The Kidneys and Regulation of Water and Inorganic Ions
Diuretics and Kidney Disease
Drugs used clinically to increase the volume of urine excreted
are known as
Most of these agents act on the tubules
to inhibit the reabsorption of sodium, along with chloride
and/or bicarbonate, resulting in increased excretion of these
ions. Because water reabsorption is dependent upon sodium
reabsorption, water reabsorption is also reduced, resulting in
increased water excretion.
A large variety of clinically useful diuretics are avail-
able and are classiﬁ ed according to the speciﬁ c mechanisms
by which they inhibit sodium reabsorption. For example,
such as furosemide, act on the ascending limb of
the loop of Henle to inhibit the transport protein that medi-
ates the ﬁ rst step in sodium reabsorption in this segment—
cotransport of sodium and chloride (and potassium) into the
cell across the luminal membrane.
Except for one category of diuretics, called
all diuretics not only increase sodium excre-
tion but also cause increased potassium excretion, which is
often an unwanted side effect. The potassium-sparing diuret-
ics inhibit sodium reabsorption in the cortical collecting duct,
and they simultaneously inhibit potassium secretion there.
Potassium-sparing diuretics either block the action of aldoste-
rone (e.g., spironolactone or eplerenone) or block the epithelial
sodium channel in the cortical collecting duct (e.g., triamterine
or amiloride). This explains why they do not cause increased
potassium excretion. Osmotic diuretics such as mannitol are
ﬁ ltered but not reabsorbed, thus retaining water in the urine.
This is the same reason that uncontrolled diabetes mellitus
and its associated glucosuria can cause excessive water loss and
dehydration (see Figure 16–12).
Diuretics are among the most commonly used medica-
tions. For one thing, they are used to treat diseases charac-
terized by renal retention of salt and water. As emphasized
earlier in this chapter, the regulation of blood pressure nor-
mally produces stability of total-body sodium mass and extra-
cellular volume because of the close correlation between these
variables. In contrast, in several types of disease, this correla-
tion is disrupted and the reﬂ
exes that maintain blood pressure
can cause renal retention of sodium. Sodium excretion may
decrease to almost nothing despite continued sodium inges-
tion, leading to abnormal expansion of the extracellular ﬂ
Diuretics are used to prevent or reverse this renal
retention of sodium and water.
The most common example of this phenomenon is
gestive heart failure
(Chapter 12). A person with a failing
heart manifests a decreased GFR and increased aldosterone
secretion, both of which contribute to the virtual absence of
sodium in the urine. The net result is extracellular volume
expansion and edema. The sodium-retaining responses are
triggered by the lower cardiac output (a result of cardiac fail-
ure) and the decrease in arterial blood pressure that results
directly from this decrease in cardiac output.
Another disease in which diuretics are often used is
hypertension (Chapter 12). The decrease in body sodium and
water resulting from the diuretic-induced excretion of these
substances brings about arteriolar dilation and a lowering of
the blood pressure. The precise mechanism by which decreased
body sodium causes arteriolar dilation is not known.
Many diseases affect the kidneys. Infections, allergies, con-
genital defects, kidney stones (accumulation of mineral depos-
its in nephron tubules), tumors, and toxic chemicals are some
possible sources of kidney damage. Obstruction of the urethra
or a ureter may cause injury from the buildup of pressure and
may predispose the kidneys to bacterial infection. A common
cause of renal failure is poorly controlled diabetes mellitus.
The increase in blood glucose interferes with normal renal ﬁ l-
tration and tubular function (Chapter 16).
One frequent sign of kidney disease is the appearance
of protein in the urine. In normal kidneys, there is a very
tiny amount of protein in the glomerular ﬁ ltrate because the
corpuscular membranes are not completely impermeable to
proteins, particularly those with lower molecular weights.
However, the cells of the proximal tubule completely remove
this ﬁ ltered protein from the tubular lumen, and no protein
appears in the ﬁ nal urine. In contrast, diseased renal cor-
puscles may become much more permeable to protein, and
diseased proximal tubules may lose their ability to remove ﬁ l-
tered protein from the tubular lumen. The result is that pro-
tein appears in the urine.
Although many diseases of the kidney are self-limited and
produce no permanent damage, others worsen if untreated.
The symptoms of profound renal malfunction are relatively
independent of the damaging agent and are collectively known
literally, “urine in the blood.”
The severity of uremia depends upon how well the
impaired kidneys can preserve the constancy of the internal
environment. Assuming that the person continues to ingest a
normal diet containing the usual quantities of nutrients and
electrolytes, what problems arise? The key fact to keep in mind
is that the kidney destruction markedly reduces the number of
functioning nephrons. Accordingly, the many substances, par-
ticularly potentially toxic waste products, that gain entry to
the tubule by ﬁ ltration build up in the blood. In addition, the
excretion of potassium is impaired because there are too few
nephrons capable of normal tubular secretion of this ion. The
person may also develop acidosis because the reduced number
of nephrons fail to add enough new bicarbonate to the blood
to compensate for the daily metabolic production of nonvola-
The remarkable fact is how large the safety factor is in
renal function. In general, the kidneys are still able to perform
their regulatory function quite well as long as 10 percent of
the nephrons are functioning. This is because these remaining