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Régulation de la natrémie : des concepts physiopathologiques à la pratique clinique

Régulation de la natrémie : des concepts physiopathologiques à la pratique clinique. Bertrand Souweine, Clermont-Ferrand. Concepts physiopathologiques. NATREMIE. Taux de sodium dans le sang (Larousse, 1997) Natrémie est mesurée habituellement dans le sérum Natrémie exprimée en millimol/L

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Régulation de la natrémie : des concepts physiopathologiques à la pratique clinique

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  1. Régulation de la natrémie : des concepts physiopathologiques à la pratique clinique Bertrand Souweine, Clermont-Ferrand

  2. Concepts physiopathologiques

  3. NATREMIE • Taux de sodium dans le sang (Larousse, 1997) • Natrémie est mesurée habituellement dans le sérum • Natrémie exprimée en millimol/L • Raisonnement : • / Kg H2O plasmatique • en milliosmol

  4. Rappels physiopathologiques Osmolarité : nb osmol / kg de plasma Osmolalité : nb osmol / kg d’eau Aquaporines Prix Nobel de chimie 2003

  5. H2O Na

  6. Rappels physiopathologiques L’eau diffuse librement entre les compartiments L’eau diffuse librement à travers la plupart des membranes Certaines molécules (urée éthanol) diffusent également librement Tonomoles : molécules non librement diffusibles Les tonomoles induisent un gradient osmotique  transfert d’eau

  7. Eau diffuse pour égaliser [molécules]  pression osmotique A l’équilibre, la pression osmotique est partout identique A A A H2O B A H2O A B A AB B C B Transfert d’eau entre C1 et C2  [tonomole] C1 = [tonomole] C2 8 tonomoles dans compartiment 1 (C1) 4 tonomoles dans compartiment 2 (C2) Tonomoles A, B, AB, C N=12 Nb Tonomole C1 /Vol C1 = Nb Tonomole C2 / Vol C2 8 / Vol C1 = 4 / Vol C2 Vol C1 / Vol C2 = 2

  8. Eau diffuse pour égaliser [molécules] A l’équilibre, la pression osmotique est partout identique Urée Urée Urée Urée A Urée A Urée A B Urée N=12 Urée A Urée Urée A B A Urée AB B Urée Urée C B H2O 4 tonomoles / unité de volume Osmolalité = 8 / unité de volume

  9. Compartiments hydriques 60% Poids Eau : 2/3 du poids de l’organisme Extra cellulaire 1/3 Intra cellulaire 2/3 Secteur interstitiel 3/4 Secteur vasculaire 1/4 Secteur Cellulaire

  10. Schematic representation of body fluid compartments in man a 70-kg adult Verbalis 2003

  11. Solutés EC + Soluté IC Osmolalité = = 285 mosmol/kgH2O H2O totale Nae + Ke 2 x (Nae + Ke) Osmolalité Osmolalité = = H2O totale H2O totale Na+> 90% Solutés EC K+ > 90% Solutés IC A l’équilibre, l’osmolalité est partout identique POsmol = Interstitielosmol = Cellosmol PNa reflète l’osmolalité

  12. Osmolalité reflète H2O totale • Si numérateur constant [2x(Nae+Ke)]  osmolalité   inverse du dénominateur H2O totale • Osmolalité reflète l’hydratation cellulaire • PNa reflète l’hydratation cellulaire Si POsmol (PNA)  ; et 2x(Nae+Ke)= constant ; H2O totale Hypernatrémie reflète une deshydratation cellulaire Si POsmol (PNA) ; et 2x(Nae+Ke)= constant ;  H2O totale Hyponatrémie reflète une hyperhydratation cellulaire

  13. Osmolalité reflète H2O totale Capital Na reflète VEC • Si Osmolalité constante • toute  osmEC   // de VEC osmEC  2 x Na ; capital Na reflète VEC Si osmEC [capital Na] et Posmol = Constant VEC  Si osmEC [capital Na] et Posmol= Constant VEC 

  14. Les sorties de Na de K et d’eau sont réglées au niveau du rein Adaptation du capital Na pour maintenir la volémie Adaptation de la tonicité pour maintenir le volume cellulaire Shiau YF, Ann Intern Med 1985

  15. Collecting duct Proximal convoluted tubule Connecting tubule Distal convoluted tubule Short loop nephron: absence of thin ascending limb 70-80% of human nephrons Thick ascending limb Thin descending limb Thin ascending limb Long loop nephron

  16. Réabsorption tubulaire NaCl apical basal apical basal

  17. Ascending limbs: impermeable for water Thin decending limb permeable for water (AQP1) solute impermeable Fluid volume entering the bend: upper limit of the urine flow if no further water reabsorpsion occurs Proximal tubule Isoosmotic to plasma: water is isoosmotically reabsorbed Na+is the major driving force Thick ascending limb: diluting segment: separation of solutes from water Na+/K+/2Cl- Impermeable for water: osmolality decreases along the lenght

  18. From fish to philosopher: the story of our environment Smith H 1953 The early provertebrates resided in a salt water environementwhose composition was similar to that of their own extracellular fluid. Therefore these animals could ingest salt water freely without altering the composition of their miluieu interieur

  19. As early vertebrates migrated into freshwater streams the development of a more water impermeable tegument was necessary to avoid fluid dilution by the hypoosmotic fresh water environement

  20. the concentrating capacity of the mammalian kidney contributed to the evolution of various biologic species including man. the glomerulus developed enabling the fish to filtrate excess fluid from the blood the subsequent development of the tubule in vertebrates was seminal for preservation of sodium and excretion af excess solute-free water

  21. Mécanisme de concentration à contre courant d‘après Rose BD

  22. The water permeability of the collecting tubules is extremely low but increases in the presence of AVP d‘après Rose BD

  23. Distal tube of the nephron Cytosolic storage vesicles C-terminus phosphorylation of AQP-2 PKA ATP cAMP AQP-2 insertion H2O Adenylate cyclate Gs Basolateral membrane Apical membrane AVP V2 Urine Sang

  24. Thick ascending limb Reabsorption of Na+/K+/Cl- Increase in interstitium tonicity Delivery of hypotonic fluid to distal tube Urea poorly reabsorbed and retained in the tubule Under vasopressin, tubular fluid equlibrates with the hypertonic interstitium low urea permeability allow its concentration to increase The increase in interstitial tonicity creates the obsmotic gradient that abstracts water from the descending limb Urea is reabsorbed and constitutes a significant component of the medullar interstitial tonicity [Na] in the tubular > interstitium passive reabsorption of NaCl in the water impermeable thin ascending limb Model of urinary concentration

  25. Mechanisms of urine concentration Thiazide: no impact on concentrating capacity Na+/Cl- ⇘ by age, renal disease Glomerular filtration H2O Na+/Cl- H2O urea delivery of water determined by glomerular filtration rate, proximal tubule H2O and solute reabsorption H2O • Generation of medullary hypertonicity by • normal functioning of thick ascending limb • urea delivery • normal medullar blood flow Cl-/Na+ membranes permeable to urea ⇘[urea] medullary  urea movement into the medulla ⇘ dietary intake of protein vasopressin ⇗ AVP release/action: nephrogenic or central diabetes insipidus ⇘ Cl-/Na+ reabsorption Loop diuretics, osmotic diuretics, interstitial disease

  26. Mechanisms of urine dilution Na+/Cl- Thiazide diuretics ⇘Na+/Cl- reabsorption alter diluting capacity not concentrating capacity Glomerular filtration ⇘ age, volume depletion, CHF, cirrhosis, nephrotic syndrome H2O Na+/Cl- delivery of water determined by glomerular filtration rate, proximal tubule H2O reabsorption and Na+/Cl- reabsorption ⇘ Cl-/Na+ reabsorption loop diuretics, osmotic diuretics, interstitial disease Cl-/Na+ Collecting duct impermeable to water in absence of vasopressin or other antidiuretic substances ⇗ water permeability by AVP, drugs

  27. Adaptation de la tonicité • 1% de  osmolalité  mécanisme d’adaptation • Contrôle des entrées : soif • Contrôle des sorties : excrétion rénale H2O régie par l’ADH • Sécrétion d’ADH : 2 stimuli • Hypovolémie et Hypotension indépendamment de la tonicité • Hypertonie plasmatique • Rein : réabsorption/sécrétion H2O et Na indépendamment • 50 mosmol/L <Uosmol < 1200 mosmol/L

  28. AVP secretion in response to increases in plasma osmolality versus decreases in blood volume or blood pressure in human subjects d’après Robertson GL

  29. Relationship between plasma AVP concentrations and plasma osmolality under conditions of varying blood volume and pressure d’après Robertson GL

  30. Plasma water sodium : [Na+]pw 1.11 - 25.6 [Na+]pw = 1.11(Nae + Ke)/TBW - 25.6

  31. [Na+]pw = 1.11(Nae + Ke)/TBW - 25.6 Total body water osmolality = plasma water osmolality [Na+]pw = G/ Ø(Nae + Ke)/TBW - G/ Ø = slope y-intercept = Nguyen, AmJ Physiol Ren Physiol 2004

  32. [Na+]pw = 1.11(Nae + Ke)/TBW - 25.6 [Na+]pw = G/ Ø.(Nae + Ke)/TBW - Ø: effectiveness of ions as independent osmotically active particles Osmotic coefficient for NaCl = 0.93 and for NaHCO3 = 0.96 [104/128 x 0.93] + [24/128 x 0.96] Ø = 0.94 Nguyen, AmJ Physiol Ren Physiol 2004

  33. Quantitatively, Ke will have a net incremental effect on the [Na+]pw ECF ICF Ke and [K+]PW Both Ke and [K+]pw must independently affect [Na+]pw Ke in a 70-kg man, TBW = 42 liters, KICF = 3,750 mmol (150 mmol/l x 25 liters) KISF = 62 mmol (4.4 mmol/l x 14 liters) KPl = 14 mmol (4.6 mmol/l x 3 liters) Nguyen, AmJ Physiol Ren Physiol 2004

  34. y-intercept = Nguyen, AmJ Physiol Ren Physiol 2004

  35. Titze J, AJKD 2002 do not contribute to the distribution of water between the EC and IC spaces failure to consider osmotically inactive Nae and Ke will result in an overestimation of [Na+]pw Nguyen, AmJ Physiol Ren Physiol 2004

  36. osmolPl tend to lower [Na+]pw osmolICF will tend to increase [Na+]pw VPl = 1/5 de VEC osmolECF will tend to increase [Na+]pw OsmolECF = osmotically active, extracellular non-Na+ and non-K+ osmoles OsmolICF = osmotically active, intracellular non-Na+ and non-K+ osmoles osmolECF + osmolICF will tend to increase [Na+]pw Nguyen, AmJ Physiol Ren Physiol 2004

  37. Plasma water non-Na+ and non-K+ osmoles: glucose, Ca2+, Mg2+, Cl-… Plasma water non-Na+ and non-K+ osmoles: glucose, Ca2+, Mg2+, Cl-… will have a dilutional effect by obligating the retention of water in the plasma space Nguyen, AmJ Physiol Ren Physiol 2004

  38. Parameter G/Ø ⇗ (Nae + Ke)/TBW ⇗ (Naosm inactive + Kosm inactive)/TBW ⇘ (osmolECF + osmolICF)/TBW ⇗ [K+]PW ⇘ osmolPW/VPW ⇘ Effect of increase in the parameter on [Na+]PW Physiological parameters that determine [Na+]PW Kurt I, Kidney int 2005

  39. Quantification of renal water excretion Posmol Cosmol = Volume of urine Isotonic to plasma V = urine volume Uosmol osmolurine = Uosmol x V Cwater = free solute water Cosmol = osmolar clairance volume needed to excrete solutes at the the concentration of solutes in the plasma Cwater = volume of free-solute water that had been added or subtracted from the isotonic portion of the urine (Cosmol) to create either hypotonic or hypertonic urine

  40. Quantification of renal water excretion Cwater = V x (1-Uosmol/Posmol) V = Cosmol + Cwater  Cwater = V - Cosmol Cosmol = (Uosmol x V)/Posmol Cwater = V - (Uosmol x V)/Posmol = V x (1-Uosmol/Posmol) Hypotonic urine = Uosmol < Posmol and Cwater > 0 Isotonic urine = Uosmol = Posmol and Cwater = 0 Hypertonic urine = Uosmol > Posmol and Cwater < 0 Excretion of free water in a polyuric patient without water intake:  the patient become hypernatremic Failure to ecrete free water in settings of increase water intake:  the patient become hyponatremic

  41. Quantification of renal water excretion Uurea is a major component of Uosmol urea crosses cell membrane readily ureado not influence PNa and vasopressin release

  42. V Cosmol + Cwater = = OsmolU + Posmol Posmol = 310 mosmolKg, PNa = 144 mmol/L Uosmol = 620 mosmol, UNa = 5 mmol/L, UK = 43 mmol/L Diurèse = 1 L Cwater = V x (1-Uosm/Posm) = 1 x (1-620/310) = 1 x (1-2) = -1 litre Réponse rénale est-elle vraiment adéquate ? Cwater(e)= V x (1-[UNa+UK/PNa]) Cwater(e)= 1 x (1-[5+43/144]) = 1x (1-0.33) = +0.67 litre La réponse rénale est inadéquate

  43. Quantification of renal water excretion Cwater(e)= V x (1-[UNa+UK]/ PNa)

  44. Increase Decrease Suppression of thirst Suppression of vasopressin Stimulation of thirst Stimulation of vasopressin Disorder involving urine dilution with water intake Disorder involving urine concentration with water intake Dilute urine Concentrated urine Hyponatremia Hypernatremia Plasmaosmol 280-290 mOsmol/KgH2O Parikh C

  45. Dysnatrémie en pratique clinique

  46. Hypernatremia PNa > 144 (?) PNa >150 mmol/L in 0.2% of the 7836 patients admitted to a general hospital during a 3-month study period Palewsky PM Ann Intern Med 1996

  47. Primary Diagnoses for Patients with Hypernatremia PNa >150 mmol/L Palewsky PM Ann Intern Med 1996

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