Urine production physiology

bulk handling def

mass unregulated reabsorption of water and essential solutes from the glomerular filtrate back into the bloodstream

location of bulk handling

proximal tubule

~70% of filtered water and sodium reabsorbed in proximal tubule

location of fine tuning urine content

distal tubule and collecting duct

most important solute to be reabsorbed

sodium → drives reabsorption of other substances and consumes 80% of kidney’s oxygen use

mechanism of solute reabsorption

sodium = active transport via sodium-potassium ATPase pump

glucose, lactate and amino acids = active transport → requires sodium movement to drive transport

process of sodium reabsorption across tubular epithelium (4)

1. sodium is reabsorbed by active transport → net decrease in lumen electrical charge

2. electrochemical gradient drives anion reabsorption to balance electrical charge

3. water moves by osmosis to follow the increase in osmolarity in the ECF

4. concentration of other solutes in lumen increases as fluid voluem decreases → permeable solutes reabsorbed by diffusion (inc. K+, Ca2+, urea)

type of capillary that reabsorbs majority of filtrate

peritubular capillaries inc. vasa recta (peritubular capillaries that dip into the medulla)

transport of glucose, amino acids and lactate across proximal tubule cell (3)

1. Sodium enters proximal tubule cells through SGLT protein (secondary active transporter) -> moves down its electrochemical gradient

   • SGLT protein pulls glucose into the cell against its concentration gradient

2. Sodium pumped out of the proximal tubule cell to basolateral side of cell by sodium potassium ATPase

   • Glucose diffuses out the basolateral side of the cell using the GLUT protein

3. Sodium is pumped out by sodium-potassium ATPase

tubular maximum - def

max rate of reabsorption that can be achieved for glucose → saturation occurs

renal threshold - def

plasma concentration at which saturation occurs

function of H+ secretion in proximal convoluted tubule vs distal nephron

proximal convoluted tubule: H+ in exchange for Na+ reabsorption -> secretion = functionally due to need to reabsorb bicarbonate ions

distal nephron: to regulate pH

renin-angiotensin system - renin release to aldosterone (4)

1. drop in EC volume or increase in Na+ concentration in filtrate stimulates renin release from granular cells of kidney → stimulates production of angiotensin I from angiotensinogen

   • Angioteninogen = produced by and secreted from the liver

2. Angiotensin I converted to angiotensin II via ACE -> angiotensin II = potent vasoconstrictor

   • ACE - synthesised in endothelial cells the line blood vessels -> lungs = major source because of the high density of capillaries

3. Angiotensin II acts on adrenal cortex to secrete aldosterone

4. Aldosterone acts on kidney -> promotes sodium reabsorption in exchange for potassium secretion

   • Fall in pressure

origin of renin

granular cells of afferent arteriole - >derived form arterial smooth muscle cells

granules contain renin

location of macular denser cells

specialised epithelial cells of ascending limb of loop of henle → forms part of juxtaglomerular apparatus

in contact with afferent and efferent arteriole

function of macula densa cells

detect amount of sodium in ascending limb of loop of henle and communicate with smooth muscle cells of afferent arteriole for tubular glomerular feedback and renin release

macular denser cell in response to high sodium (effects on map) (6)

1. high sodium detected in ascending limb

2. release of ATP from basolateral membrane → converted to adenosine

3. adenosine binds to receptors on afferent arteriole smooth muscle cells to stimulate vasoconstriction → decrease glomerular hydrostatic blood pressure

4. adenosine binds to receptors on juxtaglomerular cells to inhibit renin release → increased Na+ reabsorption

5. decreased filtrate Na+ and icnreased water reabsorption → increased ECF plasma volume

6. icnreased MAP

how does ECF voluem depletion affect MAP

decreased plasma volume → decreased pre-load → decreaed stretch in cadiac msucle wall → decrease force of contraction → decrease stroke volume → decreased CO → decreased MAP

goal of countering ECF volume depletion

increased MAP by increased CO and or TPR

pathways to increasing MAP following ECF volume depletion (5)

to increase CO → increase plasma volume by increasing Na+ reabsorption (drives water reabsorption)

• RAAS activation → increase renin → increase ang II → increase Na+ reabsorption

• vasopressin release → act on collecting tubule cells for increased aquaporins

• baroreflex → sympathetic nerves release noradrenaline to bind to beta1-adrenoceptors → acts on heart muscle to increase HR + force of contraction

to increase TPR → stimulate vasoconstriction

• myogenic response → decreased stretch in afferent arteriole → increased vasoconstriction

• baroreflex → sympathetic nerves release noradrenaline to bind to alpha1-adrenoceptors → acts on blood vessel smooth muscle

how can renal sodium excretion be altered (3)

1. RAAS

2. sympathetic nervous system → baroreflex

3. atrial natriuretic peptide → opposes RAAS

effects of RAAS on sodium balance (3)

angiotensin II: efferent arteriolar constriction and inceased Na/H exchanger activity in proximal convoluted tubule

aldosterone: icnreased epithelial NaC activity

effects of sympathetic nervous system on sodium balance (2)

noradrenaline: afferent arteriolar constriction and increased Na/H exchanger activity in proximal convoluted tubule

effects of atrial natriuretic peptide on sodium balance (2)

opposes RAAS

afferent arteriolar dilation → increased filtration

reduced epithelial Na+ channel activity → reduced reabsorption of sodium

sources of sodium input (3)

diet and intravenous

sources of sodium output (3)

urine

faeces

skin

receptors that detetc sodium balance (3)

carotid baroreceptors

cardiac atrial baroreceptors

renal arterial pressure receptors

high vs low sodium intake effect on weight

High sodium intake -> gradual increase in urine sodium output over a couple of days

• Positive balance = increasing weight due to increased water retention

Low sodium intake -> gradual decrease in urine sodium output over a couple of days

• Negative balance = decreasing weight due to decreased water retention

effect of 1L normal saline infusion on plasma fluid volume

change in blood volume of 0.25L -> saline is distributed across body and plasma volume only makes up 25% of total water volume

normal extracellular osmolarity - cortex vs medulla

cortex = 300mOsM

medulla = 300mOsM to 1200mOsM

production of concetrated urine process (6)

1. Isosmotic fluid leaving proximal tubule becomes increasingly more concentrated in the descending limb

2. Removal of solute in the thick ascending limb creates hypo-osmotic fluid

3. vasopressin binds to vasopressin receptor on basolateral membrane of collecting duct cell

4. receptor activates cAMP second messenger system

5. signalling cascade stimualtes exocytosis of vesicles containing aquaporin2 proteins to apical membrane

6. water absorbed by osmosis into medullarly interstital space → diffuse into vasa recta (higher osmolarity)

causes of medullary concentration gradient (2)

presence of sodium and urea

Sodium = pumped out esp. in ascending limb of loop of Henle

Urea = 50% reabsorbed so it can enter medulla interstitial to contribute to medullary concentration gradient

cells of ascending loop of henle on water reabsorption (2)

Cells of ascending loop of Henle lack aquaporins -> water cannot follow solute into cell

Tight junctions between cells also prevent water movement out of tubular lumen

requirements for production of concentrated urine (3)

• Na/ K/ 2Cl co-transporters

• Aquaporin 2

• cAMP

vasopressin and diluted urine

Absence of vasopressin = no aquaporins on apical membrane to allow for movement of water into the medullary interstitial fluid

osmolarity of collecting tubule lumen remains low despite increasing osmolarity gradient in medullary interstitial space

Sodium still being absorbed so osmolarity can decrease further than 100mOsM

water inputs (3)

diet

metabolism

IV

water outputs (4)

urine

lungs

skin

faeces

consequence of negative water balance

fluid output is higher than fluid intake

concentrated urine and thirst -> increase water intake and prevent further water loss

location of osmoreceptor cells

anterior hypothalamus

function of osmoreceptor cells in response to icnrease/ decrease ECF osmolarity

Stretch receptors communicate with brain to maintain ECF osmolarity

Decrease in ECF osmolarity -> cell expands (water moves into cell)

Increase in ECF osmolarity -> cell shrinks (water moves out of cell)

increase in vasopressin concentration on osmolarity

linear positive linear relationship until max vasopressin production reached and osmolarity plateaus

decreasing ECF volume on vasopressin concentration

slow initial increase in vasopressin

large decrease in ECF triggers rapid vasopressin production

importance of ascending limb of loop of henle (2)

Production of dilute urine -> sets up for production of dilute urine if positive water balance

Allows for addition of sodium into medullary concentration gradient -> sets up for production of concentrated urine if negative water balance

urine osmolarity range

3-1200mOsm/kg H2O

must excrete 600mOsM of solute per day + at least 500mL of water per day

location and function of Na/K ATPase

basolateral membrane of entire nephron

drives Na reabsorption along nephron

location and function of Na/H exchanger

luminal membrane of proximal convoluted tubule

bulk sodium reabsorption (associated with bicarbonate reabsorption)

location and function of Na/K/2Cl co-transporter

luminal membrane of thick ascending limb of loop of Henle

sodium reabsorption and maintenence of medullary concentration gradient

location and function of Na/Cl co-transporter

luminal membrane of distal convoluted tubule

sodium reabsorption

location and function of epithelial sodium channel

luminal membrane of connecting tubule and collecting duct

fine tuning of reabsorption and sodium excretion

Na/K/2Cl co-transporter antagonist

loop diuretics inc. frusemide

Na/Cl co-transporter antagonist

thiazides

epithelial sodium channel antagonist

amiloride

dissociation constant def

ratio of concentration of dissociated ions in solution to ionic molecule

pH equation

For every 1 unit increase in pH there is a ten fold decrease in [H+]

henderson hasselbalch equation

bicarbonate buffer system

CO2+H2O < - > H2CO3 < - > H+ + HCO3-

removing CO2 from solution will cause partial shift to icrnease formation of carbonic acid → increase pH

henry’s law def

ability of a gas to dissolve in solution is dependent on partial pressure of gas and solubility of the gas in the solution

If a = solubility constant of CO2 -> [H₂CO₃]_aq = aPO_aqCO₂

major physiological buffers (5)

• Bicarbonate

• Phosphate

• Ammonium/ ammonia

• Proteins

• Haemoglobin

location of phosphate buffer system

intracellular fluid → buffers pH of ICF and urine

location of carbonic acid-bicarbonate buffer system

ECF

locations of protein buffer system - Hb, AA, plasma proteins

regulation of pH in ECF and ICF

Haemoglobin buffer system -> RBCs only

Amino acid buffers -> all proteins

Plasma protein buffers

All three buffer systems interact extensively with the other two buffer systems

major storage location of calcium and phosphate ions

bones

low pH: formation of dihydrogen phosphate → calcium release from bone → osteoporosis

buffer systems that absorb hydrogen ions from most absorbed per litre to least

bicarbonate

haemaglobbin

plasma protein

phosphate

isohydric principle and implication

all buffer systems in the body are interconnected → altering one will impact all others

typically only assess bicarbonate system → knowing what happens in barcarbonate system = know what is happening to al systems

base forms of acids (2)

volatile acids → can be converted to a gas

fixed acids → cannot be made into a gas

how are volatile and fixed acids eliminated

volatile = via lungs

fixed = via kidneys

most prominent volatile acids

most prominent = CO2 and bicarbonate

source of fixed acids (3)

normal metabolism of proteins and phospholipids results in generation of suluric acid

strenuous exercise can result in generation of substantial lactic acid

Dietary and pharmacological acid

• Eg. aspirin -> forms salicylic acid in the liver

Ketoacidosis def

large amounts of ß-hydroxybutyric acid and acetoacetic acid

role of respiration in controllign arteriole pH

short term regulation → alterations in PaCO2 can alter pH of CSF

role of central chemoreceptors on pH

1. increase in PaCO2 = decreased pH

2. decrease in pH detected by central chemoreceptors

3. central chemoreceptors stimualte DRG and VRG in CNS

4. DRG and VRG send signals to increase respiratory rate

response to acidosis (5)

1. Increase in arterial PCO2 = decrease pH

2. Decreased pH in CSF detected by chemoreceptors 

3. Chemoreceptors stimulate respiratory muscles

4. Increased respiratory rate -> increased elimination of CO2 at alveoli

5. Homeostasis restored -> normal arterial PCO2

response to alkalosis (5)

1. Decrease in arterial PCO2 = increase pH

2. Increase pH in CSF inhibits arterial chemoreceptors -> less stimulation

3. Chemoreceptors inhibit respiratory muscles

4. Decrease respiratory rate -> decreased elimination of CO2 at alveoli

5. Homeostasis restored -> normal arterial PCO2

regulation of bicarbonate buffer system

carbonic anhydrase catalyses CO2 -> H+ and bicarbonate

long term regulation of pH - buffer systems at work

bicarbonate buffer system → recovering bicarbonate from the filtrate lowers blood pH

phosphate buffer system → H+ actively pumped into filtrate to form H2PO4- with HPO4^2-

ammonium → not membrane permeable

tubular regulation of acid-base balance in proximal convoluted tubule -low blood pH (6)

1. CO2 combines with water within tubule cell -> forms H2CO3 (carbonic anhydrase)

2. H2CO3 rapidly dissociates to form H+ and bicarbonate ion

3.  

   1. H+ is secreted into the filtrate via H+  ATPase on apical membrane -> secondary active transport via Na/H exchanger promotes further H+ secretion

   2. HCO3- enters peritubular capillary blood either via symport with sodium ion or via antiport with chloride ions  -> Na/HCO3 exchangers  on basolateral membrane facilitates Na and HCO3- reabsorption

4. Secreted H+ combines with HCO3- in filtrate to form carbonic acid -> for every HCO3- that enters peritubular capillary blood, one HCO3- in the filtrate disappears (forms carbonic acid with H+)

5. H2CO3 formed in filtrate dissociates to release CO2 and H2O -> apical membrane of epithelial cells has carbonic anhydrase

6. CO2 diffuses into the tubule cell -> triggers further H+ secretion

regulation of pH in collecting duct - low blood pH

1. CO2 combines with water within type A intercalated cell of collecting duct -> forms H2CO3

2. H2CO3 rapidly dissociates to form H+ and bicarbonate ions

3.  

   1. H+ is secreted into the filtrate via H+ ATPase on apical membrane

   2. HCO3- enters peritubular capillary blood via antiport carrier in HCO3-/ Cl- exchange process -> bicarbonate recovery

4. Secreted H+ combines with HPO4^2- in tubular filtrate to form H2PO4^-

5. H2PO4- is excreted in the urine

(phosphate buffer)

amino acid metabolism for regulation of pH in proximal convoluted tubule (3)

1. PCT cells metabolise glutamine to NH4+ and HCO3- -> deamination

2.  

   1. NH4+ = weak acid that is secreted into the filtrate -> replaces H+ on Na/ H antiport carrier for secondary active transport

   2. One bicarbonate ion enters peritubular capillary blood via symport carrier per NH4+ secreted

3. NH4+ excreted in urine

• Ammonia allows acid secretion without carbonic anhydrase

electroneutrality equation

sum of cations = sum of anions

electroneutrality - ions measured

Only measure bicarbonate, sodium and chloride ions -> sometimes potassium

Major plasma cation = sodium -> minor = potassium

Major plasma anion = bicarbonate -> minor = chloride

anion gap equation

[unmeasured anions]-[unmeasured cations]

Large anion gap indicates large amount of unknown anions -> indication of metabolic acidosis

cause of increase in anion gap and conditions its called (4)

Fall in unmeasured cations

• Hypokalaemia

• Hypomagnesemia 

Rise in unmeasured anions

• Hyperalbuminemia

• Increase in organic anions 

cause of increase in cation gap and conditions its called (5)

Rise in unmeasured cations

• Hyperkalaemia

• Hypermagnesemia

• Lithium intoxication

• Paraproteinemia

Fall in unmeasured anions

• Hypoalbuminemia

signs of respiratory acidosis

High PCO2 and low pH

High bicarbonate = chronic

Normal bicarbonate = acute

possible causes of respiratory acidosis (3 categories)

• Impaired lung function -> impaired gas exchange or alveolar PCO2 ventilation

• Impaired ventilatory movement -> paralysis of respiratory muscles, chest injury, extreme obesity

• Narcotic or barbiturate overdose or injury to brain stem -> depression of respiratory centres resulting in hypoventilation and respiratory arrest

signs of respiratory alkalosis

Low PCO2 and high pH

Normal or slight decrease in bicarbonate = acute

Low PCO2 = chronic

causes of respiratory alkalosis

• Strong emotions -> pain, anxiety, panic attack, fear

• Hypoxia -> asthma, pneumonia, high altitude

• Brain tumour or injury -> abnormal respiratory controls

signs of metabolic acidosis

Normal or decreased PCO2 and low pH

Normal PCO2 = acute

Decreased PCO2 = chronic

causes of metabolic acidosis

Normal anion gap = caused by loss of bicarbonate or generation or ingestion of HCl → eg. diarrhoea

Increased anion gap = caused by generation or retention of organic or fixed acids → eg. lactic acidosis, ketoacidosis, chronic renal failure

signs of metabolic alkalosis

Increased PCO2 and high pH

Bicarbonate will be elevated

causes of metabolic alkalosis (4)

• Vomiting or loss of gastric acid

• Selected diuretics -> cause K+ depletion and water loss leading to sodium reabsorption and H+ secretion

• Ingestion of sodium bicarbonate

• Excess aldosterone -> excessive absorption of sodium leading to increased H+ secretion