water and sodium homeostasis 2013

8/11/2019 Water and Sodium Homeostasis 2013

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Sodium and Water

MetabolismA C J Hutchesson


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Body Composition

70 kg man:

Water ~ 42 L Sodium ~ 3.8 moles

Potassium ~ 3.1 moles

Calcium ~ 25 moles


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Fluid Compartments

Extracellular Intravascular

Interstitial

Cerebrospinal fluid

aqueous/vitreous humours

Intracellular

Cytosol Organelles

Pathological transudates, exudates


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Fluid Compartment volumes

Measured by dilution; e.g. with:

Total body water urea, D2O 42 L

ECF Sucrose, Inulin 12.5 L

Plasma Evans Blue, 131I 3 L

Interstitial fluid 9.5 L

ICF TBW - ECF 29.5 L


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Fluid Balance

(Adult, temperate climate)Intake(mL)

Output(mL)

Water 1300 Urine 1500

Food 800 Skin (insensible) 450

Water of oxidation 300 Respiratory tract 350

Faeces 100

2400 2400


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Fluid Balance in Infancy

Adult (70 kg) Term infant (3 kg)

Litres % wt Litres % wt

TBW ~ 42 ~ 60% ~ 2.4 ~ 80%

ECF ~ 12.5 ~ 20% ~ 1.2 ~ 40%

ICF ~ 29.5 ~ 40% ~ 1.2 ~ 40%

Turnover ~ 2.4 ~3% 0.3-0.45 10-15%


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Control of Water Homeostasis

Regulated by osmolality and volume

Intake

Thirst, access to fluids Output

Insensible

Renal Countercurrent multiplier: loop of Henle

Countercurrent exchange: collecting duct


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Osmolality

Osmotic Pressure:

pressure exerted by all dissolved solutes.

Osmolarity no. particles/L solutionOsmolality no. particles/kg solvent

Osmolality preferred; temp/solvent independent

Colloid osmotic pressure (Oncotic pressure):

pressure exerted by colloid alone.


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Osmolality - Measurement Colligative properties

Freezing point depression (usual method)

Vapour pressure

Boiling point elevation

Calculation

E.g: 1.86(Na++ K+) + Urea + Glucose

Colloid osmotic pressure

Direct measurement

Surrogates - protein, albumin


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Functions of Osmolar

pressure Homeostasis

Support

Water transport - osmotic gradients

Gut wall Capillaries

Urine concentration


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Ernest Starling

First hormone (secretin)

Frank-Starling law of theheart

Absorbtion of water andelectrolytes by distalconvoluted tubule

Capillary transport -Starling equation


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Starling Equation

J= Kf{(Pc- Pi) - (c- i)}

where:

J= net fluid movement across capillary Pc= capillary hydrostatic pressure

Pi= interstitial hydrostatic pressure

c= capillary oncotic pressure i= interstitial oncotic pressure

Kf= filtration coefficient - depends on capillary permeability to water = reflection coefficient -depends on capillary permeability to protein

(0 for capillaries permeable to proteins; e.g. liver; 1 for impermeablecapillaries, e.g. glomerulus)


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Starling Forces in capillaries(Numbers are for illustration)

Water

Solutes Water Waste

Lymph

Vein

30

HP

6

OP

28

8 mmHg -7 mmHg

6

OP

30

17

HP

Artery


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Excess tissue fluid - Oedema

Increased venous pressure

cardiac failure

varicose veins

Reduced oncotic pressure

hypoalbuminaemia

Increased capillary permeability inflammation


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Antidiuretic Hormone/Vasopressin

Nonapeptide Secreted by cells in supraoptic and

paraventricular nuclei, projecting to posteriorpituitary

Activates adenylate cyclase:

Increased water permeability of collecting duct(increased aquaporin 2 expression, via V2 receptor)

Increases osmolar gradient in medulla activity of epithelial Na+channel (ENaC)

urea countercurrent exchange (UT-A1 action ininner medullary collecting ducts)

Vasoconstriction (V1 receptor)


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Antidiuretic Hormone/Vasopressin


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Stimuli to ADH secretion

Hypertonicity (>2% increase) Osmoreceptors in hypothalamus (SON/PVN)

Hypovolaemia (>10% decrease) Baroreceptors in carotid sinus/right atrium

Stress Pain, trauma

Drugs

Opiates, barbiturates, nicotine, clofibrate Chlorpropamide, tolbutamide

Vincristine, vinblastine

Carbamazepine

Nausia


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Relationshipbetween plasma

osmolality and(a) ADH,(b) thirst,(c) hypovolaemia

From Oxford Textbook of Mdeicine ($th ed)

Stimuli to ADH secretion

(a)

(b)

(c)


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Aquaporins

Family (at least 11) of transmembrane waterchannels

Allow passage of neutral molecules;selectivity depends on channel size.

Positive charges within channel repelprotons; water (polar molecule) rotates withinchannel to negotiate it.


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Aquaporins

Three functional groups:

Aquaporins - AQP 0,1,2,4,5,6

waterAquaglyceroporins - AQP 3,7,8

water,glycerol, urea

Neutral solute channels - AQP 9water, glycerol, urea, purines, pyrimidines


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Aquaporins and the kidney

Aquaporin Location

1

2

Proximal convoluted tubule

Renal collecting ducts (apical membrane)ADH-sensitive

3 Renal collecting ducts (basal membrane)Also transports urea

4 Renal collecting ducts (basal membrane)

Hypothalamus (SON), blood-brain barrier

(9 Hypothalamus (SON), blood-brain barrier)


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Aquaporin 2

Found on apical surface of collecting duct cells.

Expression increased by ADH viacAMP:-

Insertion of AQP 2 into cell membrane

Upregulation of AQP 2 synthesis

Inhibited by mercuric chloride.

Expression decreased by lithium.

Mutations associated with autosomal recessivenephrogenic diabetes insipidus (DI).


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From Gattone et al, Nature Medicine 9, 1323 - 1326 (2003)

Renal tubular actions ofVasopressin


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From Laboratory of Molecular Genetics, University of Malta

Renal concentration of urine


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Diabetes Insipidus - Aetiology

Cranial (ADH deficiency) Inherited (v. rare; incl. DIDMOAD)

Idiopathic (>30% of cases)

Trauma, tumour, granulomas, infection, vascular Nephrogenic (ADH resistance)

Familial (X-linked recessive)

Idiopathic

Metabolic - high Ca++, low K+ Chronic renal disease

Drugs (e.g: Li+, amphotericin, glibenclamide)

Vascular (sickle-cell disease)


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Diabetes Insipidus - Investigation

Establish polyuria

Water deprivation (8 hr) test Stop if wt loss >3% TBW. Avoid surreptitious drinking

Desmopressin (DDAVP) post-deprivation Distinguishes CDI (urine concentration and NDI (no

response)

Plasma vasopressin During hypertonic saline infusion

After dehydration (distinguish CDI and NDI)

Therapeutic trial of desmopressin


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Interpretation of Water Deprivation

TestUrine osmolality (mosmol/l)

DiagnosisPost-deprivation Post-DDAVP> 750 > 750 Normal

< 300 > 750 CDI

< 300 < 300 NDI

300 - 750 > 750 Partial CDIorpartial NDIorpolydipsia


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Sodium balance

Intake - usually 100-200 mmol/day (6-12 g)

minimum ~15 mmol/day Losses

Sweat < 10 mmol/day

Faeces < 10 mmol/day

Urine 100 - 200 mmol/day 25,000 mmol/day filtered by glomeruli;

>99% resorbed


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Composition of ECF and ICF

ECF (mmol/l) ICF (mmol/l)

Cations: Na+ 140 12

K+ 4 150Mg++ 1.0 15

Anions: Cl- 100 4

HCO3-

24 8PO4

-- 1 73

Proteins 15 40


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The Renin-Angiotensin system

Renin

Angiotensinogen

Aldosterone

Angiotensin I

Angiotensin II

Bradykinin

Angiotensinconverting enzyme

Inactivemetabolites

Liver

Kidney

Lung

ADHVasoconstriction

Na retention


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Control of plasma sodium

Renal blood flow

Plasma volume

Renin

Angiotensin IAngiotensin II

Aldosterone

Na+ K+

Thirst urine Na+excretion

urine K+excretion

Plasma volume Na+concentration


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Renin

Secreted from juxtaglomerular apparatus

Secretion stimulated by: Decreased renal perfusion pressure

Sympathetic nerve stimulation Decreased [Na+] in DCT

Secretion reduced by: Rise in plasma [K+]; atrial natriuretic peptide (ANP)

Proteolytic enzyme, releasing decapeptideangiotensin I from angiotensinogen

AT-I further cleaved to AT-II in lung


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Aldosterone

Main mineralocortocoid; essential for life.

Synthesised by zona glomerulosa of adrenalcortex

Secretion stimulated by: Angiotensin II

Plasma Na+

Plasma K+

Receptor also binds cortisol (and prednisolone)

Protected in kidney by 11-OH steroid dehydrogenase(inhibited by carbenoxolone, glycorrhyyzoids)


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Salt and water homeostasis:

interrelationships (1)

Problem Response

High plasmaconcentration

Reduce water lossIncrease plasma volume

Low plasma volume Reduce sodium loss

Increase plasma concentration


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interrelationships (2)Plasma volume renin

Angiotensin II

Aldosterone

Na+retentionPlasma osmolality

ADH

Water retentionThirst

Waterintake

(>10%)(>10%)


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ADH osmolality, RAS blood pressurePlasma osmolality Mean arterial pressure

ADH Aldosterone

AQP2 ENaC

Water reabsorbtion

Sodium reabsorbtion


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Other hormones/factors

Natriuretic peptides

Digoxin-like immunoreactivity/Ouabain Renal dopamine, PgE2?


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Natriuretic peptides

First recognised 1981

ANP (atrial)

N-terminal (ANP 99-126) active

C-terminal processed to other active peptides? Urodilatin (ANP 95-126)

Alternative renal processing of prohormone

Function unknown

BNP (brain/B-type); found in brain, ventricles CNP (C-type); mainly brain, also endothelium

DNP; little known


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Natriuretic peptides Secretion

Atrial (ANP) and ventricular (BNP) stretch

Prepro-NP cleaved to NP and N-terminal NP

Functions (NP receptors A, B)

Linked to cGMP signalling cascade Increase GFR

Antagonise renin/aldosterone axis Promote sodium excretion

Antagonise ADH Reduce thirst and water resorbtion

Degradation NP receptor C, neutral endopeptidase


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fluid overloadPlasma volume renin

Angiotensin II

Aldosterone

Na+retentionPlasma osmolality

ADH

Water retentionANP, BNP


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Natriuretic peptides and heart

failure (1) Screening

Selection for echocardiography (gold

standard) High plasma levels of:

ANP Volume overloadANP 99-126 short half-life; c.f. glucose

ANP 1-98 long half-life; c.f.HbA1c

BNP Systolic dysfunction BNP, N-terminal BNP


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Natriuretic peptides and heart

failure (2) Prognosis

Independent predictor of mortality

Monitoring Response to treatment

Therapy Synthetic analogues - nesiritide not verified

(NEJM, 2005)

Neutral endopeptidase inhibitors; also block AT-IIdegradation.


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Treatment of Heart Failure

Sodium restriction - diet Water removal - diuretics

Renin-angiotensin blockade

ACE inhibition (-prils)

Angiotensin receptor type 2 blockade (sartans)

Aldosterone antagonism (spironolactone)

Renin antagonism (Aliskiren)

(Sympathetic nervous system blockade; -blockers)


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Drugs affecting the RAS

Renin

Angiotensinogen

Aldosterone

Angiotensin I

Angiotensin II

Bradykinin

Angiotensinconverting enzyme

Inactivemetabolites

Liver

Kidney

Lung

ADHVasoconstriction

Na retention

Aliskiren

ARBs(Sartans)

Spironolactone

ACE inhibitors


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Sodium measurement

Direct (no dilution step)

Measures activity in water compartment

Direct ion-selective electrode

Indirect (volumatic dilution step)

Measures concentration in whole serum

Indirect ion-selective electrode Atomic emission spectroscopy

Flame photometry


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Hyponatraemia - Aetiology

Artefactual Pseudohyponatraemia - lipaemia, high protein

Appropriate

High glucose, urea Fluid overload

Cardiac, liver, or renal failure; nephrotic syndrome

Euvolaemic SIADH, low cortisol, hypothyroidism, IVI

Dehydration Addisons, vomiting/diarrhoea, burns, sweating


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Hyponatraemia - aetiology


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Mineralocorticoid deficiency

Addisons disease Auto-immune (>80%)

TB; other infections (incl. HIV)

Tumour, lymphoma, amyloid

Haemochromatosis

X-linked adrenoleukodystrophy

AR resistance to ACTH

Congenital adrenal hyperplasia

Pseudohypoaldosteronism (aldosteroneresistance)


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Addisons - clinical

Presentation Low BP, low Na+, high K+, high urea, low glucose

Diagnosis Plasma cortisol while stressed

Short Synacthen test (ACTH analogue) ACTH level - adrenal v pituitary failure

High plasma 17-OH progesterone in classical CAH

Management

Hydrocortisone, fludrocortisone replacement

Monitoring BP, U&E, cortisol day curve, 24-h urine free cortisol

Plasma renin (esp in children)


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Syndrome of Inappropriate

Antidiuresis (SIADH) Diagnostic criteria:

Low Na+, low plasma osmolality

Urine osmolality > plasma osmolality Persistent excess renal Na+excretion

No hypotension, hypovolaemia or oedema

Normal renal, adrenal and thyroid function NB: plasma ADH analysis no thelpful


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Hyponatraemia - Clinical features

Usually asymptomatic if Na+>120 mmol/l

Mild:

anorexia, headache, nausia + vomiting, lethargy Moderate:

personality change, muscle cramps, weakness,confusion, ataxia

Severe: drowsiness, diminished reflexes, fits, coma, death


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Hyponatraemia - Management Treat cause

Volume expand if dehydrated

Hydrocortisone in Addisons

Diuretics and fluid restrict if hypervolaemic

ACE inhibitors, spironolactone in CCF

(Renin inhibition; aliskiren)

V2 receptor antagonists; tolvaptan, (conivaptan)

Gradual increase in Na+

(


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Central pontine myelinolysis

Rapid correction ofhyponatraemia

Osmotic damage to brainstem

H t i ti l


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Hypernatraemia - aetiology Excess Na+intake (rare)

IVI, infant feeds, sea water, drugs

Excess mineralocorticoid action Na+usually borderline high, due to thirst and water

retention

Cushings, Conns, CAH (some)

11-OH steroid dehydrogenase inhibition;carbenoxolone, licorice

Poor water intake

Poor access, inability to drink, IVI, thirst deficiency

Water loss Extrarenal: fever, thyrotoxicosis

Renal: osmotic diuresis, DI


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Hypernatraemia - clinical

Clinical features

Thirst (absent in hypovolaemia)

Irritability

Hypotonia

Seizures

Death

Management Cause

Gradual reduction of plasma Na+(


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Hypernatraemia - aetiology


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Haemodialysis


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Principles of Dialysis and

Haemofiltration Removal of fluid and solutes depends

on:

Membrane pore size Pressure across membrane

Composition of dialysis fluid


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Principles of Dialysis and

Haemofiltration

water and sodium homeostasis 2013

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