Block 6 Renal Physio Dr Shams W Xpl

The presence of high urinary glucose, bicarbonate and phosphate suggest dysfunction of the
proximal tubule. This segment is responsible for reabsorption of all filtered glucose, 95% of
filtered phosphate and 80% of filtered bicarbonate.
Feedback when incorrect: You did not select the correct response. The presence of high urinary
glucose, bicarbonate and phosphate suggest dysfunction of the proximal tubule. This segment is
responsible for reabsorption of all filtered glucose, 95% of filtered phosphate and 80% of filtered
bicarbonate.

Most sodium (65 ‐ 70% of filtered load) reabsorption occurs in the proximal tubule. This
reabsorption is coupled to the reabsorption of filtered bicarbonate, glucose and amino acids in
the early proximal tubule and chloride in the later parts of the proximal tubule.
For further reading around tubular handling of Na+ see Vander's Renal Physiology

The clearance (volume of plasma cleared of a substance in a given time) is calculated by the
equation GFR = U X V / P, where U = urine concentration; V = urine flow (volume/unit time) and
P = plasma concentration. Clearance is usually expressed as mL/min, so his urine flow is
calculated as 100/2/60 = 0.8 mL/min; Once filtered, inulin is effectively inert, so it's clearance is
equal to the rate of filtration. His plasma inulin concentration was 0.05 mmol/L and his urine
inulin concentration was 6 mmol/L. This gives 6 X 0.8 / 0.05 = 96 mL/min ‐ the closest value to
100 mL/min.

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The water permeability of the nephron is relatively invariant except in the collecting duct. Only
in the collecting duct are there receptors (V2 subtype) for ADH (antidiuretic hormone) which are
coupled to adenylate cyclase ‐ sensitive membrane expression of aquaporin 2 (AQP2). Insertion
of AQP2 into the apical plasma membrane of principal cells allows equilibration of water with
the medullary interstitiium and therefore concentration of the tubular fluid. As cAMP is
degraded by intracellular phosphodiesterases, AQP2 is retrieved into the cell and the water
permeability falls. Water equilibration with the interstitium is reduced and the urine becomes
more dilute.
For further reading see Vander's Renal Physiology and/or Mollina's Endocrine Physiology

Most potassium reabsorption occurs in the proximal tubule, mostly in the late proximal tubule
and is driven by passive diffusion due to the small positive luminal potential difference (which is
positive), and solvent drag.
For further reading on renal handling of potassium see Vander's Renal Physiology

Constriction of the afferent arteriole increases vascular resistance and reduces blood flow. Flow
into the glomerular capillaries therefore decreases resulting in a reduction of capillary
hydrostatic pressure, and therefore reduced GFR. However since both GFR and RBF change
proportionately ‐ FF remains unchanged.

This patient is in acute renal failure brought about by the NSAID. Synthesis of renal
prostaglandins produces a vasodilatory effect on the afferent arterioles that counteract the
vasoconstrictor effects of angiotensin II. Inhibition of prostaglandin synthesis compromises the
ability of the afferent arteriole to dilate, inadequate vasodilation of the afferent arteriole results
in a reduction of glomerular capillary hydrostatic pressure, thus reducing GFR, which causes a
reduction in urine production and consequently raised serum levels of creatinine and BUN.
Constriction of the efferent arteriole would increase GFR not decrease it and inhibition of
synthesis would not dilate the efferent arteriole but constrict the efferent arteriole. The action
of prostaglandins is preferentially on the afferent arteriole. NSAIDs inhibit the production of
prostaglandins not stimulate it.
For more information on the role of prostaglandins in the kidney and NSAIDS and acute renal
failure See Current Diagnosis & Treatment: Nephrology & Hypertension

The majority of the filtered load of calcium is reabsorbed in the proximal tubule. Parathyroid
hormone inhibits calcium reabsorption in the proximal tubule, leading to increased delivery to
more distal nephron segments. These more distal segments then increase their reabsorption of
calcium via the glomerulotubular balance mechanism. Also, in contrast to its effects in the
proximal tubule, PTH stimulates calcium reabsorption in the distal tubule. This effect, combined
with the glomerular tubular balance mechanism reduces fractional excretion of calcium.

Na+ is absorbed out of the lumen in most parts of the nephron. In the proximal tubule, the
concentration remains the same as in plasma. Na+ concentration in the tubular fluid is reduced
throughout the distal nephron, because it is absorbed. But the lowest concentration is reached
in the papillary collecting duct due to amiloride ‐ sensitive absorption through ENaC.
For further reading around tubular handling of Na+ see Vander's Renal Physiology.

Around 50% of the filtered urea is reabsorbed in the proximal tubule by passive absorption. The
concentration of urea rises along the proximal tubule due to water absorption ‐ it is the
concentration gradient from lumen to plasma that provides the driving force for mostly
paracellular urea absorption in the proximal tubule which delivers fluid to the loop of Henle.
Medullary interstitial urea concentration is higher than in the lumen of the thin loops of Henle,
so urea is secreted into the lumen by facilitated diffusion ‐ (the thin loops express urea
transporters for this purpose) and the concentration in the tubular fluid rises further. From the
thick ascending limb onwards, the urea permeability of the distal tubule and cortical collecting
duct is close to zero. As water is reabsorbed in the collecting duct system, the concentration of
urea continues to rise and may become 40 ‐ 50 times that in plasma! In the inner medullary
collecting duct, urea is reabsorbed by facilitated diffusion driven by the high urea concentration
in the lumen. It is this process that provides the driving force for diffusion of urea into the loop
of Henle. In the presence of high circulating levels of ADH water absorption in the cortical and
outer medullary portions of the collecting duct is increased ‐ which further increases the luminal
concentration of urea. ADH also increases the urea permeability of the inner medullary
collecting duct ‐ allowing more urea to enter the inner medullary interstitium. This increases the
osmotic pressure of the interstitium and therefore the concentrating ability of the kidney as a
whole.
For further reading on the role of urea and its renal handling see Vander's Renal Physiology

An increased blood volume will increase the activity of both high and low pressure
baroreceptors, that brings about a decrease in sympathetic tone. Decreased activity of the renal
nerve supply to the kidney decreases arterial resistance and therefore GFR. Simultaneously,
reduced catecholamine release reduces proximal tubule reabsorption of sodium, chloride,
bicarbonate and water. This in combination with increased release of natriuretic peptides brings
about a rise in excretion of salt and water.

The major classes of diuretics act in the proximal tubule (carbonic anhydrase inhibitors); thick
ascending limb (loop diuretics); the distal tubule (thiazides) or collecting duct (potassium sparing
diuretics). They all reversibly inhibit sodium entry mechanisms ‐ specific to that particular
nephron segment.
The relative potency of different classes of diuretics depends on the quantity of filtered sodium
reabsorbed at a particular site as well as the capacity of more distal sites to deal with the
increased delivery of salt and water.
The proximal tubule absorbs as much as 67% of the filtered load of NaCl. The loop of Henle 30 ‐
35%; the distal tubule around 5% and the collecting duct about 4%.
Intuitively, since the proximal tubule is the site of the greatest sodium reabsorption, it might be
expected that inhibition of sodium bicarbonate ‐ dependent fluid absorption would be the most
potent. However, this is not the case. The reason for this is that the more distal segments
(particularly the loop of Henle, but also the distal tubule and collecting duct absorb more
sodium in response to increased flow. As a result of flow‐ dependent increased reabsorption in
these distal segments, the diuretic action of carbonic anhydrase inhibitors is relatively weak.
The most potent diuretics are those that inhibit salt transport from the loop of Henle, which
reabsorbs the second greatest fraction of the filtered load of Na and water. The ability of the
distal tubule and collecting duct to cope with the increased load resulting from loop inhibition is
limited since these segments have only limited sodium‐absorbing capacity. Inhibition of salt
transport in the thick ascending limb ‐ also leads to dissipation of the medullary concentration
gradient, vital to the urinary concentrating mechanism.

The major barrier to filtration of proteins resides partly in the basement membrane and the
space between the foot processes of podocytes.

Ca2+ ‐ions are absorbed in three regions of the nephron. The proximal tubule, the thick
ascending limb and the distal tubule. In the thick ascending limb, Ca2+ reabsorption is
dependent on the activity of NKCC2. The reason for this is that the coordinated activity of
NKCC2 with K+ secretion through ROMK channels and Cl‐ exit through the basolateral
membrane results in the generation of a lumen positive potential which is the driving force for
paracellular absorption of cations ‐ including Ca2+. NCCT is not expressed in the thick ascending
limb but in the distal tubule. Here, absorption occurs through Ca2+ channels. Absorption
through these channels is indirectly coupled to Na+ absorption and is stimulated by PTH, in
contrast to the proximal tubule where PTH inhibits Ca2+ reabsorption. PTH has no direct action
in the thick ascending limb.
Further information about calcium handling in the DCT is available in Vander's Renal Physiology

The highest amounts of potassium is absorbed in the proximal tubule ‐ but the concentration
remains essentially the same as that in plasma. The thick ascending limb of Henle's loop absorbs
potassium from the tubular fluid and the concentration falls to something like 2 mmol/L by the
time the fluid reaches the macula densa. The distal tubule and collecting duct both secrete
potassium and the concentration in the tubular fluid in these segments is higher than in plasma.
For further reading about tubular handling of K+ see Vander's renal Physiology

Renal blood flow (Q) like that of other vascular beds is determined by the change in pressure
and resistance (Q = ΔP.R). In the kidney resistance is provided by the afferent and efferent
arterioles. The resistance of both of the resistance vessels is modulated by a variety of
vasoactive substances. Dopamine and bradykinin are both vasodilator peptides. Dilation of the
afferent and efferent arterioles reduces R and therefore blood flow increases.
Stimulation of α ‐ adrenergic receptors in the afferent arteriole would constrict these vessels.
This constriction would increase R, and reduce blood flow not increase it. These receptors are
expressed in both the afferent and efferent arterioles, though the afferent arteriole has the
highest levels of expression. Similarly, stimulation of AT1 receptors in the afferent arteriole (as
well as in the efferent arteriole) would also cause constriction of both vessels and reduce blood
flow.
Increased activity of stretch activated Ca2+ channels (by whatever mechanism) causes an
increase in intracellular Ca2+ ions and a contraction of vascular smooth muscle. This contraction
would lead to vasoconstriction, an increase in R and a reduction in blood flow.
A brief description of the control of renal blood flow is available in Clinical Anesthesiology and
discussion of the renal effects of dopamine can be found in UpToDate

This patient's symptoms are consistent with her having an ADH‐secreting small cell carcinoma
leading to inappropriate ADH secretion (SIADH). This condition is most often seen with
neurologic disease, malignancy and after major surgery. The persistent secretion of ADH results
in a gradual reduction in plasma Na+ level. You should realize that the reduction in plasma Na+
depends on both the severity of the concentrating defect and the level of water intake.
Increased ADH does not cause hyponatremia in the absence of a source of water for intake. In
patients suffering from malignancy, reduced appetite may limit the amount of fluid intake and
their plasma Na+ may be in the normal range on initial presentation. Only when fluids are
administered does hyponatremia manifest itself.
ADH acts through V2 receptors in the renal collecting duct to promote cAMP ‐ dependent
insertion of Aquaporin 2 water channels into the apical membrane of principal cells. The
increased water permeability of the collecting duct promotes water absorption and excretion of
a concentrated urine. This retention of free water leads to hyponatremia and decreased plasma
osmolality without alterations in acid ‐ base status or changes in plasma potassium. Activation of
vascular V1 receptors activates the Gq ‐ protein signaling cascade causing contraction of
vascular smooth muscle and increased total peripheral resistance.
ACTH may also be secreted by small cell carcinomas but would produce symptoms more like
Cushing's syndrome (hypertension, weight gain, hyperglycemia, buffalo hump, etc) rather than
hyponatremia.
Release of ADH is associated with an increase not a decrease in the thirst mechanism.
More information on SIADH can be found here in "Quick Answers"
A useful summary and comparision of high and low ADH levels can be found in Greenspan's
Basic & Clinical Endocrinology

If GFR (from the clearance of inulin) is approximately 100 mL/min and he is producing 100/120 =
0.825 mL of urine, then 99.2 mL or 99.2% of the filtered water is reabsorbed.
Feedback when incorrect: You did not select the correct response. If GFR (from the clearance of
inulin) is approximately 100 mL/min and he is producing 100/120 = 0.825 mL of urine, then 99.2
mL or 99.2% of the filtered water is reabsorbed.

Ingesting 1L of isotonic saline increases the volume of the ECF which includes the plasma
volume. This results in an increase in plasma volume. The largest fraction of the plasma volume
is in the systemic veins, so increased venous pressure raises capillary hydrostatic pressure
including that in the peritubular capillaries. This dilution of the plasma proteins reduces the
concentration of plasma proteins, thereby decreasing oncotic pressure. These changes in
Starling's forces suppress proximal tubular fluid reabsorption and promote renal salt and water
excretion.

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Inhibition of Na+‐Cl‐ cotransport (by NCCT) by thiazide diuretics in the distal convoluted tubule
inhibits reabsorption of NaCl which is the basis of its diuretic effect, but also reduces the
reabsorption of Ca2+ . A reduction in intracellular Na+ increases the driving force for Ca2+ exit
across the basolateral membrane via a Na+/Ca2+ exchanger in distal tubule cells, thereby
increasing Ca2+ absorption into the blood.
Inhibition of carbonic anhydrase by drugs such as acetazolamide inhibits reabsorption of
bicarbonate, but this has little effect on calcium excretion.
Inhibition of salt transport through NKCC2 in the loop of Henle by compounds such as
Furosemide (Lasix®) also inhibits calcium reabsorption. This is because transcellular movement
of salt generates a lumen positive potential difference that drives the paracellular absorption of
cations. Reduction of this potential difference by loop diuretics leads to loss of divalent cations
in the urine, and this may lead to hypocalcemia (and hypomagnesemia).
Drugs such as Amiloride inhibit sodium reabsorption through ENaC, in the late distal tubule and
collecting duct system. This causes a reduction in excretion of potassium (hence the name
potassium‐sparing) but has little effect on calcium excretion. Likewise, mineralocorticoid
antagonists such as spironolactone act as potassium sparing diuretics because the activity of
ENaC is dependent on circulating levels of aldosterone.
For further reading around tubular transport mechanisms see Vander's renal physiology
For further reading about diuretics and their actions see Goodman & Gillman

Potassium secretion in the distal tubule and collecting duct is flow dependent. Inhibition of salt
transport in the thick ascending limb reduces medullary osmolarity and increases fluid delivery
to the distal tubule and collecting duct. This reduces luminal K+ concentration, thus increasing
the driving force for potassium secretion from Principal cells. The increased delivery of sodium
to these nephron segments stimulates sodium reabsorption which raises the driving force for
potassium secretion increasing potassium loss.
Inhibition of salt transport in by whatever mechanism decreases not increases secretion in the
thick ascending limb, since the function of the transporters and channels are functionally linked
through the respective ionic driving forces.
Because inhibition of salt transport in the thick ascending limb leads to a decrease in
extracellular fluid volume, proximal tubule reabsorption increases. Aldosterone and ADH levels
will also be increased. Aldosterone and ADH stimulate potassium secretion in the distal tubule
and collecting duct which exacerbates the potassium loss.

The calculation is straightforward. The solute load being 150 mosmol and the maximum
concentrating ability 600 mosmol/kg H2O. This solute output will require a minimum urine
volume of 150/600 = 0.25 kg H2O per 24 hour = 250 mL. This is about 50% of the daily water
intake of an infant of this age, so only modest reductions in fluid intake or increases in solute
excretion can lead to dehydration in infants.

Increased renal plasma flow (clearance of PAH) without a change in blood pressure indicates a
decrease in renal vascular resistance. Dilation of the efferent arteriole would increase
glomerular capillary outflow, thus reducing capillary hydrostatic pressure which causes GFR
(creatinine clearance) to decrease. A reduced GFR with an increase in plasma flow causes the fall
in filtration fraction, since FF=GFR/RPF.
• Dilatation of the afferent arteriole, would increase capillary hydrostatic pressure and
therefore GFR and RPF.
• Constriction of the afferent arteriole would reduce hydrostatic pressure, GFR and RPF.
• Constriction of the efferent arteriole would reduce plasma flow, but increase capillary
hydrostatic pressure and therefore GFR.

Increased salt intake leads to volume expansion of the extracellular fluid and resultant increased
stretch in the walls of the afferent arteriole (as well as other baroreceptors elsewhere in the
body). The baroreceptor function of the afferent arteriole results in decreased sympathetic
nerve activity which produces vasodilation of glomerular afferent arterioles. This increases
glomerular filtration rate by increasing glomerular capillary hydrostatic pressure. The proximal
tubule receives direct innervation from the sympathetic nerves, which normally stimulate Na+
reabsorption. The decreased sympathetic nerve activity resulting from the baroreceptor reflex
reduces reabsorption of NaCl and water by the proximal tubule.
ANP is release is increased (not decreased) by volume expansion due to the increased venous
return that occurs on volume expansion. However, ANP causes dilatation of the afferent
arteriole. Not constriction.
In the volume expanded state, delivery of NaCl and water to the macula densa is increased. Via
the tubuloglomerular feedback system, this results in suppression of renin release by the
juxtaglomerular apparatus and reduced circulating aldosterone.
Expansion of the plasma volume will dilute plasma proteins, so oncotic pressure will fall not
increase.
Further reading on the response to salt loading and the control of body fluid volume can be
found in Vander's Renal Physiology