Urinary S5 (Done) Flashcards
How can water intake and excretion affect plasma osmolarity?
If Intake > Excretion then plasma osmolarity decreases
If Intake < excretion then plasma osmolarity increases
How much water and how many osmoles are ingested per day?
Describe how excretion is matched to preserve water balance and plasma osmolarity
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
Outline the regulation of Plasma osmolarity
Osmolarity sensor:
Hypothalamic osmoreceptors
Two efferent pathways:
ADH:
- Acts on kidney*
- Affects urine output*
Thirst:
- Acts on brain to affect urge to drink
Describe hypothalamic osmoreceptors
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)
Describe the hypothalamic response to increased or decreased osmolarity
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
What is the ADH negative feedback loop?
ADH is released in response to increased osmolarity
Decreased renal water excretion
Osmolarity decreases
Result is a feedback loop that stabilises osmolarity
Apart from increased plasma osmolarity what can stimulate thirst?
ECF volume decrease
What are the two factors involved in salt appetite?
Hedonistic appetite (Because it tastes good)
Regulatory appetite (to ensure adequate intake)
When does the thirst response stop?
When suffieicent water intake achieved
Before GI absorption, metering mechanism unknown
What is the affect of ADH on the kidney?
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
Compare the sensitivity of the mechanisms which trigger ADH release and thirst
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)
What is the effect of decreased plasma osmolarity on the kidney?
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
Why is a hyperosmotic interstitium required for reabsorption of water in the Collecting duct?
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
Describe the effects of ADH on aquaporins in the CD
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
What affect does ADH have on the basolateral membrane of CD cells?
No effect
Describe the permeability of the basolateral membrane of CD cells
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
Describe how ADH release is a product of both osmotic and haemodynamic forces
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)
Describe two clinical concequences of inappropriate ADH secretion
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.)
Describe the Corticopapillary osmotic gradient
What mechanisms contribute to its formation?
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)
Describe the recycling of urea
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
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
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.
What limits the final gradient between the Loop of Henle and interstitium?
Diffusional processes
Describe the concequence of NaKCC transport inhibitors (Loop diuretics) on the medullary gradient
Interstitium becomes iso-osmotic and copious dilute urine is produced as the desc. limb cannot remove water from the tubule
What maintains the diffusion gradient set up by counter-current multiplication?
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
Describe the features of the vasa recta
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
Describe the process of counter current exchange
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
Where is most body calcium stored?
What happens when ECF levels of Ca2+ fall?
99% stored in bone
ECF levels can be corrected by using the bone as a source of Ca2+
Describe the ECFs relationship with the intestines, bone and kidneys in terms of calcium balance
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
What hormones are involved in regulation of Ca2+?
What other substance is regulated by these hormones?
PTH, Calcitriol and calcitonin
PO4(3-)
Describe the distribution of Ca2+ as compared to PO4(3-)
Ca2+:
Bone and ECF
PO4(3-):
ECF and ICF
Describe the distribution of Ca2+ within the ECF
How does this affect kindey filtration of Ca2+?
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
How does plasma pH affect ECF Ca2+?
Shifts the distribution of Ca2+ between its different forms (unbound, bound, complexed to anion)
What is the renal threshold of Ca2+ and PO4(3-) equivalent to?
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
What is PTH’s effect on the renal threshold of calcium?
Increases absorption, raising the renal threshold
What are the specific functions of the intestines in regards to calcium homeostasis?
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
What are the specific functions of the kidney in regard to calcium homeostasis?
Filters 250mmol a day (98-99% reabsorbed)
65% reabsorbed in the PCT
20-25% in the LoH
10% in DCT under control of PTH
What are the actions of Calcitriol (1,25-(OH)2D) on the bone and intestines?
Increases availability of Ca2+ and PO4(3-) by increasing intestinal absorption
Promotes osteoblast activity and maturation of osteoclast precursor cells
What are the actions of Calcitriol (1,25-(OH)2D) on the kidney?
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
What are the actions of Calcitriol on the body not including the bone, intestine or kidney?
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
What are the actions of PTH on the bone?
Aids bone remodelling by stimulation of osteoclast activity hence increasing plasma Ca2+ and PO4(3-)
Slowly stimulates osteoblast activity
What are the actions of PTH on the kidney?
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)
What are the major factors influenceing bone growth and turnover?
Calcium, phospahte and magnesium metabolism
PTH, Calcitriol and other hormones and factors
E.g. Androgens, Oestrogens, Thyroid hormones, Cortisol, Insulin, Growth hormone etc
What are the common causes of hypercalcaemia?
Primary hyperparathyroidism
Haematological and Non-haematological malignancy
What are the clinical manifestations of hypercalcaemia?
Hint: Might be useful to group these by body system
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
How do different forms of hyperparathyroidism affect plasma Ca2+ conc?
Primary:
Raised
Secondary:
Low or normal
Tertiary:
Raised
What are the differnces between primary, secondary and tertiary hyperparthyroidism?
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
How does malignancy lead to hypercalcaemia?
Secretion of:
Parathyroid hormone related peptides:
Amino acid homology with PTH induces PTH like actions
Cytokines:
TNF
IL-1
Transforming growth factor alpha
Prostaglandins
How can primary hyperparathyroidism and humoral hypercalcaemia of malignancy be differentiated?
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
Describe management of a patient with acute hypercalcaemia
General:
Hydration
Loop diuretics (E.g. Furosemide)
Specific:
Bisphosphonates
Calcitonin
Treat underlying conditions
How do renal stones manifest clinically?
May be asymptomatic, only an incidental finding on abdominal imaging
Haematuria
Pain and complications associated with renal tract obstruction
What are some of the mechanisms by which renal stones formation may occur?
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
What are some inhibitors of renal stone formation?
Citrate
Pyrophosphate
Glycosaminoglycans
RNA fragments
Magnesium
What are the stages of evaluation for a suspected kidney stone?
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
Describe medical management of renal stones
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
