1. Sodium and Water: What Laboratory Scientists Need to Know Graham Jones Staff Specialist in Chemical Pathology St Vincent’s Hospital, Sydney Presented RCPA/AACB Chemical Pathology training Course, February 2004, Adelaide

2. Objectives Measurement Physiology Pathology Lab-based knowledge

3. Sodium Measurement Most Australian Laboratories use Ion Sensitive Electrodes (ISE) May be direct or indirect Indirect –Dilution of the sample –Most automated analysers –Affected by lipid and protein concentrations Direct –No dilution of the sample –Blood gas machines –Vitros analysers

4. What we measure Analyte: Sodium Measurand: –activity of sodium ions per volume of sample (indirect) –Activity of sodium ions per mass of water* (concentration) * expressed per volume of plasma

5. Sodium Measurement: Interferences Analytical –Electrodes are very specific –In the presence of increased amounts of non- aqueous components we get reduced values with indirect methods (pseudohyponatraemia) Pre-analytical –Drip-arm –Wrong patient –Gross haemolysis (dilution with intracellular fluid)

6. Drip arm contamination Common diluents: –Normal saline: 154 mmol/L Na and Cl –5% dextrose: 278 mmol/L glucose –4% & 1/5th saline: 222 mmol/L gluc, 31 Na & Cl Results tend to values in diluent –eg Na of 170 unlikely to be drip-arm Osmolality tends to be normal Measuring glucose, albumin and protein helpful

7. Artefacts: examples Questions: Could it be pathology? Could it be artefact? * * ** * * ** * *

8. How good are we Average analytical CV about 1% Gives SD of about 1.4 mmol/L for normal result 95% of results in a 5.6 mmol/L range (+/- 2SD) Biological variation –Within person 0.6 % –Between person variation 0.6% Acceptable CV is <0.75 x within person CV –Not acceptable!!

9. Water Measurement Clinical –Weight (change in weight) –Physical examination: pulse, blood pressure, JVP, lung auscultation, oedema Concentration of blood components –High albumin#, high sodium may mean low water content of samples. # or prolonged tourniquet for albumin –Low albumin or low sodium may mean high water concentration of samples –5% dehydration highly significant

10. Water and electrolytes: Other Tests Serum –Urea, Creatinine –Glucose –Osmolality (and osmolar gap) –Albumin, Total Protein –Lipids Urea –Sodium –Osmolality –Creatinine

11. Physiology

12. Body Sodium Sodium: major extracellular cation –Approx 10 mmol/L intracellularly –140 mmol/L extracellularly Intake: 100 - 200 mmol/day Excretion: –Faecal: 10 mmol/d –Sweat: 10-20 mmol/d –Renal: the rest (ie matches intake) Equally distributed in extracellular fluid –ie drain fluid –except urine and gastro-intestinal fluid!

13. Sodium and Water Sodium and Water homeostasis are inextricably linked “where sodium goes, water follows” Measure sodium concentration –Affected by changes in water and sodium Clinical effects due to movement of water in and out of cells

14. Salt and Water regulation Water –Thirst (regulates input) –Vasopressin (ADH) (regulates output) Sodium –Renin-Angiotensin-Aldosterone (RAA) –Natriuretic peptides –Both regulate output

15. Vasopressin (ADH) Hormone from Posterior pituitary Released in response to high osmolality Released in response to low volume –Low volume over-rides low osmolality Increases permeability of kidney distal tubule Controls renal WATER excretion –Low ADH -> high urine volume, low urine osmo –High ADH -> low urine volume, high urine osmo Also potent vasocontrictor

16. Vasopressin (ADH) Dehydration Hypernatraemia (Increased osmolality) ADH Release Reduced renal water loss Reduced BP Vasocontriction EuvolaemiaConcentrated Urine

17. Renin-angiotensin-aldosterone (RAA) Low renal perfusion -> renin release –eg hypovolaemia, heart failure, shock. Renin converts Angiotensinogen to Angiotensin I ACE converts AI to AII AII releases Aldosterone from adrenal gland Aldosterone acts in proximal tubule –resorbs sodium, excretes potassium Controls urine SODIUM excretion

18. RAA Response to Dehydration Dehydration Reduced Renal Perfusion Vasocontriction Renal Sodium resorption Renin release Euvolaemia Angiotensin I Production Aldosterone releaseAngiotensin II Production Incr Plasma osmolality, ADH, thirst ACEI Low urine sodium

19. Renal Water & Sodium Handling Active sodium Passive water Sodium only (no water) Makes dilute urine Water: ADH-sensitive Sodium: 25 mol/d Water: 150 L/d Sodium: 100-200 mmol/d Water: 1-2 L/d Sodium: Aldosterone-sensitive

20. Additional Mechanisms Thirst –Responds to high osmolality and low volume –Powerful but slow regulator Natrurietic Peptides –Atrial (ANP, atrium); Brain (BNP, ventricle) –Respond to stretch (over filling) –Causes renal sodium and water loss –Blocks RAA, causes vasodilation –Markers of heart failure, HT

21. Pathology

22. Sodium and Water balance In normals: –Sodium in = sodium out –Water in = water out With changes: –Systems try to correct changes –eg dehydration -> water retention With defects in systems: –other mechanisms try and correct defect –eg DI, thirst can correct body interior

23. Clinical Derangements Water –Too much, too little, just right Sodium –Too much, too little just right Combination leads to sodium concentration

24. Sodium - Clinical Effects Hypernatraemia - draws water out of cells Hyponatraemia - water drawn into cells –Main effects on brain!! >160twitching, siezures, coma >150weakness, lethargy <130nausea, drowsiness <120vomiting, confusion <110convulsions, coma Depends on rate of change and other factors

25. Hyponatraemia

26. Hyponatraemia: Important Diagnoses Diuretics Renal Failure Addison’s disease Hypothyroidism Liver failure Heart Failure SIADH Artefacts

27. Hyponatraemia diagnosis Hyponatraemia Measure plasma osmolality Normal Drip-arm Pseudohyponatraemia: - Hyperlipidaemia - Hyperproteinaemia Decreased True Hyponatraemia Increased Hypertonic Hyponatraemia: - Hyperglycaemia - Hyperglycinaemia (post TURP) Measure Urine Sodium and osmolality, state of hydration Urine sodium >20 mmol/LUrine sodium <20 mmol/L Exclude common drugs, eg diuretics

28. Hyponatraemia diagnosis Hyponatraemia Measure plasma osmolality Normal Drip-arm Pseudohyponatraemia: - Hyperlipidaemia - Hyperproteinaemia Decreased True Hyponatraemia Increased Hypertonic Hyponatraemia: - Hyperglycaemia - Hyperglycinaemia (post TURP) Measure Urine Sodium and osmolality, state of hydration Urine sodium >20 mmol/LUrine sodium <20 mmol/L Exclude common drugs, eg diuretics

29. Drugs and Hyponatraemia Diuretics (sodium loss) –Eg thiazides, frusemide, indapamide Potentiate ADH secretion (water retention) –barbiturates; narcotics; oral hypoglycaemics; antineoplastics; anticonvulsants, antidepressants –miscellaneous (clofibrate, isoprenaline, nicotine derivatives) Potentiate ADH action (water retention) –Chlorpropamide, paracetamol, indomethacin

30. Hyponatraemia diagnosis Hyponatraemia Measure plasma osmolality Normal Drip-arm Pseudohyponatraemia: - Hyperlipidaemia - Hyperproteinaemia Decreased True Hyponatraemia Increased Hypertonic Hyponatraemia: - Hyperglycaemia - Hyperglycinaemia (post TURP) Measure Urine Sodium and osmolality, state of hydration Urine sodium >20 mmol/LUrine sodium <20 mmol/L Exclude common drugs, eg diuretics

31. Low Sodium and Normal Osmolality Normal Osmolar gap –Drip Arm –Glucose high, included in osmolar gap calculation High Osmolar Gap –Pseudohyponatraemia –High total protein (>100 g/L) –High Lipids Triglycerides Lipoprotein X

32. Pseudohyponatraemia Reduced measured sodium (and other analytes) in indirect measurements Caused by increase in non-aqueous components –Triglycerides > 30 mmol/L –Protein > 100 g/L Sodium molality is normal Sodium molarity is low Normal measured osmolality (high osmolar gap) Normal result in blood gas analyser BODY THINKS SODIUM IS NORMAL

33. Hyperosmolar Hyponatraemia (dilutional hyponatraemia) High extracellular osmolality –Glucose (normal osmolar gap) –Glycine (raised osmolar gap) Occurs after TURP Draws water out of cells With treatment glucose returns into cells –Water follows glucose into cells –Sodium level increases –Sodium rise = glucose(mmol/L)/4 –Eg Sodium 125 mmol/L Glucose 40 mmol/L * * * * * * * * * * * * ** * * ** * * * * * * * ** * * * * * * *

34. True Hyponatraemia Low osmolality Normal osmolar gap Further investigation indicated –Clinical evaluation of state of hydration –Spot urine sample sodium Osmolality

35. Hyponatraemia: further investigation Measure Urine sodium and osmolality, determine state of hydration Urine sodium > 20 mmol/L Urine sodium < 20 mmol/L Patient Hypovolaemic Renal losses (UPO>1) - Diuretic therapy - Addisons Disease - Salt-losing nephritis - Proximal RTA Osmotic diuresis (UPO  1) - glucose, urea Patient Euvolaemic Chronic water overload - SIADH (U osmo>200) - Hypothyroidism - Cortisol deficiency (UPO>1) Acute Water Overload - Stress, post surgery - Psychogenic polydipsia (UPO<1) Patient Overloaded Renal failure - acute, chronic

36. Hyponatremia: low Urine sodium Patient Hypovolaemic Extra-renal losses (UPO>1) - vomiting, diarrhoea - skin loss, pancreatitis Patient Oedematous Renal sodium retent’n - cirrhosis, CCF - nephrotic synd. Patient Euvolaemic Fluid depletion and hypotonic replacement SIADH with fluid restriction Measure Urine sodium and osmolality, determine state of hydration Urine sodium > 20 mmol/L Urine sodium < 20 mmol/L

37. Sodium in urine Vital investigation for sodium abnormalities Spot urine most useful Normal range: NOT USEFUL Decision point: 20 mmol/L –Only when patient has true hyponatraemia Consider effects of salt (RAA) and water (ADH) 24 hour urine –In normals reflects daily intake –Can be useful for assessing replacement

38. Hyponatraemia: Important Diagnoses Diuretics - History Renal Failure - creatinine Addison’s disease - Cortisol, Synacthen test Hypothyroidism - TFTs Liver failure - LFTs Heart Failure – History, BNP SIADH

39. True Hyponatramia Euvolaemic (slight overload) Urine sodium > 20 mmol/L (RAAS not on) Urine osmolality > 200 (ADH present) No renal, cardiac, liver or adrenal problems Response to water restriction CNS lesions, lung lesions, cancer

40. SIADH Increased ADH Water retention in Kidney Urine osmolality high (>200 mosm/kg) Hypervolaemia (not dehydrated) Inhibition of RAAS HyponatraemiaUrine sodium > 20 mmol/L

41. Hypernatraemia

42. Hypernatraemia diagnosis “Dehydration until proven otherwise” 1. Exclude artefact (drip arm) 2. Not enough water –Not enough in too sick, old, young, restrained; thirst center lesion –Too much out DI, GIT, renal 3. Too much salt –Iatrogenic, sea water drowning, Conn’s

43. Hypernatraemia Patient Dehydrated U Na > 20 mmol/L Salt ingestion (tablets, sea water, iv hypertonic saline or Na Bicarbonate) Mineralocorticoid excess syndromes (only with inadequate fluid intake) Determine state of hydration and measure urine sodium and osmolality. U Na 800) - too young, too old, too sick, prevented, oesophageal stricture, thirst centre damage Non-renal water loss (Uosmo > 800) - GI loss, skin loss Diabetes insipidus with inadequate fluid intake (U osmo < 300) U Na > 20 mmol/L Renal Sodium loss - osmotic diuresis (UPO  1) - diuretics with decreased water intake - renal disease Patient Hypervolaemic Patient Euvolaemic U osmo < 800 Diabetes insipidus - central - nephrogenic U osmo > 800 Insensible water losses - lung - skin

44. Polyuria

45. 1.Distinguish from urinary frequency Timed collection can be useful High Urine osmo makes polyuria unlikely 2. Consider causes Diabetes mellitus (osmotic) Drugs: Diuretics, lithium Diabetes insipidus (insufficient ADH) Psychogenic polydipsia (depressed ADH) Renal failure (polyuria)

46. Polyuria investigation Urine osmolality >400: not present at time of testing Approx 300: osmotic, eg diabetes, renal <200: Diabetes Insipidus, Psychogenic polydipsia Biochemically indistinguishable Needs water deprivation test

47. Laboratory Knowledge Laboratory –Type of assay –Alternatives (blood gas, osmolality) –What drip-arm sample look like Hyponatraemia –Interpretation of serum osmolality –Pseudohyponatraemia, dilutional hyponatraemia –Importance of drugs –Requires spot urine Na and osmo –“Reference intervals” are not required for urine sodium Hypernatraemia usually dehydration Polyuria –Spot urine –Cannot separate DI and polydipsia

48. Closing thoughts Sodium measurements very common Sodium and water must be considered together Diagnosis of disorders requires both clinical and laboratory investigation Drug history and urine samples are vital www.sydpath.com.au