Metabolic Acidosis

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Metabolic Acidosis

• Mazen Kherallah, MD, FCCP
• Internal Medicine, Infectious Disease and
  Critical Care Medicine

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Basis of Metabolic Acidosis
H HCO3- ? H2O CO2
(Exhaled)
Added acids
Loss of NaHCO3
New A- No New A- (rise
in plasma AG) (no rise in plasma AG)
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Overproduction of Acids

• Retention of anions in plasma (increased anion
  gap)
• L-lactic acidosis
• Ketoacidosis (?-hydroxybutyric acid)
• Overproduction of organic acids in GI tract
  (D-lactic acidosis)
• Conversion of alcohol (methanol, ethylene glycol)
  to acids and poisonous aldehydes
• Excretion of anions in the urine (normal plasma
  anion gap)
• Ketoacidosis and impaired renal reabsorption of
  ?-hydroxybutyric acid
• Inhalation of toluene (hippurate)

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Actual Bicarbonate LossNormal Plasma Anion Gap

• Direct loss of NaHCO3
• Gastrointestinal tract (diarrhea, ileus, fistula
  or T-tube drainage, villous adenoma, ileal
  conduit combined with delivery of Cl- from urine)
• Urinary tract ( proximal RTA, use of carbonic
  anhydrase inhibitors)
• Indirect loss of NaHCO3
• Failure of renal generation of new bicarbonate
  (low NH4 excretion)
• Low production of NH4 (renal failure,
  hyperkalemia)
• Low transfer of NH4 to the urine (medullary
  interstitial disease, low distal net H secretion)

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Rate of Production of H
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Is hypoxemia present?
Plasma osmolal gap
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Diagnostic Approach to Metabolic Acidosis

• Confirm that metabolic acidosis is present
• Has the ventilatory system responded
  appropriately
• Does the patient have metabolic acidosis and no
  increase in plasma anion gap
• Has the plasma anion gap risen appropriately

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Metabolic Acidosis with Elevated Plasma Anion Gap

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KetoacidosisCauses

• Ketoacidosis with normal ?-cell function
• Hypoglycemia
• Inhibition of ?-cell (?-adrenergics)
• Excessive lipolysis
• Ketoacidosis with abnormal ?-cell function
• Insulin-dependent diabetes mellitus
• Pancreatic dysfunction

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Ketoacids

• ? hydroxybuturic acid a hydroxy acid
• Acetoacetate a real ketoacid
• Acetone it is not an acid

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Production of Ketoacids
Insulin
TG
Adrenaline
Hormone sensitive lipase
Glucose
?-GP
Fatty acids
Fatty acids
Adipocyte
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Control of Ketoacid Production in the Liver
Liver
Fatty acids ???Acetyl-CoA ??? Ketoacids
High glucagon Low insulin
Fatty acids ATP
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Production of Ketoacids

• Ketoacids are produced at a rate of not more than
  1.3 mmol/min
• Maximum rate of production would be 1500- 1850
  mmol/day
• The brain can oxidize 750 mmol/day
• The kidney will oxidize 250 mmol/day

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Removal of Ketoacids
Oxidation ATP Brain
TG
Fatty acids
Liver
Oxidation ATP
1500
Adipocyte
750
200
Kidney
H ? HB-
400
150
Ketoacids and NH4 in urine
200
150
Acetone in breath
ATP in other organs
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Excretion of ?-HB- NH4 has no net acid base
effect
ECF
HCO3-
HCO3- CO2
H ?-HB-
Glutamine
?-HB- NH4
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Excretion of ?-HB- NH4

• If NH4 are excreted, HCO3- are added to the
  body, and balance for H and is restored.
• To the degree that ?-HB- are excreted with Na
  and K, a deficit of HCO3- Na and K may occur

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Conversion of Ketoacids to Acetone

• Acetoacetate- H NADH ? ?-HB- NAD
• Acetoacetate- H? Acetone CO2

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Balance of Ketoacids
NADH H NAD
AcAc-
?-HB-
If the patient has NADH accumulation in
mitochondria, such as in hypoxia and during
Alcohol metabolism, the equilibrium of the
equation is displaced to the right Thus the
quick test will be low
Acetone (nitroprusside test)
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Alcoholic Ketoacidosis
Low ECF ?-adrenergics
-
? cells
Low net insulin

Acetyl- CoA

TG
Ketoacids
Fatty acids
-
Ethanol
Brain ATP
-
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Rate of Production of H
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Stoichiometry of ATP and O2

• The ratio of phosphorus to oxygen is 31
• 6 ATP can be produced per O2
• Consumption of at rest is close to 12 mmol/min
• The amount of ATP needed per minute is 12 X 6, or
  72 mmol/min

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Lactic Acid

• Dead-end product of glycolysis
• Produced in all tissues
• Most from tissues with high rate of glycolysis,
  gut, erythrocytes, brain, skin, and skeletal
  muscles
• Total of 15 to 20 mEq/kg is produced per day
• Normal lactic level is maintained at 0.7-1.3
  mEq/L
• Eliminated in liver (50), kidneys (25), heart
  and skeletal muscles

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Glucose
Glucose-1-ph
Glucose-6-ph
Glycogen
ATP ADP
Fructose-5-ph
ATP ADP
NAD H3PO4 NADHH
Fructose-1.6-diph
2 Glyceraldehyde-3-ph
1,3 Diphosphoglycerate
ADP ATP
ADP ATP
3-phosphoglycerate
Phosphoenolpyruvate
2-phosphoglycerate
Pyruvate
NADHH NAD
Lactate- H
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Formation of Lactic Acid in the Cytosols
Lactate Dehydrogenase
Pyruvate NADH H ???? Lactate NAD
1 time
10 times
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Utilization of Lactic Acid
Lactate itself cannot be utilized by the body,
and blood Lactate levels are therefore dependent
on pyruvate metabolism
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Pyruvate can be Utilized by Three Pathways

• Conversion to acetyl-CoA and oxidization to CO2
  and H2O by Krebs cycle
• Transamination with glutamine to form alanine and
  ?-ketogluarate
• Gluconeogenesis in the liver and kidney Cori
  Cycle

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Gluconeognesis
Oxaloacetate
Glucose
Glycolysis
Krebs
2 Pyruvate
CO2 H2O 36 ATP
PDH
LDH
Transamination
Alanine
2 Lactate 2 ATP
2H
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Lactate Dehydrogenase LDH
Pyruvate NADH H ???? Lactate NAD
(NADH) (H)
Lactate Pyruvate X Keq -------------------
NAD
Keq is the equilibrium constant of LDH
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Glucose
ADP ATP
-
H Lactate-
Na HCO3- ??? CO2 H2O
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L-Lactic AcidosisOverproduction of L-lactic Acid

• Net production of L-lactic acid occurs when the
  body must regenerate ATP without oxygen
• 1 H is produced per ATP regenerated from glucose
• Because a patient will need to regenerate 72 mmol
  of ATP per minutes, As much as 72 mmol/min of H
  can be produced in case of anoxia
• 2ATP?2 ADP 2 Pi biologic work
• Glucose 2 ADP 2 Pi ? 2 H 2L-Lactate- 2
  ATP

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L-Lactic AcidosisOverproduction of L-lactic Acid

• Rapid increase in metabolic rate strenuous
  exercise
• Increase Glycolysis
• Normal Lactate/Pyruvate ratio suggest that the
  cause is not related to anaerobic metabolism or
  anoxia

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L-Lactic AcidosisUnderutilization of L-lactic
Acid

• Decreased gluconeogesis liver problems,
  inhibitors by drugs
• Decreased Transamination malnutrition
• Decreased oxidation anaerobic conditions, PDH
  problems

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Lactic Acidosis
Type A
Type B

• Severe hypoxemia
• Acute circulatory shock (poor delivery of O2)
• Severe anemia (low capacity of blood to carry O2)
• Prolonged seizures
• Exhausting exercise

• PDH problems thiamin deficiency or an inborn
  error
• Decreased gluconeogenesis, liver failure,
  biguanide, alcohol
• Excessive formation of lactic acid malignant
  cells, low ATP, inhibition of mitochondrial
  generation of ATP cyanide, uncoupling oxidation
  and phosphorylation, alcohol intoxication

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Lactic Acidosis in Sepsis

• Normal lactate/Pyruvate ratio
• Increasing Do2 Does not reduce lactate level
• Inhibition of pyruvate dehydrogenase
• Increase pyruvate production by increased aerobic
  glycolysis
• Hypoxia and hypoperfusion

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Ethanol-Induced Metabolic Acidosis
Acetaldehyde
Ethanol
NADH H
NAD
L-Lactate
Pyruvate
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Decreasing Rate of Metabolism in Specific Organs
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Organic Acid Load from the GI TractD-Lactic
Acidosis

• Bacteria in GI tract that convert cellulose into
  organic acids
• Butyric acid provide ATP to colon
• Propionic acid and D-lactic acid
• Acetic acid
• Total of 300 mmol of organic acids is produced
  each day 60 acetic acid, 20 propionic and
  d-lactic acids, and 20 butyric acid

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Organic Acid Load from the GI TractD-Lactic
Acidosis

• Slow GI transit lead to bacterial growth blind
  loop, obstruction, drugs decreasing GI motility
• A change in bacterial flora secondary to
  antibiotic usage large population of bacteria
  producing D-lactic
• Feeding with carbohydrate-rich food will
  aggravate D-lactic acidosis in patients with GI
  bacterial overgrowth

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Metabolic Acidosis Caused by Toxins
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Basis of Metabolic Acidosis
H HCO3- ? H2O CO2
(Exhaled)
Added acids
Loss of NaHCO3
New A- No New A- (rise
in plasma AG) (no rise in plasma AG)
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Metabolic Acidosis With Normal Plasma Anion Gap

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Normal Renal Response to Acidemia

• Reabsorb all the filtered HCO3-
• Increase new HCO3- generation by increasing the
  excretion of NH4 in the urine

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Renal Tubular Acidosis

• Inability of the kidney to reabsorb the filtered
  HCO3-
• Inability of the kidney to excrete NH4

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Metabolic Acidosis with Normal Plasma Anion Gap

• Excessive excretion of NH4
• Increased renal excretion of HCO3-
• Low excretion of NH4

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Increased Renal Excretion of NH4Negative Urine
Net Charge/High Urine Osmolal Gap

• Gastrointestinal Loss of HCO3-
• Acid ingestion
• Acetazolamide ingestion
• Recovery from chronic hypocapnea
• Expansion acidosis
• Overproduction of acids with the rapid excretion
  of their conjugate base Toluene

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Diarrhea

• Should be more than 4 liters per day
• Normal kidney can generate 200 mmol of HCO3 as a
  result of enhanced excretion of NH4
• Normal anion gap with acidosis and negative urine
  net charge and increased osmolality

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An 80-year-old man with pyelonephritis, developed
diarrhea after a course of antibiotics, what is
the diagnosis?
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Acid IngestionAnion of the Acid is Cl-

• HCl
• NH4Cl
• Lysine-HCl
• Arginine-HCl

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Acetazolamide Ingestion

• Inhibition of carbonic anhydrase
• Bicarbonaturia
• Metabolic acidosis with loss of bicarbonate in
  the urine
• Normal anion gap

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Recovery from Chronic Hypocapnea

• During hyperventilation and hypocanea, the low
  PCO2 will be compensated by decreased bicarbonate
• If the stimulus for hyperventilation and
  hypocapnea resolved, the lag period before the
  bicarbonate is corrected will give metabolic
  acidosis

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Expansion Acidosis
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Metabolic Acidosis Caused by ToxinsNormal Plasma
Osmolal GapToluene (Glue Sniffing)
Toluene
Benzyl alcohol
Benzoate- H
Glycine
To urine along with Na, K, NH4
Hippurate- H
H2O CO2 to exhaled air
HCO3- NH4
Glutamine
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Excessive Excretion of HCO3-Inadequate Indirect
Reabsorption of filtered HCO3-
HCO3- Na
HCO3- Na H2CO3
Na
H HCO3- CO2 H2O
H
HCO3-
CA
CA
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Indirect Reabsorption of HCO3- Using the
Transport of NH4
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Excessive Excretion of HCO3-Inadequate Indirect
Reabsorption of filtered HCO3-Proximal RTA

• A defect in proximal H secretion
• Excretion of NaHCO3 in the urine
• Metabolic acidosis and no increase in AG
• Bicarbonaturia at onset
• Decreased filtered bicarbonate
• Decreased Bicarbonaturia

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Excessive Excretion of HCO3-Inadequate Indirect
Reabsorption of filtered HCO3-Proximal RTA
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Indirect Reabsorption of HCO3- Using the
Transport of NH4
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Reduced Renal Excretion of NH4Distal RTA

• Reduced excretion of NH4
• Failure to regenerate the needed HCO3
• Decreased NH3 in the medullary interstitium
  high urine pH
• Decreased transfer of NH3 to the lumen of the
  collecting duct

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What is the urine pH?
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Metabolic Acidosis in Renal Failure

• Normal AG acidosis results from failure of the
  kidney to generate new HCO3- from a reduced rate
  of synthesis and excretion of NH4
• Increased AG acidosis results from the reduced
  GFR, with accumulation of anions HPO4

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Ken Has a Drinking Problem

• 26 year old man consumed an excessive quantity of
  alcohol during the past week, in the last 2 days
  he has been eaten little and has vomited on many
  occasions.
• He has no history of DM
• P.E. revealed marked ECF contraction, alcohol is
  detected in his breath

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Ken Has a Drinking Problem

• Large Na deficit due to renal Na excretion
  dragged out by HCO3 from vomiting
• Hypokalemia results from excessive loss of K in
  the urine due to hyperaldpsteronism secondary to
  ECF contraction and because of bicarbonturia
• Metabolic acidosis with high anion gap of 20
• AG is grater than the fall in plasma bicarbonate
  20gt10
• Alcoholic ketoacidosis secondary to relative
  insulin deficiency plus L-lactic acidosis
  secondary to low ECF and ethanol

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Alcoholic Ketoacidosis
Low ECF ?-adrenergics
-
? cells
Low net insulin

Acetyl- CoA

TG
Ketoacids
Fatty acids
-
Ethanol
Brain ATP
-
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An Unusual Case of Ketoacidosis

• A 21-year-old woman has had DM for 2 years and
  requires insulin. Six months ago, she presented
  with lethargy, malaise, headache, and metabolic
  acidosis with normal plasma anion gap, her
  complaints and the acid-base disturbance have
  persisted for 6 months. She denies taking
  acetazolamide, halides, or HCl equivalents
• While taking her usual 34 units of insulin per
  day, she frequently had glycosuria and ketonuria
  but no major increase in AG

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An Unusual Case of Ketoacidosis

• Metabolic acidosis with mildly elevated AG and
  positive urine net charge suggest RTA secondary
  of low proximal or distal H secretion associated
  with hypokalemia
• Do you agree?

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An Unusual Case of Ketoacidosis

• Calculated osmolality is 269 and osmolal gap is
  411 indicating the presence of a large number of
  unmeasured osmoles
• NH4 was 120 mmol/L in the urine indicating normal
  response to acidosis
• ?-HB acid level is 234 mmol/L
• Thus acidosis was not evident because of marked
  ketonuria

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Gluconeognesis
Oxaloacetate
Glucose
Glycolysis
Krebs
2 Pyruvate
CO2 H2O 36 ATP
PDH
LDH
Transamination
Alanine
2 Lactate 2 ATP
2H
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Excretion of ?-HB- NH4

• If NH4 are excreted, HCO3- are added to the
  body, and balance for H and is restored.
• To the degree that ?-HB- are excreted with Na
  and K, a deficit of HCO3- Na and K may occur

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A Stroke of Bad Luck

• 42 year old man has hypertension and rare alcohol
  binges, last night he consumed half a bottle of
  whiskey. This morning he was found unconscious
  and has intracerebral hemorrhage. There was no
  ECF volume contraction
• Laboratory results now and after 2 hours with no
  change.

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A Stroke of Bad LuckAlcoholic Ketoacidosis

• Metabolic acidosis with elevation of 30 due to
  overproduction of acid
• L-lactic acid level was 7 mmol/L
• ?-HB level was 16 mmol/L
• The rest would be Acetoacetate and probably
  D-lactic acid

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A Superstar of Severe Acidosis

• A patient walked into the emergency room because
  of SOB
• PE revealed near normal ECF volume and
  hyperventilation
• His GFR was normal
• pH 6.79, PCO2 9, HCO3 1, AG 46, normal osmolal
  gap

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What is the diagnosis?

• Diabetic ketoacidosis
• Alcoholic ketoacidosis
• Type A lactic acidosis
• Type B lactic acidosis
• D-Lactic acidosis
• Toxins

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Type B Lactic Acidosis

• Low rate of acid production, otherwise acidosis
  would have killed the patient
• Normal ECF volume rules out DKA and AKA
• No history of GI problem rules out D-lactic
  acidosis
• L-Lactic acid level was higher than 30 mmol/L and
  the patient was taking metformin for the
  treatment of NIDDM

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Acute Popsicle Overdose

• 56 year old man developed diarrhea while
  traveling abroad for several months. He took
  antibiotics an a GI motility depressant, he
  consumed many popsicles to quench his thirst.
• Condition deteriorated and presented with
  confusion and poor coordination

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Acute Popsicle Overdose
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D-Lactic Acidosis

• Metabolic acidosis with elevated AG of 7 and
  decreased HCO3 of 15 indicating
• Mixed type metabolic acidosis increased AG
  (overproduction of acid) and normal AG
  (bicarbonate loss in diarrhea)
• D-Lactic acid was 10 mmol/L
• Bacteria in the GI were fed sugar from the
  popsicles and started producing D-Lactic acids
  plus CNS toxins

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The Kidneys Are Seeing Red

• 27 year old patient noticed progressive weakness
  when climbing stairs during the past several
  months. There was no diarrhea or evidence of
  problem in the GI tract. There was no special
  findings in the physical examination

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Distal RTA

• Normal AG metabolic acidosis
• Low rate of NH4 excretion
• Little excretion of HCO3 in urine following
  bicarbonate therapy, rules out proximal RTA
• The diagnosis is distal RTA