Use of Diuretics in Chronic Kidney Disease Patients

C H A P T E R

64 Use of Diuretics in Chronic Kidney Disease Patients Arthur Greenberg Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC, United States diuretics is necessary 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.

Abstract Diuretics are commonly prescribed to treat the sodium retention, volume expansion, and hypertension characteristic of chronic kidney disease (CKD). With reduced renal function, delivery of the drugs to their renal tubular sites of action is impaired, potentially leading to diminished potency. In addition, reduced glomerular filtration rate and alterations in sodium transport at other tubular sites can reduce the natriuretic effect of delivered drug. To use diuretics effectively in CKD, clinicians must understand these changes in diuretic pharmacokinetics and pharmacodynamics. This chapter reviews the sites and mechanisms of action of diuretics, describes how diuretic pharmacologic characteristics are affected by CKD, and details how best to overcome diuretic resistance. Much of the focus is on the loop agents, which are the most potent class of diuretics and the mainstay of treatment in CKD patients. As increasing attention is being paid to the role of thiazides and mineralocorticoid antagonists, the use of other classes of diuretics is also covered, as is the use of diuretics to treat specific subsets of CKD patients.

SITE AND MECHANISM OF ACTION OF DIURETICS

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. Chronic kidney disease (CKD) is one such state, and diuretics are an important therapeutic tool in CKD for treatment of volume overload, edema, and hypertension. The delivery of diuretics to the sites at which they work and their pharmacodynamics and pharmacokinetics, relative potency, and clinical effects and utility are markedly affected by changes in renal function. A detailed understanding of the mechanism of action of Chronic Renal Disease, Second Edition https://doi.org/10.1016/B978-0-12-815876-0.00064-4

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 mineralocorticoid receptor antagonists (MRAs), which reach the nuclear aldosterone receptor from the basolateral side of collecting duct cells. Glomerular filtration of diuretics 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 the proximal tubule. Weak acids, amiloride, and triamterene, are secreted via the organic base pathway. Once they reach the proximal tubular lumen, diuretics move downstream in the glomerular filtrate to their specific site of action. On binding to their receptors, diuretics block transport of sodium and accompanying anions or cations at that site (Table 64.1). Diuretics vary in potency, which depends on the fraction of filtered sodium reabsorbed at the site where the diuretic inhibits transport, sodium delivery to the inhibited site, and the potential for sodium reabsorption distal 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

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© 2020 Elsevier Inc. All rights reserved.

TABLE 64.1

Sites of Action of Diuretic Drugs

VIII. THERAPEUTIC CONSIDERATIONS

Drug Class

Agents

Site of Action

Maximal FE Na

Transport Site

Carbonic anhydrase inhibitors

Acetazolamide

Proximal tubule

5e8%

Carbonic anhydrase, lumen, and proximal tubular cell

Loop agents

Furosemide

Thick ascending limb loop of Henle

15e20%

NKCC2

Distal convoluted tubule

10e15%

NCCT

Bumetanide

Other

Torsemide Thiazides

Hydrochlorothiazide Chlorthalidone Chlorothiazide

NaCl cotransporter

Numerous others ENaC blockers

Amiloride

Collecting duct

3e5%

ENaC

Collecting duct

3e5%

ENaC

Triamterene Mineralocorticoid receptor antagonists

Spironolactone Eplerenone

Also block effect of aldosterone to stimulate basolateral Na/K ATPase

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

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PHARMACOKINETICS

out of the proximal tubule, distal segments of the nephron, including especially the loop of Henle and the distal convoluted 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 the reabsorption of up to 20% of the filtered sodium load, an amount that cannot ordinarily be reabsorbed at more distal sites in its entirety. The operative word here is ordinarily.

PHARMACOKINETICS The pharmacokinetics of diuretics in health and various 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 glomerular filtration rate (GFR) are shown in Tables 64.2 and 64.3.5e8 The bioavailability of orally administered furosemide is approximately 50%, compared with 80% for bumetanide and torsemide. However, the reported values vary widely. When switching from intravenous (IV) to oral furosemide, a doubling of the dose is a reasonable starting point for achieving a similar effect. No change in initial dose and less expected variability apply to bumetanide and torsemide. Just as results of bioavailability studies vary, so do reported diuretic renal and nonrenal clearances, protein binding, volume of distribution, and overall pharmacokinetics.3,4,9e15 Any dosing recommendations based on pharmacokinetics should be employed with circumspection, and clinicians should anticipate the need to follow the clinical response closely and titrate the dose accordingly. The presence of reduced renal function alters the relative potency of the three commonly used loop agents. For each drug, absolute renal excretion and hence delivery to its site of action diminishes as renal function declines. Factors that may contribute to diminished delivery include reduced GFR, reduced renal blood flow, diminished protein binding with increased apparent volume of distribution, and competition with TABLE 64.2

TABLE 64.3

Pharmacokinetics of Loop Diuretics in Patients with Impaired Renal Function Furosemide

Bumetanide

Torsemide

Clearance (mL/min/kg)

0.8

1.6

0.9e1.05

Fraction of dose excreted unchanged in urine, %

9.0

5.2

2.6e2.8

Plasma half-life, hours

2.6

1.6

7

From Voelker and as summarized from published sources by Brater.

3.8e5.2 6

other organic acids for tubular secretion.4,16,17 Changed metabolism of diuretics also contributes to diminished delivery. The kidney is not the sole route of excretion of diuretics. Nonrenal excretion of bumetanide and torsemide via the liver is unaffected by changes in renal function. Nonrenal excretion of furosemide, in contrast, occurs via glucuronidation, which is accomplished in the kidney and diminished when renal function is reduced. With relatively preserved nonrenal elimination, excretion of bumetanide and torsemide is in effect shunted away from the kidney. As shown in Table 64.2, with normal renal function, roughly equivalent fractions of administered furosemide or bumetanide are excreted via the kidney (w60%), the site of action of these drugs. With impaired renal function (Table 64.3), the absolute fraction of all three drugs excreted by the kidneys is reduced compared with normal, but the reduction for furosemide is less. The fraction of furosemide excreted by the kidneys (9%) is approximately twice that of bumetanide (5%). Thus, the relative potency of bumetanide especially and torsemide compared with furosemide is reduced in patients with impaired kidney function. Diuretic binding to protein falls as renal function worsens, likely due to displacement by other accumulated anions. With hypoalbuminemia, as in nephrotic syndrome, protein binding is diminished and the volume of distribution of diuretics increases, further reducing delivery.13,17,18 In animal studies, mixing albumin with furosemide before administration reverses some of the resistance.19 Furosemide may bind to

Pharmacokinetics of Loop Diuretics in Subjects with Normal Kidney Function Furosemide

Bumetanide

Torsemide

Bioavailability, %

11e90 (53)

58e89 (80)

79e91 (80)

Time to peak plasma concentration, hours

1e5 (1.6)

0.5e2 (1.3)

1

Clearance (mL/min/kg)

1.5e4.4 (2.2)

1.8e3.8 (2.6)

0.33e1.1 (0.6)

Fraction of dose excreted in urine unchanged, %

49e94 (60)

36e69 (65)

22e34 (27)

Plasma half-life, hours

0.3e3.4 (1.0)

0.4e1.5 (1.2)

0.8e6.0 (3.3)

Median values shown in parentheses. Summarized from published sources by Brater.5

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64. USE OF DIURETICS IN CHRONIC KIDNEY DISEASE PATIENTS

luminal albumin present due to proteinuria. Inhibition of binding of furosemide to luminal albumin by a competitive inhibitor like warfarin augmented the diuretic effect observed during in vivo renal tubular perfusion.20 Studies in humans with hypoalbuminemia or nephrotic syndrome have not shown a pharmacokinetic benefit of coadministration of furosemide and albumin. However, the favorable hemodynamic effect of albumin infusion can increase sodium excretion with submaximal but not maximal doses of furosemide.21e23 Inhibition of intraluminal furosemide binding to albumin by warfarin does not result in a significant augmentation of natriuresis in the clinical setting.24

PHARMACODYNAMICS The standard way to assess the ability of a diuretic to increase urinary sodium excretion is to relate sodium excretion to urinary diuretic excretion, because the latter is a direct measure of the amount of diuretic reaching its luminal site of action. As loop diuretics bind to the electroneutral NKCC2 Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle which cotransports a sodium ion, a potassium ion, and two chloride ions across the luminal membrane, one would predict that a plot of sodium excretion as a function of diuretic excretion (Figure 64.1) 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

Fractional excretion of sodium (%)

25

20

15

are already saturated and increasing diuretic excretion 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 with normal individuals.25 At any given rate of furosemide excretion, the fractional excretion of sodium is higher in patients with reduced GFR (Figure 64.1). This is likely a function of 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 64.1 also provides a basis for the notion of a ceiling dose of loop diuretic. Administration of additional furosemide beyond the amount needed to reach the plateau of the sigmoid curve would not produce any additional benefit. In patients with normal renal function, the doses of loop agents required to reach maximal sodium excretion are furosemide 40 mg, bumetanide 1 mg, and torsemide 15e20 mg, hence the standard doses for these agents. With advanced renal functional impairment, only 9% of furosemide is excreted by the kidney, compared with 60% with normal renal function. The ceiling dose would therefore be expected to be five- or six-fold higher, i.e. approximately 200 mg.25 The dose actually noted to reach saturation in the study shown in Figure 64.1 was 160 mg. Using a slightly higher value for clinical purposes leads to reasonable limits for ceiling doses of loop agents with reduced GFR in the range of 160e240 mg for furosemide, 6e10 mg for bumetanide, and 100e200 mg for torsemide.2,6,7,26 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 furosemide, bumetanide, and torsemide (20:1:20) compared with normal renal function (40:1:10e20)6,7,27 Relative to furosemide, the potency of bumetanide especially and torsemide to some degree are diminished in patients with impaired kidney function.

10

DIURETIC BRAKING, TOLERANCE, AND RESISTANCE

5

0

0

0.5 5 Fractional furosemide excretion rate (μg/ml)

FIGURE 64.1 Relationship between fractional delivery of furosemide 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 reference 25.

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.1,28 The principal cause is the acute reduction in intravascular volume with compensatory activation of a number of effectors including the renineangiotensinealdosterone system and the sympathetic nervous system, which together can reduce GFR

VIII. THERAPEUTIC CONSIDERATIONS

DIURETIC BRAKING, TOLERANCE, AND RESISTANCE

Weight

Dietary Na intake or excretion

or alter the physical factors responsible for proximal tubular sodium and fluid reabsorption. 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, because treatment with captopril and the a-adrenergic blocker prazosin does not abrogate its development.29 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.30 Because these two effects predictably develop together in the setting of repeated diuretic dosing, making a precise distinction is not essential. The overall sequence is familiar to clinicians and patients alike. With first administration of an adequate dose, diuretics promote a conspicuous increase in urine output that is associated with net negative sodium balance, a reduction in weight, and lessening of edema. Over time, patients reach a steady state where the diuretic response to that same dosing regimen is less. Individual doses promote a smaller diuresis and natriuresis. Daily sodium balance may become neutral with no further weight loss occurring (Figure 64.2). One important cause of diuretic tolerance is sequential 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

Excretion

Intake

Braking phenomenon

Furosemide Time (days)

FIGURE 64.2 Diuretic tolerance or braking. Upper panel shows net sodium balance, and lower panel shows weight change in response to furosemide, which was given during the period indicated. Reproduced with permission from reference 101 where it was redrawn with permission from Seely JF, Levy M. Control of extracellular fluid volume. In: Brenner BM, Rector FC, editors. The kidney. Philadelphia: WB Saunders; 1981.

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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 administration of furosemide, distal tubule cells undergo hypertrophy associated with increases in content of structural proteins, including the thiazide-inhibitable NaCl cotransporter (NCCT) and the Na/K ATPase that contribute to sodium transport and retention in this segment.30e33 Over time, these adaptations increase. Diuretic resistance is present if a dose significantly higher than the dose that produces maximal natriuresis 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 resistance in patients with impaired kidney function were previously discussed (see Pharmacokinetics). The principal pharmacodynamic reason for diuretic resistance with impaired kidney function is selfevident. Despite the augmented fractional excretion of sodium that occurs with reduced kidney function (Figure 64.1), absolute sodium excretion is reduced in proportion to the reduction in filtered load and GFR.34 Diuretics are more effective when dietary sodium intake is restricted. A cause of apparent diuretic resistance 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 function, the duration of action of furosemide is approximately 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 64.3, panel A). It is clear from this figure that the administered furosemide works. It effectively increases sodium excretion during its period of activity. However, because net negative sodium balance has not been achieved, the clinically apparent effect is diuretic resistance. Imposition of a low-sodium diet (Figure 64.3, panel B) reduces the amount of sodium available for retention during the interval when the diuretic effect is absent. To some degree, this pharmacodynamic effect would be less significant with the longer acting torsemide. Finally, augmented reabsorption of fluid due to persistence or augmentation of the factors that led to diuretic braking or tolerance can contribute to a need

VIII. THERAPEUTIC CONSIDERATIONS

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64. USE OF DIURETICS IN CHRONIC KIDNEY DISEASE PATIENTS

UNa V m mol 6 hr–1

(a) 300

Strategies to Address Inadequate Diuretic Responsiveness due to Braking, Tolerance, or Resistance

High salt intake

200

100

0

Control days F DAY 1

F DAY 2

F DAY 3

Low salt intake

(b) 105 95

UNa V m mol 6 hr–1

60 50 40 30 20 10 0

Control days F DAY 1

F DAY 2

F DAY 3

FIGURE 64.3 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 function. Height of bars indicates sodium excretion. White portions indicate excretion below ingestion rate, and black bars indicate excretion above ingestion rate. Gray area shows time period and magnitude of sodium retention during time periods when intake exceeds excretion. Note difference in 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 quantity of sodium excreted during the periods of diuretic action (black bars). The net natriuresis was thus very small. In the study depicted in panel b, dietary sodium was restricted. Little sodium was excreted during the comparable intervals after the diuretic effect dissipated. However, because there was little dietary sodium available for retention during ingestion of the restricted sodium diet, a significant net natriuresis occurred. Reproduced with permission from reference 28.

for higher diuretic doses. Strictly speaking, this is not diuretic resistance. The combination of mechanisms responsible for an inadequate diuretic response must be addressed simultaneously to ensure a clinically adequate diuresis (Table 64.4).

Select an Appropriate Diuretic Dose The dose of diuretic required to reach maximal efficacy is higher in patients with impaired kidney function than it is in individuals with normal kidney function. Using a standard 40 mg dose of furosemide in a patient with an estimated GFR (eGFR) of 20 mL/min/1.73 m2 or a patient with hypoalbuminemia from nephrotic syndrome will predictably have limited effect. Start instead with 80 mg or 160 mg. Alternatively, start with a modest dose but plan to rapidly titrate the dose upward if no effect is observed. In the outpatient setting, patients can be counseled to observe the weight change that follows dosing and increase or decrease the dose to obtain the desired effect. Furosemide is only 50% bioavailable, whereas 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. This is especially important in patients who are discharged from the hospital coincident with the dosage and route change. The fraction of diuretic excreted unchanged in the urine is a measure of the delivery of the diuretic to its site of action. Compared with normal renal function, with reduced kidney function, the fraction of furosemide excreted in the urine is better maintained than the comparable fractions for bumetanide and torsemide. Higher relative doses of bumetanide and torsemide will be required to treat CKD patients. Assure that the Duration of Diuretic Effect is Adequate As shown in Figure 64.3, reabsorption of sodium after the drug effect has dissipated may counterbalance any sodium excreted during the period of active natriuresis. 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 carefully conducted trial showed equivalent blood pressure lowering in CKD patients given a single daily dose of torsemide or a bioequivalent dose of furosemide in divided doses.15 After establishing by titration a dose that is effective, repeat it on a BID or TID schedule to assure continuous inhibition of sodium reabsorption. Limit Sodium Intake CKD is no different than any other situation requiring diuretics. Limiting intake of sodium reduces the magnitude of natriuresis required. In addition, reducing the amount of dietary sodium available for

VIII. THERAPEUTIC CONSIDERATIONS

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DIURETIC BRAKING, TOLERANCE, AND RESISTANCE

TABLE 64.4

Mechanisms and Possible Solutions for Diuretic Resistance in Patients with Impaired Renal Function

Observed Limitation

Possible Mechanism

Possible Solution

Overall and segmental fractional sodium excretion already increased

Limits effect of less potent diuretics

Start with a loop diuretic instead of a thiazide

Decreased proximal tubule secretion of diuretic

Competition with other organic acids for secretion

Avoid using with drugs that interfere with organic acid secretion such as cimetidine, methotrexate, sulfonamides, trimethoprim

Decreased renal elimination

Undiminished extrarenal clearance diverts drug from site of action

Note relative decrease in bumetanide and torsemide efficacy; increase dose

Enhanced sodium reabsorption in nephron segments downstream to site of action

Increased number of NCCT transporters in DCT cells, DCT hypertrophy

Use thiazide or metolazone for synergy; either effective despite reduced GFR

Diuretic is short acting

Delivery of diuretic below threshold toward the end of dosing interval

Follow diuretic response carefully and redose appropriately. Consider continuous IV infusion

NCCT, sodium chloride cotransporter; DCT, distal convoluted tubule; GFR, glomerular filtration rate. Modified from reference 17.

retention during intervals between diuretic doses promotes the achievement of net negative balance (Figure 64.3). As patient compliance with prescribed sodium restriction is variable, measurement of 24hour sodium excretion in the steady state can be useful to confirm adherence. 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 thiazide inhibitable NCCT NaCl cotransporter.30e33 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.35e37 The addition of metolazone may in some circumstances produce a profound diuresis.38 Because the effect of metolazone is protracted, it may take several days for the maximal effect to develop. Patients should be alerted to the possibility 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 urinary output 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 a week. In patients limited to IV diuretics, chlorothiazide, 250 or 500 mg 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 augmenting the effect of loop agents even in patients with CKD stages 3 to 539,40 (Figure 64.4).

Administer the Drug via Continuous 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 administration. To some degree, bolus administration is inefficient. The very high blood level occurring soon after administration 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. Although the fractional sodium excretion response to similar achieved rates of urinary furosemide excretion is the same for IV and bolus dosing, compared with bolus dosing, continuous infusion of bumetanide has been shown to produce greater sodium loss.25,41 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 continuous infusion protocol led to significantly greater absolute and fractional sodium excretion and a larger diuresis.42 However, repeated bolus dosing can certainly be effective if urine output is monitored and the medication dose and frequency of administration is adjusted. One clinical advantage of continuous dosing is that it requires less attention compared with repeated bolus dosing on an as-needed basis. Having an effective continuous dose running “in the background” may be advantageous compared with a dosing scheme that requires active intervention and in which repeat bolus dosing may be delayed. In a different patient population, acute decompensated CHF, no efficacy difference was found with continuous compared

VIII. THERAPEUTIC CONSIDERATIONS

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64. USE OF DIURETICS IN CHRONIC KIDNEY DISEASE PATIENTS Diet containing 100 mEq sodium 80 mEq potassium

Serum potassium (mEq/L)=

3.0 Serum 2.5 creatinine 2.0 (mg/dl) = Δ

3.5 3.0 2.5

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 Hospital days

8

9

10

11

FIGURE 64.4 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 reference 39.

with bolus dosing when both were given on a regular basis per protocol.43 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 bolus dosing. Continuous IV dosing may be safer in that respect.44,45

USE OF AGENTS OTHER THAN LOOP DIURETICS IN CKD

is increased. Several studies have shown a high rate of development of hyperchloremic metabolic acidosis in elderly patients treated with conventional doses of acetazolamide for glaucoma.46e48 In a study comparing 27 elderly glaucoma patients (mean age 69.1
7.4 years) with age-matched controls, 4 patients (14.8%) developed mild acidosis (7.29 < pH  7.31), 10 (37%) moderate acidosis (7.20 < pH  7.29), and 1 (3.7%) severe acidosis (pH 7.15). Acidosis was not observed in the controls. In a second study, tCO2 levels were inversely correlated with acetazolamide levels, which themselves correlated closely with drug dosage adjusted for creatinine clearance.

Carbonic Anhydrase Inhibitors A brief course of acetazolamide may be particularly useful in patients with CKD who have developed metabolic alkalosis in clinical settings such as after receiving nasogastric suction or after a course of loop diuretics. Acetazolamide may be preferred to a thiazide when a second agent is needed to supplement a loop diuretic and metabolic alkalosis is present. When metabolic alkalosis is absent, however, carbonic anhydrase inhibitors should be used only with great caution in CKD. Patients with impaired renal function are at increased risk for development of metabolic acidosis due to diminished ammonium production and diminished renal reserve, with an inability to compensate when acid production or bicarbonate loss

Thiazides Conventional wisdom over many years has held that thiazides are not effective in patients with impaired kidney function. The pertinent KDIGO Guideline makes the observation that most clinicians switch from a thiazide to a loop agent in patients with CKD 4, and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure advises adding a loop agent in patients with CKD 41,49e52 The role of thiazides is evolving as a result of accumulating evidence that thiazides do retain efficacy in patients with CKD.53,54 Two early studies examined this question. The first included 17 individuals with creatinine clearances ranging from 5e133 mL/min. Half had creatinine

VIII. THERAPEUTIC CONSIDERATIONS

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USE OF AGENTS OTHER THAN LOOP DIURETICS IN CKD

clearances at or below 53 mL/min. Bemetizide, 25 mg, resulted in an increase in absolute sodium excretion throughout the clearance range that was proportional to the clearance value. A second study by the same investigators, also in people with a wide range of creatinine clearances, noted an increase in fractional sodium excretion after a thiazide alone. The combination of low dose HCTZ (25 mg) and 40 mg furosemide produced a significant increase in absolute sodium excretion compared with baseline. However, the difference in absolute excretion of sodium with HCTZ alone was not significant compared with placebo.55,56 The creatinine clearances in the subset of patients with CKD ranged from 4e75 mL/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, fractional sodium excretion, and weights in patients with stages 3e5 CKD. Using a double-blind, placebocontrolled, randomized crossover design, patients either received placebo, 25 mg HCTZ, 40 mg 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 weight reduction. Despite the lack of consistent weight reduction, mean arterial pressure fell significantly in both studies in all three diuretic groups.40,57 An open label, parallel treatment

study compared the effect of chlorthalidone 25 mg in 60 patients with impaired kidney function (mean eGFR 39, range 15e59 mL/min/1.73 m2) to its effect in 60 patients with normal kidney function (mean eGFR 76, range 60e104 mL/min/1.73 m2). After 8 weeks of treatment, systolic blood pressure changes were similar, decreasing 20 mm Hg (95% confidence interval 22 to 18) and 23 mm Hg (26 to 19), respectively. The blood pressure decrement was similar in the subgroups with CKD 3b, 4, and 558 (Figure 64.5). Studies have examined the effect of add-on thiazide therapy to further reduce blood pressure, proteinuria, or albuminuria in patients with CKD already receiving ACEI or ARB treatment. Some compare a thiazide with a calcium channel blocker, noting a more favorable effect on albuminuria for the thiazide but a tendency for a larger short-term fall in eGFR. Most of these studies are small. They use heterogeneous submaximal doses of different thiazides in patients at varying stages of CKD who may or may not also be receiving maximal doses of loop diuretics, ACEIs, or ARBs. The studies provide evidence that thiazides can be beneficial in this setting. However, their design does not permit separating a specific antialbuminuric effect of the thiazide itself from the blood pressure lowering effect.59,60 One such study, a randomized crossover trial, examined addition of spironolactone 25 mg or hydrochlorothiazide 50 mg to the regimen of 21 patients with CKD stages 1e3 who were already taking enalapril. After 4 weeks of treatment, systolic blood pressure fell from 130
18 to 125
20 mg Hg (p < 0.05) with spironolactone and from 129
18 to 124
19 mm Hg (p ¼ NS)

170 100

90

150

140

80

DBP, mm Hg

SBP, mm Hg

160

130 70 120

110

60 screening 0 1 2

4

Time, weeks

6

8

screening 0 1 2

4

6

8

Time, weeks

FIGURE 64.5

Means of systolic blood pressure (SBP, left) and diastolic blood pressure (DBP, right) in hypertensive individuals with eGFR<60 mL/min/1.73 m2, closed circles, n ¼ 60 and hypertensive individuals with 60 mL/min/1.73 m2  eGFR  104 mL/min/1.73 m2, open circles, n ¼ 57 who received chlorthalidone, 25 mg daily, from week zero. Patient numbers and graphs are for per protocol groups. Reproduced with permission from reference 58.

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64. USE OF DIURETICS IN CHRONIC KIDNEY DISEASE PATIENTS

with hydrochlorothiazide, as albumin excretion fell from 1600 (25e75% IQR 1047e2152) to 1125 mg/day (IQR 500e1750) (p < 0.05), with spironolactone and from 1417 (IQR 868e1965) to 935 mg/day (IQR 266e1603) (p < 0.05) with hydrochlorothiazide. In the spironolactone group, 12 patients (57%) experienced a >30% reduction in urinary albumin:creatinine ratio as did 17 (81%) of the hydrochlorothiazide-treated patients. Daily urine protein excretion fell from a mean of 1.7 (IQR 1.3e2.2) to 1.5 g (IQR 0.8e2.3) (p < 0.05) with spironolactone and from 1.7 (IQR 1.3e2.1) to 1.3 g (IQR 0.6e2) (p < 0.05) with hydrochlorothiazide. Weight fell with both regimens and the fall in albumin excretion correlated with the reduction in eGFR and blood pressure. Results were similar in a third group that received hydrochlorothiazide 50 mg plus amiloride 5 mg.61 Taken together, these trials provide additional support for rejecting the notion that thiazides should be stopped when some arbitrary low threshold of GFR is reached, as they retain utility in lowering blood pressure and may reduce albuminuria or proteinuria. The observed effects may be due to some other cause than a natriuresis. This is not a new observation.62 Potential mechanisms, including diminished pressor response to catecholamines and angiotensin II, calcium desensitization of smooth muscle, nitric oxide release, and activation of potassium channels, have been reviewed.53 Notably, intraarterial infusion of hydrochlorothiazide, but not the thiazide-like agent indapamide, causes a forearm vasodilator response both in normal individuals and those with Gitelman syndrome who lack the distal convoluted tubule NCC thiazide receptor.63 Results from large-scale trials also support the use of thiazides. In a post hoc analysis of the subgroup of patients in the ALLHAT trial with eGFR below 60 mL/ min/1.73 m2, chlorthalidone was noted to be more effective than amlodipine or lisinopril in preventing stroke and congestive heart failure, and noninferior in preventing coronary heart disease, cardiovascular disease events, or ESRD. These differences (except for a lower incidence of heart failure compared with amlodipine) did not persist at late follow-up, but patients were no longer being treated per protocol at that point. As such, this study provides evidence for efficacy of chlorthalidone in improving outcomes in CKD. Systolic blood pressure was slightly lower in the ALLHAT chlorthalidone group, although ALLHAT was not designed to assess patients with diminished renal function specifically, and patients with serum creatinine (S[Cr]) above 2.0 mg/dL or proteinuria were excluded.64,65 Considerable support for the use of thiazide-type diuretics was provided by the SPRINT trial, which, in contrast to ALLHAT, was specifically designed to examine

cardiovascular outcomes in patients with impaired kidney function. Its study protocol recommended that thiazide diuretics be chosen as initial antihypertensive therapy. Fully 46.8% of the 1330 intensively treated CKD patients and 30.1% of the 1316 CKD patients that received standard therapy were receiving a thiazidetype diuretic at last visit, although no breakdown between the two formulary agents, chlorthalidone and hydrochlorothiazide/amiloride, was provided. The study demonstrated reduced rates of major cardiovascular events and all-cause death in its intensive blood pressure control group, a large plurality of whom were receiving thiazides to achieve the blood pressure goal.66 A potential role of thiazide therapy compared with loop diuretic therapy to lessen the risk of development of secondary hyperparathyroidism in CKD has been suggested by an analysis of the Chronic Renal Insufficiency Cohort. In this patient population, eGFR ranged from 20 to 70 mL/min/1.73 m2. In the subset of patients receiving diuretics, the adjusted daily calcium excretion was 39.6 mg/24 h (37.2e42.2, 95% CI). In the subset receiving loop diuretics alone, it was 55.0 mg/24 h (50.8e59.5, p < 0.05 vs. no diuretic). In the subset receiving thiazides alone, it was 25.5 mg/24 h (23.3e27.8, p < 0.05 vs. no diuretic). In the subset receiving both, it was 30.3 mg/24 h (26.6e34.5, p < 0.05).67 PTH levels were higher in the loop diuretic-treated patients compared with patients who received no diuretics, but there was no difference between thiazide-treated patients and the controls. The adjusted odds ratio for secondary hyperparathyroidism, defined as a PTH65 pg/mL, was higher for participants treated with loop diuretics than for those 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 substitution of a thiazide is far from established.68 Little guidance is available on the choice of thiazide or thiazide-type diuretic to use in patients with CKD. Drug potency varies between agents. In normal individuals, the amount of drug estimated to produce a 10 mm Hg reduction in systolic BP is 1.4 mg for bendroflumethiazide, 8.6 mg for chlorthalidone, and 26.4 mg for hydrochlorothiazide.69 Chlorthalidone is often recommended because of its longer duration of action, and the large-scale trials cited above used it exclusively or favored it over hydrochlorothiazide, but its longer

VIII. THERAPEUTIC CONSIDERATIONS

USE OF AGENTS OTHER THAN LOOP DIURETICS IN CKD

duration of action may predispose to a higher risk of complications.64,66,70 Formal comparisons in patients with CKD are lacking.

Mineralocorticoid Receptor Antagonists Two MRAs are currently approved for use by the US FDA, spironolactone and eplerenone. The former is nonspecific, with lesser but still significant affinity for progesterone and androgen receptors, a characteristic responsible for its endocrine side effects, including gynecomastia, diminished libido, and menstrual irregularities. Eplerenone is a more specific MRA. It has fewer off-target effects but is also less potent and more expensive. The pharmacokinetics of neither agent is significantly affected by renal functional impairment. Both these agents have steroid chemical structures. New, nonsteroidal agents, including finerenone, which has a dihydropyridine structure, are under development.71e74 MRAs are highly effective in lowering blood pressure in patients with normal renal function and resistant hypertension. They have long been used as add on therapy in that setting.75 However, any benefit of lowering blood pressure in CKD patients, particularly individuals already receiving an ACEI or ARB, has to be considered in the context of the risk of hyperkalemia. Studies in patients with CKD document similar efficacy of MRAs for blood pressure control and provide reassurance that if used with care, the risk of hyperkalemia is not prohibitive. One such study retrospectively examined 88 patients with resistant hypertension who were begun on spironolactone. The baseline drug regimen included an ACEI or ARB in 90% of patients. Thirty-four patients had CKD, defined as an eGFR <60 mL/min/1.73 m2. Mean systolic blood pressure fell from 153
18 to 143
20 mm Hg (p ¼ 0.006), from baseline to first clinic visit after starting spironolactone in the CKD patients, and from 150
17 to 135
17 mm Hg (p < 0.001), in the patients without CKD. In both groups, about half of patients responded with a blood pressure drop, but half were nonresponders. Serum potassium (S[K]) increased by 0.5
0.6 mEq/L in the CKD group vs. 0.3
0.5 mEq/L in the patients without CKD, a difference that was not statistically significant. Hyperkalemia, defined as S[K] >5.5%, occurred in 5.7% of CKD patients compared with none of the non-CKD patients (p ¼ 0.07). In a multivariable model, only eGFR <45 mL/min/1.73 m2 was associated with a higher risk of hyperkalemia. The dose of spironolactone was less than 25 mg in 93% of individuals. Length of follow-up beyond one return visit was not specified, and whether more patients would have responded with longer follow-up or developed hyperkalemia is unknown.76 In a retrospective study of 36 patients with resistant hypertension, all with stage 3 CKD,

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in whom spironolactone (mean dose 23.6
10.5 mg) or eplerenone (mean dose 60.4
33.9 mg) was added to a preexisting drug regimen that included an ACEI or ARB, systolic blood pressure after a median of 312 days dropped from 162
22 to 138
14 mm Hg, p < 0.0001, and diastolic blood pressure from 87
17 to 74
12 mm Hg, p < 0.0001. The eGFR decreased from 48.6
8.7 to 41.2
11.5 mL/min/1.73 m2 (p ¼ 0.002). S [K] increased from 4.0
0.5 to 4.4
0.5 mEq/L (p ¼ 0.0001), with 8 (22%) patients developing hyperkalemia (S[K] >5 mEq/L) at any time, including 3 (8%) with a value of S[K] above 5.5 mEq/L.77 In a study of patients with mild to moderate CKD (eGFR 30e89 mL/min/ 1.73 m2) spironolactone, 25 mg, or placebo was used as an add on to maximal ACEI or ARB therapy over a 40 week period. Patients who developed hyperkalemia during a one-month open label spironolactone run in period were dropped from the study before randomization. Of the 112 patients who went forward, fewer than 1% developed S[K] 6.0 mEq/L. Eleven patients (9 on spironolactone) developed hyperkalemia in the S[K] 5.5e5.9 mEq/L range. At 40 weeks, the drop in ambulatory systolic blood pressure was 6 mg Hg (95% CI 8 to 1) in the spironolactone treated group vs. 1 mm Hg (3 to 1) in the placebo group (p < 0.01). In this group of patients who were already receiving maximal ACEI or ARB therapy, the only predictor of hyperkalemia was baseline S[K] > 5.0 mEq/L78 Another study noted eGFR<45 mL/min/1.73 m2 and treatment-induced drop in systolic blood pressure >15 mm Hg as risk factors for hyperkalemia.79 An influential population-based study showed an increased rate of hyperkalemia morbidity and mortality following publication of the RALES study, and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure cautions against initiating aldosterone receptor antagonists in patients with a basal S[K] exceeding 5 mEq/L.50,80 Even so, these small but granular studies provide reassurance that MRAs can be used safely in patients with mild to moderate reductions in GFR. Eplerenone has a shorter half-life than spironolactone. Its use has been suggested as an alternative to spironolactone in CKD because its effect will dissipate sooner if hyperkalemia develops. Conventional strategies to permit use of MRAs in CKD include restriction of potassium intake, supplementation with bicarbonate to provide a nonreabsorbable anion (excretion of which may enhance potassium excretion), and concomitant use of kaliuretic loop diuretics. Patiromer and sodium zirconium cyclosilicate have recently been approved as potassium lowering agents.81,82 Published data specifically addressing hyperkalemia risk in patients with CKD stages 3b, 4, and 5 are lacking; no studies systematically address the effect of concurrently prescribed

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kaliuretic loop or thiazide diuretics or bicarbonate on hyperkalemia risk.83 In summary, MRAs effectively lower blood pressure in patients with reduced GFR, including those receiving ACEIs or ARBs, but their safe use requires ongoing vigilance regarding the possible development of hyperkalemia. Mineralocorticoid receptors are now known to be present not only in principal cells of the collecting duct but also in a variety of other cells or tissues, among them the heart, brain, vascular smooth muscle, and glomerular podocytes. At these sites, activation of the mineralocorticoid receptor has pleiotropic effects to increase the release or activation of vasoconstrictors and inflammatory or profibrotic cytokines, promote cardiac and kidney fibrosis, contribute to insulin insensitivity, and cause glomerular podocyte damage with worsened proteinuria. As a result, increasing attention has been drawn to the use of MRAs in patients with CKD to reduce proteinuria, reduce risk of ESRD, and improve cardiovascular outcomes.84,85 As aldosterone levels increase in 30e50% of patients after initiation of ACEI or ARB therapy, a phenomenon called aldosterone escape or breakthrough, adding MRA therapy to the regimen of CKD patients already receiving ACEI or ARB therapy could be especially attractive.72 Addition of spironolactone or eplerenone has been demonstrated to reduce proteinuria by 38e61% in such patients or to reduce albuminuria by 33e48%.86e90 This practice has been the subject of several systematic reviews or meta-analyses. Although they confirm that added MRAs reduce blood pressure and proteinuria or albuminuria, increase the rate of development of hyperkalemia, and modestly lower GFR over the short term, none of the small studies that form the basis of this conclusion was designed or powered to assess hard, patient-centered outcomes such as cardiovascular events, mortality, or development of ESRD. Thus, neither individual studies nor the comprehensive reviews provide compelling evidence to date regarding whether MRAs have an indication in CKD beyond management of refractory hypertension.84,91e93 Large-scale trials with the potential to provide more definitive data are underway83 (https://clinicaltrials.gov/ct2/show/NCT02540993).

USE OF DIURETICS FOR TREATMENT OF HYPERTENSION IN CKD Extracellular volume overload is an important contributor to hypertension in CKD patients, and correction of volume overload with diuretics is a key part of treatment. When appropriately dosed, loop diuretics are plainly effective in reducing extracellular volume and lowering blood pressure in CKD patients.15,94 Although this principle is generally accepted, diuretics appear to be underutilized in CKD patients, perhaps

because of prescriber concerns about the tendency of these agents to lower eGFR if clinical or subclinical volume depletion is induced. A large study evaluating treatment of hypertension in 26 Italian CKD clinics observed furosemide use (the loop diuretic prescribed virtually exclusively) 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. A fixed dose combination of losartan 50 mg/hydrochlorothiazide 12.5 mg was found to be inferior to losartan 50 mg plus nifedipine 20e40 mg for lowering blood pressure in CKD patients, highlighting the need to choose an appropriate diuretic in an adequate dosage.

DIURETIC COMPLICATIONS Diuretic complications have been extensively reviewed.45,95 Metabolic derangements resulting from use of thiazide or loop diuretics include hyponatremia, 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 ACEIs or ARBs as well as MRAs in this population may mitigate hypokalemia or result in frank hyperkalemia. Spironolactone may contribute to the development of metabolic acidosis.96 When present, hypokalemia is readily managed with potassium supplementation or addition of a potassium-sparing agent. Hyponatremia carries an adverse prognosis in CKD patients, as it does in the general population.97,98 Hyponatremia is much more common with the thiazides, which block sodium transport in the distal convoluted tubule diluting sites. Recently, a genetic risk factor for thiazide-induced hyponatremia related to altered prostaglandin transport and diminished water excretion has been identified.99 In any event, thiazide diuretics 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 also be responsible for the reluctance of some clinicians to prescribe diuretics. However, hyperuricemia is amenable to therapy with allopurinol. Hypomagnesemia may be a particular problem in renal transplant patients with CKD who receive both diuretics and tacrolimus. Clinicians should be vigilant for this complication, supplement magnesium, and stop proton pump inhibitors, if coprescribed, as required. Finally, diuretics may exacerbate urinary incontinence. Reported diminished adherence to diuretics is 3e4 times more prevalent among patients with urinary incontinence, a factor that may contribute to apparent refractoriness to diuretics.100

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REFERENCES

CONCLUSION As CKD is commonly associated with sodium retention, which contributes importantly to hypertension, diuretics are often prescribed to CKD patients. The potent loop agents remain the mainstay of diuretic therapy, but their proper use requires an understanding of their altered pharmacokinetics and pharmacodynamics in CKD. Repeating an inadequate dose is futile; it is essential to use upward dosage titration to identify an effective dose, which can then be repeated. Short-acting agents, such as furosemide and bumetanide, should be given more than once per day to assure that the antinatriuresis characteristic of the diuretic-free interval does not negate the natriuresis achieved while active drug is present. Recent data, confirmed by the SPRINT trial, suggest that thiazides have persistent benefit with improved outcomes even in advanced CKD. They need not be abandoned at some arbitrary level of GFR.66 Mineralocorticoid antagonists are particularly useful add-on agents both for blood pressure control and to reduce proteinuria and slow disease progression in CKD, although clinicians should maintain vigilance for hyperkalemia when an agent of this class is used.

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14. Goto S, Yoshitomi H, Miyamoto A, Inoue K, Nakano M. Binding of several loop diuretics to serum albumin and human serum from patients with renal failure and liver disease. J PharmacobioDyn 1980;3:667e76. 15. Vasavada N, Agarwal R. Role of excess volume in the pathophysiology of hypertension in chronic kidney disease. Kidney Int 2003; 64:1772e9. 16. Brater DC. Resistance to loop diuretics. Why it happens and what to do about it. Drugs 1985;30:427e43. 17. Wilcox CS. New insights into diuretic use in patients with chronic renal disease. J Am Soc Nephrol 2002;13:798e805. 18. Rane A, Villeneuve JP, Stone WJ, Nies AS, Wilkinson GR, Branch RA. Plasma binding and disposition of furosemide in the nephrotic syndrome and in uremia. Clin Pharmacol Ther 1978;24:199e207. 19. Pichette V, Geadah D, du SP. Role of plasma protein binding on renal metabolism and dynamics of furosemide in the rabbit. Drug Metab Dispos 1999;27:81e5. 20. Kirchner KA, Voelker JR, Brater DC. Binding inhibitors restore furosemide potency in tubule fluid containing albumin. Kidney Int 1991;40:418e24. 21. Fliser D, Zurbruggen I, Mutschler E, Bischoff I, Nussberger J, Franek E, Ritz E. Coadministration of albumin and furosemide in patients with the nephrotic syndrome. Kidney Int 1999;55:629e34. 22. Akcicek F, Yalniz T, Basci A, Ok E, Mees EJ. Diuretic effect of frusemide in patients with nephrotic syndrome: is it potentiated by intravenous albumin? BMJ 1995;310:162e3. 23. Phakdeekitcharoen B, Boonyawat K. The added-up albumin enhances the diuretic effect of furosemide in patients with hypoalbuminemic chronic kidney disease: a randomized controlled study. BMC Nephrol 2012;13:92. 24. Agarwal R, Gorski JC, Sundblad K, Brater DC. Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome. J Am Soc Nephrol 2000;11:1100e5. 25. Brater DC, Anderson SA, Brown-Cartwright D. Response to furosemide in chronic renal insufficiency: rationale for limited doses. Clin Pharmacol Ther 1986;40:134e9. 26. Rudy DW, Gehr TW, Matzke GR, Kramer WG, Sica DA, Brater DC. The pharmacodynamics of intravenous and oral torsemide in patients with chronic renal insufficiency. Clin Pharmacol Ther 1994;56:39e47. 27. Allison ME, Lindsay MK, Kennedy AC. Oral bumetanide in chronic renal failure. Postgrad Med J 1975;51(Suppl. 6):47e50. 28. Wilcox CS, Mitch WE, Kelly RA, Skorecki K, Meyer TW, Friedman PA, Souney PF. Response of the kidney to furosemide. I. Effects of salt intake and renal compensation. J Lab Clin Med 1983;102:450e8. 29. Wilcox CS, Guzman NJ, Mitch WE, Kelly RA, Maroni BJ, Souney PF, Rayment CM, Braun L, Colucci R, Loon NR. Naþ, Kþ, and BP homeostasis in man during furosemide: effects of prazosin and captopril. Kidney Int 1987;31:135e41. 30. Ellison DH. Diuretic drugs and the treatment of edema: from clinic to bench and back again. Am J Kidney Dis 1994;23:623e43. 31. Ellison DH, Velazquez H, Wright FS. Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietary salt intake and chronic diuretic infusion. J Clin Investig 1989; 83:113e26. 32. Chen ZF, Vaughn DA, Beaumont K, Fanestil DD. Effects of diuretic treatment and of dietary sodium on renal binding of 3H-metolazone. J Am Soc Nephrol 1990;1:91e8. 33. Kaissling B, Stanton BA. Adaptation of distal tubule and collecting duct to increased sodium delivery. I. Ultrastructure. Am J Physiol 1988;255:F1256e68. 34. Ellison DH. Treatment of disorders of sodium balance in chronic kidney disease. Adv Chron Kidney Dis 2017;24:332e41.

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35. Brater DC, Pressley RH, Anderson SA. Mechanisms of the synergistic combination of metolazone and bumetanide. J Pharmacol Exp Ther 1985;233:70e4. 36. Marone C, Muggli F, Lahn W, Frey FJ. Pharmacokinetic and pharmacodynamic interaction between furosemide and metolazone in man. Eur J Clin Investig 1985;15:253e7. 37. Greenberg A, Wallia R, Puschett JB. Combined effect of bumetanide and metolazone in normal volunteers. J Clin Pharmacol 1985;25:369e73. 38. Gunstone RF, Wing AJ, Shani HG, Njemo D, Sabuka EM. Clinical experience with metolazone in fifty-two African patients: synergy with frusemide. Postgrad Med J 1971;47:789e93. 39. Wollam GL, Tarazi RC, Bravo EL, Dustan HP. Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am J Med 1982;72:929e38. 40. Dussol B, Moussi-Frances J, Morange S, Somma-Delpero C, Mundler O, Berland Y. A pilot study comparing furosemide and hydrochlorothiazide in patients with hypertension and stage 4 or 5 chronic kidney disease. J Clin Hypertens 2012;14:32e7. 41. Rudy DW, Voelker JR, Greene PK, Esparza FA, Brater DC. Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy. Ann Intern Med 1991;115: 360e6. 42. Sanjay S, Annigeri RA, Seshadri R, Rao BS, Prakash KC, Mani MK. The comparison of the diuretic and natriuretic efficacy of continuous and bolus intravenous furosemide in patients with chronic kidney disease. Nephrology 2008;13:247e50. 43. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O’Connor CM. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797e805. 44. Gerlag PG, van Meijel JJ. High-dose furosemide in the treatment of refractory congestive heart failure. Arch Intern Med 1988;148: 286e91. 45. Greenberg A. Diuretic complications. Am J Med Sci 2000;319: 10e24. 46. Chapron DJ, Gomolin IH, Sweeney KR. Acetazolamide blood concentrations are excessive in the elderly: propensity for acidosis and relationship to renal function. J Clin Pharmacol 1989;29:348e53. 47. Maisey DN, Brown RD. Acetazolamide and symptomatic metabolic acidosis in mild renal failure. Br Med J 1981;283:1527e8. 48. Heller I, Halevy J, Cohen S, Theodor E. Significant metabolic acidosis induced by acetazolamide. Not a rare complication. Arch Intern Med 1985;145:1815e7. 49. Reubi FC, Cottier PT. Effects of reduced glomerular filtration rate on responsiveness to chlorothiazide and mercurial diuretics. Circulation 1961;23:200e10. 50. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ. National heart LaBIJNCoP, national high blood pressure education program coordinating committee: the seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. J Am Med Assoc 2003;289:2560e72. 51. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43:S1e290. 52. Chapter 2: lifestyle and pharmacological treatments for lowering blood pressure in CKD ND patients. Kidney Int Suppl 2012;2: 347e56. 53. Karadsheh F, Weir MR. Thiazide and thiazide-like diuretics: an opportunity to reduce blood pressure in patients with advanced kidney disease. Curr Hypertens Rep 2012;14:416e20.

54. Sinha AD, Agarwal R. Thiazide diuretics in chronic kidney disease. Curr Hypertens Rep 2015;17:13. 55. Knauf H, Cawello W, Schmidt G, Mutschler E. The saluretic effect of the thiazide diuretic bemetizide in relation to the glomerular filtration rate. Eur J Clin Pharmacol 1994;46:9e13. 56. Knauf H, Mutschler E. Diuretic effectiveness of hydrochlorothiazide and furosemide alone and in combination in chronic renal failure. J Cardiovasc Pharmacol 1995;26:394e400. 57. Dussol B, Moussi-Frances J, Morange S, Somma-Delpero C, Mundler O, Berland Y. A randomized trial of furosemide vs hydrochlorothiazide in patients with chronic renal failure and hypertension. Nephrol Dial Transplant 2005;20:349e53. 58. Cirillo M, Marcarelli F, Mele AA, Romano M, Lombardi C, Bilancio G. Parallel-group 8-week study on chlorthalidone effects in hypertensives with low kidney function. Hypertension 2014;63: 692e7. 59. Hoshino T, Ookawara S, Miyazawa H, Ito K, Ueda Y, Kaku Y, Hirai K, Mori H, Yoshida I, Tabei K. Renoprotective effects of thiazides combined with loop diuretics in patients with type 2 diabetic kidney disease. Clin Exp Nephrol 2015;19:247e53. 60. Ishimitsu T, Ohno E, Nakano N, Furukata S, Akashiba A, Minami J, Numabe A, Matsuoka H. Combination of angiotensin II receptor antagonist with calcium channel blocker or diuretic as antihypertensive therapy for patients with chronic kidney disease. Clin Exp Hypertens 2011;33:366e72. 61. Morales E, Caro J, Gutierrez E, Sevillano A, Aunon P, Fernandez C, Praga M. Diverse diuretics regimens differentially enhance the antialbuminuric effect of renin-angiotensin blockers in patients with chronic kidney disease. Kidney Int 2015;88: 1434e41. 62. Jones B, Nanra RS. Double-blind trial of antihypertensive effect of chlorothiazide in severe renal failure. Lancet 1979;2:1258e60. 63. Pickkers P, Hughes AD, Russel FG, Thien T, Smits P. Thiazideinduced vasodilation in humans is mediated by potassium channel activation. Hypertension 1998;32:1071e6. 64. Rahman M, Pressel S, Davis BR, Nwachuku C, Wright Jr JT, Whelton PK, Barzilay J, Batuman V, Eckfeldt JH, Farber MA, Franklin S, Henriquez M, Kopyt N, Louis GT, Saklayen M, Stanford C, Walworth C, Ward H, Wiegmann T. Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med 2006;144:172e80. 65. Rahman M, Ford CE, Cutler JA, Davis BR, Piller LB, Whelton PK, Wright Jr JT, Barzilay JI, Brown CD, Colon Sr PJ, Fine LJ, Grimm Jr RH, Gupta AK, Baimbridge C, Haywood LJ, Henriquez MA, Ilamaythi E, Oparil S, Preston R. Long-term renal and cardiovascular outcomes in antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT) participants by baseline estimated GFR. Clin J Am Soc Nephrol 2012;7: 989e1002. 66. Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, Cushman WC, Hawfield AT, Johnson KC, Lewis CE, Oparil S, Rocco MV, Sink KM, Whelton PK, Wright Jr JT, Basile J, Beddhu S, Bhatt U, Chang TI, Chertow GM, Chonchol M, Freedman BI, Haley W, Ix JH, Katz LA, Killeen AA, Papademetriou V, Ricardo AC, Servilla K, Wall B, Wolfgram D, Yee J. Effects of intensive BP control in CKD. J Am Soc Nephrol 2017;28:2812e23. 67. Isakova T, Anderson CA, Leonard MB, Xie D, Gutierrez OM, Rosen LK, Theurer J, Bellovich K, Steigerwalt SP, Tang I, Anderson AH, Townsend RR, He J, Feldman HI, Wolf M. Chronic renal insufficiency cohort (CRIC) study group: diuretics, calciuria and secondary hyperparathyroidism in the chronic renal insufficiency cohort. Nephrol Dial Transplant 2011;26:1258e65. 68. Kovesdy CP, Kalantar-Zadeh K. Diuretics and secondary hyperparathyroidism in chronic kidney disease. Nephrol Dial Transplant 2011;26:1122e5.

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69. Peterzan MA, Hardy R, Chaturvedi N, Hughes AD. Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthalidone, and bendroflumethiazide on blood pressure, serum potassium, and urate. Hypertension 2012;59:1104e9. 70. Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, Bergus GR. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006;47:352e8. 71. Yang P, Huang T, Xu G. The novel mineralocorticoid receptor antagonist finerenone in diabetic kidney disease: progress and challenges. Metabolism 2016;65:1342e9. 72. Schwenk MH, Hirsch JS, Bomback AS. Aldosterone blockade in CKD: emphasis on pharmacology. Adv Chron Kidney Dis 2015;22: 123e32. 73. Filippatos G, Anker SD, Bohm M, Gheorghiade M, Kober L, Krum H, Maggioni AP, Ponikowski P, Voors AA, Zannad F, Kim SY, Nowack C, Palombo G, Kolkhof P, KimmeskampKirschbaum N, Pieper A, Pitt B. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J 2016;37:2105e14. 74. Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, Remuzzi G, Rossing P, Schmieder RE, Nowack C, Kolkhof P, Joseph A, Pieper A, Kimmeskamp-Kirschbaum N, Ruilope LM. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. J Am Med Assoc 2015;314:884e94. 75. Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 2003;16:925e30. 76. Heshka J, Ruzicka M, Hiremath S, McCormick BB. Spironolactone for difficult to control hypertension in chronic kidney disease: an analysis of safety and efficacy. J Am Soc Hypertens 2010;4:295e301. 77. Pisoni R, Acelajado MC, Cartmill FR, Dudenbostel T, Dell’Italia LJ, Cofield SS, Oparil S, Calhoun DA. Long-term effects of aldosterone blockade in resistant hypertension associated with chronic kidney disease. J Hum Hypertens 2012;26:502e6. 78. Edwards NC, Steeds RP, Chue CD, Stewart PM, Ferro CJ, Townend JN. The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease. Br J Clin Pharmacol 2012;73:447e54. 79. Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am J Nephrol 2009;30:418e24. 80. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 2004;351:543e51. 81. Weir MR, Mayo MR, Garza D, Arthur SA, Berman L, Bushinsky D, Wilson DJ, Epstein M. Effectiveness of patiromer in the treatment of hyperkalemia in chronic kidney disease patients with hypertension on diuretics. J Hypertens 2017;35(Suppl. 1):S57e63. 82. Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, Qunibi W, Pergola P, Singh B. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 2015;372:222e31. 83. Hill NR, Lasserson D, Thompson B, Perera-Salazar R, Wolstenholme J, Bower P, Blakeman T, Fitzmaurice D, Little P, Feder G, Qureshi N, Taal M, Townend J, Ferro C, McManus R, Hobbs FR. Benefits of Aldosterone Receptor Antagonism in Chronic Kidney Disease (BARACK D) trial-a multi-centre, prospective, randomised, open, blinded end-point, 36-month study of 2,616 patients within primary care with stage 3b chronic kidney disease to compare the efficacy of spironolactone 25 mg once daily in addition to routine care on mortality and cardiovascular outcomes versus routine care alone: study protocol for a randomized controlled trial. Trials 2014;15:160.

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84. Shavit L, Lifschitz MD, Epstein M. Aldosterone blockade and the mineralocorticoid receptor in the management of chronic kidney disease: current concepts and emerging treatment paradigms. Kidney Int 2012;81:955e68. 85. Hirsch JS, Drexler Y, Bomback AS. Aldosterone blockade in chronic kidney disease. Semin Nephrol 2014;34:307e22. 86. Tsuboi N, Kawamura T, Okonogi H, Ishii T, Hosoya T. The longterm antiproteinuric effect of eplerenone, a selective aldosterone blocker, in patients with non-diabetic chronic kidney disease. J Renin Angiotensin Aldosterone Syst 2012;13:113e7. 87. Morales E, Millet VG, Rojas-Rivera J, Huerta A, Gutierrez E, Gutierrez-Solis E, Egido J, Praga M. Renoprotective effects of mineralocorticoid receptor blockers in patients with proteinuric kidney diseases. Nephrol Dial Transplant 2013;28:405e12. 88. Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 2005;28:2106e12. 89. Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, Patni R, Beckerman B. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 2006;1:940e51. 90. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009;20:2641e50. 91. Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis 2008;51:199e211. 92. Bolignano D, Palmer SC, Navaneethan SD, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev 2014:CD007004. 93. Currie G, Taylor AH, Fujita T, Ohtsu H, Lindhardt M, Rossing P, Boesby L, Edwards NC, Ferro CJ, Townend JN, van den Meiracker AH, Saklayen MG, Oveisi S, Jardine AG, Delles C, Preiss DJ, Mark PB. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis. BMC Nephrol 2016;17:127. 94. Vasavada N, Saha C, Agarwal R. A double-blind randomized crossover trial of two loop diuretics in chronic kidney disease. Kidney Int 2003;64:632e40. 95. Sica DA. Hypertension, renal disease, and drug considerations. J Clin Hypertens 2004;6:24e30. 96. Gabow PA, Moore S, Schrier RW. Spironolactone-induced hyperchloremic acidosis in cirrhosis. Ann Intern Med 1979;90:338e40. 97. Kovesdy CP, Lott EH, Lu JL, Malakauskas SM, Ma JZ, Molnar MZ, Kalantar-Zadeh K. Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation 2012;125:677e84. 98. Hoorn EJ, Zietse R. Hyponatremia and mortality: moving beyond associations. Am J Kidney Dis 2013;62:139e49. 99. Ware JS, Wain LV, Channavajjhala SK, Jackson VE, Edwards E, Lu R, Siew K, Jia W, Shrine N, Kinnear S, Jalland M, Henry AP, Clayton J, O’Shaughnessy KM, Tobin MD, Schuster VL, Cook S, Hall IP, Glover M. Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. J Clin Investig 2017;127:3367e74. 100. Patel M, Vellanki K, Leehey DJ, Bansal VK, Brubaker L, Flanigan R, Koval J, Wadhwa A, Balasubramanian N, Sandhu J, Kramer H. Urinary incontinence and diuretic avoidance among adults with chronic kidney disease. Int Urol Nephrol 2016;48: 1321e6. 101. Quamme GA. Loop diuretics. In: Dirks JH, Sutton RAL, editors. Diuretics. Physiology pharmacology & clinical use. Philadelphia: W. B. Saunders Company; 1986. p. 86e116.

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QUESTIONS AND ANSWERS Question 1 A 63-year-old man with IgA nephropathy returns to CKD clinic for follow-up. He has no complaints and reports good compliance with his sodium and potassium restricted diet. Current medications include ramipril 10 mg, amlodipine 10 mg, and chlorthalidone 25 mg. Blood pressure is 128/78 mm Hg. Physical examination is unremarkable. No edema is present. Laboratory values: BUN 17, S[Cr] 1.9, eGFR 36 mL/ min/1.73 m2, S[Na] 138 mmol/L, S[K] 5.2 mmol/L, S [Cl] 105 mmol/L, and tCO2 23 mmol/L. Urine protein: creatinine ratio (UPCR) 1.1 g/g. Which one of the following is the best course of action now? A. B. C. D. E.

Stop ramipril Add sodium bicarbonate 650 mg BID Stop chlorthalidone, substitute furosemide Continue current regimen Add sodium polystyrene sulfonate resin in sorbitol three times weekly

Answer: D The patient is doing well, with excellent blood pressure control. Although renal function is worse than the level at which conventional wisdom holds that thiazides are effective, several recent papers suggest that thiazides do lower blood pressure at this level of renal function, perhaps through a mechanism other than diuresis. Thus, Answer C is incorrect. The potassium level is not high enough to warrant other measures (A, B, or E) to lower it.

Question 2 A 45-year-old woman with polycystic kidney disease presents for follow-up. She has noted difficulty focusing on intellectual tasks and mild memory impairment. Although she had significant difficulty with depression a year ago before sertraline was begun, in the interval, her insomnia and depressed mood have not recurred. Having read on a website that vasopressin may promote cyst growth, she has increased fluid intake to at least 3 L per day. She has smoked one pack of cigarettes per day since age 22. Medications include hydrochlorothiazide 25 mg, lisinopril 10 mg daily, sertraline 50 mg, and extended release metoprolol 25 mg daily. Physical examination discloses a well-appearing woman with blood pressure 131/82 mm Hg. The kidneys are not palpable. No edema is present. Laboratory values: BUN 13 mg/dL, S[Cr] 1.6 mmol/ L, eGFR 37 mL/min/1.73 m2, S[Na] 128 mmol/L, S[K] 3.9 mmol/L, S[Cl] 103 mmol/L, tCO2 22 mmol/L, and

glucose 98 mg/dL. Urine osmolality 205 mOsm/kg and urine sodium concentration 55 mmol/dL. Which one of the following is the best approach now? A. B. C. D. E.

Urge the patient to drink only when thirsty Stop hydrochlorothiazide, begin furosemide Stop hydrochlorothiazide and sertraline Obtain chest CT Stop lisinopril

Answer: B The patient’s symptomatic hyponatremia may potentially be caused by several factors. Hydrochlorothiazide blocks sodium transport at the distal convoluted tubule diluting site and interferes with urinary dilution. Sertraline and other SSRIs are common causes of the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). Ingestion of water in excess of thirst is unlikely to be a cause of hyponatremia on its own at this level of renal function, but it will lead to hyponatremia if renal diluting ability is impaired by hydrochlorothiazide or SIADH. ACEIs have rarely been reported to cause SIADH, but lisinopril is much less likely to contribute to the hyponatremia than sertraline or hydrochlorothiazide, so Answer E is wrong. It might be possible to correct the hyponatremia simply by urging the patient to reduce water intake, but she would still likely be at risk, so A is wrong. Furosemide blocks urinary concentration and is much less likely to cause hyponatremia; most cases of loop diuretic-induced hyponatremia occur in the setting of congestive heart failure, which itself may have been the cause. The patient benefitted significantly from the sertraline, so it would make sense to try to maintain her on this therapy by stopping the hydrochlorothiazide alone (B) rather than both drugs (C). As an initial step, one would observe the response to stopping hydrochlorothiazide before looking for a lung tumor as a cause of SIADH, so D is wrong.

Question 3 A 72-year-old man with ischemic cardiomyopathy (ejection fraction 35%) and presumed hypertensive nephrosclerosis returns for follow-up. He reports worsening dyspnea and edema despite following a low-salt diet. Specific questions about his dietary choices indicate that his salt intake is likely quite high. Current medications include furosemide 120 mg BID, carvedilol 25 mg BID, lisinopril 20 mg daily, ASA 81 mg daily, and diltiazem 240 mg daily. Pulse is 58 bpm with blood pressure 150/90 mm Hg. The jugular veins are seen 2 cm above the sternal angle and the chest is clear. No gallop is present. One plus edema is present bilaterally. Laboratory values: BUN 33 mg/dL, S[Cr] 2.8 mg/dL, eGFR 31 mL/min/1.73 m2, and S[K] 4.4 mg/dL.

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QUESTIONS AND ANSWERS

In addition to recounseling the patient on a reduced sodium diet, which one of these changes in his therapeutic regimen is most appropriate now? A. B. C. D. E.

Add metolazone 2.5 mg three days per week Stop furosemide, substitute torsemide Increase diltiazem Increase furosemide to 160 mg BID Add spironolactone 25 mg

Answer: A The patient demonstrates diuretic resistance. Despite being on a high dose of furosemide, volume overload and blood pressure are not controlled. There is no major advantage of torsemide over twice daily furosemide in this setting, and changing to a new loop agent would require dose finding, so B is incorrect. Simply increasing furosemide (D) is unlikely to be effective. Spironolactone is useful for refractory hypertension, but it is unlikely to provide enough diuretic effect in this case (E). Increasing diltiazem may be unwise at this pulse rate and will not improve sodium balance. Although it requires the addition of another medicine, adding metolazone is likely to have a pronounced additive or synergistic effect to furosemide on sodium excretion.

Question 4 A 53-year-old woman with long-standing type II diabetes mellitus is referred by her primary care physician for management of recent onset hypertension and edema. She is presently managed with insulin glargine 30 U HS and insulin aspart 5 U tid with meals, plus sliding scale, as well as losartan 100 mg. At presentation, her weight is 90 kg with height 61 inches, BMI 37.5 kg/ m2, and blood pressure 150/92 mm Hg. The balance of the physical examination is remarkable only for obesity and trace bilateral ankle edema. Laboratory values: S[Cr] 1.8 mg/dL with eGFR 31 mL/min/1.73 m2, serum albumin (S[Alb]) 3.2 g/dL. UPCR is 3.2 g/g. You begin furosemide 40 mg daily, counsel her on a 4 g sodium diet, and arrange follow-up in a month. On her return, the patient reports that the furosemide is working well. She has a brisk urine output right after she takes the drug. On examination, her weight is 90.3 kg, blood pressure 148/92 mm Hg, and trace bilateral ankle edema persists. Which of the following is the best course of action now? A. B. C. D. E.

Counsel on 500 mg sodium diet Add hydrochlorothiazide 25 mg Add spironolactone 25 mg Change furosemide to 40 mg BID Switch to bumetanide 2 mg daily

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Answer: D From the patient’s description, the furosemide is having its desired effect as a diuretic, but the patient has not lost weight or experienced an improvement in blood pressure or fluid overload. Reducing sodium intake would help (see Figure 64.3), but a 500 mg sodium diet (A) is unlikely to be achievable. Switching to another short-acting loop agent even at a higher dose (E) would not solve the problem of having diuretic activity of too brief a duration. The correct strategy is to add a second dose of furosemide to prolong its activity. Adding additional agents (B and C) would help, at the cost of more polypharmacy.

Question 5 A 26-year-old man with frequently relapsing minimal change nephropathy presents to the emergency room. He developed leg swelling over the several preceding days. Before that, he had been well. He was taking no medications and had normal renal function and no proteinuria. His last relapse was 18 months ago. His blood pressure was 105/68 mm Hg and the balance of the examination was remarkable only for 2þ bilateral leg edema. Laboratory values: BUN 8 mg/dL, S[Cr] 0.9 mg/dL, and S[Alb] 2.4 g/dL. The emergency room physician prescribes 40 mg furosemide IV to little effect. The reason for this patient’s poor response to furosemide is most likely which one of the following? A. B. C. D. E.

Diuretic braking Diuretic tolerance Reduced bioavailability Diminished protein binding Hypertrophy of distal convoluted tubule sodium reabsorptive sites

Answer: D Diuretic braking refers to the reduced diuretic effect that occurs after the first or just a few doses of diuretic and tolerance to the reduced effect that occurs later and which is sometimes due to the hypertrophy of distal tubule sodium reabsorptive sites that occurs in response to the increased load of sodium passing that site after a loop agent is administered. This patient has not required diuretic therapy in some time and is thus diuretic naı¨ve. So, the failure of the first dose of furosemide to act cannot be attributed to A, B, or E. Bioavailability of orally administered drugs may be reduced by gut edema, but the furosemide was given IV, bypassing the gut. Therefore, C is not relevant. Loop diuretics are highly protein bound in plasma. When hypoalbuminemia is present, the apparent volume of distribution increases, and delivery to the proximal tubule site where

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furosemide is secreted into the lumen is diminished. Hence, D is the reason why a dose of furosemide that would have been expected to work at this level of renal function did not.

Question 6 A 63-year-old man with CKD due to diabetic nephropathy is admitted to the CCU after the sudden onset of chest pain and dyspnea. Home medications include aspirin, losartan, insulin, and furosemide 40 mg daily. Blood pressure is 140/95 mm Hg. Physical examination discloses rales midway up the chest and trace bilateral ankle edema is present. The chest radiograph shows mild pulmonary edema. Cardiac enzyme studies and ECG disclose a non-ST segment elevation myocardial infarction. Kidney function is at baseline. Laboratory values: BUN 42 mg/dL, S[Cr]1.5 mg/dL, and eGFR 50 mL/min/1.73 m2. The patient is treated with supplemental oxygen, heparin, and a b-blocker, and aspirin and losartan are continued. You advise that furosemide be given with a goal of net negative fluid balance of 2 L over the course of the day. The CCU staff administers furosemide, 80 mg, intravenously. The next morning, you note that in response to the furosemide, the urine output was 1200 mL over the ensuing 4 hours. However, overall fluid balance for

the first 24 hours in the hospital was positive, with intake 2200 mL in and output 1800 mL (all urine). The patient continues to require supplemental oxygen. Renal function is unchanged. At this point, you reiterate the goal of establishing net negative fluid balance and recommend which one of the following? A. B. C. D. E.

Furosemide 160 mg IV Furosemide 80 mg followed by a continuous infusion Stop losartan Bumetanide 4 mg IV Add chlorothiazide 250 mg IV BID

Answer: B Furosemide 80 mg was effective in increasing urine output, but net negative fluid balance was not achieved because the diuretic effect was not sustained throughout the day. The patient could be managed effectively with repeated boluses of furosemide 80 mg if they are given. However, that option was available the day before but not utilized. It would thus make sense to switch to a continuous infusion titrated to a dose that will achieve negative balance. A single larger dose of furosemide or comparable dose of bumetanide would not solve the problem so A and D are incorrect. There is no evidence of diuretic tolerance as yet, so chlorothiazide is not indicated. Renal function is stable, so there is no reason to believe stopping losartan would improve the diuresis.

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