Water Balance and

Regulation of Osmolality
Inolyn
 Contents:
Renal mechanisms for urine concentration
 Countercurrent multiplication by the loop of Henle
 Action of ADH in the collecting ducts
Feedback control of plasma osmolality
Mechanism of ADH action in the kidney
Failure to concentrate the urine
Differential diagnosis of hypernatremia
Failure to dilute the urine
Differential diagnosis of hyponatremia

Inolyn, 2007
 The Urinary System

Vander’s Renal Physiology, Fig. 1-1, pp. 5

Inolyn, 2007
 Structure of the
kidney

Vander’s Renal Physiology, Fig. 1-4, pp. 11

Inolyn, 2007
 Anatomy of the glomerulus

Vander’s Renal Physiology, Fig. 1-4, pp. 8

Inolyn, 2007
 Basic renal process

Inolyn, 2007 Vander’s Renal Physiology, Fig. 1-7, pp. 17

 Renal mechanisms for urine
concentration
N plasma osmolality: 290 mosm/kg (5 mosm/ kg BB)
Homeostatic maintenance  kidney – adjust the rate
of water excretion
 A zone must be created within the renal medulla where the
tissue fluid osmolality is high
• Loop of Henle
 The tubules forming the final segment of the nephron must
conduct the urine through this concentrated zone (water
reabsorption can occur passively by osmosis)
• Collecting ducts
• Vasopressin (ADH)

Inolyn, 2007
 Countercurrent multiplication by the
loop of Henle
Loop structure  longitudinal gradient of
concentration
Countercurrent: fluid flow – descending
limb () – ascending limb ()

Inolyn, 2007
 Properties of the descending and
ascending limbs of a long Henle’s loop
The descending limb
 Highly permeable to H2O
 Does not actively extrude Na
The ascending limb
 Actively transports NaCl out of tubular lumen
into the surrounding interstitial fluid
 Impermeable to H2O  salt leaves the
tubular fluid without H2O following along

Inolyn, 2007
 Mechanism of countercurrent
multiplication
Step 1 - 6

Human Physiology, Sherwood, Fig. 14-28, pp. 542-3

Inolyn, 2007
Inolyn, 2007
Inolyn, 2007
Inolyn, 2007
 Action of ADH in the collecting duct

Distal and collecting tubule 

impermeable to water except in the
presence of ADH
Vasopressin (ADH)
 produced by specific neuronal cell bodies in
the hypothalamus – stored in the posterior
pituitary gland
 Secretion – stimulated by a H2O deficit

Inolyn, 2007
 Vasopressin  the basolateral membrane of the tubular
cells (the distal and collecting tubules) through the
circulatory system

Human Physiology, Sherwood, Fig. 14-29, pp. 544 The Renal System, Fig. 3.7; pp. 43

Inolyn, 2007
 Mechanism of ADH action in the kidney

Other intrarenal action of ADH:

  activity of NaCl reabsorptive mechanism in the thick
ascending limb of loop of Henle
  permeability of the inner medullary collecting duct to
urea
  intensification of the medullary interstitial
concentration gradient
ADH  separate action - different receptor (V1)
 intracellular Ca mobilization 
vasoconstriction of the arteriols  BP 
Inolyn, 2007
 Feedback control of plasma osmolality

Water deprivation  plasma osmolality  

detected by osmoreceptor (specialized neural
cells in the hypothalamus)
  thirst  seek and ingest water
  activate supraoptic and paraventricular
hypothalamic nuclei  ADH secretion
Ingestion of large volume of water  plasma
osmolality   osmoreceptor reduce activity 
 Thirst suppressed
 Inhibit ADH release

Inolyn, 2007
 The Renal System, Fig. 3.5 & 3.6; pp. 42
Inolyn, 2007
 Feedback control of plasma osmolality

ADH  effective in regulation of plasma osmolality

 Small peptide (9 AA), very short half-life in circulation  not
prolonged after its release
 Release of ADH from hypothalamus (osmoreceptor signal) 
action in kidney: rapid events (minute, no delay)
Non-osmotic stimuli  secrete ADH
 Haemodynamic changes – 5-10% (hypovolemia  baroreceptor)
 hypothalamus  ADH secretion 
 Pain, nausea, and stress  ADH secretion 
 Alcohol  ADH secretion 

Inolyn, 2007
 Vander’s Renal Physiology, Fig. 7-14, pp. 123
Inolyn, 2007
 Condition required for urinary
concentration
To concentrate the urine
 Adequate solute delivery to the loop of Henle
 Normal function of the loop of Henle
 ADH release into the circulation
 ADH action on the collecting ducts
To dilute the urine
 Adequate solute delivery into the loop of Henle and
early distal tubule
 Normal function of the loop of Henle and early distal

tubule
 No ADH in the circulation

Inolyn, 2007
 A case of polyuria
RU, 46-yo man
 For several weeks  passing large volume of urine (colourless
“like water”) and excessive thirst (drink 5 ls/ more water/ d) 
passing similar volume of urine
 No history of similar complain, never diagnosed with DM, never
had known kidney disease
 He has some ‘emotional problems’ over the years
 Family history: unremarkable
 Patient: reformed smoke, does not drink alcohol
Examination:
 Little agitated- but quite well
 Skin, lips, mouth: rather dry
 BP: 130/80, pulse: 84 x/’
Urine specimen: very pale colour, glucose (-), blood (-), protein (-)

Inolyn, 2007
  What might be causing his polyuria and
thirst?
 What determines how concentrated the
urine is under normal condition?

Inolyn, 2007
 Failure to concentrate the urine
Mechanism Clinical example

Failure to generate medullary

concentration gradient
Poor solute deliver to the loop of Low GFR (chronic renal failure)
Henle
Impaired action of thick ascending Loop diuretic therapy (Furosemide)
limb of Loop
Failure of ADH Effect

No ADH released Central DI (hypothalamic/ pituitary

lesion)
No ADH action in kidney Nephrogenic DI (collecting duct cell
dysfunction)

Inolyn, 2007 The Renal System, Tab. 3.3; pp. 43

Distinguishing central DI and nephrogenic DI …
Water deprivation test
 Initially well hydrated (urine osm quite low)  water deprivation period  N: in 9-12 h –
urine osm   administration of exogenous ADH

The Renal System, Fig. 3.8 & 3.9; pp. 44

Inolyn, 2007
 Failure to concentrate the urine
Causes of central DI:
 Tumours, trauma, irradiation of cerebrovascular accident 
destroy relevant regions of hypothalamus/ pituitary stalk/ posterior
pituitary
 Sarcoidosis
Causes of nephrogenic DI
 Inherited: faulty structure and impaired function of V2 receptor/
AQP2 water channel
 Acquired:
• Infection/ obstruction of the collecting duct  interference steps after
generation of cAMP  prevent AQP translocation to apical membrane
• Hypokalemia
• Hypercalcemia
Inolyn, 2007
 Differential diagnosis of hypernatremia

Water deficit with proportionately smaller Na deficit

 Renal: osmotic/ loop diretic (during water restriction)
 Extrarenal: skin (excessive sweating); gut (colonic
diarrhea)
Water deficit alone
 Renal: central or nephrogenic DI
Sodium loading with normal or reduced body
water
 Enteral/ parenteral alimentation
 Intravenous/ oral salt administration
Inolyn, 2007
 Differential diagnosis of hypernatremia

Whatever the underlying cause, sustained/

severe hypernatremia  impaired thirst
mechanism (~ brain damage, impaired
availability of/ access to water)
The finding of hyperNa  no guide to the
total body Na status  independently
assess using clinical clues – hypo/
hypervolaemia
Inolyn, 2007
 Failure to dilute the urine
Inappropriate water retention
 Rule out low GFR
 Exclude the use of diuretic drugs acting on
the thick asc limb (furosemide)/ early distal
tubule (thiazide)
 Determine that ADH is not released (ADH 
stimulated by  plasma osmolality,
hypovolaemia, stress, nausea, pain)

Inolyn, 2007
 Differential diagnosis of hyponatremia

Sodium deficit with relative water retention

 Renal: thiazides & loop diuretics (during water drinking),
adrenocortical failure
 Extrarenal: gut (vomiting)
Water retention alone
 SIADH: ectopic ADH secretion from tumour, lung disease, CNS
disease, drugs (phenothiazines, vincristine, cyclophosphamide)
 Hypothyroidism
Sodium retention with relatively greater water retention
 Generalized oedema states: CHF, cirrhosis, nephrotic syndrome
 Chronic renal failure

Inolyn, 2007
 Differential diagnosis of hyponatremia

Management of hyponatremia:
 Define the aetiology and reverse the causative
condition
 Hypovolaemic states  volume replacement and iv
NaCl infusion
 Hypervolaemic states  Na restriction, water
restriction
 SIADH and related condition  restriction of water
Hyponatremia  no reliable guide to the total
body Na and volume status  clinical clues

Inolyn, 2007
 The case..
Severe renal impairement  excluded (N
plasma Cr, never used loop diuretics)
Hypothalamic DI  excluded (plasma ADH level
when patient was dehydrated and hyperosmolar;
cerebral CT scan  no structural damage in
hypothalamus/ pituitary fossa)
Patient had been receiving psychiatric treatment
for 1 month (agitated and hypomanic) – Lithium
carbonate 500 mg bd  plasma [Li]: 0,9 mmol/l

Inolyn, 2007
 The case..
Diagnosis: lithium-induced nephrogenic DI
Result of plasma ADH: high ~  plasma osmolality
Cerebral CT scan: N
Management:
 Maintain adequate water intake
 If Lithium th/ to be continued  close monitoring of plasma Li
level: 0,4-0,8 mmol/ L
 If polyuria and thirst persist  amiloride (blocks uptake of Li and
Na through the apical cation channel on the cortical collecting
duct)

Inolyn, 2007
Thank You
 Clinical features of hypovoalemia &
hypervolaemia

Hypovolaemia Hypervolaemia
Symptoms Thirst Ankle swelling
Dizziness on standing Breathlessness
Confusion

Signs Low JVP Oedema

Postural hypotension Raised JVP
Dry mouth Pulmonary crepitations
Reduced skin turgor Hypertension
Reduced urine output (sometimes)
Weight loss Weight gain

Inolyn, 2007