Renal Physiology (Kidney)

How much water weight are humans

50-60%

What determined body water as fraction of weight

1. muscle and fat

   • fat has very little water, muscle has most water weight

   • as we age we loose muscle mass (65% as infants and 46-52% when 60+)

   • women have less muscle = less body water mass

Most important determinants of body water weight

1. age

2. sex

3. fat %

3 places water is found

1. interstitial space

2. inside cells

3. inside vascular spaces

Distribution of body water - where is it found the most?

2/3 is intracellular

1/3 is extracellular (80% of this interstitial fluid and 20% in plasma)

Aquaporin

• integral membrane proteins

• channels for rapid movement of water across all plasma membranes

• 10 types in humans, but 5 types in the plasma membranes of PCT cells

• discovered in 1990

Osmotic force

• movement of water across plasma membrane in response to osmotic gradient

• moves from high to low osmolarity

Where is sodium most abundant

• plasma and intertitial space

Where is potassium most abundant

• cells

What happens to ICF and ECF volumes if we drink water

• water is absorbed from gut into ECF

• ECF sodium osmolatity is lowered via dilution

• water will move from ECF to ICF to normalize

• both volumes increase and cell will increase because it is growing with water inside

what happens to ICF and ECF if we eat salt

1. sodium will increase in ECF and stay there because it does not normalize like water

2. water will move from ICF to ECF to normalize

3. ICF volume decreases and ECF volume increases

4. cells shrink

Leaky exchange epithelium

• allows for movement through gaps between the cells

• water can move across from ICF to plasma inside vessels between these pores

what determines ICF and Plasma volume and their relationship

• NOT solutes and osmolality

• Starling forces: hydrostatic (heart) pressure and oncotic pressure (albumin)

• capillary permeability to water

Albumin

• main protein in plasma

• capillaries have limited permeability to it because it has high molecular weight

• provides oncotic pressure in plasma > ISF

Fluid Flux

Permability X (hydrostatic pressure - oncotic pressure gradients)

Jv = Kf(delta P - delta pi) → this is how it looks

How much does kidney filter each day

144 litres via plasma (at 1L/min total and 500ml/min per kidney)

How is a kidney structured

• increasing complexity from middle outwards

• filtration takes place along perimeter of kidneys inside

Glomerulus

• allows transfer from plasma in capillary to intersistial fluid

• forms an ultra-filter, many found in each kidney which filter plasma

Starling forces that governing movement of water from capillary to bowmans space

• Glomerular Capillary pressure (PGC)

• Tubular Hydrostatic pressure (PT) - PUSH water into bowmans space

• Oncotic Pressure - KEEP water in capillary space

• Ultrafiltration Coefficient (Kf)

• Plasma Flow (QA) - maintaining starling forces

Hydrostatic Pressure Gradient

difference between hydrostatic pressure between capillary and bowmans space

• drives ultrafiltration

Oncotic pressure

• serves to hold water in capiilaries

• water retention

Glomerular filtration rate

• Calculated as Permeability X Ultrafiltration pressure

• filter 150-180 litres per day which is 100-125 ml/min

What are the determinants of glomerular filtration rate (GFR)

• Plasma flow

  • required for filtration

  • as it increases, GFR increases but there is a limitation on plasma flow so it will plateau

• Hydrostatic pressure

  • must exceed oncotic pressure for filtration (20 mmHg)

  • positive relationship after 20 mmhg

• Oncotic pressure

  • negative relationship

• ultrafiltration coefficnet

  • positive relationship

  • but there is a limitation where it wont increase GFR anymore

what is the most important determinant of GFR

renal blood flow (plasma flow)

this is determined by blood pressure and renal vascular resistance

autoregulation of renal blood flow

• blood flow is relatively constant (70-150 mmHg)

• efferent circulation can change resistance based on blood pressure (myogenic reflex)

  • will dilate if BP drops and constrict if it increases

Tubulo-glomerular feedback

• when there is too much sodium in tubule, adenosine is released which activates receptors and causes vasoconstriction to reduce GFR

Angiotensin II

• hormone that increases the resistance in the efferent arteriole

• this decreases renal blood flow but increases GFR because of the hydrostatic pressure buildup

Convection

movement of small solutes with bulk flow of water

Freely filtered

• filtered with the water

• includes sodium, potassium, chloride, glucose, bicarbonate, urea and creatine

• makes the concentration equal in both capillary and bowmans space

• bigger molecules like albumin cannot move across the membrane (perm-selectivity) which protects against their loss

movement of macromolecules from kidney capilalries to bowmans space

• determined by weight and protein charge

  • 15 kDa is the cutoff for free-filtration

• albumin is rarely excreted - very little is lost per day

What is the significance of glomerular filtration rate

• measures kidney function

• kidney disease affect GFR

How to we measure GFR

• we essentially use a molecule we know is freely-filtered then we can measure the amount filtered in a specific unit of time by looking at concentration in urine

• Inulin is used in laboratory because it wont be reabsorbed in the tubules so 100% of the amount excreted in the amount filtered

  • however it must be given intravenously in a lab

• Creatinine is used in medical practice to measure GFR

  • end product of energy metabolism in muscle cells

  • relatively constant depending on muscle mass and there is very limited excretion

How do we measure creatinine clearence

Urine flow rate (v/min) X Ratio of [urine creatinine] to [plasma creatinine]

Relationship between GFR and Pcreat

• inversely proportional

how do we assess perm-selectivity

measure total protein or albumin in urine over 24 hours

Anatomy of Nephron

1. bowmans capsule

2. proximal tubule

3. loop of henle

4. distal tubule

5. collecting duct

6. goes to bladder

normal urine volume

0.5-2 L/day

depends on how much you drink

99% of filtered water is reabsorbed

how much sodium do you filter, excrete and reabsorb each day

• filter 22,500 mmol

• excrete 150 mmol

• 99% reabsorbed

Na-K-ATPase

• maintains sodium-potassium gradient

• located on basolateral membrane of cells

Sodium Hydrogen Exchanger (NHE)

• Na into cell and hydrogen out

• allows for sodium reabsorption by allowing it to go into the proximal tubule cell then be pumped into interstital fluid by ATP-ase

Epithelial Sodium Channel (ENaC)

• allows sodium to move in and out of cell for reabsorption and excretion

proximal tubule cell

• always low sodium to maintain gradient and be able to pump sodium into interstitial fluid to allow sodium to be reabsorbed

Proximal tubule

• located immediately after bowmans capsule in nephron

• site of most reabsorption of water and solutes

  • 2/3 of all reabsorption

• uses sodium-hydrogen exchanger (NHE3)

• bicarbonate reabsorbtion

• glucose, AA, and phosphate cotransporters only found here

• very leaky

Thick Ascending Limb of Henle (the part that goes back up)

• 20-30% sodium reabsorbtion

• NKCC2 kumenal transport protein

  • inhibited by furosemide by displacing one of the chlorides

• impermeable to water

• fluid that leaves is hypotonic

Distial Tubule

• located after loop of Henle in nephron

• reabsorbs 5 to 10% of filterred sodium and water

• uses NCC transporter

• inhibted by thiazides

  • less potent than furosemide

• important in urinary dilution

Collecting duct of nephron

• last step before bladder

• reabsorbed 1-3% of sodium

• uses ENaC transporter

• more aldosterone-receptors

• Vasopressin receptors increase water reabsorption

• facilitates potassium secretion

• low capacity for transport but can generate large concentration gradient

Relationship between reabsorption rate of glucose and Plasma glucose

• positive relationship until you reach maximum, then it plateaus

Renal Threshold

This is the threshold of plasma glucose concentration in which the body can no longer reabsorb the amount lost and we start to have a net loss of glucose in urine

• normally we are under the threshold, we don’t want to start loosing glucose because its valuable

Sodium-glucose cotransporters

• avoid the loss of glucose in urine (600 cals/day)

where are receptors that regulate sodium levels located

vascular compartment

Water gained and lost in the body

Gained

• 2.2 L/day from food and drink

• 0.3 L/day from metabolism

Lost

• 0.9 L/day from skin and lungs (sweat and water vapour in breath)

• 1.5 L/day in urine

• 0.1 L/day in feces

2.5 L/day in and out

where are sensors for water balance located?

inside cells in the intracellular fluid - the volume inside cells tells us water need

(grape vs raisin)

what two nuclei in the hypothalamus play a role in water balance and what do they do

1. Suprasotic nucleus (SON)

2. Paraventricular nucleus (PVN)

they signal to posterieur pituitary for release of hormones and send signals to areas of hypothalamus that regulate thirst

Hypothalamic Osmoreceptors

• cells in anterior hypothalamus

• stretch-inhibited cation channels

• the cells that regulate water balance

  • when the cells shrink which causes the channels to open and depolarize cell (causing action potential)

  • leads to increased AVP (arginine vasopressin) release and thirst

Vasopressin (AVP, ADH)

• main hormone responsible for water balance

• increases when high osmolality is sensed, which indicates not enough water present to dilute solutes

• decreases when there is low osmolarity, indicating the cells have enough water

• directly related to level of thirst as well