Introduction to Renal Physiology (Excretory System)
Basic renal functions
Fluid balance
Electrolyte balance
Elimination of metabolic waste products
Components of the system
Urinary bladder and associated plumbing
Kidneys
Basic Anatomy of the Kidney
Notice that the only portal into the kidney is the renal artery, the
only portals out of it are the renal vein and the ureter. Therefore,
everything in the renal artery must wind up in the renal vein or the
ureter.
Basic anatomy of the nephron
Juxtamedullary (20%); Cortical (80%)
Renal Circulation
About 25% of cardiac output (about 1250 ml;/min) enters renal
artery. Nearly all of it gets into the glomerular capillaries.
The only blood supply to the renal medulla is the blood in the
peritubular capillaries of the juxtamedullary nephrons. That’s only
20% of all nephrons.
Therefore, cortex has a rich blood supply, medullary blood supply is
much smaller, and moves slowly.
Basic Renal Processes
Glomerular filtration (about 180 L/day = 45 gallons/day = 125
ml/min)
Secretion (into lumen of nephron)
Reabsorption (from lumen of nephron)
Normal urine production (about 1 L/day – 0.5% of filtrate!)
Glomerular filtrate is essentially protein-free plasma. Urine has
very different composition. This can’t be true unless various
solutes are reabsorbed from and secreted into the lumen of the
nephron
Glomerular Filtration
Forces affecting filtration
Hydrostatic pressure in glomerular capillaries (+55 mm Hg)
Colloid osmotic pressure of plasma (-30 mm Hg)
Hydrostatic pressure in lumen of Bowman’s capsule (-15 mm Hg)
Net driving force = +55 – 30 – 15 = 10 mm Hg
Why is hydrostatic pressure in glomeruli so high? Glomerular
capillaries empty into an arteriole, a resistance vessel
Hydrostatic pressure in glomerular capillaries can be varied by
varying sympathetic input to afferent arterioles (not much
sympathetic innervation to efferent arterioles).
Note that filtration can’t occur if glomerular pressure falls to 45 mm
Hg. This happens with arterial pressure below about 60 mm Hg.
No filtration = no urine = renal shutdown
Why doesn’t GFR change with arterial pressure?
1. Juxtaglomerular apparatus: Just outside entrance to Bowman’s
capsule, afferent arteriole, efferent arteriole and the macula densa
(distal convoluted tubule) all come together; collectively called the
juxtaglomerular apparatus. When pressure goes up in afferent
arteriole (increased arterial pressure), it presses harder against
macula densa. Macula densa then secretes a vasodilator onto the
efferent arteriole. This tends to keep glomerular pressure from
changing with arterial pressure.
2. Autoregulation: When PO2 goes up or PCO2 goes down, smooth
muscle constricts. When arterial pressure goes up, increased flow
through afferent arteriole causes local increase in PO2 and decrease
in PCO2. Smooth muscle in afferent arteriole constricts, tending to
keep pressure in glomerulus constant.
Reabsorption from lumen of the nephron
Since 180 L/day are filtered and 1 L/day is lost in urine, 179 L/day
(99.5%) must be reabsorbed
Only mechanism for getting water out of nephron and into
interstitial fluid is osmosis.
Therefore, if 99.5% of volume is reabsorbed, 99.5% of the solutes
must be reabsorbed.
There must be lots of active transport of solutes out of the
nephron.
Some generalities about reabsorption
Usually highly active for things that are “useful”. Glucose, for
example, is 100% reabsorbed. None enters the urine in healthy
people.
Usually nonexistent for things that are toxic
Since more than 99% of the fluid is reabsorbed, more than 99% of
the solutes must be reabsorbed. This can’t happen without active
transport
Sodium, a cation, is about 40% of the total solutes in plasma, so
another 40% has to be anions that maintain electrical neutrality
It’s mathematically impossible to reabsorb 99+% of the solutes
without reabsorbing at least 99% of the sodium
Sodium reabsorption occurs by active transport, driven by a
membrane ATPase in the basolateral membranes of the epithelial
cells of nephrons
Sodium is pumped out of the nephron’s epithelial cells and into the
interstitial fluid, is replaced by sodium diffusing out of the lumen
and into those cells. It diffuses from the interstitial fluid into the
peritubular capillaries. Net effect: sodium leaves the lumen of the
nephron, enters renal venules and leaves via renal vein
Active transport of other actively reabsorbed solutes (glucose,
amino acids, etc.) is linked to and dependent on active transport of
sodium
Of the sodium that is filtered, about 67% is reabsorbed in the
proximal convoluted tubule. Another 25% is reabsorbed in the loop
of Henle
Therefore, 8% of the filtered sodium gets as far as the distal
convoluted tubule. Most of that is reabsorbed.
The distal tubule is the only part of the nephron in which sodium
reabsorption is controlled (by the hormone, aldosterone). The
amount of sodium in the body (and, therefore, the volume of the
extracellular fluid) is regulated by varying the amount of sodium
reabsorbed in the distal convoluted tubule
Renal Reabsorption of Glucose
All the filtered glucose - 100% - is reabsorbed in the proximal
convoluted tubule.
You can’t possibly reabsorb 100% of anything without active
transport: at some point it must move uphill in concentration.
There are glucose carrier proteins involved in the active
reabsorption of glucose. They have a finite capacity – once all
glucose binding sites are occupied, they can’t bind more
Therefore, there is a maximum rate at which glucose can be
reabsorbed. It’s called the transport maximum (Tm). Tm for
glucose is around 400 mg/minute
Since Tm for glucose = 400 mg/minute, we can ask, “How much
glucose enters the lumen of the nephron per minute?” It must be
less than 400 mg, otherwise not all the glucose could be reabsorbed
The amount of any substance entering the lumen of the nephron per
minute is the tubular load. It’s the concentration of that substance
in plasma x the volume of plasma entering the lumen of the nephron
per minute (the GFR)
Plasma glucose concentration is around 1 mg/ml = 100 mg/100 ml =
100 mg% = 100 mg/dl = about 3 mM
GFR is around 125 ml/minute
Tubular load for glucose is, therefore, 125 ml/min x 100 mg/dl =
125 mg/minute. Since Tm for glucose = 400 mg/minute, the tubular
load is totally reabsorbed
What happens if plasma glucose levels rise?
Consuming a meal with lots of sugar in it causes a transient increase
in plasma glucose levels (typically to not more than 200 mg/dl after
a nice big piece of heavily frosted birthday cake). This increases the
tubular load for glucose to 125 ml/minute x 200 mg/dl = 250
mg/min. This is less than Tm, so all the glucose is reabsorbed in the
proximal tubule
Plasma glucose levels that go as high as 300 mg/dl (tubular load =
375 mg/minute) are still totally reabsorbed. But if plasma glucose
levels get much higher, Tm for glucose is exceeded and some glucose
enters the urine. For example, if plasma glucose concentration rises
to 500 mg/dl, tubular load for glucose becomes 625 mg/minute and
225 mg of glucose enters the urine per minute. That 325 grams (=
11 ounces; about ¾ pound!) per day.
What happens in diabetes?
There are two disorders called diabetes. One, the most common
endocrine disorder, is diabetes mellitus (diabetes = having a large
volume of urine; mellitus = honey-like; same root word as
mellifluous)
Diabetes mellitus patients have elevated plasma glucose levels.
When those levels exceed 300 mg/dl, not all glucose is
reabsorbed.
The glucose that enters the urine increases urine volume
osmotically. It’s been known for centuries that the urine
produced by most people who produce large volumes of urine is
sweet (attracts dog, flies, physicians)
Diabetes Insipidus
Diabetes insipidus (diabetes = having a large volume of urine;
insipidus = without flavor) is also an endocrine disorder. I’ll come
back to it later
Sodium Reabsorption and Water Reabsorption
Active reabsorption of sodium causes passive reabsorption of an
equal amount of anions, mostly chloride.
The reabsorption of sodium and chloride create the osmotic
gradients that cause nearly all of the reabsorption of water (about
180 liters/day) in the nephrons
Passive Reabsorption
Some substances are reabsorbed passively, but wind up much
more concentrated in urine than in plasma. Huh?
Water is reabsorbed osmotically, and diffuses across membranes
faster than any other water-soluble substance.
Water reabsorption creates concentration gradients
(concentration in tubular fluid > than that in plasma) for
everything that isn’t actively reabsorbed.
Substances that can cross the membranes of the nephron diffuse
out, down their concentration gradients. They can’t diffuse out as
fast as water, so their concentrations in the tubular fluid
increase. Urea diffuses at about half the rate that water does. Its
concentration in urine is about 50x its concentration in plasma
Tubular Secretion
A number of things are actively transported into the lumen of the
nephron (secreted)
Some important members of this group are H+, K+, and many
organic anions
The organic anions include detoxified foreign compounds, including
pharmaceuticals
Plasma Clearance
It’s usually easy to measure the rate at which something is excreted:
measure its concentration in urine and the rate of urine production.
The product = rate of excretion
It’s useful to ask how much plasma contains the amount of some
substance that appears in the urine per minute. That volume of
plasma is called the plasma clearance of that substance.
Plasma clearance = (Urine Conc’n x Urine Flow rate)/Plasma Conc’n
The more efficiently the kidneys remove a substance from plasma,
the higher the plasma clearance for that substance
Inulin Clearance and GFR
Inulin (NOT insulin) is a polysaccharide in artichokes, onions and
garlic. It is freely filtered in the glomerulus, so it enters the lumen
of the nephron at the same concentration it has in plasma
Inulin is neither reabsorbed (passively or actively), nor secreted into
the lumen of nephrons. Therefore, the amount of inulin in the urine
is the amount that entered the lumen of the nephron
The amount of inulin that entered the nephron per minute is the
plasma inulin concentration x the volume of plasma filtered per min
Hey! Wait a minute! Isn’t the volume of plasma filtered per minute
the GFR? Indeed, it is. So inulin clearance = GRF. That’s how GFR
was first measured.
There’s usually no inulin in plasma, but other ways of measuring
GFR have been worked out. The most common is to measure
creatinine clearance. Creatinine is a normal plasma constituent, is
freely filtered, very weakly reabsorbed and not secreted. Its
plasma clearance is a pretty good approximation of GFR.
P-Aminohippuric acid (= PAH) is a compound that’s freely filtered,
not reabsorbed, but actively secreted into the lumen of the
nephron so vigorously that nearly all is removed from plasma.
Therefore, PAH clearance = renal plasma flow. Since plasma is
about 50% of the volume of blood, knowing renal plasma flow
means we also know renal blood flow
The numbers that I have been casually tossing around (GFR = 125
ml/min; renal blood flow = 1200 ml/min; etc.) are all traced to
measuring inulin and PAH clearances. Note that the kidneys
receive about 20% of cardiac output
Long Term Regulation of Arterial Pressure
Renal Function Curve
Regulation of Urine Volume
You might recall that I said juxtamedullary nephrons have a special
function. Now I’ll tell you what it is.
In these nephrons, peritubular capillaries are long, straight vessels
that follow the loops of Henle into the full depth of the renal
medulla. They’re called vasa recta (= straight vessels).
Some important properties of the loop of Henle are:
1. Descending (thin) limb is highly permeable to water, doesn’t
pump sodium much.
2. Ascending (thick) limb has vigorous sodium pump, very low
water permeability.
Let’s do a little thought experiment. Pretend that all the fluids in
this system (tubular fluid, interstitial fluid, and plasma) are
equilibrated, none is moving, sodium pumps aren’t running
Therefore, osmolarity everywhere is the same, about 310 mOsm
Let’s start the fluid flowing in the lumen of the nephron and turn on
the sodium pump in the ascending limb of the loops of Henle.
The result? The interstitial fluid osmolarity around the loops of
Henle will go up. Result of that? Osmolarity in tubular fluid in
descending limbs will go up. Result of that? Sodium concentration
in next bit of fluid entering ascending limb will be higher than it
was. Result of that? Sodium pump in ascending limb will reabsorb
sodium faster.
Therefore, osmolarity of interstitial fluid will increase even more,
further increasing osmolarity in tubular fluid in descending limb,
further increasing rate of sodium reabsorption in ascending limb.
This is a positive feedback loop. If it continues indefinitely, all the
sodium on the planet will eventually be in the interstitial fluid in
someone’s kidneys.
Why doesn’t that happen? Because blood is flowing in the vasa
recta, and sodium (high interstitial fluid level) diffuses into it.
At some point, the rate at which sodium is lost by diffusion and the
rate at which it’s reabsorbed from the lumen become equal. At
that point, the system is stable.
The diffusion of sodium into the vasa recta, the pumping of sodium
from the lumen of the ascending limb of the loop of Henle, and
diffusion between the medullary and cortical interstitial spaces
results in a stable osmotic gradient in the renal medulla.
Near the cortex, where the high blood flow prevents it from
changing, all the fluids are about 310 mOsm
Deep in the medulla, the osmolarity is around 1200 mOsm
A stable gradient exists between those two extremes. So, as we go
deeper and deeper into the medulla, the osmolarity progressively
increases from 310 to 1200 mOsm
So what? Be patient, I’ll get to that.
Countercurrent Multiplication
The stable osmotic gradient in the renal medulla is only possible
because all of the following are true:
1. Descending limb of loop of Henle is highly permeable to salt and
water
2. Ascending limb of loop of Henle has highly active sodium pump
3. The two limbs of the loop of Henle are close to each other
4. Fluid flows in opposite directions in the two limbs
5. Blood flow in the vasa recta is sluggish
Interacting fluids flowing in opposite directions in parallel pipes is
called countercurrent flow. The mechanism by which an osmotic
gradient is created in the renal medulla is called the countercurrent
mechanism
So what?
Every collecting duct passes through the osmotic gradient created
by only 20% of the nephrons.
If collecting ducts are very permeable to water, they’ll lose about
75% of their volume and will become 1200 mOsm instead of 310
mOsm.
If collecting ducts are impermeable to water, the fluid leaving them
(urine) will have the same volume and osmolarity as the fluid that
entered them (about 310 mOsm).
Therefore, if there was a way to control collecting duct permeability
to water, we could control volume of fluid lost in urine (and, as an
incidental effect, the urine osmolarity)
Good news! There is a way to do it.
Antidiuretic Hormone
Remember the hypothalamus? It has osmoreceptors that monitor
the osmolarity of plasma.
When plasma osmolarity is above normal (during dehydration), the
osmoreceptors secrete a hormone, antidiuretic hormone (= ADH).
Antidiuresis = reduced urine production.
ADH increases collecting duct water permeability, thus, more water
reabsorption. Result is lower volume of more concentrated (darker)
urine. Low ADH levels let collecting ducts remain pretty
impermeable to water. Hence, larger volumes of urine, which is
more dilute.
This is the most important mechanism for regulating extracellular
fluid volume, which is how we regulate arterial pressure over the
long term.