DR MODUPE KUTI

FWACP (Lab Med)

Water is the most abundant constituent in the body

50% of weight in women;
60% of weight in men
Difference due to adipose tissue composition

Total Body Water divided into 2 compartments

Extracellular : 25 45%
Intravascular plasma water
(25%)
Extravascular interstitial fluid (75%)
Intracellular : 55 75%

Interfaces between
Extracellular and Intracellular fluids Cell membranes
Intravascular and Interstitial Capillary walls

Movement of fluids between

Extracellular and Intracellular
Osmolality (solute or particle concentration of a fluid, expressed as
milliosmoles per kilogram of water (mosmol/kg).
Water crosses cell membranes to achieve osmotic equilibrium (ECF
osmolality = ICF osmolality).
normal plasma osmolality is 275 290 mosmol/kg
Osmolality can measured or calculated 1.8[Na + Cl] + Urea (mg/dL)/6 + Glucose (mg/dL)/18

Major ECF solutes Sodium, Chloride, Bicarbonate

Major ICF solutes Potassium, Organic Phosphates (ATP, creatine
phosphate, phospholipids)
Differences due to disparities in permeability, and the presence of
transporters and active pumps

Intravascular and Interstitial

Starlings Forces
capillary hydraulic pressure from blood pressure
colloid osmotic pressure oncotic pressure (proteins)
Occurs across the capillary wall

For steady state, water intake must equal water excretion

Physiologic influences for both actions

Water intake
Water Ingestion
Primary Stimulus is thirst mediated either by an increase in effective osmolality
or a decrease in ECF volume or blood pressure.
Osmoreceptors, located in the anterolateral hypothalamus, are stimulated by a
rise in tonicity.
Urea and glucose are ineffective osmoles

Water Excretion
Normal individuals have an obligate water loss consisting of
Urine, Stool, and Evaporation from the skin and respiratory tract.

 Physiologic Regulation

principal determinant of water excretion is arginine vasopressin (AVP) synthesized

in the supraoptic and paraventricular nuclei of the hypothalamus and secreted by
the posterior pituitary gland.
Binding to V2 receptors on the basolateral membrane of principal cells in the
collecting duct leads to the insertion of water channels into the luminal membrane.
The net effect is passive water reabsorption along an osmotic gradient from the
lumen of the collecting duct to the hypertonic medullary interstitium.
The major stimulus for AVP secretion is increased osmolality
Effective osmolality is primarily determined by the plasma Na concentration
because major ECF solutes are Na salts,
Nonosmotic factors that regulate AVP secretion include effective circulating
(arterial) volume, nausea, pain, stress, hypoglycemia, pregnancy, and numerous
drugs.

 85 to 90% of all Sodium is extracellular, actively pumped out of the cell by the NaK

ATPase pump
ECF volume is a reflection of total body Sodium content
Volume regulatory mechanisms ensure that Sodium loss balances Sodium gain.
Normal Na concentration in plasma : 135 145mmol/L

Sodium Intake
Typical western diet consume approximately 150 mmol of NaCl daily.
Excess Na in diet ECF expansion increased renal excretion

Sodium Excretion
Regulation of excretion is main determinant of Na balance
Major regulatory mechanism is tubular Na reabsorption
Most important determinant of Na reabsorption is reninangiotensin system,
acting via aldosterone
Filtered Sodium
About 60% is reabsorbed in PCT
25 to 30% in the thick ascending limb of the loop of Henle (Loop diuretics)
5% in the DCT (thiazide-sensitive)
Final Na reabsorption in the cortical and medullary collecting duct (Aldos)

HYPOVOLEMIA generally refers to a state of combined salt and water loss exceeding
intake leading to ECF volume contraction
Causes
Renal
Diuretics

thiazides, loop
act on specific parts of the tubules
Osmotic Diuresis
increased filtration of
glucose poorly controlled diabetes
mannitol tubules are impervious, neurosurgery
protein hyperalimentation (high protein)
Hypoaldosteronism
Hypoadrenalism e.g. Addisons disease
Salt Wasting Nephropathies Tubule and interstitial renal disorders
Diabetes Insipidus
Central or Nephrogenic
Acute Tubular Necrosis
Diuretic phase, glomerulus recovers before tubule

 Extrarenal

Gastrointestinal (vomiting, nasogastric suction, drainage, fistula, diarrhea)

About 9L of fluids enter GIT/24hrs : 2L ingestion, 7L secretion
Almost 98% is reabsorbed, faecal loss is 100 200ml/day
Enhanced secretion or impaired reabsorption
Skin/respiratory (insensible losses, sweat, burns)
Insensible water loss typically about 500ml/24hr
Increased during febrile illness, prolonged heat exposure,
Increased water /salt loss through sweat
Hyperventilation, mechanically ventilated persons, neonates

 Third space loss (burns, peritonitis, pancreatitis)

ECF, but is not in equilibrium with ECF or ICF, effectively lost
burns subcutaneous tissue
retroperitoneal space in acute pancreatitis
peritoneal cavity in acute peritonitis
Severe Hemorrhage

Pathophysiology
ECF volume contraction decreased plasma volume decreased preload decreased
cardiac output hypotension triggers baroreceptors in the carotid sinus and aortic
arch activation of the sympathetic nervous system and the reninangiotensin system
Main CVS goal maintain mean arterial pressure and cerebral and coronary perfusion
Main Renal goal restoring ECF volume by decreasing GFR and filtered load of sodium AND
by increasing proximal tubular and collecting duct (RASAldo) absorption
of Na

Clinical Features

History may help define aetiology vomiting, diarrhoea, polyuria

Other symptoms not specific fatigue, weakness, cramps, thirst and postural dizziness
oliguria, cyanosis, diminished skin turgor and dry mucous
membranes
Signs Decreased JVP, Postural hypotension/tacchycardia

Biochemical Changes Increased Urea, Creatinine

Urine Na, Urine Osmolality change depend on aetiology

HYPONATREMIA
Plasma Sodium Concentration < 130mmol/L
Typically associated with hypoosmolality < 280 mosmol/kg
Most commonly due to impaired excretion of free water

Impaired filtration and delivery of water to the diluting sites in the nephron
Chronic Renal Failure
Cortisol Deficiency, Hypothyroidism

Impaired reabsorption of Na and Cl in excess of water in the thick

ascending limb of the loop of Henle and in the distal nephron
Diuretics, especially thiazide
Hypoaldosteronism
Salt Wasting Nephropathy
Maintenance of a dilute urine due to impermeability of the collecting duct to
water in the absence of AVP
Syndrome of inappropriate AVP secretion ( neuropsychaitric diseases,
malignant tumours, pulmonary diseases)
AVP release due to pain, nausea

Primary or psychogenic polydipsia:

Inability to excrete a free water load because renal excretory
capacity is exceeded; > 12L per day

Primary Sodium Loss, in excess of water

GIT loss in vomiting, diarrhea, fistulas

Pseudohyponatremia
Normal plasma osmolality
Hyperlipidemia
Hyperproteinemia

Clinical Features
Related to osmotic water shift leading to increased ICF volume,
specifically brain swelling and edema mainly neurologic
Headache, lethargy, confusion, obtundation, stupor, seizures, coma
Severity is dependent on the rapidity of the development of the
condition as well as the absolute decrease in plasma [Na]

Investigation
Plasma Osmolality
Urine Osmolality
Urine [Na]
Urine [K]

HYPERNATREMIA
is defined as a plasma Na concentration > 145 mmol/L
is a state of hyperosmolality
Associate ICF volume contraction

Causes
due to primary Na gain or
water loss commonest cause

The appropriate response to hypernatremia

1. increased water intake stimulated by thirst and
2. the excretion of the minimum volume of maximally concentrated
urine reflecting AVP secretion in response to an osmotic stimulus

Causes of Free Water Loss

Renal or Extra renal
Renal Causes most common cause
Diuretics
Loop diuretics interfere with the countercurrent mechanism,
impairing renal concentrating ability
Osmotic Diuresis Presence of nonreabsorbed substances, glucose, mannitol
Water is lost in excess of Na
Diabetes Insipidus - nonosmotic urinary water loss
Central characterised by impaired AVP secretion
trauma, neurosurgery, granulomatous disease,
vascular accidents, infection, idiopathic
may also be familial

Nephrogenic resulting from endorgan (renal) resistance to actions of AVP

congenital V2 receptor or aquaporin gene defects
acquired drugs (lithium), hypercalcemia, hyperkalemia
Extrarenal
Increased insensible water loss Sweating, Fever, Hyperventilation
Osmotic diarrheas lactulose, sorbitol, viral gastroenteritis

Clinical Features ICF volume contraction decreased brain cell volume

typically neurologic: altered mental status, weakness,
neuromuscular irritability, focal neurologic deficits, coma, seizures
symptoms of underlying disease

Investigations
Urine volume
Urine Osmolality
Urine [Na]

Potassium is the major intracellular cation

Normal plasma K concentration is 3.5 to 5.0 mmol/L; ICF is about 150 mmol/L.

The ratio of ICF to ECF K concentration (normally 38:1) is crucial for normal
neuromuscular function (gradient maintained by the basolateral Na, K-ATPase
pump actively transports K in and Na out of the cell in a 2:3 ratio)

The K intake of individuals on an average western diet is 40 120 mmol/d

Following a meal, absorbed K enters facilitated by insulin release and basal

catecholamine levels.

Eventually, however, the excess K is excreted in the urine

Potassium Excretion Renal Excretion is the major route of elimination of

dietary and other sources of [K]
Some 90% of filtered K is reabsorbed by the proximal convoluted tubule and
loop of Henle
K delivery to the DCT and CCD roughly equals the dietary intake
Net excretion depends on K status: excess or depletion, regulates total body
balance
Principal cell is responsible for K secretion in the DCT and CCD
Regulation

a)
b)

Aldosterone secreted in response to renin and angiotensin or hyperkalemia

exchanges Na for either K or Hydrogen.
Hyperkalemia increases K secretion

Hypokalemia defined <3.5 mmol/L

Results from
1.
Decreased net intake
2.
Shift into cells
3.
Increased net loss

Decreased Intake Rarely a sole cause, may exacerbate when other mechanism present

Redistribution into cells

Movement of K+ into cells may transiently decrease the plasma K+ concentration
without altering total body K+ content.

Insulin therapy, Stress induced catecholamine release, administration of B2 agonists

increase intracellular shift of K

Anabolic states with rapid cell growth ; patients with pernicious anemia treated
with vitamin B12 or with neutropenia after treatment with GCSF

Renal Loss
Causes most cases of chronic hyperkalemia
Primary hyperaldosteronism (Mineralocorticoid excess states) Conns
syndrome, Adrenal hyperplasia, Adrenal carcinoma, Renin secreting
tumors, Renovascular hypertension

Non aldosterone mineralocorticoid excess states Congenital adrenal

hyperplasia, Cushings syndrome
Non Renal Loss
Every body fluid has a higher [K] than plasma
Loss of ANY body fluid in amounts above physiologic will cause hypokalaemia
Saliva, Large bowel secretions, Vomiting, Nasogastric secretions

Clinical Features Fatigue, myalgia, Muscular weakness of the extremities due to lower
resting membrane potential
Respiratory muscle weakness, paralysis
Inversion of the T wave, prominent U wave
prolonged PR interval, increased risk of ventricular arrhythmias
Investigation
24 hr Urine [K]
PSEUDOHYPOKALEMIA
Patients with marked leucocytosis and normokalemia may have a low measured
plasma [K] concentration due to white blood cell uptake of K at room temperature.
Avoid by storing blood sample on ice or rapidly separating plasma/serum from cells

Hyperkalemia defined as [K] > 5.0mmol/L

Pseudohyperkalemia
artificial elevated plasma [K] due to movement out of the cells immediately prior to
or following venepuncture
Contributory factors
prolonged use of torniquet
Repeated fist clenching
Hemolysis
Marked leucocytosis
Thrombosis
Repeat with proper venepuncture, use plasma (not serum),

1.
2.

Increased intake rarely the sole cause, overzealous parenteral replacement

Release from cells
1. Intravascular hemolysis
2. Tumor lysis syndrome
3. Rhabdomyolysis
4. Metabolic Acidosis result of intracellular buffering of [H]
5. Insulin deficiency promotes movement of K out of the cells

3.

Decreased renal loss Cause of most chronic hyperkalemia

Renal Failure Acute (increased release from cells acidosis and catabolism
Chronic when GFR falls below 10 15ml/min
oliguric
Decreased K secretion
Primary hypoaldosteronism adrenal insufficiency
impaired Na reabsorption

Secondary hypoaldosteronism heparin, ACEi, NSAID

Pseudohypoaldosteronism resistance to aldosteronism
tubuloinsterstitial disease, K sparing
diuretics

Clinical Features
Partial depolarisation of the membrane with impaired excitability
Muscle weakness, Flaccid paralysis
Cardiac toxicity increased T wave amplitude (peaked T waves)
ventricular arrhythmias, asystole