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1
Q

How can water intake and excretion affect plasma osmolarity?

A

If Intake > Excretion then plasma osmolarity decreases

If Intake < excretion then plasma osmolarity increases

2
Q

How much water and how many osmoles are ingested per day?

Describe how excretion is matched to preserve water balance and plasma osmolarity

A

Most people ingest 1 - 1.5L of water and 600-1000mOsm/day

Urine osmolarity is therefore 500 - 700mOsm/L as 1 - 1.5L/day must be excreted

There is an inverse relationship between urine output per day and urine osmolarity

3
Q

Outline the regulation of Plasma osmolarity

A

Osmolarity sensor:

Hypothalamic osmoreceptors

Two efferent pathways:

ADH:

    • Acts on kidney*
    • Affects urine output*

Thirst:

- Acts on brain to affect urge to drink

4
Q

Describe hypothalamic osmoreceptors

A

Located in the Organum Vasculosum of the Laminae Terminalis (OVLT) of the hypothalamus

They have a fenestrate epithelium that exposes cytosol directly to systemic circulation

Sneses change in plasma osmolarity

Signals secondary responses leading to the two posible outcomes (ADH release and Thirst)

5
Q

Describe the hypothalamic response to increased or decreased osmolarity

A

Increased:

Conditions of predominant loss of water and hence increase in osmolarity (As little as 1%) stimulates release of ADH from posterior pituitary

Increased fluid osmolarity also stimulates the hypoathlamus to create thirst, encouraging the intake of water, this is the only way to fully compensate for a deficit of water

Decrease:

Decrease in osmolarity inhibits ADH secretion

6
Q

What is the ADH negative feedback loop?

A

ADH is released in response to increased osmolarity

Decreased renal water excretion

Osmolarity decreases

Result is a feedback loop that stabilises osmolarity

7
Q

Apart from increased plasma osmolarity what can stimulate thirst?

A

ECF volume decrease

8
Q

What are the two factors involved in salt appetite?

A

Hedonistic appetite (Because it tastes good)

Regulatory appetite (to ensure adequate intake)

9
Q

When does the thirst response stop?

A

When suffieicent water intake achieved

Before GI absorption, metering mechanism unknown

10
Q

What is the affect of ADH on the kidney?

A

Increased levels of ADH result in a smaller volume of urine produced (increased reabsorption)

Glomerulus:

Vasoconstriction (decreased GFR)

Thick ascending limb of loop of henle:

Increased Na+, K+ and Cl- reabsorption

DCT:

Increased water reabsorption in late DCT

Collecting duct:

Increased water and urea reabsorption

Increased K+ secretion

11
Q

Compare the sensitivity of the mechanisms which trigger ADH release and thirst

A

ADH release can be triggered by a 1% change in plasma osmolarity

Stimulus for thrist response requires significant increase in osmolarity or decrease in ECF volume (<10% changes)

12
Q

What is the effect of decreased plasma osmolarity on the kidney?

A

Lack of ADH stimulation means no aquaporin in later DCT and CD

Limited water intake

Tubular fluid is hypo-osmotic, passes through the hyperosmotic renal pyramid with no change in water content

Loss of large amount of dilute urine

Diuresis

13
Q

Why is a hyperosmotic interstitium required for reabsorption of water in the Collecting duct?

A

ADH stimulates the appearance of aquaporins on the apical cell membrane of CD cells

There is no ‘active transport’ of water

Therefore a gradient is required to shift water, moves from the relatively hypoosmotic tubule to the relatively hyperosmotic interstitium

14
Q

Describe the effects of ADH on aquaporins in the CD

A

Apical membranes do not contain Aquaporin 2 in absence of ADH

When ADH is released it binds to an extracellular GPCR and stimulates the insertion of aquaporin 2 channels into apical membrane

With the removal of ADH stimulation AQU2 is removed from the apical membrane by endocytosis

15
Q

What affect does ADH have on the basolateral membrane of CD cells?

A

No effect

16
Q

Describe the permeability of the basolateral membrane of CD cells

A

Contain AQU3 + 4 even in absence of ADH so is always permeable to water

Any water which enters the cell moves through these channels into the interstitium to be reabsorbed into peritubular capillaries

17
Q

Describe how ADH release is a product of both osmotic and haemodynamic forces

A

ADH release changes in response to plasma osmolarity

However the magnitude of response and the set point at which that response occurs is governed by haemodynamic forces

Changes in blood pressure and volume effect the ADH response to change in osmolarity

Decreased ECV/Blood pressure:

Set point for ADH release is set to lower osmolarity and the gradient with which the ADH response scales is increased (Smaller increases in osmolarity produce larger ADH responses)

This is because volume conservation is more important than osmolarity should volume crash

Increased ECV/Blood pressure:

Opposite occurs

Set point for ADH release is raised

Gradient for scaling of ADH response is decreased (larger increases in osmolarity produce smaller increases in ADH response)

18
Q

Describe two clinical concequences of inappropriate ADH secretion

A

Diabetes Insipidus:

Pituitary gland doesn’t produce adequate ADH or kidney is ADH insensitive

Resulting in losses of large amount of dilute urine

Can be managed with ADH injections or ADH nasal spray

Syndrome of inappropriate ADH hormone secretion(SIADH):

Excessive release of ADH from posterior pituitary or other source

Dilutional hyponatraemia results (increased ECV and decreased osmolarity/Na+ conc.)

19
Q

Describe the Corticopapillary osmotic gradient

What mechanisms contribute to its formation?

A

Iso-osmotic at cotico-medullary border

Medullary interstitium is hyperosmotic up to 1000mOsm/L at papilla

Essential mechanisms for it’s production and maintenance:

Active NaCl transport in thick ascending limb

Recycling of Urea

Counter current exchange (vasa recta)

20
Q

Describe the recycling of urea

A

Urea is reabsorped from medullary CD

Moves into interstitium and can diffuse back into the Loop of Henle (asc. limb)

High levels of urea in the interstitium causes it to move into the asc. limb passively

ADH decreases fractional excretion and increases recycling

21
Q

Ok guys, lemme get real with you for a second

This next bit is hard to do in a flashcard, and doesn’t make too much sense to me to break up into multiple flashcards, it’s just something you’ve gotta be able to visualise all happening together.

So, with that said…

Describe the process of counter-current multiplication starting from iso-osmotic tubule and interstitial fluid

A

Phase 1:

Na+ is pumped out of ascending limb into interstitium to a maximum gradient of 200mOsm/L

    • 200mOsm/L in asc. limb*
    • 400mOsm/L in interstitium*

Water flows out of the fluid in the decending tubule by osmosis and raises intertubular osmolarity in the descending limb

- Desc. limb becomes 400mOsm/L

Fresh fluid enters from the PCT and the concentrated fluid in the descending limb is moved to the ascending limb

    • 400mOsm/L fluid moves into asc. limb*
    • Equal with interstitium*

Phase 2:

Na+ pump continues action and produces another 200mOsm/L gradient between ascending limb and interstitium

    • 500mOsm/L in interstitium*
    • 300mOsm/L in asc. limb*

Osmosis from descending limb is now working over a higher gradient, so fluid in descending limb becomes even more concentrated then before

- 500mOsm/L in desc. limb

More water enters from PCT, same effect as last time

Phase 3:

Na+ pumping continues in asc. limb and raises the interstitial osmolarity further

- 700mOsm/L in asc. limb

All processes occur in tandem

- Quoted osmolarities are typical of the bottom of the loop, once the system is stable a gradient is observed moving down the interstitium, desc. limb and asc. limb of the Loop of Henle. If you can explain why, you’re set.

22
Q

What limits the final gradient between the Loop of Henle and interstitium?

A

Diffusional processes

23
Q

Describe the concequence of NaKCC transport inhibitors (Loop diuretics) on the medullary gradient

A

Interstitium becomes iso-osmotic and copious dilute urine is produced as the desc. limb cannot remove water from the tubule

24
Q

What maintains the diffusion gradient set up by counter-current multiplication?

A

Counter-current exchange between interstitium and vasa recta

Osmotic gradient would be quickly destroyed if osmoles were washed out of the interstitium by excess diffusion into blood

25
Q

Describe the features of the vasa recta

A

Blood flow is low (5-10% of renal perfusion flow to medulla)

Compromise made between delivering nutrients and maintaining medullalry hypertonicity

Arranged in a hairpin configuration with entry and exit through the same region of the kidney

Thus creating the counter current exchange system

26
Q

Describe the process of counter current exchange

A

Vasa recta blood is iso-osmotic as it enters the hyperosmotic kidney medulla

As it descends Na+, Cl- and urea diffuse in

Osmolarity of blood increases as it moves towards tip of hairpin loop

Blood ascending to the cortex is hyper-osmotic compared to interstitium so water diffuses in

Diffusion of both water and osmoles from the interstitium maintains the hyper-osmolarity of the medulla

27
Q

Where is most body calcium stored?

What happens when ECF levels of Ca2+ fall?

A

99% stored in bone

ECF levels can be corrected by using the bone as a source of Ca2+

28
Q

Describe the ECFs relationship with the intestines, bone and kidneys in terms of calcium balance

A

Intestines:

400mg absorbed

200mg lost

1000mg oral intake and 800mg excreted

Bone:

500mg absorbed by bone and lost from bone per day

Kidney:

10,000mg filtered per day

9,800mg reabsorbed

200mg excreted

Overall:

No net loss or gain in Ca2+ in the ECF per day

29
Q

What hormones are involved in regulation of Ca2+?

What other substance is regulated by these hormones?

A

PTH, Calcitriol and calcitonin

PO4(3-)

30
Q

Describe the distribution of Ca2+ as compared to PO4(3-)

A

Ca2+:

Bone and ECF

PO4(3-):

ECF and ICF

31
Q

Describe the distribution of Ca2+ within the ECF

How does this affect kindey filtration of Ca2+?

A

Free unbound Ca2+ = 50%

Protein bound (mainly albumin) = 45%

Complexed with anions (E.g. HCO3 and citrate) = 5%

With regards to the kidney:

Only the free unbound Ca2+ can be freely filtered across the glomerulus

32
Q

How does plasma pH affect ECF Ca2+?

A

Shifts the distribution of Ca2+ between its different forms (unbound, bound, complexed to anion)

33
Q

What is the renal threshold of Ca2+ and PO4(3-) equivalent to?

A

The normal plasma concentration of each ion (in unbound form)

Therefore maximal absorption of these ions via transporters is equivalent to their normal plasma concentrations

34
Q

What is PTH’s effect on the renal threshold of calcium?

A

Increases absorption, raising the renal threshold

35
Q

What are the specific functions of the intestines in regards to calcium homeostasis?

A

20-40% (25mmol) of dietary Ca2+ absorbed

2-5% mmol secreted back into the lumen

Increases absorption in children, pregnancy, lacation and decreases with advancing age

Complexes Ca2+ (E.g. With phytates, oxalates) which reduces absorption

36
Q

What are the specific functions of the kidney in regard to calcium homeostasis?

A

Filters 250mmol a day (98-99% reabsorbed)

65% reabsorbed in the PCT

20-25% in the LoH

10% in DCT under control of PTH

37
Q

What are the actions of Calcitriol (1,25-(OH)2D) on the bone and intestines?

A

Increases availability of Ca2+ and PO4(3-) by increasing intestinal absorption

Promotes osteoblast activity and maturation of osteoclast precursor cells

38
Q

What are the actions of Calcitriol (1,25-(OH)2D) on the kidney?

A

Inhibits renal 1-alpha-hydroxylase (Converts calcifediol to calcitriol) by increasing intestinally absorped phosphate

Promotes synthesis of 24,25-(OH)2D (inactive form of Vit D)

Small effect on renal calcium and phosphate reabsorption

39
Q

What are the actions of Calcitriol on the body not including the bone, intestine or kidney?

A

Regulates a wide variety of celluar/tissue functions:

Cell differentiation and proliferation

May decrease proliferation in some tumours

Inhibition of cell growth

Stimulation of insulin secretion

Modulation of immune and haemopoietic systemes

Inhibits renin production

40
Q

What are the actions of PTH on the bone?

A

Aids bone remodelling by stimulation of osteoclast activity hence increasing plasma Ca2+ and PO4(3-)

Slowly stimulates osteoblast activity

41
Q

What are the actions of PTH on the kidney?

A

Increases Ca2+ and Magnesium reabsorption

Decreases phosphate and bicarbonate reabsorption

Simulates conversion of 25-(OH)D to 1,25-(OH)2D by renal 1-alpha-hydroxylase (Conversion of Calcifediol to Calcitriol)

42
Q

What are the major factors influenceing bone growth and turnover?

A

Calcium, phospahte and magnesium metabolism

PTH, Calcitriol and other hormones and factors

E.g. Androgens, Oestrogens, Thyroid hormones, Cortisol, Insulin, Growth hormone etc

43
Q

What are the common causes of hypercalcaemia?

A

Primary hyperparathyroidism

Haematological and Non-haematological malignancy

44
Q

What are the clinical manifestations of hypercalcaemia?

Hint: Might be useful to group these by body system

A

GI:

Anorexia

Nausea/vomiting

Constipation

Rarely acute pancreatitis

Cardiovascular:

Hypertension

Shortened QT interval on ECG

Renal:

Polyuria and polydipsia

Nephrocalcinosis (rarer)

CNS:

Cognitive difficulty and apathy, depression

Drowsiness, coma

45
Q

How do different forms of hyperparathyroidism affect plasma Ca2+ conc?

A

Primary:

Raised

Secondary:

Low or normal

Tertiary:

Raised

46
Q

What are the differnces between primary, secondary and tertiary hyperparthyroidism?

A

Primary:

Overactivity of the parathyroid glands (Can be due to parathyroid adenoma, carcinoma or hyperplasia)

Secondary:

A physiolgical response to low Vit D levels that increases PTH secretion to raise plasma Ca2+ back to normal values (ideally)

Tertiary:

As a result of secondary hyperparathyroidism that leads to hyperplasia and loss of response to serum calcium levels

47
Q

How does malignancy lead to hypercalcaemia?

A

Secretion of:

Parathyroid hormone related peptides:

Amino acid homology with PTH induces PTH like actions

Cytokines:

TNF

IL-1

Transforming growth factor alpha

Prostaglandins

48
Q

How can primary hyperparathyroidism and humoral hypercalcaemia of malignancy be differentiated?

A

Serum Ca2+ and PO4(3-):

Calcium raised in both

Phosphate raised in both

PTH:

Raised in primary HPT

Lowered in HHM

Calcitriol:

Raised in primary HPT

Lowered in HHM

49
Q

Describe management of a patient with acute hypercalcaemia

A

General:

Hydration

Loop diuretics (E.g. Furosemide)

Specific:

Bisphosphonates

Calcitonin

Treat underlying conditions

50
Q

How do renal stones manifest clinically?

A

May be asymptomatic, only an incidental finding on abdominal imaging

Haematuria

Pain and complications associated with renal tract obstruction

51
Q

What are some of the mechanisms by which renal stones formation may occur?

A

Urine supersaturation with calcium oxalate

Lowered pH favours uric acid stone formation and may promote calcium oxalate stones

Low pH also increases absorption of citrate and reduces citrate synthesis (citrate opposes stone formation)

Low levels of Na+, K+, Cl- etc (low ionic strength) incrases risk of crystal formation

52
Q

What are some inhibitors of renal stone formation?

A

Citrate

Pyrophosphate

Glycosaminoglycans

RNA fragments

Magnesium

53
Q

What are the stages of evaluation for a suspected kidney stone?

A

History:

Underlying predisposing conditions

Dietary excess, inadequate fluid intake, excessive fluid loss

Blood screen:

Ca2+, PTH, PO4(3-), urate

Acid base status

Urine screen:

Urinalysis - pH, sediments

Culture - Urea splitting organsims

Radiograph:

Opaque stones - Calcium oxalate/phosphate, cystine

Radiolucent - Urate, xanthine

Biochemical stone analysis

54
Q

Describe medical management of renal stones

A

Hydration:

2L a day

Increases urine output

Diet:

Restriction of oxalate and sodium

Can also restrict Ca2+ and animal proteins

Referral:

Urology for lithotripsy/surgery

Lithotrypsy is breaking up the stone with shock waves