Body Water Balance & Diabetes Insipidus

Question 1

What is hypo and hypernatraemia (values)?

Answer 1

Plasma sodium [Na+] or [Na+]p normal 135-145 mmol/l
=Hypernatraemia [Na+] > 145 mmol/l
=Hyponatraemia [Na+] < 135 mmol/l

Question 2

What is plasma osmolarity in terms of hyper and hypotonic?

Answer 2

Plasma osmolality p normal ~ 282-296mosmol/kg
calculated approximation: p  2x[Na+] + [urea] + [glucose]
hypertonic = hyperosmolar p > 296 (>299 often used)
hypotonic = hyposmolar p < 282

Question 3

ADH

Answer 3

antidiuretic hormone = vasopressin

Question 4

SIADH

Answer 4

syndrome of inappropriate ADH

Question 5

Polyuria

Answer 5

excessive urine volume (>2ml/kg/hr, or 3litres/day)

Question 6

Polydipsia

Answer 6

excessive fluid intake (usual defn by assoc polyuria)

Question 7

Diabetes insipidus

Answer 7

• deficiency of ADH action, (hypotonic polyuria)

- with inability concentrate urine

Question 8

Diabetes mellitus

Answer 8

• deficiency of insulin action with raised plasma

glucose which can drive an osmotic diuresis

Question 9

DDAVP

Answer 9

= a synthetic ADH with little pressor activity
= 1-deamino-8-D-arginine vasopressin
=longer half-life

Question 10

Oedema

Answer 10

-Expansion of extracellular spaces with fluid which
collects in dependent areas (ankles, sacral), typical causes are:
=heart failure, liver failure, nephrotic syndrome.
-Usually indicates increase in body water, Na+ and ECF vol.

Question 11

Why do we need appropriate levels of ADH?

Answer 11

• retain to replace losses
• excrete sufficient to allow renal function
• excrete excess water

Question 12

Describe body water balance

Answer 12

-Water used in all cells continuously
-Water lost continuously:
=kidney > 400ml/day
=Normal urine volume 0.6-1.5 litres
=skin, respiration, gut  500ml/day

• Need to take in water regularly= Thirst
• Normal intake, adult, temperate climate 0.9 to 2-2.5 litres

Question 13

Describe how thirst is linked to ADH release

Answer 13

-Coordinated in diencephalon, hypothalamus nuclei= supraoptic and paraventricular nuclei, make ADP, trickles down in nerve terminals to posterior pituitary, released to circulation
=Stimulated from osmo sensor, third ventricle
=Thirst centre nearby
=Coordinate with each other for water balance

-Ascending tracts= baroreceptor afferents (blood pressure) and SNA pain afferents
=High level stimulation= change ADH by feeding into system

Question 14

How does thirst occur?

Answer 14

• Feedback loop
• If plasma osmolarity rises= thirst= stimulates desire to drink water at higher CNS= decreased plasma osmolarity as plasma fluids diluted= closes off feedback loop

Question 15

What does thirst require?

Answer 15

• Sufficient alertness

- Access to water

Question 16

Why is thirst important?

Answer 16

•Important when fluid intake has been inadequate
=e.g. high insensible losses (traveller in desert)
=e.g. high GI tract losses ( esp. GI infections)
•Important in high urinary losses (polyuria)
=e.g. untreated diabetes mellitus
=or diabetes insipidus
-Dangerous when thirst is not intact, when intake is inadequate as risk of hypernatraemia

Question 17

How can we measure thirst?

Answer 17

• Semi quantitatively
• 10 scale, marking how relatively thirsty they are
• Can plot how thirst rises with plasma osmolarity

Question 18

What is loss of thirst?

Answer 18

• Loss of thirst (adipsia) can occur with hypothalamic damage
• Difficult to treat – often use fixed fluid intake

Question 19

What are the 2 key mechanisms in regulating body water balance?

Answer 19

• Thirst feedback loop, linear response as thirst rises with plasma osmolarity
• ADH feedback loop, as plasma osmolarity rises ADH release rises, need to be able to make and release and kidneys need to be responsive (V2 receptors, urine concentrated so water retained) and feedback loop needs to be able to switch off and on

Question 20

What are the causes of polydipsia and polyuria?

Answer 20

-Hypothalamus
=Damage to primary stimulation of thirst centre and osmo-sensors, inhibitory or excitatory lesions (primary polydipsia= excess, inadequate= adipsia)
-Pituitary
=Lack of ADH (cranial diabetes insipidus)
-Kidney
=Resistance to ADH (nephrogenic diabetes insipidus)

Question 21

Describe Vasopressin

Answer 21

-Short peptide
-Derived from large precursor peptide (pre-pro-vasopressin)
=contains component called neurophysin and c-terminal glycopeptide that are cleaved off during processing
-Moves down axons in vesicles, processing
=Arginine vasopressin, 9 amino acids with cysteine bond, short half-life

Question 22

Where does vasopressin act?

Answer 22

• V1A= maintain blood volume and circulation (role at high AVP)- constrict vessels= much higher levels needed
• V1B= role in ACTH release and stress response, pituitary
• V2= cAMP, kidneys, appropriate retention of water, maintain osmolality, vaptan inhibits receptors, very little levels up to 6
• Low affinity to oxytocin receptors in uterus

Question 23

Where is the actin of vasopressin in the kidneys?

Answer 23

• Distal tubule, final adjustment (second half and whole of collecting ducts)
• Aquaporin 2 in apical cells, highly sensitive, channel rare when ADH turns off so water permeability drops

=Intermedullary concentration gradient in kidney
=Thick ascending limb sodium chloride channels (pull water out)
=Inner medulla loop of Henle for urea channels

Question 24

What factors affect ADH release?

Answer 24

-Non-osmotic stimuli 
=low BP, pain
-Pressor action
=V1 receptors
-Increased plasma osmolality

Question 25

What are the problems with ADH action?

Answer 25

-Problems arise from both:- =inadequate ADH action (Diabetes Insipidus, DI) -ADH in excess of needs of water balance =non-osmotic ADH release =physiologically appropriate (haemorrhage) =physiologically inappropriate (SIADH)

Question 26

How is disorders of thirst and ADH linked to natremia?

Answer 26

-Thirst= hypernatraemia -ADH= hyponatraemia -Effective lower normal p determined by [ADH] low enough for max urine dilution =Gives water excretion > 15ml/min = > 21L/day -Effective upper normal p determined by threshold for thirst to drive persistent water seeking =Occurs when ADH also driving max urine concentration (u>1000mosmol/kg

Question 27

Describe excess water loss

Answer 27

-Polyuria - if loss is renal -Thirsty, “drinking to keep up with output” -If intake inadequate [Na+] increases, plasma osmolality increases ± BP =presents as polyuria, If cannot “drink to keep up” then collapse + confusion

Question 28

Describe excess water retention

Answer 28

-Usually little symptoms initially -Later [Na+] decreases and plasma osmolality decreases =Confusion, drowsiness, nausea, even fits =presents as unexplained confusion

Question 29

Describe excessive polyuria

Answer 29

excessive = >2ml/kg/hr =70kg person > 3.36 litres = inappropriately high and causing negative fluid balance  if > 2 litres when [Na]p > 145mmol/l or persistently thirsty (inc during night)

Question 30

What are the causes of polyuria?

Answer 30

(i) Diabetes insipidus (cranial or nephrogenic) (ii) Habitual/psycogenic polydipsia (iii) Osmotic diuresis e.g. glucose (diabetes mellitus) mannitol, hypercalcaemia (iv) Renal impairment (unusual)

Question 31

How do you investigate polyuria?

Answer 31

(1)accurate fluid balance to determine if polyuria >2ml/kg/hr, urine volume high and persistent thirst/ [Na]p>145mmol/l so high (2)check glucose, Ca2+, urea, creatinine - identify cases of osmotic diuresis or renal impairment, inability to concentrate urine (3)check urine never normally concentrated =random urine samples including early morning- less than 600mosmol/kg so dilute (4) water deprivation test - show if unable to concentrate urine =p and [Na]p rise as negative water balance DI if u still < 600mosmol/kg when p >300 mosmol/kg +/or [Na]p > 145mmol/l (5) if DI, give DDAVP (1µg im) - if no effect - nephrogenic DI =if u rises so > 600mosmol/kg, then cranial DI

Question 32

How is a water deprivation test performed?

Answer 32

-12 hours prior to test =Can have fluids overnight + breakfast -During test (up to 8hrs) – no fluids, dry snacks =Patient supervised =Hourly weight, BP, urine sample (vol +πu) =2 hourly blood (Na+, πp, ± AVP) -Stop test if πu>600, of if danger (weight loss>3%, hypotensive+ dizzy etc) when water depleted (πp>296 or[Na+]>145) give DDAVP

Question 33

What are the types of diabetes insipidus and the results of the water deprivation test?

Answer 33

- Cranial DI= <300 initially and after dehydration but >600 after DDAVP - Nephrogenic DI= all <300 - Partial DI/ Habitual /Psychogenic polydipsia= 300-600 initially and after dehydration but <600 after DDAVP (wash out medullary concentration gradient)

Question 34

What is hypertonic saline test?

Answer 34

- Infuse with saline solution more concentrated than blood - Plasma osmolality rises - Measure blood samples and check ADH levels - Graph - If it responds= rises, flat= abnormal so diabetes insipidus

Question 35

What are the causes of cranial diabetes insipidus?

Answer 35

-Neurosurgery – pituitary or hypothalamus -Head injury -“Idiopathic” -Other Hypothalamic/pituitary disease =large pituitary tumour =cyaniopharyngoma =histiocytosis X =sarcoidosis =metastasis -Major Haemorrhage =postpartum (Sheehan’s syndrome) =aneurysm -Genetic =isolated AVP gene (A.Dom, secondary loss of post pit cells-delayed dom negative) =DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic, Atrophy, Deafness)

Question 36

Describe gestational DI (in pregnancy)

Answer 36

``` -Vasopressinases in placenta – degrade AVP, little effect on DDAVP, resolve 1st week post partum =Sub-clinical DI  overt DI =?others limited synthetic capacity  overt DI ```

Question 37

What are the causes of nephrogenic diabetes insipidus?

Answer 37

-Inherited =majority V2R X-linked, reports of v mild DI in females (variable X inactivation) =others AQP2 Ch12 – A.Recessive or A.Dom (C-term mutat→basolat in A.Dom) -Acquired =hypercalcaemia =hypokalaemia =resolution after urinary tract obstructive =secondary effect of psychogenic polydipsia =Lithium therapy effect =Demeclocycline

Question 38

What is the overall treatment for diabetes insipidus?

Answer 38

•Cranial DI – replace AVP – use dDAVP =dDAVP = long acting, can give just x2/day, more selective for V2R renal effects -peptide – intranasal spray/drops --tablets (desmopressin) --injections (inpatients, diagnosis) •Nephrogenic DI – other measures to ↓polyuria

Question 39

Describe cranial diabetes insipidus treatment

Answer 39

1) Treat other hypothalamo-pituitary deficiencies =(cortisol, thyroxine, sex steroids, ?GH) 2) Give replacement for vasopressin = Desmopressin/DDAVP =Desmopressin spray (nasal 10μg/spray: 1-2sprays bd) =Desmotabs tablets (oral typically 100-200μg tds) =DDAVP injection (rarely long-term, caution typically - initially 1μg sc/IM, wait until wears off then 1-4 μg sc/IM/day over 1-2 doses =to diagnose diabetes insipidus - 2μg DDAVP sc, warn < 500ml fluid/next 8hrs =(Similar treatment may be useful in troublesome gestational DI.)

Question 40

Describe nephrogenic diabetes insipidus treatment

Answer 40

1)Think of causes – treat them if possible ?[K+]↓, [Ca2+]↑, Lithium or demeclocycline treatment….. 2) Some treatment of partial benefit, consider - thiazide/amilorids diuretics paradoxically lower urine volumes - indomethacin – limit renal prostaglandins - lower salt diet limit urinary osmotic load ± lower protein diet =In partial DI ± occasionally try drugs with SIADH tendency, (eg chlorpropamide may ↑renal receptors and response to ADH

Question 41

How is SIADH diagnosed?

Answer 41

``` (1) Is the patient dehydrated? =If so Na+ and water loss, identify if urine is site of excess salt loss (2) Is the patient oedematous? =If so treat the cause of the oedema (3) If neither (1) nor (2) check for =thyroid or adrenal/ACTH deficiency ``` SIADH - show inappropriately concentrated urine show urine osmolality>500 or >2x plasma osmolality when plasma [Na+]<135 and/or plasma osmolality < 280 -Hyponatraemia with normal ECF (kidney adaptions to reduce water reabsorption from PCT), urine sodium >20mmol, not on diuretics and adrenal glands normal

Question 42

What are the causes of SIADH?

Answer 42

•Intracranial Lesions/disease - of diverse kinds (interfere with feedback= trauma, surgery, CNS infection, Stroke) •Intrathoracic disease, especially infections, pneumonia (affect baroreceptor feedback) •Neoplasms, especially lung/mediastinal/ pancreatic (secrete ADH ectopically) •Drugs antipsychotics e.g. phenothiazines sedatives e.g. morphine, barbiturates -CARDISH= chemotherapy, antidepressants, recreational, diuretics, inhibitors (ACE, SSRI), sulfonylurea, hormones (desmopressin) 5 C’s chlorpropamide, clofibrate chlorpromazine carbamazepine chlorthiazide (and other thiazides) •Miscellaneous nicotene, pain (especially post-op)

Question 43

What is the treatment for SIADH?

Answer 43

-confirm diagnosis -fluid restrict (1000ml/d, then < 800ml/d if needed) -occasionally require demeclocycline (cause partial nephrogenic DI) -normalise [Na+] slowly ( <10mmol/l/day) -New options = aquaretics – V2 receptor antagonists e.g. Tolvaptan (may also reduces decline in PKD) - combined V2-V1a antagonists e.g. conivaptan (roles in SIADH, heart failure etc, less effective in cirrhosis)

Question 44

How does Addison's Disease lead to hyponatraemia?

Answer 44

-Loose mineralocorticoids and glucocorticoids -1-Aldosterone↓ (+/- adrenaline), ADH not↓=imbalance, salt wasting leads to dehydration and reduced blood pressure, increases K+, acidosis 2-non-osmotic ADH stimuli –↓vol, nausea, pain 3-↓GC effects – impair water loss

Question 45

How does ACTH/ GC deficiency lead to hyponatraemia?

Answer 45

-Thyroid hormone, sex steroids, GH -Decreased GC effects- impair water loss =central effect increased ADH at given plasma osmolality =renal effect decreased renal water excretion =decreased glucose so non-osmotic ADH stimulus

Question 46

What is the triple phase response after pituitary surgery?

Answer 46

- Cranial DI followed by SIADH followed by cranial DI again-Urine output fluctuates massively - Usually then remains as cranial DI - Damage to pituitary stalk allows partially processed forms are released= have long half life so dont get cleared from blood quickly, released for several days mean there is too much then is cleared

Question 47

What happens to serum and urine osmolality?

Answer 47

- Urine has low sodium level due to excess of water= low osmolality - Serum has high sodium and so high osmolality (lack of water being reabsorbed into blood)