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ReferencesThis is the thiazide induced hyponatremia reference mentioned by Friedman: Thiazide-Induced Hyponatremia: Reproducibility by Single Dose Rechallenge and an Analysis of PathogenesisThis 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 analysisAnd 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 - PMCHere’s the abstract that Amy mentioned: Abstract P174: Incidence of Hyponatremia on Spironolactone in Patients With a Prior Episode of Chlorthalidone-Induce HyponatremiaWe mentioned the issue of solute intake again and this favorite reference: Impact of solute intake on urine flow and water excretionJoel 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 myxedemaAmy mentioned this reference: The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre studySome 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 insipidusHere’s a reference on fetal vs maternal sodium gradient: Fetal diuretic responses to maternal hyponatremia: contribution of placental sodium gradient | Journal of Applied PhysiologyRoger mentions the nephrogenic syndrome of antidiuresis: Nephrogenic Syndrome of Inappropriate Antidiuresis - PMCThe NEJM manuscript looking at water dilution in schizophrenia: Mechanisms of Altered Water Metabolism in Psychotic Patients with Polydipsia and HyponatremiaTragic case of water loading Woman dies after being in water-drinking contest - Los Angeles TimesThe case report that Josh mentioned: Self-induced water intoxication without predisposing illnessRoger 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=1And here’s an instructive case: Electrolyte Abnormalities in a Man With Plasma Cell Leukemia - American Journal of Kidney DiseasesAmy’s VoG on Legionella and Hyponatremia association with hyponatremiafirst 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 criteriasensitivity 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 hypophosphatemiahttps://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 — HyponatremiaDiureticsMild 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 HyponatremiaThe 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 depletionPotassium depletionDirect inhibition of urinary dilution through decreased NaCl reabsorptionIf 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 DifferentLoop 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/LPlasma Na <110 mEq/LThis 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 FailureRenal failure impairs the ability to maximally dilute urine after a water load.Potential mechanism:Osmotic diuresis in the remaining nephronsSevere hyponatremia is relatively uncommon when patients remain non-oliguric.Risk increases as GFR approaches zero.SYNDROME OF INAPPROPRIATE ADH SECRETIONIntroductionSIADH is:CommonAssociated with a wide range of clinical conditionsCharacterized by nonphysiologic ADH activityAn unusual physiologic state in which water excretion is impaired while Na excretion remains relatively intactSee Table 23-3.PathogenesisSee 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 retentionSodium excretion…produces hyponatremia.In chronic SIADH, sodium loss may become as important as or more important than the initial water retention.Potassium LossHyponatremia causes cellular swelling.Cells adapt by ejecting intracellular solutes, including:PotassiumThe released potassium is subsequently excreted by the kidney.Chronic AdaptationA new steady state develops over approximately a couple of weeks.At steady state:Na intake = Na outputContributing mechanisms include:Relative ADH resistanceReduced urine osmolalityReduced aquaporin expressionImportantly, water ingestion remains essential. Without water intake, SIADH cannot produce hyponatremia.Patterns of ADH Secretion in SIADHFour patterns are described.Type A — Erratic ADH SecretionADH secretion is essentially independent of osmotic regulation.Type B — Reset OsmostatADH 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 ADHADH regulation appears normal around normal plasma osmolality.But ADH cannot be completely suppressed when plasma osmolality falls.Type D — Normal Measured ADHPossible explanations:Increased renal sensitivity to ADHAnother unidentified antidiuretic factorAcid-Base and Potassium Balance in SIADHInteresting 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 SIADHSIADH can result from:Increased hypothalamic ADH productionEctopic ADH productionPotentiation of ADH’s renal effectExogenous ADH or related hormonesCNS / Neuropsychiatric DiseaseNeuropsychiatric disorders can promote ADH release:DirectlyThrough cortical neuronal pathways stimulating the hypothalamusExamples:Approximately 20% of patients with subarachnoid hemorrhageApproximately 20–35% after transsphenoidal pituitary surgeryAdrenal insufficiency may contribute following pituitary surgery.Psychiatric patients may have abnormalities at several levels:Water intakeADH secretionRenal responsiveness to ADHAgain, much water intake is habitual rather than thirst-driven.HIVHyponatremia has been reported in approximately 40% of patients with HIV infection.Potential mechanisms include:Volume depletionAdrenal insufficiencySIADHPneumocystis pneumoniaMalignancyCNS diseaseDrugsMany drugs have been associated with SIADH, although most only rarely produce clinically significant hyponatremia.CyclophosphamideIncreases 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.ChlorpropamideOral hypoglycemic agent.Increases NaCl reabsorption in the TAL.Increases sensitivity to ADH.NSAIDsIncrease 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 DiseaseAssociated conditions include:PneumoniaAsthmaAtelectasisEmphysemaPneumothoraxTuberculosisAcute respiratory failurePossible 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 SurgeryTransient SIADH may occur for 2–5 days after major surgery.Pain afferents can directly stimulate hypothalamic ADH secretion.Ectopic ADH ProductionClassic association:Small-cell carcinoma of the lungExogenous ADH and OxytocinOxytocin: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 bleedingDDAVP for:NocturiaPlatelet dysfunctionCentral diabetes insipidusIdiopathic SIADHOccasionally no cause is identified.Consider:Occult malignancyTemporal arteritisThese patients may have low serum uric acid because of increased urinary uric acid clearance.CEREBRAL SALT WASTINGRare syndrome associated with cerebral disease, particularly:Subarachnoid hemorrhagePhenotype:HyponatremiaHigh urine NaLow serum uric acidVolume depletionVolume depletion is the key proposed distinction from SIADH.A theoretical factor released from the injured brain may cause:Renal salt wastingUric acid wastingBNP has been proposed as one candidate.ADRENAL INSUFFICIENCYHyponatremia is common in adrenal insufficiency.Separating the contributions of:Cortisol deficiencyVolume 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 ↑HYPOTHYROIDISMHypothyroidism is often listed in the differential diagnosis of hyponatremia, but it is actually a rare cause of clinically significant hyponatremia.RESET OSMOSTATPatients fulfill many criteria for SIADH but regulate osmolality around a lower set point.Described in:Hypovolemic statesPsychosisChronic malnutritionPregnancyPossible mechanisms include:Baroreceptor-mediated ADH stimulationAltered cellular metabolism in malnutritionPregnancy-related hormonal effectsDuring pregnancy, hCG may promote release of ovarian relaxin.Potential mechanisms:Vasodilation → relative effective volume depletionDirect effects on osmoreceptor regulationPRIMARY POLYDIPSIAOccurs in approximately 7% of patients with schizophrenia.Clinical clues:Weight gain during the day from water accumulationExcessive water drinkingDry mouth from medicationsThere 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/kgSymptomatic hyponatremia after drinking 3–4 L of water while anxiously awaiting a drug testSevere cases often involve stacked etiologies:Primary polydipsiaThiazidesAntipsychoticsNausea-induced ADHStress-induced ADHLow-solute intake / beer potomaniaPSEUDOHYPONATREMIA AND NON-HYPOOSMOLAR HYPONATREMIANormal Plasma OsmolalityClassic PseudohyponatremiaNormally, approximately 930 mL of each liter of plasma is water.With severe:HyperlipidemiaHyperproteinemia…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 / HysteroscopyAbsorption of non-electrolyte irrigation solutions can produce complex abnormalities.Probably historical enough to skip?Hyponatremia With Increased Plasma OsmolalityHyperglycemiaInteresting 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.MannitolMannitol can cause hyperosmolar hyponatremia.The amount of circulating mannitol can be estimated using the osmolar gap.IVIGSome IVIG preparations contain maltose, which can accumulate and contribute to hyperosmolar hyponatremia.