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References
Chapter 19, Part 3 August 30, 2023
Joel and Roger mentioned the most common cause seems to be Sjögren’s syndrome for an acquired distal RTA. We mentioned this in an earlier episode and referenced this example of an absence of the H+ ATPase, presumably from autoantibodies to this transporter. Here’s a case report: Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosis
Joel mentioned this paper in the New England Journal of Medicine in which there were patients who had hyperkalemia with a distal RTA: Hyperkalemic Distal Renal Tubular Acidosis Associated with Obstructive Uropathy | NEJM in this setting, some patients
Anna mentioned this article on “ampho-terrible:” It’s the holes!!! Yano T, Itoh Y, Kawamura E, Maeda A, Egashira N, Nishida M, Kurose H, Oishi R. Amphotericin B-induced renal tubular cell injury is mediated by Na+ Influx through ion-permeable pores and subsequent activation of mitogen-activated protein kinases and elevation of intracellular Ca2+ concentration. Antimicrob Agents Chemother. 2009 Apr;53(4):1420-6
Josh mentioned this study on furosemide’s effect on the TAL: Furosemide-induced urinary acidification is caused by pronounced H+ secretion in the thick ascending limb
Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride - Kidney International
Melanie mentioned treatment of patients with cystinosis Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients | Clinical Kidney Journal | Oxford Academic
Amy shared her observations regarding base supplements including Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis - PubMed and Dosage of potassium citrate in the correction of urinary abnormalities in pediatric distal renal tubular acidosis patients - PubMed
Roger mentioned that he has had good luck with Moonstone Nutrition drinks alkali citrates for kidney health
We referred to David Goldfarb’s teaching on kidney stones in patients with acidification defects: A Woman with Recurrent Calcium Phosphate Kidney Stones (we also referenced this in an earlier episode but this one is a fan favorite).
Joel mentioned the concern of bone loss in distal RTA: Incomplete renal tubular acidosis in 'primary' osteoporosis and Abnormal distal renal tubular acidification in patients with low bone mass: prevalence and impact of alkali treatment
JC mentioned Ehlers-Danlos syndrome with renal tubular acidosis and medullary sponge kidneys. A report of a case and studies of renal acidification in other patients with the Ehlers-Danlos syndrome
Lety mentioned concerns of encrustation of stents in stone forming individuals Potassium Citrate as a Preventive Treatment for Double-J Stent Encrustation: A Randomized Clinical Trial
Joel schooled us in toluene and the presentation which appears to be an RTA- https://journals.lww.com/JASN/Abstract/1991/02000/Glue_sniffing_and_distal_renal_tubular_acidosis_.3.aspx
Melanie mentioned this work by Alan Yu’s lab on a mechanism of hypercalciuria Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease
Furosemide/Fludrocortisone Test and Clinical Parameters to Diagnose Incomplete Distal Renal Tubular Acidosis in Kidney Stone Formers and an accompanying editorial by Goldfarb Refining Diagnostic Approaches in Nephrolithiasis: Incomplete Distal Renal Tubular Acidosis
Here’s a nice piece on ifosfamide and phosphate from Josh New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2
Here’s this crazy piece on excessive bicarbonate - Gas production after reaction of sodium bicarbonate and hydrochloric acid
Josh points out that the pH can be important for inotropy: An effect of pH upon epinephrine inotropic receptors in the turtle heart
Mel’s favorite from Halperin because of the pun: Renal tubular acidosis (RTA): recognize the ammonium defect and pHorget the urine pH
Amy’s VOG on RTA and Osteoporosis
KI Review on acidosis and bone health: Effects of acid on bone
Guideline on congenital RTA: Distal renal tubular acidosis: ERKNet/ESPN clinical practice points
AJKD article on acidosis and bone health: Serum Bicarbonate and Bone Mineral Density in US Adults
Citrate reversing CsA induced acidosis effects: Citrate reverses cyclosporin A-induced metabolic acidosis and bone resorption in rats

Outline: Chapter 19 Metabolic Acidosis part 3
Renal Tubular Acidosis
Acidosis from diminished net tubular acid secretion
Three types
Type 1 (Distal)
Type 2 (Proximal)
Type 4 (…)
The acidosis of renal failure could be added to this group
But NH4+ per nephron is normal
This is a problem of too few nephrons, not tubular acidosis
Nephrons able to maximally acidify the urine
Type 1 Distal RTA
Decrease in net H secretion in the collecting duct
Minimal urine pH rises from 4.5 to 5.3
HCO3 can fall below 10
Three mechanisms
Defect in H-ATPase found in cortex and medulla
Sjögren syndrome
Can be genetic chloride bicarbonate exchanger
This pumps bicarbonate out basolateral membrane after it is generated in the splitting of water to form H
Defect in cortical Na reabsorption
Voltage-dependent defect
Concurrent K secretion defect
Found in urinary obstruction and sickle cell
Volume deficiency can decrease Na delivery to distal nephron
Decreased amount of Na reabsorption can cause a reversible type 1 RTA of this type
Increased membrane permeability
Amphotericin
pH of 5.0 is 250× plasma
Table 19-7
Fractional excretion of bicarbonate in distal RTA
Normally negligible since bicarbonate can’t exist with pH down around 5
In distal RTA it may be as high as 6.5; FEHCO3 is 3%
If pH goes up over 7 this can rise to 5–10%
Usually in infants
As they age their urine pH falls a bit
This is called type 3
Plasma K
H-ATPase defects have low K
Patients also have downregulation of H-K-ATPase
Downregulation of NaCl reabsorption in proximal tubule
Decreased filtered bicarbonate means less bicarbonate to absorb with Na, hence more Na excretion from proximal tubule
This increases distal sodium delivery and increases aldosterone
Voltage defect also has decreased renal K clearance → hyperkalemia
Differentiate from type 4 RTA by looking at urine pH
Lower in type 4
Higher in voltage-dependent distal RTA
Nephrocalcinosis
Hypercalciuria, hyperphosphatemia, nephrolithiasis, and nephrocalcinosis are frequent
Comes from bones buffering the acidosis
Kidney decreases reabsorption of these so they are lost in urine
Two other factors
Low urinary citrate
Hypokalemia drives this
Acidosis drives this
High urine pH (CaPhos stones)
All corrected by correcting the metabolic acidosis
Incomplete Type 1
Defective urinary acidification but not acidemic
Increased proximal NH3 production lowers urinary H
Low urinary citrate
Can progress to complete type 1
Etiology of Type 1
Sjögren syndrome, rheumatoid arthritis
19-8
Clinical manifestations
Stones
Hypokalemia
Growth defects
Diagnosis
NAGMA and elevated urine pH
5.3 in adults
5.6 in children
Differentiate Type 1 vs Type 2
Give bicarbonate drip
1 mEq/kg/hr
Urine pH remains high with Type 1
Does not go up as it does with proximal Type 2
Incomplete distal RTA
Give acid load
0.1 mmol/kg
Urine pH remains >5.3 in classic
Falls in normal patients (usually below 5)
Treatment
Treat metabolic acidosis
Minimize potassium loss
Reduce bone catabolism
Prevent stones
Alkali requirement
Adults: 1–2 mEq/kg/day
Children: 4–14 mEq/kg/day
Alkali
Sodium bicarbonate
Sodium citrate
Potassium citrate if hypokalemia persists despite correcting acidosis
Or for calcium stone disease
Treat hypokalemia
Type 2 Proximal RTA
Decreased HCO3 reabsorption
90% of bicarbonate reabsorption happens in proximal tubule
Bicarbonate wasting starts normally at 26–28 mmol/L (Tm for bicarbonate)
In RTA 2 the Tm falls to a lower level (maybe 17)
Serum bicarbonate falls to 17 and stabilizes
Type 2 RTA is self-limiting
Typically HCO3 around 14–20
Distal acidification intact
Carbonic anhydrase inhibitor can block 80% of proximal HCO3 reabsorption
Only 30% of filtered bicarbonate excreted due to distal H secretion
Total absence of proximal reabsorption results in HCO3 11–12
Clinical difference in treatment
In Type 2, giving bicarbonate and raising serum HCO3 above Tm → more wasted in urine
FEHCO3 can reach 15% with normal serum HCO3
Urine pH >7.5
Below Tm, urine pH <5.3
In Type 1, curve relating HCO3 excretion to plasma HCO3 similar to normal (with increased obligatory urine HCO3 due to higher urine pH)
Defect in HCO3 reabsorption
Can be isolated
Or part of Fanconi syndrome
Pathogenesis (three steps)
Na-H exchange (apical membrane)
Na-K-ATPase (basolateral membrane)
Carbonic anhydrase
Intracellular
Luminal
Multiple myeloma most common adult cause
Ifosfamide
Can also cause phosphate wasting, NDI, and Type 1 RTA
K balance
Common but variable
Mild hypokalemia at baseline due to increased Na wasting → hyperaldosteronism
Worse with bicarbonate therapy
Distal delivery of nonreabsorbable anion increases obligate cation loss
Figure 19-7
Bone disease
Rickets (children), osteomalacia/osteopenia (adults)
Up to 20%
Phosphate wasting and vitamin D deficiency may contribute
Impaired growth
No nephrocalcinosis or nephrolithiasis
Lower urine pH
Nonreabsorbable amino acids and organic anions bind calcium
Etiology
19-9
Idiopathic and cystinosis (children)
Carbonic anhydrase inhibitors
Multiple myeloma
Diagnosis
NAGMA and pH <5.3
Look for Fanconi syndrome
Raise serum HCO3 and watch urine pH rise
FEHCO3 15–20%
Treatment
Correct acidosis to allow normal growth
Difficult due to rapid urinary loss
May need 10–15 mEq/kg/day
HCO3 or citrate
More than 20 mEq HCO3 can cause stomach rupture from CO2 generation
Small dose thiazide to increase proximal Na reabsorption and HCO3 reabsorption
Idiopathic Type 2 may improve after years
Type 4 RTA
Aldosterone deficient or resistant
Normally stimulates H secretion and K secretion
Loss causes hyperkalemia and metabolic acidosis
Hyperkalemia antagonizes NH4 generation
High K may outcompete NH4 on Na-K-2Cl in TALH
Less ammonium recycling
Less NH3 available in collecting duct
Correcting hyperkalemia can correct acidosis
Metabolic acidosis generally mild
HCO3 >15
Urine pH <5.3 (generally, not always)
Mineralocorticoid can treat but causes hypertension and sodium retention
Often responds to loop diuretic
Rhabdomyolysis can cause high anion gap metabolic acidosis
Symptoms
Respiratory compensation increases 4–8 fold → dyspnea
pH <7.0–7.1
Fatal ventricular arrhythmias
Reduced cardiac contractility
Decreased response to inotropes
Neurological
Lethargy to coma
More related to CSF pH than plasma
Less neurologic symptoms than respiratory acidosis
BBB more permeable to CO2 than HCO3
Skeletal problems
Decreased growth
Kids/infants: anorexia, nausea, listlessness
Treatment
General principles
Correct with HCO3
No alkali required for lactic or ketoacidosis
Goal: pH >7.2
Equations on page 629 need “log”
Example: pH 7.1, pCO2 20, HCO3 6
Raise HCO3 to 8 if pCO2 stays 20
Raise to 10 if pCO2 rises
Paragraph “regardless…” highlights risks of bicarbonate
Bicarbonate deficit
Deficit = HCO3 space × HCO3 deficit per liter
HCO3 space
50% body weight (normal)
60% (mild–moderate acidosis)
70% (severe, HCO3 <8–10)
Example: 70 kg, raise HCO3 6→10 using 0.7 space = 196 mEq
Rough guideline; does not account for ongoing acid production
Early large bump in bicarbonate
Drifts down as bicarbonate moves intracellularly
Plasma potassium
K depletion can cause metabolic acidosis
Metabolic acidosis increases K
“Normal” K may mask depletion (see DKA)
Beware correcting acidosis in hypokalemia
Heart failure
Bicarbonate comes with sodium load
Comment that bicarbonate moves into cell
But Na remains extracellular
Dialysis can be used

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