Renal Flashcards
Cortex
Outer layer of kindey
Medulla
Inner layer of kidney
Divided into conical structures: renal pyramids
Renal pyramids
Part of medulla
Papilla at apex and filtrate enters into renal pelvis to ureter for storage
Renal artery
Supplies blood to kindly to be filtered
Branches quickly, and migrate between pyramidal structures
Arcuate artery
Branching arteries fuse at border of cortex and medulla
Branching off are afferent arterioles - capillary networks that act as filtration sites
Glomerular capillaries
Sites of filtration
Afferent arterioles
Branch into glomerular capillaries
Efferent arterioles
From glomerular capillaries, branch into another capillary network
Feeds peritubular network
Peritubular capillaries
If afferents/efferents are within cortex, bring O2 to cortex
Cortical/Superficial glomeruli
Close to surface of cortex, 85% of glomeruli
Efferent from these feel peritubular network
Juxtamedullary glomeruli
Border between medulla and cortex, 15% of glomeruli
Feed vasa recta which provides O2 to medulla
Nephron
Functional unit of kidney, most renal physiology associated with the nephron Each kidney contains more than a million Filtration part: glomerulus Tubule structure: single cell tube from glomerulus to papilla 4 functional parts: 1. Proximal tubule 2. Loop of Henle 3. Distal tubule 4. Collecting duct
Superficial/cortical nephron
Associated with surface glomeruli
Deep/Juxtamedullary nephron
Associated close to border
Long loops that extend deep into medulla, allow for concentration
First to be affected by bladder/kidney infection
Proximal tubule
Workhorse of kidney, bulk of transport occurs here
Loop of Henle
Receives fluid from proximal tubule
Long loop in deep nephron
Thin descending limb, descending into medulla, curves to thin ascending limb which merges into thick ascending limb
Fluid moves from loop to distal tubule
Distal tubule
Fluid empties to collecting duct
Collecting duct
Serves many nephrons, opens to renal papilla
Filtration
Moving from glomerular capillary to Bowman’s space to be secreted
Secretion
From lumen of interstitial environment into tubule to be secreted
Reabsorption
Opposite of secretion, urine compartment back to circulatory compartment
Bowman’s Capsule
Contains glomerulus, substances from from vascular compartment to urine compartment
Filtration barriers
- Fenestrated Capillary Endothelium
- Basement membrane
- Slit diaphragm
Fenestrated capillary endothelium
Glomerular capillary cells, big pores (80Å), large filtrations, does not allow cell components of blood to move across
If you see blood, barrier is damaged or bleeding is downstream
Does not allow large MW proteins
Basement membrane
Porous gel structure, things percolating through: smaller substances move more quickly and larger substances have a harder time
Negatively charged
Slit diaphragm
Pores smaller than basement membrane, covers space between protocyte foot processes
Protocyte cells
Cover basement membrane using cytoplasmic projections that have smaller foot processes
Spaces they do not cover is covered by slit diaphragm
Size and charge restriction of filtration barrier
Anything smaller than 10, 000 MW has easy clearance, anything larger than 100, 000MV cannot pass through layers of filtration, things of negative charge cannot pass though barriers negative charge
Albimum
Not present in urine, though is of small size
Carries negative charge
Physiological proteins are usually negatively charged and do not appear in urine - disease can take away negative charge and proteins end up in urine
Heparin Sulfate
Source of negative charge in basement membrane
Driving force of filtration
Hydrostatic pressure within glomerular capillary
Opposing force against filtration
Oncotic pressure within capillary and hydrostatic pressure within Bowman’s space oppose filtration
Pnet of filtration
Pnet = (PCG + PoncBS) - (PBS + PoncGC) Must be positive for filtration to occur BS: Bowman's Space GC: Glomerular capillary Efferent end has lower pressure than afferent end - same hydrostatic but oncotic pressure increase due to lack of filtration of some substances which causes increase concentration
Glomerular filtration rate
GFR = KfPnet
GFR = Kf(PGC - PBS - PoncGC)
Kf: ultrafiltration coefficient
Constricting afferent arteriole (filtration)
PGC goes down, filtration rate decreases
Constrict efferent arteriole (filtration)
PGC increases, filtration increases
Dilate efferent arteriole (filtration)
PGC goes down, filtration rate decreases
Dilate afferent arteriole (filtration)
PGC increases, filtration increases
Increasing renal blood flow (filtration)
Increase in filtration rate
Afferent arteriol dilation
Prostaglandins, kinins, dopamine, ANP, NO
Afferent arteriol constriction
Angio II (high dose), noradrenaline, endothelin, adenosine, vasopressin
Efferent arteriole constriction
Angio II (low dose)
Efferent arteriole dilation
Angio II blockade
Myogenic response to afferent arterioles (BP)
BP increase stretches smooth muscle of afferent arteriolar wall, causing stretch sensitive Ca2+ channels to open, causing Ca2+ influx and muscle contraction
Vasoconstriction minimizes increase in PGC
Decrease in BP reduces tonic level of afferent arteriolar smooth muscle contraction, vasodilation will sustain PGC
Tubularglomerular Feedback
Cells differentiate where distal tubule meets afferent arteriole: Juxtaglomerular Apparatus
Macula densa cells detect increased GFR and signal (paracrine) smooth muscle of afferent arteriole, which constricts to bring down GFR
Clearance of solute
Cx (ml/min) = ([U]V)/[P]
Urinary excretory rate of a substance is proportional to its plasma concentration
Inulin
Type of sugar, clinical use as creatine, freely filtered but does not interact with nephron
Can be used to measure renal clearance and GFR
GFR = Cx = ([U]V)/[P]
Creatine clearance can be used to determine stages of kidney disease
Cockcroft-Gault formula
Creatinine clearance = ([140 - age (years)] x weight (kg))/serum creatinine (micromole/L)
Multiply by 1.2 for men
Paracellular pathways
Reabsorption by bypassing cell, entering back into blood from lumen through tight junctions
Uses electrochemical gradients
Transcellular route
Material enters cell of tubule through apical membrane, then leaves through basolateral membrane
Two step, classified as active
1. Entering apical membrane, electrochemical gradient pulls Na in, transporters on membrane (symporters, aniporters and channels)
2. Must be active leaving cell, against concentration gradient and cell is negative, leaves basolateral membrane using Na/K-ATPase pump
Transcellular sodium reabsorption in early proximal tubule
Apical membrane transporters: Na/H exchanger and Na-solute cotransporters (20-25)
Until collecting duct, Na is linked to absorption or secretion of another molecule
Movement across basolateral membrane becomes coupled to HCO3, and Na/K-ATPase
Transcellular sodium reabsorption in mid proximal tubule
All necessary molecules are absorbed, so Na reabsorption becomes linked to chloride absorption
Basolateral membrane: Na/K-ATPase
Transcellular sodium reabsorption in late proximal tubule
Apical membrane transporters: Na/H and Cl/base
Basolateral membrane: Na/K-ATPase
Transcellular sodium reabsorption in the thick ascending limb
25% of Na reabsorption
Na/K/Cl triporter on apical membrane
Basolateral membrane: Na/K-ATPase
Transcellular sodium reabsorption in the early distal tubule
2-5% of Na reabsorption
NaCl cotransporter on apical membrane
All cells in early distal tubule use this transporter
Basolateral membrane: Na/K-ATPase
Transcellular sodium reabsorption in the late distal tubule
Sodium transport confined to principle cells: 75% of cells in this area
Absorption of Na not linked to anything else: epithelial sodium channel on apical membrane
Basolateral membrane: Na/K-ATPase
Collects rest of sodium so only 4% is left in urine
Antinatriuretic
Decreases in sodium excretion from kidneys
Natriuresis
Process of Na secretion by the kidneys
Promoted by ventricular and atrial natriuretic peptides and calcitonin (Na excreted)
Inhibited by chemicals such as aldosterone (Na conserved)
Angiotensin
Stimulates Na/H exchanger
Norepinephrine
Sympathetic stimulation, Na/H transporter and Na/K-ATPAase pump
More excretion into interstitial space, and therefore increase in transport into cell
Activates a2 receptor, which activates Gai protein: decrease in cAMP and PKC activity which stimulates Na/H exchanger
Activates a1 receptor, which activates Gaq protein which increase PLC to increase Ca and stimulate Na/K-ATPase
Gai protein
- Activated by a2 receptor
Activated by NE - Activated by AT1 receptor
Activated by AII
Decrease cAMP and PKC activity, which stimulates Na/H exchanger
Gaq protein
- Activated by a1 receptor
Activated by NE to activate PLC to increase Ca, which stimulates Na/K-ATPase
Aldosterone
Targets principle cells in late distal tubule and collecting duct to increase Na reabsorption
Steroid hormone that binds to mineralocorticoid receptor in cytoplasm, enters nucleus and stimulates transcription of channels to be put in membrane and Na/K-ATPases
Atrial Natriuretic Peptide (ANP)
Targets principle cells in late distal tubule to block ENaC causing an increase in Na and water excretion
Appears to be linked to cGMP levels, or allosteric modification, or cGMP ENaC binding (phosphorylating channel via cGMP-dependent PK)
Loop Diuretics
Target Loop of Henle Most effective diuretic Shuts down Na/K/Cl triporter: binds to where Cl would Na cannot be reabsorbed Causes drop in blood pressure
Thiazides
Target late distal tubule
Limits Na excretion
Cl site of channel
K-Sparing Diuretic
Least affective
Target Na Channel
Diuresis
Increase in urine output caused by excess substances in blood which need to be filtered
Water permeable parts of nephron
Proximal tubule and thin descending limb
Water impermeable parts of nephron
Ascending limb, distal tubule and collecting duct
Water absorption in proximal tubule
Sodium reabsorption drives water reabsorption
Na is absorbed from urine compartment, and osmolality decreases in tubular fluid
As Na is deposited in interstitial compartment, osmolality increases there
2/3 of filtered water is reabsorbed along with Na
Water absorption in descending limb
No Na reabsorption
Absorption of Na in ascending limb causes gradient for water reabsorption in descending limb
ADH function
Alters permeability characteristics of late distal tubule and collecting duct, making them water permeable and making urine less dilute
Very fast acting molecule
ADH and principle cells
Receptor for ADH in membrane, causes increase in cAMP which activated PKA
PKA phosphorylates water channels in vesicles just below apical membrane, which fuse with membrane and allow water into cell
Channels are turned off by phosphatase
Balance of potassium
Most of K is located inside cell (98%), plasma potassium is ~4.6mM, increases and decreases cause changes in heart functions such as arrhythmias
Kidneys are only organ that can filter K, cannot handle large amount of K after meals and therefore K is quickly absorbed into intracellular compartments
Triggered by insulin and epinephrine: Na/K-ATPase
Very gradually leaks out of cells into ECF to be handled by kidneys
K reabsorption in proximal tubule
Major site of K reabsorption
80%
K reabsorption in Loop of Henle
Second major site of K reabsorption
10%
Principle cell K secretion
Reverse movement, leaving blood: pumped back into cell with Na/K-ATPase, and sent back into lumen via passive K channels on apical membrane
K lost though urine
If kidneys stopped working, K would continue to exit cell until gradient was equal, flow of urine from kidneys maintains constant gradient for K to be excreted
Diuretics and K
Alter water flow, and therefore increase K excretion
Must be observed for arrhythmias
Some block K entry to cell, as Na reabsorption in blocked
Principle cation of ICF
K
Principle cation of ECF
Na
Changes in osmolarity
ECF changes rapidly, and ICF responds (equilibrium)
Osmotic concentration
OC = (# dissociated particles) x solute OC = nC
Osmotic gradient
OG = n(DELTA)C
Osmotic pressure
pi,
Ponc = RTnC
Isotonic
No changes in cell volume: no gradient between cell and external environment
Hypotonic
Osmotic gradient inside cell is much greater, water moved from outside to inside cell to try to equalize osmotic gradient
Most likely cell will rupture
Hypertonic
Cell shrinks
Concentration outside cell is much higher
Effective osmotic gradient
(sigma)n(DELTA)C
Effective osmotic pressure gradient
(DELTA)Pi
(sigma)RTn(DELTA)C
Sigma
Reflection coefficient
Isotonic infusion
Infusion into ECF, does not change osmolarity
Water infusion
ECF increases, dilution of ECF and osmolarity drops
Becomes hypotonic
Some water shifts into ICF: they will eventually become osmotically the same at the expense of cell swelling
Brain cells cannot deal with swelling
Water balance sheet
Losses of water from lungs, faces, sweat
Kidneys account for most of water lost: obligatory urine volume per day (500-600mL, less is kidney failure, and urine can enter plasma)
Maximum water released daily: 18-20L
Osmoreceptors
Specialized cells in hypothalamus
Connected to thirst centre in hypothalamus, drive us to consume fluids
Activated ADH centre to retain fluid
Supraoptic neurons
From osmoreceptors
Long axons into terminals in posterior pituitary to simulate release of ADH
Released into portal circulation circulation of pituitary into body circulation
Paraventricular neurons
From osmoreceptors
Long axons into terminals in posterior pituitary to simulate release of ADH
Released into portal circulation circulation of pituitary into body circulation
Normal plasma osmolality
~290
Less than 280 is osmotic threshold
Usually ADH circulating, prevents 18L of urine production each day
Baroreceptors
Hemodynamic control of ADH secretion
Pressure drop causes activation (loss of volume), override osmoreceptors to stimulate ADH and kidney now retains water
When pressure goes back to normal, baroreceptors band control back to osmoreceptors
Volume contraction
Causes steep osmotic response - extreme ADH release
Extra volume decreases ADH response
Diabetes insipidus
Central or nephrogenic
Ascending tubule, distal tubule and collecting duct water impermeable
Central diabetes insipidus
No ADH is produces
Nephrogenic diabetes insipidus
Kidney does not respond to ADH, principle cells may not have receptors (not phosphorylated or not translated)
Osmotic gradient for water movement
At end of Loop of Henle, the filtrate is very dilute
At distal tubule, gradient causes water to be reabsorbed from filtrate
Need hyper osmotic range in collecting duct in medulla: increase osmolarity of interstitial fluid to continue reabsorption go water
NaCl is deposited in interstitial compartment to increase gradient around collecting duct
Edema
Water retained in interstitial environment (with high concentrations of Na)
Swelling in different regions of the body (joints, pulmonary)
Prevented by kidney daily to regulate sodium excretion: reacting to receptors
Low blood pressure
Interaction of basal motor centre, sympathetic stimulation of kidney
Sodium absorption triggered by norepinephrine release and brings water volume back up
Renin-Angiotensin Aldosterone system
Sympathetic nerve stimulates (low blood pressure)
Production and release of renin from afferent arterial granular cells
Cleaves angiotensin to make angiotensin I
Angiotensin I
Angiotensin I moves though system to lungs and gets cleaved to angiotensin II by converting enzyme
Converting enzyme
Cleaves angiotensin I to angiotensin II in lungs
Angiotensin II
Kidney, heart and liver can make small amounts
Most powerful vasoconstrictor that body can produce
Increase blood pressure though vasoconstriction, increase in percussion pressure in organs
Stimulates area in brain that is important for thirst to trigger uptake
Targets proximal tubule and Na/H exchanger to stimulate increase Na absorption by proximal tubule
Stimulates release of aldosterone from adrenal target
Renin release
Stimulated by sympathetic nerve activity from systemic baroreceptors (blood pressure)
Stimulated by intrarenal baroreceptors (afferent arterial pressure)
Stimulated by macula densa (tubular flow)
Negative feedback from AII
ACE inhibitors
Prevent angiotensin II conversions
AT1 receptor blockers
Reduce affects of AII by reducing their binding
Feedback control in regulating effective circulating volume
Active when increase in volume
Stimulates release of ANP from myocytes in atria
Change in glomerular filtration rate: vasodilator and dilates afferent arteriole bringing more blood to capillary
Physiological pH
Normal shift between pH 7.38-7.42
7.40 = 40nM of H+
Very small amount of H ions involved in keeping concentration in this range
Mainly concerned with CO2 concentration
Carbonic anhydrase
Catalyzes formation of bicarbonate from hydration of CO2
Acidosis
Increased acidity of blood, caused by pulmonary problems, digestion of proteins to form amino acids
Fixed acids taken out by kidney
Fixed acid
Produced in the body from sources other than carbon dioxide, and is not excreted by the lungs
Sulfuric acid, lactic acid, ketoacids
Common GI disturbances affecting pH
Vomiting, diarrhea
Vomiting
Dramatic affect on pH
Lose stomach contents which contain H
Cells must produce H lost, so they generate bicarbonate
H is moved to stomach, bicarbonate it moved to interstitial compartment which causes alkalosis
Diarrhea
Loss of bicarbonate from lumen of intestine, H is pumped out of cells into interstitial compartment which causes acidosis
Buffers
Used to prevent large swings in pH
1. HCO3 in extracellular fluid
2. Proteins, hemoglobin, phosphates in cells
3. Phosphates, ammonia in urine
Should also release H in order to drop pH down
Best within linear range of titration curve: equal amounts of H acceptors and donors
Intracellular buffers
Proteins, ie. Hb binding to H to act as buffer
Plasma compartment buffers
HCO3
Bind H, and therefore have no affect on pH
Bicarbonate as a buffer
Major buffer pairing is bicarbonate and CO2
As long as you have a 20:1 ratio of HCO3:0.03PCO2 (Henderson Hassalbach equation), pH will always be 7.4
Regular bicarbonate levels is 24
Renal handling of bicarbonate
Most bicarbonate is reabsorbed by proximal tubule (80%)
No transporters to move bicarbonate over apical membrane: comes as H from Na/H transporter and CO2, H is secreted again and HCO3 is transport is coupled to Na over basolateral membrane
Distal nephron absorbs remaining 20% of bicarbonate
New bicarbonate
If H from bicarbonate formation in cell binds to another buffer
Acidotic kidney (>24h)
Generating more bicarbonate, occurs in proximal tubule
Glutamine is metabolized in proximal tube cell and bicarbonate is transported out of cell
NH4 is formed and is excreted though urine compartment: takes roll of H in Na/H exchanger
Respiratory acidosis
Increase in PCO2, regular amount of HCO3
Metabolic acidosis
Regular PCO2, decrease in HCO3
Respiratory alkalosis
Decrease in PCO2, regular HCO3
Metabolic alkalosis
Regular PCO2, increase in HCO3
Metabolic disturbances
Primary disturbances in HCO3
Respiratory disturbances
Primary disturbances in PCO2
Anion gap
Normal is 12
Na-Cl+HCO3
Compensation
Body maintains ratio of 20:1 bicarbonate:0.03PCO2
