guideline 12 diuretik pada ckd.docx
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GUIDELINE 12: USE OF DIURETICS IN CKD
Diuretics are useful in the management of most patients with CKD. They reduce
ECF volume; lower blood pressure; potentiate the effects of ACE inhibitors,
ARBs, and other antihypertensive agents; and reduce the risk of CVD in CKD.
Choice of diuretic agents depends on the level of GFR and need for reduction in
ECF volume.
12.1 Most patients with CKD should be treated with a diuretic (A).
12.1.a Thiazide diuretics given once daily are recommended in patients with
GFR 30 mL/min/1.73 m2(CKD Stages 1-3) (A);
12.1.b Loop diuretics given once or twice daily are recommended in patients with
GFR
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BACKGROUND
Diuretics are generally necessary in CKD for control of extracellular fluid (ECF)
volume expansion and for their associated effects on blood pressure. Based on the
results of ALLHAT, JNC 7 recommends diuretics as preferred agents in the general
population with essential hypertension to lower blood pressure and reduce CVD
risk.
5,5a
Guidelines 8,9,10recommend diuretics in combination with ACE inhibitorsand ARBs in diabetic kidney disease and nondiabetic kidney disease with spot urine
total protein to creatinine ratio of 200 mg/g, as preferred agents in nondiabetic
kidney disease with spot urinetotal protein to creatinine ratio of
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RATIONALE: REVIEW OF PHYSIOLOGY AND PHARMACOLOGY
A thorough application of the determinants of diuretic response is a prerequisite for
the proper use of diuretics in CKD.
Sodium Retention in CKD
Sodium retention occurs when sodium intake exceeds sodium excretion and leads to
ECF volume expansion. ECF volume expansion is common in CKD and is an
important cause of hypertension (Table 146). In principle, the mechanism of
decreased sodium excretion in CKD is reduced glomerular filtration of sodium,
increased tubular reabsorption of sodium, or both. It is useful to think of two patterns
of altered pathophysiology:
Sodium retention due to decreased filtered load.In principle, ECF volume expansion
could lead to compensatory decrease in tubular reabsorption of sodium, re-
establishment of the steady-state of sodium balance, with resultant hypertension, butwithout other manifestations of ECF volume expansion. It appears that tubular
reabsorption is not truly appropriately suppressed. This is the most common pattern
observed in CKD.530 Large increases in ECF volume may arise if sodium intake is
very high or reduction in GFR is severe (for example, CKD Stage 4-5).
Sodium retention due to increased tubular reabsorption.Compensatory mechanisms
may not be adequate, leading to large increases in ECF volume expansion with
accompanying signs and symptoms. Conditions causing increased sodium
reabsorption include nephrotic syndrome, heart failure, or cirrhosis. Drugs may also
cause increased sodium reabsorption, including fludrocortisone (aldosterone), some
estrogen compounds, and nonsteroidal anti-inflammatory agents.531 Patients with
increased sodium reabsorption may not be in a steady state of sodium balance and are
said to have a "tendency for sodium retention."
Use of D iuretics as Antihypertensive Agents
Diuretics act primarily by decreasing tubular sodium reabsorption, thereby increasing
sodium excretion, reversing ECF volume expansion, and lowering blood pressure.
Similarly, diuretic therapy can facilitate the response to other antihypertensive agents
in CKD. Of course, reversal of ECF volume expansion depends on the balance of the
diuretic effect on sodium excretion and ongoing sodium intake. Failure of diuretictherapy to lower blood pressure and restore ECF volume may be caused by excessive
sodium intake or inadequate diuretic action.
Long-term therapy with thiazide diuretics may also reduce blood pressure by
mechanisms other than reducing ECF volume. As a corollary, a blood pressure
reduction with thiazide-type diuretics may occur even in the absence of a significant
diuresis.
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Fig 56. Determinants of diuretic response. Sodium excretion rate as a function of
tubular delivery of diuretic. "A" represents pharmacokinetic determinants of
diuretic response for an orally administered diuretic. The solid sigmoidal-shaped
dose-response curve has three components: threshold (diuretic delivery rate
sufficient to first produce a diuresis); efficiency (rate of delivery that produces anoptimal response for any amount of diuretic entering the urine); and maximal
response (urinary delivery of diuretic above which no additional diuretic
response can occur). "B" represents altered pharmacodynamic determinants in
"diuretic resistance," in which the normal simoidal-shaped curve is shifted
downwards and to the right. Diuretic delivery necessary to achieve a threshold
response can vary substantially in diuretic resistance.
Principles of Diuretic Action
Diuretic action is a coordinated process, which first relies on an adequate amount of
the drug having reached its site of action, the renal tubule (Fig 56). When a diuretic isgiven intravenously there is no concern about bioavailability; alternatively, when
administered orally, the rate and extent of absorption of a diuretic become important
considerations in the pattern of the diuretic response. Once present in the circulation,
a diuretic must gain entry into the renal tubule in a sufficient concentration to exceed
the threshold for response; thereafter, there exists an optimal rate of drug delivery
leading to and a rate of a maximal response (Fig 56, solid dose-response line).
Additional diuretic delivery does not produce a greater response.526,527The response is
also dictated by a variety of other factors, including the "braking phenomenon." The
braking phenomenon (postdiuretic sodium retention) describes avid sodium retention
that can develop in response to a rapid diuresis, thereby limiting response to further
doses of diuretics. The braking phenomenon may occur during either short-term or
long-term therapy and is due to hemodynamic and neurohumoral changes produced
by rapid diuresis. In CKD, the tubular secretory capacity for a diuretic is lowered,
often in parallel with the reduction in GFR. Thus, higher blood levels are required to
effect tubular delivery sufficient to prompt a diuresis.
Under normal circumstances, the aforementioned pattern of response is fairly
predictable. In CKD, two different response patterns emerge. In the absence of a
tendency to retain sodium, there is a normal sigmoidal-shaped dose-response
relationship (Fig 56,solid dose-response line). In the presence of a tendency to retain
sodium, the normal dose-response curve shifts rightward and downward, indicating astate of "diuretic resistance," in which a greater drug delivery rate is required to
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exceed the threshold for initiating a response, thereby attenuating the maximal
response (Fig 56,hatched dose-response line).534,535
The plasma half-life of a diuretic determines its frequency of administration. The
plasma half-life of loop diuretics is fairly short, with the exception of torsemide. This
is of clinical importance in that once a short-acting loop diuretic has beenadministered, its effect disappears fairly quickly and well before the next diuretic
dose, particularly if it is being given once daily. Shortly after the diuretic effect has
waned, sodium reabsorption is increased, which may be sufficient to completely
nullify the gain from the prior natriuresis. This rebound antinatriuretic effect (braking
phenomenon) attenuates the normal dose-response relationship and can last several
hours, thus limiting the efficacy of therapy. It can be overcome by administering
multiple daily doses of the diuretic.535,536
Potenti ation of E ff ects of Antihypertensive Agents by Diu retics
Diuretic therapy enhances the antihypertensive effect of most antihypertensive agents.The mechanism for this effect is that most antihypertensive agents stimulate renal
tubular sodium reabsorption, thereby increasing ECF volume and blunting the
antihypertensive effect. Diuretics interfere with sodium reabsorption, lower ECF
volume, and potentiate the antihypertensive effect of the antihypertensive agent.
At the same time, reducing ECF volume activates neurohumoral pathways, especially
the renin-angiotensin system, leading to vasoconstriction and increased systemic
vascular resistance, which blunts the antihypertensive effect of diuretics. The
combination of an ACE inhibitor or ARB with a diuretic is particularly effective in
lowering blood pressure264 (Fig 57). The incremental reduction in blood pressure
during combination therapy with either an ACE inhibitor or ARB and a diuretic is
related to the degree of diuresis and therefore may be more significant when a more
potent loop diuretic is being administered.
Fig 57. Rationale for combination of ARBs or ACE inhibitors with diuretics.
Schematic depiction of additive antihypertensive effects of the combination of a
diuretic and either an ACE inhibitor or an ARB. Volume loss produced by
diuretic therapy activates the renin-angiotensin system, blunting the decline in
blood pressure. Blockade by either ACE inhibitor or ARB increases theantihypertensive response.
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Classes of Diur etics
There are three major classes of diuretics: thiazide diuretics, loop diuretics, and
potassium-sparing diuretics (Table 147). Aldosterone antagonists act in the kidney as
potassium-sparing diuretics. Their diuretic actions are discussed in Guideline 12. In
addition, aldosterone antagonists act on mineralocorticoid receptors in the heart andblood vessels and at steroid receptors in other tissues. Their clinical effects are
discussed in Guideline 7. A brief description of the pharmacodynamics and
pharmacokinetics of each class is presented below.
Thiazide Diuretics
Thiazide diuretics act by inhibiting the apical Na+-Cl-cotransport system in the distal
tubule.
Absorption.The absorption of thiazide diuretics is compound-specific and related to
formulation characteristics. For example, certain formulations of metolazone are very
slowly and erratically absorbed, while others are very rapidly and completely
absorbed. Variation in absorption is less relevant when dosing has been ongoing for a
sufficiently long enough time to have established a steady-state blood level.
Distribution.Total protein binding for thiazide diuretics is typically very high with
differing values for the various compounds that make up this drug class. The Vdfor
thiazide diuretics is also compound-specific, with chlorthalidone and metolazone
having the largest Vd, in part, since these drugs both distribute fairly heavily into redblood cells. For example, the Vd for chlorthalidone has been reported to range
between 3 and 13 L/kg. Although the relevance of a large Vd remains to be
determined, it may prolong the duration of effect.
Metabolism.The thiazide diuretics are variably metabolized. Some thiazide diuretics,
such as bendroflumethiazide and indapamide, are primarily metabolized by the liver.
Others, such as hydrochlorothiazide and metolazone, are metabolized by the kidney.
The metabolism/excretion of thiazide diuretics has not routinely served as a
determinant of compound selection.
Excretion.Thiazide diuretics are delivered to their luminal site of action by organicanion transporters in the straight segment of the proximal tubule, which is a
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consequence of their extensive protein binding. The intrinsic secretory capacity at this
site ultimately determines the amount of drug delivered into the lumen of the
proximal tubule and subsequently carried to its site of action in the distal tubule.
Glomerular filtration plays an inconsequential role in thiazide diuretic entry into the
urinary space, because of the considerable protein binding. An assortment of factors
influence drug availability for tubular secretion, including tubular transport capacity(usually correlated to the level of GFR), the quantity of circulating drug availability
for secretion (which relates to the absolute bioavailability of the compound), systemic
hemodynamics, and the time course of drug delivery. Increasing the dose will provide
sufficient systemic drug concentrations to increase tubular delivery in amounts
necessary to produce a diuretic response.537
Loop Diur etics
Loop diuretics act by inhibiting the Na+-K+-2Cl-cotransporter in the thick ascending
limb of the loop of Henle.
Absorption.The bioavailability of loop diuretics is not affected by CKD. On average,
50% of an orally administered dose of furosemide is absorbed, but the range can be
from 10% to 100%.538This wide range makes it a matter of clinical judgement as to
how much furosemide will be absorbed in an individual patientparticularly in
patients with heart failureand large doses of furosemide may be required before the
drug is deemed ineffective. Intravenous administration can be used to bypass
decreased absorption. In contrast, absorption of the two other loop diuretics marketed
in the United States, bumetanide and torsemide, is nearly complete, ranging from 80%
to 100%.
Distribution.Total protein binding for furosemide ranges from 91% to 99%. Both
torsemide and bumetanide are also heavily protein-bound. Loop diuretics are
primarily bound to albumin, which is reduced in patients with uremia and the
nephrotic syndrome. Protein binding can be reduced by up to 10% in patients with
decreased GFR. The volume of distribution (Vd) is low for all loop diuretics and is in
the order of 0.2 to 0.5 L/kg, though the Vd can increase somewhat in patients with
nephrotic syndrome.
Metabolism. The loop diuretics are variably metabolized. Torsemide is
approximately 80% cleared by the liver, a process which involves the cytochrome P 450
system. Although active metabolites of torsemide are formed, they are not present insufficient amounts to influence the overall diuretic pattern. Bumetanide is
approximately 50% metabolized by the liver and its half-life does not appreciably
change in kidney failure. Approximately 50% of a dose of furosemide is excreted
unchanged; the remainder is conjugated to glucuronic acid in the kidney. Therefore, in
patients with kidney failure, the plasma half-life of furosemide is prolonged because
both urinary excretion and conjugation by the kidney are reduced. The liver is only
responsible for about 10% of the metabolism of furosemide.
Excretion.Like thiazide diuretics, loop diuretics are delivered to their luminal site of
action by organic anion transporters in the straight segment of the proximal tubule.
The intrinsic secretory capacity at this site determines the amount of drug that isconveyed into the proximal tubule lumen and subsequently carried to its site of action
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at the loop of Henle. Tubular delivery of loop diuretics is reduced in CKD, but the
relationship between the rate at which a loop diureticis excreted and the response in
CKD is similar to that in normal subjects. For example, in patients with a GFR of
approximately 15 mL/min, only 10% to 20% of the amount of most loop diuretics is
secreted into tubular fluid as in normal subjects.539
Potassium-Sparing Diuretics
There are two principal types of potassium-sparing diuretics, those that inhibit
epithelial sodium channels (triamterene and amiloride) and those that inhibit
mineralocorticoid receptors (aldosterone antagonists). For both types, the site of
action is in the collecting tubule.
Absorption.The absorption of potassium-sparing diuretics is quite variable and, to a
degree, formulation-dependent, particularly for triamterene. If a potassium-sparing
diuretic is administered as a component of a fixed-dose antihypertensive preparation,
its absorption may also be influenced by the compounding procedure for suchcombinations.540
Distribution.The total protein binding is low for amiloride and its Vdis in the order
of 5 to 7 L/kg. The total protein binding for triamterene and its active sulfate ester
metabolite are 60% to 70% and 90%, respectively. The total protein binding forspironolactone and its metabolites is about 90%.
Metabolism.Amiloride is predominantly cleared by the kidney and liver disease has
little effect on its pharmacokinetics. Triamterene is extensively metabolized to a
major hydroxytriamterene sulfate metabolite. Spironolactone is converted to several
metabolites with the active compounds 7-a-thiomethylspirolactone and canrenone
contributing a major portion of the activity profile of this compound.
Excretion. Amiloride undergoes significant excretion by the kidney, both by
glomerular filtration and tubular secretion by the organic cation secretory pathway.
The same pattern exists for triamterene and its active metabolite hydroxytriamterene
sulfate. Amiloride and the combination of triamterene and its active metabolite are
excreted in a limited fashion in the setting of kidney failure, which can substantially
modify their pattern of activity. Spironolactone is metabolized by the liver; CKD does
not influence its pharmacokinetic pattern in a meaningful way.
Resistance to Diur etics
Diuretic resistance reflects a failure to respond adequately to a diuretic regimen, due
to alterations in pharmacokinetic determinants of tubular delivery or
pharmacodynamic determinants of diuretic action in the tubular space.
Diuretic resistance in CKD may be due to an independent cause of increased tubular
reabsorption of sodium, such as nephrotic syndrome, heart failure, cirrhosis, or use of
non-steroidal anti-inflammatory agents. Apparent diuretic resistance in CKD may also
be due to a high dietary intake of sodium. Estimating diuretic response with a 24-hour
urine collection for determination of sodium excretion rate can assist in this diagnosis.A sodium excretion rate of >100 mmol/d suggests excessive dietary sodium intake.
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Diuretic tolerance represents a pharmacodynamic alteration involving one of two
processes: (1) a short-term process driven by ECF volume loss, wherein additional
diuretic response is curtailed by the braking phenomenon; (2) a longer-term process
where the continued exposure of the distal tubule to a high sodium load results in
distal tubular cell hypertrophy and an excessive "recapture" of sodium delivered from
more proximal locations. Distal tubular hypertrophy can be altered by combining athiazide-type diuretic with a loop diuretic.541
Several mechanisms may contribute to diuretic resistance in nephrotic syndrome,
including intratubular binding of loop diuretic by filtered albumin, decreased GFR,
excessive tubular reabsorption of sodium at site proximal to the loop of Henle, or a
disease state-related resistance to diuretic action at the cellular level. Treatment of
nephrotic syndrome may require high doses of loop diuretics, a combination of loop
and thiazide diuretics, or loop diuretics with albumin infusions.
Adverse Ef fects of Diuretics
Table 148shows adverse effects due to diuretics. Electrolyte abnormalities of diuretic
therapy are related to the duration and extent of diuresis. In patients without clinical
manifestations of ECF volume expansion, large-volume diuresis is associated with
ECF volume contraction, hypotension, and reduction in GFR, leading to symptoms
and limiting further response to diuretics. Treatment includes discontinuation of
diuretics and repletion with sodium chloride. In patients with ECF volume expansion,
large-volume diuresis may occur without ECF volume contraction, hypotension, or
reduced GFR, not causing symptoms and not limiting further diuretic response,
potentially causing profound losses of potassium, hydrogen ion, and magnesium.
Water retention may also occur, especially if water intake is excessive. The resulting
clinical picture includes hypokalemia, metabolic alkalosis, hypomagnesemia, and
hyponatremia. If ECF volume contraction ensues, the fall in GFR can reduce ongoing
electrolyte losses but rarely does it "correct" the abnormalities in serum electrolytes
that have already occurred. Treatment includes discontinuation of diuretics, repletion
of urinary losses, and water restriction as necessary.
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Dietary sodium intake is an important contributor to the adverse effects of diuretics. A
high intake may prevent ECF volume depletion, thereby increasing urinary losses of
potassium, magnesium, and calcium. Conversely, restriction of dietary intake of
sodium can curtail these losses, but increase the risk of ECF volume depletion.542
Hypokalemia and metabolic alkalosis can be prevented by administration of
potassium chloride or a potassium-sparing diuretic. Potassium chloride andpotassium-sparing diuretics should be administered with caution in patients with GFR
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incidence of hypokalemia. Chlorthalidone may be effective at a lower GFR than
HCTZ.
The basis for failure of thiazide diuretics to cause a diuresis at reduced GFR is their
insufficient potency at the doses administered. If blood pressure control worsens or if
volume expansion occurs as CKD progresses from Stages 1-3 to Stages 4-5 duringtreatment with a thiazide diuretic (either as monotherapy or as fixed-dose combination
antihypertensive therapy), a loop diuretic should be substituted for the thiazide
diuretic. However, if blood pressure remains controlled, and ECF volume expansion
is not apparent, it may not be necessary to switch to a loop diuretic.
Unlike other thiazide diuretics, metolazone retains effectiveness at GFR below 30
mL/min/1.73 m2at the doses recommended in Table 149.Metolazone is very poorly
absorbed and this should be taken into account when both a dose and frequency of
dosing are being determined. Metolazone (Zaroxylyn) can be started at a dose of 2.5
to 5.0 mg daily and titrated to 10 to 20 mg daily, though these higher doses are
seldom needed. Once metolazone has effected a diuresis, it can typically be dosed asinfrequently as two to three times a week because of its very long half-life .535
Loop diuretics can be used in al l stages of CKD (Strong). Loop diuretics are the
most commonly used diuretics in CKD. In CKD Stages 4-5, furosemide should be
started at a dose of 40 to 80 mg once daily with weekly titration upwards by 25% to
50% dependent upon the response and ECF volume. Once an effective dose has been
established, the frequency with which it needs to be administered can be determined
by specific clinical needs. In the absence of specific conditions causing increased
sodium reabsorption (nephrotic syndrome, heart failure, or cirrhosis), a brisk diuretic
response occurs in response to a loop diuretic with only nominal dose titration. The
maximal natriuretic response occurs with intravenous bolus doses of 160 to 200 mg of
furosemide, or the equivalent doses of bumetanide and torsemide, and little is
accomplished by using larger doses.544 In patients with specific conditions causing
increased sodium reabsorption, the response to a loop diuretic is attenuated in
relationship to the severity of the underlying disease, and substantially higher doses of
furosemide may be necessary to achieve a diuresis.
Loop diuretics are not as effective as thiazide diuretics in lowering blood pressure in
CKD Stages 1-3. In CKD Stages 4-5, loop diuretic therapy is a useful adjunct therapy
in the treatment of hypertension. Fixed-dose combination antihypertensive products
containing a loop diuretic are currently not available in the United States.
Potassium-sparing diu retics are associated with an increased ri sk of hyperkalemia
in CKD (Strong).Potassium-sparing diuretics must be used with caution in patients
with CKD because of the risk of hyperkalemia. The risk of hyperkalemia is especially
high in patients with GFR
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Recently, aldosterone antagonists have been shown to be effective for the treatment of
heart failure with systolic dysfunction. Patients with CKD Stages 1-3 were included in
these studies, but not CKD Stages 4-5. Low initial doses are recommended with
increases in dose frequency every 1 to 2 weeks. Maximal doses may not be possible
due to hyperkalemia.
The presence of hyporeninemic hypoaldosteronism should be considered as a
contraindication to the use of potassium-sparing diuretics. Fixed-dose combination
products containing potassium-sparing diuretics and thiazide-type diuretics are
available for most potassium-sparing agents. These have not been commonly used in
CKD Stages 4-5 CKD because of the attendant risk of hyperkalemia.
Long-acting diu retics and combinations of diuretics with other antihypertensive
agents should be used to i ncrease patient adherence (Moderately Strong).Patients
have been shown to have a higher rate of compliance with medications prescribed
once per day compared to medications prescribed more than once per day (see
Guideline 5). In addition, antihypertensive medications that have a half-life of greaterthan 24 hours are more likely to sustain a significant and sustained decrease in blood
pressure over a 24-hour period, compared to antihypertensive medications with a half-
life of less than 24 hours (seeGuideline 7).
After therapeutic goals are reached, it may be more convenient to prescribe a fixed-
dose, once-daily combination of antihypertensive agents.264A variety of combination
antihypertensive agents are available (Guideline 7,Table 103), which can be used to
simplify the patients antihypertensive regimen. In patients with blood pressure 20
mm Hg or more above their goal blood pressure, a fixed dose combination with a
diuretic is a good choice for initial therapy. For patients with a GFR >30 mL/min/1.73
m2, a preferred agent in combination with a thiazide diuretic may be an appropriate
choice.
RATIONALE: RECOMMENDATIONS FOR MONITORING FOR ADVERSEEFFECTS OF DIURETICS IN CKD
Principles
Table 150 shows the general principles that should be followed when initiating
treatment with diuretics. The most common complication of diuretics is ECF volume
depletion, which may lead to hypotension, a decrease in GFR, hypokalemia, and other
electrolyte abnormalities (Table 151).
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Summary of F requency of M onitori ng
At initiation and increase in dose of diuretics, the levels of blood pressure, GFR, and
serum potassium should be measured to establish a "baseline" or "new baseline." The
frequency of monitoring depends on these baseline levels (Tables 152 and 153).
(Note: Frequency of follow-up for control of elevated blood pressure is reviewed in
Guideline 7.)
Recommendations for Detection and Management of Volume Depletion
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Definitions
Loss of 15% to 20% of ECF volume (2 to 3 L [kg] in a 70-kg adult without edema) is
associated with symptoms and signs of volume depletion (Table 151). Smaller volume
losses sometimes may be associated with the same manifestations, especially if blood
pressure is low due to concomitant use of other antihypertensive agents.
Strength of Evidence
Hypotension and decreased GFR are complications of ECF volume contraction
(Strong). The exact incidence of these adverse effects during diuretic therapy is
poorly defined, since they are drug-specific and dose-dependent, and there is
variability among patients.546Hypotension and/or a transient and abrupt decrease in
GFR are more common when diuretics are first coadministered with either an ACE
inhibitor or an ARB, particularly those agents that are excreted by the kidney.547
Hypotension is also more frequent in patients with nephrotic syndrome, heart failure,
or cirrhosis treated with large doses of diuretics. Other causes of ECF volumedepletion in CKD are listed in Table 154.
These side-effects can be avoided by gradual titration of the dose and careful
monitoring following institution of combined diuretic and ACE inhibitor or ARB
therapy. Management consists of either decreasing the dose of the diuretic (and/or the
ACE inhibitor or ARB) or by temporarily discontinuing the diuretic. In addition,
transiently increasing dietary sodium intake will facilitate recovery. A more complete
discussion of the monitoring and treatment strategies for hypotension and/or a fall in
GFR in CKD patients is described inGuideline 11.The plan is relevant to diuretic-
treated patients in that the CKD patient rarely receives diuretic therapy without also
receiving either an ACE inhibitor or an ARB.
Recommendations for Detection and Management of Electrolyte Abnormalities
Definition
For the purposes of this guideline, hypokalemia is defined as serum potassium 5.0 mEq/L, metabolic alkalosis
is defined as a serum bicarbonate concentration greater than 30 mEq/L in patients
without a disorder of ventilation, and hypomagnesemia is defined as serum
magnesium
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Strength of Evidence
The most common side-effects with diuretics are distur bances in electrolyte balance
(Strong).Hypokalemia or hyperkalemia, metabolic alkalosis, hypomagnesemia, and
hypocalciuria or hypercalciuria (usually without changes in the serum calcium
concentration) can either individually or collectively occur during diuretic therapy inCKD. As discussed earlier, most diuretic-related electrolyte side-effects are related to
the dose of diuretics and the level of dietary sodium intake. In this regard, the higher
the diuretic dose (and thereby the greater the duration of action), the greater the
expected sodium excretion and losses of other electrolytes.548
Hypokalemia (Strong).A decline in serum potassium concentration is common with
loop and/or thiazide-type diuretic administration, particularly in the elderly and in
patients with clinical manifestations of ECF volume expansion. Hypokalemia with
diuretic therapy is less common in patients with decreased GFR. Limiting dietary
sodium intake can curtail urinary potassium losses and therein lessen the risk of
hypokalemia. The risk of hypokalemia can also be attenuated, albeit in an
unpredictable fashion, by coadministration of an ACE inhibitor or an ARB.549 Ingeneral, the risk of metabolic alkalosis as a consequence of diuretic therapy parallels
the occurrence of hypokalemia. Hypokalemia in CKD is usually multifactorial
(Tables 155and156).
Treatment of hypokalemia in CKD requires careful attention to treatment of the
underlying cause. When the underlying cause is diuretic therapy, which must be
continued, there are a variety of measures to raise serum potassium, including dietary
modification, use of oral potassium supplements, and drugs, including potassium-
sparing diuretics.
Foods rich in potassium are listed in Guideline 11, Table 140. Preparations of
potassium for oral supplementation are listed in Table 157. Potassium chloride
supplementation is required for patients with hypokalemia and metabolic alkalosis.
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Other preparations (alkalinizing salts) can be used in patients with hypokalemia
without metabolic alkalosis.
ACE inhibitors, ARBs, beta-adrenergic blockers, and potassium-sparing diuretics can
be used to raise the serum potassium. Potassium supplements and drugs to raise the
serum potassium concentration should be used with caution in CKD, because the risk
of "overcorrection" with the development of hyperkalemia is appreciably higher,
particularly in CKD Stages 3 and 4.550The frequency of follow-up is a function of the
magnitude of hypokalemia. This should generally be weekly or sooner until a stableserum potassium value has been reached, at which time the frequency with which
serum potassium is monitored can be decreased to monthly or bi-monthly to coincide
with routine visits.Table 158summarizes measures to raise serum potassium in CKD.
Hyperkalemia (Strong). Hyperkalemia can occur with potassium-sparing diuretics,
and its occurrence signals the need for reduction in dose or discontinuation of therapy
with a potassium-sparing agent.551Causes and management of hyperkalemia in CKD
are discussed in detail inGuideline 11.
Hypomagnesemia (Strong).
Total body magnesium deficiency is a common occurrence with loop diuretic therapy.
It is difficult to identify on the basis of change in serum magnesium values alone.Variation in local laboratory normal ranges for magnesium values may require local
adjustment of the serum magnesium value at which therapy is initiated. Urinary
magnesium losses parallel those of potassium in loop diuretic-treated CKD patients;
thus, deficiency in total body magnesium is likely in most diuretic-treated patients
with hypokalemia.552Magnesium deficiency increases tubular secretion of potassium
and may cause or worsen hypokalemia. Firm evidence does not exist in support of
total body magnesium deficiency contributing to complications of CKD other than
interference in the release and action of parathyroid hormone and, therefore, a greater
tendency to hypocalcemia. Alternatively, in the setting of CVD (for example, heart
failure and/or supraventricular and ventricular arrhythmias), which often coexists with
CKD, magnesium deficiency can precipitate arrhythmias, and correction orprevention of magnesium imbalance is imperative.553 A number of magnesium-
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containing salts and antacids are available for treatment (Table 159).553Treatment is
usually empirical and guided by changes in serum magnesium values. All potassium-
sparing diuretics are also magnesium-sparing.
Disorders of calcium excretion (Strong).Diuretics affect systemic calcium balance
by altering urine calcium excretion in a diverse fashion: thiazide-type drugs decrease
urine calcium excretion, which is one aspect of how they cause hypercalcemia; loop
diuretics increase urine calcium excretion and therefore cause hypocalcemia.554The
hypercalciuria seen with loop diuretics can accelerate the progression of secondaryhyperparathyroidism.555The maintenance of calcium-phosphate balance in the CKD
patient is complex (see K/DOQI Clinical Practice Guidelines for Bone Disease),291
and clinicians should consider the effect of concomitant treatment with diuretics.
Specific treatment measures that effectively decrease loop diuretic-related
hypercalciuria include reduction in the diuretic dose, lowering sodium intake, and
combining a loop diuretic with thiazide diuretics.
Recommendations for Management of Other Adverse Reactions
Definitions
Other adverse reactions discussed in this section include hyperuricemia and gout,
allergic reactions, and effects on the fetus.
Strength of Evidence
Hyperur icemia and gout (Strong). ECF volume contraction increases tubular uric
acid reabsorption, decreases uric acid excretion, and thereby raises the serum uric acid
concentration, which can trigger a gouty attack. This is more common with loop
diuretics than with thiazide diuretics though it can occur with the latter. Patients with
a history of gout who are beginning diuretic therapy should be counseled about the
risk of recurrent attack. Prophylactic therapy for gout, such as colchicine and/or
allopurinol, should be considered for patients with frequent attacks.556
Al lergic reactions (Moderately Strong).All diuretics with the exception of ethacrynic
acid are sulfa derivatives. Recently, it has been determined that sulfonamide
antibiotics and other sulfa derivates are not cross-reactive.557However, patients with a
history of allergy to sulfonamide antibiotics are at increased risk of allergic reactions
to other drugs and should be counseled appropriately. Sulfa allergies can range from
skin rashes to urticarial lesions to anaphylaxis, and can be immediate on first exposure
to a sulfa-drug or gradual in onset over days to weeks. Immediate sulfa allergic
responses and/or a prior history of Stevens-Johnson syndrome or toxic epidermalnecrolysis should remain contraindications to administration of a sulfa-containing
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diuretic. However, other allergic responses are not absolute contraindications to the
use of a sulfa-type diuretic. Thiazide and loop diuretics are also associated with
photosensitivity and bulbous eruptions. The occurrence of such lesions should
preclude the continued use of the offending agent.
Ef fects on the fetus (Weak).All diuretics with the exception of spironolactone arePregnancy Class B (animal studies do not indicate a risk to the fetus and there are no
controlled human studies, or animal studies do show an adverse effect on the fetus but
well-controlled studies in pregnant women have failed to demonstrate a risk to the
fetus). Spironolactone is Pregnancy Class C (studies have shown that the drug exerts
animal teratogenic or embryocidal effects, but there are no controlled studies in
women, or no studies are available in either animals or women). Spironolactone has
anti-androgenic effects, including incomplete virilization of the male fetus. Diuretics
should be used cautiously in pregnancy. Volume contraction and electrolyte
disturbances as may occur with diuretic therapy should be avoided since they may
adversely affect the fetus.558
SUMMARY
Table 160summarizes use of diuretics in CKD.
Limitations
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There is limited information from controlled trials to guide diuretic dosing for blood
pressure control. In addition, there are very limited data concerning the antiproteinuric
effects of diuretics and the combination of diuretics and ACE inhibitors or ARBs.
Moreover, the role of diuretic therapy in CKD progression when congestive heart
failure coexists needs to be better clarified.
IMPLEMENTATION ISSUES
Diuretics are frequently used in CKD. However, educational efforts are necessary to
enhance their use to achieve blood pressure control and to improve management of
complications.Table 160contains a summary of important information about the use
of diuretics in CKD.
The clinician will need to develop a suitable system to monitor blood pressure and
volume status if these are goals linked to the titration and/or the frequency of diuretic
dosing. Education of the patient in the basics of home blood pressure monitoring as
well as periodic measurement of body weight are important components of any suchmonitoring system. Instruction in dietary sodium restriction is an essential component
of a treatment plan with a diuretic.
RESEARCH RECOMMENDATIONS
Additional clinical studies are needed to determine whether differences exist amongst
the various loop diuretics in how each influences blood pressure independent of
volume loss. Moreover, additional studies are needed to determine if the blood
pressure-lowering response to a loop diuretic is better with ACE inhibitors or ARBs.
Future controlled trials will need to explore the relationship between CKD
progression and the electrolyte changes that accompany loop diuretic administration.
Studies should also be designed to evaluate the impact on calcium-phosphate balance
and the triggering of secondary hyperparathyroidism from the hypercalciuria
produced by loop diuretic treatment. Finally, more studies are needed with
combination loop and thiazide diuretic therapy to determine if this is a more effective
and/or safer approach than high-dose therapy with a loop diuretic alone and to
determine which is the best thiazide diuretic to combine with a loop diuretic.
http://www.kidney.org/professionals/kdoqi/guidelines_bp/guide_12.htm#table160http://www.kidney.org/professionals/kdoqi/guidelines_bp/guide_12.htm#table160http://www.kidney.org/professionals/kdoqi/guidelines_bp/guide_12.htm#table160http://www.kidney.org/professionals/kdoqi/guidelines_bp/guide_12.htm#table160
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