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Time to dig deep and donate to NephJC: https://www.nephjc.com/news/2026/9/8/nephjc-fall-pledge-drive

References

This is the thiazide induced hyponatremia reference mentioned by Friedman: Thiazide-Induced Hyponatremia: Reproducibility by Single Dose Rechallenge and an Analysis of Pathogenesis

This is the study that Josh mentioned regarding genetic predisposition Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia and it was considered by Neph JC too Thiazide induced hyponatremia, a detailed phenotypic and genotypic analysis

And here’s a great review: Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology - American Journal of Kidney Diseases in this excellent review, nice summary of the potential effect of female sex on NCC density (at least in rats!) 

Melanie wanted to clarify the term “desalination.” Here are a few references:
• Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination  Mitch Halperin 10.7326/0003-4819-126-1-199701010-00003
• Ewout Hoorn refers to “Desalination” here  Current and future treatment options in SIADH - PMC

Here’s the abstract that Amy mentioned: Abstract P174: Incidence of Hyponatremia on Spironolactone in Patients With a Prior Episode of Chlorthalidone-Induce Hyponatremia

We mentioned the issue of solute intake again and this favorite reference: Impact of solute intake on urine flow and water excretion

Joel alluded to the unsteady gait from this paper that did the “total traveled way” and showed unsteady gait: Mild Chronic Hyponatremia Is Associated With Falls, Unsteadiness, and Attention Deficits - ScienceDirect and the effect on bones: Hyponatremia-Induced Osteoporosis - PMC (this paper is a beauty, if you don’t like it, we can’t be friends!)

For the mechanisms of hyponatremia in hypoadrenalism, Mel reviewed the mechanisms here and there is a good image too: Pattern Recognition versus Pathogenesis - PMC and you may also like this review from Schrier: Role of Glucocorticoid Hormones in Arginine Vasopressin Gene Regulation - ScienceDirect and mel mentioned Osmoregulation of plasma vasopressin in myxedema

Amy mentioned this reference: The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study

Some musings we (especially Josh and JC) had about SIADH: Vasopressin and oxytocin release during prolonged environmental hypoxia in the rat, Urinary output and plasma levels of antidiuretic hormone during intermittent positive-pressure breathing in the dog, A Vasopressin-Induced Change in Prostaglandin Receptor Subtype Expression Explains the Differential Effect of PGE2 on AQP2 Expression,Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis, Atrial natriuretic peptide in patients with the syndrome of inappropriate antidiuretic hormone secretion and with diabetes insipidus

Here’s a reference on fetal vs maternal sodium gradient: Fetal diuretic responses to maternal hyponatremia: contribution of placental sodium gradient | Journal of Applied Physiology

Roger mentions the nephrogenic syndrome of antidiuresis: Nephrogenic Syndrome of Inappropriate Antidiuresis - PMC

The NEJM manuscript looking at water dilution in schizophrenia: Mechanisms of Altered Water Metabolism in Psychotic Patients with Polydipsia and Hyponatremia

Tragic case of water loading Woman dies after being in water-drinking contest - Los Angeles Times

The case report that Josh mentioned: Self-induced water intoxication without predisposing illness

Roger mentioned this case: Who killed Bruce Lee? The hyponatraemia hypothesis - PMC and this classic from NEJM: Mechanisms of Altered Water Metabolism in Psychotic Patients with Polydipsia and Hyponatremia | NEJM 

Pseudohyponatremia- check out this cute video from laboratorian Joseph El-Khoury: Episode 1 (Pilot): Ending Pseudohyponatremia and here’s a great picture that helps illustrate the issue of measuring the sodium when the solid phase is larger in the plasma: https://i0.wp.com/nephsim.com/wp-content/uploads/2019/02/PseudoHyponatremia1.png?resize=768%2C564&ssl=1

And here’s an instructive case: Electrolyte Abnormalities in a Man With Plasma Cell Leukemia - American Journal of Kidney Diseases

Amy’s VoG on Legionella and Hyponatremia

 association with hyponatremia

first description: https://pubmed.ncbi.nlm.nih.gov/434629/

https://pubmed.ncbi.nlm.nih.gov/6997673/

low UrNa as mechanism of hyponatremia?

https://pubmed.ncbi.nlm.nih.gov/420455/

https://pubmed.ncbi.nlm.nih.gov/6800542/

https://pubmed.ncbi.nlm.nih.gov/6802400/

Diagnosis with serology and Winthrop criteria

sensitivity and specificity if the Winthrop criteria https://pubmed.ncbi.nlm.nih.gov/11591540/

modified criteria https://pubmed.ncbi.nlm.nih.gov/18410967/

atypical pneumonia diagnosis https://pubmed.ncbi.nlm.nih.gov/8493198/

Association with hypophosphatemia

https://pmc.ncbi.nlm.nih.gov/articles/PMC5399197/

https://pubmed.ncbi.nlm.nih.gov/16828618/

https://pubmed.ncbi.nlm.nih.gov/6997673/

Chapter 23: Hypoosmolar States — Hyponatremia

Diuretics

Mild hyponatremia is a common complication of diuretic therapy.

Acute severe hyponatremia may occur as an idiosyncratic reaction, particularly in patients drinking large volumes of water.

Thiazide-Associated Hyponatremia

The classic 1989 Friedman data:

13 patients with a history of thiazide-associated hyponatremia.

A single 50-mg dose of HCTZ produced an acute fall in serum Na.

Increased water drinking appeared to contribute.

Additional mechanisms include:

Volume depletion

Potassium depletion

Direct inhibition of urinary dilution through decreased NaCl reabsorption

If excessive water intake is important:

Uric acid may be low.

BUN may be low.

Clinically significant diuretic-associated hyponatremia is almost always associated with thiazides rather than loop diuretics.

Why Thiazides Are Different

Loop diuretics:

Reduce the hypertonicity of the medullary interstitium.

Impair the kidney’s ability to concentrate urine.

Can therefore actually be used as part of the treatment of SIADH.

Thiazides:

Do not disrupt the medullary concentration gradient in the same way.

Impair urinary dilution.

Can promote Na and K loss in excess of water.

One cited example:

Urine Na + K = 156 mEq/L

Plasma Na <110 mEq/L

This is desalination: urinary fluid contains more effective cation than the plasma, so its loss can further lower serum sodium.

In susceptible patients:

Serum Na can begin falling within 6–24 hours.

Most cases occur within 2 weeks of starting a thiazide.

The largest physiologic effect occurs with the earliest doses.

After several weeks, patients generally reach a new steady state.

Renal Failure

Renal failure impairs the ability to maximally dilute urine after a water load.

Potential mechanism:

Osmotic diuresis in the remaining nephrons

Severe hyponatremia is relatively uncommon when patients remain non-oliguric.

Risk increases as GFR approaches zero.

SYNDROME OF INAPPROPRIATE ADH SECRETION

Introduction

SIADH is:

Common

Associated with a wide range of clinical conditions

Characterized by nonphysiologic ADH activity

An unusual physiologic state in which water excretion is impaired while Na excretion remains relatively intact

See Table 23-3.

Pathogenesis

See Figure 23-3.

Ingested water is retained because of ADH-mediated effects on the kidney.

Yet patients generally do not develop edema because sodium remains in balance.

The combination of:

Water retention

Sodium excretion

…produces hyponatremia.

In chronic SIADH, sodium loss may become as important as or more important than the initial water retention.

Potassium Loss

Hyponatremia causes cellular swelling.

Cells adapt by ejecting intracellular solutes, including:

Potassium

The released potassium is subsequently excreted by the kidney.

Chronic Adaptation

A new steady state develops over approximately a couple of weeks.

At steady state:

Na intake = Na output

Contributing mechanisms include:

Relative ADH resistance

Reduced urine osmolality

Reduced aquaporin expression

Importantly, water ingestion remains essential. Without water intake, SIADH cannot produce hyponatremia.

Patterns of ADH Secretion in SIADH

Four patterns are described.

Type A — Erratic ADH Secretion

ADH secretion is essentially independent of osmotic regulation.

Type B — Reset Osmostat

ADH retains its normal relationship with plasma osmolality.

The entire relationship is shifted to a lower set point.

Serum Na is often relatively stable around 125–130 mEq/L.

Patients may appropriately dilute their urine in response to a water load once they reach their lower osmotic set point.

Type C — Failure to Completely Suppress ADH

ADH regulation appears normal around normal plasma osmolality.

But ADH cannot be completely suppressed when plasma osmolality falls.

Type D — Normal Measured ADH

Possible explanations:

Increased renal sensitivity to ADH

Another unidentified antidiuretic factor

Acid-Base and Potassium Balance in SIADH

Interesting question:

Why does Na become diluted without equivalent dilution of K or bicarbonate?

Potential mechanisms:

H moves into cells.

Renal H clearance increases.

ADH directly stimulates H secretion.

Dilutional hypokalemia is partly prevented by movement of intracellular K out of cells.

Hypokalemia can occur, particularly when plasma osmolality falls below approximately 240 mOsm/kg.

ETIOLOGY OF SIADH

SIADH can result from:

Increased hypothalamic ADH production

Ectopic ADH production

Potentiation of ADH’s renal effect

Exogenous ADH or related hormones

CNS / Neuropsychiatric Disease

Neuropsychiatric disorders can promote ADH release:

Directly

Through cortical neuronal pathways stimulating the hypothalamus

Examples:

Approximately 20% of patients with subarachnoid hemorrhage

Approximately 20–35% after transsphenoidal pituitary surgery

Adrenal insufficiency may contribute following pituitary surgery.

Psychiatric patients may have abnormalities at several levels:

Water intake

ADH secretion

Renal responsiveness to ADH

Again, much water intake is habitual rather than thirst-driven.

HIV

Hyponatremia has been reported in approximately 40% of patients with HIV infection.

Potential mechanisms include:

Volume depletion

Adrenal insufficiency

SIADH

Pneumocystis pneumonia

Malignancy

CNS disease

Drugs

Many drugs have been associated with SIADH, although most only rarely produce clinically significant hyponatremia.

Cyclophosphamide

Increases renal sensitivity to ADH.

Particularly associated with IV rather than oral administration.

Patients are often instructed to drink large quantities of water because of concern for hemorrhagic cystitis.

Severe and occasionally fatal hyponatremia has occurred.

Chlorpropamide

Oral hypoglycemic agent.

Increases NaCl reabsorption in the TAL.

Increases sensitivity to ADH.

NSAIDs

Increase the renal action of ADH.

Mechanism: inhibition of renal prostaglandin synthesis.

PGE normally antagonizes ADH activity.

NSAIDs alone rarely cause severe SIADH but can worsen pre-existing hyponatremia, particularly with concomitant volume depletion.

Pulmonary Disease

Associated conditions include:

Pneumonia

Asthma

Atelectasis

Emphysema

Pneumothorax

Tuberculosis

Acute respiratory failure

Possible mechanism:

Reduced pulmonary venous return may activate volume receptors.

Some patients therefore have a low urine sodium.

Reset osmostat has been described with tuberculosis.

Major Surgery

Transient SIADH may occur for 2–5 days after major surgery.

Pain afferents can directly stimulate hypothalamic ADH secretion.

Ectopic ADH Production

Classic association:

Small-cell carcinoma of the lung

Exogenous ADH and Oxytocin

Oxytocin:

Is synthesized by the hypothalamus.

Normally regulates uterine function and lactation.

Also possesses meaningful antidiuretic activity.

Administration during pregnancy has caused hyponatremic seizures in both mother and fetus.

Practical considerations:

Avoid administering large amounts in D5W.

Prefer isotonic saline when appropriate.

Limit unnecessary water intake.

Other ADH-related therapies mentioned:

Vasopressin for GI bleeding

DDAVP for:

Nocturia

Platelet dysfunction

Central diabetes insipidus

Idiopathic SIADH

Occasionally no cause is identified.

Consider:

Occult malignancy

Temporal arteritis

These patients may have low serum uric acid because of increased urinary uric acid clearance.

CEREBRAL SALT WASTING

Rare syndrome associated with cerebral disease, particularly:

Subarachnoid hemorrhage

Phenotype:

Hyponatremia

High urine Na

Low serum uric acid

Volume depletion

Volume depletion is the key proposed distinction from SIADH.

A theoretical factor released from the injured brain may cause:

Renal salt wasting

Uric acid wasting

BNP has been proposed as one candidate.

ADRENAL INSUFFICIENCY

Hyponatremia is common in adrenal insufficiency.

Separating the contributions of:

Cortisol deficiency

Volume depletion

…can be difficult.

Cortisol replacement can rapidly normalize serum sodium.

The mechanism appears strongly ADH-mediated because ADH antagonism can reverse the defect.

ADH is co-secreted with CRH. Cortisol normally provides negative feedback on both:

Cortisol ↓ → CRH ↑ → ADH ↑

HYPOTHYROIDISM

Hypothyroidism is often listed in the differential diagnosis of hyponatremia, but it is actually a rare cause of clinically significant hyponatremia.

RESET OSMOSTAT

Patients fulfill many criteria for SIADH but regulate osmolality around a lower set point.

Described in:

Hypovolemic states

Psychosis

Chronic malnutrition

Pregnancy

Possible mechanisms include:

Baroreceptor-mediated ADH stimulation

Altered cellular metabolism in malnutrition

Pregnancy-related hormonal effects

During pregnancy, hCG may promote release of ovarian relaxin.

Potential mechanisms:

Vasodilation → relative effective volume depletion

Direct effects on osmoreceptor regulation

PRIMARY POLYDIPSIA

Occurs in approximately 7% of patients with schizophrenia.

Clinical clues:

Weight gain during the day from water accumulation

Excessive water drinking

Dry mouth from medications

There may also be a central abnormality of thirst regulation, with the osmotic threshold for thirst shifted below the threshold for ADH release.

Examples:

Reported Na 84 mEq/L with Uosm 74 mOsm/kg

Symptomatic hyponatremia after drinking 3–4 L of water while anxiously awaiting a drug test

Severe cases often involve stacked etiologies:

Primary polydipsia

Thiazides

Antipsychotics

Nausea-induced ADH

Stress-induced ADH

Low-solute intake / beer potomania

PSEUDOHYPONATREMIA AND NON-HYPOOSMOLAR HYPONATREMIA

Normal Plasma Osmolality

Classic Pseudohyponatremia

Normally, approximately 930 mL of each liter of plasma is water.

With severe:

Hyperlipidemia

Hyperproteinemia

…plasma water may fall as low as approximately 720 mL/L.

The sodium concentration in the plasma water remains normal, but sodium expressed per liter of total plasma appears low.

Thus:

Measured serum Na is low.

Effective plasma osmolality remains normal.

Direct ion-selective electrodes can identify the true sodium concentration, while methods involving sample dilution may reproduce the artifact.

TURP / Hysteroscopy

Absorption of non-electrolyte irrigation solutions can produce complex abnormalities.

Probably historical enough to skip?

Hyponatremia With Increased Plasma Osmolality

Hyperglycemia

Interesting terminology issue: the chapter refers to hyperglycemia-associated hyponatremia as “pseudohyponatremia.”

The key point is that treatment should target the hyperglycemia, not the sodium concentration itself.

Traditional correction:

Na increases approximately 1.6 mEq/L for every 100 mg/dL fall in glucose.

At very high glucose concentrations, the correction may be closer to:

2.4 mEq/L per 100 mg/dL, particularly above glucose ~400 mg/dL.

Mannitol

Mannitol can cause hyperosmolar hyponatremia.

The amount of circulating mannitol can be estimated using the osmolar gap.

IVIG

Some IVIG preparations contain maltose, which can accumulate and contribute to hyperosmolar hyponatremia.

Roger’s Hydrogen to pH table

References

December 19, 2023

Joel had a patient with severe hypothyroidism and hyponatremia- case report

Mel reviewed the endocrine factors that can contribute to hyponatremia in this report (from the 2020 ASN quiz and questionnaire): Pattern Recognition versus Pathogenesis - PMC and amy shared this too: Impact of etiology, age and gender on onset and severity of hyponatremia in patients with hypopituitarism: retrospective analysis in a specialised endocrine unit

JC mentioned reports of sodium loss from biliary sodium as a cause of hyponatremia: Severe Persistent Hyponatremia: A Rare Presentation of Biliary Fluid Loss - PMC , Hyponatremia after Choledochostomy and T Tube Drainage  but here’s a reference that did measure biliary sodium concentration in children and found the concentration in bile was similar to plasma (which can lead to significant sodium losses! But not hyponatremia unless replete with dilute fluids ;) 10.1001/archpedi.1986.02140200045024

Here’s a set of articles by Tom Berl on hyponatremia- the first on solute intake and the second in setting of CKD (enjoy! These are really great!): Impact of solute intake on urine flow and water excretion (this figure is brilliant!) and  Dysnatremias in Patients With Kidney Disease - PMC  Especially enjoy Figure 6! (and check out notes from chapter 9 that review reduced ability to maximally dilute the urine in older individuals- plus here’s a few more great references on the aging kidney: THE AGING KIDNEY: PHYSIOLOGICAL CHANGES - PMC, Urine Concentrating and Diluting Ability During Aging - PMC , Aging and physiological changes of the kidneys including changes in glomerular filtration rate

We quickly referred to the Everest trial of tolvaptan in CHF and Anna shared the reference. 

Roger mentioned the weight gain that occurs in hyponatremia and marathon running: this study in the NEJM showed that the risk of hyponatremia was greatest in those with longer race times, more weight gain: https://www.nejm.org/doi/10.1056/NEJMoa043901

Amy’s VOG on Gastric Secretions

Dr. Boyer: https://medicine.yale.edu/profile/james-boyer/

Dr. Boyer’s review on his original work on bile salts: https://pmc.ncbi.nlm.nih.gov/articles/PMC4091928/ 

Gastric secretions

From 1961! https://pubmed.ncbi.nlm.nih.gov/13714620/

From 1959! https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/expphysiol.1960.sp001428

Secretions (2 book in PDF form)

Basic Concepts of Fluid and Electrolyte Therapy (see page 14) https://www.researchgate.net/publication/369203977_BASIC_CONCEPTS_OF_FLUID_AND_ELECTROLYTE_THERAPY_2nd_Edition

Basic Facts of Body Water and Ions (see page 96) https://link.springer.com/book/10.1007/978-3-662-38375-9

Chapter 23: Hypoosmolar States — Hyponatremia

PATHOPHYSIOLOGY

Plasma Sodium and Plasma Osmolality

Plasma sodium is the main determinant of plasma osmolality.

Hyponatremia = Na <135 mEq/L, which usually reflects hypoosmolality.

Why this matters:

Low plasma osmolality causes water to move into cells.

This cellular overhydration produces the symptoms of hyponatremia, particularly in the brain.

The Basic Mechanism of Hyponatremia

Two questions provide a useful framework:

How do patients develop hyponatremia?

Why do they remain hyponatremic?

Generation of Hyponatremia

Either solute loss (Na or K) or water retention can produce hyponatremia.

However, most fluid losses are approximately isoosmotic to plasma.

Isoosmotic fluid loss by itself is neutral with respect to plasma sodium.

It becomes a problem when the lost fluid is replaced with hypoosmotic fluid.

Thus, hyponatremia is usually fundamentally a disorder of water gain relative to solute.

Hypoosmolality generally cannot develop without water intake.

Perpetuation of Hyponatremia

The normal response to falling plasma osmolality is suppression of ADH.

Reduced ADH → dilute urine and increased water excretion.

ADH secretion progressively falls as plasma osmolality falls.

ADH secretion essentially ceases when:

Plasma osmolality falls below approximately 275 mOsm/kg, or

Serum Na approaches 135 mEq/L.

Figure 23-1 appears closer to 280 mOsm/kg.

With maximal ADH suppression:

Urine osmolality falls to approximately 40–100 mOsm/kg H₂O.

Specific gravity falls to approximately 1.001–1.003.

The kidney can potentially excrete >10 L/day of dilute urine.

Because the normal kidney can clear enormous quantities of free water, some defect in renal water excretion is generally required for hyponatremia to persist.

Major exception: primary polydipsia, where water intake overwhelms otherwise intact renal water excretion.

Requirements for Free-Water Excretion

Free-water excretion depends on two processes:

Generation of dilute tubular fluid

NaCl is reabsorbed without water in the diluting segments.

Primarily the thick ascending limb of the loop of Henle.

To a lesser degree, the distal tubule.

See Table 23-1.

Excretion of that dilute fluid

Requires the collecting tubules to remain relatively impermeable to water.

This requires suppression of ADH.

Failure of either process can reduce free-water clearance.

In almost every clinical case, the dominant problem is excess ADH activity, usually from:

SIADH

Decreased effective circulating volume

Important exceptions include:

Oliguric kidney failure

Primary polydipsia

Low-solute intake / “tea and toast” physiology? Not discussed here.

Using Urine Osmolality as an ADH Readout

Urine osmolality provides a functional assessment of ADH activity.

Uosm <100 mOsm/kg: ADH is appropriately suppressed.

Uosm >100 mOsm/kg: ADH effect is present.

In clinically significant ADH-mediated hyponatremia, Uosm is often >300 mOsm/kg.

Thought Experiment: It Doesn’t Take Much

Assume:

Daily solute load = 400 mOsm

Daily water intake = 2 L

If the kidney can dilute urine to 200 mOsm/kg:

400 mOsm ÷ 200 mOsm/kg = 2 L urine

All 2 L of ingested water can be excreted.

But if minimum urine osmolality rises only slightly to 220 mOsm/kg:

400 ÷ 220 = 1.8 L urine

That leaves approximately 200 mL/day of retained water.

Over days or weeks, even this modest impairment can produce progressive hyponatremia.

Why doesn’t suppression of thirst protect the patient?

Because much of human water consumption is habitual, social, or cultural rather than driven strictly by osmotic thirst.

ETIOLOGY

See Table 23-2.

The disorders in which water excretion is impaired are much more important causes of hyponatremia than disorders in which water excretion remains normal.

Effective Circulating Volume Depletion

Effective circulating volume refers to the fluid that is effectively perfusing tissues.

It may be reduced in patients with either decreased or increased total extracellular volume.

True Volume Depletion

Loss of both:

Intravascular fluid

Interstitial fluid

Potential sources:

GI tract

Kidneys

Skin

Other Causes of Reduced Effective Circulating Volume

Decreased vascular resistance

Example: advanced liver disease

Reduced cardiac output

Example: heart failure

Why Effective Volume Depletion Causes Hyponatremia

Effective volume depletion affects:

Thirst

Potassium balance

Water excretion

ADH

Hypovolemia sensed through arterial baroreceptors is a potent non-osmotic stimulus for ADH secretion.

Reduced Delivery to the Diluting Segments

Volume depletion can also cause:

Reduced GFR

Increased proximal Na reabsorption

Reduced fluid delivery to the diluting segments

This theoretically reduces free-water generation even without ADH.

However, how important is this mechanism?

ADH antagonists can largely reverse impaired water excretion in:

Heart failure

Cirrhosis

Adrenal insufficiency

…without necessarily improving tissue perfusion.

That argues that ADH is doing much of the work.

Severity of Disease Matters

The tendency toward increased ADH and reduced distal delivery increases with the severity of effective volume depletion.

Thus:

Worse heart failure → greater risk of hyponatremia

Worse cirrhosis → greater risk of hyponatremia

Hyponatremia generally does not occur until disease is relatively advanced.

In heart failure, even Na <137 mEq/L is associated with reduced survival.

A seemingly minor reduction in sodium may therefore reflect a major impairment in renal water excretion.

Water Intake Still Matters

The severity of hyponatremia is strongly influenced by how much water the patient consumes.

Ultramarathoners

May lose 10–14 L of sweat.

Sweat contains approximately 20–100 mEq/L of Na + K.

Replacement fluids may contain carbohydrates but relatively little solute.

Symptomatic hyponatremia can develop.

Serum Na may fall below 120 mEq/L.

Cholera

Severe diarrhea from cholera may contain:

Stool Na approximately 120–140 mEq/L.

Low-solute replacement solutions increase the risk of hyponatremia.

Concurrent Potassium Depletion

Potassium depletion can worsen hyponatremia.

K leaves cells to replenish extracellular potassium.

Electroneutrality is partly maintained by Na moving into cells.

This lowers extracellular Na concentration.

Normally, falling plasma osmolality would suppress ADH and permit water excretion.

If ADH remains elevated because of volume depletion, this compensatory mechanism is blocked.

Giving KCl alone can therefore partially correct hyponatremia by reversing the transcellular cation exchange.

Hard to believe Edelman isn’t invoked here.

References

This is the famous Edelman equation from JCI in 1958 by Isodore Edelman! Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water (not to be confused by Isildur House of Isildur - Tolkien Gateway

Joel mentioned his slide deck on Edelman: https://pbfluids.com/wp-content/uploads/2023/04/QN_III-The-Edelman-Equation-full-lecture-from-2020-07-30.pdf

This is an excellent review (with great figures) on Osmotic homeostasis by Danziger and Zeidel in CJASN 

Joel and JC mentioned the work from Joseph Verbalis on hyponatremia- this is an excellent review that includes population data from NHANES plus striking images of the osteopenic bones in hyponatremic rats! Check this out! Hyponatremia‐induced osteoporosis - Verbalis - 2010 - Journal of Bone and Mineral Research - Wiley Online Library

Joel and JC mentioned “reference 2” from the chapter by Kleeman and others on diuretic induced hyponatremia which invoked hypokalemia as an important player: Diuretic-Induced Hyponatremia | Annals of Internal Medicine

We couldn't help flirting with diarrhea a little Secretory diarrhoea: mechanisms and emerging therapies - PMC

We talked about cravings for those with salt losses and here’s one example Gitelman syndrome in a South African family presenting with hypokalaemia and unusual food cravings - PMC

PBFluids classic: Saltiest Sodium. Dumbest Dude

Volume Depletion versus Dehydration: How Understanding the Difference Can Guide Therapy here’s one of many articles that argues for choosing language wisely. 

Amy’s VOG references:

PMC3041494

42321668

41846300

42195166

33374011 

PMC3041494

PMC12884999

3102222 

42060832 

41201721 

32401639 

Link to Goljian Physiology Spotify! Episode 2 is Fluid and Hemodynamics: https://open.spotify.com/show/1uD6090Kkg01b4zr2ouNiM?si=e7f609e0d9634840

Outline: Chapter 22

Introduction to Disorders of Osmolality

Hyponatremia and hypernatremia are common clinical problems

Reflect abnormalities of water balance that may or may not be accompanied by changes in Na balance

Water Distribution and Osmotic Pressure

TBW makes up 60% of lean body weight in men

50% of lean body weight in women

60% intracellular

40% extracellular

One-fifth of extracellular water is in the intravascular space

Breakdown

70 kg man

TBW = 42 L

25 L intracellular

17 L extracellular

3 L of the 17 L is intravascular

Osmotic forces determine the distribution of water

Each compartment has one major solute that holds water within the compartment

Na → extracellular compartment

K → intracellular compartment

Plasma proteins → plasma space

Urea is an ineffective osmole

Physiologic Effects of Changes in Plasma Osmolality

Figure 22-1

Na pulls water from the intracellular compartment

Increases extracellular volume

Decreases intracellular volume

Even though Na is locked in the extracellular compartment

Administering Na increases osmolality everywhere by changing water distribution

Increases extracellular volume

Decreases intracellular volume

Example

Adding 210 mEq Na to 17 L ECF would mathematically increase concentration by 12.5 mEq/L (210/17)

Actually only raises serum Na by ~5

Water moves from cells

Na remains trapped in ECF

Ultimately diluted in TBW

210/42 L = 5 mEq/L

Adding water

Expands both compartments

Dilutes osmolality in both compartments

Giving isotonic saline

Expands extracellular compartment only

Does not change intracellular volume

Changes in osmolality and intracellular volume

Responsible for symptoms of hypo- and hypernatremia

In these examples

Extracellular volume is increased

Sodium concentration may be high, low, or normal

Meaning of Plasma Sodium Concentration

Na, glucose, and urea are the primary extracellular osmoles

Gives osmolality calculation

Under normal conditions

Glucose and BUN contribute <10 mOsm/L

Therefore

Plasma osmolality ≈ 2 × plasma Na

Hypernatremia represents hyperosmolality

Hyponatremia usually reflects hypo-osmolality

Exception: hyperglycemia

Plasma Sodium Concentration and Total Body Osmolality

If plasma Na reflects plasma osmolality

And plasma osmolality is in equilibrium with total body osmolality

Then plasma Na reflects total body osmolality

Since

Total body osmolality = (ECF solutes + ICF solutes) / TBW

And

Na and K (plus accompanying anions) are the major extracellular and intracellular solutes

Then

Plasma Na ≈ (Na + K) / TBW

Figure 22-2

Key Edelman figure

Loss of potassium

K moves out of cells

To maintain electroneutrality

Na enters cells

Lowers serum Na

Or Cl leaves with K

Lowers intracellular osmolality

Water moves from cells to ECF

Dilutes serum Na

Or extracellular H dissociates from buffers and enters cells

Combines with intracellular buffers

No net movement of solute

Water still leaves cells

Serum Na diluted

Suggests K loss is responsible for much diuretic-induced hyponatremia (Ref 2)

DKA example

0.45% NS with 40 mEq KCl is insufficient to correct hyperosmolality

Hyponatremia and Hypernatremia

Can result from alterations in

Na

K

Water

Usually due to water abnormalities

Exception

Thiazides

Loss of both Na and K contributes

Toxicity of K prevents excess K from producing hypernatremia

Diarrhea

Isosmotic to plasma

Ionic composition varies

Secretory diarrhea (cholera)

Na + K approximately equals plasma Na

Causes volume depletion

Does not cause hypernatremia

Osmotic diarrhea

Fecal Na + K between 30 and 110

Nonreabsorbed solutes account for remainder

Causes hypernatremia

Diarrheal illness

Often causes fever

Increases insensible losses

Also stimulates ADH and thirst

Usually water balance remains near normal

Infants commonly become hypernatremic

Regulation of Plasma Osmolality

Daily variation in water intake and loss alters plasma osmolality

Water intake

Drinking

Water content of food

Water of oxidation

Carbohydrates metabolized to CO2 and H2O

Water retention lowers plasma osmolality

Water loss

Urine

Feces

Skin

Respiratory tract

Water loss raises plasma osmolality

Water intake and excretion are tightly regulated

Osmoreceptors in hypothalamus

After water load

Plasma osmolality falls

ADH release inhibited

Urinary water loss increases

Hyperosmolality

Stimulates thirst

Stimulates ADH

Increases water intake

Decreases water loss

Regulation disrupted by

Neurologic disorders

Hypothalamus

Posterior pituitary

Renal disorders

Impaired concentrating or diluting ability

Nonosmotic stimuli

Volume depletion

Osmoregulation versus Volume Regulation

Table 22-2

Plasma osmolality

Ratio of solute to water

Extracellular volume

Determined by absolute amount of Na and water

Two examples

Exercising on a hot day

Loss of dilute sweat

↑ Plasma osmolality (Na)

↓ Extracellular volume

SIADH

↓ Plasma osmolality (Na)

↑ Extracellular volume

Nice exercise at bottom of page 691

Isotonic saline

Does not change osmolality

Hypothalamus not activated

Increased volume suppresses renin

Increases ANP

Water load

Inhibits ADH

Produces dilute urine

Rapid restoration of volume

Only transient volume expansion

Little effect on renin or ANP

NaCl without water

Expands extracellular volume

Stimulates renal NaCl loss

Also stimulates thirst and ADH

Produces small volume of concentrated urine

Similar to intake

Volume Depletion versus Dehydration

They are not synonyms

Urine Osmolality and Specific Gravity

Relation Between Intake and Output

Simply comparing ins and outs is inadequate

Composition of fluids may differ markedly

Replacing urinary losses with free water

Produces hyponatremia

References

Biff Palmer! Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023

Josh what is sensed- pCO2 or pH and some exploration suggests that it is not settled! Sensing, physiological effects and molecular response to elevated CO2 levels in eukaryotes - PMC and this one with catchy title: Out of thin air: Sensory detection of oxygen and carbon dioxide - PMC

If anna does VOG on Haldane- we’ll need references 

The Response of Extracellular Hydrogen Ion Concentration to Graded Degrees of Chronic Hypercapnia: The Physiologic Limits of the Defense of pH - PMC (this is the correct reference for figure 20-3 reference). 

JC shared some info from Dr. Adrogue 

Josh mentioned potential differences between people with respect to oxygen sensors and this study of sherpas: [Association of polymorphisms of 1772 (C-->T) and 1790 (G-->A) in HIF1A gene with hypoxia adaptation in high altitude in Sherpas] and this excellent review: Sensing hypoxia: physiology, genetics and epigenetics - PMC

VOG from Amy on renal failure with respiratory acidosis https://pubmed.ncbi.nlm.nih.gov/38936337/

Joel and Roger mention these two perspectives on alkali therapy for respiratory acidosis the first from Adrogué and Madias, the second from David Goldfarb: Alkali Therapy for Respiratory Acidosis: A Medical Controversy - American Journal of Kidney Diseases
Sodium bicarbonate therapy for acute respiratory acidosis

Joel mentioned this paper: https://www.nejm.org/doi/pdf/10.1056/NEJM196607212750301 the “carbon dioxide response curve for chronic hypercapnia in man by Bracket, Wingo et al. NEJM 1969 

Josh mentioned a study in female ewes that showed a chloride excretion. Acute renal response to rapid onset respiratory acidosis and followed up with this: No renal dysfunction or salt and water retention in acute mountain sickness at 4,559 m among young resting males after passive ascent

This was also studied by Pitts and Giebisch and others: THE EXTRARENAL RESPONSE TO ACUTE ACID-BASE DISTURBANCES OF RESPIRATORY ORIGIN - PMC giebisch and Pitts (the original paper says “with the technical assistance of mary ellen parks and martha MacLeod but on the JCI website, they remedied this and made Parks and MacLeod authors) 

Joel mentioned the negative Diablo trial Effect of Acetazolamide vs Placebo on Duration of Invasive Mechanical Ventilation Among Patients With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial

Outline: Chapter 20

Respiratory Acidosis

Clinical disorder characterized by

Reduced arterial pH

Elevation of pCO2

Variable increase in HCO3

Increased pCO2 is also seen in metabolic alkalosis

But here it is appropriate

And secondary

PATHOPHYSIOLOGY AND ETIOLOGY

Metabolism generates 15,000 mmol of CO2 per day

CO2 is not an acid, but

Combines with H2O to form H2CO3

H2CO3 dissociates to HCO3 and H+

Most H+ combines with intracellular buffers

Hemoglobin in RBCs

HCO3 leaves the cell via the chloride exchanger

Net result

CO2 generated is primarily carried in blood as HCO3

Little change in pH

Process reverses in the alveoli

As H+Hb is oxygenated, H+ is released

H+ combines with HCO3 to form H2CO3

Carbonic anhydrase breaks H2CO3 into H2O and CO2

CO2 is exhaled

Control of Ventilation

Alveolar ventilation

Provides oxygen for oxidative metabolism

Eliminates metabolically produced CO2

Main stimuli for respiration

Reduced arterial pO2

Increased pCO2

Controlled in chemosensitive areas of the medulla

Respond to CO2-induced changes in cerebral pH

Initial hypoxic stimulation comes from carotid body chemoreceptors

Figure 20-1 is wild

pCO2 is maintained within narrow limits despite

Large daily CO2 load

Variable respiratory quotient

Variable metabolic rate

Minute ventilation rises 1–4 liters for every 1 mmHg rise in pCO2

pO2 does not significantly stimulate ventilation until arterial pO2 <50–60 mmHg

Actually starts earlier

Increased ventilation lowers pCO2 which inhibits respiration

If pCO2 is fixed, pO2 of 70–80 mmHg will stimulate respiration

Figure 20-2

Development of Hypercapnia

Because CO2 is such a potent respiratory stimulant

Respiratory acidosis is usually due to decreased minute ventilation

Not increased CO2 production

Table 20-1 lists causes

CO2 retention in intrinsic pulmonary disease

Due to ventilation/perfusion mismatch

Hypercapnia is beneficial

Allows excretion of produced CO2 at lower minute ventilation

Consequences

Increased pCO2 decreases pH

Increased bone and cellular buffering

Increased renal H secretion

Raises serum HCO3

Relationship Between Hypercapnia and Hypoxemia

All hypercapnic patients breathing room air have lower alveolar and arterial pO2

Total alveolar partial pressures must equal atmospheric pressure

Hypoxemia generally occurs earlier and is more severe than hypercapnia

CO2 diffuses 20× faster than O2

Compensation by increasing ventilation in normal lung segments

Improves CO2 elimination

Cannot substantially increase O2 because Hb already saturated

Acute asthma example

Mucus plugging and bronchoconstriction cause hypoxemia

Hypoxemia and mechanoreceptors stimulate ventilation

Produces respiratory alkalosis

Respiratory acidosis is a late finding

Respiratory resistance rises

Maximal minute ventilation falls

pCO2 rises

First normalizes

Then becomes elevated

Therefore

Normal pCO2 in acute asthma indicates severe disease

Generalization to other lung diseases

Even small increases in pCO2 indicate severe respiratory disease

Hypoxemia-induced hyperventilation delays hypercapnia

But there is 16-fold variability in sensitivity to hypoxemia

Less sensitive individuals develop respiratory acidosis more readily

Regulation of Ventilation in Chronic Respiratory Acidosis

Two common statements

Respiratory centers become less sensitive to CO2 over time

Hypoxia becomes the primary respiratory stimulus

Insensitivity to CO2

Chemoreceptors primarily respond to pH

Chronic respiratory acidosis increases HCO3

Therefore less pH change despite elevated pCO2

Less respiratory stimulation

Worsening hypercapnia and hypoxia

Similarly

Diuretic-induced metabolic alkalosis suppresses ventilation

Dependence on hypoxemia

Patients with chronic respiratory acidosis rely on hypoxia to drive breathing

Loss of CO2 stimulation due to

Renal compensation raising HCO3

Diuretics raising HCO3

Making pH less dependent on pCO2

Hypoxia drives ventilation when pO2 falls below ~80

Makes oxygen administration potentially dangerous

Can suppress respiratory drive

Oxygen also reverses hypoxic vasoconstriction

Increases V/Q mismatch

Acute Respiratory Acidosis

Body poorly adapted to acute elevations in pCO2

HCO3 cannot buffer H2CO3

See Eq 20-4

Must use hemoglobin and proteins as buffers

See Eq 20-5

HCO3 rises 1 mEq/L for every 10 mmHg increase in pCO2

Example

pCO2 rises to 80

HCO3 rises to 28

pH falls to 7.17

Without buffering

pH would be 7.10

Not dramatically different

Etiology

Acute exacerbations of lung disease

Severe asthma

Pulmonary edema

Drug overdose

Sleep apnea syndromes

Central

Obstructive

Mixed

Chronic hypercapnia uncommon in isolated OSA

CO2 cleared during wakefulness

OSA + structural lung disease + obesity

Reduced daily alveolar ventilation

Persistent CO2 retention

Obesity hypoventilation syndrome

Mechanical ventilation

Inadequate respiratory rate can cause respiratory acidosis

Fixed ventilation means increased CO2 production can cause respiratory acidosis

Cardiac arrest

Suggests sodium bicarbonate

Arterial ABG may miss severity due to poor pulmonary blood flow

Mixed venous blood may be better guide

Enteral or parenteral overfeeding

Chronic Respiratory Acidosis

After 3–5 days

HCO3 rises 3.5 mEq/L for every 10 mmHg rise in pCO2

Example

pCO2 = 80

4 × 3.5 = 14

HCO3 should be 38

pH ~7.30

Allows tolerance of pCO2 values of 90–110

Exogenous alkali

Unnecessary

Useless

Easily excreted

Etiology

COPD

Genetic variation in sensitivity to hypoxemia and CO2

Blue bloaters

Low response to CO2

Hypoxia becomes primary respiratory stimulus

Pink puffers

Strong CO2 response

Tachypnea develops early

Compensation for loss of lung tissue

Pickwickian syndrome

Obesity hypoventilation syndrome

Book mistakenly says hyperventilation

Chest wall weight impairs breathing

More complex than that

Weight loss only helps some patients

Progesterone can improve condition

Suggests central respiratory defect

May coexist with OSA

Unlike OSA, Pickwickian patients have chronic respiratory acidosis

SYMPTOMS

Neurologic

Headache

Blurred vision

Restlessness

Anxiety

Can progress to

Somnolence (CO2 narcosis)

Tremor

Asterixis

Delirium

Increased CSF pressure

Papilledema

Due to increased cerebral blood flow

Symptoms due to CSF acidemia

Less common in metabolic acidosis

HCO3 crosses BBB poorly

Less common in chronic respiratory acidosis

Less severe acidemia

Arrhythmias

Peripheral vasodilation

Hypotension

Particularly when pH <7.1

Cor pulmonale

Peripheral edema

Can occur despite normal GFR

Suggests relationship between respiratory acidosis and renal sodium handling

Or possibly hypoxia

DIAGNOSIS

Last full paragraph on page 659 discusses ambiguity of ABGs

Nicely done

Figure 20-6

Two additional examples

Both instructive

Final sentence

“In summary, the confidence bands are useful guides in the interpretation of acid-base measurements. However, this interpretation cannot proceed in a vacuum and must be correlated with a complete history and physical examination.”

Use of the Alveolar-Arterial Oxygen Gradient

Derivation

1 atmosphere = 760 mmHg

Water vapor = 47 mmHg

Nitrogen = 563 mmHg

Leaves ~150 mmHg oxygen

No net movement of water or nitrogen

Therefore O2 + CO2 must account for remaining pressure

PAO2 = PIO2 − PACO2

Must multiply CO2 by 1.25 to account for respiratory quotient

PAO2 = PIO2 − (1.25 × PACO2)

Since CO2 diffuses rapidly

PACO2 ≈ PaCO2

Normal values

PIO2 = 150

PaCO2 = 40

PAO2 = 150 − (1.25 × 40)

PAO2 = 100

Normal A-a gradient

5–10 mmHg in young adults

15–20 mmHg in elderly

A-a gradient = PAO2 − PaO2

Combined equation

A-a gradient = PIO2 − (1.25 × PaCO2) − PaO2

A-a gradient increased in intrinsic pulmonary disease

Oxygen has difficulty entering blood

May also be increased in some extrapulmonary disorders

No explanation given

Normal A-a gradient argues against pulmonary disease

Suggests

Central hypoventilation

Primary metabolic alkalosis

Chest wall weakness

Respiratory muscle weakness

TREATMENT

Complete discussion beyond scope of text

Acute Respiratory Acidosis

Give oxygen for hypoxia

Correct underlying cause of hypercapnia

Or intubate

Sodium bicarbonate

Role not well defined

May help if pH <7.15

Especially severe asthmatics on ventilators

Avoid in

Pulmonary edema

Can worsen congestion

CNS effects

Does not protect CNS because HCO3 does not cross BBB

Increased pCO2

Must monitor mixed venous pH

Late metabolic alkalosis

Rare according to author

Tromethamine (THAM)

Binds hydrogen

Rapidly cleared by kidneys

“THAM is of uncertain safety”

Chronic Respiratory Acidosis

Goals

Adequate oxygenation

Improve effective alveolar ventilation if possible

Rarely need to treat pH directly

Beware oxygen

Can act as respiratory depressant

Dietary modifications

Reduce carbohydrates

Improves respiratory drive for unclear reasons

Weight reduction

Improves respiratory mechanics

Target pO2 60–65

Reduces pulmonary vasoconstriction

Reduces secondary polycythemia

Mechanical ventilation

Lower pCO2 gradually

Rapid correction can induce metabolic alkalosis

Seizures

Coma

Effect of superimposed metabolic alkalosis

Metabolic alkalosis depresses ventilation

Discontinue diuretics

Give saline

Acetazolamide

Acetazolamide caveats

Need appropriate bicarbonate target, not normal

Can transiently increase pCO2 before diuretic effect

May be due to partial inhibition of carbonic anhydrase in RBCs needed for CO2 carrying capacity

References

Chapter 19, Part 3 August 30, 2023Biff Palmer’s Ted Talk-Why not? Biff Palmer at TEDxSMU 2013

Anna mentioned this issue of lactic acidosis in a panic disorder: The Lactic Acid Response to Alkalosis in Panic Disorder | The Journal of Neuropsychiatry and Clinical Neurosciences

Reminder of important clinical lesson: Lactate: panicking doctor or panicking patient? - PMC

Melanie regaled the group with an excerpt (page 351) Cohen, J. J., Kassirer, J. P. (1982). Acid-base. United States: Little, Brown.

Biff Palmer! Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023

Melanie loves this study of chronic respiratory alkalosis on participants to traveled to the High ALpine research station on the Jungfraujoch in the Swiss Alps Chronic Respiratory Alkalosis — The Effect of Sustained Hyperventilation on Renal Regulation of Acid–Base Equilibrium | NEJM (and here’s a great picture: Services: Jungfraujoch Research Station - Climate and Environmental Physics (CEP)

JC mentioned that there are cells in the carotid body which are called glomus cells Neurobiology of the carotid body.

JC discussed respiratory alkalosis in cirrhosis and here’s a review he had melanie write that addresses this topic: Acid Base Disorders in Cirrhosis - Advances in Kidney Disease and Health and here are some reviews he likes: The hyperventilation of cirrhosis: progesterone and estradiol effects and Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunction and Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction Proteins

The finding of respiratory alkalosis in pregnancy is not a new concept. Here’s a study from 1962: Acid-base balance of arterial blood during pregnancy, at delivery, and in the puerperium - American Journal of Obstetrics & Gynecology

Melanie reminded us of the Charlie Brown sad face that occurs after bicarbonate infusion and delay in bicarbonate movement to the CSF! Spinal-Fluid pH and Neurologic Symptoms in Systemic Acidosis | NEJM (part 2 of chapter 11)

Josh mentioned this report from Andrew Tarulli (a great neurologist previously at BIDMC who has moved to Overlook Hospital in NJ) Central Neurogenic Hyperventilation: A Case Report and Discussion of Pathophysiology | Allergy and Clinical Immunology | JAMA Neurology

He also mentioned this important transporters that affect the pH. The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates mouse cerebrospinal fluid pH

Refractory Central Neurogenic Hyperventilation: A Novel Approach Utilizing Mechanical Dead Space

Outline: Chapter 21

Respiratory Alkalosis

Increased pH, low pCO2, variable reduction in HCO3

Differentiate from metabolic acidosis where pH is decreased

(but pCO2 and HCO3 are likewise decreased)

PATHOPHYSIOLOGY

Primary decrease in pCO2 when effective alveolar ventilation is increased beyond that needed to eliminate daily CO2 production

How does the body respond to hypocapnia

Mass action

Reduction in H+ induced by hypocapnia can be minimized by lowering HCO3

One: rapid cell buffering

Two: later decrease in net renal acid secretion → lower HCO3

These two strategies explain the difference between acute and chronic respiratory alkalosis

Acute Respiratory Alkalosis

Within 10 minutes, H ions move into extracellular fluid

H+ combines with HCO3 → fall in plasma HCO3

Converted to CO2 and H2O

H+ comes from intracellular buffers

Protein, phosphate, hemoglobin

H+ may also come from alkalemia-induced increase in cellular lactic acid production (1)⁉️

Enough H+ enters ECF to lower HCO3 by 2 mEq for each 10 mmHg decrease in pCO2 (Fig 20-3)

Example: pCO2 falls to 20

HCO3 falls by 4 → ~20 mEq/L

pH ~7.63

Not very efficient at protecting pH

Without compensation pH would be ~7.70

Chronic Respiratory Alkalosis

Compensatory ↓ renal H secretion

Begins within 2 hours

Not complete for 2–3 days

Due to parallel rise in tubular cell pH

Manifested by

HCO3 loss

Decreased NH4 in urine

4 mEq drop in HCO3 for each 10 mmHg decrease in pCO2

Example: pCO2 20 → HCO3 16 → pH ~7.53

ETIOLOGY

Respiration governed by two sets of chemoreceptors

Central (respiratory center in brainstem)

Peripheral (carotid bodies at bifurcation, aortic bodies at arch)

Central chemoreceptors

Stimulated by ↑ pCO2 or metabolic acidosis

Peripheral chemoreceptors

Stimulated by hypoxia (and acidosis)

Thus hyperventilation can be produced by

Hypoxemia

Anemia

Reduction in arterial pH

Other stimuli

Pain

Anxiety

Mechanoreceptors

Direct stimulation of respiratory center

Table 21-1

Hypoxemia

Respiratory response occurs in stages

Stage 1

Peripheral chemoreceptor activation

Hyperventilation → respiratory alkalosis

Increased cerebral pH inhibits central respiratory center

Limits hyperventilation

No significant hyperventilation until pO2 < 50–60 mmHg

If lung disease prevents pCO2 reduction

Hypoxia stimulates ventilation at PaO2 < 70–80 mmHg

Stage 2⁉️

Persistent hypoxemia → ↓ HCO3

Lowers pH toward normal

Removes alkalosis inhibition

Allows greater ventilatory response

Pulmonary Disease

Common in pneumonia, PE, interstitial fibrosis

Also pulmonary edema (though acidosis more common)

Hyperventilation may be due to hypoxemia

Often not corrected by oxygen

Other contributors

Mechanoreceptors in airways, lungs, chest wall

Signals via vagus nerve

Juxtacapillary receptors (interstitium)

Irritant receptors (epithelium)

Activated by inflammation or inhaled irritants

(asthma, pneumonia)

These contribute to dyspnea even without hypoxia

Direct Stimulation of Medullary Respiratory Center

Cortical input (psychogenic hyperventilation)

Retained amines in hepatic failure (not prostaglandins⁉️)

Bacterial toxins (gram-negative sepsis)

Salicylates

Progesterone (pregnancy, luteal phase)

Persistent acid CSF after rapid correction of metabolic acidosis

NaHCO3 raises extracellular pH

Peripheral chemoreceptors reduce ventilation → ↑ pCO2

CO2 crosses BBB rapidly, HCO3 does not

Brain senses ↑ pCO2 → ↓ CSF pH

Paradoxical prolongation of hyperventilation

Neurologic disorders

Pontine tumors → local acidosis → ↓ CSF pH → ↑ ventilation

Hypocapnia in acute cerebral accidents

Mechanical Ventilation

Overventilation can cause respiratory alkalosis

Correct by

Increasing dead space (no explanation given 🤷🏻‍♂️)

Decreasing tidal volume

Decreasing respiratory rate

SYMPTOMS

Due to increased CNS and peripheral nerve excitability

Lightheadedness

Altered consciousness

Paresthesias (extremities, circumoral)

Cramps

Carpopedal spasm

Syncope

Cardiac

Supraventricular and ventricular arrhythmias

Mechanisms

Impaired cerebral function

Increased membrane excitability

↓ cerebral blood flow

35–40% reduction if pCO2 drops by 20 mmHg

Psychogenic hyperventilation symptoms

Dyspnea

Headache

Chest pain

Symptoms more prominent in acute disease (rapid pH change)

Electrolytes

↓ phosphate (as low as 0.5–1.5 mg/dL)

Due to intracellular shift

Increased glycolysis → ↑ phosphorylated compounds

DIAGNOSIS

Tachypnea

But could be acidosis or alkalosis

Consider sepsis

Compensation equations can be ambiguous

Example: 7.48 / 20 / XX / 16

Could be chronic respiratory alkalosis

Or acute respiratory alkalosis + metabolic acidosis 😖

Case 21-1

5-year-old with AMS, playing with aspirin

TREATMENT

Usually not necessary

Do NOT give

Respiratory depressants

HCl

Paper bag rebreathing

↑ inspired CO2

Can correct acute respiratory alkalosis

If chronic → may leave patient with metabolic acidosis

Can treat with NaHCO3

“Give a mouse a cookie” 😉

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