AACE: Salt and Water: Not So Simple

Transcription

1 AACE: Salt and Water: Not So Simple Mark L. Zeidel, M.D Herrman L. Blumgart Professor of Medicine Harvard Medical School Chair, Department of Medicine Physician-in-Chief Beth Israel Deaconess Medical Center Boston, Massachusetts

2 Each of these creatures survives in the Galapagos by highly effective management of salt and water 2

3 Case 1 Case 2 Case 3 Case 4

4 Case 1 A 56 year old man discovers that he has hypertension when he uses a blood pressure machine in a pharmacy. He is seen by his PCP, who notes a blood pressure of 155/95 on multiple readings. After salt restriction fails to alter the blood pressure, the patient is started on hydrochlorothiazide, 25 mg/day. His blood pressure is 140/85 on follow-up. Routine electrolytes reveal: Na + 135; K + 3.0; Cl - 96; HCO 3-29, BUN 32 and Cr 0.9. How does thiazide lower BP? Since he continues the thiazide, why does he not go into shock? Why is he now alkalotic, hypokalemic, with a high BUN/Cr ratio? 1 4

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6 Filter 180l/d PNa = 140 FL = 25,200 meq/d Na+ transport along the nephron NaCl 60-80% NaCl 5% NaCl 25% NaCl 3% NaCl 5% Hoenig and Zeidel CJASN 2014;9:

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8 Defense Against Volume Depletion Sensors of Volume Depletion Extrarenal Renal Effector Mechanisms Sympathetic Outflow Renin-Angiotensin Aldosterone Anti-Diuretic Hormone Effectors act on the kidney.

9 Extrarenal volume sensors

10 Renal sensors of volume depletion renin release Baroreceptors in the afferent arteriole Sympathetic input to the JG apparatus Macula densa feedback (fall in tubular flow in distal nephron either because of GFR or proximal reabsorption)

11 Defense Against Volume Depletion Sensors of Volume Depletion Extrarenal Renal Effector Mechanisms Sympathetic Outflow Renin-Angiotensin Aldosterone Anti-Diuretic Hormone Salt Hunger and Thirst

12 Sympathetic Effector Mechanisms Cardiac Output Preload Increased Venous Return Renal Salt Retention Direct, R-A-A system Increased Cardiac Performance Increased Contractility Increased Heart Rate Peripheral Arterial Resistance Circulating Catecholeamines, Angiotensin II

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14 What does Renin do?

15 Filter 180l/d PNa = 140 FL = 25,200 meq/d Na+ transport along the nephron NaCl 60-80% NaCl 5% NaCl 25% NaCl 3% NaCl 5% Hoenig and Zeidel CJASN 2014;9:

16 Angiotensin II Potent systemic vasoconstrictor Retention of sodium and water throughout the nephron (especially in proximal tubule) Regulation of glomerular filtration rate Stimulates release of aldosterone

17 Filter 180l/d PNa = 140 FL = 25,200 meq/d Na+ transport along the nephron NaCl 60-80% NaCl 5% NaCl 25% NaCl 3% NaCl 5% Hoenig and Zeidel CJASN 2014;9:

18 Angiotensin II and catecholeamines increase sodium reabsorption in proximal tubule Angiotensin Catecholamines NB. sodium and bicarbonate reabsorption are intimately linked! L. Lee Hamm et al. CJASN 2015;10:

19 Aldosterone Primary effect is to increase sodium reabsorption in the distal nephron

20 The Aldosterone Paradox: Volume Depletion: NaCl retention with minimal K+ secretion Hyperkalemia: Waste K+ without Na+ retention Volume Depletion Hyperkalemia Biff F. Palmer CJASN 2015;10:

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22 Case 1 A 56 year old man discovers that he has hypertension when he uses a blood pressure machine in a pharmacy. He is seen by his PCP, who notes a blood pressure of 155/95 on multiple readings. After salt restriction fails to alter the blood pressure, the patient is started on hydrochlorothiazide, 25 mg/day. His blood pressure is 140/85 on follow-up. Routine electrolytes reveal: Na + 135; K + 3.0; Cl - 96; HCO 3-29, BUN 32 and Cr 0.9. How does thiazide lower BP? Since he continues the thiazide, why does he not go into shock? Why is he now alkalotic, hypokalemic, with a high BUN/Cr ratio? 1 22

23 So, we ve explained why he does not go into shock. Why does this therapy treat hypertension? BP is down, CO is the same so SVR must be decreased. How does this happen? Guyton et al

24 Salt load alters skin Na + storage in rats.

25 Interstitial Storage of sodium detected on Na-MRI

26 How peripheral Na + storage might influence peripheral vascular tone

27 Case 2 A group of Russian cosmonauts is placed in a space capsule for 6 months to simulate a flight to Mars. All intake is controlled and they receive low salt and high salt diets. Urine and stool outputs are recorded. Titze JM JCI 2017 How are total body sodium and BP controlled over the long term? How is thirst affected by changes in salt intake? 1 27

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29 Chronic Sodium Balance Long term increase in salt intake led to: Reduced, not increased water intake. Increased salt excretion and increased ureagenesis and urea retention. Increased catabolism

30 Case 3 A 67 year old man suffers a major MI, from which he recovers. One month later he notes increased edema, dyspnea on exertion, and 2 pillow orthopnea. PE reveals P = 120, BP = 100/65, RR = 22, afebrile. Exam notable for distended neck veins, rales 1/3 up, a palpable S3, and 2+ pitting edema to the mid calf. Serum Na + 125, K + 3.0, HCO 3-32, Cl - 81, BUN 36, Cr 1.1 Urine Na + is 2. Urine osmolality is 685; Serum Osmolality is 262. Volume and Osmoregulation Why does his total body salt go up? Why is he hyponatremic, hypokalemic and alkalotic?

31 Extrarenal volume sensors

32 Filter 180l/d PNa = 140 FL = 25,200 meq/d Na+ transport along the nephron NaCl 60-80% NaCl 5% NaCl 25% NaCl 3% NaCl 5% Hoenig and Zeidel CJASN 2014;9:

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34 CNS Control: Sympathetic Output Salt Hunger Thirst Neuro-somatic physiology

35 Control of Resting Sympathetic Tone Guyenet Nature Reviews Neuroscience 7, (May 2006) doi: /nrn1902 NTS, Nucleus Tractus Solitarius; AP, Area Postrema; SFO, Subfornical Organ; OVLT, organum vasculosum lamina terminalis

36 Rostral Ventrolateral Medulla and Sympathetic Outflow Guyenet Nature Reviews Neuroscience 7, (May 2006) doi: /nrn1902

37 Control of RVLM Input into Sympathetic Outflow Guyenet Nature Reviews Neuroscience 7, (May 2006) doi: /nrn1902

38 Map of Mouse Brainstem

39 Neuron specific Knockouts loxed allele of Your Favorite Gene lox YFG Cre lox Monosynaptic Rabies Mapping Tools GCaMPS6 Ca 2+ Probes sense neural activation lox Cre expressing Neurons (Neuron specific cre mice) Chemo genetics Clozapine Noxide(CNO) Cre dependent AAV virus expressing DREADDs (allowing for Chemical Control of Neuronal Activity) Cre dependent AAV virus expressing lightactivated channelrhodopsin (ChR2) (allowing for Blue Light Control of Neuronal Activity) Cre dependent Adeno Asssociated Virus Off On Opto genetics Na + ChR2 ChR2 Blue light Cre CNO Off On DREADD DREADD Cre DREADD

40 Control of Salt Appetite Resch, JM et al Neuron 96: , 2017 Salt depletion, AII and Chronic Aldo stimulate NTS neuron firing.

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42 Case 3 A 67 year old man suffers a major MI, from which he recovers. One month later he notes increased edema, dyspnea on exertion, and 2 pillow orthopnea. PE reveals P = 120, BP = 100/65, RR = 22, afebrile. Exam notable for distended neck veins, rales 1/3 up, a palpable S3, and 2+ pitting edema to the mid calf. Serum Na + 125, K + 3.0, HCO 3-32, Cl - 81, BUN 36, Cr 1.1 Urine Na + is 2. Urine osmolality is Volume and Osmoregulation 685; Serum Osmolality is 262. Why does his total body salt go up? Why is he hyponatremic, hypokalemic and alkalotic?

43 Case 4 A 45 year old woman with a history of depression presents wtih disorientation and inappropriate behavior. Her husband notes that she has had nausea recently and has eaten little, but has continued to take her thiazide and amitryptaline. PE reveals a BP of 125/70 and lethargy. She is oriented to person only, exhibiting intact cranial nerves and slurred speech. Na + 108; Urine Na + is 28. Serum Osmolality is 221; Urine osmolality is 685. Why is she hyponatremic?

44 Hyperosmolality: a major stimulus for ADH release thirst adapted from Robertson et al, Am J Med 1982

45 Volume Status Modulates ADH Release Robertson, G. J Clin Endocrinol Metab. 1976;42:613 20

46 Osmoreceptor functions of the OVLT (organum vasculosum of the lamina terminalis) nuclei and SON (superoptic nucleus) control thirst and vasopressin release, respectively. Danziger J, and Zeidel M L CJASN

47 Neurobiology of Thirst and ADH release Nat. Rev Neurosci 18:

48 Genetically targeted stimulation of glutamatergic neurons (i.e. VGluT2+) in the MnPO

49 Stimulation causes water consumption in 18/22 (82%) ChR2+ mice, and never in controls

50 Thirst responds to environmental cues

51 Thirst adapts to anticipated rather than real changes in body fluid osmolality.

52 David B. Mount CJASN 2014;9:

53 The medullary interstitium has a concentration >4 times that of its surrounding fluid, and must be both generated and maintained. Danziger J, and Zeidel M L CJASN

54 Danziger J, and Zeidel M L CJASN Cellular action of vasopressin

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56 ADH IS NOT PRESENT ADH IS PRESENT Large volume of Small volume of dilute urine concentrated urine* *provided the interstitium is concentrated (H 2 O moves along gradient with the help of aquaporins)

57 Rebecca at the well: Camel Physiology

58 Salt and Water: Not So Simple Mark L. Zeidel, M.D Herrman L. Blumgart Professor of Medicine Harvard Medical School Chair, Department of Medicine Physician-in-Chief Beth Israel Deaconess Medical Center Boston, Massachusetts