Prof. László Rosivall MD. PhD. DSc.

1. Prof. LászlóRosivallMD. PhD. DSc. Pathomechanism of salt and water metabolism Budapest 2003

2. Content • I. Introduction • Role of salt and water metabolism in every day life • The frequency and diagnosis of imbalance of salt and water metabolism. • Types and pathomechanism of hyponatremic • and hypernatremic states • III. Basic principals of therapy.

4. . 25 PRESSURE . 20 BASAL VOLUME OSMOLALITY PLASMA VASOPRESSIN (pg/ml) 15 . 10 . . . 5 0 -20 -10 0 10 20 -30 PERCENT CHANGE Relation of plasma vasopressin to the percentage change in plasma osmolality (triangles), volume (open circles), and pressure (solid circles).

5. Factors Affecting Tubular Sodium Reabsorption Hormonal factors Renin-angiotensin-aldosterone system Renal prostaglandin system Renal kallikrein-kinin system Atrial natriuretic peptide Physical and hemodynamic factors Renal perfusion pressure Peritubular Starling forces Renal interstitial pressure Medullary blood flow Renal nerve activity

6. Development of the disturbances in fluid and ion homeostasis Primary disease Secondary disease Disturbances in fluid and ion homeostasis (E.g.:kidney, liver, heart, CNS, stomach, gut, skin, operations, drugs) • Volume alteration • - Osmotic/Na+ -conc. alteration • - K+ - concentration changes • - H+ - concentration changes Regulation disorder (afferent and/or efferent) Aggravates primary disease Becomes distinct disease Direct cause of death

7. Hyponatraemia ( plasma concentration ) TBW (Total Body Water): ; Na+ ( Redistribution ) TBW, Na+ ; no redistribution ( pseudohyponatraemia ) Na+ / TBW < normal ( Na+ or Na+ or Na+ )

8. Hyponatraemia without TBW and Na+ alteration Mannitol effective Hyperglycaemia osmolality H2O ICV ECV ( serum - osmol ) Transitoric hypernatremia Osmotic diuresis (water and Na+ loss hypernatremia) a, hyperglycaemia hypernatraemia dehydration exists (good renal function) b, hyperglycaemia hyponatraemia no dehydration (decreased function)

9. 4480 + 800 ECV1 = = 17,6 l 300 Example for redistribution 1, Healthy man 2, Hyperglycemic patient Weight: 73 kg ; TBW ~ 40 l ; 280 mosmol / l Glycose concentration 50 mosmol / l total osmol increase : 16 x 50 = 800 11200 + 800 = 12000 mosmol 12000 : 40 l = 300 mosmol / l ICV 24 l ECV0 16 l 24 x 280 = 6720 mosmol 16 x 280 = 4480 mosmol 11200 mosmol Thus ECV0 increased by 10 % , consequently se - Na+ ca 126 maeq / l ( ~ 5 osmol / l ~ 1,5 maeq / l Na+ )

10. Pseudohyponatremia Examples: - hyperlipoproteinemia ( e.g. nephrosis ) - hyperproteinemia ( e.g. Waldenström macroglobulinemia ) Explanation e.g.: se - protein 70g/l ; se - Na+ 140 mmol/l (flame photometry) plasma water Na+: 140 / 0.93 ~ 151 mmol/l (ion selective electrode) normal: abnormal: if: se - protein 140g/l ; se - Na+ 130mmol/l (flame photometry) plasma water Na+ 130 / 0.86 ~ 151 mmol/l (ion selective electrode) Serum osmolality normal 1l 1l normal protein concentration: abnormal protein concentration:

11. Hyponatremia with decreased TB - Na+  ECV depletion Extrarenal Na+ loss Vomit Diarrhoea Fluid sequestration Peritonitis Pancreatitis Burn Renal Na+ loss Diuretics Osmotic diuresis Mineralocorticoid deficiency Renal tubular acidosis bicarbonaturia Metabolic alkalosis Salt- losing nephropathy „Anion gap” acidosis Measurement of urine Na+ - concentration < 10 mmol/ l> 20 mmol/ l

12. Renal or extrarenal NaCl or NaHCO3 loss intravascular volume Mechanism of hyponatremia in case TB - Na+ decrease cardiac output renal perfusion Activation of low and high pressure baroreceptor GFR and fluid reabsorbtion in proximal tubules renin non-osmotic ADH release angiotensin II distal fluid load thirst urine concentration Impaired urine dilution Renal water retention water intake hyponatremia

13. Diuretics Na+ - reabsorption in distal tubul Negative Na+ and H2O balance Negative K+ balance EC volumen intracellular K+ Osmotic concentration of tubular fluid GFR , proximal Na+ reabsorption ADH EC - Na+ IC urinary osmotic concentration H2OLoad of tubular diluting segment Renal water excretion renal water excretion Hyponatremia

14. Hyponatremia with increased TB - Na+ Extrarenal Decompensated heart failure Liver cirrhosis Nephrosis syndrome Renal Acute renal failure Chronic renal failure

15. Heart failure cardiac output venous pressure effective blood volume liver congestion renin-angiotensin sympathetic activity circulating catecholamines aldosterone catabolism renal vascular resistance aldosterone activity peritubular starling force (FF ) capillary hydrostatic pressure tubular Na+ - reabsorption GFR proximal Na+ reabsorption Na+ - excretion activity of high pressure baroreceptor ECV ADH Oedema

16. Na+ - excretion ECV Ascites Cirrhosis Albumin Peripheral resistance Liver circulation Portal pressure Aldosterone catabolism Splanchnic venous pooling Effective blood volume Sympathetic activity circulating catecholamines Renin - angiotensin Renal vascular resistance Aldosterone activity Peritubular capillary Starling force (FF ) Tubular Na+ - reabsorption GFR Activity of low and high pressure baroreceptor Capillary hydrostatic pressure

17. Plasma ANT ( fmol / ml ) 200 100 50 20 10 5 2 Normal EH Cirrhosis CHF

18. Nephrosis Glomerular disease "underfilled" ”overfilled" renal Na+ and H2O retention proteinuria proteinuria hipoalbuminaemia colloid osmotic pressure hipoalbuminaemia colloid osmotic pressure effective arterious blood volume ECV renin - angiotensin sympathetic activation ADH oedema

19. Renal failure GFR distal fluid load Dilution capacity ECV Decrease of Diluting Capacity in CRF (E.g. GFR 5 ml/min 7.2 l/day, 20 % into diluting segment: 1.4 l/nap; if intake > 1.4 l/nap retention)

20. Hyponatraemia with around normal TB - Na+ (no oedema, no hypervolemia) hyponatraemia , hyposmolality  euvolaemia Uosm  200 mosmol/l normal kidey, heart, liver, adrenal glands, pituitary gland and thyroid functions Deficiency of antidiuretic medication Deficiency of emotional or . physical stress UNa 20 mosmol/l Increased receptor sensitivity cause Increased renal ADH sensitivity Increased non-osmotic ADH secretion 1, Diuretic therapy with K+ - depletion (ADH ? , Na+ IC ?) 2, Hypothyroidism ( PTF, GFR, ADH ) 3, Glucocorticoid deficiency ( hypopituitarism ) GFR, ADH ? 4, Drugs ( ADH ) 5, Pain and emotional stress ( ADH ) 6, Inadequate ADH secretion syndrome ( SIADH ) SIADH

21. SIADH E.g.: oat cell carcinoma se - Na : 121 se - K : 3.7 HCO3 : 29 se - Cl : 85 se - osm : 240 mosmol / l urine - osm : 590 mosmol / l BUN : normal se - kreatinin : normal urine - Na : > 20 mosmol / l oedema :  ; fluid deprivation: development

22. ADH-like Enhanced ADH release Potentiate renal action of ADH Drugs Associated with Hyponatremia Oxytocin Deamino-D-arginine vasopressin Chlorpropamide Clofibrate Cyclophosphamide Vincristine Carbamazepine (Tegretol) Amitriptyline (Elavil) Thiothixene (Navane) Isoproterenol Nicotine Morphine Chlorpropamide Cyclophosphamide ndomethacin

23. Disorders Associated with the Syndrome of Inappropriate Antidiuretic Hormone Secretion Central nervous system disorders Encephalitis Meningitis, brain anscess Systemic lupus erythematosus Stroke Brain tumors Subdural or subarachnoid hematoma or hemorrhage Head trauma with and without skull fractured Guillain-Barré syndrome Acute psychosis Acute intermittent porphyria Central pontine myelinolysis Seizure disorders Carcinomas Lung Duodenum Pancreas Hodgkin’s disease Pulmonary disorders Pneumonia Abscess Tuberculosis Aspergillosis

24. Physiopathology of ADH Secretion . . . 10 I. „random” II. „reset” . . . . . 8 . normal range . . 6 . normal range 4 2 0 ADH III. „leak” 10 IV. „normal” . 8 . . . . . . normal range normal range . 6 4 2 250 260 270 280 290 300 310 250 260 270 280 290 300 310 Plasma osmolality 0 Plasma vasopressin as a function of plasma osmolality during the infusion of Hypertonic saline in 4 groups of patients with clinical syndrome of inappropriate antidiuretic hormone secretion (SIADH) I., Secretion divorced from osmotic stimulus III., Leak of vasopressin II., Increased sensitivity of receptors IV., Increased tubular sensitivity to vasopressin

25. Clinical features of hyponatremia Symptoms: Lethargy, fatigue, apathy Headache Vomiting Anorexia, Muscle clonus Excitement Signs: Reflex loss Cheyne - Stokes breathing Hypothermia Pathological reflexes Convulsion Coma Se - Na+ 120 mmol/l (mortality: 36%) Th: hypertonic Na+ -solution: rate: increase of se Na+:  2 mmol / l / hour

26. Mortality of Symptomatic Hyponatremia SERUM Na+ < 120mM Na+=110±8 Na+=109±8 Na+=110±8 alcoholic/cachexia (n=36) others (n=108) All cases (n=144) % Mortality Overall mortality for patients with symptomatic hyponatraema whose serum Na was ≤ 120 mM. In 114 cases from 29 articles, mean serum Na was 109 mM. Of these patients, 36 had either alcoholism or other debilitating medical illness, and their mean serum Na was 109 mM. The mortality was 67 percent in alcoholic/cachetic subjects, versus only 33 percent in the other patients.

27. Serum Na+ raised from 111 to 130 mM 2 mmol/l/hr (n=30) >0.6 mmol/l/hr (n=26) % Survival Mortality of symptomatic (serum Na of <120 mM) among patients who were treated rapidly (i.e., with hypertonic NaCl such that serum Na was increased at a mean rate of 2 mmol/liter-hr), as compared with patients who were treated slowly (i.e., with fluid restriction, isotonic NaCl, or small quantities of hypertonic NaCl) such that serum na was increased at a rate of <0.6mmol/liter-hr.

28. Brain water content in normal rabbits and two groups of hyponatremia Plasma Na+ mEq/L) 0hr 2hrs 16days Time Brain H2O (gm100gm dry wt) Osmolality (mOsm/kg H2O) Plasma Brain Plasma Plasma Brain Brain

29. Hypernatraemia (rare , more severe) 295 mosmol/l thirst TB-Na+ TB-Na+ TB-Na+

30. Hypernatraemia with decreased TB-Na+ Extrarenal Na+ loss Renal Na+ loss -Diarrhoea -Vomiting -Excessive sweating -Non-oliguric acut renal failure -Acut renal failure (reparatory phase) -Osmotic diuresis hypotonic fluid loss hypertonic plasma thirst hypothonic fluid intake no fluid intake hyponatraemia hypernatraemia

31. Increased insensible fluid loss - hyperventilation - fever - sweating Dialysis with excess loss of fluid Diabetes insipidus - Central, partial, complete - Renal Primary hypodipsia, adipsia Hypernatraemia with increased TB-Na+ Abortion induced by hypertonic salt Salt abuse Primer hyperaldosteronism Hypernatraemia normal TB-Na+

32. Hypernatraemia Symptoms -Anxiety -Lethargy -Muscle tonus -Icreased muscle tone Signs -Hyperreflexia -Convulsion -Coma -Death Se-Na+> 160 mmol/l Acut mortality 75% approx. 48h mortality 60% Hypernatraemic episode during childhood: approx. In 60% persisting damage

33. Brain water content in rabbits with experimental hypernatremia Plasmasodium 171-182mEq/L Brain H2O (gm/100gm dry wt) Brain Water content in rabbits with hypernatraemia. In experimental animals with hypernatraemia (plasma sodium of 171 to 182 meq/liter), brain water falls acutely after 1 and 4 hr of hyperosmolality. At 1 week, however, brain water returns to normal values .

34. 100 % Mortality 80 60 40 20 0 ACUTE (<24 HRS) n=22 CHRONIC (>48 HRS) n=121 Mortality of Hypernatremia (Serum Na>160 mEq/l) in Adults Comparison of published mortality of acute and chronic hypernatremia for adults. When one considers that adults with hypernatremia resulting from such grave condition as stroke with dehydration, lactic acidosis, resuscitation from cardial arrest, and hyperglycemic nonketotic coma comprise the bulk of published cases, it is not surprising that eventual mortality is formidable

35. 500 450 400 350 Plasma Osm. (mOsm/Kg) 300 250 Alert Obtund Stupor Coma Relationship between depression of sensorium and plasma osmolality (Osm) is 53 patients with blood glucose >55mmol/l, but without ketoacidosis.