renal function

role of the kidneys

• filter out small ater soluble aste products

• manages levels of ater and sodium in plasma

• produces adrenaline from adrenal gland

• erythropoietin made by the kidney

hy is sodium important?

• blood volume and pressure, stored in extracellular space so modulates ho much ater e keep in the extracellular space

aste products in urine

• urea, hydrogen ions, creatinine

hydrogen ions

• produced through metabolism

• need to remove to avoid lo pH

creatinine

• aste product produced by muscle breakdon and repair

urea

• protein breakdon gives off urea

hat is urine made from mostly?

• plasma

• it takes 200 litres of plasma to make the 2 litres of urine that e make per day

• kidney gets 1L of cardiac output per minute, multiply that by no. of minutes per day, around 1400L gets delivered to the kidney. hoever, only 200L of this gets filtered, only 2L turns into urine

• 99% of ater entering kidney is reabsorbed

urine versus blood conc of aste products

• aste products are more concentrated in the urine than in the blood

• indicates that ater is reabsorbed

• secretion to add more aste product than as initially filtered

hat substances are present in plasma but not urine?

• HCO3, glucose, albumin

• either doesn’t get filtered or all of it is reabsorbed

nephron

• a million nephrons in the kidney

• in the medulla of the kidney, loop goes into the deeper section of the medulla

• 1200L of blood passes through the nephrons every day

parts of the kidney

• cortex (outer) and medulla (inner)

parts of the nephron

• glomerulus

• proximal convoluted tubule

• loop of Henley (descending limb and thick ascending limb)

• distal convoluted tubule

• connecting tubule

• collecting duct

thick ascending limb

• does a flyby of the glomerulus

collecting duct

• collecting ducts from other nephrons merge in and it becomes the ureter

blood flo through the nephron

• blood moves in through afferent arteriole hich leads to the glomeruler capillaries

• a portion of the blood gets filtered (20%), but most gets pushed out into the efferent arteriole, then into the peritubular capillaries

• some blood gest reabsorbed into capillaries, some stuff gest secreted from capillaries into nephron

• amount of solute exccreted = amount filtered - amount rebsorbed + amount secreted

peritubular capillaries

• capillaries that rap around the rest of the nephron, colecting hat is reabsorbed out of the nephron

here does the majority of reabsorption occur?

• in the proximal tubule and loop of Henle

substances that are filtered into the nephron

• the lower the percentage of excretion, the more of the substance needs to be reabsorbed

parts of the glomerulus

• ascending limb of loop of Henle can be seen on the left

• whatever enters the proximal tubule we call “filtered”, needs to get through glomerular capillaries - size barriers

• Bowman’s capsule: fluid filled space surrounding the capillaries

size barriers

• large molecules are blocked by:

• fenestrated capillaries

• podocytes create thin filtration slits

mesangial cell

keeps the capillaries in position

endothelial pores and filtration slits

• substances to be filtered need to pass through the pores and through the negatively charged lamina and then through the filtration slit in the podocyte

does albumin get filtered?

• it’s small enough to get through but the negative charge barrier stops it from getting through

glomerular filtration rate

• clinical indicator of renal function

• volume of plasma filtered by the glomerulus per unit time

• how much plasma comes out of glomerulus and enters nephrons

• about 100 mL/min

low glomerular filtration rate

• declines with age and with conditions like diabetes

what is the main force that affects GFR?

• hydrostatic pressure in the glomerular capillary

hydrostatic pressure in the glomerular capillary

• 55 mm Hg (higher than in systemic capillaries)

• there is some oncotic pressure in the glomerular capillaries (30 mm Hg) but net filtration pressure of 10 mm Hg

• no oncotic pressure in Boman’s space drawing fluid out as there is no albumin in this space

oncotic pressure in Boman’s capsule

0

why is the pressure in the glomerular capillaries greater than in systemic capillaries?

• e don’t ant to reabsorb anything back into glomerular capillaries, so pressure needs to stay high to ensure that filtration is occurring all along their length

hypertension and kidneys

• as pressure is high in the glomerular capillaries, hypertension is very dangerous for kidneys

how is GFR modulated?

• GFR increased by dilating afferent arteriole or constricting efferent arteriole as it causes an increased hydrostatic pressure in the glomerular capillaries

what happens to renal blood flow when the afferent arteriole constricts?

• it decreases, (SNS mechanism through a1 receptors)

• to maintain GFR, we can constrict the efferent arteriole

how to measure GFR?

• inulin

• measure how much is in the blood and the rate at which its appearing in the urine

• ideal compound because:

  • it is not reabsorbed

  • it is not secreted

  • it is exogenous

  • it is not metabolised

process of using inulin to measure GFR

• e.g. we might put a conc of 4 units of inulin per 100 mL of plasma

• can measure rate of inulin appearing in the urine (e.g if it’s 4 units per minute, since there’s 4 units in 100 mL of plasma we would know that the rate of filtration is 100mL/minute)

renal clearance

• the rate of urinary excretion of a substance relative to its plasma concentration

• how quickly a substance in our plasma will be cleared

• ho many mLs orth of plasma are e clearing of the substance every minute (mLs/min)

importance of renal clearance

• important for pharmacology: need to know how frequently to dose someone with a drug

clearance calculation example

• we are actively clearing 50 mL/min

• doesn’t matter about the conc of the substance, it’s about the volume entering the nephron and the percentage of the substance cleared (percentage x volume)

clearance calculation including secretion

• penicillin - 4 units/100mL, however, 2 units are secreted per 100mL

• therefore 150mL/minute

if clearance of X is less than GFR, then

• X is being reabsorbed by the nephron

hat happens to GFR hen MAP increases?

• it doesn’t change (within a relatively typical range)

• achieved through: myogenic response and tubuloglomerular feedback

myogenic response

• reflex constriction as a result of pressure increase in afferent arteriole

macula densa

• here the afferent arteriole connects to thick ascending loop of the loop of Henle

tubuloglomerular feedback

• if GFR increases, flow through tubule increases, therefore flow through macula densa increases

• macula densa can detect levels of NaCl, if GFR is increased too high, the flow through the early parts of the nephron is too fast to absorb enough NaCl, macula densa detects high levels of NaCl

• macula densa tells afferent arteriole to constrict (by releasing adenosine)

adenosine

paracrine, travels to smooth muscle cells of afferent arteriole and tells them to constrict

juxtaglomerular apparatus

the macula densa and the afferent arteriole

ho can renal excretion be altered?

• regulating Na+ excretion:

  • renin-angiotensin system

  • sympathetic NS

  • atrial natriuretic peptide

• regulating water excretion:

  • vasopressin (anti diuretic hormone)

renin-angiotensin-aldosterone system

• recruited when blood pressure drops, in tandem with the SNS

• raises blood pressure

• causes us to reabsorb sodium

• begins with granular cells

granular cells

• cells lining the afferent arteriole

• releases renin in response to lo BP

• 
  

renin

• travels in the blood to the liver,

• liver is normally producing angiotensinogen

• renin cleaves angiotensinogen into angiotensin I

angiotensin I

• travels to lungs

• lungs produce angiotensin converting enzyme (ACE) hich converts angiotensin I to angiotensin II

angiotensin II

• increases TPR through vasoconstriction of arterioles, increases GFR by constricting efferent arteriole

• travels to the adrenal glands above the kidney and causes it to release aldosterone

• increases some Na+ reabsorption in the proximal tubule (small effect as 80-85% of Na+ is absorbed here, so small changes can have a big effect)

how does angiotensin II rescue drop in GFR due to low BP?

constricts efferent arteriole

aldosterone

• steroid hormone

• mineralocorticoid: hormone that regulates minerals (in this case, Na+)

• increases Na+ reabsorption from the collecting duct back into our circulation

sympathetic NS effect on renal excretion

• NA slightly stimulates an increase in Na+ reabsorption from proximal convoluted tubule

• main effect on afferent arteriole: effect on a1 receptors to cause constriction to ensure that blood is sent to skeletal muscles

• therefore decreases GFR

• however, the sympathetic NS also activates the renin angiotensin aldosterone system, which constricts the efferent arteriole to bring GFR back up

acute tubular necrosis

• if an artery is haemorrhaged, the SNS ill cause heavy vasoconstriction of the afferent arteriole

• this combined ith a decrease in blood volume can result in kidney ischemia - tubules die off so sodium and ater cannot be reabsorbed

• profound diuresis

is reabsorption or secretion bigger in the tubules?

• reabsorption

• 1200 L moves through the kidney per day, only 200 L enters the nephron to get filtered, most of this needs to be reabsorbed as we only produce 2L of urine per day

here is reabsorption greatest along the nephron?

• proximal tubule, descending limb, loop of Henle and ascending limb (bulk reabsorption - 85% of water and Na+ are reabsorbed)

• fine tubing occurs at distal tubule and collecting duct

hat does the inside of the proximal tubule look like?

• lots of villi to create high surface area

what is the most important solute to be reabsorbed?

• sodium, as reabsorption of everything else follos reabsorption of sodium

reabsorption in proximal tubule

1. Na+ reabsorption

2. electrochemical gradient drives anion reabsorption

3. ater reabsorption

4. permeable solute reabsorbed

Na+ reabsorption in proximal tubule

• through active transport

• Na+/K+ pumps on basolateral membrane creates conc gradient (creates lo level of Na+ in proximal tubule cells)

• therefore, only a channel is needed on luminal membrane so that Na+ can pass from tubule lumen to proximal tubule cell

• peritubular capillaries are on the right, reabsorbing all the Na+

electrochemical gradient drives anion reabsorption

• anions follo the positively charged Na+ don their electrochemical gradient

ater reabsorption

• water moves by osmosis, folloing solute reabsorption

• therefore, ater reabsorption is linked to Na+ reabsorption in theproximal tubule, cannot change one independently of the other (this is different in the distal tubule)

permeable solutes reabsorbed

• K+, Ca2+, urea, etc have channels

• they no have a concentration gradient as the ater has left, making them more concentrated in the lumen

• so they ill flo into the extracellular fluid

reabsorption into peritubular capillaries

• peritubular capillaries closely surround the proximal tubule, so everything is reabsorbed into them

• they are an extension of the afferent arteriole

active reabsorption in the proximal tubule?

• although only sodium is directly actively reabsorbed, reabsorption of all the other substances also counts as active as it required the ork of ATP in the first place to move sodium to allo these solutes to follo

reabsorption ith cotransporters

• Na+ gradient can be used ith cotransporters

• every Na+ that comes through can bring other molecules ith it too, such as glucose or amino acid transporters

• e ant to reabsorb all glucose so e have a lot of these transporters

SGLT-2 inhibitors

• SGLT-2 is a sodium glucose transporter

• inhibitors reduce reabsorption of sodium and glucose

• ork in diabetics to reduce plasma glucose levels, it leaves in the urine

glomerular hyperfiltration

• in diabetic nephropathy and hypertension

• too much pressure on glomerular capillaries

• so much glucose in the plasma that SGLT-2s are orking really hard, but ith every glucose molecule reabsorbed, Na+ is also reabsorbed

• macula densa detects lo Na+, thinks that GFR must be lo, dilates afferent arteriole, increases pressure in glomerular capillaries too high

• therefore SGLT-2 inhibitors can be used in diabetes to protect glomeruli

hy does glucose appear in the urine of a diabetic?

• abnormally high levels of glucose in the plasma

• SGLT-2s are saturated, can’t absorb any more glucose - tubular/transport maximum

reabsorbing HCO3-

• in the proximal tubule, there is a Na+/H+ exchanger - Na+ enters the proximal tubule cell, and the H+ enters the lumen

• H+ combines ith HCO3- to form H2CO3

• CA converts H2CO3 to H2O and CO2

• CO2 is reabsorbed a it has a conc gradient

• then CO2 combines ith H2O to form H2CO3, hich then splits into HCO3- and H+

• HCO3- is filtered into blood

• H+ is used again in the exchanger

• e can reabsorb almost 100% of HCO3-

oxygen consumed by kidney

• 80% of oxygen consumed by the kidney tied to reabsorption of ater, chloride, glucose, amino acids, urea

• tied to secretion of potassium, hydrogen ions

effect of aldosterone in the collecting duct

• increases activity of sodium/potassium pump on basolateral membrane

• increased expression of EnACs on luminal membrane

• increased potassium secretion

• increased activity of hydrogen ATPase on luminal membrane

increased potassium secretion

• increased activity of sodium/potassium pump results in increased K+ conc in the cells

• therefore K+ channel on luminal membrane allos secretion of K+ into the lumen

hydrogen ATPase

• on the luminal membrane

• kicks hydrogen out into the lumen

ho is electrical neutrality maintained in the presence of aldosterone?

• for every to Na+ ions reabsorbed as a result of aldosterone, e secrete one K+ and one H+ to maintain electrical neutrality

hyperaldosteronism

• Na+ reabsorbed increases, BP goes up

• hyperkalemic (lo K+)

• alkalotic (getting rid of too much H+)

sodium input

• diet (food 7 drink) = 150 mmol on average consumed

• intravenous (normal/isotonic saline) = 0 mmol

sodium output

• urine = 140 mmol

• faeces = 8 mmol

• skin = 2 mmol

high sodium intake

• takes a few days for the body to adjust to Na+ balance

• each step is about a day and represents urine sodium output

• if e suddenly increase our sodium intake, our sodium input incrases dramatically (dark grey square)

• takes a hile for our urine output to match this, takes a hile for aldosterone levels to drop enough so that e can excrete the sodium

• results in a temporary positive sodium balance

hy does it take a hile for the body to adjust to Na+ balance changes?

• as aldosterone is a steroid hormone, sloer acting, longer lasting hormone

• e don’t ant dramatic immediate changes as Na+ balance affects cardiovascular system

positive sodium balance

• results in you retaining ater

• results in an increase in eight

• 9 extra grams of sodium results in one L of water retained

low sodium intake

• takes a while for your sodium output to catch up, so initially you’re urinating out more sodium than you’re taking in

• negative sodium balance, drop weight

how does infusion of normal saline change blood volume?

• sodium is in the extracellular fluid (plasma and interstitial fluid)

• the saline will move into these fluids

• 25% of extracellular fluid is plasma

• therefore an infusion of 1L of normal saline will cause a change in blood volume of 0.25L

ideal treatment for low BV?

• could add albumin to IV drip as albumin stays in the plasma and will osmotically keep water in the plasma

• in practice artificial electrolyte solutions or blood is often used as adding albumin can result in reactions

how does the body detect sodium balance?

• judged through BP receptors:

• carotid baroreceptors

• renal arterial pressure receptors

• cardiac atrial baroreceptors

angiotensin II vs aldosterone effects on sodium reabsorption

• angiotensin II causes a mild increase in Na+ reabsorption in the PCT, therefore causes an increase in reabsorption of everything else, including water

• however, aldosterone works in the collecting duct, so it can exclusively affect Na+ reabsorption without affecting water reabsorption

what triggers renin release? (RAAS system)

• stimulated by volume depletion:

  • fall in pressure at preglomerular (afferent) arteriole

  • reduction in sodium chloride delivery (signals reduced GFR) to macula densa

  • sympathetic nerve activation (recognised via baroreceptors)

atrial natriuretic peptide

• if stretch increases in the atrium, there must be an increase in plasma volume

• atrial natriuretic peptide released (short acting hormone)

• in collecting duct, ANP decreases reabsorption (opposite effect of aldosterone)

• removes ENaCs from the luminal membrane of the collecting duct to reduce Na+ reabsorption

here does secretion occur?

proximal tubule, distal tubule and collecting duct

hat affects diameter of afferent arteriole?

• tubuloglomerular feedback (either ay)

• myogenic response (either ay)

• sympathetic NS (const.)

• ANP (dilate)

hat affects efferent arteriole

• ANG II (constriction)

damage to kidneys caused by medication

• ACE inhibitor (decreased Ang II, dilation of efferent arteriole)

• loop diuretic: drop in blood volume

• NSAID: block production of prostaglandins, which cause relaxation of the afferent arteriole. if they’re blocked, constriction of the afferent arteriole occurs

• major decrease in GFR