GUIDELINE 12 diuretik pada ckd.docx

8/14/2019 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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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.


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.
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