Formation of urine 1 Flashcards
5 major stages of urine formation
1: glomerulus: filtration of blood
2: proximal tubule: reabsorption of filtrate, secretion into tubule
3: loop of henle: concentration of urine
4: distal tubule: modification of urine
5: collecting duct: final modification of urine
Three major functions of the nephron
Filtration of blood to produce a filtrate
Reabsorption of water, ions and organic nutrients from filtrate
Secretion of waste products into tubular fluid
Basal renal processes: filtration
Force for filtration is:
- blood pressure
- differing diameter of afferent and efferent arterioles
Glomerular filtration rate
=125mL/min (180L/day)
Rate at which glomerular filtrate is produced
GFR can be measured clinically and used as an indicator of renal function
Ultrafiltration
Filtration on a molecular scale
Glomerular filtration
All small molecules are filtered
- electrolytes
- amino acids
- glucose
- metabolic waste
- some drugs, metabolites
Cells and large molecules remain in the blood
- red blood cells
- lipids
- proteins
- most drugs, metabolites
Pathway filtrate must go through
1: Pores in glomerular capillary epithelium
2: The basement membrane of Bowman’s capsule (includes contractile mesangial cells)
3: Epithelial cells of Bowman’s capsule (podocytes) via filtration slits into capsular space
Filtration pressure equation
(PGC)-(PBS+PiGC)
PGC
Pressure within glomerular capillary
Hydrostatic pressure=45mmHg
Plasma protein pressure
Osmotic pressure=25mmHg
PBC
Pressure within Bowman’s capsule
Hydrostatic pressure=10mmHg
Autoregulation of renal blood flow
Subject to autoregulation over broad range of systemic BPs (90-200mmHg)
Persists in denervated kidneys so it is not a neuronal or hormonal response but a local effect
Two hypothesis for autoregulation of renal blood flow
Myogenic- autoregulation is ue to response of renal arterioles to stretch
Metabolic- renal metabolites modulate vasodilation
Changes in GFR can also alter systemic blood pressure
- Drop in filtration pressure caused drop in GFR
- Lower GFR means less Na+ enters the proximal tubule
- The macula densa senses a change in tubular Na+ levels
- This stimulates juxtaglomerular cells to release renin into the blood
- Renin release leads to generation of angiotensin II
- Ang II is a vasoconstrictor which causes BP to increase
- Increased BP causes filtration pressure to increase and GFR returns to normal
Renin-angiotensin system
Homeostasis disturbed (decreased GFR)
Renin release
Angiotensin activation
Elevation of blood pressure and blood volume
Homeostasis restored (increased GFR)
Homeostasis
Reabsorption from the proximal tubule
Glomerular filtrate enters the proximal tubule where
- 60-70% filtered water, Na+, HCO3-, Cl-, K+ and urea are reabsorbed from PT
Almost complete reabsorption of
- glucose
- amino acids
- small amount of filtered proteins
Na+/K+/ATPase drives reabsorption
Na+/K+/ATPase pumps out Na+ from cells into blood against chemical and electrical gradients
Process requires energy in the form of adenosine triphosphate
Accompanied by entry of K+ ions which rapidly diffuses out of cell
Ratio of transport is 3 Na+ leaving cell: 2 K+ entering cell
Na+ reabsorption from the PT
PT cells have low intracellular Na+ concentration due to the action of the Na+/K+/ATPase
PT cells have overall negative charge due to the presence of intracellular proteins
Water reabsorption from the PT
60-70% filtered water reabsorbed in PT- active transport of Na+ out of PT is driving force
Movement of solutes reduces osmolality of tubular fluid and increases osmolality of interstitial fluid
Net flow of water from tubule lumen to lateral spaces occurs by transcellular and paracellular routes
Transcellular routes involve aqauporin channels on apical and basolateral surfaces
No active water reabsorption along nephron- occurs by osmosis and follows sodium
PT highly permeable to water
Aquaporin 1
Abundant distribution in proximal tubule
Wide distribution
Aquaporin 2
Present in collecting duct on apical surface
Expression controlled by ADH
Aquaporin 3 and 4
Present on basolateral surface of collecting duct cells
Glucose reabsorption from the PT
Glucose is co-transported into the PT cell with sodium
Glucose is co-transported into the PT cell with sodium very efficiently so very little is excreted
SGLT2 inhibitors
New drug for controlling type 2 diabetes?
Idea is to make diabetic patients excrete more glucose leading to an overall hypoglycaemic effect
Further reabsorption in the PT
Potassium
- 70% of filtered K+ reabsorbed in PT, mostly passively via tight junctions
Urea
- 40-50% filtered urea is reabsorbed passively in the PT down its concentration gradient
Amino acids
- 7 independent transport processes for reabsorption of AAs from the PT (depends on type of aa)
- high Tm for transport so that as much as possible is reabsorbed from PT
Proteins
- reabsorbed from the PT via receptor mediated endocytosis
Protein reabsorption from the PT
Small amounts of protein pass into filtrate via the glomerulus
They are reabsorbed by pinocytosis
Vesicles transported into cell, degraded by lysosomes and amino acids returned to blood
Only limited transport capacity
Proteinuria is a sign of glomerular damage and impending renal failure
Secretion into the PT
Some endogenous substances and drugs cannot be filtered at glomerulus (size or protein binding)
Specialised pumps in PT can transport compounds from the plasma into the nephron
Two kinds of pumps
- for organic acids
- for organic bases
OAT
Organic anion transporter
MRP
Multi-drug resistant protein
a-KG
a-ketoglutarate
Secretion of PAH into the PT
PAH secreted into PT from blood
Not an endogenous compound so can be used as a tool to measure tubular secretion
Transported into PT cells from blood with a-ketoglutarate or other di/tri carboxylases
Transported out of PT cells in exchange for another anion present in the PT lumen
PAH
Para-amino hippurate
Organic endogenous acids secreted into urine by the PT
cAMP
Bile salts
Hippurates
Oxalate
Prostaglandins
Urate
Organic acids drugs secreted into urine by the PT
Acetozolamide
Chlorothiazide
Furosemide
Penicillin
Probencid
Salicylate
Hydrochlorothiazide
Bumetanide
Some organic endogenous bases secreted into urine by the PT
Creatinine
Dopamine
Adrenaline
Noradrenaline
Histamine
Choline
Thiamine, guanidine
Some organic base drugs secreted into urine by the PT
Atropine
Isoproterenol
Cimetidine
Morphine
Quinine
Amiloride
Procainamide
