C H A P T E R
56
Use of Diuretics in Chronic Kidney
Disease Patients
Arthur Greenberg
Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
INTRODUCTION
The natriuretic diuretics interfere with renal tubular
reabsorption of sodium, leading to loss of sodium and
other solutes. This effect is beneficial in circumstances
characterized by sodium accumulation with an attendant
increase in total body sodium and extracellular volume.
CKD is one such state, and diuretics are an important
therapeutic tool in CKD for treatment of volume over-
load, edema and hypertension.
The delivery of diuretics to the sites at which they
work and their pharmacodynamics and pharmacoki-
netics, relative potency, and clinical effects and utility
are markedly affected by changes in renal function. A
detailed understanding of the mechanism of action of
diuretics is necessary in order to anticipate the changes
in their activity in CKD and employ them effectively.1,2
Most of this discussion focuses on the potent loop
diuretics, which are the mainstay of therapy for patients
with reduced renal function.
SITE AND MECHANISM OF ACTION
OF DIURETICS
Diuretics act from the luminal side of the renal tubule
by binding to a solute transporter, or in the case of the
carbonic anhydrase inhibitors, an enzyme that indirectly
promotes sodium reabsorption. Exceptions to this rule
are the aldosterone receptor antagonists, which reach the
nuclear aldosterone receptor from the basolateral side
of collecting duct cells. Glomerular filtration of diuret-
ics is negligible because they are highly protein bound.
Acetazolamide, the loop agents, and the thiazides are
weak organic anions that are secreted into the proximal
tubular lumen via the organic acid secretory pathway in
P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease.
DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00056-1
the proximal tubule. Weak acids, amiloride and triam-
terene are secreted via the organic base pathway.1 Once
they reach the proximal tubular lumen, diuretics move
downstream in the glomerular filtrate to their specific
site of action. Upon binding to their receptors, diuretics
block transport of sodium and accompanying anions or
cations at that site (Table 56.1).
Diuretics vary in potency, which depends on the frac-
tion of filtered sodium reabsorbed at the site where the
diuretic inhibits transport, sodium delivery to the inhib-
ited site, and the potential for sodium reabsorption dis-
tal to the site. For example, the proximal tubule diuretics
have limited ability to increase overall renal sodium
excretion. Although treatment with acetazolamide may
cause an increase of up to 8% in sodium delivered out
of the proximal tubule, distal segments of the nephron,
including especially the loop of Henle and the distal con-
voluted tubule, can easily reabsorb the increased sodium
load with which they are presented. Little net increase
in sodium excretion results. In contrast, the loop agents
block the Na-K-2Cl (NKCC2) transporter responsible for
reabsorption of up to 20% of the filtered sodium load, an
amount that cannot ordinarily be reabsorbed distally in
its entirety. The operative word here is ordinarily.
PHARMACOKINETICS
The pharmacokinetics of diuretics in health and vari-
ous disease states have been extensively reviewed.3,4
The pharmacokinetics of the loop agents in patients with
normal renal function and in individuals with reduced
GFR are shown in Tables 56.2 and 56.3.58 The bioavail-
ability of orally administered furosemide is approxi-
mately 50%, compared to 80% for bumetanide and
torsemide. However, the reported values vary widely.3
682 2015 Elsevier Inc. All rights reserved.
2012
 Pharmacokinetics 683
TABLE 56.1Sites of Action of Diuretic Drugs

Maximal
Drug Class Agents Site of Action FE Na Transport Site Other

carbonic anhydrase acetazolamide proximal 58% Carbonic anhydrase, lumen

inhibitors tubule and proximal tubular cell

}
loop agents furosemide thick ascending 1520% NKCC2
limb loop of
bumetanide Na-K-2Cl co-transporter
Henle
torsemide

}
thiazides hydrochlorothiazide distal 1015% NCCT
convoluted
chlorthalidone NaCl co-transporter
tubule
chlorothiazide
numerous others
ENaC blockers amiloride
triamterene
collecting duct 35%
} ENaC
epithelial sodium channel
aldosterone
antagonists
spironolactone
eplerenone
collecting duct 35%
} ENaC
epithelial sodium channel
Also block effect of
aldosterone to stimulate
basolateral Na/K ATPase

FE Na: fractional excretion of sodium, NKCC2: sodium-potassium-2-chloride co-transporter, NCCT: sodium chloride co-transporter, ENaC: epithelial sodium channel, Na/K
ATPase: sodium-potassium adenosine triphosphatase.

TABLE 56.2 Pharmacokinetics of Loop Diuretics in Subjects diuretic renal and non-renal clearances, protein bind-
with Normal Kidney Function ing, volume of distribution, and overall pharmacoki-
Furosemide Bumetanide Torsemide netics.3,9,4,1015 Any dosing recommendations based on
pharmacokinetics should be employed with circumspec-
Bioavailability, % 1190 (53) 5889 (80) 7991 (80) tion, and clinicians should anticipate the need to follow
Time to peak plasma 15 (1.6) 0.52 (1.3) 1 the response closely and titrate the dose as needed.
concentration, hours The presence of reduced renal function alters the rela-
Clearance (mL/min/kg) 1.54.4 (2.2) 1.83.8 (2.6) 0.331.1 (0.6) tive potency of the three commonly used loop agents.
Fraction of dose excreted 4994 (60) 3669 (65) 2234 (27)
For each drug, absolute renal excretion and hence
in urine unchanged, % delivery to its site of action diminishes as renal func-
tion declines. Factors that may contribute to dimin-
Plasma half-life, hours 0.33.4 (1.0) 0.41.5 (1.2) 0.86.0 (3.3)
ished delivery include reduced GFR, reduced renal
Summarized from published sources by Brater.5
blood flow, diminished protein binding with increased
Median values shown in parentheses.
apparent volume of distribution, and competition with
other organic acids for tubular secretion.4,16,17 Changed
TABLE 56.3 Pharmacokinetics of Loop Diuretics in Patients metabolism of diuretics also contributes to diminished
with Impaired Renal Function delivery. The kidney is not the sole route of excre-
Furosemide Bumetanide Torsemide tion of diuretics. Non-renal excretion of bumetanide
and torsemide via the liver is unaffected by changes in
Clearance (mL/min/kg) 0.8 1.6 0.91.05 renal function. Non-renal excretion of furosemide, in
Fraction of dose excreted 9.0 5.2 2.62.8 contrast, occurs via glucuronidation, which is accom-
unchanged in urine, % plished in the kidney and diminished when renal func-
Plasma half-life, hours 2.6 1.6 3.85.2 tion is reduced. With relatively preserved non-renal
7 6
elimination, excretion of bumetanide and torsemide is
From Voelker and as summarized from published sources by Brater.
in effect shunted away from the kidney. As shown in
Table 56.2, with normal renal function roughly equiva-
When switching from IV to oral furosemide, a doubling lent fractions of administered furosemide or bumetanide
of the dose is a reasonable starting point for achieving a are excreted via the kidney (~60%), the site of action
similar effect. No change in initial dose and less expected of these drugs. With impaired renal function (Table
variability apply to bumetanide and torsemide. Just as 56.3), the absolute fraction of all three drugs excreted
results of bioavailability studies vary, so do reported by the kidneys is reduced compared to normal, but the

VIII. THERAPEUTIC CONSIDERATIONS

684 56. Use of Diuretics in Chronic Kidney Disease Patients
reduction for furosemide is less. The fraction of furo-
semide excreted by the kidneys (9%) is approximately
twice that of bumetanide (5%). Thus the relative potency
of bumetanide especially and torsemide compared to
furosemide is reduced in patients with impaired kidney
function.
Diuretic binding to protein falls as renal function
worsens, likely due to displacement by other accumu-
lated anions.14 With hypoalbuminemia, as in nephrotic
syndrome, protein binding is diminished and the
volume of distribution of diuretics increases, fur-
ther reducing delivery.13,17,18 In animals studies, mix-
ing albumin with furosemide before administration
reverses some of the resistance.19 Furosemide may
bind to luminal albumin present due to proteinuria,
and inhibition of binding of furosemide to luminal
albumin by a competitive inhibitor like warfarin aug-
mented the diuretic effect observed during in vivo renal
tubular perfusion.20 Studies in humans with nephrotic
syndrome have not shown a pharmacokinetic ben-
efit of co-administration of furosemide and albumin.
However, the favorable hemodynamic effect of albumin
infusion can increase sodium excretion with submaxi-
mal but not maximal doses of furosemide.21,22 Neither
does inhibition of intraluminal furosemide binding to
albumin result in a significant augmentation of natri-
uretic effect.23
PHARMACODYNAMICS
The standard way to assess the ability of a diuretic to
augment urinary sodium excretion is to relate sodium
excretion to urinary diuretic excretion since the latter is
a direct measure of the amount of diuretic reaching its
luminal site of action. As loop diuretics bind to the elec-
troneutral NKCC2 Na-K-2Cl co-transporter in the thick
ascending limb of the loop of Henle which co-transports
a sodium ion, a potassium ion, and two chloride ions
across the luminal membrane, one would expect that a
plot of sodium excretion as a function of diuretic excre-
tion (Figure 56.1) would be a sigmoid curve. At low
excretion rates, few diuretic receptors are occupied by
bound drug and inhibited, so sodium excretion is little
increased. At high diuretic excretion rates, all receptors
are already saturated and increasing diuretic excre-
tion further has little additional effect. In between, the
slope of the change in sodium excretion as a function of
diuretic excretion or delivery is steep.
When expressed as fractional excretion of sodium,
the response to furosemide in patients with impaired
kidney function is augmented compared to normal indi-
viduals.24 At any given rate of furosemide excretion, the
fractional excretion of sodium is higher in patients with
reduced GFR (Figure 56.1). This is likely a function of
VIII. THERAPEUTIC CONSIDERATIONS
25
Fractional excretion of sodium (%)
20
15
10
5
0
0 0.5 5
Fractional furosemide excretion rate (g/ml)
FIGURE 56.1 Relationship between fractional delivery of furo-
semide into urine and fractional excretion of sodium after a 2-hour
furosemide infusion. Mean (S.E.M.). Data are shown as symbols
with brackets for patients with impaired kidney function and a
shaded curve for normal individuals. Reproduced with permission from
Reference24.
the adaptive mechanism for reduced GFR. To excrete
the same daily load of ingested sodium, the fractional
sodium excretion must be higher with reduced GFR. The
curve in Figure 56.1 also provides a basis for the notion
of a ceiling dose of loop diuretic. Administration of addi-
tional furosemide beyond the amount needed to reach
the plateau of the sigmoid curve would not produce any
additional benefit. In patients with normal renal func-
tion, the doses of loop agents required to reach maximal
sodium excretion are furosemide 40 mg, bumetanide
1mg, and torsemide 1520 mg, hence the standard
doses for these agents. With advanced renal functional
impairment, only 9% of furosemide is renally excreted,
compared with 60% with normal renal function. The
ceiling dose would therefore be expected to be five- or
six-fold higher,24 i.e. approximately 200mg. The dose
actually noted to reach saturation in the study shown
in Figure 56.1 was 160mg. Using a slightly higher value
for clinical purposes leads to reasonable limits for ceil-
ing doses of loop agents with reduced GFR in the range
of 160240mg for furosemide, 610mg for bumetanide,
and 100200 mg for torsemide.2,6,7,25 No advantage
would be expected from higher doses, although the
risk of toxicity would be higher. Note the difference in
equivalency ratio for impaired renal function for furo-
semide, bumetanide, and torsemide (20:1:20) compared
to normal renal function (40:1:1020).6,7,26 Relative to
furosemide, the potency of bumetanide especially and
torsemide to some degree are diminished in patients
with impaired kidney function.
 Diuretic Braking, Tolerance, and Resistance
DIURETIC BRAKING, TOLERANCE,
AND RESISTANCE
The diuretic and natriuretic effect of a diuretic drug
may decrease after the first dose and diminish further
over time. Some authors reserve the term braking to
describe the reduction in response to a diuretic that occurs
after the first dose.1,27 The principal cause is the acute
reduction in intravascular volume with compensatory
activation of a number of effectors including the RAAS
and the sympathetic nervous system, which together
can reduce GFR or alter the physical factors respon-
sible for proximal tubular sodium and fluid reabsorp-
tion. As shown in a series of elegant studies by Wilcox
et al., increased activity of these neurohumoral systems
is not solely responsible for diuretic braking since treat-
ment with captopril and the -adrenergic blocker prazo-
sin does not abrogate its development.28 A second cause
of reduced diuretic efficacy is tolerance, a term used by
many authors to refer to the reduction in diuretic effect
seen with chronic use that develops in most patients.1
Others employ the term tolerance to describe the first
dose effect and braking to describe the subsequent effect.29
Since these two effects predictably develop together in
the setting of repeated diuretic dosing, making a precise
distinction is not essential. The overall sequence is famil-
iar to clinicians and patients alike. With first administra-
tion of an adequate dose, diuretics promote a conspicuous
increase in urine output that is associated with net nega-
tive sodium balance, a reduction in weight, and lessening
of edema. Over time, patients reach a steady state where
Excretion
Dietary Na intake
or excretion
Intake
Weight
Braking phenomenon
Furosemide
Time (days)
FIGURE 56.2 Diuretic tolerance or braking. Upper panel shows
net sodium balance and lower panel weight change in response to
furosemide, which was given during the period indicated. Reproduced
with permission from Reference30 where it was redrawn with permis-
sion from Seely JF and Levy M. Control of Extracellular Fluid Volume. In:
Brenner BM and Rector FC: The Kidney. Philadelphia, WB Saunders, 1981.
VIII. THERAPEUTIC CONSIDERATIONS
685
the diuretic response to that same dosing regimen is less.
Individual doses promote a smaller diuresis and natriure-
sis. Daily sodium balance may become neutral with no
further weight loss occurring (Figure 56.2).
One important cause of diuretic tolerance is sequen-
tial reabsorption of solute at renal tubular sites more
distal to the site of action of the administered diuretic.
Loop agents are potent because they block the very large
fraction of filtered sodium load reabsorbed in the loop.
Under usual circumstances, transport sites in the distal
convoluted tubule and collecting duct reabsorb some
but not all of the extra filtrate reaching these sites after
administration of loop agents. The distal convoluted
tubule can undergo structural changes that augment
sodium reabsorptive capacity. Studies by Ellison et al.
and by others have shown that in response to adminis-
tration of furosemide, distal tubule cells undergo hyper-
trophy associated with increases in content of structural
proteins including the thiazide-inhibitable NaCl co-
transporter (NCCT) and Na/K ATPase that contribute
to sodium transport and retention in this segment.29,3133
Over time, these adaptations increase.
Diuretic resistance is present if a dose significantly
higher than the dose that produces maximal natriure-
sis under normal circumstances is required to produce
a similar effect. Diuretic resistance can occur either on a
pharmacokinetic basis due to reduced delivery of active
drug to its site of action or on a pharmacodynamic basis
with reduced responsiveness to drug that is delivered.
The potential pharmacokinetic reasons for diuretic resis-
tance in patients with impaired kidney function were
previously discussed (see Pharmacokinetics).
The principal pharmacodynamic reason for diuretic
resistance with impaired kidney function is self-evident.
Despite the augmented fractional excretion of sodium
that occurs with reduced kidney function (Figure 56.1),
absolute sodium excretion is reduced in proportion to
the reduction in filtered load and GFR.
Diuretics are more effective when dietary sodium
intake is restricted. A cause of apparent diuretic resis-
tance in both patients with normal renal function and
those with abnormal renal function is reabsorption
of sodium at a time when the effect of a short-acting
diuretic has worn off. In patients with normal renal func-
tion, the duration of action of furosemide is approxi-
mately 6 hours. Once the diuretic effect dissipates, the
patient enters a compensatory sodium retentive state, i.e.
diuretic braking occurs. If sodium intake is high enough,
the sodium retained during that interval will reduce the
net negative balance to a significant degree, leading to
apparent diuretic resistance (Figure 56.3, panel a). It is
clear from this figure that the administered furosemide
works. It effectively increases sodium excretion dur-
ing its period of activity. However, since net negative
sodium balance has not been achieved, the clinically
686 56. Use of Diuretics in Chronic Kidney Disease Patients

(a) High salt intake Finally, augmented reabsorption of fluid due to

300
persistence or augmentation of the factors that led to
diuretic braking or tolerance can contribute to a need
for higher diuretic doses. Strictly speaking, this is not
UNa V m mol 6 hr1

200
diuretic resistance. The combination of mechanisms
responsible for an inadequate diuretic response must
be addressed simultaneously to ensure a clinically ade-
quate diuresis (Table 56.4).
100

Strategies to Address Inadequate Diuretic

Responsiveness due to Braking, Tolerance, or
0
Control days F DAY 1 F DAY 2 F DAY 3 Resistance
A. Select an Appropriate Diuretic Dose
(b) Low salt intake
105 The dose of diuretic required to reach maximal efficacy
is higher in patients with impaired kidney function. Using
95 a standard 40mg dose of furosemide in a patient with an
eGFR of 20mL/min/1.73m2 or a patient with hypoal-
60 buminemia from nephrotic syndrome will predictably
have limited effect. Start instead with 80mg or 160mg.
UNa V m mol 6 hr1

50 Alternatively, start with a modest dose with the expec-

40
30
20
10
0
Control days F DAY 1 F DAY 2 F DAY 3
FIGURE 56.3 Apparent diuretic resistance. Effect of dietary
sodium intake on overall sodium balance after administration of a
single daily dose of furosemide to subjects with normal renal func-
tion. Height of bars indicates sodium excretion. White portions
indicate excretion below ingestion rate, black bars excretion above
ingestion rate. Hatched area shows time period and magnitude of
sodium retention during time periods when intake exceeds excre-
tion. Note difference between scale on ordinate of each panel. In the
study depicted in panel a, when subjects ingested a liberal sodium
intake, the quantity of sodium retained during the intervals after the
diuretic effect had dissipated (gray areas) was similar to the quan-
tity of sodium excreted during the periods of diuretic action (black
bars). The net natriuresis was thus very small. In the study depicted
in panel a, dietary sodium was restricted. Little sodium was excreted
during the comparable intervals after the diuretic effect dissipated.
However, since there was little dietary sodium available for retention
during ingestion of the restricted sodium diet, a significant net natri-
uresis occurred. Reproduced with permission from Reference27.
apparent effect is diuretic resistance. Imposition of a low
sodium diet (Figure 56.3, panel b) limits the availability
of sodium to be retained when diuretic effect is absent.
To some degree, this pharmacodynamic effect is less sig-
nificant with the longer acting torsemide.
tation of rapidly titrating the dose upward if no effect is
observed. In the outpatient setting, patients can be coun-
seled to observe the weight change that follows dosing and
increase or decrease the dose to obtain the desired effect.
Furosemide is only 50% bioavailable while the
other loop agents have 80% bioavailability. Anticipate
the need to double the dose of furosemide to achieve
comparable activity when switching from IV to oral
administration.
The fraction of diuretic excreted unchanged in the
urine is a measure of delivery of diuretic to its site
of action. Compared to normal renal function, with
reduced kidney function, the fraction of furosemide
excreted in the urine is better maintained than the com-
parable fractions for bumetanide and torsemide. Higher
relative doses of bumetanide and torsemide will be
required to treat CKD patients.
B. Assure that the Duration of Diuretic
Effect is Adequate
As shown in Figure 56.3, reabsorption of sodium
after the drug effect has dissipated may counterbal-
ance any sodium lost during the period of active natri-
uresis. Torsemide may have a longer period of action
than the other loop agents, but the advantage is less in
patients with reduced kidney function. Even so, a care-
fully conducted trial did show equivalent blood pres-
sure lowering in CKD patients given a single daily dose
of torsemide or a bioequivalent dose of furosemide in
divided doses.34 After establishing by titration a dose
that is effective, repeat it on a BID or TID schedule to
assure continuous inhibition of sodium reabsorption.

VIII. THERAPEUTIC CONSIDERATIONS

 Diuretic Braking, Tolerance, and Resistance 687
TABLE 56.4Mechanisms for Diuretic Resistance in Patients with Impaired Renal Function and Possible Solutions

Observed Limitation Possible Mechanism Possible Solution

Overall and segmental fractional sodium
excretion already increased
Decreased proximal tubule secretion of
diuretic
Decreased renal elimination
Enhanced sodium reabsorption in nephron
segments downstream to site of action
Diuretic is short acting
Limits effect of less potent diuretics
Competition with other organic acids for
secretion
Undiminished extrarenal clearance diverts
drug from site of action
Increased number of NCCT transporters in
DCT cells, DCT hypertrophy
Delivery of diuretic below threshold toward
the end of dosing interval
Start with a loop diuretic instead of a thiazide
Avoid using with drugs that interfere with
organic acid secretion such as cimetidine,
methotrexate, sulfonamides, trimethoprim
Note relative decrease in bumetanide and
torsemide efficacy; increase dose
Use thiazide or metolazone for synergy; either
effective despite reduced GFR
Follow diuretic response carefully and redose
appropriately. Consider continuous IV infusion

Modified from Reference17.

NCCT: sodium chloride co-transporter, DCT: distal convoluted tubule, GFR: glomerular filtration rate.

C. Limit Sodium Intake E. Administer the Drug via Continuous

CKD is no different than any other situation requir-
ing diuretics. Limiting intake of sodium reduces the
magnitude of natriuresis required. Also, reducing the
amount of dietary sodium available for retention dur-
ing intervals between diuretic doses promotes the
achievement of net negative balance (Figure 56.3).
D. Block Reabsorption of Sodium in
Sequential Nephron Segments
As discussed in Diuretic Braking, Tolerance, and
Resistance, much of the tolerance seen with chronic
dosing of the potent loop agents is due to augmented
reabsorption in the distal convoluted tubule at the thia-
zide inhibitable NCCT NaCl co-transporter.29,3133 In
patients with normal renal function, the addition of a
thiazide or metolazone to a loop agent has a synergistic
or at least additive effect on sodium excretion.3537 It is
a well-known clinical observation that the addition of
metolazone may in some circumstances produce a pro-
found diuresis.38 Since the effect of metolazone is pro-
tracted, it may take several days for the maximal effect
to develop. Patients should be alerted to the possibil-
ity of development of an excessive response after a few
days of treatment, and they should be advised to track
weight loss and seek advice if it exceeds the desired
goal. It is often appropriate to prescribe metolazone,
when used with furosemide, on an intermittent basis
with dosing on alternate days or just two or three times
per week. In patients receiving intravenous diuretics,
chlorothiazide, 250 or 500mg given intravenously twice
daily, is a suitable dose for synergy. When given alone,
the thiazides have reduced potency in CKD. However,
several studies have documented their utility in aug-
menting the effect of loop agents even in patients with
CKD stages 353941 (Figure 56.4).
Intravenous Infusion
Continuous infusion of a loop agent may offer the
advantage of maintaining a therapeutic level of diuretic
over a more extended period than bolus administra-
tion. To some degree, bolus administration is inefficient.
The very high blood level occurring soon after admin-
istration may be well above the plateau level of the
sigmoid-shaped dose response curve. Toward the end
of the dosing interval, the blood level may be below
the threshold for efficacy. Compared to bolus dosing,
continuous infusion of bumetanide has been shown
to produce a greater sodium loss.42 Furosemide bolus
vs. continuous infusion was examined in a population
of CKD patients given either a bolus dose or the same
total dose of diuretic with 25% given as a loading dose
and 75% infused continuously over 4 hours. The con-
tinuous infusion protocol led to significantly greater
absolute and fractional sodium excretion and a larger
diuresis.43 However, repeated bolus dosing can cer-
tainly be effective if urine output is monitored and the
dose and frequency adjusted. One clinical advantage
of continuous dosing is that it requires less attention
compared to repeated bolus dosing on an as needed
basis. Having an effective continuous dose running in
the background may be advantageous compared to a
dosing scheme that requires active intervention and in
which repeat bolus dosing may be delayed. In a differ-
ent patient population, acute decompensated CHF, no
efficacy difference was found with continuous com-
pared to bolus dosing when both were given on a regu-
lar basis per protocol.44
The risk of diuretic ototoxicity is low with current
doses of loop diuretics. Reversible ototoxicity may
be noted when drug accumulates due to CKD. This is
more likely with the higher peak levels achieved with

VIII. THERAPEUTIC CONSIDERATIONS

688 56. Use of Diuretics in Chronic Kidney Disease Patients

Diet containing 100 mEq sodium 80 mEq potassium

Serum 3.5 3.0 Serum

potassium 3.0 2.5 creatinine
(mEq/L)= 2.5 2.0 (mg/dl) =

56
Weight 54
(Kg) 52
50

300
Urinary 250
sodium 200
excretion 150
(mEq/24 hr) 100
50
KCL 80 mEq/day

Hydrochlorothiazide 50 mg/day
Furosemide 480 mg/day

0 1 2 3 4 5 6 7 8 9 10 11
Hospital days

FIGURE 56.4 Additive natriuretic effect of hydrochlorothiazide to furosemide in a patient with CKD. Note that urine sodium excretion
rose and weight fell coincident with addition of hydrochlorothiazide (HCTZ) to furosemide beginning on day 3. Reproduced with permission from
Reference39.

bolus dosing. Continuous IV dosing may be safer in
that regard.45,46
USE OF AGENTS OTHER THAN
LOOP DIURETICS IN CKD
Carbonic Anhydrase Inhibitors
A brief course of acetazolamide may be particu-
larly useful in patients with CKD who have devel-
oped metabolic alkalosis in clinical settings such as
nasogastric suction or after a course of loop diuretics.
Acetazolamide may be preferred to a thiazide when
an additional agent is needed with a loop diuretic and
metabolic alkalosis is present.
When metabolic alkalosis is absent, however, car-
bonic anhydrase inhibitors should be used only with
great caution in CKD. Patients with impaired renal
function are at increased risk for development of met-
abolic acidosis due to diminished ammonium produc-
tion and diminished renal reserve with an inability to
compensate when acid production or bicarbonate loss
is increased. Several studies have shown a high rate of
development of hyperchloremic metabolic acidosis in
elderly patients treated with conventional doses of acet-
azolamide for glaucoma.4749 In a study comparing 27
elderly glaucoma patients (mean age 69.1 7.4 years)
to age-matched controls, 4 patients (14.8%) developed
mild acidosis (7.29<pH7.31), 10 (37%) moderate aci-
dosis (7.20<pH7.29), and 1 (3.7%) severe acidosis
(pH 7.15). Acidosis was not observed in the controls.49
In a second study, tCO2 levels were inversely corre-
lated with acetazolamide levels which themselves cor-
related closely with drug dosage adjusted for creatinine
clearance.47
Thiazides
When used alone, thiazides are widely believed not
to be effective in patients with impaired kidney func-
tion.1,39,50 When using a thiazide diuretic to treat hyper-
tension, most clinicians stop the drug in CKD patients
once the eGFR falls below 30mL/min/1.73m2 or the
serum creatinine reaches 1.71.9mg/dL.This is still con-
sidered the standard approach.4
A recent review, however, has focused attention on
the possibility that thiazides retain utility in hyperten-
sion in CKD even as GFR declines.51 Two early stud-
ies have examined this question. The first included 17
individuals with creatinine clearances ranging from
5133 mL/min. Half of the patients had creatinine
clearances at or below 53mL/min. Bemetizide, 25mg,

VIII. THERAPEUTIC CONSIDERATIONS

 Use of Agents Other Than Loop Diuretics in CKD
resulted in an increase in absolute sodium excretion
throughout the clearance range that was proportional
to the clearance value.52 A second study by the same
investigators, also in individuals with a wide range of
creatinine clearances, noted an increase in fractional
sodium excretion after a thiazide alone. The combina-
tion of low dose HCTZ (25mg) and 40mg furosemide
produced a significant increase in absolute sodium
excretion compared to baseline. However, the differ-
ence in absolute excretion of sodium with HCTZ alone
was not significant compared to placebo.52,53 The cre-
atinine clearances in the subset of patients with CKD
ranged from 475mL/min, and the absolute increment
in sodium excretion was reported for the group as a
whole only. This makes assessment of the efficacy at
the lower GFR range difficult. Two more recent studies
using diuretics in CKD compared blood pressure, frac-
tional sodium excretion and weights in patients with
stage 35 CKD. Using a double-blind, placebo-con-
trolled, randomized crossover design, patients either
received placebo, 25mg HCTZ, 40mg furosemide or
both. Fractional sodium excretion increased and weight
fell in the combination diuretic group in both studies. In
one study, but not the other, fractional sodium excretion
rose with HCTZ. Furosemide alone at this low dose did
not result in an increase in fractional sodium excretion,
but it did lower weight in one of the two studies. HCTZ
alone did not result in a weight reduction. Despite
the lack of consistent weight reduction, mean arterial
pressure fell significantly in both studies in all three
diuretic groups.41,54 At least one additional study also
demonstrated an effect of chlorthalidone to reduce
blood pressure without a diuretic effect in patients with
advanced CKD.55
Taken together, these trials suggest that thiazides
may potentially be useful in lowering blood pressure in
CKD patients and that this effect may be due to some
other effect than a natriuresis. These potential mecha-
nisms, including diminished pressor response to cat-
echolamines and angiotensin II, calcium desensitization
of smooth muscle, nitric oxide release, and activation
of potassium channels, have been reviewed.51 Finally,
in a post hoc analysis of the subgroup of patients in the
ALLHAT trial with eGFR below 60mL/min/1.73m2,
chlorthalidone was noted to be more effective than
amlodipine or lisinopril in preventing stroke and con-
gestive heart failure and non-inferior in preventing
coronary heart disease, cardiovascular disease events or
ESRD, providing evidence for efficacy of chlorthalidone
in improving outcomes in CKD.56 Systolic blood pres-
sure was slightly lower in the chlorthalidone group.57 It
is important to note that ALLHAT was not designed to
assess patients with diminished renal function specifi-
cally, and patients with serum creatinine above 2.0mg/
dL were excluded.
VIII. THERAPEUTIC CONSIDERATIONS
689
A potential role of thiazide therapy compared to loop
diuretic therapy to lessen the risk of development of
secondary hyperparathyroidism in CKD has been sug-
gested by an analysis of the Chronic Renal Insufficiency
Cohort (CRIC). In this patient population, eGFR ranged
from 20 to 70mL/min/1.73m2. In the subset of patients
receiving diuretics, the adjusted daily calcium excre-
tion was 39.6mg/24h (37.242.2, 95% CI). In the sub-
set receiving loop diuretics alone it was 55.0mg/24h
(50.859.5, p<0.05 vs. no diuretic). In the subset receiv-
ing thiazides alone it was 25.5 mg/24 h (23.327.8,
p<0.05 vs. no diuretic). In the subset receiving both, it
was 30.3mg/24h (26.634.5, p<0.05).58 PTH levels were
higher in the loop diuretic treated patients compared
to patients who received no diuretics, but there was no
difference between thiazide treated patients and the
controls. The adjusted odds ratio for secondary hyper-
parathyroidism, defined as a PTH 65pg/mL, was
higher with loop diuretics than with no diuretics. The
odds of developing secondary hyperparathyroidism
were not increased in patients receiving thiazides or in
patients receiving both diuretics. The reduction in odds
in the latter group was seen only in patients with stage 2
or 3 CKD. Thiazides were not protective in patients with
stage 4 CKD. As the accompanying editorial pointed
out, however, whether these biochemical differences
mean that an improvement in clinical outcomes such
as reduced cardiovascular morbidity or mortality, or
reduced fracture rate will result from addition or substi-
tution of a thiazide is far from established.59
Aldosterone Receptor Antagonists
Aldosterone receptor antagonists have pleiotropic
effects with potentially favorable cardiovascular effects
beyond their effect on sodium balance, and they are par-
ticularly useful as adjunctive therapy in patients with
resistant hypertension.6062 Aldosterone antagonists may
have a role in further reducing proteinuria in patients
receiving angiotensin-converting enzyme inhibitors
or angiotensin receptor blockers.63 However, drugs in
this class can raise S[K], leading to safety and suitabil-
ity concerns. The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure cautions against ini-
tiating aldosterone receptor antagonists in patients with
a basal S[K] exceeding 5mmol/L.64 Large-scale trials of
aldosterone inhibitors note only a modest effect of spi-
ronolactone on S[K]. In the RALES study, S[K] levels
rose a mean of 0.3mmol/L, and serious hyperkalemia
was observed in only 2% of patients who received spi-
ronolactone.65 However, patients with advanced CKD
S[Cr] above 2.5mg/dL) were excluded from this trial.
Population-based studies have shown an increased
rate of hyperkalemia morbidity and mortality since
690 56. Use of Diuretics in Chronic Kidney Disease Patients
the RALES study, raising further concern,66 and clini-
cians remain wary of using potassium-sparing agents in
patients with impaired renal function.
Two small-scale, retrospective cohort studies directly
examining the effect of aldosterone receptor antago-
nists in CKD patients have been published. The first
compared effects of spironolactone in patients with and
without CKD (stage III or greater, 34 patients). Similar
decrements in systolic (10.0 19.8 vs. 14.9 16.9mmHg,
p = 0.24) and diastolic (3.4 8.6 vs. 6.2 9.4mmHg,
p = 0.16) pressure were observed in patients with and
without CKD.67 S[K] rose 0.5 0.6mmol/L in the CKD
patients vs. 0.3 0.5mmol/L (p = 0.12) in the patients
with normal renal function. In 5.7% of CKD patients
and no patients with normal renal function, the S[K]
rose above 5.5mmol/L (p = 0.07). The small size of the
study leaves it subject to type II error. In a multivariable
analysis, spironolactone dose was not a risk factor for
development of hyperkalemia, but eGFR below 45mL/
min was. The change in S[K] correlated inversely with
eGFR. A similar study examined stage 3 CKD patients
with resistant hypertension in whom spironolactone (32
patients) and eplerenone (4 patients) were used as add-
on therapy.68 Treated patients experienced a fall in sys-
tolic blood pressure from 162 22 to 138 14mmHg
(P < 0.0001) and in diastolic blood pressure from 87 17
to 74 12mmHg (P < 0.0001). S[K] increased from 4.0
0.5 to 4.4 0.5mmol/L (P = 0.0001). With a median fol-
low-up of 312 days, 8 patients (22%) developed hyper-
kalemia, defined as S[K] exceeding 5.0mmol/L. Three
patients (8%) had S[K] values exceeding 5.5mmol/L. In
the aggregate, 19 of 270 (7%) blood draws disclosed S[K]
values above 5.0mmol/L and 7 of 270 (2.6%) measure-
ments were above 5.5mmol/L.
Eplerenone has a shorter half-life than spironolac-
tone. Its use has been suggested as an alternative to
spironolactone in CKD because its effect will dissipate
sooner if hyperkalemia develops.69 Eplerenone also has
a more favorable side-effect profile than spironolactone.
However, eplerenone is much more costly than spirono-
lactone. Conventional strategies to permit use of an aldo-
sterone inhibitor in CKD include restriction of potassium
intake, supplementation with bicarbonate to provide a
non-reabsorbable anion (excretion of which may enhance
potassium excretion), and concomitant use of kaliuretic
loop diuretics.
DIURETICS FOR TREATMENT OF
HYPERTENSION IN CKD
Extracellular volume overload is an important contrib-
utor to hypertension in CKD, and correction of volume
overload with diuretics is a key part of treatment.70 When
appropriately dosed, loop diuretics are plainly effective
VIII. THERAPEUTIC CONSIDERATIONS
in reducing extracellular volume and lowering blood
pressure in CKD patients.15,34 Although this principle is
generally accepted, diuretics appear to be underutilized
in CKD patients. A large study evaluating treatment of
hypertension in 26 Italian CKD clinics observed furose-
mide use (the loop diuretic prescribed virtually exclu-
sively) in only 27% of stage 3, 42% of stage 4 and 51%
of stage 5 patients. In more than half of the patients who
were receiving a loop diuretic, the dose was deemed
inadequate.71 A fixed dose combination of losartan
50mg/hydrochlorothiazide 12.5mg was found to be infe-
rior to losartan 50mg plus nifedipine 2040mg for lower-
ing blood pressure in CKD patients, highlighting the need
to choose an appropriate diuretic in an adequate dosage.72
DIURETIC COMPLICATIONS
Diuretic complications have been extensively
reviewed.46,69 Metabolic derangements resulting from
use of thiazide or loop diuretics include hyponatre-
mia, hypokalemia, hypomagnesemia, hyperuricemia,
hyperglycemia, and metabolic alkalosis. Hypokalemia
and metabolic alkalosis become less of a problem as
renal function worsens. In addition, concomitant use
of angiotensin-converting enzyme inhibitors or angio-
tensin receptor blockers as well as aldosterone receptor
inhibitors in this population may mitigate hypokalemia
or result in frank hyperkalemia. Spironolactone may
contribute to the development of metabolic acidosis.73
When present, hypokalemia is readily managed with
potassium supplementation or addition of a potas-
sium-sparing agent. Hyponatremia carries an adverse
prognosis in CKD patients,74 as it does in the general
population.75 Hyponatremia is much more common
with the thiazides, which block sodium transport in the
distal convoluted tubule diluting sites.76 Thiazide diuret-
ics should be stopped and a loop agent substituted if
continued diuretic therapy is required in CKD patients
with hyponatremia. Hyperuricemia can be a relative
contraindication for diuretic use. Gout combined with
the unsuitability of NSAID treatment in CKD patients
may be responsible for the reluctance of some clini-
cians to prescribe diuretics. However, hyperuricemia
is amenable to therapy with allopurinol or febuxostat.
Hypomagnesemia may be a particular problem in renal
transplant patients with CKD who are receiving diuret-
ics and tacrolimus. Clinicians should be vigilant for this
complication and supplement magnesium as required.
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