Channel Your Enthusiasm

References
Chapter 19, Part 12
Metabolic acidosis June 14, 2023
References
Chapter 19, Part 2
Roger mentioned MELAS syndrome MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options
Josh mentioned this blog on lactate- Understanding lactate in sepsis & Using it to our advantage
We discussed the Warburg effect The Warburg Effect: How Does it Benefit Cancer Cells? - PMC and here’s a case from skeleton key- Skeleton Key Group Case #28: Mysterious Acidosis in Cancer - Renal Fellow Network
Otto Warburg won the Nobel Prize in Physiology and Medicine in 1931 for describing how animal tumors produce large quantities of lactic acid (Wikipedia)
Joel calls it the Lactate saline reflex, but the accepted term of art is Lacto-Bolo reflex The origins of the Lacto-Bolo reflex: the mythology of lactate in sepsis
Buffer agents do not reverse intramyocardial acidosis during cardiac resuscitation.
Josh mentioned this article the BICAR-ICU Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial - The Lancet
Roger shared 3 quotes to make the point that there has been little movement in our knowledge the past 40 years:
Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study from Cooper in the Annals
Lactic Acidosis and Bicarbonate Therapy | Annals of Internal Medicine from Robert Hollander
Lactic acidosis from Nick Madias
Josh mentioned the use of sodium bicarbonate for CKD Eubicarbonatemic Hydrogen Ion Retention and CKD Progression - Kidney Medicine (Madias) Bicarbonate therapy for prevention of chronic kidney disease progression (from Wesson), Sodium Bicarbonate Prescription and Extracellular Volume Increase: Real‐world Data Results from the AlcalUN Study
Amy’s VoG on metabolic acidosis/KDIGO guidelines
Very nice JASN review that describes the mechanisms of how metabolic acidosis leads to CKD progression
First description by THE Dr. Bright
1930 Lancet description of benefit
2009 RCT that the 2012 KDIGO guidelines sort of based their 2b recommendations off of
2020 BiCARB Study
2021 META Analysis
We discussed methanol toxicity : Case Study: Methanol Poisoning from Adulterated Liquor | Food Safety, Acute methyl alcohol poisoning: a review based on experiences in an outbreak of 323 cases and josh poking at the osmolar gap: PulmCrit- Toxicology dogmalysis: the osmolal gap and shared these guidelines: METHANOL | extrip-workgroup and Roger loves this: Urine fluorescence using a Wood's lamp to detect the antifreeze additive sodium fluorescein: a qualitative adjunctive test in suspected ethylene glycol ingestions
From China to Panama, a Trail of Poisoned Medicine - The New York Times (diethylene glycol) . The Accidental Poison That Founded the Modern FDA - The Atlantic
Outline: Chapter 19 Metabolic Acidosis
Etiologies and Diagnosis
Lactic Acidosis
Pyruvate → lactate (LDH; NADH → NAD+)
Normal production: 15–20 mmol/kg/day
Metabolized in liver/kidney → pyruvate → glucose or TCA
Normal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/L
Causes:
↑ production: hypoxia, redox imbalance, seizures, exercise
↓ utilization: shock, hepatic hypoperfusion
Malignancy, alcoholism, antiretrovirals
D-lactic acidosis
Short bowel/jejunal bypass
Glucose → D-lactate (not metabolized by LDH)
Symptoms: confusion, ataxia, slurred speech
Special assay needed
Tx: bicarb, oral antibiotics
Treatment
Underlying cause
Bicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactate
Target pH > 7.1; prefer mixed venous pH/pCO2
Ketoacidosis (Chapter 25 elaborates)
FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)
Requires:
↑ lipolysis (↓ insulin)
Hepatic preference for ketogenesis
Causes:
DKA (glucose > 400)
Fasting ketosis (mild)
Alcoholic ketoacidosis
Poor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysis
Mixed acid-base (vomiting, hepatic failure, NAGMA)
Congenital organic acidemias, salicylates
Diagnosis:
AG, osmolar gap (acetone, glycerol)
Ketones: nitroprusside only detects acetone/acetoacetate
BHB can be 90% of total (false negative)
Captopril → false positive
Treatment:
Insulin +/- glucose
Renal Failure
↓ excretion of daily acid load
GFR < 40–50 → ↓ ammonium/TA excretion
Bone buffering stabilizes HCO3 at 12–20 mEq/L
Secondary hyperparathyroidism helps with phosphate buffering
Alkali therapy controversial in adults
Ingestions
Salicylates
Symptoms at >40–50 mg/dL
Early: respiratory alkalosis → Later: metabolic acidosis
Treatment: bicarb, dialysis (>80 mg/dL or coma)
Methanol
Metabolized to formic acid → retinal toxicity
Osmolar gap elevated
Tx: bicarb, ethanol/fomepizole, dialysis
Ethylene glycol
→ glycolic/oxalic acid → renal failure
Same treatment + thiamine/pyridoxine
Other
Toluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)
GI Bicarbonate Loss
Diarrhea, bile/pancreatic drainage → loss of alkaline fluids
Ureterosigmoidostomy → Cl-/HCO3- exchange in colon
Cholestyramine → Cl- for HCO3-

References
Part 2, March 1, 2023
The alkaline tide phenomenon in studies that measured both the alkaline tide and acid secretion, the bicarbonate accumulation increased in linear fashion with the acid secretion. Melanie thought this was first recognized in the 60’s but later found this manuscript from 1939 in JCI! ALKALINE TIDES - PMC
Melanie mentioned this old study that explores the respiratory response of metabolic acidosis and finds it “incomplete” compared to expected. EVALUATION OF RESPIRATORY COMPENSATION IN METABOLIC ALKALOSIS and there’s another image in a review by Michael Emmett Figure 1. Metabolic Alkalosis: A Brief Pathophysiologic Review - PMC
(here’s the image from JCI)
The effect of changes in blood pH on the plasma total ammonia level - Surgery
This is an interesting case that Melanie mentioned with the help of Stew Lecker Trust the Patient: An Unusual Case of Metabolic Alkalosis - PMC
Got Calcium? Welcome to the Calcium-Alkali Syndrome : Journal of the American Society of Nephrology a favorite review of the “calcium alkali” syndrome- previously called milk alkali syndrome but now milk is not commonly part of the syndrome (as with Dr. Sippie).
Lety mentioned this issue with a new contaminant of street drugs: Tranq Dope: Animal Sedative Mixed With Fentanyl Brings Fresh Horror to U.S. Drug Zones
Here are two references that illustrate how the urine pH changes over the course of the day. Circadian variation in urine pH and uric acid nephrolithiasis risk The diurnal variation in urine acidification differs between normal individuals and uric acid stone formers - PMC
Notes for Melanie’s VOG on reference 47: Maladaptive renal response to secondary hypercapnia in chronic metabolic alkalosis
From Biff Palmer Figure 4- Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023 - American Journal of Kidney Diseases
Anna’s VOG-
GI composition of cats or something
Outline: Chapter 18Metabolic Alkalosis
Elevation of arterial pH, increased plasma HCO3, and compensatory hypoventilation
High HCO3 may be compensatory for respiratory acidosis
HCO3 > 40 indicates metabolic alkalosis
Pathophysiology: Two Key Questions
How do patients become alkalotic?
Why do they remain alkalotic?
Generation of Metabolic Alkalosis
Loss of H+ ions
GI loss: vomiting, GI suction, antacids
Renal loss: diuretics, mineralocorticoid excess, hypercalcemia, post-hypercapnia
Administration of bicarbonate
Transcellular shift
K+ loss → H+ shifts intracellularly
Intracellular acidosis
Refeeding syndrome
Contraction alkalosis
Same HCO3, smaller extracellular volume → increased [HCO3]
Seen in CF (sweating), illustrated in Fig 18-1
Common theme: hypochloremia is essential for maintenance
Maintenance of Metabolic Alkalosis
Kidneys normally excrete excess HCO3
Example: Normal subjects excrete 1000 mEq NaHCO3/day with minor pH change
Impaired HCO3 excretion required for maintenance
Table 18-2
Mechanisms of Maintenance
Decreased GFR (less important)
Increased tubular reabsorption
Proximal tubule (PT): reabsorbs 90% of filtered HCO3
TALH and distal nephron manage the rest
Contributing factors:
Effective circulating volume depletion
Enhances HCO3 reabsorption
Ang II increases Na-H exchange
Increased tubular [HCO3] enables more H+ secretion
Distal nephron HCO3 reabsorption
Stimulated by aldosterone (↑ H-ATPase, ↑ Na reabsorption)
Negative luminal charge impedes H+ back-diffusion
Chloride depletion
Reduces NaK2Cl activity → ↑ renin → ↑ aldosterone
Luminal H-ATPase co-secretes Cl → low Cl increases H+ secretion
Cl-HCO3 exchanger needs Cl gradient → low Cl impairs HCO3 secretion
Key conclusion: Cl depletion > volume depletion in perpetuating alkalosis
Albumin corrects volume but not alkalosis
Non-N Cl salts correct alkalosis without fixing volume
Hypokalemia
Stimulates H+ secretion and HCO3 reabsorption
Transcellular shift (H/K exchange) → intracellular acidosis
H-K ATPase reabsorbs K and secretes H
Severe hypokalemia reduces Cl reabsorption → ↑ H+ secretion
Important with mineralocorticoid excess
Respiratory Compensation
Hypoventilation: 0.7 mmHg PCO2 ↑ per 1 mEq/L HCO3 ↑
PCO2 can exceed 60
Rise in PCO2 increases acid excretion (limited effect on pH)
Epidemiology
GI Hydrogen Loss
Gastric juice: high HCl, low KCl
Stomach H+ generation → blood HCO3
Normally recombine in duodenum
Vomiting/antacids prevent recombination → alkalosis
Antacids (e.g., MgOH)
Mg binds fats, leaves HCO3 unbound → alkalosis
Renal failure impairs excretion
Cation exchange resins (SPS, MgCO3) → same effect
Congenital chloridorrhea
High fecal Cl-, low pH → metabolic alkalosis
PPI may help by reducing gastric Cl load
Renal Hydrogen Loss
Mineralocorticoid excess & hypokalemia
Aldosterone → H+ ATPase stimulation, Na+ reabsorption → negative lumen → ↑ H+ secretion
Diuretics (loop/thiazide)
Volume contraction
Secondary hyperaldosteronism
Increased distal flow and H+ loss
Posthypercapnic alkalosis
Chronic respiratory acidosis → ↑ HCO3
Rapid correction (ventilation) → unopposed HCO3 → alkalosis
Gradual CO2 correction needed
Maintenance: hypoxemia, Cl loss
Low chloride intake (infants)
Na+ reabsorption must exchange with H+/K+
H+ co-secretion with Cl impaired if Cl is low
High dose carbenicillin
High Na+ load without Cl
Nonresorbable anion → hypokalemia, alkalosis
Hypercalcemia
↑ Renal H+ secretion & HCO3 reabsorption
Can contribute to milk-alkali syndrome
Rarely causes acidosis via reduced proximal HCO3 reabsorption
Intracellular H+ Shift
Hypokalemia
Common cause and effect of metabolic alkalosis
H+/K+ exchange → intracellular acidosis → ↑ H+ excretion
Refeeding Syndrome
Rapid carb reintroduction → cellular shift
No volume contraction or acid excretion increase
Retention of Bicarbonate
Requires impaired excretion to become significant
Organic anions (lactate, acetate, citrate, ketoacids)
Metabolism → CO2 + H2O + HCO3
Citrate in blood transfusion (16.8 mEq/500 mL)
8 units → alkalosis risk
CRRT + citrate anticoagulant
Sodium bicarbonate therapy
Rebound alkalosis possible with acid reversal (e.g., ketoacidosis)
Extreme cases: pH up to 7.9, HCO3 up to 70
Contraction Alkalosis
NaCl and water loss without HCO3
Seen in vomiting, diuretics, CF sweat
Mild losses neutralized by intracellular buffers
Symptoms
Often asymptomatic
From volume depletion: dizziness, weakness, cramps
From hypokalemia: polyuria, polydipsia, weakness
From alkalosis (rare): paresthesias, carpopedal spasm, lightheadedness
More common in respiratory alkalosis due to rapid pH shift across BBB
Physical exam not usually helpful
Clues: signs of vomiting
Diagnosis
History is key
If unclear, suspect:
Surreptitious vomiting
CF
Secret diuretic use
Mineralocorticoid excess
Use urine chloride
Table 18-3: urine Na is misleading in alkalosis
Table 18-4: urine chemistry changes with complete HCO3 reabsorption
Vomiting: low urine Na, K, Cl + acidic urine
Sufficient NaCl intake prevents this stage
Exceptions to low urine Cl:
Severe hypokalemia
Tubular defects
CKD
Distinguishing from respiratory acidosis
Use pH as guide
Caution with typo (duplicate pCO2)
A-a gradient might help
Treatment
Correct K+ and Cl− deficiency → kidneys self-correct
Upper GI losses: add H2 blockers
Saline-responsive alkalosis
Treat with NaCl
Mechanisms:
Reverse contraction component
Reduce Na+ retention → promote NaHCO3 excretion
↑ distal Cl delivery → enable HCO3 secretion via pendrin
Monitor urine pH: from 5.5 → 7–8 with therapy
Give K+ with Cl, not phosphate, acetate, or bicarbonate
Saline-resistant alkalosis
Seen in edematous states or K+ depletion
Edema (CHF, cirrhosis): use acetazolamide, HCl, dialysis
Acetazolamide: may ↑ CO2 via RBC carbonic anhydrase inhibition
Mineralocorticoid excess: K+ + K-sparing diuretic (use caution)
Severe hypokalemia:
eNaC Na+ reabsorption must be countered by H+ if no K+
Corrects rapidly with K+ replacement
Restores saline responsiveness
Renal failure: requires dialysis

References
Chapter 19, Part 1
Metabolic acidosis June 14, 2023
American Society of Nephrology | Medical Students - Kidney TREKS this is the program that Josh mentioned at Mount Desert Island!
Effects of pH on Potassium: New Explanations for Old Observations - PMC here’s the review melanie from Peter Aronson that clarifies the fact that there are no H+-K+ antiporters outside the kidney but rather coupled transport-
We discussed whether we like “Winter’s formula” Quantitative Displacement of Acid-Base Equilibrium in Metabolic Acidosis | Annals of Internal Medicine
Dr. R. W. Winters was charged with larceny https://www.nytimes.com/1982/05/16/nyregion/ex-columbia-u-doctor-charged-with-larceny.html
JCI - The Maladaptive Renal Response to Secondary Hypocapnia during Chronic HCl Acidosis in the Dog this was a classic experiment exploring the respiratory response to an infusion of HCl but the animals were maintained in a high pCO2 milieu (not generalizable to humans!)
Here’s the thoughtful Pulmcrit post (by Josh Farkas) that Josh mentioned regarding correction of anion gap for hypoalbuminemia: Mythbusting: Correcting the anion gap for albumin is not helpful
JC mentioned that the anion gap does change in cirrhosis when the albumin is very low but using the correction factor may not change the clinical findings Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunction
Diagnostic Importance of an Increased Serum Anion Gap | NEJM Melanie mentioned the work of Patricia Gabow on the anion gap. In this review, she refers to work that she had done to try to identify all the organic anions in the anion gap but it falls short.
Also, check out this critical look at the delta/delta: The Δ Anion Gap/Δ Bicarbonate Ratio in Lactic Acidosis: Time for a New Baseline?
Roger mentioned near drowning in the Dead Sea and the unusual electrolytes in that instance. Near-Drowning in the Dead Sea: A Retrospective Observational Analysis of 69 Patients
We discussed this classic NEJM article by Daniel Batlle The Use of the Urinary Anion Gap in the Diagnosis of Hyperchloremic Metabolic Acidosis
Amy mentioned this review from Uribarri and Oh in JASN on the urine anion gap: The Urine Anion Gap: Common Misconceptions
Joel has a great blog post on the urine osmolar gap. urine osmolar gap – Precious Bodily Fluids
Anna’s VoG on the bicarb deficit: Kurtz, I Acid-Base Case Studies, 2nd Edition. Trafford Publishing 2004. And the Fernandez paper that derived a better equation
Reference for Josh’s VoG: Key enzyme in charge of ketone reabsorption of renal tubular SMCT1 may be a new target in diabetic kidney disease
Severe anion gap acidosis associated with intravenous sodium thiosulfate administration
Unexpectedly severe metabolic acidosis associated with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathy
Sodium Thiosulfate Induced Severe Anion Gap Metabolic Acidosis
Sodium Thiosulfate and the Anion Gap in Patients Treated by Hemodialysis

Outline: Chapter 19 Metabolic Acidosis
Overview
Low arterial pH
Reduced HCO3
Compensatory hyperventilation (↓ pCO2)
Bicarb < 10 strongly suggests metabolic acidosis (renal compensation for respiratory alkalosis does not go that low)
Pathophysiology
H+ + HCO3- <=> H2CO3 <=> CO2 + H2O
Acidosis results from H+ addition or HCO3 loss
Response to Acid Load
Extracellular buffering
Example: Add 12 mmol H+/L → HCO3 falls from 24 → 12 → pH drops to 7.1 (40 to 80 nmol/L)
Intracellular and bone buffering
55–60% buffered intracellularly and in bone
12 mEq/L acid load only reduces serum HCO3 by ~5 mEq/L
H+ into cells → K+ out (hyperkalemia)
Notably in diarrhea or renal failure
Less effect with organic acidosis (e.g., DKA, lactic acidosis)
Respiratory compensation
Stimulates chemoreceptors → ↑ tidal volume (more than RR)
Decreases pCO2, increases pH
Begins within 1–2 hours; peaks at 12–24 hours
Winters formula alternative: for every 1 mEq ↓ HCO3, pCO2 ↓ by 1.2
Chronic: respiratory compensation is blunted by renal adaptation
Renal hydrogen excretion
50–100 mEq/day acid generated from diet
90% filtered HCO3 reabsorbed in PT
Acid secreted:
10–40 mEq via titratable acid (TA)
30–60 mEq via NH3/NH4 (can ↑ to 250 mEq in acidosis)
TA: phosphate (DKA → ketones act as TA)
Max excretion up to 500 mEq/day in severe acidosis
Generation of Metabolic Acidosis
Mechanisms
Inability to excrete H+ (slow)
Addition of H+ or loss of HCO3 (rapid)
Anion Gap (AG)
Normal: 5–11 (falling due to rising Cl-)
Mostly due to negatively charged proteins (albumin)
Adjust for albumin: AG ↓ 2.5 per 1 g/dL albumin ↓
Revised: AG = unmeasured anions - unmeasured cations
↑ AG = addition of unmeasured anions (e.g., lactate, ketones)
Hyperchloremic acidosis: ↓ HCO3 replaced by ↑ Cl (normal AG)
Delta–Delta Analysis
Adjust AG for albumin
Normal ΔAG:ΔHCO3 = 1.6:1 (early 1:1)
<1 → high + normal AG acidosis
Other causes of AG variation
High AG without acidosis: hemoconcentration, alkalosis
Low AG: hypoalbuminemia, ↑ unmeasured cations (lithium, IgG, lab artifact)
Urine Anion Gap (UAG)
Normal = ~0; should be very negative (< -20) in acidosis
Type 1 & 4 RTA → UAG positive or near zero
Invalid in ketoacidosis or volume depletion (Na retention → ↓ distal acidification)
Urine Osmolal Gap
Estimate NH4+ via osmolar gap
Requires urine Na, K, glucose, urea
Etiologies and Diagnosis
Lactic Acidosis
Pyruvate → lactate (LDH; NADH → NAD+)
Normal production: 15–20 mmol/kg/day
Metabolized in liver/kidney → pyruvate → glucose or TCA
Normal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/L
Causes:
↑ production: hypoxia, redox imbalance, seizures, exercise
↓ utilization: shock, hepatic hypoperfusion
Malignancy, alcoholism, antiretrovirals
D-lactic acidosis
Short bowel/jejunal bypass
Glucose → D-lactate (not metabolized by LDH)
Symptoms: confusion, ataxia, slurred speech
Special assay needed
Tx: bicarb, oral antibiotics
Treatment
Underlying cause
Bicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactate
Target pH > 7.1; prefer mixed venous pH/pCO2
Ketoacidosis (Chapter 25 elaborates)
FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)
Requires:
↑ lipolysis (↓ insulin)
Hepatic preference for ketogenesis
Causes:
DKA (glucose > 400)
Fasting ketosis (mild)
Alcoholic ketoacidosis
Poor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysis
Mixed acid-base (vomiting, hepatic failure, NAGMA)
Congenital organic acidemias, salicylates
Diagnosis:
AG, osmolar gap (acetone, glycerol)
Ketones: nitroprusside only detects acetone/acetoacetate
BHB can be 90% of total (false negative)
Captopril → false positive
Treatment:
Insulin +/- glucose
Renal Failure
↓ excretion of daily acid load
GFR < 40–50 → ↓ ammonium/TA excretion
Bone buffering stabilizes HCO3 at 12–20 mEq/L
Secondary hyperparathyroidism helps with phosphate buffering
Alkali therapy controversial in adults
Ingestions
Salicylates
Symptoms at >40–50 mg/dL
Early: respiratory alkalosis → Later: metabolic acidosis
Treatment: bicarb, dialysis (>80 mg/dL or coma)
Methanol
Metabolized to formic acid → retinal toxicity
Osmolar gap elevated
Tx: bicarb, ethanol/fomepizole, dialysis
Ethylene glycol
→ glycolic/oxalic acid → renal failure
Same treatment + thiamine/pyridoxine
Other
Toluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)
GI Bicarbonate Loss
Diarrhea, bile/pancreatic drainage → loss of alkaline fluids
Ureterosigmoidostomy → Cl-/HCO3- exchange in colon
Cholestyramine → Cl- for HCO3-
Renal Tubular Acidosis (RTA)
Type 1 (Distal)
↓ H+ secretion in collecting duct → urine pH > 5.3
Etiologies: Sjögren, RA, amphotericin
Features: nephrocalcinosis, stones, hypokalemia
Diagnosis: NAGMA, persistent ↑ urine pH
Treatment: alkali (1–2 mEq/kg/d adults; 4–14 kids), K+ if needed
Type 2 (Proximal)
↓ HCO3 reabsorption
Bicarb threshold reduced → self-limited
Causes: multiple myeloma, Fanconi, ifosfamide
Features: rickets/osteomalacia, no stones, pH variable
Diagnosis: NAGMA, pH < 5.3, high FE HCO3 when HCO3 loaded
Treatment: alkali (10–15 mEq/kg/d), thiazides
Type 4
Aldo deficiency/resistance → hyperkalemia + mild acidosis
K+ inhibits NH4 generation
Tx: correct K+, consider loop diuretics
Symptoms
Hyperventilation (dyspnea)
pH < 7.0–7.1 → arrhythmias, ↓ contractility
Neurologic: lethargy → coma (CSF pH driven)
Skeletal growth issues in children
Treatment Principles
No alkali needed for keto/lactic acidosis unless pH < 7.2
Bicarbonate Deficit
Deficit = HCO3 space * (desired - actual HCO3)
HCO3 space: 50–70% of body weight
Watch for:
K+ shifts: beware hypokalemia when correcting acidosis
Na+ load in CHF
Dialysis if necessary

We are a bit slappy at the beginning of the episode since we had just recorded our conversation with the Glaucomfleckens.

References
Chapter 18 Metabolic alkalosis!
Part 1 February 23, 2023
It is chloride depletion alkalosis, not contraction alkalosis classic review by Galla and Luke, the metabolic alkalosis mavens who review the role of chloride.
On the mechanism by which chloride corrects metabolic alkalosis in man and this is the study when they induced a metabolic alkalosis and studied the effect of treating with KCl vs NaPhos and found the former (with chloride) reversed the alkalosis but not the sodium containing protocol.
Some elegant reports on the increased proximal reabsorption of bicarbonate above normal stimulated by Ang II.
Tubular transport responses to angiotensin | American Journal of Physiology-Renal Physiology
Crosstalk between the renal sympathetic nerve and intrarenal angiotensin II modulates proximal tubular sodium reabsorption - Pontes - 2015 - Experimental Physiology - Wiley Online Library
THE RENAL REGULATION OF ACID-BASE BALANCE IN MAN. III. THE REABSORPTION AND EXCRETION OF BICARBONATE 1949 this is the correct figure for 11.14 and shows what happens when filtered bicarb exceeds normal threshold in normal human (men) and appears in the urine.
Masterful review Symposium on acid-base homeostasis. The generation and maintenance of metabolic alkalosis by Seldin and Rector
And a modern review from Michael Emmet! Metabolic Alkalosis - PMC (so many favorite reviews on this exciting topic!) and this one from Soleimani Metabolic Alkalosis Pathogenesis, Diagnosis, and Treatment: Core Curriculum 2022 both of these elaborate on pendrin’s role.
The effect of prolonged administration of large doses of sodium bicarbonate in man (Clin Sci. 1954 Aug;13(3):383-401)
Kidney v Renal: KDIGO versus Don’t
Plus: We got a little off topic and discussed the Kidney Failure Risk Equation: https://kidneyfailurerisk.com/

Outline: Chapter 18Metabolic Alkalosis
Elevation of arterial pH, increased plasma HCO3, and compensatory hypoventilation
High HCO3 may be compensatory for respiratory acidosis
HCO3 > 40 indicates metabolic alkalosis
Pathophysiology: Two Key Questions
How do patients become alkalotic?
Why do they remain alkalotic?
Generation of Metabolic Alkalosis
Loss of H+ ions
GI loss: vomiting, GI suction, antacids
Renal loss: diuretics, mineralocorticoid excess, hypercalcemia, post-hypercapnia
Administration of bicarbonate
Transcellular shift
K+ loss → H+ shifts intracellularly
Intracellular acidosis
Refeeding syndrome
Contraction alkalosis
Same HCO3, smaller extracellular volume → increased [HCO3]
Seen in CF (sweating), illustrated in Fig 18-1
Common theme: hypochloremia is essential for maintenance
Maintenance of Metabolic Alkalosis
Kidneys normally excrete excess HCO3
Example: Normal subjects excrete 1000 mEq NaHCO3/day with minor pH change
Impaired HCO3 excretion required for maintenance
Table 18-2
Mechanisms of Maintenance
Decreased GFR (less important)
Increased tubular reabsorption
Proximal tubule (PT): reabsorbs 90% of filtered HCO3
TALH and distal nephron manage the rest
Contributing factors:
Effective circulating volume depletion
Enhances HCO3 reabsorption
Ang II increases Na-H exchange
Increased tubular [HCO3] enables more H+ secretion
Distal nephron HCO3 reabsorption
Stimulated by aldosterone (↑ H-ATPase, ↑ Na reabsorption)
Negative luminal charge impedes H+ back-diffusion
Chloride depletion
Reduces NaK2Cl activity → ↑ renin → ↑ aldosterone
Luminal H-ATPase co-secretes Cl → low Cl increases H+ secretion
Cl-HCO3 exchanger needs Cl gradient → low Cl impairs HCO3 secretion
Key conclusion: Cl depletion > volume depletion in perpetuating alkalosis
Albumin corrects volume but not alkalosis
Non-N Cl salts correct alkalosis without fixing volume
Hypokalemia
Stimulates H+ secretion and HCO3 reabsorption
Transcellular shift (H/K exchange) → intracellular acidosis
H-K ATPase reabsorbs K and secretes H
Severe hypokalemia reduces Cl reabsorption → ↑ H+ secretion
Important with mineralocorticoid excess
Respiratory Compensation
Hypoventilation: 0.7 mmHg PCO2 ↑ per 1 mEq/L HCO3 ↑
PCO2 can exceed 60
Rise in PCO2 increases acid excretion (limited effect on pH)
Epidemiology
GI Hydrogen Loss
Gastric juice: high HCl, low KCl
Stomach H+ generation → blood HCO3
Normally recombine in duodenum
Vomiting/antacids prevent recombination → alkalosis
Antacids (e.g., MgOH)
Mg binds fats, leaves HCO3 unbound → alkalosis
Renal failure impairs excretion
Cation exchange resins (SPS, MgCO3) → same effect
Congenital chloridorrhea
High fecal Cl-, low pH → metabolic alkalosis
PPI may help by reducing gastric Cl load
Renal Hydrogen Loss
Mineralocorticoid excess & hypokalemia
Aldosterone → H+ ATPase stimulation, Na+ reabsorption → negative lumen → ↑ H+ secretion
Diuretics (loop/thiazide)
Volume contraction
Secondary hyperaldosteronism
Increased distal flow and H+ loss
Posthypercapnic alkalosis
Chronic respiratory acidosis → ↑ HCO3
Rapid correction (ventilation) → unopposed HCO3 → alkalosis
Gradual CO2 correction needed
Maintenance: hypoxemia, Cl loss
Low chloride intake (infants)
Na+ reabsorption must exchange with H+/K+
H+ co-secretion with Cl impaired if Cl is low
High dose carbenicillin
High Na+ load without Cl
Nonresorbable anion → hypokalemia, alkalosis
Hypercalcemia
↑ Renal H+ secretion & HCO3 reabsorption
Can contribute to milk-alkali syndrome
Rarely causes acidosis via reduced proximal HCO3 reabsorption
Intracellular H+ Shift
Hypokalemia
Common cause and effect of metabolic alkalosis
H+/K+ exchange → intracellular acidosis → ↑ H+ excretion
Refeeding Syndrome
Rapid carb reintroduction → cellular shift
No volume contraction or acid excretion increase
Retention of Bicarbonate
Requires impaired excretion to become significant
Organic anions (lactate, acetate, citrate, ketoacids)
Metabolism → CO2 + H2O + HCO3
Citrate in blood transfusion (16.8 mEq/500 mL)
8 units → alkalosis risk
CRRT + citrate anticoagulant
Sodium bicarbonate therapy
Rebound alkalosis possible with acid reversal (e.g., ketoacidosis)
Extreme cases: pH up to 7.9, HCO3 up to 70
Contraction Alkalosis
NaCl and water loss without HCO3
Seen in vomiting, diuretics, CF sweat
Mild losses neutralized by intracellular buffers
Symptoms
Often asymptomatic
From volume depletion: dizziness, weakness, cramps
From hypokalemia: polyuria, polydipsia, weakness
From alkalosis (rare): paresthesias, carpopedal spasm, lightheadedness
More common in respiratory alkalosis due to rapid pH shift across BBB
Physical exam not usually helpful
Clues: signs of vomiting
Diagnosis
History is key
If unclear, suspect:
Surreptitious vomiting
CF
Secret diuretic use
Mineralocorticoid excess
Use urine chloride
Table 18-3: urine Na is misleading in alkalosis
Table 18-4: urine chemistry changes with complete HCO3 reabsorption
Vomiting: low urine Na, K, Cl + acidic urine
Sufficient NaCl intake prevents this stage
Exceptions to low urine Cl:
Severe hypokalemia
Tubular defects
CKD
Distinguishing from respiratory acidosis
Use pH as guide
Caution with typo (duplicate pCO2)
A-a gradient might help
Treatment
Correct K+ and Cl− deficiency → kidneys self-correct
Upper GI losses: add H2 blockers
Saline-responsive alkalosis
Treat with NaCl
Mechanisms:
Reverse contraction component
Reduce Na+ retention → promote NaHCO3 excretion
↑ distal Cl delivery → enable HCO3 secretion via pendrin
Monitor urine pH: from 5.5 → 7–8 with therapy
Give K+ with Cl, not phosphate, acetate, or bicarbonate
Saline-resistant alkalosis
Seen in edematous states or K+ depletion
Edema (CHF, cirrhosis): use acetazolamide, HCl, dialysis
Acetazolamide: may ↑ CO2 via RBC carbonic anhydrase inhibition
Mineralocorticoid excess: K+ + K-sparing diuretic (use caution)
Severe hypokalemia:
eNaC Na+ reabsorption must be countered by H+ if no K+
Corrects rapidly with K+ replacement
Restores saline responsiveness
Renal failure: requires dialysis

References
I said I used MDCalc but I was mistaken I use MedCalX which is nice but getting dated.
We talked about this out of print book that we love: Cohen, J. J., Kassirer, J. P. (1982). Acid-base. United States: Little, Brown.
Josh mentioned this article that looked at over 17,000 samples with simultaneous measured and calculated bicarbonate and found a very small difference. Comparison of Measured and Calculated Bicarbonate Values | Clinical Chemistry | Oxford Academic
Base deficit or excess- Diagnostic Use of Base Excess in Acid–Base Disorders | NEJM (check out the accompanying letter to the editor from Melanie challenging this article! Along with colleagues Lecker and Zeidel Diagnostic Use of Base Excess in Acid-Base Disorders )
Melanie loves this paper which shows a nice correlation between arterial and venous pH but the rest of the comparisons are disappointing - Comparison of arterial and venous pH, bicarbonate, Pco2 and Po2 in initial emergency department assessment - PMC
A nomogram for the interpretation of acid-base data is figure 17-1 in the book, this manuscript with the ! in the conclusion creates the acid-base map.
We debated about whether we like Winter’s formula: Quantitative displacement of acid-base equilibrium in metabolic acidosis (melanie does b/c it used real patients).
Amy’s Voice of God on Dietary Acid Load
Review of dietary acid load: https://pubmed.ncbi.nlm.nih.gov/23439373/, https://pubmed.ncbi.nlm.nih.gov/38282081/, https://pubmed.ncbi.nlm.nih.gov/33075387/
Survey data from kidney stone formers regarding sources of dietary acid load: https://pubmed.ncbi.nlm.nih.gov/35752401/
Urine profile for vegans and omnivories (urine pH and cations/anions): https://pubmed.ncbi.nlm.nih.gov/36364731/
SWAP-MEAT pilot trial: https://pubmed.ncbi.nlm.nih.gov/39514692/ looked at urine profile on plant based meat diet (Beyond Meat) versus animal based meat diet
Not all plant meat substitutes are the same in terms of net acid load: https://pubmed.ncbi.nlm.nih.gov/38504022/
Frassetto paper showing that the dietary acid load effect is mostly from sodium chloride: https://pubmed.ncbi.nlm.nih.gov/17522265/
Healthy eating is probably more important than plant based diet for CKD: https://pubmed.ncbi.nlm.nih.gov/37648119/, https://pubmed.ncbi.nlm.nih.gov/32268544/
KDIGO 2024 guidelines: https://kdigo.org/guidelines/ckd-evaluation-and-management/
Association (or lack thereof) of a pro-vegetarian diet and sarcopenia/protein energy wasting in CKD: https://pubmed.ncbi.nlm.nih.gov/39085942/

Outline Chapter 17 Introduction to simple and mixed acid-base disorders
Introduction to Simple and Mixed Acid-Base Disorders
Disturbances of acid-base homeostasis are common clinical problems
Discussed in Chapters 18-21
This chapter reviews:
Basic principles of acid-base physiology
Mechanisms of abnormalities
Evaluation of simple and mixed acid-base disorders
Acid-Base Physiology
Free hydrogen is maintained at a very low concentration
40 nanoEq/L
1 millionth the concentration of Na, K, Cl, HCO3
H+ is highly reactive and must be kept at low concentrations
Compatible H concentration: 16 to 160 nanoEq/L
pH range: 7.8 to 6.8
Buffers prevent excessive variation in H concentration
Most important buffer: HCO3
Reaction: H+ + HCO3 <=> H2CO3 <=> H2O + CO2
H2CO3 exists at low concentration compared to its products
Henderson-Hasselbalch Equation (HH Equation)
Understanding acid-base can use both H+ concentration and pH
Measurement of pH
Must be measured anaerobically to prevent CO2 loss
Measurement methods:
pH: Electrode permeable to H+
PCO2: CO2 electrode
HCO3: Calculated using HH Equation
Alternative: Add strong acid, measure CO2 released
PCO2 * 0.03 gives mEq of CO2
Measured vs. Calculated HCO3
pKa of 6.1 and PCO2 coefficient (0.03) vary
Measurement of CO2 prone to error
Debate remains unresolved
Differences affect anion gap calculations
Arterial vs. Venous Blood Gas (ABG vs. VBG)
Venous pH is lower due to CO2 retention
Venous blood may be as accurate as arterial for pH if well perfused
Pitfalls in pH Measurement
Must cool ABG quickly to prevent glycolysis
Air bubbles affect gas readings
Heparin contamination lowers pH
Arterial pH may not reflect tissue pH
Reduced pulmonary blood flow skews results
End tidal CO2 > 1.5% indicates adequate venous return
Regulation of Hydrogen Concentration
HCO3/CO2 as the Principal Buffer
High HCO3 concentration
Independent regulation of HCO3 (renal) and PCO2 (lungs)
Renal Regulation of HCO3
H secretion reabsorbs filtered bicarbonate
Loss of HCO3 in urine equates to H retention
H combines with NH3 or HPO4, forming new HCO3
Pulmonary Regulation of CO2
CO2 is not an acid but forms H2CO3
Lungs excrete 15,000 mmol of CO2 daily
Kidneys excrete 50-100 mmol of H daily
H = 24 * (PCO2 / HCO3)
pH compensation via respiratory and renal adjustments
Acid-Base Disorders
Definitions
Acidemia: Decreased blood pH
Alkalemia: Increased blood pH
Acidosis: Process lowering pH
Alkalosis: Process raising pH
Primary PCO2 abnormalities: Respiratory disorders
Primary HCO3 abnormalities: Metabolic disorders
Compensation moves in the same direction as the primary disorder
Diagnosis requires extracellular pH measurement
Metabolic Acidosis
Low HCO3 and low pH
Causes:
HCO3 loss (e.g., diarrhea)
Buffering of non-carbonic acid (e.g., lactic acid, sulfuric acid in renal failure)
Compensation: Increased ventilation lowers PCO2
Renal excretion of acid restores pH over days
Metabolic Alkalosis
High HCO3 and high pH
Causes:
HCO3 administration
H loss (e.g., vomiting, diuretics)
Compensation: Hypoventilation
Renal HCO3 excretion corrects pH unless volume or chloride depleted
Respiratory Acidosis
Due to decreased alveolar ventilation, increasing PCO2
Compensation: Increased renal H excretion raises HCO3
Acute phase: Large pH drop, small HCO3 increase
Chronic phase: Small pH drop, large HCO3 increase
Respiratory Alkalosis
Due to hyperventilation, reducing CO2 and raising pH
Compensation: Decreased renal H secretion, leading to bicarbonaturia
Time-dependent compensation (acute vs. chronic phases)
Mixed Acid-Base Disorders
Multiple primary disorders can coexist
Example:
Low arterial pH with:
Low HCO3 → Metabolic acidosis
High PCO2 → Respiratory acidosis
Combination indicates mixed disorder
Extent of renal and respiratory compensation clarifies diagnosis
Compensation does not fully restore pH
Example: pH 7.4, PCO2 60, HCO3 36 → Combined respiratory acidosis & metabolic alkalosis
Acid-Base Map illustrates normal responses to disturbances
Clinical Use of Hydrogen Concentration
H+ vs. pH Relationship
H = 24 * (PCO2 / HCO3)
Normal HCO3 cancels out 24, so H = 40 nMol/L
pH to H conversion:
Increase pH by 0.1 → Multiply H by 0.8
Decrease pH by 0.1 → Multiply H by 1.25
Example: Salicylate Toxicity
7.32 / 30 / xx / 15
Goal: Alkalinize urine to pH 7.45 (H+ = 35 nMol/L)
Bicarb needs to reach 20 for compensation
Potassium Balance in Acid-Base Disorders
Metabolic Acidosis
H+ buffered in cells, causing K+ to move extracellularly
K+ rises ~0.6 mEq/L per 0.1 pH drop
Less predictable in lactic or ketoacidosis
DKA-associated hyperkalemia due to insulin deficiency
Hyperkalemia can induce mild metabolic acidosis
Respiratory Acid-Base Disorders
Minimal effect on potassium levels