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NephJC Fall Pledge Drive 2026
mercredi 23 septembre 2026 • Durée 03:35
Chapter Twenty-Three: Hypoosmolal States–Hyponatremia part 2 of 3
Saison 1 · Épisode 34
vendredi 18 septembre 2026 • Durée 01:37:50
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: 10.7326/0003-4819-126-1-199701010-00003 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.
Lire plus Réduire Chapter Twenty-Three: Hypoosmolal States–Hyponatremia
Saison 1 · Épisode 34
dimanche 16 août 2026 • Durée 01:37:50
Chapter Twenty-Two: Introduction to Disorders of Osmolality
Saison 1 · Épisode 33
lundi 29 juin 2026 • Durée 01:09:33
Chapter Twenty: Respiratory Acidosis
Saison 1 · Épisode 32
mercredi 3 juin 2026 • Durée 01:44:54
Chapter Twenty One: Respiratory Alkalosis
Saison 1 · Épisode 31
mardi 24 mars 2026 • Durée 01:06:52
Chapter Nineteen: Metabolic Acidosis, part 3
Saison 1 · Épisode 30
dimanche 22 février 2026 • Durée 01:57:58
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
Chapter Nineteen: Metabolic Acidosis, part 2
Saison 1 · Épisode 29
samedi 11 octobre 2025 • Durée 01:45:11
Chapter Eighteen: Metabolic Alkalosis, part 2
Saison 1 · Épisode 27
mardi 22 juillet 2025 • Durée 01:39:59
Chapter Nineteen: Metabolic Acidosis, The Show, part 1
Saison 1 · Épisode 28
lundi 2 juin 2025 • Durée 01:45:11
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:
,
,
We quickly referred to the Everes t 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’s review on his original work on bile salts: https://pmc.ncbi.nlm.nih.gov/articles/PMC4091928/
Secretions (2 book in PDF form)
Chapter 23: Hypoosmolar States — Hyponatremia
Plasma Sodium and Plasma Osmolality
Plasma sodium is the main determinant of plasma osmolality.
Hyponatremia = Na <135 mEq/L , which usually reflects hypoosmolality.
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 .
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:
Decreased effective circulating volume
Important exceptions include:
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
Daily solute load = 400 mOsm
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 :
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.
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.
Other Causes of Reduced Effective Circulating Volume
Decreased vascular resistance
Example: advanced liver disease
Why Effective Volume Depletion Causes Hyponatremia
Effective volume depletion affects:
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:
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:
…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.
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.
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 .
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.
Lire plus Réduire
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
One-fifth of extracellular water is in the intravascular space
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
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
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
Na remains trapped in ECF
Ultimately diluted in TBW
Expands both compartments
Dilutes osmolality in both compartments
Expands extracellular compartment only
Does not change intracellular volume
Changes in osmolality and intracellular volume
Responsible for symptoms of hypo- and hypernatremia
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
Glucose and BUN contribute <10 mOsm/L
Plasma osmolality ≈ 2 × plasma Na
Hypernatremia represents hyperosmolality
Hyponatremia usually reflects hypo-osmolality
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
Total body osmolality = (ECF solutes + ICF solutes) / TBW
Na and K (plus accompanying anions) are the major extracellular and intracellular solutes
Plasma Na ≈ (Na + K) / TBW
To maintain electroneutrality
Lowers intracellular osmolality
Water moves from cells to ECF
Or extracellular H dissociates from buffers and enters cells
Combines with intracellular buffers
No net movement of solute
Suggests K loss is responsible for much diuretic-induced hyponatremia (Ref 2)
0.45% NS with 40 mEq KCl is insufficient to correct hyperosmolality
Hyponatremia and Hypernatremia
Can result from alterations in
Usually due to water abnormalities
Loss of both Na and K contributes
Toxicity of K prevents excess K from producing hypernatremia
Secretory diarrhea (cholera)
Na + K approximately equals plasma Na
Does not cause hypernatremia
Fecal Na + K between 30 and 110
Nonreabsorbed solutes account for remainder
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
Carbohydrates metabolized to CO2 and H2O
Water retention lowers plasma osmolality
Water loss raises plasma osmolality
Water intake and excretion are tightly regulated
Osmoreceptors in hypothalamus
Urinary water loss increases
Impaired concentrating or diluting ability
Osmoregulation versus Volume Regulation
Determined by absolute amount of Na and water
Nice exercise at bottom of page 691
Does not change osmolality
Hypothalamus not activated
Increased volume suppresses renin
Rapid restoration of volume
Only transient volume expansion
Little effect on renin or ANP
Expands extracellular volume
Stimulates renal NaCl loss
Also stimulates thirst and ADH
Produces small volume of concentrated urine
Volume Depletion versus Dehydration
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
Lire plus Réduire
Clinical disorder characterized by
Variable increase in HCO3
Increased pCO2 is also seen in metabolic alkalosis
But here it is appropriate
PATHOPHYSIOLOGY AND ETIOLOGY
Metabolism generates 15,000 mmol of CO2 per day
Combines with H2O to form H2CO3
H2CO3 dissociates to HCO3 and H+
Most H+ combines with intracellular buffers
HCO3 leaves the cell via the chloride exchanger
CO2 generated is primarily carried in blood as HCO3
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
Provides oxygen for oxidative metabolism
Eliminates metabolically produced CO2
Main stimuli for respiration
Controlled in chemosensitive areas of the medulla
Respond to CO2-induced changes in cerebral pH
Initial hypoxic stimulation comes from carotid body chemoreceptors
pCO2 is maintained within narrow limits despite
Variable respiratory quotient
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
Increased ventilation lowers pCO2 which inhibits respiration
If pCO2 is fixed, pO2 of 70–80 mmHg will stimulate respiration
Development of Hypercapnia
Because CO2 is such a potent respiratory stimulant
Respiratory acidosis is usually due to decreased minute ventilation
Not increased CO2 production
CO2 retention in intrinsic pulmonary disease
Due to ventilation/perfusion mismatch
Hypercapnia is beneficial
Allows excretion of produced CO2 at lower minute ventilation
Increased pCO2 decreases pH
Increased bone and cellular buffering
Increased renal H secretion
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
Cannot substantially increase O2 because Hb already saturated
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
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
Respiratory centers become less sensitive to CO2 over time
Hypoxia becomes the primary respiratory stimulus
Chemoreceptors primarily respond to pH
Chronic respiratory acidosis increases HCO3
Therefore less pH change despite elevated pCO2
Less respiratory stimulation
Worsening hypercapnia and hypoxia
Diuretic-induced metabolic alkalosis suppresses ventilation
Patients with chronic respiratory acidosis rely on hypoxia to drive breathing
Loss of CO2 stimulation due to
Renal compensation 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
Acute Respiratory Acidosis
Body poorly adapted to acute elevations in pCO2
Must use hemoglobin and proteins as buffers
HCO3 rises 1 mEq/L for every 10 mmHg increase in pCO2
Not dramatically different
Acute exacerbations of lung disease
Chronic hypercapnia uncommon in isolated OSA
CO2 cleared during wakefulness
OSA + structural lung disease + obesity
Reduced daily alveolar ventilation
Obesity hypoventilation syndrome
Inadequate respiratory rate can cause respiratory acidosis
Fixed ventilation means increased CO2 production can cause respiratory acidosis
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
HCO3 rises 3.5 mEq/L for every 10 mmHg rise in pCO2
Allows tolerance of pCO2 values of 90–110
Genetic variation in sensitivity to hypoxemia and CO2
Hypoxia becomes primary respiratory stimulus
Compensation for loss of lung tissue
Obesity hypoventilation syndrome
Book mistakenly says hyperventilation
Chest wall weight impairs breathing
Weight loss only helps some patients
Progesterone can improve condition
Suggests central respiratory defect
Unlike OSA, Pickwickian patients have chronic respiratory acidosis
Somnolence (CO2 narcosis)
Due to increased cerebral blood flow
Symptoms due to CSF acidemia
Less common in metabolic acidosis
Less common in chronic respiratory acidosis
Particularly when pH <7.1
Can occur despite normal GFR
Suggests relationship between respiratory acidosis and renal sodium handling
Last full paragraph on page 659 discusses ambiguity of ABGs
“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
No net movement of water or nitrogen
Therefore O2 + CO2 must account for remaining pressure
Must multiply CO2 by 1.25 to account for respiratory quotient
PAO2 = PIO2 − (1.25 × PACO2)
Since CO2 diffuses rapidly
5–10 mmHg in young adults
A-a gradient = PAO2 − PaO2
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
Normal A-a gradient argues against pulmonary disease
Primary metabolic alkalosis
Respiratory muscle weakness
Complete discussion beyond scope of text
Acute Respiratory Acidosis
Correct underlying cause of hypercapnia
Especially severe asthmatics on ventilators
Does not protect CNS because HCO3 does not cross BBB
Must monitor mixed venous pH
Rapidly cleared by kidneys
“THAM is of uncertain safety”
Chronic Respiratory Acidosis
Improve effective alveolar ventilation if possible
Rarely need to treat pH directly
Can act as respiratory depressant
Improves respiratory drive for unclear reasons
Improves respiratory mechanics
Reduces pulmonary vasoconstriction
Reduces secondary polycythemia
Rapid correction can induce metabolic alkalosis
Effect of superimposed metabolic alkalosis
Metabolic alkalosis depresses ventilation
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
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Neurobiology of the carotid body
.
Increased pH, low pCO2, variable reduction in HCO3
Differentiate from metabolic acidosis where pH is decreased
(but pCO2 and HCO3 are likewise decreased)
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
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
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
Not very efficient at protecting pH
Without compensation pH would be ~7.70
Chronic Respiratory Alkalosis
Compensatory ↓ renal H secretion
Not complete for 2–3 days
Due to parallel rise in tubular cell pH
4 mEq drop in HCO3 for each 10 mmHg decrease in pCO2
Example: pCO2 20 → HCO3 16 → pH ~7.53
Respiration governed by two sets of chemoreceptors
Central (respiratory center in brainstem)
Peripheral (carotid bodies at bifurcation, aortic bodies at arch)
Stimulated by ↑ pCO2 or metabolic acidosis
Peripheral chemoreceptors
Stimulated by hypoxia (and acidosis)
Thus hyperventilation can be produced by
Direct stimulation of respiratory center
Respiratory response occurs in stages
Peripheral chemoreceptor activation
Hyperventilation → respiratory alkalosis
Increased cerebral pH inhibits central respiratory center
No significant hyperventilation until pO2 < 50–60 mmHg
If lung disease prevents pCO2 reduction
Hypoxia stimulates ventilation at PaO2 < 70–80 mmHg
Persistent hypoxemia → ↓ HCO3
Removes alkalosis inhibition
Allows greater ventilatory response
Common in pneumonia, PE, interstitial fibrosis
Also pulmonary edema (though acidosis more common)
Hyperventilation may be due to hypoxemia
Often not corrected by oxygen
Mechanoreceptors in airways, lungs, chest wall
Juxtacapillary receptors (interstitium)
Irritant receptors (epithelium)
Activated by inflammation or inhaled irritants
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)
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
Pontine tumors → local acidosis → ↓ CSF pH → ↑ ventilation
Hypocapnia in acute cerebral accidents
Overventilation can cause respiratory alkalosis
Increasing dead space (no explanation given 🤷🏻♂️)
Decreasing respiratory rate
Due to increased CNS and peripheral nerve excitability
Paresthesias (extremities, circumoral)
Supraventricular and ventricular arrhythmias
Impaired cerebral function
Increased membrane excitability
35–40% reduction if pCO2 drops by 20 mmHg
Psychogenic hyperventilation symptoms
Symptoms more prominent in acute disease (rapid pH change)
↓ phosphate (as low as 0.5–1.5 mg/dL)
Due to intracellular shift
Increased glycolysis → ↑ phosphorylated compounds
But could be acidosis or alkalosis
Compensation equations can be ambiguous
Example: 7.48 / 20 / XX / 16
Could be chronic respiratory alkalosis
Or acute respiratory alkalosis + metabolic acidosis 😖
5-year-old with AMS, playing with aspirin
Can correct acute respiratory alkalosis
If chronic → may leave patient with metabolic acidosis
“Give a mouse a cookie” 😉
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Melanie mentioned treatment of patients with cystinosis
Amy’s VOG on RTA and Osteoporosis
Outline: Chapter 19 Metabolic Acidosis part 3
Acidosis from diminished net tubular acid secretion
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
Decrease in net H secretion in the collecting duct
Minimal urine pH rises from 4.5 to 5.3
Defect in H-ATPase found in cortex and medulla
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
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
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%
As they age their urine pH falls a bit
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
Higher in voltage-dependent distal RTA
Hypercalciuria, hyperphosphatemia, nephrolithiasis, and nephrocalcinosis are frequent
Comes from bones buffering the acidosis
Kidney decreases reabsorption of these so they are lost in urine
High urine pH (CaPhos stones)
All corrected by correcting the metabolic acidosis
Defective urinary acidification but not acidemic
Increased proximal NH3 production lowers urinary H
Can progress to complete type 1
Sjögren syndrome, rheumatoid arthritis
NAGMA and elevated urine pH
Differentiate Type 1 vs Type 2
Urine pH remains high with Type 1
Does not go up as it does with proximal Type 2
Urine pH remains >5.3 in classic
Falls in normal patients (usually below 5)
Children: 4–14 mEq/kg/day
Potassium citrate if hypokalemia persists despite correcting acidosis
Or for calcium stone disease
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
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
Or part of Fanconi syndrome
Pathogenesis (three steps)
Na-H exchange (apical membrane)
Na-K-ATPase (basolateral membrane)
Multiple myeloma most common adult cause
Can also cause phosphate wasting, NDI, and Type 1 RTA
Mild hypokalemia at baseline due to increased Na wasting → hyperaldosteronism
Worse with bicarbonate therapy
Distal delivery of nonreabsorbable anion increases obligate cation loss
Rickets (children), osteomalacia/osteopenia (adults)
Phosphate wasting and vitamin D deficiency may contribute
No nephrocalcinosis or nephrolithiasis
Nonreabsorbable amino acids and organic anions bind calcium
Idiopathic and cystinosis (children)
Carbonic anhydrase inhibitors
Look for Fanconi syndrome
Raise serum HCO3 and watch urine pH rise
Correct acidosis to allow normal growth
Difficult due to rapid urinary loss
May need 10–15 mEq/kg/day
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
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 NH3 available in collecting duct
Correcting hyperkalemia can correct acidosis
Metabolic acidosis generally mild
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
Respiratory compensation increases 4–8 fold → dyspnea
Fatal ventricular arrhythmias
Reduced cardiac contractility
Decreased response to inotropes
More related to CSF pH than plasma
Less neurologic symptoms than respiratory acidosis
BBB more permeable to CO2 than HCO3
Kids/infants: anorexia, nausea, listlessness
No alkali required for lactic or ketoacidosis
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
Deficit = HCO3 space × HCO3 deficit per liter
60% (mild–moderate acidosis)
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
K depletion can cause metabolic acidosis
Metabolic acidosis increases K
“Normal” K may mask depletion (see DKA)
Beware correcting acidosis in hypokalemia
Bicarbonate comes with sodium load
Comment that bicarbonate moves into cell
But Na remains extracellular
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Josh mentioned this article the BICAR-ICU
Roger shared 3 quotes to make the point that there has been little movement in our knowledge the past 40 years:
Amy’s VoG on metabolic acidosis/KDIGO guidelines
Very nice JASN review that describes the mechanisms of how metabolic acidosis leads to CKD progression
2009 RCT that the 2012 KDIGO guidelines sort of based their 2b recommendations off of
Outline: Chapter 19 Metabolic 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
↑ production: hypoxia, redox imbalance, seizures, exercise
↓ utilization: shock, hepatic hypoperfusion
Malignancy, alcoholism, antiretrovirals
Short bowel/jejunal bypass
Glucose → D-lactate (not metabolized by LDH)
Symptoms: confusion, ataxia, slurred speech
Tx: bicarb, oral antibiotics
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)
Hepatic preference for ketogenesis
Poor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysis
Mixed acid-base (vomiting, hepatic failure, NAGMA)
Congenital organic acidemias, salicylates
AG, osmolar gap (acetone, glycerol)
Ketones: nitroprusside only detects acetone/acetoacetate
BHB can be 90% of total (false negative)
Captopril → false positive
↓ 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
Early: respiratory alkalosis → Later: metabolic acidosis
Treatment: bicarb, dialysis (>80 mg/dL or coma)
Metabolized to formic acid → retinal toxicity
Tx: bicarb, ethanol/fomepizole, dialysis
→ glycolic/oxalic acid → renal failure
Same treatment + thiamine/pyridoxine
Toluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)
Diarrhea, bile/pancreatic drainage → loss of alkaline fluids
Ureterosigmoidostomy → Cl-/HCO3- exchange in colon
Cholestyramine → Cl- for HCO3-
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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
GI loss: vomiting, GI suction, antacids
Renal loss: diuretics, mineralocorticoid excess, hypercalcemia, post-hypercapnia
Administration of bicarbonate
K+ loss → H+ shifts intracellularly
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
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
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
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
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
Hypoventilation: 0.7 mmHg PCO2 ↑ per 1 mEq/L HCO3 ↑
Rise in PCO2 increases acid excretion (limited effect on pH)
Gastric juice: high HCl, low KCl
Stomach H+ generation → blood HCO3
Normally recombine in duodenum
Vomiting/antacids prevent recombination → alkalosis
Mg binds fats, leaves HCO3 unbound → alkalosis
Renal failure impairs excretion
Cation exchange resins (SPS, MgCO3) → same effect
High fecal Cl-, low pH → metabolic alkalosis
PPI may help by reducing gastric Cl load
Mineralocorticoid excess & hypokalemia
Aldosterone → H+ ATPase stimulation, Na+ reabsorption → negative lumen → ↑ H+ secretion
Diuretics (loop/thiazide)
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
Nonresorbable anion → hypokalemia, alkalosis
↑ Renal H+ secretion & HCO3 reabsorption
Can contribute to milk-alkali syndrome
Rarely causes acidosis via reduced proximal HCO3 reabsorption
Common cause and effect of metabolic alkalosis
H+/K+ exchange → intracellular acidosis → ↑ H+ excretion
Rapid carb reintroduction → cellular shift
No volume contraction or acid excretion increase
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)
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
NaCl and water loss without HCO3
Seen in vomiting, diuretics, CF sweat
Mild losses neutralized by intracellular buffers
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
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:
Distinguishing from respiratory acidosis
Caution with typo (duplicate pCO2)
Correct K+ and Cl− deficiency → kidneys self-correct
Upper GI losses : add H2 blockers
Saline-responsive alkalosis
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)
eNaC Na+ reabsorption must be countered by H+ if no K+
Corrects rapidly with K+ replacement
Restores saline responsiveness
Renal failure : requires dialysis
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Outline: Chapter 19 Metabolic Acidosis
Compensatory hyperventilation (↓ pCO2)
Bicarb < 10 strongly suggests metabolic acidosis (renal compensation for respiratory alkalosis does not go that low)
H+ + HCO3- <=> H2CO3 <=> CO2 + H2O
Acidosis results from H+ addition or HCO3 loss
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)
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
50–100 mEq/day acid generated from diet
90% filtered HCO3 reabsorbed in PT
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
Inability to excrete H+ (slow)
Addition of H+ or loss of HCO3 (rapid)
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)
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)
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)
Estimate NH4+ via osmolar gap
Requires urine Na, K, glucose, urea
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
↑ production: hypoxia, redox imbalance, seizures, exercise
↓ utilization: shock, hepatic hypoperfusion
Malignancy, alcoholism, antiretrovirals
Short bowel/jejunal bypass
Glucose → D-lactate (not metabolized by LDH)
Symptoms: confusion, ataxia, slurred speech
Tx: bicarb, oral antibiotics
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)
Hepatic preference for ketogenesis
Poor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysis
Mixed acid-base (vomiting, hepatic failure, NAGMA)
Congenital organic acidemias, salicylates
AG, osmolar gap (acetone, glycerol)
Ketones: nitroprusside only detects acetone/acetoacetate
BHB can be 90% of total (false negative)
Captopril → false positive
↓ 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
Early: respiratory alkalosis → Later: metabolic acidosis
Treatment: bicarb, dialysis (>80 mg/dL or coma)
Metabolized to formic acid → retinal toxicity
Tx: bicarb, ethanol/fomepizole, dialysis
→ glycolic/oxalic acid → renal failure
Same treatment + thiamine/pyridoxine
Toluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)
Diarrhea, bile/pancreatic drainage → loss of alkaline fluids
Ureterosigmoidostomy → Cl-/HCO3- exchange in colon
Cholestyramine → Cl- for HCO3-
Renal Tubular Acidosis (RTA)
↓ 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
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
Aldo deficiency/resistance → hyperkalemia + mild acidosis
K+ inhibits NH4 generation
Tx: correct K+, consider loop diuretics
Hyperventilation (dyspnea)
pH < 7.0–7.1 → arrhythmias, ↓ contractility
Neurologic: lethargy → coma (CSF pH driven)
Skeletal growth issues in children
No alkali needed for keto/lactic acidosis unless pH < 7.2
Deficit = HCO3 space * (desired - actual HCO3)
HCO3 space: 50–70% of body weight
K+ shifts: beware hypokalemia when correcting acidosis
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