Sodium and Water

Metabolism
A C J Hutchesson
Body Composition
• 70 kg man:
– Water ~ 42 L
– Sodium ~ 3.8 moles
– Potassium ~ 3.1 moles
– Calcium ~ 25 moles
Fluid Compartments
• Extracellular
– Intravascular
– Interstitial
– Cerebrospinal fluid
– aqueous/vitreous humours
• Intracellular
– Cytosol
– Organelles
• Pathological
– transudates, exudates

Fluid Compartment volumes
Measured by dilution; e.g. with:

• Total body water urea, D
2
O 42 L
• ECF Sucrose, Inulin 12.5 L
– Plasma Evans Blue,
131
I 3 L
– Interstitial fluid 9.5 L
• ICF TBW - ECF 29.5 L
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
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%
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
Osmolality
• Osmotic Pressure:
– pressure exerted by all dissolved solutes.
Osmolarity no. particles/L solution
Osmolality no. particles/kg solvent
Osmolality preferred; temp/solvent independent

• Colloid osmotic pressure (Oncotic pressure):
– pressure exerted by colloid alone.
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
Functions of Osmolar
pressure
• Homeostasis

• Support

• Water transport - osmotic gradients
– Gut wall
– Capillaries
– Urine concentration
Ernest Starling
• First hormone (secretin)

• Frank-Starling law of the
heart

• Absorbtion of water and
electrolytes by distal
convoluted tubule

• Capillary transport -
Starling equation


Starling Equation
J = K
f
{(P
c
- P
i
) - (
c
- 
i
)}

where:
• J = net fluid movement across capillary
• P
c
= capillary hydrostatic pressure
• P
i
= interstitial hydrostatic pressure
• 
c
= capillary oncotic pressure
• 
i
= interstitial oncotic pressure
• K
f
= 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 impermeable
capillaries, e.g. glomerulus)

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
Excess tissue fluid - Oedema
• Increased venous pressure
– cardiac failure
– varicose veins
• Reduced oncotic pressure
– hypoalbuminaemia
• Increased capillary permeability
– inflammation
Control of Osmolality
osmotic pressure (~2%) Blood volume (~10%)
ADH Thirst
Water resorbtion Water uptake
Osmotic pressure Blood volume
Antidiuretic Hormone/Vasopressin
• Nonapeptide
• Secreted by cells in supraoptic and
paraventricular nuclei, projecting to posterior
pituitary
• 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 in
inner medullary collecting ducts)
– Vasoconstriction (V1 receptor)
Antidiuretic Hormone/Vasopressin
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
Relationship
between plasma
osmolality and
(a) ADH,
(b) thirst,
(c) hypovolaemia
From Oxford Textbook of Mdeicine ($th ed)
Stimuli to ADH secretion
(a)
(b)
(c)
Aquaporins
• Family (at least 11) of transmembrane water
channels

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

• Positive charges within channel repel
protons; water (polar molecule) rotates within
channel to negotiate it.
Aquaporins
• Three functional groups:
– Aquaporins - AQP 0,1,2,4,5,6
water
– Aquaglyceroporins - AQP 3,7,8
water,glycerol, urea
– Neutral solute channels - AQP 9
water, glycerol, urea, purines, pyrimidines
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)
Aquaporin 2
• Found on apical surface of collecting duct cells.
• Expression increased by ADH via cAMP:-
– Insertion of AQP 2 into cell membrane
– Upregulation of AQP 2 synthesis

• Inhibited by mercuric chloride.
• Expression decreased by lithium.

• Mutations associated with autosomal recessive
nephrogenic diabetes insipidus (DI).
From Gattone et al, Nature Medicine 9, 1323 - 1326 (2003)
Renal tubular actions of
Vasopressin
From Laboratory of Molecular Genetics, University of Malta
Renal concentration of urine
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)
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
Interpretation of Water Deprivation
Test
Urine osmolality (mosmol/l)
Diagnosis Post-deprivation Post-DDAVP
> 750 > 750 Normal
< 300 > 750 CDI
< 300 < 300 NDI
300 - 750 > 750 Partial CDI
or partial NDI
or polydipsia
Sodium - Functions
• Maintenance of extracellular fluid volume
• Na
+
/K
+
ATPase (“sodium pump”)
– Signalling, secretion, contraction
– Active transport processes
• Antiporters; e.g. calcium
• Coporters; e.g. glucose in kidney
– Water transport
• Bulk transport
• Maintenance of intracellular volume
– Thermogenesis
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
Composition of ECF and ICF
ECF (mmol/l) ICF (mmol/l)
Cations: Na
+
140 12
K
+
4 150
Mg
++
1.0 15
Anions: Cl
-
100 4
HCO
3
-
24 8
PO
4
--
1 73
Proteins 15 40
The Renin-Angiotensin system
Renin
Angiotensinogen
Aldosterone
Angiotensin I
Angiotensin II
Bradykinin
Angiotensin
converting enzyme
Inactive
metabolites
Liver
Kidney
Lung
ADH Vasoconstriction
Na retention
Control of plasma sodium
 Renal blood flow
 Plasma volume
 Renin
Angiotensin I
Angiotensin II
 Aldosterone
Na
+
K
+

 Thirst
 urine Na
+
excretion
 urine K
+
excretion
 Plasma volume  Na
+
concentration
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 decapeptide
angiotensin I from angiotensinogen
• AT-I further cleaved to AT-II in lung
Aldosterone
• Main mineralocortocoid; essential for life.
• Synthesised by zona glomerulosa of adrenal
cortex
• 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)
Salt and water homeostasis:
interrelationships (1)
Problem Response
High plasma
concentration
Reduce water loss
 Increase plasma volume
Low plasma volume Reduce sodium loss
 Increase plasma concentration
Salt and water homeostasis:
interrelationships (2)
 Plasma volume
 renin
 Angiotensin II
 Aldosterone
 Na
+
retention
 Plasma osmolality
 ADH
 Water retention
 Thirst
 Water
intake
(>10%)
(>10%)
Salt and water homeostasis:
ADH  osmolality, RAS  blood pressure
Plasma osmolality Mean arterial pressure
ADH Aldosterone
AQP2 ENaC
Water reabsorbtion
Sodium reabsorbtion
Other hormones/factors
• Natriuretic peptides
• Digoxin-like immunoreactivity/Ouabain
• Renal dopamine, PgE
2
?
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
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
Salt and water homeostasis:
fluid overload
 Plasma volume
 renin
 Angiotensin II
 Aldosterone
 Na
+
retention
 Plasma osmolality
 ADH
 Water retention
 ANP, BNP
Cardiac failure
 Plasma volume
 renin
 Angiotensin II
 Aldosterone
 Na
+
retention
 Plasma osmolality
 ADH
 Water retention
 ANP, BNP
 Renal perfusion
Cardiac remodelling
Oedema
Natriuretic peptides and heart
failure (1)
• Screening
– Selection for echocardiography (gold
standard)
– High plasma levels of:
• ANP Volume overload
– ANP 99-126 short half-life; c.f. glucose
– ANP 1-98 long half-life; c.f.HbA1c
• BNP Systolic dysfunction
– BNP, N-terminal BNP
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-II
degradation.

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)
Drugs affecting the RAS
Renin
Angiotensinogen
Aldosterone
Angiotensin I
Angiotensin II
Bradykinin
Angiotensin
converting enzyme
Inactive
metabolites
Liver
Kidney
Lung
ADH Vasoconstriction
Na retention
Aliskiren
ARBs
(Sartans)
Spironolactone
ACE inhibitors
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
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
– Addison’s, vomiting/diarrhoea, burns, sweating
Hyponatraemia - aetiology
Mineralocorticoid deficiency
• Addison’s disease
– Auto-immune (>80%)
– TB; other infections (incl. HIV)
– Tumour, lymphoma, amyloid
– Haemochromatosis
– X-linked adrenoleukodystrophy
– AR resistance to ACTH
• Congenital adrenal hyperplasia
• Pseudohypoaldosteronism (aldosterone
resistance)
Addison’s - 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)
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 not helpful
SIADH
• Causes: Numerous!
– Malignancy - many (usually small-cell lung)
– Other lung disease
– CNS disease - e.g. infections, trauma, SAH,
Guillain-Barre
– Other - e.g. drugs, acute pophyria, psychosis
• Management
– Fluid restriction (500 ml/24 h)
– Demeclocycline
– V2 receptor antagonists; tolvaptan, (conivaptan)
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
Hyponatraemia - Management
• Treat cause
– Volume expand if dehydrated
– Hydrocortisone in Addison’s
– Diuretics and fluid restrict if hypervolaemic
– ACE inhibitors, spironolactone in CCF
– (Renin inhibition; aliskiren)
– V2 receptor antagonists; tolvaptan, (conivaptan)
• Gradual increase in Na
+
(<12 mmol/l/24 h)
– Risk of acute demyelination over next 4 days
– Rapid fall permits more rapid correction
• Mortality high if Na
+
< 110 mmol/l
Central pontine myelinolysis
Rapid correction of
hyponatraemia
Osmotic damage to brainstem
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
– Cushing’s, Conn’s, 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
Hypernatraemia - clinical
• Clinical features
– Thirst (absent in hypovolaemia)
– Irritability
– Hypotonia
– Seizures
– Death
• Management
– Cause
– Gradual reduction of plasma Na
+
(<10 mmol/l/24h)
Hypernatraemia - aetiology
Haemodialysis
Principles of Dialysis and
Haemofiltration
• Removal of fluid and solutes depends
on:
– Membrane pore size
– Pressure across membrane
– Composition of dialysis fluid
Principles of Dialysis and
Haemofiltration