A New Perspective on Hyponatremia


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A comprehensive and concise review of hyponatremia with multiple pictures easy to understand for deep learners and medical students

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A New Perspective on Hyponatremia

  1. 1. A New Perspective onA New Perspective onHyponatremiaHyponatremiaby Steve Chenby Steve ChenDirector of Nephrology,Shin-Chu Branch of Taipei Veterans General Hospital
  2. 2. SodiumSodiumReference Range:136 – 145 meq/L
  3. 3. SodiumSodiumHyponatremia is Na+< 135 meq/L
  4. 4. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS Serum NaSerum Na++< 135 meq/L< 135 meq/L– Symptoms due to brain edema:Symptoms due to brain edema:headache & vomiting ifheadache & vomiting if NaNa++< 120< 120meq/Lmeq/L– CNS symptoms:CNS symptoms:convulsions ifconvulsions if NaNa++< 113 meq/L< 113 meq/L– CV symptoms:CV symptoms:CV collapse ifCV collapse if Na < 100 meq/LNa < 100 meq/LHyponatremia
  5. 5. HyponatremiaHyponatremiaCauses an osmotic fluid shift fromplasma into brain cells
  6. 6. Hyponatremic encephalopathyHyponatremic encephalopathy Hospital acquired:SIADHPost-operative state: 3-4 L hypotonic fluidin 2 days in female  fatalEncephalitis in children: fatal Risk factors:Children : non-osmotic stimuli of ADH↑brain/intracranial volumeFemale: sex steroid inhibitbrain adaptation Hypoxemia
  7. 7. Hyponatremic encephalopathyHyponatremic encephalopathyOutpatient :MedicationsPsychogenic polydipsiaWaterintoxification in infantsMarathon runnersHip fractureS/P colonoscopy : ADH↑frombowel manipulation + polyethelene glycol for bowel preparationRecreational drug:
  8. 8. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS Pathophysiology: CNSPathophysiology: CNS– Water shifts into brain cellsWater shifts into brain cells– ApathyApathy –– Altered ConsciousnessAltered Consciousness– AgitationAgitation –– ConvulsionsConvulsions– HeadacheHeadache –– ComaComa– Risk of brain damage > during treatmentRisk of brain damage > during treatment– Cerebral demyelination syndrome(CDS)Cerebral demyelination syndrome(CDS)Hyponatremia
  9. 9. Cerebral Demylination SyndromeCerebral Demylination SyndromeCDSCDSrisk factorsrisk factors Development of Hypernatremia ↑S-Na > 25 meq /L in 48Hrs Hypoxemia Hypokalemia Mal-nutrition Severe liver disease Alcoholism Severe burns Cancer U osm ≤ 150 Kg/L
  10. 10. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS Serum OsmolalitySerum Osmolality– Number of osmoles (osmotically activeNumber of osmoles (osmotically activeparticles) in the serumparticles) in the serum– Normal rangeNormal range 275 to 295 mosm/L275 to 295 mosm/LFluid Balance2[Serum Na+] + ------------ + ------------Glucose BUN18 2.8
  11. 11. ELECTROLYTE DISORDERSELECTROLYTE DISORDERSHyponatremiaHyponatremiaFlow of D.D.Flow of D.D.PlasmaOsmolalityNormal (275-295)IsotonichyponatremiaLow (< 275)HypotonichyponatremiaHigh (> 295)HypertonichyponatremiaHypovolemic Hypervolemic Euvolemic
  12. 12. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS HypertonicHypertonic HyponatremiaHyponatremia (P(Posmosm > 295)> 295)– Large quantities of solute in ECFLarge quantities of solute in ECF– Water moves from ICF ECFWater moves from ICF ECF– HyperglycemiaHyperglycemia most common causemost common cause Each 100 mg/dl plasma glucose will serumEach 100 mg/dl plasma glucose will serumNaNa++by 1.6 meq/Lby 1.6 meq/L– TreatmentTreatment Volume replacementVolume replacementHyponatremia, hypertonic
  13. 13. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS IsotonicIsotonic HyponatremiaHyponatremia (P(Posmosm 275 - 295)275 - 295)– ““PseudohyponatremiaPseudohyponatremia””– Artifact in serum NaArtifact in serum Na++measurementmeasurement 2° High levels of plasma proteins and lipids2° High levels of plasma proteins and lipids– Etiology:Etiology: HyperlipidemiaHyperlipidemia HyperproteinemiaHyperproteinemiaHyponatremia, isotonic
  14. 14. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS HypotonicHypotonic HyponatremiaHyponatremia (P(Posmosm < 275)< 275)Plasma OsmolalityNormal (275-295)IsotonichyponatremiaLow (< 275)HypotonichyponatremiaHigh (> 295)HypertonichyponatremiaHypovolemic Hypervolemic EuvolemicHyponatremia, hypotonic
  15. 15. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS HypovolemicHypovolemic HyponatremiaHyponatremia– RenalRenal NaNa++lossloss Urine NaUrine Na++> 20 meq/L> 20 meq/L Etiology:Etiology:– Diuretic useDiuretic use– Salt-wasting nephropathy (renal tubular acidosis, chronicSalt-wasting nephropathy (renal tubular acidosis, chronicrenal failure, interstitial nephritis)renal failure, interstitial nephritis)– Osmotic diuresis (glucose, urea, mannitol,Osmotic diuresis (glucose, urea, mannitol,hyperproteinemiahyperproteinemia– Mineralocorticoid (aldosterone) deficiencyMineralocorticoid (aldosterone) deficiency
  16. 16. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS HypovolemicHypovolemic HyponatremiaHyponatremia– ExtrarenalExtrarenal NaNa++lossloss Urine NaUrine Na++< 20 meq/L< 20 meq/L Etiology:Etiology:– Volume replacement with hypotonic fluidsVolume replacement with hypotonic fluids– GI loss (vomiting, diarrhea, fistula, tube suction)GI loss (vomiting, diarrhea, fistula, tube suction)– Third-space loss (burns, hemorrhagic pancreatitis,Third-space loss (burns, hemorrhagic pancreatitis,peritonitis)peritonitis)– Sweating (cystic fibrosis)Sweating (cystic fibrosis)
  17. 17. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS HypovolemicHypovolemic HyponatremiaHyponatremia– TreatmentTreatment Re-expansion of ECF withRe-expansion of ECF with isotonic salineisotonic saline Correction of underlying disorderCorrection of underlying disorder
  18. 18. To calculate Na deficitTo calculate Na deficitSodium deficit = total body water X(desired Na - present Na)TBW = body wt x 0.6 males0.5 females
  19. 19. Sodium DeficitSodium Deficit Na deficit= Vd of plasma Na x Na deficit per liter﹝ ﹞ Vd of plasma Na = TBWa = 0.5 x LBW if﹝ ﹞female =0.6 x LBW if man 60Kg woman, Thiazide 5 days, acute confusion,plasma Na = 108meq/L. If Na =120 is safe,﹝ ﹞ ﹝ ﹞sodium deficit= 0.5x 60x﹙120-108 =360﹚ Urine Na> 40meq/L indicates Normovolemiarestored NS supplied for fear of postsupply overdiuresis
  20. 20. Post-N/S diuresis: turn off ADHPost-N/S diuresis: turn off ADHU osm <100 mOsmInitial rate before P-Na targeted:ongoing freewater loss =UV x [ 1-( UNa+UK / PNa+PK ) ]Later rate after P-Na targeted:freewater loss= UV x [ 1-( UNa+UK-oral Na+K-IV
  21. 21. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS EuvolemicEuvolemic Hyponatremia(1)Hyponatremia(1)– SIADHSIADH Hypotonic hyponatremiaHypotonic hyponatremia Inappropriately elevated urine osmolality (usually > 200Inappropriately elevated urine osmolality (usually > 200mosm/kg)mosm/kg) Elevated urine NaElevated urine Na++(> 20 meq/L)(> 20 meq/L) Clinical euvolemiaClinical euvolemia Normal adrenal, renal, cardiac, hepatic, and thyroid functionNormal adrenal, renal, cardiac, hepatic, and thyroid function
  22. 22. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS EuvolemicEuvolemic Hyponatremia(2)Hyponatremia(2)– Etiology:Etiology: HypothyroidismHypothyroidism Pain, stress, nausea, psychosis (stimulates ADH)Pain, stress, nausea, psychosis (stimulates ADH) Drugs: ADH, nicotine, sulfonylureas, morphine,Drugs: ADH, nicotine, sulfonylureas, morphine,barbs, NSAIDS, APAP, Carbamazepine,barbs, NSAIDS, APAP, Carbamazepine,Phenothiazines, TCAs, Colchicine, Clofibrate,Phenothiazines, TCAs, Colchicine, Clofibrate,Cyclophosphamide, Isoproterenol, Tolbutamide,Cyclophosphamide, Isoproterenol, Tolbutamide,MAOIsMAOIs
  23. 23. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS EuvolemicEuvolemic Hyponatremia(3)Hyponatremia(3)– Etiology:Etiology: Water intoxication (psychogenic polydipsia)Water intoxication (psychogenic polydipsia) Glucocorticoid deficiencyGlucocorticoid deficiency Positive pressure ventilationPositive pressure ventilation PorphyriaPorphyria Essential (reset osmostat orEssential (reset osmostat or sick cell syndromesick cell syndrome))
  24. 24. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS Treatment of Severe Hyponatremia(4)Treatment of Severe Hyponatremia(4)– Indications:Indications: Serum NaSerum Na++< 120 meq/L< 120 meq/L Rapid development ( NaRapid development ( Na++> 0.5 meq/L/hr)> 0.5 meq/L/hr) Patient in extremis (coma, seizures)Patient in extremis (coma, seizures)– 3% Saline Solution (513 meq/L) @3% Saline Solution (513 meq/L) @ 25 - 10025 - 100ml/hrml/hr NaNa++should not exceed 0.5 – 1.0 meq/L/hrshould not exceed 0.5 – 1.0 meq/L/hr
  25. 25. Time Classification of SIADH-Time Classification of SIADH-HyponatremiaHyponatremiaDuration ClinicalsettingRisk TherapyAcute <48Hr Post-operativeBrain cellswelling↑﹝Na by up﹞to 5meq/L/HChronic UnknownOr > 48HrMany Cerebraldemyelinationsyndrome↑﹝Na﹞<0.33meq/L/H
  26. 26. Therapy for SIADHTherapy for SIADH Aggressive Tx only for Pts with coma/seizure:↑ Na up to 5meq/L to control CNS S/S; then﹝ ﹞↑ Na 8meq/L/D﹝ ﹞≦ Slow correction when brain cell size normal↑ Na 8meq/L/D to prevent CDS﹝ ﹞≦ 3%NaCl 1cc/Kg/Hr= ↑ Na 1meq/L/Hr﹝ ﹞ Even slower correction if manutrition orhypercatabolic state(poor availability of K ororganic osmoles
  27. 27. SIADH with chronic hyponatremiaSIADH with chronic hyponatremiaA 50Kg,SIADH due to tumor, plasmaNa 120meq/L, asymptomatic﹝ ﹞TBW=30L; ICF 20LTotal ICF osmoles normally=20x2x140=5600If ICF osmoles unchanged,ICF=5600/2x120=23.2LTime(hr)=140-120/0.5=40Hr Therapeutic goal: To lose 3L of EFW within 40Hr
  28. 28. Treatment guidelinesTreatment guidelinesAdministration of oral or IV Na+(3%)SupplementsEncourage foods high in Na+Fluid restrictionMonitor Neurological StatusNormovolemic hyponatremia:V2 antagonist– Vaprisol (conivaptan) – IV infusion– Samsca (tolvaptan) - PO
  29. 29. Renal water channels: AQPRenal water channels: AQP Aquaporins: AQP 0 ~ 12 AQP 0: Cataract AQP 1 in proximal & thin descending LOH:re-absorption of most filtered fluid= partialNDI AQP 2 in apical of collecting duct: urineconcentration= NDI AQP 3 & 4 in baso-lateral of collecting duct: AQP 5: SS AQP 7 in apical of S3 proximal: 10% aswater route; glycerol re-absorption AQP 11 in intracellular vesicles: PCKDSei Sasaki: Tokyo Medical and Dental
  30. 30. AQP 2 binding protein complexAQP 2 binding protein complexTrafficking of AQP2Mis-routing to baso-lateral membraneinstead of apicalSPA-1: a GTP-ase activating protein forRap1Cytoskeleton protein actinSei Sasaki: Tokyo Medical and DentalUniversity
  31. 31. Urinary concentration modulationUrinary concentration modulation↑c AMPAQP2 traffickingand expression
  32. 32. Post-3%N/S free water diuresisPost-3%N/S free water diuresis Psychogenic polydipsia DC of DDAVP Water intoxification in infants Hypotonic fluid plus DDAVP forovercorrection of hyponatremia Case:70Kg, TBW 35, S-Na 110meq/L1L 3% NaCl  11.2 meq/L↑by closed system equation 22meq/L if 3L free water diuresis
  33. 33. Post-3%N/S natriuresisPost-3%N/S natriuresisSIADHCerebral salt wastingCase:SIADH with fixed urine osmolality600 1L 3% NaCl  11 meq/L ↑by a closed systemequation 7 meq/L ↑ if 1L urine Na+K=250 meq/L
  34. 34. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS HypervolemicHypervolemic Hyponatremia(1)Hyponatremia(1)– Without advanced renal insufficiencyWithout advanced renal insufficiency Urine NaUrine Na++< 20 meq/L< 20 meq/L Cirrhosis, ascites, CHF, Nephrotic syndromeCirrhosis, ascites, CHF, Nephrotic syndrome– Advanced acute or chronic renal insufficiencyAdvanced acute or chronic renal insufficiency Urine NaUrine Na++> 20 meq/L> 20 meq/L Renal failure (inability to excrete free water)Renal failure (inability to excrete free water)
  35. 35. ELECTROLYTEELECTROLYTEDISORDERSDISORDERS HypervolemicHypervolemic Hyponatremi(2)Hyponatremi(2)– TreatmentTreatment Optimize treatment for underlying disorderOptimize treatment for underlying disorder Judicious salt and water restrictionJudicious salt and water restriction ++ DiureticsDiuretics ++ DialysisDialysis
  36. 36. Hypouricemia in hyponatremiaHypouricemia in hyponatremiavolume mechanism ReferenceSIADH N/↑ water↑Thiazide-inducedhyponatremia↑/↓ water↑ Fichman et al,AJM 1971Polydipsia-inducedhyponatremia↑ water↑ Hanihara etal, JCP 58,256-260, 1997CSW ↓ ANF→Proximal tubuleMaesaka et al,CN 33, 1990Hyperbilirubinemiasevere↓ Cholaemia→ Proximal tubuleTinatul et al,JMAT 1970
  37. 37. Trickle-down hyponatremiaTrickle-down hyponatremiaOh et al, JASN 8: 108A, 1997Oh et al, JASN 8: 108A, 1997subgroups ↓Solutes ↓ADH ReferenceI. Tea/ToastpotomaniaToast: ↓Protein;Thiazide forHTN: ↓NaclTea:electrolyte-free waterBoulanger et al,NDT 14: 2714-15, 1999II. SlimpotomaniaLow proteinintake/NaCl;Exercise↑Water Thaler et al,AJKD 31:1028-31, 1998III. Beerpotomania↑CHO+fat+alcohol;↓Protein+NaCl↑Water Oh et al,1997
  38. 38. Beer PotomaniaBeer Potomania cH2O= Solute excretion/ Uosm﹙1-Uosm/Posm﹚ Dependence of water clearance on dailysolute excretion at low urine osmolality(<100) Uosm=80mOsm/kg(<100)solute 300mOsm; cH2O=2.7L;solute 600, cH2O=5.4;solute 900, cH2O=8.1L Total solute excretion = urea + 2x﹙Na+K﹚urea= 50x7+100 ~ 150=450( for 70gprotein intake)Thaler et al, AJKD 1998
  39. 39. Basal water channels(BWC)Basal water channels(BWC) Vasopressin-independent water permeabilityhigh in the inner MCDLankford et al, AJP 261: 554-566, 1991 Hereditary DI in ratEdwards et al, AJP 239: 84-91, 1980 A different AQP: severe impaired urinaryconcentrating ability in transgenic micelacking AQP1 water channelsMa et al, JBC 273:4296-99,1998 Predominant in the neonatal stage :physiological DI in waterload≧20ml/Kg→water diuresis Chlopropamide↑
  40. 40. BWC>>AQP2BWC>>AQP2Halperin et al, Clinical Nephrology 56: 339-345, 2001Halperin et al, Clinical Nephrology 56: 339-345, 2001 In the neonatal stage Trickle-down hyponatremia:Low volume delivery to MCDlow GRF/↑ re-absorption of filtrate in proximal tubule↑water permeability in cortical distal nephronlow solute excretion rate: Urea+NaCllow protein diet (low urea)low NaCl intake ± large non-renal or prior renal NaCl lossADH suppression
  41. 41. The Janus effect: 2 faces ofThe Janus effect: 2 faces ofAldosteroneAldosteroneChronic L-NAME
  42. 42. Sodium Channel: ENaCSodium Channel: ENaCModes of ENaC regulationModes of ENaC regulation
  43. 43. Aldosterone/Vasopressin in CDAldosterone/Vasopressin in CDE Na C Na K ATP aseNaKV2RAquaporinH2OMRATPc AMPPKANedd4-2AldosteroneSgkNedd4-2: neural precursor cell expressed developmentally down-regulated 4-2Sgk: serum and glucocorticoid inducible kinase
  44. 44. Aldosterone/Vasopressin/CaSRAldosterone/Vasopressin/CaSRin CDin CDE Na CROMKNa K ATP aseDepolarize+Aldosterone+NaKV2RAquaporinH2OCaSRCaSR
  45. 45. Angiotensin II in CNT and CCDAngiotensin II in CNT and CCDE Na CROMK1Na K ATP aseNaK Proteintyrosinekinase(c-Src)V2RAT1RA candidate for an aldosterone-independent mediator of K preservationduring volume depletion
  46. 46. Clinical correlation of ENaCClinical correlation of ENaCVivek Bhalla et al: JASN 19: 1845-54,2008
  47. 47. Processing of natriuretic peptideProcessing of natriuretic peptideConvertaseSignal peptidase
  48. 48. Corin: new insights into ANPCorin: new insights into ANPCorin: a transmembrane serine proteaseidentified in the heartConvert pro-ANP to active ANPLack of corin →Salt sensitive HTN in miceSingle nucleotide polymorphism→African Americans with HTN and cardiachypertrophy Q Wu et al: KI 75: 142-146, 2009
  49. 49. Mutations of renal Na channelsMutations of renal Na channels Liddle syndrome: β and γ subunits of amiloride-sensitiveENaC Gordon syndrome: WNK1 and WNK4 kinases Glucocorticoid remediable aldosteronism: aldosteronesynthase/11 β hydroxylase Adrenal hyperplasia: 11α hydroxylase/β hydroxylase Apparent mineralocorticoid excess: mineralocorticoidreceptor, 11 βhydroxystreoid dehydrogenase Progersterone induced hypertension: mineralocorticoidreceptor Psuedo-hypoaldosteronism (PHA)
  50. 50. PseudoHypoAldosteronism: PHAPseudoHypoAldosteronism: PHABonny et al, JASN 13: 2399-2414, 2002Bonny et al, JASN 13: 2399-2414, 2002Clinical Gene DefectsType I: ARADRenal: salt wasting/hypo-NaHyper-KMetabolic acidosisPAC↑/PRA↑Extra-renal: chest, GI, skinRenal : spontaneous remissionENaCMineracorticoid receptorType II: AD( Gordon syndrome )Renal: HTNHyper-KHCMAnormal PAC; PRA↓A: 1q31-q42B: WNK4C: WNK1Type III:Acquired(obstructivenephropathy; UTI;lead; amyloidosis)GFR↓; Excessive salt lossHyper-KHCMAPAC↑/PRA↑Transient PHA
  51. 51. Chloride channel: CLCChloride channel: CLChCLC-Ka(rCLC-K1)hCLC-Kb(rCLC-K2)CLC-5Location TALH,basolateralTALH, DCT,αIC basolateralPCT, αICintracelluarshunt by HATPaseDisease NDI, DDAVP-insensitive(Clcnk1)Tyep III Barttersyndrome(CLCNKB)Mixed Bartter-Gitelman(CLCNKB)XLRnephrolithiasis(Dent’s: CLC-5)↓Receptor-mediatedendocytosis
  52. 52. Variants of Bartter’s syndromeVariants of Bartter’s syndromeIsrael Zelikovic, NDT 18: 1696-1700, 2003Israel Zelikovic, NDT 18: 1696-1700, 2003Defectivetransporter/proteinClinical LocusType I NKCC2 (TAL) Antenatal 15qType II ROMK (TAL/CD) Antenatal 11qType III ClC-Kb (TAL,DCT) Classic 1p36Type IV Barttin (β of CIC-Ka/CIC-Kb)BSND(Deafness)1p31ADHypercalciuriaCaSR(PT/TAL/DCT/CD)Hypocalcemia 3q
  53. 53. Bartter’s syndrome in THALBartter’s syndrome in THALNKCCROMKNa K ATP aseCa, Mg pHNa/KK2ClCaSRNegativePositiveClC-Kb213
  54. 54. Bartter with Sensori-NeuralBartter with Sensori-NeuralDeafnessDeafnessBSNDBarttin forms heterodimerswith ClC-Ka in thin ALHwith ClC-Kb in thickALH→ NDIwith ClC-K in marginal cells of striavascularis (inner ear) & vestibular dark cells
  55. 55. Gitelman’s / Bartter’s syndromeGitelman’s / Bartter’s syndromeGitelman’s Bartter’sMolecular level ↓TSC in DCT ↓NKCC, ROMK, orClAge at onset Teenage ChildrenClinical Tetany Failure to thriveMimicked by Thiazides Loop diureticsPlasma Mg ↓ ↓D.D. Hypocalciuria HypercalciuriaUosm ↓
  56. 56. Thiazide-induced hyponatremiaThiazide-induced hyponatremiaRenal salt wasting: via TSC in DCTWater retention:hypovolemia-induced ADH releasedirect effect of ↑distal water reabsorption( via PGE2↓; indomethacin↑)Magaldi et al, NDT 15: 1903-5, 2000↑thirst and water intakeNo calcium wasting
  57. 57. Salt transport in DCTSalt transport in DCTTSCNa2ClV2RInactiveTSC dimer TSCmonomerAT1RMRSPAK
  58. 58. Vasopressin/CaSR in DCTVasopressin/CaSR in DCTTSCTRPV5Na K ATP asepH pHNaCa2ClCaSRPositivePositiveCaSRCaATPaseNCXV2RKinaseSPAK
  59. 59. Salt-losing nephropathySalt-losing nephropathySalt-losing nephropathy withinappropriate secretion of ANP( 10 ~47fmol/ml): no cardiac or cerebralabnormality pseudo-barttersyndrome: concentaring power highly-conserved;normokalemic metabolic alkalosis; no responseto indomethacin therapy Granulomatous interstitial nephritis&uveitis:non-caseating granuloma6-M steroid therapyPrimary renal candidiasis:caseating renal granuloma→medullary destruction
  60. 60. Milk alkali syndromeMilk alkali syndrome↑Free P-Ca++ /Mg++CaCO3 in duodenum + ferment H+→ Free Ca++ in lumen;if low HPO4 in GI (poor intake)→ Free P-Ca++ ↑ via para-cellular routeHypercalcemia GFR↓
  61. 61. Anorexia nervosa + AntacidsAnorexia nervosa + AntacidsMitchell Lewis HalperinMitchell Lewis HalperinP-Na=118mM ; U-Na 44mMpH=7.2; P-HCO3=9P-K=2.0mM; U-K=17mMK deficit >120P-Ca 2.56mM; P-alb 2.7g/dlUV>6L; Uosm=150P-Mg 1.5mM