting pCO2 in metabolic acidosis
• In metabolic acidosis the expected pCO2 can be estimated from the HCO3
Expected pCO2 = (1.5 x HCO3) + 8 ± 2
• If the pCO2 is higher than predicted then there is an addition respiratory acidosis
• If the pCO2 is lower than predicted there is an additional respiratory alkalosis
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• Example:
– Expected pCO2 = (1.5 x HCO3) + 8 ±2– Expected pCO2 = 18-22– Actual pCO2 is 19, which is within the predicted range,
indicating a simple metabolic acidosis
Predicting pCO2 in metabolic acidosis
7.23 / 78 / 19 / 8 pH / pO2 / pCO2 / HCO3
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• Example:
– Expected pCO2 = (1.5 x HCO3) + 8 ±2– Expected pCO2 = 24-28– Actual pCO2 is 34, which is above the predicted range,
indicating an additional respiratory acidosis
Predicting pCO2 in metabolic acidosis
7.15 / 112 / 34 / 12 pH / pO2 / pCO2 / HCO3
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Respiratory disorders
• Metabolic compensation for respiratory acid-base disorders is slow.
• So the predicted bicarbonate needs to be calculated for pre-compensation, called acute, and after compensation, called chronic.
– Chronic compensation is complete so the pH will be closer to normal at the expense of increased alteration of serum bicarbonate.
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Why is metabolic compensation slow?
• The lungs ventilate 12 moles of acid per day as carbon dioxide
• The kidneys excrete less than 0.1 mole of acid per day as ammonia, phosphate and free hydrogen ions
• The high excretion capacity of the lungs relative to the kidneys means that metabolic disorders are rapidly compensated by the lungs while respiratory disorders take hours to days for compensation by the kidneys.
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Metabolic acidosis
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In respiratory acidosis,
increases in CO2 drive the buffer reaction
to the left
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In respiratory acidosis, the
acid is known it and it is
always CO2
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In metabolic acidosis, the increase in H+ comes with an associated anion and that anion can be just about anything.
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Determining what anion is present in metabolic acidosis is a basic skill of hospital medicine.
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=
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Defining the anion gap
K+, Ca++
Mg++, IgG
Lactate–
Albumin
PO4–
IgA
Cl + HCO3 + Anions = Na + Cations
Cl + HCO3 + Anions – Cations = Na
Anions – Cations = Na – (Cl + HCO3)
Define (Anions – Cations) as the anion gap
Anions Gap = Na – (Cl + HCO3)
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K+, Ca++
Mg++, IgG
Lactate–
Albumin
PO4–
IgA
Normalanion
gap
Anions Gap = Na – (Cl + HCO3)
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Normal anion gap Increased anion gap
=
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What is the anion?
It is either chloride Or it is not chloride
Non-anion gap anion gap
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Non-anion gap metabolic
acidosis
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NAGMA
GI loss of HCO3
Diarrhea
Surgical drains
Fistulas
Ureterosigmoidostomy
Obstructed ureteroileostomy
Cholestyramine
Renal loss of HCO3
Renal tubular acidosis
Proximal
Distal
Hypoaldosteronism
Chloride intoxicationDilutional acidosis
HCl intoxication
Chloride gas intoxication
Early renal failure
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pH = 5.5Cl = 154 mmol/L
Plasma volume3 litersPlasma Cl = 105
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Decreases in bicarbonate force the reaction to the left, replacing the bicarbonate and increasing H+
Increases in exogenous acid drive the reaction to the right, bicarbonate is consumed
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in both, the end result is an increase
in H+ and a decrease in HCO3
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In NAGMA we will use the “loss of HCO3” model
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NAGMA
GI loss of HCO3
Diarrhea
Surgical drains
Fistulas
Ureterosigmoidostomy
Obstructed ureteroileostomy
Cholestyramine
Renal loss of HCO3
Renal tubular acidosis
Proximal
Distal
Hypoaldosteronism
Chloride intoxicationDilutional acidosis
HCl intoxication
Chloride gas intoxication
Early renal failure
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140 102 4.4 24135 100 5.0 35135 50 5.0 90135 50 5.0 90
Plasma
Bile
Pancreas
Small intestines
Large intestines
110 90 35 40
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Ureterosigmoidostomy Ureteroileostomy
Urine pH=5.5 Serum pH=7.4
100 fold difference
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NAGMA
GI loss of HCO3
Diarrhea
Surgical drains
Fistulas
Ureterosigmoidostomy
Obstructed ureteroileostomy
Cholestyramine
Renal loss of HCO3
Renal tubular acidosis
Proximal
Distal
Hypoaldosteronism
Chloride intoxicationDilutional acidosis
HCl intoxication
Chloride gas intoxication
Early renal failure
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Renal causes of a non-anion gap is calledRenal Tubular Acidosis (RTA)• RTA is a failure of the kidney
to
– reabsorb all of the filtered bicarbonate
– or synthesize new bicarbonate to replace bicarbonate lost to metabolism
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Daily acid load
• Protein metabolism consumes bicarbonate
– 1 mmol/kg
– 2 mmol/kg in children
– 4 mmol/kg in infants
• This bicarbonate must be replaced to maintain homeostasis
• The kidney does this
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Normal bicarbonate handling
• Normal plasma HCO3
concentration is 24 mmol/L
• Normal GFR is 100 mL/min, or 0.1 L per minute
• 1440 minutes in a day
• 24 × 0.1 × 1440 =
3,456 mmol of bicarbonate are filtered a day (filtered load)
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The kidney’s role in HCO3 handling is not excretory, it needs to synthesize new bicarbonate. All of the filtered bicarbonate must be reclaimed before the kidney can synthesize new HCO3 to compensate for the daily acid load
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Bicarbonate handling• The proximal tubule needs to
reabsorb 3,456 mmol of bicarbonate that is filtered every day.
• Proximal tubule
• The kidney must synthesize 50-100 mmol per day of new HCO3 to replace HCO3 lost buffering the daily acid load.
• Cortical collecting tubule
3456 mmol/day 50-100 mmol/day
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Proximal tubule: reabsorption of filtered bicarbonate
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Bicarbonate handling• The proximal tubule needs to
reabsorb 3,456 mmol of bicarbonate that is filtered every day.
• Proximal tubule
• The kidney must synthesize 50-100 mmol per day of new HCO3 to replace HCO3 lost buffering the daily acid load.
• Cortical collecting tubule
3456 mmol/day 50-100 mmol/day
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Distal tubule, completion of reabsorption and replacing bicarbonate lost to the daily acid load.
Electrogenic movement
of sodium into thetubular cells (eNaC)
H+ pumped into the tubular lumen ATPase
Maintain the 1000 fold concentration gradient
3 step process:
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Fate of excreted hydrogen ion
The minimal urine pH is 4.5. This is a H+ concentration a 1000 times that of plasma.
ButIt still is only 0.04 mmol/L
In order to excrete 50 mmol (to produce enough bicarb-onate to account for the daily acid load) one would need…
1,250 liters of urine.
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Fate of excreted hydrogen ion
Ammonium
Titratable acid
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• Excretion of the daily acid load as free hydrogen is limited by a minimum urinary pH of 4.5– Only 0.1% of the daily acid load is excreted this way
• Titratable acid is urinary phosphate – Titratable acid carries a significant portion of the
daily acid load
– Limited by dietary phosphate
– Does not respond to changes in the acid load
• Ammonium carries the bulk of the daily acid load– In response to an acid load the kidney will increase
production of ammonia (NH3) in order to accept additional protons to carry the load
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3 steps in renal
bicarbonate handling
3456 mmol/day
50-100 mmol/day
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Each step can fail which causes RTA
and NAGMA3456 mmol/day
50-100 mmol/day
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Proximal RTA (Type 2)
• The Tm is the maximum plasma concentration of any solute at which the proximal tubule is able to completely reabsorb the solute.
• Beyond the Tm the substance will be incompletely reabsorbed and spill in the urine.
• In Proximal RTA the Tm for bicarbonate is reduced from 26 to 15-20 mmol/L.
Na+
H2OHCO3 Glucose
Amino Acids
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Damage to the proximal tubule decreases its Tm from 28 to somewhere in the mid-teensTm for HCO3 at 15
Serum HCO3 is > Tm so HCO3 spills into the urine
Proximal RTA (Type 2)
24 mmol/L
15 mmol/L
pH 8
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Proximal RTA (Type 2)
15 mmol/L
15 mmol/L
pH 5
Serum HCO3 then falls
When it falls to the Tm (15 mmol/L) the kidney appears to work normally
Homeostasis resumes but at a decreased HCO3
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Proximal RTA (Type 2)
12 mmol/L
12 mmol/L
pH 5
If the patient encounters an acid load, they synthesize new bicarbonate to return the serum HCO3 to altered Tm (15)
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Proximal RTA: etiologies
• Acquired– Acetylzolamide – Ifosfamide – Chronic hypocalcemia– Multiple myeloma– Cisplatin– Lead toxicity– Mercury poisoning– Streptozocin– Expired tetracycline
• Genetic– Cystinosis– Galactosemia– Hereditary fructose
intolerance– Wilson’s disease
• Hyperparathyroidism• Chronic hypocapnia
– Intracellular alkalosis
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Proximal RTA: consequences
• Loss of potassium (hypokalemia)
• Bone disease
– Bone buffering of the acidosis
• Decreased growth
• Not typically complicated by stones
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Each step can fail which causes RTA
and NAGMA3456 mmol/day
50-100 mmol/day
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Distal RTA, the Murphy’s Law of distal HCO3
handling
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Distal RTA, the Murphy’s Law of distal HCO3
handling
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Distal RTA (Type 1)
Failure can happen at any one of the three steps in urinary acidification
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Distal RTA: Voltage dependent
• Only variety of distal RTA which is hyperkalemic
• Differentiate from type 4 by failure to respond to fludrocortisone.– Obstructive uropathy– Sickle cell anemia– Lupus– Triameterene– Amiloride
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Distal RTA: H+ Secretion
• Called classic distal RTA
• Most common cause of distal RTA– Congenital– Lithium– Multiple myeloma– Lupus– Pyelonephritis– Sickle cell anemia– Sjögren’s syndrome– Toluene (Glue sniffing)– Wilson’s disease
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Distal RTA: Gradient defect
• Amphotercin B
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Distal RTA: consequences
• Bones– Chronic metabolic
acidosis results in bone buffering.
• Bicarbonate• Phosphate • Calcium
• Kidney stones– Calcium phosphate
stones• Due to hypercalciuria• Increased urine pH• Decreased urinary
citrateWell Mr. Osborne, it may not be kidney stones after all.
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Each step can fail which causes RTA
and NAGMA3456 mmol/day
50-100 mmol/day
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Type 4 RTA: Hypoaldosteronism
• Chronic hyperkalemia of any etiology decreases ammonia- genesis
• Without ammonia to convert to ammonium total acid excretion is modest
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• Acidosis stimulates NH3 production
• NH3 is needed to excrete the H+ in the urine
• Alkalosis suppresses NH3 production
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Intracellularalkalosis
With increases in serum potassium, potassium shifts inside the cells
To maintain electroneutrality, H+ moves out of the cells
Intracellular alkalosis decreases intrarenal ammonia production
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Hypoaldosteronism: Type 4
• Chronic hyperkalemia decreases ammoniagenesis
• Without ammonia acid excretion is modest
• Urinary acidification is intact
• Acidosis is typically mild without significant bone or stone disease
• Primary problem is high potassium
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anion gap metabolic acidosis
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The anion gap metabolic acidosis
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The anion gap acidosis
• Uremia (mild)• Ingestions
– Methanol– Ethylene glycol
• Ketoacidosis– DKA– Starvation– Alcoholic
• Sepsis
• L-Lactic acidosis– Salicylate intoxication– Ischemia– Cyanide intoxication
• Nitroprusside
– Malignancy– Metformin– Liver failure– Thiamine deficiency
• D-Lactic acidosis• Pyroglutamic acidosis
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GOLDMARK
• G Glycols
• O Oxoproline: pyroglutamic acidosis
• L L-lactic acidosis
• D D-Lactic acidosis
• M Methanol
• A Aspirin
• R Renal failure
• K Ketoacidosis
AN Mehta, JB Emmett , M Emmett, Lancet, 372, 9642, p 892, 2008
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Lactic acidosis
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Lactic acidosis
• Type A– Tissue hypoxia
• Shock– Septic– Hemorrhagic– Neurogenic– Cardiogenic
• Respiratory failure• Anemia• CO poisoning
• Type B– Mitochondria
failure• Cyanide• Malignancy• Medications
– Anti-HIV– Metformin– Aspirin
• Thiamine deficiency
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D-lactate
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Ketoacidosis, a consequence of using fat as energy
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Diabetic ketoacidosis
• Type 1 diabetes• No ability to
produce insulin• Without
exogenous insulin patients are dependent on ketones for energy
• So despite blood sugars 4-10x normal, patients act as if they are hypoglycemic
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Diabetic ketoacidosis
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ingestions
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AspirinCauses type B lactic acidosis
Stimulates respiration so it also causes respiratory alkalosis
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Methanol ingestion
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Metabolic alkalosis
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Addition of bicarbonate
• One ampule of Na Bicarbonate is 50 mmol of HCO3
• One 325 mg pill is 4 mmol of HCO3
• One tsp of baking soda is 60 mmol of HCO3
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Contraction alkalosis
• Volume deficiency increases the kidneys excretion of hydrogen ions
• Enhanced sodium reabsorption in the proximal tubule increases reclaiming filtered bicarbonate
• Increased angiotensin increases AT2 which stimulates aldosterone
• Aldosterone increases intercalated cell hydrogen secretion, increasing synthesis of new bicarbonate
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Excess mineralcorticoid activity• Secondary hyperaldosteronism
• Primary hyperaldosteronism
• Cushing’s syndrome
• Congenital adrenal hyperplasia
• Hyperreninism (renal artery stenosis)
• Licorice
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Metabolic alkalosis can be divided into chloride responsive and chloride resistant categories
Saline responsive patients have a low urine chloride (less than 20 mmol/L)
Saline resistant patients have high urine chloride (greater than 20 mmol/L)
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Chloride responsive
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Chloride unresponsive
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