Endocrine func of kidney Flashcards
3 endocrine functions of kidney?
renin prodn
EPO func and prodn
VitD activation and funcn - control of Ca and Phosphate
whats erythropoiesis?
what does it allow
RBC production
= O2 supply to organs and tissues
what does lack of erythrocytes (RBCs) ->?
anaemia
- fatigue
- reduced exercise tolerance
- red brain funcn
- inc risk of CVD
affect of hypoxia on RC prodn?
increases it
high altitude = hypoxia) -> inc red cell mass (haematocrit
When is EPO gene transcription increased?
low oxygen
low iron
low haematocrit
What is the main adult and foetal site of EPO production?
adult: cortical fibroblasts
foetal: liver
What detects low O2 levels?
hypoxia inducible transcription factors
What happens in the case of normal oxygen?
HIF-1a degraded
proline on HIF-1a is hydroxylated
it binds with Von Hippel Lindau
complex formed with E3 ubiquitin ligand complex
protein broken down into amino acids = proteasomal degradation
What happens in the case of low oxygen?
in hypoxia- hydroxylation is inhibited and HIF-1a is stabilised, forms complex w HIF-1b
HIF-1a forms a complex with HIF-1b
this forms a complex with AHNT
production of erythropoetin mRNA
(– hypoxia response elements -> gene transcription)
what happens to HIF1-alpha in case of
a) normal O2
b) hypoxia
a) degraded (binds to Von Hippel Lindau… E3 Ub ligase complex… protein -> free units_
b) hydroxn inhibited. HIF-1a stabilised, forms complex with HIF1-b…. -> nucleus, complex w AHNT (hypoxia responsive element) -> gene transcription activated
what is EPO gene trans controlled by?
cellular Fe and O2 levels
What type of receptor is EPO receptor and wheres it expressed?
homodimeric receptor on red cell rpecursors
What does signalling of the EPO receptor lead to?
less RBC apoptosis
more proliferation
more differentiation
alow redn, inc O2 carrying abilities
What’s the link between EPO and Ang II?
Ang II increases EPO production
Why is EPO considered a dangerous drug if abused?
increased risk of clots and hypertension
describe how/why Ang II increases EPO production in bone marrow
done to ↑ differentiation of stem cells in retic.
↑eryth production in bone marrow = ↑Hb levels = ↑O2 levels + carrying capacity –> kidneys ☺ so can produce EPO if sufficient O2
interaction between EPO and Ang II?
how about ACEi and ARB?
Ang II probably -> ↑ EPO prodn
- ACEi and ARB reduce EPO prodn
whats EPO treatment associated with?
decr plasma volume
What are consequences of failure to produce EPO?
reduced production of erythrocytes and oxygen delivery to tissues
impaired quality of life = reduced exercies capacity
transfusion requirement- Fe overload, blood-bourne infection
risk of left ventricular hypertrophy
CVD risk in patients with CKs and anaemia vs those without
effect of EPO on endurance/ excersice capacity?
↑ haematocrit (eryth content of blood)
= ↑ exercise capacity (VO2 max)
= ↑ endurance
= drug of abuse
What are normal Hb levels for men and women?
men: 14-17.5gm/dL
women: 12.3-15.3gm/dL
4 things to monitor regarding EPO?
Hb target: 100-120g/L
BP (EPO induced hypotension)
thrombosis
anaemia teams
EPO produced by cortical fibroblasts in response to? (2)
hypoxia
low iron
EPO affect on erythrocyte prodn in bone marrow?
increases
… inc O2 delivery to tissue
what system does EPO interact with?
Renin-angiotensin
Why are calcium and phosphate serum concs tightly regulated?
as vital for:
muscle function
cardiac function
bone metabolism
what 2 things is only Ca vital for?
Ca: nerve function and blood clotting
what things is only Phosphate vital for?
multiple cellular funcs inc
- energy metabolism
- cell signalling
whats body Ca and phosphate content the balance between?
gut absortpion and renal excretion
both widely distributed in tissues with a huge reservoir in bone- can release back into blood if needed
2 key hormones involved in control of Ca and phosphate?
Vit D
parathyroid hormone
organs involved in Ca and phosphate homeostasis?
gut: absorption
bone pool: for exchange
kidneys: excretion
What is activated Vitamin D important in the regulation of?
- serum calcium - uptake and reabsorption
- serum phosphate
- bone turnover - normal osteoclast and osteoblast activity
induces calcium sensor expression on parathyroid glands
supresses 1a hydroxylase and promotes 24 hydroxylase negative feedback - other
How is Vitamin D activated?
sun - UV light turns it into cholecalciferol
25-hydroxylase turns it into 25(OH)D3
DBP turns it into 25(OH)2D3 via 1a-hydroxylase
then taken up from filtrate by PTEC
where is Vitamin D activated?
in proximal tubule epithelial cells..
then active form transported back to blood
where does rate limiting step happen?
in kidney proximal tubular epithelium:
25(OH)D3 –> 25(OH)2D3 via 1a-hydroxylase
if have non func kidney, why will you not get active vit D3?
as rate limiting step happens inin kidney proximal tubular epithelium:
25(OH)D3 –> 25(OH)2D3 via 1a-hydroxylase
What is 25(OH)2D3 (vitamin D3) converted into if theres too much?
inactivated…
24-hydroxylase turns it into calcitroic acid in cell (soluble and inactive)
transfer to nucleus to promote gene transcription
How is gene transcription of vitamin D increased?
activated vitamin D binds to IDBP
activation of vitamin D receptor
increased gene transcription
Role of Vit D?
- promotes Ca and phosphate uptake form intestinal lumen
- vital for osteoblast and osteoclast activity (bone turnover and remodelling)
- increases Ca reabsorption form tubule
- helps maintain normal serum Ca
- induces Ca sensor expression on parathyroid glands (-ve feedback)
- suppresses 1a-hydroxylase and promotes 24-hydroxylalse in kidney (-ve feedback)
how does low Ca act as signal to increase serum Ca?
hint: PTH
caused by low Ca -> PTH released from parathyroid -> inc bone resorption (more released) -> inc serum Ca
what does parathyroid affect?
releases PTH (works to inc Ca levels), affects:
- kidney: 25vitD -> 1,25vitD -> inc intestinal Ca absorption in gut
- bone: inc bone resorption
what happens regarding PTH when serum levels of Ca successfully increased?
signal sent to parathyroid to stop making PTH
What happens in the case of renal failure and low calcium regarding Vit D, Ca, PTH?
low Ca:
- kidney: 25vitD -> 1,25vitD -> CANT DO!!
- only bone: inc bone resorption -> inc serum Ca
therefore serum Ca lower
consequence of constantly stim Parathyroid?
hyperparathyroidism
- parathyroid glands create too much PTH in the bloodstream
hyperphosphataemia
- abnormally high serum phosphate levels- from increased phosphate intake, decreased phosphate excretion, or a disorder that shifts intracellular phosphate to extracellular space
What is ectopic calcification?
inappropriate biomineralization occurring in soft tissues.
Ectopic calcifications are typically composed of calcium phosphate salts, including hydroxyapatite, but can also consist of calcium oxalates and octacalcium phosphate as seen in kidney stones.
= severe bone pain on moving
long term CVD - harm
not always kidney disease- calcification of vessels
(see veins on xray)
2 types of (ectopic) calcification
arterial (see veins on xray) soft tissue (severe bone pain)
What treatments prevent bone disease and ectopic calcification?
- 1a-hydroxylated vitD replacement
- phosphate restriction
- phosphate binders
- calcimimetics
if all fails- parathyroidectomy
what do calcimimetics do?
used in what disease state?
work by decreasing the levels of PTH (responsible for maintaining proper levels of both calcium and phosphorus in the body).
The right amount of these substances in the body helps to prevent progressive bone disease.
(good for parathyroidism)
phosphate binders: Ca/ renal Ca based depending on?
serum Ca with/ before food every time!
take w lots of phosphate meds
vit D/ PTH
what to monitor?
how to treat
Ca, phosphate, PTH
treat w varying doses:
- alfacalcidol: inc Ca uptake in gut (bad if have inc Ca)
- cinacalcet
- Ca (supplement)
phosphate control = dialy battle. encourage, advice
when are phosphate binders given? (for phosphate control- preventing bind disease and ectopic calcification)
before food everytime!!
thick chalky tablets
unpleasant
what is vitD?
steroid hormone
- rate limiting step in kidney
(vit D precursors intake/meds need func liver and kidney to actuate)
whats Vit D intimately involved with?
Ca and phosphate homeostasis
interactions between
Vit D and PTH
exchange of ions between gut, blood, kidneys, bones
how do kidnyes maintain bone density?
create enz to activate partially vit D and inc blood Ca.
and not constantly release Ca and phosphate from bone
