PSL301 Renal System

How much of person’s body weight is water?

50-60%

what determines the amount of water in a body

the ratio of fat/muscle

on average, what people have more fat and therefore less water?

women, older, and chronic illness (reduction in muscle = reduction in water)

how is the percentage of water broken up in the body?

2/3 is ICF, 1/3 ECF

\-ECF is broken into 80% ISF and 20% plasma

what is the total amount of water in a body approximately

42L

Properties of aquaporins

family of integral membrane proteins, provide channels for the rapid movement of water molecules, there are ten kinds known

what are the amounts/kinds of aquaporins in the RBCs and the plasma membrane of PCT cells

RBC: 2x10^5 copies of AQP-1 channel

PCT cells: 5 different types of aquaporin types

solutes vs ions

solutes = particles dissolved in a water solution

ions = electrolytes, charged solutes (cation +, anion -)

osmolality

the concentration of solutes in water which generates an osmotic force

\-more solute = higher osmolarity

osmotic force

the movement of water across a semi-permeable membrane in response to an osmotic gradient (different in osmolality in compartments)

\-water moves from compartment with low osmolality to compartment with high osmolality

what is the osmolality between the different fluid compartments

the osmolality is the same in each of the fluid compartments

\-number of solutes per volume = same

how do the solute concentrations differ between compartments?

the concentration of solutes is equal amongst the compartments but the types are different

\-there is low Na+ inside the cells (ICF) and high Na+ outside the cells (ECF)

Properties of the Na+-K+ pump (ATPase)

maintains the concentrations of high K+ outside and low Na+ inside the cells; pumps 3 Na+ out with 2 K+ in using hydrolysis of ATP

what are some drugs that can inhibit the Na+-K+ pump

ouabain = steroid derivative

digoxin = steroid glycoside, used in treatment of cardiac failure

how much energy does the pump use?

30% of the cell’s energy

how does the Na+ balance and water work?

Na+ is restricted to the ECF and is the main ECF osmole, water crosses the membranes to equalize the osmolality in the ECF and ICF

what happens if you drink water alone?

it is absorbed into the ECF, lowering the ECF Na+ concentration (dilute) and the osmolality, then water moves from the ECF to the ICF, and both the volumes of the ICF and ECF increase (hypotonic = bigger)

what happens if you eat salt?

it increases the ECF Na+ content and concentration (Na+ stays in the ECF), leading to an increase in the ECF osmolality and water moving from the ICF to ECF, meaning there is a decrease in ICF volume and increase in ECF volume (hypertonic = shrink)

what does the leaky exchange epithelium allow for

movement through the gaps between cells

how is water flux determined

by Starling forces

what are the Starling forces ?

\-hydrostatic pressure gradient (generated by the pumping of the heart) = large concentration of small particles

\-oncotic pressure gradient (generated by albumin) = small concentration of large particles

\-capillary permeability to water

properties of albumin

main plasma protein = 40g/L in the plasma (low in the ISF), MW of 68,000; capillaries = limited permeability, provides the oncotic pressure in the plasma > ISF

what is the equation for fluid flux

= permeability x (hydrostatic pressure gradient - oncotic pressure gradient)

\-Jv = Kf (∆P - ∆π)

what are the directions of the hydrostatic and oncotic pressures

hydrostatic pressure = going into the ECF from blood

oncotic pressure = going into the blood from ECF

how could a seizure result from a marathon runner drinking too much water

if no solutes, then there is a decease in the Na+ concentration, so water will cross the cell membrane from ECF to ICF and the brain swells → increasing intracranial pressure and causing the seizure

\-treat w/ IV concentrated saline

what are the values for cardiac output, renal blood flow and renal plasma flow

CO = 5L/min

Renal Blood Flow = 1L/min

Renal Plasma Flow = 500 ml/min

what are the starling forces associated with ultrafiltration

\-Glomerular Capillary Pressure (PGC)

\-Tubular Hydrostatic Pressure (PT)

\-Oncotic pressure (πA)

\-ultrafilration coefficient (Kf)

\-Plasma Flow (QA) = important to maintain the forces

what does the hydrostatic pressure gradient vs the oncotic favour?

hydrostatic = favours the movement into open space

oncotic = favours keeping water in the vascular compartment

what are some values for ∆P and πA of the glomerulus

∆P = 38-40 mmHg

πA = 20-25 mmHg

What is the glomerular filtration rate

150-180 L/day or 100-125 ml/min

what are the determinants of the ultrafiltration?

Kf = limited by the length of the capillary (but increases as the rate increases, then levels off)

P = increases as the rate increases

πA = when increase, then decrease the rate (reduce the movement out)

QA = increases as the rate increases, but reach a physical limitation

how is the cardiac output divided with the kidneys

20% of the CO is divided by each kidney

what is the most important determinant of the GFR

Renal blood flow (plasma flow)

what is plasma flow determined by

arterial pressure (BP) and renal vascular resistance

how does the auto-regulation of the Renal blood flow and GFR work

keeps a relatively constant over MABP of 70-150 mmHg by a myogenic reflex in the afferent arterioles:

\-BP falls = arterioles dilate = increase flow + rate

\-BP rises = arterioles constrict = decrease flow + rate

how does tubulo-glomerular feedback work?

adenosine release → VSMC contraction in the afferent arteriole → increased resistance in the afferent arteriole → reduced plasma flow → reduced GFR

how does changes in the efferent arteriole affect the GFR

increases resistance in the efferent arteriole = constrict = increase GFR

what can affect the efferent arteriole

angiotensin II will cause an increased resistance

\-can be linked to kidney disease

convection

the movement of small solutes with the bulk flow of water

what solutes are freely filtered

Na+, K+, glc, Cl-, HCO3-, urea and creatinine

Glomerular Perm-selectivity

as the molecules get larger, the permeability decreases, with (+) > neutral > (-) as the order of the three permeabilites from most to least at any given size

why is GFR measured?

it correlates well with the clinical consequences of reduced kidney function (as GFR falls, consequences increase)

what do you need to measure GFR

\-freely filtered solute that is neither reabsorbed nor secreted by the tubules therefore the amount filtered per unit time = the amount excreted per unit time

clearance = GFR

what is a good marker for this in a research lab?

inulin → b/c no reabsorption by the tubule and its clearance = GFR

\-BUT, needs to be given intravenously and generally administered in a lab

what is used to measure GFR in a clinical lab? why?

creatinine in the serum and urine

\-used by it is produced from muscles constant from day to day, is freely filtered and with limited secretion

\-therefore clearance = urine flow rate x \[urine creatinine\]/\[plasma creatinine\]

\-the normal value is 90-120 mL/min

how if GFR related to plasma creatinine

inversely proportional

how is perm-selectivity measured?

measure the total protein (

review of the kidney filtration and albumin properties

kidney filters 150-170 L/day and 1000mg of albumin enters Bowman’s space, but the kidney only excretes 10 mg albumin/day

how does diabetes mellitus link to the glomerulus

there is abnormal glomerular function b/c the glomerulus is injured by diabetes and impairs the permselectivity of it so that increased amounts of protein cross the wall → leading to an eventual decline in the ultrafiltration

what are the structures (tubules) of a nephron from start to finish

Bowman’s capsule → Proximal Tubule → descending limb → loop of henle → ascending limb → distal tubule → collecting duct

what is the normal urine volume and how much water is reabsorbed every day ?

normal urine vol = 0.5-2 L/day

>99% of filtered water is reabsorbed

how much water is filtered out of Bowman’s capsule and how much is then reabsorbed

20% of the volume is filtered, and >19% is reabsorbed

how much sodium is filtered, excreted and then reabsorbed every day

filtered > 22,500 mmol/day

excrete 150 mmol/day

>99% of it is reabsorbed

how do the kidney epithelial cells reabsorb Na+

the cells re polarized, which allows for directional transport

\-different transport proteins are in the luminal (apical) and basolateral (blood) membrane

\-the Na-K+ ATPase is localized to the basolateral membrane

Sodium Hydrogen Exchanger (NHE)

-a antiporter

\-for sodium reclamation

\-on luminal side

\-dependent on the Na+K+ ATPase

\-switches Na+ into proximal tubule for H+ out, into lumen

Sodium Co-transporter (SGLTs, NaP)

drives the Na+ reabsorption with other solutes involved

\-on the luminal side

\-takes Na+ down its conc gradient with glc or P

Epithelial Sodium Channel (ENaC)

\-allows it to move down the conc gradient

\-Na+ moves from high conc in the lumen to low conc inside the proximal tubule

\-water follows the Na+

Model for tubular reabsorption and secretion

\-low IC cell Na+ concentration driven by Na+K+ ATPase in the basolateral membrane

\-luminal Na+ enters the cell down large electrochemical gradient (cell interior is negative)

\-Na+ entering the cell exits the basoleteral membrane through the Na+K+ ATPase

\-reabsorption or secretion of the other solutes is linked to Na+ though the luminal membrane transporter proteins

In general, how do the nephron segments differ?

\-specific luminal transport proteins, the “leakiness” of the tubule to water and solutes, the nature of the tight junctions between the cells, the presence of channels (ie. aquaporins), and the presence of hormone receptors (ie. aldosterone, vasopressin, angiotensin II)

Proximal Tubule

\-the site of bulk reabsorption of Na+, Cl-, H2O, K+, and HCO3-

\-most important transport = NHE3

\-mechanism for bicarbonate reabsorption

\-site of glc, P, amino acid cotransporters

\-very leaky-isotonic reabsorption of Na+

Thick Ascending Limb of Loop of Henle (TAL)

\-reabsorbs 20-30% of filtered Na+

\-transport = Na-K-2Cl (NKCC2)

\-very impermeable to water

\-fluid leaving thick ascending limb = less concentrated than the plasma (hypotonic)

\-salt added to medullary interstitium without water = concentrates medulla (for urine)

what drug can inhibit the NKCC2 ?

furosemide = dispalaces Cl, so more salt and water remain in the lumen

distal convoluted tubule

\-reabsorbs 5-10% of filtered Na+, water

\-NCC transporter

\-important for urinary dilution (maintaining the conc of Na+ in the lumen)

what can inhibit the NCC

thiazides = cause Na+ loss, they are less potent than furosemides b/c this segment reabsorbs less Na+

Collecting Duct

\-reabsorbs 1-3% of the filtered Na+

\-transporter = ENaC

\-has aldosterone receptors = increase reabsorption of Na+

\-has vasopressin (ADH) receptors = increase aquaporins for water

\-less permeable to Cl- b/c the lumen is (-)

\-PD facilitates K+ secretion

\-low capacity but capable of generating large conc gradients

how does filtration, reabsorption, and excretion relate to plasma glc conc

\-filtration = proportional to conc, does not saturate

\-reabsorption = proportional to conc until maximum transport is reached (Tm)

\-excretion = excretion is zero until the renal threshold is reached (kidney reabsorbs until too much)

glc transport

\-Na+-glc symporter ion = the apical (luminal) side, moves glc from low to high with Na+ down gradient

\-GLUT transporter = basolateral side, moves glc from high to low

\-want to avoid losing glucose in the urine, therefore normally free

\-two transporters = one proximal, low affinity, high capacity vs one more distal, high affinity, low capacity

summary of the tubular function

\-bulk reabsorption of Na+, H2O, Cl- and HCO3- = in the proximal tubule and loop

\-regulation of Na+, H2O, Cl-, HCO3-, and K+ = collecting duct

\-proximal tubule = leaky, no large gradients

\-collecting duct = tight, large gradients possible

\-organic solute transporters = all proximal

what is the normal vs recommended intake of Na+

average = 150 mmol/day

recommended max = 100

how to lose and gain Na+

lose = excessive sweating, diarrhea, vomiting, hyperglycemia, diuretics, blood loss, deceased intake

gain = diet

what are the percentages of Na+ reabsorption for each nephron segment

proximal tubule = 70%

loop = 20-30%

distal tubule - 5-10%

collecting duct = 1-3%

what is used to sense a Na+ deficit

gauging the plasma volume

wat do the carotid and aortic arch receptors (baroreceptors) do

gauge the amount of fluid being delivered to the brain

\-sense wall tension: volume and pressure

what is the Renin Angiotensin system

Angiotensinogen -Renin→ Angiotensin I -ACE→ Angiotensin II → kidney to increase Na+ and water retention

How does SympNS activation affect the Renin Angiotensin System

SNS increased the production of renin

how does the afferent arteriole affect the Renin Angiotensin System

senses low pressures = converge on the kidney to increase production of renin

what regulates renin secretion

low arterial BP = increased renin

high SympNS activity = high renin

low Na+ intake = high renin

How does angiotensin II affect the proximal tubule

increases the activity of the NHE3 so there is an increase of Na+ in the tubule

how does angiotensin II affect the distal convoluted tubule

it increases the Na+ and Cl- reabsorption by acting on the NCC

= chhanges the set point so less Na+ exiting the tubule

How does angiotensin II affect the efferent arteriole

increases its resistance = enhance the starling forces which favour reabsorption

\-increases the filtration fraction and increases the oncotic pressure in the capillaries

how does angiotensin II affect the collecting duct

it acts on the adrenal cortex which produces aldosterone which has receptors on the CD and that results in the transcription of more channels = enhance reabsorption of Na+ and K+ secretion

how does a swimming pool affect the body?

water pressure increases on the intersitial = drive water and Na+ into the vascular compartment and the baroreceptors sense the increasing volume and pressure

how does eating too much sodium affect the system

it increases the baroreceptor activation which decreases the SympNS activation and thus shuts down the renin angiotensin system

what does the atrial stretch receptor do?

the myocytes secrete ANP in response to atrial stretch

\-increased vascular volume = increases stretch = increased ANP = increases GFR + reduces the Na+ reabsorption in the CD (b/c ANP inhibits the channels

what is normal water balance

intake = 2.2L/day + metabolic production = 0.3 L/day

\- output of 2.5 L/day → overall = 0

what are the percentages of water reabsorption in the tubules

70% Proximal, 15% loop, 15% DCT and CD

what is a normal filtered volume and excretion

filtered volume of 150L,

pathway in the brain for vasopressin release

the Suprasoptic Nucleus (SON) and the Paraventricular nucleus (PVN) = connected to the pituitary gland = produces the vasopressin

location, properties and pathway of the hypothalamic osmoreceptors

located in the anterior hypothalamus OVLT, are stretch inhibited cation channels

\-Pathway = 1. osmoreceptor cells shrink → 2. channels open → 3. cations enter and depolarize cell → 4. generate AP → 5. increased AVP secretion and thirst

where is AVP made and secreted from

made in hypothalamus, secreted by posterior pituitary

what are the differences in permeability of the loop of henle

descending = water permeable and salt impermeable

ascending = water impermeable, salt permeable

how is the counter current multiplication structured in the loop

there is an increasing Na+ in the descending and a decreased Na+ in the ascending which leads to a dilute osmolality in the tubular lumen + higher conc in the descending + lower in the ascending

how does vasopressin work?

binds receptors on the CD → cAMP system → cell inserts AQP2 water pores into the apical membrane → water absorbed by osmosis into blood

(vasopressin renders the luminal membrane permeable to water)

how to make concentrated urine

1. hypertonic medullary interstitium
2. NaCl added form thick ascending limb and urea from MCD
3. countercurrent arrangement of vessels in medulla prevents removal of solutes
4. vasopressin opens water channels (aquaporin 2) in lumen of CD
5. water moves from lumen to hypertonic interstitium

excretion of dilute urine

1. fluid leaving thick ascending limb is always dilute
2. no ADH: collecting duct is relatively impermeable to water
3. NaCl reabsorbed by DCT, CCD, and MCD so urine becomes progressively more dilute
4. minimum urine osmolality = 50 mosmol/kg

how much urine can humans excrete with excess water?

> 500 ml of urine / hour

\-meaning vasopressin would be suppressed and urine osmolality is low (50-100 mosmol/L)

how much urine can humans excrete with water depletion

< 20 mL/hour

\-meaning vasopressin is high and urine osmolality is high (800-1200 mosmol/kg)

what does DDAVP do?

\-it is synthetic vasopressin

\-leads to a rapid increase in urine osmolality and decrease in urine flow

central diabetes insipidus

\-vasopressin deficiency

\-could be caused by trauma = ie. abnormal posterior pituitary

\-inacts a thirst to maintain water balance

What is the overall K+ balance in the body ?

diet = 50-100 mmol/day

100% absorbed in gut

>90% excreted in urine, small amount in stool