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- 1. Sodium Disorders: An Endo-specificClinical Primer August 11, 2022 Amy Yau, MD, FACP, FASN Assistant Professor of Clinical Medicine Division of Nephrology [email protected] @amyaimei
- 2. Sodium Disorders =Water Disorders
- 3. Key Hormones MaintainVolume and Tonicity • Kidneys are good at 2 things: Water and Sodium retention • Na reabsorption Angiotensin II (AT2) and aldosterone • Na secretion ANP • Water reabsorption Anti-diuretic hormone (ADH)
- 4. AT2 and Aldo vasoconstriction and Na retention ATII ATII ADH H2O H+
- 5. Aldo is stimulatedby low BP and hyperkalemia “Aldosterone Paradox”
- 6. In hypovolemia AT2 and Aldo elevated Aldo
- 7. Aldo In hyperK more distal Na b/c only Aldo elevated Aldo
- 8. ADH waterretention ATII ATII ADH H2O H+
- 9. ADH responds totonicity and volume Rose and Post, Clinical Physiology of ABE Disorders, 5th edition
- 10. But in hypovolemic(or perceived hypovolemic) states, Tonicity is sacrificed in Defense of Volume Rose and Post, Clinical Physiology of ABE Disorders, 5th edition
- 11. ANP natriuresis(in retained renal perfusion) Theilig and Wu, Am J Physiol Renal Physiol, 2015 Rose and Post, Clinical Physiology of ABE Disorders, 5th edition ANP ENac
- 12. Of note, Ageand Kidney Disease Impair Dilution and Concentration • AKI/CKD • If advanced CKD UOSm ranges from 200-300 mOsm/kg • Due to reduced GFR (impaired free water excretion), volume expansion, urea osmotic diuresis • Older age • UOsm range 92 mOsm/kg 400-700 mOsm/kg by 80s • Due to reduced GFR • Increased medullary blood flow Karam and Tuazon, Clin Geriatr Med, 2013 Cowen et al, Endo Metab Clin North Am, 2013 Epstein, JASN, 1996 Lindeman et al, J Lab Clin Med, 1966 Rose and Post, Clinical Physiology of ABE Disorders, 5th edition
- 13. Of note, bewareblood gas analyzers 86.5% of values on blood gas were lower than lab values Jain et al, Int J Emerg Med, 2009
- 14. Hyponatremia < 135 mEq/L Grattaglianoet al, J Prim Health Care, 2018 Zhang and Li, Eur Ger Med, 2020 In Hospital Mortality 11.7% Prevalence - General wards 6% - ICU 17% - Outpatient 4-7% Symptoms - Acute: seizure, coma, cardiac arrest - Chronic: AMS/MCI, falls, osteoporosis, nausea, vomiting
- 15. Main Mechanisms ofHyponatremia
- 16. Grattagliano et al,J Prim Health Care, 2018 30% 20% 8% 5% 35% Traditional Schema
- 17. But, assessing volumeis hard Peacock and Soto, Congest Heart Fail, 2010
- 18. …even in volumedepleted patients McGarvey et al, Br J Sports Med, 2010
- 19. Even objective measures(for volume) are limited Kalantari et al, Kidney International, 2013
- 20. Newer Schema US HyponatremiaRecommendations, Verbalis et al, Am J Med, 2013 EU Hyponatremia CPG, Spasovski et al, NDT, 2014
- 21. Step 1: Confirm“True/Hypotonic” Hyponatremia Other effective osmoles cause water movement
- 22. ADH is off ADHis on Question is, is it appropriate or inappropriate based on UrNa Assess ADH response (free water retention or high free water intake) Step 2: Look at urine assess ADH response
- 23. Assess Aldo response Aldois off (or on diuretic/CKD) (High ADH is inappropriately elevated) Aldo is on (High ADH appropriate) Step 3: Look at urine assess Aldo response
- 24. Assess Aldo response Aldois off (or on diuretic/CKD) (High ADH is inappropriately elevated) Aldo is on (High ADH appropriate) Step 4: Check volume
- 25. Often Adrenal andThyroid Function not checked in Euvolemic Hyponatremia Barnes et al Katoch et al Tzoulis et al Greenberg et al Cuesta et al Diker-Cohen et al Number of pts 110 SIADH 100 with AMS, hypoNa 139 hypoNa 1524 SIADH 573 SIADH 564 euv hypoNa TFTs (%) 50.9 100 61.1 64 91 69 Adrenal Function Test (%) 91.1 100 31.7 33 84 29 % of pts dx with hypothyroid/AI 3.6/3.6 8/2 0/0.7 NR 0/3.8 1/1 Prevalence of thyroid disorder/AI in hyponatremia ~3% Prevalence of hyponatremia in patients with hypopituitarism was 9.6% In 80.7%, hyponatremia was key to diagnosis Diker-Cohen et al, Int and Emer Med J, 2018 Miljic et al, Endocrine, 2017
- 26. Adrenal insufficiency removesnegative feedback of ADH and CRH release
- 27. Urine studies ofAI will look like SIADH Primary AI - Hypovolemic hypoNa +/- hyperK - No aldo (UrNa inappropriately high) - ADH on (Uosm high) Secondary AI - Euvolemic hypoNa - +/- aldo (UrNa variable) - ADH on (Uosm high) ECV expansion ANP release (UrNa high)
- 28. Despite ICPi relatedAI SIADH is still most common cause of hyponatremia in these patients Seethapathy et al, NDT, 2021 • 2458 pts on ICPi • 1519 (62%) with hypoNa within 1 year • 135 (6%) with Na < 125 • 9 cases due to endocrinopathy • 9 with AI • 6 with concomitant hypothyroid 7% 35% 20%
- 29. Questionable link ofhypothyroidism and hypoNa, but consider if myxedema coma or TSH > 50 mIU/mL Liamis et al, Eur J Endocrin, 2017
- 30. But if itdoes exist, may be due to low aldosterone Marks et al, The Lancet, 1978 In 10 patients with myxedema coma, after thyroid repletion… urine aldosterone excretion and plasma aldosterone levels increased.
- 31. SIADH is Diagnosisof Exclusion Winn Seay et al, AJKD Core Curriculum 2019 Nausea, vomiting, pain Genetic – X linked recessive GOF T2AVP receptor (OMIM 300539)
- 32. Management of Hyponatremia •If symptomatic 100 mL 3% saline 100 mL 3% saline 100 mL 3% saline Should raise Na by ~ 6 mEq/L per day US Hyponatremia Recommendations, Verbalis et al, Am J Med, 2013 EU Hyponatremia CPG, Spasovski et al, NDT, 2014 • If asymptomatic • If acute 10-12 mEq/L per day • If chronic 6-8 mEq/L per day • No mortality benefit to rapid correction
- 33. Rate of correction:SLOW • Risk of ODS • Na < 110 (caution in 110-120) • Hypokalemia • Alcoholism • Malnutrition • Liver disease Kwon and Handler, Curr Opin Cell Biol, 1995
- 35. Chronic Management willdepend on Mechanism
- 36. Approach 1: Reducewater intake
- 37. Approach 2a: Diluteurine (water diuresis) Turn off ADH - Restore renal perfusion, stop diuretics - Stop ADH stimulus (pain, nausea) - Treat AI, TFTs - Vaptan (antagonize ADH) - Reduce efficacy of ADH (Lasix) - Improve urinary dilution (renal disease)
- 38. Approach 2b: Solutediuresis 9g salt tabs = 153 mmol (~1L NS) 30 g urea = 500 mmol
- 39. Approach 3: Other(saline +/- DDAVP, dialysis) Dialysis
- 40. For SIADH specifically,how effective are therapies?
- 41. U/P ratio canpredict SIADH mgmt outcome @NephroMD
- 42. Summary of Hyponatremia •Main mechanisms: high free water intake, impaired free water loss • Use urine to assess ADH and aldo responses • Confirm “true” hyponatremia • SIADH = dx of exclusion (rule out AI and thyroid disorder) • Mechanism AI: CRH release, loss of neg feedback of ADH • Mechanism hypothyroidism: unknown, hypo-aldosterone? • U/P (Furst Equation) can help predict mgmt outcome • Correct SLOWLY (goal 6-8 mEq/L in 24 hours)
- 43. Hypernatremia >145-150 mEq/L Ahmad andWisberg, Critical Care Medicine, 3rd Ed Arzhan, Kidney 360, 2022 Bataille et al, BMC Nephrology, 2014 Out of Hospital Acquired HyperNa Mortality 28% (Na > 155 compared to normal) Odds Ratio 34.41 Prevalence - ICU 9% Symptoms AMS, lethargy, weakness, irritability, seizures, coma, thirst
- 44. Mechanisms of Hypernatremia ImpairedFree Water Intake IN ADDITION TO… Increased salt intake Hypervolemic Renal Water Loss Eu-or Hypovolemic Free Water Diuresis Osmotic/Solute Diuresis Extrarenal Hypotonic Fluid Loss Hypovolemic (vomiting, diarrhea, sweating, respiratory losses) (diuretic use, urea, glucosuria) (hypertonic saline, bicarb amp/1:1 drip, salt poisoning)
- 45. Key to assessmentis Urine Osm (or sg) • UrOsm range is 50-1400 mOsm/kg • Polyuria could be a clue, but this may be red herring in cases of primary polydipsia or solute diuresis Last 2 digits of sg x 30 = urine osmolality
- 46. If your patientis hyperNa and UrOsm > POsm, kidneys are trying to retain water • May have partial DI, but clearly able to retain some degree of free water… • Give more free water • Assess for component of solute diuresis
- 47. If your patientis hyperNa and UrOsm < POsm, then you have diabetes insipidus Altered metabolism of vasopressinase in pregnancy (esp if liver disease) If no liver disease, may have subclinical central DI
- 48. What if yoususpect DI, but normoNa? Assess for polyuria… Rose and Post, Clinical Physiology of ABE Disorders, 5th edition
- 49. 3 Ways toAssess Inappropriate Water Diuresis
- 50. Water Deprivation Test •Correct diagnosis in 80% of pts Limitations • Partial DI may have some effect to DDAVP • Chronic primary polydipsia • washes out medullary concentration gradient • downregulates AQP2 • mimic nephrogenic DI • Chronic central DI • downregulate AQP2 (inadequate DDAVP response) Rose and Post, Clinical Physiology of ABE Disorders, 5th edition
- 51. 3 Ways toAssess Inappropriate Water Diuresis
- 52. Copeptin is indirect assessmentof ADH Refardt et al, Clin Endo, 2019
- 53. Management of Hypernatremia ImpairedFree Water Intake Increased salt intake Hypervolemic Renal Water Loss Eu-or Hypovolemic Free Water Diuresis Osmotic/Solute Diuresis Extrarenal Hypotonic Fluid Loss Hypovolemic Rx: Give Water + Restore BP if needed + Lasix if needed Low protein diet, Insulin if needed Central: DDAVP Nephrogenic: TZD, Cai, NSAID
- 54. Rate of correction:FASTER is better Alshayeb et al, Am J Med Sci, 2011 Chauhan et al, CJASN, 2019 Slow correction with HR 2.63 for 30 day mortality Mortality rate 18% Mortality rate 46% Only 27% normoNa at 72 hours
- 55. Summary of Hypernatremia •Main mechanisms: • impaired free water access • + either high salt intake, extrarenal hypotonic fluid loss, or renal water loss (free v. osmotic) • Use urine and copeptin to assess for DI • FASTER correction is better (at last > 6 mEq/L in 24 hours, likely > 12 is ok)
- 56. Questions? Amy Yau, MD,FACP, FASN Assistant Professor of Clinical Medicine Division of Nephrology [email protected] @amyaimei
Editor's Notes
- #2 Sodium disorders is a broad topic Focus on physiology, diagnosis, and brief overview of management options
- #3 AII stimulated by low BP (renin release) Aldo stimulated by low BP (AT2) and hyperkalemia ADH stimulated by central osmoregulators ANP inhibits Na reabsorption in medullary collecting tubule, may also reduce Na reabsorption in PT (due to change in hydraulic pressure or DA release) Stimulated by volume expansion ANP also direct vasodilator increase GFR more natiuresis (like this is partially the key) via afferent dilation, efferent constriction, but does not interfere with response to chronic volume expansion ANP – direct vasodilator, increases UrNa and water excretion may diminish Na reabsprition in PT vi a deep juxtaglom nephrons
- #4 AII stimulated by low BP (renin release) Aldo stimulated by low BP (AT2) and hyperkalemia ADH stimulated by central osmoregulators ANP inhibits Na reabsorption in medullary collecting tubule, may also reduce Na reabsorption in PT (due to change in hydraulic pressure or DA release) Stimulated by volume expansion ANP also direct vasodilator increase GFR more natiuresis (like this is partially the key) via afferent dilation, efferent constriction, but does not interfere with response to chronic volume expansion ANP – direct vasodilator, increases UrNa and water excretion may diminish Na reabsprition in PT vi a deep juxtaglom nephrons
- #5 Model of regulatory pathways for the mineralocorticoid receptor (MR) in intercalated cells: hyperkalemia and volume depletion. This figure depicts pathways that involve the differential phosphorylation state of the MR in principal versus intercalated cells (type A-IC; type B-IC), that are likely the key to the distinct responses of these cells in two different scenarios. (A) The first scenario involves conditions when only aldosterone is present (as in hyperkalemia). In this case, hyperkalemia leads to aldosterone secretion while no angiotensin II is present. Here, MR is phosphorylated in intercalated but not in principal cells. These conditions lead to aldosterone-mediated Na+ reabsorption via the epithelial sodium channel in principal cells, which drives K+ secretion also in principal cells. (B) In contrast, when both angiotensin II and aldosterone are present (as in intravascular volume depletion), the MR is dephosphorylated downstream of angiotensin II, and the activity of this receptor is thus restored in intercalated cells. In addition, as a result of aldosterone signaling both pendrin and H+-ATPase are upregulated, and in turn there is a decrease drive for K+ secretion. Modified from reference 69.
- #6 Model of regulatory pathways for the mineralocorticoid receptor (MR) in intercalated cells: hyperkalemia and volume depletion. This figure depicts pathways that involve the differential phosphorylation state of the MR in principal versus intercalated cells (type A-IC; type B-IC), that are likely the key to the distinct responses of these cells in two different scenarios. (A) The first scenario involves conditions when only aldosterone is present (as in hyperkalemia). In this case, hyperkalemia leads to aldosterone secretion while no angiotensin II is present. Here, MR is phosphorylated in intercalated but not in principal cells. These conditions lead to aldosterone-mediated Na+ reabsorption via the epithelial sodium channel in principal cells, which drives K+ secretion also in principal cells. (B) In contrast, when both angiotensin II and aldosterone are present (as in intravascular volume depletion), the MR is dephosphorylated downstream of angiotensin II, and the activity of this receptor is thus restored in intercalated cells. In addition, as a result of aldosterone signaling both pendrin and H+-ATPase are upregulated, and in turn there is a decrease drive for K+ secretion. Modified from reference 69.
- #7 Model of regulatory pathways for the mineralocorticoid receptor (MR) in intercalated cells: hyperkalemia and volume depletion. This figure depicts pathways that involve the differential phosphorylation state of the MR in principal versus intercalated cells (type A-IC; type B-IC), that are likely the key to the distinct responses of these cells in two different scenarios. (A) The first scenario involves conditions when only aldosterone is present (as in hyperkalemia). In this case, hyperkalemia leads to aldosterone secretion while no angiotensin II is present. Here, MR is phosphorylated in intercalated but not in principal cells. These conditions lead to aldosterone-mediated Na+ reabsorption via the epithelial sodium channel in principal cells, which drives K+ secretion also in principal cells. (B) In contrast, when both angiotensin II and aldosterone are present (as in intravascular volume depletion), the MR is dephosphorylated downstream of angiotensin II, and the activity of this receptor is thus restored in intercalated cells. In addition, as a result of aldosterone signaling both pendrin and H+-ATPase are upregulated, and in turn there is a decrease drive for K+ secretion. Modified from reference 69.
- #8 ADH stimulated by central osmoregulators ANP inhibits Na reabsorption in medullary collecting tubule, may also reduce Na reabsorption in PT (due to change in hydraulic pressure or DA release) Stimulated by volume expansion ANP also direct vasodilator increase GFR more natiuresis (like this is partially the key) via afferent dilation, efferent constriction, but does not interfere with response to chronic volume expansion ANP – direct vasodilator, increases UrNa and water excretion may diminish Na reabsprition in PT vi a deep juxtaglom nephrons
- #9 Solid circles – volume loss Open circles – osmotic changes sensed ccentrally
- #10 As % change in volume/pressure increases (to the RIGHT) it takes a higher osmolality to cause ADH release As % change in volume/pressure decreases (to the LEFT) small osmolality changes cause high ADH release Changes in osmolaliry by 1% vasopressin release Changes in BP by 10% vasopressin release Ie tonicity is sacrificed in the defense of volume Beyond water reabsorption vasopressin has a vasoconstrictor effect
- #11 Anp acts on IMCD – affects Na reabsorption in principal cell (passive Na entry through Enac and Na/K pump) Another Na channel in rprincipal cell of CD (CNG) (may also be an ANP target) UrANP binds to NPR-A receptor converts GTP to cGMP inhibit CNG, Na/K, and TRPV4/2 nnatiuresis ANP reduces vasopressin stimulated water permeability and posphyrlation of AQP2 TRP4/2 is Ca entry into CD (reduce AP of CD) // Burton rose: physiologic role of ANP as natiureitc agent is uncertain If BP is elevated by volume expansion natriuretic effect of ANP is unmasked (inn rats if you improve renal PP, then ANP effect is seen in animals with heart failure and cciirrhosis; possible that urodilatin and BNP are more important natriuretic hormones ANP can suppress aldosterone release Increase in filtered load is essential roANP effect
- #12 Normal urine osm range is 50-1400 Average age 31 yo, Uosm was 52 mOsm/kg compared to 92 mOsm/kg in average age 84 yo ============= Yoon review - renin formatulion and release reduced ACCEi on BP a, renal functional and proteinuria blunted imaging animals; elderly with decreased HTn response to ACEi - elderly with lower ability to conserve Na (esp if salt restricted, source 16) - lower AII secretion - impaired tubular concentrating ability and higher risk of volume deletion and hyponatremia (prostaglandin dependent) - aged rats: renal mRNA expression reduced renal ACE levels reduced prior to plasma ACE level reduction, changing renal response to systemic RAS (reductions in GFR and renal plasma flow exaggerated in older rats with administration of AII - more renal sensitivity to AII —> further reduction in GFR when kidney exposed to RAS stimuli (hypovolemia, hypotension) // Karam - reduced kidney mass - single nephron hypothesis, shunting of blood to renal medulla, reduced GFR, diluting and concentrating ability reduced - source 38: kuna indianns —> free of CV disease and HTN did still show reduction in GFR and renal plasma flow - ability to general free water depends on: adequate delivery of solute to diluting region as result of renal perfusion and GFR, intact distal diluting site, suppression of ADH (source 44) - impaired diluting: reduction in GFR (min UOsm men with mean age 31 was 52 mOsm/kg and 92 mOks/mg with mean age 84 yo men after water fading (FWC lowest in older group), but similar when expressed as mL/min/GFR - rats show downreulation of V2 receptors impair renal concentrating ability; during 12 hour water deprivation test, pts 60-79 yo with 20% lower maximal urine osmolality and 100% increase in minimal urine flow rate an d50% decrease in ability to conserve solutes (source 47), after 24 hour water deprivation test, maximal urine sg reduced from 1.030 (40 yo) to 10.023 (89 yo) source 48) - reduced ability to conserve Na in response to low Nna diet (intake to 10 mEq/day —>elderly with more exaggerated natriuresis after water load (source 50) unclear MOA, but may be due to reduced nephron # and Aldo secretion Source 51: old pts with higher PT Na reabsorption compared to younger, but offset by lower distal Na reabsorption —> therefore Na retention is favored, also impaired AII response, and more Na escretipion at night (circadian variation) // Hendi lehsem - in Israel elderly (65-86) v. 45-58 pts - older less thirsty, respond less to thirst - nocimpairmment of salt appetite, though they had reduced dietary Na intake (but when corrected for reduced dietary energy intake similar to young pts) // Epstein - half time for renal Na excretion rate < 25 yo was 17.6 h, if > 60 yo, half time was -30.9 h (age influences kidneys ability to conserve Na) - RBF and GFR decline per nephron —> enhanced conservation of Na by kidney is proposed - b/c grr I s lower, there is a slower response to na conservation in elderly - perhaps reduced Aldo secretion rate or response (unsure) —> but this predisposes elderly to hemodynamic instability in the setting of Na loss - increased Na retention (?) > 40 yo, pts with. Lower Na excretion compared to < 40 yo after 2L NS bolus, and older pts with more natriuresis at night than younger (source 68), source 69 showed elderly (66.5 yo v. 29.2 yo) excreted more Na, K, and total solutes at night -old kidney may have defect in pressure natriuretic capacity —> at increasing renal perfusion pressures young kidneys had increased Na excretion but old kidneys did not have natriuresis trepans (source 70), source 71 with altered AII response may be the cause (3-5 mo pts to 19-22 mo rats) —> increased FF with similar hemodynamics in young and old rats, but high AII infusion with natiurestic and diuretic response seeing young rats compared to older rats summary: in older individuals if na intake impncreased, geriatric pts may dvll expanded ECF - with age —> reduced plasma renin activity (in synthesis and impaired release) —> lower infrarenal baseline levels of AII In sprague daily rats —> acute interruption of RAASI with ACEi or ARB —> renal vasodilation in old but not young rats with similar responses to AII administration in both age groups (still sensitive to AII, but older kidneys control more by endogenous AII than in younger rats) - although AII levels did not alter between 40v 85 yo people, renin activity and plasma Aldo levels lower in 85 yo population - age —> decreased in basal, upright posture, and volume depleted plasma aldosterone (source 63), progressive decrease in abase and stimulated plasma renin activity and urinary Aldo levels (source 64) - ANP, some studies show increase in basal haANP in older 68 yo v. 24 yo volunteers, possibly means the rate of compensatory ANP secretion in response to volume stimulus exceeds capacity of processing enzymes —> release of immature ANP and reduced bio activity Disappearance rate of exogenous ANP is prolonged in elderly - reduced renal concentrating ability with age - may be due to reduced GFR, but another study (source 91) supposed increase in medullary blood flow (washouts medullary tonicity and decline in efficacy of countercurrent system, defect in solute transport from tubular lumen to medulla), esp if 50 yo or older - increasing age —> in AVP levels after 3% saline, young pts had osmolality increase 2.5 old plasma AVP, but older pts with plasma AVP increase 4.5 times (index of sensitivity of osmoreceptor, more sensitive in older groups —> changes with age) - teleologically possible that heightended sensitivity of AVP in response to hyperosmolality may serve to compensate for reduced renal ability to conserve water in aging - peak plasma AVP response in hypotensive pts grater in young than old —> means diminished release of AVP in response to orthostasis is more common in the elderly than the young likely due to vasomotor center in afferent limb of baroreceptor reflex - ex: if fluid intake suppressed —> geriatric pts may manifest elevations of Na more Thani n younger pts - renal diluting ability - urine osm 52 v. 92, unr eflow, etc - although AVP levels decrease in response to water loading in old and young pts, mean plasma AVP levels higher at base.ine and throughout study in older pts - ascending limb of Henle is not impaired in rat subjects in aging - mild diluting defect with aging likely due to modest GFR decline (does not appear to be due to AVP) // Cowen - change in body composition - less TBW b/cc more fat, less muscle) 5-10% - reduction in GFR, increase PT fluid reabsorption (FF) - impaired diluting capacity - impaired concentrating ability (peak 400-500 mosm/kg water (source 25) likely due to intrinsic renal factors not eAVP levels (b/c higher AVP levels in elderly) - secretion and end organ effects ov AP altered by age (elderly healthy pts with basal AVP levels equal to or more than young controls, although some studies show no difference, but elderly do have more AVP secretion per unit change in plasma osmolality than younger —> increase in osmoreceptor sensitivity in elderly, lower AVP response to orthostasis in elderly compared to young (defect not in baroreceptor, but from vasomotor center to hypothalamus - elderly with more ANP secretion (which may suppress AVP during head out water immersion) (ANP suppresses osmotically stimulated AVP in young and elderly), but not 100% clear - AVP levels generally higher in elderly like due to decreased V2R expression or second messenger response —> loss in maximal urinary concentration (suggested in rat models) - thirst osmoreceptors is 5-10 mOsm/kg above that for AVp release older males - no change in thirst sensation despite significant increases in serum Na and plasma osmolalityy compared to elderly - blunted thirst response to osmotic changes in elderly (although other studies cast doubt) (? arb with hyponatremia? Amy comment) /// Book - newborns with shorter loop, low interstitial naCl and urea conc, decreased ADH response (esp in premies) - able to dilute, impaired concentration - immature intracellular secondary messenger system thus low response to ADH, and cAMP degradation is increased, V2R receptors present in early gestation but does not change during the first weeks of life - more UTA transporters reduces interstitial urea concentration and inhibits water transport a ross principal cells // Sporn 5 pts with oliguria, 70-86 yo, Uvolume little value, concentration of total solutes in urine was limited re: decreased renal perfusion nfrom ATI and here UrNa is helpful Rosinger etal - compared USG and UOSm from NHANES data, tsimane forager horticulteralists in Bolivia, hadza hunter gatherers in Tanzania - age with reduced US and UOSm, tsimane and hazda no change with age age-related decline in Usg (B= −0.0008 g/ml/10yr; SE<0.0001; P<0.0001; n=1,908) and Uosm (B= −22.4 mOsm/kg/10yr; SE=3.3; P<0.0001; n=3,964) among US adults,
- #13 Although direct ion selective electrode > indirect…. Jain – 86.5% on ABG lower than AA (auto analyzer)with borderline hypoNa (120-135) and Na < 120, mean difference was 7.4 mmol/L and 12.8 mmmol/L
- #14 Grattagliano - a recent review of 53 studies: mild hyponatremia in 22% of geriatric hospitalized pts, 6% and 17% of ppl to general ward/ICU wards - prevalence 4-7% in outpatients, 19% nursing home residents - frequency of causes: SAIDH (35%), hypovolemia (30%), hypervolemia (20%), diuretics 8%, primary polydipsia 5%, AI 2%; usually multifactorial - specific meds: SSRI, RAASi, AED, antiarrhythmics, PPI - this study: 19 GPs in southern Italy, >65 yo, incidence 8% of 2569 pts - more likely in chronic conditions, arterial hypertension, DM, CHF, CVD, CHF, CAD, CKD, use of all drug classes higher in hyponatremic pts (diuretics, RAASi, opioids, antiarrhythmics), higher risk with more drugs, risk with 4 drugs ws 7x higher than use of six drugs More hyponatremima if RAASi + diuretic than diuretic alone - average age in 70s Zhang - look at prevalence and in hospital mortality, - average age 84.6 yo - prevalence 24.7%, inpatients PMH: respiratory distress 5%, tumors 23.1%, CV disease 19.9%, CNS disease, 8.9%, ortho disease 6.1% - meds: PPI 59.7%, loop 57.4%, K preserving diuretics 29.5%, RAASi 20%, Ted 12.5%, NSAID 12.4% - in hospital mortality rate 11.7%, longer LOS OR mortality with mild/mod-sev 1.89/2.66 Elhosiny - abs associ with hyponatremia Brinkkoetter - prevalence inpatients 22.2% geriatric, 6% non geriatric - Na < 125 with 4.5% v. 0.8% - kidney reduced capacity to dilute urine with age, accumulation of hyponatremia associated comorbidities, drug prescriptions Clinical sx: osteoporosis, falls, fractures, AMS/MCI, mortality - improv’t in ADL, MMSE more pronounced in hyponatremia group —> clear trend towards ADL improvement
- #16 https://www.cureus.com/articles/59381-the-conundrum-of-volume-status-assessment-revisiting-current-and-future-tools-available-for-physicians-at-the-bedside Frequency of causes 35% siadh, 30% hypovolemic, 20% hypervolemic, 8% due to diuretics, 5% due to primary polydipsia, 2% due to AI, usually multifactorial (grattagliano et al)
- #17 https://www.cureus.com/articles/59381-the-conundrum-of-volume-status-assessment-revisiting-current-and-future-tools-available-for-physicians-at-the-bedside mcgarvy
- #18 https://www.cureus.com/articles/59381-the-conundrum-of-volume-status-assessment-revisiting-current-and-future-tools-available-for-physicians-at-the-bedside mcgarvy
- #19 https://www.cureus.com/articles/59381-the-conundrum-of-volume-status-assessment-revisiting-current-and-future-tools-available-for-physicians-at-the-bedside mcgarvy
- #20 EU guidelines v. US guidelines https://pubmed.ncbi.nlm.nih.gov/24569496/ Role of uric acid? Role of CKD, dialysis, etc?
- #21 Hypertonic – other osmoles cause water movement (from cell and water retention via ADH) Isotonic – proteins and lipids affects plasma water volume Hypertonic affects plasma water volume – measurement of Na via indirect ion specific electrote potentiometry, and assumes volume = water + protein/lipids and assumes Na is lower due to higher plasma volume, iSTAT analyzers (direct ion specific electrote potentiometry) may help as most labs use indirect for BMP However, iSTAT machines are unreliable with lower Na levels
- #22 Key: your pt has to be hyponatremic at the time of urine study evaluation (best if not received IVF recently) ADH off < 100 Mechanism primary polydipsia Dilutes renal medulla Mechanism low solute intake - Impaired free water excretion Assess aldo response … (unless on diuretics or CKD, or some other item affecting normal renal handling of Na) Reset osmostat Reset osmostat Inn pregnancy: hcg may mildly reset osmostat causing mild hyponatremia of 5 mEq/L Normal response to water load (compard to SIADH)
- #23 Key: your pt has to be hyponatremic at the time of urine study evaluation (best if not received IVF recently) ADH off < 100 Mechanism primary polydipsia Dilutes renal medulla Mechanism low solute intake - Impaired free water excretion Assess aldo response … (unless on diuretics or CKD, or some other item affecting normal renal handling of Na) Reset osmostat Reset osmostat Inn pregnancy: hcg may mildly reset osmostat causing mild hyponatremia of 5 mEq/L Normal response to water load (compard to SIADH)
- #24 Key: your pt has to be hyponatremic at the time of urine study evaluation (best if not received IVF recently) ADH off < 100 Mechanism primary polydipsia Dilutes renal medulla Mechanism low solute intake - Impaired free water excretion Assess aldo response … (unless on diuretics or CKD, or some other item affecting normal renal handling of Na) Reset osmostat Reset osmostat Inn pregnancy: hcg may mildly reset osmostat causing mild hyponatremia of 5 mEq/L Normal response to water load (compard to SIADH)
- #25 52% (n=13/25) less than 125 mEq/L 60% of the hyponatremic pts were due to nonfunctioning pituitary macroadenoma ===================== Diker - 11% of idiopathic SIADH found to have underlying cause - AI morning AM less than 140 nmol/L or peak < 500 nmol/L at 30 or 60 min - in 564 euvolmic pts, 9 with endiccroniopathy, 555 with SIADH (of which 99 idiopathic) - 3 with central hypothyroidism and hypoadrenalism (table 2) - 3 with isolated hypothyroidism - 3 with isolated hypoadrenalism - but TFTs only in 69% of case and adrenal function in only 29% of subjects - all with suggestive medical histories and clinical presentations; 29^ with both - in 1524 pts in EU in hyponatremia registry - only 21% with cortisol and TSH 64% with TSH, 33% with cortisol Mechanism/association - hypothyroidism - maybe only in context of myxedema coma? - in severe cases (ie myxedema or TSH > 50 mIU/mL with sx (Apoplexy) - vasopressin is tonically suppressed by GC - so ai + low BP —> vasopressin release - similar to siadh - 3.8% of euv hypo —> undx secondary AI // Miljic - non osmotic stimulation of vasopressin - sx causino AVP secretion may also be from N?V/hypotension/hypoglycemia - stress dose steroids suppress inappropriate AVP secretion —> water excretion with free water clearance with AQP excretion and promotes Na retention by MC effect - primary AI with GC and MC deficiency —> hypovolemic hyponatremia —> dehydration and excessive renal Na losses - secondary AI - euvolemic hyponatremia - secondary AI almost always assoc with other pituitary hormone deficiencies - 260 inputs with hypopituitarism —> 25 with hyponatremia; 12/260 with mild-mod hyponatremia 13 pts with sev hyponatremia - 219 new dx of hypopit - 75% with secondary AI, 60% with complete hypopit - prevalence in pts with hypipit was 9.6%, 80.7% with hyponatremia as key to dx (of which 22% were symptomatic) - RF for hypoNa and hypopit (old age > 65 yo, severity of hypopit ie re: # of pituitary deficiencies) - most prevalent cause: nonfunctioning pituitary macro adenoma (60%) -in pts with hypopit > 80 yo, hyponatremia seen I n80.6% of pts, if over 60-64 yo range - hyponatremia in hypo pot ranging from 40-60%; in our study 68% with hypoNa were over 60, 44% were over 70 yo // Cuesta - prospective, single center, Na < 130, 576 pts with euvolemic hyponatremia, 573 with SIADH - 18% malignancy associated, 26% CCNS, pulmonary 19%, drugs 8%, 3.8% (of 573 siadh pts) initially dx as SIAD —> recclassified as secondary AI based on cortisol measurements *9/22 with undx hypopit, 13/22 with secondary AI due to exogenous steroid administration) - un dx pituitary disease responsible for 1.5% of euvolemic hyponatremia - tzoulis and bolus (source 15) - routine clinical practice, only 35% with hypoNa had basal plasma ccortisol, and 2% had synacthen testing; another source (10) only 33% with documentation of cortisol measured - 185 pts in endothelial unit found that 28 (15.1%)had AI (secondary to pituitary failure) - 09:00 AM cortisol > 19.9 mcg/dL unlikely to reflect AI (any anywhere from 10 mcg/dL - 15 mcg/dL for random cortisol in acutely ill pts In pts with chronic PO GC intake - steroid deficient if prolonged PO doses - 22 pts with secondary AI (9 with new onset hypopit, 13 on background of chronic exogenous Gc administration - in this cohort, 26% with said from CNS, p19% pulmonary, 18% malignancy, 8% drug related, 10% posted, 5% sepsis, 8% idiopathic - INH steroids with pulmonary disease? - 6 pts with AI due to exogenous steroids - acutely ill (hypotensive _ hyponatremia) // Spital - reduced gfr/ increased PT reabsorption —> inability to maximally dilute but it was not substantiated - rat study with hypophysectomy (induce GC def) without episode or MC def —> impaired ability to excrete PO water load - gill et al - 4 pts with AI administering hydrocortisone improved diluting capacity despite lack of cchange on GFR - two other studies showed in complete inherited central DI rats —> abnormal urinary response to water loading (H0: permeability of distal tubular segments, or through decreased delivery to diluting sites due to changes in infrarenal and systemic hemodynamics which were abnormal) - adrenalectomized rats —> administering MC restored maximal diluting cg capacity (did not normalize urine flow rate) —> may have direct stimulatory effect on solute reabsorption from diluting segment TAL) - supported by sonnenblick work source 13 ; Aldo increases free water clearance due to reduction n UOsm (little change in urine flow0 - in post adrenalectomy dogs —> still with normal response to water load, and again no effect on rabbit cortical ascending limb - dogs and rats adrenalectomized —> diminished excretion of water despite low ADH levels suggests steroids may be needed for distal nephron permeability - isolated renal medullary tubules from rats post adrenalectomy shown to have greater cAMP conc than controls (which is believed to mediate ADH induced increase in distal nephron permeability) —> but mixed results - direct effects on ADH secretion in Ahmed et al but steroids may also have influence on effective circulating volume —> which has direct effectt on ADH release - in vivo - no inhibitory effect of steroids on ADH action, but in vitro data also show that adrenal steroids enhance hydroosmoticc response to ADH // Diederich - 185 pts with Na < 130 in an endo unit 28 pts with euvolemic hyponatremia with hypopit and secondary AI - in 25 cases due to empty sella, Meehan, pit tumors - 12 cases recurrent hyponatremia documented - mean age was 68 years old - clinical s/sx: missing/scanty pubic or axillary hair, pale/doughy skin, small testicles in men - common sx: N, V, confusion, disorientationn, somnolence, coma - 21/28 pts were women, mean 68 years, mean age of men 67 years - on admission 75% complain of nausea, emesis, 32% disoriented, confused, 36% precommatose/comatose, many compiled of abdominal pain, headache, diarrhea, vertigo - when pts recovered from acute illness - 54% reported weakness and tiredness in preceding years, 32% wit unexplained weight loss - sources 10/11 show cortisol is physiologic tonic inhibitor of vasopressin secretion - inadequate thirst and stimulation of AVP secretion by stressors aggravate hyponatremia —> then UrNa loss due to extracellular volume expansion (ANP increase or for renin/aldo suppression) - severe hypothyroidism (primary) assoc with SIADH like syndrome 10 Raff H. Glucocorticoid inhibition of neurohypophysial vasopres- sin secretion. American Journal of Physiology 1987 252 R635 – R644. 11 Erkut ZA, Pool C & Swaab DF. Glucocorticoids suppress corticotropin-releasing hormone and vasopressin expression in human hypothalamic neurons. Journal of Clinical Endocrinology and Metabolism 1998 83 2066–2073. //
- #26 Cortisol inhibit ADH (deficiency allows ADH secretion) Cortisol deficiency causes CRH and ACTH release Primary AI (adrenal gland loss) GC and MC deficiency hypovolemic hyponatremia +/- hyperkalemia UrNa high, UrOsm high Secondary AI (ACTH loss) loss of GC euvolemic hyponatremia (b/c MC can still be stim by AII, hyperK) Usually associated with other pituitary hormone deficiencies UrNa may be low or high, UrOsm high Unsuppressed ADH may cause ECF expansion ANP release ================ Utd: Low BP and low CO but UrNa is not low…. - interrupt neg feedback loop with cortisol suppresses ADH release 2’ AI (hypopit) secondary to low ACTH witout hyperK or hypovolemia Primary AI – salt wasting and hypovolemia Cortisol deficiency due to increased CRH (ADH secretagogue) Ccortisol is neg feedback on CRH and ACTH Cortisol directly suppresses ADH secretion - renal salt wasting (due to aldo deficiency) volume depletion
- #27 Cortisol inhibit ADH (deficiency allows ADH secretion) Cortisol deficiency causes CRH and ACTH release Primary AI (adrenal gland loss) GC and MC deficiency hypovolemic hyponatremia +/- hyperkalemia UrNa high, UrOsm high Secondary AI (ACTH loss) loss of GC euvolemic hyponatremia (b/c MC can still be stim by AII, hyperK) Usually associated with other pituitary hormone deficiencies UrNa may be low or high, UrOsm high Unsuppressed ADH may cause ECF expansion ANP release ================ Utd: Low BP and low CO but UrNa is not low…. - interrupt neg feedback loop with cortisol suppresses ADH release 2’ AI (hypopit) secondary to low ACTH witout hyperK or hypovolemia Primary AI – salt wasting and hypovolemia Cortisol deficiency due to increased CRH (ADH secretagogue) Ccortisol is neg feedback on CRH and ACTH Cortisol directly suppresses ADH secretion - renal salt wasting (due to aldo deficiency) volume depletion
- #28 Of 2458 patients treated with ICPi, 62% with hyponatremia (6% with Na < 124) within first year. Only 9 cases (0.3% with endocrinopathy) Seethapathy - AI with ICPi - retrospective observational study - at 12 months - grade 3/4 hyponatremia - average age 64 yo (58% male) 62% with hyponatremmia < 134, 6% with Na < 124, within first year - Severe hyponatremia - only 9 cases (0.3%) with endocrinopathy Table 4 with 9 Endo pt characteristics, all resolved with steroids (not clear the regimen)
- #29 Unclear link – degree of hypoNa and TFT’s not correlated, may have more relationship to free T3, however Wolf in pts with TSH > 100, 2/138 with hypona from other causes / TSH > 20, 43/764 (5.6%) hypoNa 3/43 (0.39% unclear etiology) Described in post-thyroidectomy pts after RAIA - Vannuci: Post thyroidectomy patients after RAIA with hypothyroidism in 4/101 pts (average pre Na 138.5 132 mEq/L) Unclear mechanism Severe myxedema reduced CO ADH release Hypothyroidism reduced GFR proximal tubular dysfunction Hypothyroidism SIADH (impaired osmoregulation or decreased AVP clearance) Marks: 10 myxedema pts after thyroxine dosage aldosterone plasma and urine excretion rate increased ====== Wolf - of 488 hyponatremic pts, no clinically relevant hyponatremia attributed only to hypothyroidism - in pts with TSH> 20 were seen, 5.62% (43) had hyponatremia) - no correlation of TFT and Na // Vannucci - post thyroidectommy pas (after RAIA) —> frequency of hypothyroidism associated was 4% (other sx?) 1 day post - therapy - post TSH was 93.4 mU/L +/- 22.2 Post Na 138.7 // Ching sun - 10 pts with primary hypothyroidism, mean age 51.5 years, median TSH 193 uU/mL, Na mild (135) in healthy ambulatory patients // Letter - aldosterone excretion rate and plasma Aldo low in hypothyroid pts in response to chelimsky case Cites marks et al lancet: // Agathis - Myxedema sources 1,2 Swiss article
- #30 Marks: 10 myxedema pts after thyroxine dosage aldosterone plasma and urine excretion rate increased ====== Wolf - of 488 hyponatremic pts, no clinically relevant hyponatremia attributed only to hypothyroidism - in pts with TSH> 20 were seen, 5.62% (43) had hyponatremia) - no correlation of TFT and Na // Vannucci - post thyroidectommy pas (after RAIA) —> frequency of hypothyroidism associated was 4% (other sx?) 1 day post - therapy - post TSH was 93.4 mU/L +/- 22.2 Post Na 138.7 // Ching sun - 10 pts with primary hypothyroidism, mean age 51.5 years, median TSH 193 uU/mL, Na mild (135) in healthy ambulatory patients // Letter - aldosterone excretion rate and plasma Aldo low in hypothyroid pts in response to chelimsky case Cites marks et al lancet: // Agathis - Myxedema sources 1,2 Swiss article
- #31 One cclue to volume could be uric acid < 4 (FeUA > 10%) NSIAD – 21 cases coming from 5 pts, males majority GOF T2AVP receptor gene (mirros nephrogenic DI) – free water reabsorption – increase UrConc Burton rose: ADH increases renal prostaglandin which antagonize its ydroosmotic and vascular effects (neg feedback) NSAIDs increase ADH indued water reabsorption and can lead to Uosm > 200 moosm/kg Renal PG also with natriuretic effect via reduced Na reabsorption in TAL and CD
- #32 Symptomatic = seizing, unable to protect airway Bolus v. drip (more control with bolus, although both effective) Risk of ODS: alcoholism, malnutrition, liver disease, and hypokalemia Na < 110 (rare if > 120)
- #33 https://pubmed.ncbi.nlm.nih.gov/7495565/
- #35 If unable to turnoff ADH (ie hypervolemic states, SIADH) hypertonic saline (monitor ECF) Or if worried about turning off ADH due to correction rate (hypovolemia) with DDAVP clamp (keep ADH on)
- #36 If unable to turnoff ADH (ie hypervolemic states, SIADH) hypertonic saline (monitor ECF) Or if worried about turning off ADH due to correction rate (hypovolemia) with DDAVP clamp (keep ADH on)
- #37 If unable to turnoff ADH (ie hypervolemic states, SIADH) hypertonic saline (monitor ECF) Or if worried about turning off ADH due to correction rate (hypovolemia) with DDAVP clamp (keep ADH on)
- #38 9g of salt tabs = 1L of NS = 153 mmol 30g of urea = 500 mmol of urea
- #39 If unable to turnoff ADH (ie hypervolemic states, SIADH) hypertonic saline (monitor ECF) Or if worried about turning off ADH due to correction rate (hypovolemia) with DDAVP clamp (keep ADH on) Of note: there is no data showing that improving Na improves mortality, may improve morbidity
- #40 Free water restriction – not very helpful, requires UOP > fluid intake (so say uosm is fixed at 800 mL/L, making 1L of urine), free water restriction should be 500 mL or less (1/3 did not correct with Na > 130) Effuse – salt tablets (3g/day)without much improvement in SIADH Urea – did help Na correction (normonatremmia in 33%) – dose range from 7.5-90 g/day for 4.5 days Refardt (Jasn) – empa 25 mg + fluid restriction – larger Na increase v. placebo What is the solute load of salt tablets? Molecular weight of sodium chloride is 58.4 so 1 gram is 17 mmol (1 g /58.4 g/mol = 0.017 moles * 1000 mmol/mol) Osm of 9g of salt tabs = 1L of NS = 153 mmol 30g of urea = 500 mmol of urea Furst equation can predict
- #43 Definition Incidence In ICU pts – 9% of pts, develops during ICU stay in around 6% (ahmad and Wisberg, Criticcal Care Medicine, 3rd edition 2008 Na > 155 compared normonnatremia, OR for inhospital mortality and discharge to hospice or SNF were 34.41, 21.24, 12.21 respectively (causal or correlated) Symptoms Sx when OSM is more than 30-35 above baseline
- #44 Insipidus: tasteless Diabetes (Greek means to siphon – pass through) Can have mixed osmotic and free water diuresis Electrolyte free water clearance equation If solute diuresis is Na it’s likely appropriate
- #45 Many algorithms use UrOsm cut offs, but I find that ccomparing to Posm is most helpful In many algorithms re: Uosm cut offs are based on estimated daily solute load of western diet (600-800 mOsm per day) or toniccity related to plasma Hickey hare test – risk of increased ECF osmotic diuresis which would counteract vasopressin’ effect
- #46 Can have mixed osmotic and free water diuresis Electrolyte free water clearance equation
- #47 Insipidus: tasteless Diabetes (Greek means to siphon – pass through) Central (adipsic is a subset related to central DI typically) related to thirst impaired Nephrogenic Dispogenic (primary polydipsia) Gestational Essential hypernatremia is due to osmoreceptor defect ADH release is mediated on high BP (ECF/barorecceptors) Pregnancy may exac central di (macroprolactinoma may increase due to pregnancy Seehan Lymphoccytic hypothysitis (rare AI disease) Transient: metabolism of vasopressinase altered (usually if liver disorder such as AFLD, severe preeclampsia) DI resolves several weeks as liver disease recovers Inccidence: 2-4/100k pregnancies usually in tri2/3 (Hague)
- #49 In many algorithms re: Uosm cut offs are based on estimated daily solute load of western diet (600-800 mOsm per day) Hickey hare test – risk of increased ECF osmotic diuresis which would counteract vasopressin’ effect
- #50 *If your pt is hypernatremic, you’ve already deprived them of water…and you can just to DDAVP challenge Uosm > 800 when hyperNa means urine is maximally concentrated
- #51 Water peprivation limited – esp if pt has partial DI, chronic primary polydipsia (long standing water diuresis blunts renal medullary cconcentrationg radient and down regulates AQ2 in PT and CD mimics nephrogenic DI Goalsis to lose around 3% of body weight, long standing central DI with downreguation of AQP2 inadepate increase inn Uosm due to lack of adequate water reabsorption
- #52 *If your pt is hypernatremic, you’ve already deprived them of water…and you can just to DDAVP challenge
- #53 Fenske – copeptin with hypertonic saline; 250 mL bolus of 3% saline given, then rate of 0.15 mL/kg per minute Na 150, then measured copeptin, free water administration Hickey and hare 1944 – indirect measure of renal function were used to detect AVP; Hickey and hare – (2.5?)5% saline infused at 0.05 mL/kt/hr for 0-2 hours, and Urine volume and uOsm monitored Also they looked at UrCl and water in DI Winzeler – copeptin with arginine; arginine can also stimulate posterior pituitary, then measured plasma copeptin over time
- #54 Restore BP/stabilize patient (with isotonic saline if needed) Give back free water If they are also hypervolemic, may need to give back more free water than free water loss associated with natriuresis Stop free water losses Non-renal: Diarrhea, vomiting, etc Renal: Central: DDAVP Nephrogenic: TZD, acetazolamide, NSAID (can still use desmopressin if suppespect partial nnephrogenic DI), demeclocycline low Na, low protein diet Nephrogenic DI: Thiazide diuretics: thiazides induce mild hypovolemia which increase proximal tubular reabsorption of sodium and water causing decrease in distal delivery of water to the ADH-sensitive sites in the collecting tubules and reducing the urine output improving polyuria. Also, thiazide increase expression of AQP2 in the collecting duct enhancing water reabsorption. Acetazolamide – blocking carbonic anhydrase activates tubular glomerular feedback lowering GFR to decrease urine output despite a lack of ADH activity. Cenntral DI – burton p 778 table 24-6
- #55 Risk of cerebral edema with fast correction Alshayeb – Na > 155 Slow correction (< 6 in a day) Chahan Rapid > 12 Slow < 12