Kidney failure

what are the 5 ways kidneys maintain homeostasis?

-excretion of metabolic products
-regulation of body fluid osmolarity and volume
-regulation of electrolyte balance
-regulation of acid-base balance
-production, secretion of hormones
-control of ca2+, parathyroid hormone, vitD, phosphate, FGF, EPO, ANP

what is the kidneys structure?

outer cortex and inner medulla
medulla has renal pyramids
renal pyramids\= conical structures

what are nephrons?
how many nephrons in each kidney?

functional unit of the kidney
cleaning of blood takes place here, urine forms here
10^6
urine goes into collecting ducts, then into renal pelvis

what are the 2 main types of nephrons?

cortical nephrons
-majority, structure in cortec
juxtamedullary nephrons
-15%, long structure, join into common collecting ducts

where are the nephron's glomeruli?

in the cortex

what is the nephron made up of?

single later of endothelial cells

what is the renal corpuscle made of?

Bowman's capsule + glomerulus

What is the juxtaglomerular apparatus?
what is the nephron structure actually like in the kidney?
ie folding of nephron

part between ascending limb and DCT is actually
between afferent and efferent arterioles

What is the juxtaglomerular apparatus?

region where the distal tubule of the nephron passes between afferent and efferent arterioles

specialised endothelial cells for autoregulation and renin release
salt and water balance

what are the functions of the nephron?
-renal corpuscle
-tubular system

renal corpuscle\= initial blood filtration
tubular system\= controls conc and content of urine

what is the functional relationship between the vascular and tubular elements?
what 2 capillary beds are in series and what do they do?

glomerulus-
high hydrostatic pressure, FILTRATION
peritubular capillaries
low pressure REABSORPTION+SECRETION

what are vasa recta?

peritubular capillaries branching off efferent arterioles

what are the 3 main processes to modify urine composition and volume?

filtration - fluid from blood to nephron
reabsorption - lumen to blood
secretion - blood to lumen

excretion from body

what is urinary excretion \= to

filtered - reabsorbed + secreted

how much of cardiac output do the kidneys receive?

25%
1300ml blood
600ml/min plasma

how much of the blood/plasma coming to the kidneys is actually filtered?
what is GFR?
what happens to the rest of the blood?
rate of urine production

20% is filtered
other 80% leaves via efferent arteriole to systemic circulation
20% is reabsorbed in peritubular capillaries

GFR\= rate of which plasma is filtered by kidneys
urine formed 1ml/min

glomerular filtration def

fluid driven from capillaries into bowmans capsule across glomerular filter by CAPILLARY HYDROSTATIC PRESSURE for filtrate formation

why do efferent arterioles have smaller diameter than afferemt?

to maintain glomerular capillary hydrostatic pressure

What are podocytes?

specialised epithelial cells of glomerulus
that have foot processes (pedicels)
extend and wrap around capillaries (interdigitate)
separated from endothelia by BM

what do mesangial cells do?

support, provide structure
keep BM free of debris/protein
have contractile function

filtration slits are...

where fluid moving out of capillary cross endothelia
large molecules cant cross

what are the 3 layers of the glomerular filter?
what charge do endothelia and BM have, and what does this mean?

endothelia-BM-podocytes
endothelia and BM are -ve charge, so repel - molecules

GFR definition
and value

volume of fluid entering bowmans capsule per unit time
180l/day , 120ml/min
99% reabsorbed

How much glucose is reabsorbed?

100%

why is more na and cl filtered compared to k?

because ECF conc K+ is low

what forces cause ultrafiltration?

starling forces
drive fluid from lumen of capillary across filtration barrier into bowmans space

-capillary hydrostatic
-colloid osmotic
-bowman space
-net filtration

what happens to renal flow when there is an INCREASE IN ARTERIOLAR RESISTANCE?
afferent arteriolar constriction

aff arteriolar constricition
decrease hydrostatic pressure in glomerular capillary
GFR falls
renal plasma flow falls

what happens to renal flow when there is an INCREASE IN ARTERIOLAR RESISTANCE?
efferent arteriolar constriction

eff arteriolar constricition
increase hydrostatic pressure in glomerular capillary
GFR increases
renal plasma flow falls

what happens to GFR if there is change in colloid osmotic pressure?

increase colloid pressure
decrease GFR

what happens to GFR if there is change in bowmans space pressure?

increase bowmans space pressure
decrease GFR

what happens to GFR if there is a change in filtration coefficient?

increase filtration coefficient
increase GFR

what efficiency does GFR show?

how efficiently the kidney filters water from the blood

what is clearance of inulin used for?
and why?
(PAH)

indicator of GFR, clearance of inulin\=GFR
-freely filtered
-not reabsorbed
-not secreted
-not metabolsised by kidney
-no effect on renal function
-easily measured in urine

for inulin mass filtered\=mass excreted
what is the equation for mass filtered?
what is the equation for mass excreted?

mass filtered\= plasma conc x filtration rate
mass excreted\= urine conc x urine flow rate

UV/P

how are inulin measurements taken?

inulin infused via iv
steady state reached after few hours
then measure

what is the clearance of inulin and is it always constant?

120ml/min
always constant regardless of plasma conc

creatinine clearance to meausre GFR

easier to measure
iv fusion not needed
close to constant
urine collection and 1 serum
Skmm mass and age needs to be considered

equationfor filtration fraction

FF\=
GFR/PAH

equation for RBF

RBF\=
RPF/ (1-haematocrit)

what is the relationship between RPF, GFR and filtrate

RPF determines GFR
high GFR means high filtrate

what is clearance of PAH an indicator of?

RPF
PAH is freely filtered and secreted

PAH secretion
removal of PAH

PAH secretion removes all PAH from peritubular fluid
at low plasma conc all PAH in kidneys is removed
all of PAH is removed at first pass
secrteion at PCT
all that enters os excreted

equation for total mass PAH excreted \= total mass presented to kidney

plasm conc x plasma volume per unit time

how does measuring PAH underestimate RPF?

because some RPF goes to none secreting parts of kidney
so even if max transport isnt exceeded, PAH is not all lost

what is filtration fraction?

proportion of plasma that forms filtrate
20%

relationship between FF, colloid osmotic pressure, tubular reabsorption

high FF
high colloid pressure in peritubular capillaries
greater tubular reabsorption

changes in FF
-afferent arteriolar constriction
-efferent arteriolar constriction

-afferent arteriolar constriction
low GFR, RPF
no change in FF
-efferent arteriolar constriction
high GFR, low RPF
higher FF

what constant arteriolar pressure is RBF and GFR maintained at?
whats this mechanism?

90-180mmHg
autoregulation

what are the 2 mechanisms involved in autoregulation?

changes in afferent arteriolar resistance
-myogenic\= aff arteriole contracts in pressure and stretch
-tubuloglomerular feedback\= nacl in filtrate sensed by macula densa of JGA

myogenic mechanism of autoregulation

vascular smooth muscle of arteriole
pressure/stretch
voltage gated ca channels open
ca into cell contraction

tubuloglomerular feedback mechanism of autoregulation

increase in RBF means more NaCl delivered in tubular fluid
to macula densa of JGA
adenosine contracts arteriole
vasoconstriction

what cotransporter activity is present in macula densa of JGA?
what are macula densa cells?

Na+K+2Cl-
on apical membrane
specialised epithelial cells

how do vasoconstrictors affect RBF?
and how?

decrease RBF
-symp nerves, angiotensin II
AGII \> efferent constriction \> maintains GFR

how do vasodilators affect RBF?
and how?

increase RBF
-PGs
dampen AGII and symp effects
prevents severe vasoconstriction

what happens if there is low RBF and patient takes NSAID or COXi?

block PG synthesis
excessive vasoconstriction
ischaemia
renal tubular necrosis

when might glucose be excreted in urine?

if renal threshold is exceeded
-untreated DM
-hyperthyroidism
-fanconi syndrome
-familial glucosuria
-pregnancy
-drugs

what is familial renal glucosuria?

- mutations in Na+/glucose symporter SGLT2
- relatively benign
- normal blood glucose, but high urine glucose due to impaired reabsorption.

what is gout?

high level of uric acid in plasma
forms crystals
inflammatory deposits in joints
either overproduction or decreased renal excretion

what is type 2 renal tubular acidosis?

impaired ability to reabsorb bicarbonate
fanconi syndrome in children
growth retardation, kidney stones, bone disease, renal failure

what is plasma conc of Na+?

135-145

what is plasma conc of K+?

3.5-5

what is plasma conc of Cl-?

100-106

what is plasma conc of HCO3-?

21-28

what is plasma conc of H+?

37-43

what is plasma conc of glucose?

3.9-5.6

what is plasma conc of protein?

60-84

what is normal GFR?

120

what is normal RPF?

600

what is normal PCV?

40%

what is normal RBF?

1L/min

what is normal CO?

5L/min

how is the epithelia in the nephron arranged?

joined at the base by tight junction
with lateral spaces

what is the apical/lumen membrane?

membrane adjacent to tubular fluid
lumen of nephron

what is the basolateral membrane?

membrane adjacent to peritubular fluid
capillary

what are the 2 main transport pathways in epithelial cells?

-transcellular/transepithelial transport
\=across cells
-paracellular transport
\=between cells

what is the primary active transport mechanism in the nephron and where is it located?
what environment does this pump create?

Na+K+ATPase
basolateral membrane
increase in extracellular na, decrease intracellular na
sets up electrochemical gradient for reabsorption

peritubular capillaries
hydrostatic pressure
colloid pressure

low hydrostatic 10mmhg
colloid osmotic pressure is 30mmhg
favours fluid reabsorption

what solutes are reabsorbed in proximal tubule?

Na (most of)
water
Cl-
K+
glucose (nearly all)
amino acids

why and how is PCT very water permeable?

leaky tight junctions and aquaporin1
prevents build up of significant osmotic gradients

tubular fluid and plasma conc in PCT

isotonic

how is Na reabsorbed in PCT?

readily enter epithelial cell
across apical membrane
gradient made by Na+K+ATPase

what are the 4 mechanisms involved in Na+ transport?
in PCT

-NaH+ exchang
-Na entry coupled to other solutes
-Na enters cell alone (Na channel)
-Na moves passively through tight junctions and into lateral space

via Na+K+ATPase pump creating gradient

what other important substances are reabsorbed in PCT?

all of glucose
trace proteins that cross barrier reabsorbed via endocytosis
HCO3-

why is HCO3- reabsorption difficult?
how is this overcome?

apical membrane is impermeable to HCO3-
indirect method involving carbonic anhydrase on apical membrane and epithelia

what does HCO3- reabsorption depend on?

active H+ secretion
in exchange for Na+ ions
NHE3

steps of HCO3- reabsorption
inside cell

inside cell
1.hydration of co2 to form carbonic acid via CA
2.carbonic acid H2CO3 dissociates to H+ and HCO3-
3.HCO3- in cell leaves via basolateral membrane
4.H+ transported into tubular lumen by Na+H+ exchange

steps of HCO3- reabsorption
outside cell, within lumen

outside cell
1.H+ combines with HCO3- to form H2CO3
2.H2CO3 dissociates to CO2 and water, via CA at apical membrane
3.CO2 and water diffuse across epithelial cells

what is the net result for HCO3- in PCT?

reabsorption of HCO3- from lumen
1 hco3- removed from lumen \= 1 hco3- in peritbular fluid

can HCO3- be used to correct acidosis or alkalosis?
and why/how?

cannot be used for acidosis as more reabsorption cant occur
can correct alklaosis as less reabsorption will happen, more excretion of HCO3- in urine
HCO3-Na+ transporter on basolateral memb inhibited

H2O transport in PCT
permeability?
what are the 2 ways water reabsorption can occur?
what does reabsorption of water here cause?

permeability to water is high
-paracellular\= across leaky tight junctions
-transcellular\= via water channels AQP1
water moves passively, freely
causes SOLVENT DRAG

what causes H20 reabsorption in PCT?

-osmotic pressure gradient
-increased oncotic pressure

-na reabsorption
-proteins in peritubular capillary

what is solvent drag?

solutes like na, cl, k, mg, ca
are carried along with flow of water

in PCT after water reabsorption
tubular fluid is \___?\___ to plasma

tubular fluid is isosmotic to plasma

K+ transport in PCT
how much is reabsorbed?
what type of transport?
how does K+ come in and out?

67% reabsorbed
paracellular transport
active transport K+ inward- Na+K+ATPase
passive diffusion outward- solvent drag

Cl- transport in PCT
how much is reabsorbed?
what type of transport?
due to which antiporters?

80% reabsorbed
electrical and conc gradient favours it
passive transport both paracellular and transcellular
Na+H+ Cl-Base antiporters

Urea transport in PCT
how much is reabsorbed?
what type of transport?

50% reabsorbed
passively down conc gradient
paracellular and transcellular

how much filtrate remains after passage through PCT?

30-40%

what are the properties of descending thin limb of lOh?
what ions are here?
what type of movement?

highly permeable to water AQP1
less NaCl and urea
movement is passive
passive reabsorption

what are the properties of ascending thick limb of lOh?
what is reabsorbed here?

impermeable to water
20-30% Na Cl K reabsorbed

thick ascending limb
what is the process of ion reabsorption?

1. Na K 2CL enter cell via apical membrane symporter
2. Cl leaves cell by passive diffusion via cl channels
3. most K leaks back into lumen via k channels, some is reabsorbed
4. tubular lumen now positive, driving paracellular diffusion of na,k,mg,ca
5. na enters cell via Na+H+ antiporter, leading to HCO3- reabsorption
6. na is pumped out across basolateral memb by sodium pump
7. na enters cell from tubular fluid