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Flashcards in Six Deck (16):

Explain tubular transport maximum especially as it pertains to glucose? What is splay? What causes it?

Although the proximal tubule is remarkably adept at bulk transport
of solute and water, there is a maximum threshold or Tm,
above which, solutes will appear in the urine. For example, in
normal subjects the Tm for glucose is 375 mg/min. This is far
greater than the normal filtered load of glucose of 125 mg/min.

Interestingly, glucose can usually be detected in the urine
when the plasma glucose concentration is <300 mg/dL. Indeed,
glucosuria is common with plasma glucose concentrations
between 180-200 mg/dL. This deviation from predicted is
referred to as splay. Splay, is a phenomenon that occurs because
of Tm heterogeneity between nephrons. It is believed to reflect
a disproportionately high glomerular filtration rate compared to
proximal tubule reabsorptive capacity in some nephrons. Consequently,
at plasma glucose levels of 180-200 mg/dL, one can
begin to detect small amounts of glucose in the urine.


How is unidirectional, vectorial support accomplished? What differences are there between paracellular and transcellular support? What are the differences between the three parts of the proximal tube and what is the purpose of the differences?

The presence of unique proteins (ion channels and transporters)
in the apical versus the basolateral membrane confers
polarity and, thus, provides a mechanism for unidirectional
(vectorial) transport of solute and water. For example, sodium
transport generally occurs from the apical to basolateral side
of the epithelial cell. Fluid and solute movement may occur
through the cell interior (known as transcellular transport) or
between cells (known as paracellular transport). In general,
transcellular transport requires the expenditure of energy
while paracellular transport is usually a passive process.
The proximal tubule is divided into three segments, S1,
S2, and S3. S1 comprises the early convoluted segment (also
known as the pars convoluta), S2 consists of the late convoluted
segment and early straight segment (the straight portion
of the proximal tubule is known as the pars recta) and
S3 constitutes the remainder of the pars recta. Each of these
segments is endowed with distinct ultrastructural features
that are well suited to carry out their specialized tasks. For
example, the vast reabsorptive capacity of S1 is supported by
a prodigious energy supply (numerous basolateral infoldings
and mitochondria) and abundant surface area (numerous tall
apical microvilli). The tight junctions in S1 consist of different
transmembrane proteins (claudins/occludins) than the later
segments. For example, S3 possesses tight junction proteins that are more permeable to chloride and sodium, which may
facilitate their paracellular absorption. Moreover, the tight
junctions of S3 are highly impermeable to amino acids and
glucose, which minimizes paracellular back-leak of these solutes
(allowing for complete reabsorption of these solutes in
the proximal tubule). The axial heterogeneity of the proximal
tubule is logically designed; performing bulk transport in the
early segments and “fine-tuning” in the later segments.


Why is sodium potassium ATPase important in the PT? How does it accomplish its purpose? What other transporters rely on it?

The sodium/potassium-ATPase (Na/K-ATPase) is a ubiquitous
multi-subunit transport protein that maintains sodium and potassium gradients across all mammalian cells. It contains
a catalytic alpha subunit, beta subunit (which is involved
in insertion/localization of the protein), and an FXYD protein
that appears to regulate the activity of the transporter.
The kidney Na/K-ATPase provides the energy (directly or
indirectly) for the transport of virtually all of the solutes and
water reabsorbed in the proximal tubule (Fig. 6.2). The kidney
Na/K-ATPase is confined to the basolateral membrane
of the proximal tubular epithelial cell. Extrusion of sodium
from the proximal tubular basolateral cell membrane reduces
the intracellular sodium concentration (usually <10 mEq/L).
The low intracellular sodium concentration provides a favorable
chemical gradient for the movement of sodium from the
tubular lumen to the interior of the cell (facilitated by unique
ion channels and transport proteins). Continuous basolateral
sodium extrusion maintains the low intracellular sodium concentration.
Sodium uptake by the proximal tubular cell is
coupled to the reabsorption of several important filtered solutes
(this is an example of facilitated diffusion), including

• Glucose (via Na/glucose linked cotransporters, SGLT)
• Amino acids (via Na/amino acid linked cotransporters)
• Bicarbonate (via Na/H exchange, NHE)
• Phosphate (via Na/Pi cotransporters, NPT)


Aside from the sodium linked transporters, what other transporters are important to function in the PT?

• Glucose channels (GLUT)
• Water channels (aquaporins or AQPs)
• Organic Cation Transporter proteins (OCT)
• Organic Anion Transporter proteins (OAT)
• Kidney specific Chloride Channels (CLC-K)


Describe the transport of glucose in the PT?

Two carrier proteins are responsible for glucose transport in
the proximal tubule, SGLT-2 and SGLT-1 (Fig. 6.3) SGLT-2
is a high capacity, low affinity transporter that is expressed
mainly in the early proximal tubule. SGLT-1 is a low capacity,
high-affinity transporter that is expressed in the late proximal
tubule. This arrangement facilitates bulk transport of glucose in
the early proximal tubule, while decreasing the tubular glucose
concentration to very low levels in the late proximal tubule.
Intracellular glucose exits the cell down its concentration gradient
via specific glucose channels known as GLUT-2.


Describe amino acid transport in the PT? Describe cystinuria.

Sodium-coupled amino acid transport involves several transport
proteins with overlapping substrate specificities. In general,
three protein systems exist for amino acid transport in the
proximal tubule: (1) sodium/neutral amino acid transporters
(most amino acids in plasma are neutral), (2) sodium/dibasic
(anionic) amino acid transporters, and (3) sodium/dicarboxylic
(cationic) amino acid transporters (Fig. 6.4). There appear to be several members in each of these families and mutations
have been described in some. In addition, the sequential
arrangement of low-affinity and high-affinity transporters
(analogous to SGLT-2 and SGLT-1) is also present for the
amino acid transport system, thus maximizing recovery of
amino acid from the filtrate. The exit of amino acids through
the basolateral membrane involves a diverse (but ill-defined)
group of amino acid transport proteins.

Cystinuria is an autosomal dominant disorder characterized
by impaired transport of cystine (and other dibasic
amino acids). Several mutations of the dibasic/cystine
cotransporter (boAT, rBAT, see Fig. 6.4) have been the
described. These mutations may affect either subunit of a
large protein that belongs to the heteromeric amino acid
transport family (HATs). The presence of recurring cystine
stones is a hallmark of this clinical disorder.


Describe bicarbonate reabsorption.

Bicarbonate reclamation is an important function of the
proximal tubule and is essential for maintenance of acid-base homeostasis. Acid-base physiology will be described in detail
in chapter 13. Briefly, bicarbonate in the filtrate combines with
a hydrogen ion secreted via NHE-3 (Fig. 6.5). Hydrogen ion
combines with bicarbonate to produce carbonic acid (H2CO3),
which, is degraded to water and CO2 via carbonic anhydrase
IV. Carbonic anhydrase IV is located on the luminal brush
border membrane of the proximal tubule. Intracellular CO2
(either derived from plasma or via diffusion from the lumen)
is converted to bicarbonate via carbonic anhydrase II. Intracellular
bicarbonate is then transported to the peritubular capillary
via a sodium-bicarbonate cotransporter (NBC).


Describe phosphate transport in the PT. What modulates it? How? What are the clinical manifestations?

Sodium/phosphate-coupled cotransport is another important
function of the proximal tubule. Approximately 80% of the filtered
phosphate is reabsorbed in the proximal tubule primarily
through two NPT transporters (NPT2a and NPT2c) (Fig. 6.6).
While many factors appear to influence phosphate transport in
the proximal tubule, parathyroid hormone (PTH) plays a pivotal
role. An increase in PTH induces endocytosis of NPT2a
and increases phosphate excretion. Hypophosphatemia is a
common clinical disturbance in patients with increased PTH.
Considerable new evidence suggests that fibroblast growth
factor-23 (FGF-23) inhibits phosphate transport through alterations in the expression of NPT. The phosphaturic effect
of FGF-23 is believed to play a pivotal role in clinical diseases
characterized by hypophosphatemia (such as rickets).


Describe calcium and Mg reabsorption in the PT. How much is absorbed in the PT?

Kidney micropuncture studies suggest that 50% of the filtered
load of calcium and 30% of magnesium is reabsorbed in the
proximal tubule. Most of this occurs through paracellular
pathways in S2 and is believed to depend on concentration and
electrical gradients. The reabsorption of calcium and magnesium
tends to parallel sodium and water reabsorption. Specific
regulatory systems do not appear to participate in calcium or
magnesium transport in the proximal tubule.


Describe water reabsorption in the PT?

The presence of AQ-1 in the apical and basolateral membrane
of the proximal tubule permits the reabsorption of vast quantities
of filtered water (nearly 100 L are reabsorbed in the proximal
tubule). The driving force for water movement is derived
from small osmotic gradients established across the cell membrane
as a result of solute transport.


Describe chloride reabsorption in the PT? Where does it occur? What else occurs there?

The later segments of the proximal tubule primarily reabsorb
sodium, chloride, and water. Since the chloride concentration
is comparatively high, relative to plasma, a favorable chemical
gradient exists for chloride reabsorption. Chloride reabsorption
in the late proximal tubule generates a lumen positive
potential (+2 mV). This potential promotes paracellular
transport of sodium. In addition, active chloride reabsorption
in the late proximal tubule is accomplished via a chlorideanion
exchange system that utilizes formic acid (Fig. 6.7).
Formic acid is generated in the tubular lumen as filtered formate
combines with hydrogen ions (derived from NHE). Formic
acid then diffuses across the membrane into the
cell. The intracellular pH promotes the dissociation of formic
acid into a hydrogen ion and formate. The hydrogen ions are
then secreted via NHE, while formate is secreted via a
chloride/formate exchange protein. While most of the sodium
is extruded from the cell via the Na/K-ATPase, several exit
pathways for chloride exist. These include KCl cotransport
(KCC), CLC-K, and chloride/bicarbonate exchange. The
exact contribution of each of these pathways to chloride transport
remains incompletely understood. Figure 6.8 summarizes
the changes in concentration of the solutes and water along the
length of the proximal tubule.


Describe protein transport in the PT. What else is transported this way? What is the purpose of this?

A modest amount of filtered protein (perhaps as high as several
grams per day) is endocytosed by the proximal tubule
(Fig. 6.9). Most of the protein is metabolized to amino acids, which, in turn, are secreted into the peritubular blood and
returned to the systemic circulation. Megalin and cubulin are
large proteins localized to the apical membrane of the proximal
tubule and appear to be the principal endocytic receptor
proteins in these cells.
In addition to protein reabsorption, the endocytic pathway
also plays a pivotal role in vitamin D homeostasis. Filtered
vitamin D (bound to vitamin D binding protein) is endocytosed
by proximal tubular epithelial cells and converted to its
active metabolite, 1-25-dihydroxyvitamin D (calcitriol) via the
action of 1-alpha hydroxylase (an enzyme highly expressed in
the mitochondria of proximal tubular epithelial cells).


Generally, describe the secretion that occurs in the PT?

A vast array of organic cations (OC) and anions (OA) are
secreted by the proximal tubule. The only common feature of
these compounds is that they possess a charge at physiologic
pH (Table 6.2). Importantly, many drugs and toxins are eliminated
from the body via renal tubular secretion. These pathways
of detoxification represent an evolutionary adaptation to
allow the excretion of a variety of noxious compounds that mammals are exposed to, or generate, during intermediary
metabolism. These pathways are often involved in clinically
significant interactions between endogenous and exogenous
compounds. For example, the drug cimetidine inhibits the
renal secretion of creatinine.


Describe Organic cation secretion, specifically carnitine.

Organic cations are taken up by the cell at the basolateral membrane
via electrogenic facilitated diffusion (ie, inner membrane
negative potential) via a uniporter (OCT) (Fig. 6.10).
Organic cations are extruded into the filtrate via electroneutral
exchange for hydrogen ion (OC/H+ exchanger). NHE provides
the hydrogen ion for OC secretion. Therefore, the
Na/K-ATPase indirectly provides the energy for cation secretion.
Some OCs are actively reabsorbed, such as carnitine.
Mutations in an OC transport protein known as OCTN2 lead
to carnitine deficiency (which can produce muscle weakness
and congestive heart failure).


Describe organic anion secretion.

Organic anions are considerably more diverse than OCs. The
physiology and molecular biology of OA secretion is correspondingly
less well understood. Multiple families of transporters
have been described. One such transporter, NaDC1
(dicarboxylate sulphate transporter), is involved in the reabsorption
of citrate. NaDC1 is highly sensitive to pH; any condition
that acidifies the proximal tubular epithelial cell (metabolic
acidosis) increases reabsorption of citrate (therefore,
decreasing its urinary excretion). Hypocitraturia is an important
risk factor in the pathogenesis of kidney stone formation.


Describe the regulation of fluid reabsorption in the PT? What effect does filtration fraction have? Why? What effect does GFR have? Why?

These determinants
are analogous to the Starling forces that govern glomerular
filtration rate. The primary physical determinant favoring
water reabsorption in the proximal tubule is the peritubular
capillary oncotic pressure. The peritubular capillary oncotic
pressure is high because the ultrafiltrate is usually protein free,
which concentrates the protein in the efferent arteriole. Regulation
of fluid reabsorption can be affected via alterations in
peritubular capillary hemodynamics. For example, efferent
arteriolar vasoconstriction results in an increase in GFR coupled
with a decrease in renal plasma flow (i.e., increased filtration
fraction). Therefore, the plasma that enters the peritubular
capillary will have a high plasma protein concentration
(and oncotic pressure). This promotes net fluid reabsorption.
Conversely, a decrease in filtration fraction would decrease
efferent arteriolar protein concentration and reduce proximal
tubular water uptake.

It has long been known that changes in glomerular filtration
rate are balanced by equivalent changes in fluid reabsorption
in the proximal tubule (Fig. 6.11).

44 C l i n i c a l Imp l i c at i o n
If a fixed quantity of fluid is reabsorbed each day (178 L
of 180 L filtered) then an increase in GFR to 185 L should
result in the excretion of 7 L of urine. However, this is undesirable since urine losses of this magnitude could
produce life-threatening volume depletion. Hence, the
proximal tubule varies reabsorption to compensate for
changes in glomerular ultrafiltration. Specifically, the
proximal tubule reabsorbs a constant fraction, rather than
absolute volume, of the glomerular filtrate. In the example
above, an increase in glomerular filtration from 180 to
185 L/d only increases the urine output about 500 mL/d.

The mechanism of glomerulotubular balance is incompletely
understood. However, load dependence in the proximal
tubule is thought to participate. Thus, an increase in the
filtered load of glucose, amino acids, and bicarbonate promotes
a parallel increase in their sodium-coupled transport
(with water following passively).