Para-cellular movement incorporatesThe transepithelial electrochemical Na gradient drives passive Na reabsorption in the proximal and thick ascending limb of the nephron. Not so for later nephron segments where the net (passive) force favors movement into the lumen. Na can also move passively in the proximal tubule (without active transport) via “solvent drag” where the movement of water (driven by active Na transport) sweeps additional Na and Cl along with it (a sort of mass-action) out of the lumen into the lateral intracellular space. The leakiness of the nephron (facillitating passive reabsorption) is greatest in the proximal, and decreases along the nephron to the papillary collecting ducts.Trans-cellular movement incorporates 1) passive entry from the lumen via the “apical” membrane into the cell down an electro-chemical gradient. The proximal, TAL and DCT use various co-transporters and exchangers, while in the collecting ducts Na enters via Na channels.2) Active extrusion of Na out the basal-lateral membrane via a Na-K+ pump which maintains intracellular Na low and K high. This exchange keeps the voltage at 70 mV (cell interior negative vsinterstitium, or lumen) depending on pump activity and the voltage gradient it creates.
Cations and anions
RENAL HANDLING OF ORGANIC
CATIONS & ORGANIC ANIONS
Transport of Sodium (Na+)
The filtered load of Na+ is the product of the glomerular filtration rate
(GFR, 180 liters/day) and the plasma Na+ concentration (142 mM), or
approximately 25,500 mM/day (equivalent to the Na+ in approximately
1.5 kg of table salt, more than nine times the total quantity of Na+
present in the body fluids.
With a typical Western diet consuming approximately 120 mM of Na+
per day, the kidneys reabsorb approximately 99.6% of the filtered Na+
by the time the tubule fluid reaches the renal pelvis.
The filtered load of Na is
25,500 mM/day, but the
intake is only 120
mM/day and the output
is 100 mM/day excreted
plus about 20 mM in the
feces and sweat.
Thus, the intake equals
output, so the body is in
filtered Na load
along the each
Yellow boxes are the
amount of filtered which is
Green boxes represent
the amount of filtered
which remains in each
portion of the nephron.
Transport of ions, and particularly of sodium from the lumen
to the blood across the tubular wall is through two
Transport is driven by two general mechanisms;
1) active transport in an energy (ATP) utilizing fashion
where ions are pumped against their electrochemical
gradient (“uphill”), and
2) passively down their electrochemical gradient
(“downhill”) along the gradients created by the active
Net pathway for sodium (Na) reabsorption from tubular lumen to capillary
Start here with
End here with
to a passive flow
There is a net driving
force due to the
active pump forcing
Na into the
interstitium, but a net
favoring the lumen to
draw Na back via
Sodium movement across the thin limbs (descending
and ascending limbs) of the loop of Henle
Virtually entirely passive down its electrochemical
gradient and paracellular.
Sodium movement across Thick Ascending Limb
(TAL) of the loop of Henle
Transcellular Na reabsorption includes
1) The Na/K/2Cl co-transporter (NKCC2) which couples inward
movement of these three ions in an electroneutral (2+ &2-) process
driven by the downhill gradient of Na and Cl into the cell. Much of
the K+ entering the cell is extruded via K channels down its own
2) The Na+-H+ exchanger exchanging sodium for hydrogen in an
Sodium movement across Distal Convoluted
Sodium reabsorption in the distal tubule is almost entriely due to
Electroneutral passive apical Na entry is due to an Na/Cl cotransporter
Unlike the NKCC2, this is independent of K+
The net movement of transcellular sodium in the DCT is driven by an
ATP-utilizing basal-lateral Na+-K+ pump
Sodium movement across Collecting Tubules:
The relatively modest Sodium reabsorption in the collecting tubules is
entirely transcellular via the “principal cells.”
Na enters the apical membrane via a “voltage-gated sodium channel” or
The basolateral movement of sodium out of the cell is driven by an
energy requiring Na-K pump which establishes the gradient driving apical
The movement of Na+ out of the lumen into the cell makes the lumen
negatively charged, and the movement of K out of the cell, primarily into
the basolateral interstitium makes the cell negative, for a net
transepithelial voltage of -40 mV.
The hormones aldosterone and vasopressin can change this site of
Sodium movement across Medullary Collecting
The inner and outer medulalry collecting ducts reabsorb only a small
amount of sodium (3% of filtered load) and this is probably via ENaC on
the apical membrane and the Na-K pump driving Na movement on the
basal lateral membrane.
Cl- transport and reabsorption:
Most Cl follows along with Na reabsorption, but the exact nature for the
movement is somewhat different.
In the Proximal tubule: Early proximal tubule Cl reabsorption is mostly
paracellular via solvent drag driven by the lumen negative potential.
However, in the late proximal it is reabsorbed by a predominantly by
transcellular pathway, driven by apical H+ exchange and active transport
with Na and a K cotransporter. The lumen becomes positive actually
retarding Cl reabsorption.
Thick ascending limb (TAL): Cl is primarly reabsorbed by the NaK2Cl
co-transsporteracross the apical membrane, and basal lateral Cl
channels along with active transport of sodium drive Cl into the
Distal Tubule: Apical Cl reabsorption occurs via a Na/Cl ccotransporter
and is driven by Cl following Na active extrusion via a Na/K pump.
Collecting ducts: The principal cell has an electrogenic pump that
creates a -40 mV lumen negative potential that drives Cl- out of the
lumen via paracellular routes.
However, the other cell type (the intercallated cell) drives transcellular Cl
movement powered by a basalateral H+ pump.
• Produced primarly in the liver as a bi-product of amino acid
• The MAIN pathway for the body to eliminate this “waste product” is
through the kidney.
• Urea is freely filtered by the kidney, then both secreted and
reabsorbed (overall, there is net reabsorption, so the clearance of urea
is 60% less than the GFR).
• Proximal tubule and medullary collecting duct are the main sites for
• The thin limbs of the loop of Henle are the primary sites for secretion.
Water leaves the proximal tubular lumen dragging urea, so
reabsorption is linked to flow. However, urea does not leave as
efficiently as sodium, so the luminal urea concentration rises, creating
a diffusion gradient out of the tubule.
In the loop of Henle, in the medullary interstitium, urea concentration
is high. The thin limbs of the loop have a urea transporter (UT2)
which secretes urea into the lumen via facillitated diffusion. Luminal
concentration rises to 110% of the filtered load by the end of the loop.
In the medullary collecting duct, urea is reabsorbed by apical and
basalateral facillitated transport (UT) due to the high luminal urea
concentration. This movement into the deep medulla helps keep
interstitial urea concentration high for the countercurrent system.
• Glucose in the blood is tightly regulated by insulin at 4-5 mM (70-100
• Glucose is freely filtered by the glomerulus, by 98% of the filtered
glucose is reabsorbed by the proximal tubule.
• Normally, virtually no glucose appears in the urine.
• Proximal glucose transport is active coupled to sodium transport via
sodium-glucose co-transporters (SGLT) on the apical membrane and
across the basalateral membrane by facillitated diffusion (via GLUT 1
• In the early proximal it is driven by a high capacity, low affinity
transporter (SGLT2), but later along the proximal by a low capacity, high
affinity transporter (SGLT1).
While glucose is normaly totally reabsorbed, if the plasma levels start to
increase, the filtered load will increase and it can surpass the ability of
the nephron to totally reabsorb it. This maximum level is referred to as
the “transport maximum (Tm).” It reflects a point where the SGLT
transporters are totally saturated, so any filtered glucose beyond that
maximal amount reabsorbed will begin appearing in the urine.
Coupled to the saturation of the transporters, the clearance of glucose
(which is normally zero) will begin to rise, reflecting a fraction of the total
filtered which now appears in the urine.
Glucose filtration (yellow), reabsorption
(red) and excretion (green) vary as the
transport maximum of the nephron is
reached at around 250 mg/dL.
Glucose clearance is normally 0, but
beyond the capacity of the nephron to
reabsorb, it starts increasing as a
percentage of the filtered load spills over
into the urine.
The body does not want to lose their nutrient substrate amino acids, so
while the kidney freely filters them, they are normally totally reabsorbed.
Apical amino acid transport is typically active by a sodium-dependent co-
transporter, though some amino acids are reabsorbed via Na-
independent facilitated diffusion.
On the basal lateral membrane most amino acids exit the cell by
In some cases, due to similar molecular structures, the amino acids may
exhibit competitive inhibition of transport.
Amino acid transport kinetics are similar to glucose, in that they exhibit a
transport maximum and may saturate if plasma levels are too high.
Reabsorption of other molecules by the kidney.
Oligopeptides: filtered oligopeptides are totally reabsorbed in the
Proteins: proteins (and protein fragments) are typically not filtered, but
those that are get reabsorbed by receptor-mediated
endocytosis, metabolized and taken back into the blood stream, so that
only trace amounts show up in the urine.
Carboxylates (pyruvate and lactate) are products of anaerobic glucose
matabolism and are sued as intermediates in the citric acid cycle. These
are totally conserved by reabsorption by the kidney
Organic anions and cations are metabolic products secreted by the late
Phosphate: Similar to calcium, 90% of filtered ionic free phosphate is
reabsorbed by the kidney, mostly in the proximal.
Calcium in the plasma:
The total concentration of calcium in plasma is normally 2.2 to 2.7 mM
Some 40% binds to plasma proteins, mainly albumin, and constitutes the
The filterable portion, approximately 60% of total plasma calcium, consists
of two moieties.
1) approximately 15% of the total, complexes with small anions such as
carbonate, citrate, phosphate, and sulfate.
2) approximately 45% of total calcium, is the ionized Ca2+ that one may
measure with Ca2+ -sensitive electrodes or dyes. It is the concentration
of this free, ionized calcium that the body tightly regulates; plasma [Ca2+
] normally is 1.0 to 1.3 mM (4.0-5.2 mg/dl).
The renal tubule has the ability to vary its reabsorption of filtered
calcium to adjust for changes in intake or increased calcium
requirements. Under normal conditions, <1% of filtered calcium is
excreted in the urine.
Calcium is reabsorbed throughout the nephron;
Most of the regulation of reabsorption occurs in the distal nephron.
In the thick ascending limb of the loop of Henle (TAL), calcium
reabsorption occurs through a primarily paracellular pathway, but
active, transcellular reabsorption may occur as well during stimulation
with parathyroid hormone (PTH).
Calcium reabsorption in the PROXIMAL TUBULE.
The proximal tubule reabsorbs approximately 65% of the filtered Ca2+, a
process that is not subject to hormonal control.
A small part of the Ca2+ reabsorbed by the proximal tubule (20% of the
65%) moves via a transcellular route.
Most proximal tubule Ca2+ reabsorption (80% of the 65%) occurs via the
Calcium Transport in the THICK ASCENDING LIMB.
The thick ascending limb (TAL) reabsorbs approximately 25% of the
Under normal conditions, about half of Ca2+ reabsorption in the TAL
occurs passively via a paracellular route, driven by the lumen-positive
Thus, it is not surprising that hormones such as AVP, which make the
transepithelial voltage more positive, indirectly increase Ca2+
The other half of Ca2+ reabsorption by the TAL occurs via the
transcellular pathway, which is stimulated by PTH .
CaSR on basal-lateral
surface may inhibit Ca
transport and NaKCl co-
Calcium enters the
passively, and most is
then extruded via active
transport out of the cell
into the basal lateral
Calcium in the DISTAL CONVOLUTED TUBULE.
This segment reabsorbs approximately 8% of the filtered Ca2+ load.
Despite the relatively small amount of Ca2+ delivered, the distal
convoluted tubule (DCT) is a major regulatory site for Ca2+ excretion. In
contrast to the proximal tubule and TAL, the DCT reabsorbs Ca2+
predominantly via an active, transcellular route.
The most important regulator of renal Ca2+ reabsorption is PTH, which
stimulates Ca2+ reabsorption in the thick ascending limb, the distal
convoluted tubule, and the connecting tubule.
(PTH does NOT have a proximal action)
PTH appears to increase the open probability of apical Ca2+ channels.
Such an increase in Ca2+ permeability would increase intracellular
[Ca2+]i, which in turn would stimulate basolateral Ca2+ extrusion
mechanisms, increase Ca2+ reabsorption, and raise plasma [Ca2+ ].
Calcium reabsorption in the Distal Convoluted Tubule (DCT)
Because only a small percentage of filtered calcium is excreted in the
urine (0.5%), and the DCT is the last major sight for reabsorption of
calcium, relatively small changes in the fraction reabsorbed in the DCT
result in large changes in the total amount of calcium lost in the urine.
Reabsorption in the DCT is regulated by PTH. When serum calcium
concentration decreases, PTH release from the parathyroid glands
increases. This effect is mediated by the calcium-sensing receptor
(CaSR) in the parathyroid gland.
PTH acts on the DCT to increase calcium reabsorption.
The distribution of potassium is very different from sodium, as it is the
most abundant intracellular cation, as 98% of the bodies K+ lies within
The circulating K+ is tightly regulated at a low 3.5-5.0 mM (compared to
145 mM for Na+).
K+ within cells is essential for maintaining cell volume, regulating
intracellular pH, controlling enzyme function, DNA, protein synthesis
and cell growth.
The ratio of intracellular to low extracellular K+ is critical in maintaining
the electrical potential across cell membrane (in both excitable and
The body must remain in “K+ balance,” such that intake equals output.
(about 80-120 mM K+/day; in and out).
Typically the kidney filters 800 mM/day, so the excretory load is about
10-15% of that filtered.
K+ handling and regulation by the kidney includes the ability both to
reabsorb and to secrete.
90% of filtered
K is reabsorbed
by the end of
the loop of
depends on the
5 distal nephron
Most (80%) of K+ reabsorption takes place in the Proximal tubule
Proximal reabsorption of 80% of the filtered load takes place by passive
paracellular movement via solvent drag and simple diffusion, driven by
the gradients established by active sodium reabsorption.
Potassium reabsorption in the proximal (because of its passive
paracellular nature) is highly dependent on fluid movement out of the
lumen, following sodium.
The basalateral Na-K pump does NOT directly affect K+ rabsorption
since the movement is mostly paracellular and not dependent on the
K+ reabsorption in the thick ascending limb accounts for an
unregulated additional 10% of the filtered load.
The thin limbs of the loop of Henle secrete K+ (passively) due to the
high K concentration in the medullary interstitium.
The TAL reabsorbs K+ by both paracellular and transcellular pathways,
Paracellular passive reabsorption is driven by both high K permeability
and the lumen positive voltage.
Transcellular reabsorption is driven by the NKCC2 co-transporter
moving sodium and K into the cell via the apical membrane, driven by
the active movement of Na (due to the basalateral Na-K pump) across
In the collecting ducts , the two cell types have different functions:
The principal cells secrete K+
Secretion requires a basalateral Na-K exchanger to let K enter the cell
against it gradient, and K channels on the apical side to allow K+ to flow
into the lumen, down its chemical gradient.
The intercalated cells reabsorb K+
Reabsorption requires an apical K+ pump to push K into the cell, and K
channels on the basalateral membrane to allow K to leave the cell down
its chemical gradient.