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Renal Physiology Overview
Jeffrey J. Kaufhold, MDDecember 2002
Lecture I
ANATOMY OF THE KIDNEY
CORTEX
MEDULLA
KIDNEYS, URETER, BLADDER
ANATOMY OF A NEPHRON
GLOMERULUS
CAPILLARY LOOP
BOWMAN’S CAPSULE/SPACE
TUBULES
PHYSIOLOGY
GLOMERULAR PHYSIOLOGY
GLOMERULAR BLOOD FLOW REGULATION
FILTRATION FRACTION
PROXIMAL TUBULE
LOOP OF HENLE
DISTAL TUBULE
COLLECTING TUBULE
TUBULE/MEDULLARY BLOOD FLOW REGULATION
COUNTERCURRENT MULTIPLIER
Lecture II
Neurohumoral control
HormonesADH
Renin-Angiotensin-Aldosterone
Effective Arterial Blood Volume
Fluid compartments
Electrolytes
Sodium
Potassium
Calcium and Phosphate
Acid - Base Balance
Endocrine Functions of the Kidney
Erythropoietin
Vitamin D
Renin
A. GLOMERULUS
The glomerulus is a bundle of capillaries that acts as a filter for the blood. The capillaries are leaky, so fluid (serum) is able to pass out of the capillary and collects in Bowman’s space. This fluid (called an Ultrafiltrate) normally has no proteins in it, but does carry anything else dissolved in it, including electrolytes and waste products that eventually will be eliminated by the kidneys. The ultra filtrate has to pass through the Glomerular Basement Membrane (GBM) on its way out of the capillary. The GBM limits the size of molecule that can pass by acting as a screen spread over the holes in the capillary lining (endothelial cell).
Filtration depends on surface area of glomerular capillary, thickness of GBM, and filtration pressure:
SNGFR = Kf x A x ( P(hydrostatic) - P(oncotic))
The amount of ultra filtrate produced is known as GFR, the Glomerular Filtration Rate. Hydrostatic pressure (or blood pressure within the capillary) is the main determinate of GFR, so lets look at the determinants of glomerular blood pressure:
Afferent arteriole regulates blood flow IN to glom.
Efferent arteriole regulates blood flow OUT of glom.
Mesangium holds the capillaries together, and can squeeze them down like a sponge.
Depending on the degree of constriction of each of these effectors, more or less fluid will be squeezed out of the glomerular capillaries, like a sponge. The pressure that builds up in the capillary is Glomerular Filtration Pressure, and the percentage of fluid squeezed out is called the Filtration Fraction.
Regulators:MediatorsEffect on arteriole
Systemic - angiotensin vasoconstriction of Aff and Eff. arterioles
- neural inputmostly constriction of both
some dilation
Local - Prostaglandinsmostly dilation of Aff.
- Nitrous OxideVasodilates both
Tubulogomerular Feedback -
A process where the tubules are able to sense the amount of urine flow through them. The net effect of TGF is vasoconstriction of afferent arteriole, mediated by adenosine.
B. PROXIMAL TUBULE
After the filtrate of plasma is produced in the glomerulus, 95% of the filtrate is normally reabsorbed in the proximal tubule. Filtration fraction will increase dramatically as a result of the affects of increased angiotensin. The increased filtration fraction results in delivery of blood to the efferent arteriole which is much more concentrated, with more proteins than normal, and the proximal tubule is bathed in this blood. Therefore there is an increased gradient between the ultra filtrate and the blood. The filtrate entering the proximal tubule is exposed to the greatly increased gradients and 99+% of the tubular fluid is reabsorbed passively. The proximal tubule also has transport proteins in its walls for reabsorbing the chemicals our body needs. If there is no transport protein for a substance or waste product, that substance is not reabsorbed and will be eliminated.
Diuretics alter this balance by inducing a state of intravascular volume depletion: although renal blood flow will be reduced in this state, angiotensin is stimulated and filtration fraction increases. Most diuretics do NOT produce a significant fall in GFR because the increase in filtration fraction overcomes the reduction in glomerular blood flow. Diuretics which have an effect in the proximal tubule block the reabsorption of filtrate, and this is how they increase urine output. However, most proximally acting diuretics are weak, due to the modification of the urine by the distal nephron.
Both of the classes of agents which work here do so by
inhibition of the lumenal carbonic anhydrase (CA) the CA
Inhibitors (Diamox) and Thiazides.
CA inhibition results in trapping of bicarbonate, and sodium, in the tubular fluid.
C. LOOP OF HENLE
1) THIN (DESCENDING) LIMB PHYSIOLOGY
The thin section of the loop of Henle is impermeable to solute on the descending limb, so water only is removed from the lumen as the urine is exposed to the ever increasing osmolarity of the renal medulla. The osmolality of the urine in the beginning of the loop of Henle is about the same as plasma (300 mOsm/Liter); by the time the urine reaches the tip of the Loop of Henle it will be 1200 mOsm/liter. On the way back up the thin Ascending limb, the loop of Henle is impermeable to WATER, so as solute is pumped out (see thick limb physiology, below) the osmolality drops from 1200 to about 50 mOsm/L.
2) THICK ASCENDING LIMB PHYSIOLOGY
Remember that this is the area of the "single effect", the
most metabolically active part of the nephron: the TAL is
responsible for generation of the medullary interstitial
hypertonicity necessary for maximal concentration of the
urine (1200 mOsm/L); by the same effect, it is responsible for net removal of sodium from the tubular fluid which results in very dilute fluid inside the tubule (50 mOsm/L) when it reaches the distal tubule.
Then, depending on the absence or presence of ADH, the urine can pass unmolested in its dilute form or have
water removed and become maximally concentrated all due to the action of the thick ascending limb.
The mechanism of the "single effect" is a pump which links the active pumping of sodium from the basolateral side of the tubule to removal of sodium and chloride from the lumen. This involves three distinct transport processes:
1) Na+/K+ ATPase at the basolateral (blood) membrane
2) NaK2CL CoTransporter protein on the lumenal side
3) K+ recycling from the cell back into the lumenal fluid
Pump #1 causes low intracellular [sodium]
Pump #2 links the passive influx of sodium from the lumen
into the cell to pull chloride and potassium into the cell
Channel #3 allows potassium to go down its gradient out of
the cell and back into the tubular fluid (which induces
the main area of lumen positive charge in the nephron)
Chloride moves passively in both directions:
half with the sodium at the basal membrane (to
maintain neutrality)
half back into the lumen due to the relative
positivity induced by the potassium channel.
Proofs:
- Pump #1 can be blocked by Ouabain, and pump #2 will stop
functioning.
- Substitution of different cations or anions will stop the
cycling of potassium by channel #3, and the normal relative lumen positivity will decrease.
Effect of “Loop” Diuretics:
Lasix and the other loop diuretics bind to the Cotransporter protein and by so doing :
a) block the maximal concentration of the urine (so medullary interstitium will be less hypertonic)
b) block the maximal DILUTION of urine by inhibiting removal of sodium from the tubular fluid;
c) neutralize the normal lumen positivity of the Thick
Ascending Limb.
How is the medullary interstitial gradient maintained?
By a very simple countercurrent exchange principle widely used in nature. The best example of how it works can be found in the wing of the penguin: Warm blood leaving the body passes through a series of arteries which are wound around veins returning cold blood from the wing. The warm arterial blood passes heat to the cold venous blood to minimize heat loss and rewarm the blood as it returns from the wing.
In the kidney, the same plexus of arteries and veins wraps around the tubules, especially the loop of Henle. Instead of heat, the blood and tissue exchange water and solute to keep the sodium and urea at a high concentration in the kidney tissue, and takes water out of this sensitive area.
D. DISTAL TUBULE
Tonicity of fluid is not affected in the distal tubule, but the relative concentrations of cations changes.
Specifically, this is the site of Na+/K+ exchange mediated by aldosterone which favors reabsorption of sodium.
Also the site of Na+/H+ exchange which can produce the
socalled "contraction alkalosis" induced by diuretics.
Finally the site of H+/K+ exchange, with which hypokalemia can induce or maintain a metabolic alkalosis.
The only diuretic which does not act in the lumen of the nephron is spironolactone, which exerts its effect in the cells of the distal tubule, where the receptors for Aldosterone are located. It gets there via renal blood flow independent of GFR.
E. Collecting Ducts
Area of action of ADH, AntiDiuretic Hormone.
ADH acts upon the connecting and collecting tubules (not the distal tubule) to increase permeability of the tubules to water; the presence of ADH leads to maximally concentrated urine because the water is sucked back up into the highly concentrated medulla.
In the presence of ADH, the collecting tubule is permeable to water and so water (and urea) are resorbed by osmosis.
In the absence of ADH, the collecting ducts are impermeable and maximally dilute urine passes unmolested. The collecting ducts come together and form the renal papilla, then drain into the renal pelvis. The urine drains out of the renal pelvis into the ureter, and is taken to the bladder to await final elimination.
REFERENCES
TEXTBOOKS
1. Goodman LS., and Gilman A. The Pharmacologic basis of Therapeutics, Macmillan Publishing Co., NY, 1980.
2. Schrier RW, and Gottschalk CW. Diseases of The Kidney, Little, Brown and Co., Boston, 1988.
REVIEW ARTICLES
CLINICAL
3. Levine, SD. Diuretics, Medical Clinics of NA, Vol 73, No. 2, Mar 89: p271281.
4. Brater, DC. Use of Diuretics in Chronic Renal insufficiency and Nephrotic Syndrome, Seminars in Nephrology Vol 8, No 4 (DEC), 1988: p333341.
5. Daniels BS and Ferris TF. The Use of Diuretics in Nonedematous disorders, Sem Neph Vol8, No 4 (DEC), 1988: p342353.
6. Hura CE, Kunau RT, Stein JH. Use of Diuetics in Saltretaining States, Sem Neph Vol 8, No 4 (DEC), 1988: p 318332.
PHYSIOLOGY
7. Culpepper, RM. NaK2Cl Cotransport in the Thick Ascending Limb of Henle, Hosp. Prac. June 15, 1989: p217242.
8. Brennan, S. and Suki, WN. Methods for Study of the Effects of Diuretics, Sem. Neph. Vol 8, No 3 (SEPT) 1988: p213224.
9. DuBose, T. and Good, DW. Effects of Diuretics on Renal AcidBase Transport, Sem. Neph. Vol 8, No 3 (SEPT) 1988: p282294.
10. Friedman, Peter A. Biochemistry and Pharmacology of Diuretics, Sem Neph. Vol 8, No 3 (SEPT) 1988: p 198212.
11. Velazqueq, H. and Giebisch G. Effect of Diuretics on Specific Transport Systems: Potassium, Sem. Neph. Vol 8, No 3 (SEPT) 1988: p 295304.