Acid-Base and Electrolyte Teaching Case

Diuretic Resistance
Ewout J. Hoorn, MD, PhD,1 and David H. Ellison, MD 2

Diuretic resistance is defined as a failure to achieve the therapeutically desired reduction in edema despite a
full dose of diuretic. The causes of diuretic resistance include poor adherence to drug therapy or dietary so-
dium restriction, pharmacokinetic issues, and compensatory increases in sodium reabsorption in nephron sites
that are not blocked by the diuretic. To illustrate the pathophysiology and management of diuretic resistance,
we describe a patient with nephrotic syndrome. This patient presented with generalized pitting edema and
weight gain despite the use of oral loop diuretics. Nephrotic syndrome may cause mucosal edema of the
intestine, limiting the absorption of diuretics. In addition, the patient’s kidney function had deteriorated,
impairing the tubular secretion of diuretics. He was admitted for intravenous loop diuretic treatment. However,
this was ineffective, likely due to compensatory sodium reabsorption by other tubular segments. The combi-
nation of loop diuretics with triamterene, a blocker of the epithelial sodium channel, effectively reduced body
weight and edema. Recent data suggest that plasmin in nephrotic urine can activate the epithelial sodium
channel, potentially contributing to the diuretic resistance in this patient. This case is used to illustrate and
review the mechanisms of, and possible interventions for, in diuretic resistance.
Am J Kidney Dis. -(-):---. ª 2016 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All
rights reserved.

INDEX WORDS: Diuretic resistance; pathophysiology; edema; oral loop diuretic; nephrotic syndrome;
triamterene; eNaC; epithelial Na1 channel; SCNN1B; proteinuria; kidney disease; cryoglobulinemic
membranoproliferative glomerulonephritis; hepatitis C virus.

1A) without evidence for liver cirrhosis (no fibrosis or portal hy-
Note from Feature Editor Jeffrey A. Kraut, MD: This article is pertension on ultrasound and no fibrosis on elastography).
part of a series of invited case discussions highlighting the Secondary to hepatitis C virus infection, he developed mem-
diagnosis and treatment of acid-base and electrolyte disorders. branoproliferative glomerulonephritis with 2 episodes of nephrotic
syndrome. These episodes of nephrotic syndrome resolved after
treatment with a combination of glucocorticoids and loop diuretics,
but resulted in progressive glomerular filtration rate (GFR) loss. His
INTRODUCTION estimated GFR prior to admission was 37 mL/min/1.73 m2 (as
Generalized edema can develop in nephrotic syn- calculated by the CKD-EPI [CKD Epidemiology Collaboration]
equation5). His outpatient medication consisted of bumetanide
drome, chronic kidney disease (CKD), heart failure,
(1 mg 2 times daily), losartan (25 mg once daily), and spi-
and liver cirrhosis. Usually patients with edema ronolactone (25 mg once daily). At presentation, he was alert but
respond to dietary sodium restriction in combination was concerned about edema and dyspnea. On physical examination,
with a loop diuretic.1 However, some patients become blood pressure was 145/110 mm Hg, while his body weight had
resistant to diuretics. Diuretic resistance is defined as increased by 20 kg. He had ascites, but his liver was not enlarged.
Generalized pitting edema reaching up to his scrotum was present.
failure to achieve the therapeutically desired reduction Based on the presence of edema and his laboratory results, the
in edema even when a maximal dose of diuretic is recurrence of nephrotic syndrome was established (Table 1).
employed. Box 1 summarizes the main causes of
diuretic resistance,2 which include poor adherence to Additional Investigations
diet or drug therapy, pharmacokinetic issues, and A kidney biopsy was performed (42 glomeruli, 18 with
compensatory increases in sodium reabsorption in global sclerosis). Light microscopy showed thickened glomerular
nephron sites that are not blocked by the diuretic.3
Establishing the cause of diuretic resistance is
From the 1Division of Nephrology & Transplantation,
important because it directly informs the options for Department of Internal Medicine, Erasmus Medical Center, Rot-
intervention. For example, diuretic resistance is often terdam, the Netherlands; and 2Division of Nephrology & Hyper-
treated effectively by combining a loop diuretic with tension, Department of Medicine, Oregon Health & Science
another type of diuretic.4 We present a patient to University and VA Portland Health Care System, Portland, OR.
illustrate the causes, pathophysiologic mechanisms, Received February 23, 2016. Accepted in revised form August
7, 2016.
and treatment of diuretic resistance. Address correspondence to David H. Ellison, MD, 3181 SW
Sam Jackson Park Rd, SN4N Portland, OR 97239. E-mail:
CASE REPORT ellisond@ohsu.edu
 2016 by the National Kidney Foundation, Inc. Published by
Clinical History and Initial Laboratory Data Elsevier Inc. All rights reserved.
A 55-year-old man was admitted because of edema and dyspnea. 0272-6386
He had a history of chronic hepatitis C virus infection (genotype http://dx.doi.org/10.1053/j.ajkd.2016.08.027

Am J Kidney Dis. 2016;-(-):--- 1

 Hoorn and Ellison

Box 1. Common Causes of Diuretic Resistance

 Incorrect diagnosis (eg, venous or lymphatic edema)

 Nonadherence to recommended sodium and/or fluid
restriction
 Drug not reaching the kidney
> Nonadherence
> Dose too low or too infrequent
> Poor absorption
 Reduced diuretic secretion
> Tubular uptake of diuretic impaired by uremic toxins
> Decreased kidney blood flow
> Decreased functional kidney mass
 Insufficient kidney response to drug
> Low glomerular filtration rate
> Decreased effective intravascular volume despite
elevated total extracellular fluid volume
> Activation of the renin-angiotensin system Figure 1. Patient’s course in terms of body weight and serum
> Nephron adaptation
creatinine levels during admission. Treatment periods with di-
uretics are indicated. Abbreviation: i.v., intravenous. Conversion
> Use of nonsteroidal anti-inflammatory drugs
factor for creatinine in mg/dL to mmol/L, 388.4.
Based on Hoorn et al.2

dL, a reduction in body weight, and an improvement in kidney

basement membrane and increased mesangial and endocapillary function. However, proteinuria was largely unchanged, in the
cellularity. Immunofluorescence showed positivity for immuno- nephrotic range (protein excretion, 10 g/d). Although interferon-
globulin G (IgG), IgM, C3, and k and l light chains in a granular free therapy was not available during the treatment of this pa-
pattern. Electron microscopy was not performed. tient, he is currently treated with sofosbuvir and daclatasvir.

Diagnosis DISCUSSION
Diuretic resistance caused by the recurrence of nephrotic syn-
drome secondary to hepatitis C virus–related cryoglobulinemic
This case illustrates several of the possible causes
membranoproliferative glomerulonephritis. of diuretic resistance and strategies to overcome it. In
addition to discussing diuretic resistance in this spe-
Clinical Follow-up cific patient with nephrotic syndrome, we also discuss
The patient was admitted for intravenous loop diuretic treatment mechanisms pertaining to diuretic resistance in CKD,
with a continuous infusion of 10 mg/d of bumetanide (Fig 1). heart failure, and liver cirrhosis.
Despite this treatment, he did not lose weight and therefore a There are several classes of diuretics, dictated by
thiazide type diuretic (chlorthalidone) was added after the first
week. Because this combination also failed to lower his body
their site of action in the nephron (Fig 2).2 They
weight, loop diuretics were combined with the epithelial sodium include diuretics that act on the proximal tubule,
channel (ENaC) blocker triamterene (100 mg/d). In addition, he carbonic anhydrase inhibitors; loop of Henle, loop
was treated with rituximab (1 g intravenously in weeks 2 and 3 of diuretics; distal tubule, thiazide diuretics; or collecting
admission) because of the recurrence of membranoproliferative duct, distal potassium-sparing diuretics. Distal
glomerulonephritis secondary to hepatitis C virus infection. The
combination of diuretics and B-cell depletion therapy resulted in
potassium-sparing diuretics can be further subdivided
resolution of edema, an increase in serum albumin level to 2.7 g/ into either ENaC blockers or mineralocorticoid re-
ceptor blockers (eg, spironolactone or eplerenone).
Except for mineralocorticoid receptor blockers, di-
Table 1. Laboratory Data
uretics act from the tubular lumen by blocking the
Parameter Value Reference Range function of sodium transport proteins in the apical
plasma membrane of kidney epithelial cells. This
Serum chemistry implies that for these diuretics to act, they must first
Sodium, mEq/L 141 136-145 be secreted in tubular fluid. Thus, diuretics are
Potassium, mEq/L 5.4 3.5-5.1 delivered to their site of action by tubular secretion
Creatinine, mg/dL 3.9 0.74-1.3
eGFR, mL/min/1.73 m2 16
rather than glomerular filtration. Tubular secretion of
Albumin, g/dL 1.8 3.5-5.0 diuretics primarily occurs in the proximal tubule. For
Cryoglobulins, g/L 0.02 ,0.01 most diuretics, the secretory pathways have largely
been identified and involve organic anion transporters
Urine chemistry
Protein, g/d 14 ,0.14 and multidrug resistance proteins.6 The importance of
Sodium, mEq/d 9 - this secretory process is illustrated by the observation
Note: Conversion factor for creatinine in mg/dL to mmol/ that decreased diuretic secretion into the tubular
L, 388.4. lumen is often one of the causes of diuretic resistance
Abbreviation: eGFR, estimated glomerular filtration rate. (Box 1).

2 Am J Kidney Dis. 2016;-(-):---

Treatment of Diuretic Resistance

Thiazides

G DCT
Collecting
CNT Duct
Carbonic Anhydrase
Inhibitors
Osmotic Diuretics

Loop Potassium
Diuretics Sparing
Proximal Diuretics
Tubule
Thick Ascending
Limb

Figure 2. Schematic of a nephron

shows sites of action of diuretics along the
various segments. Abbreviations: CNT, con-
necting tubule; DCT, distal convoluted tu- Loop of
bule; G, glomerulus. Henle

Both pharmacokinetic and pharmacodynamic ef- secreted.12 However, a study of patients with
fects may contribute to diuretic resistance and may nephrotic syndrome in which loop diuretics were
arise at any level of the drug absorption and delivery combined with the displacing agent sulfisoxazole was
process (Table 2).7,8 For example, nephrotic syn- unable to confirm this mechanism.13 The effects of
drome may cause mucosal edema of the intestine, adding salt-poor human albumin to intravenous loop
thereby limiting the absorption of oral diuretics.9 This diuretics are modest and vary per study.14,15 Because
may also play a role in patients with heart failure or it may also have an adverse effect, it is recommended
liver cirrhosis, although in these conditions, decreased to reserve this treatment for patients with refractory
intestinal perfusion and reduced intestinal motility are anasarca with respiratory compromise or tissue dam-
more likely to limit absorption. Even in the absence of age.16 In CKD, the secretion of diuretics may be
these factors, there is a remarkable difference in inhibited by retained organic anions, uric acid, or
bioavailability between the different types of loop acidosis.17 Because our patient had both nephrotic
diuretics. For example, the bioavailability of furose- syndrome and CKD, both mechanisms may have
mide (40%-60%) is much lower compared to bume- contributed to diuretic resistance. In heart failure or
tanide (80%) or torsemide (.91%).10,11 When an liver cirrhosis, the primary mechanism limiting
adequate plasma concentration of the diuretic is ach- diuretic secretion is usually vasoconstriction of kid-
ieved, it must be secreted adequately into the tubule ney blood vessels due to reduced cardiac output or
lumen. This process is frequently compromised in splanchnic vasodilation, respectively. In patients with
edematous disorders. In nephrotic syndrome, hypo- heart failure, the dose-response curve for loop di-
albuminemia may reduce the delivery of diuretic to uretics (fractional sodium excretion vs plasma furo-
the kidney tubule because loop diuretics are semide concentration) exhibits both a rightward and a
highly protein bound. Experimental animal models downward shift (secretory defect and decreased
of nephrotic syndrome suggested that urinary maximal response).2 In contrast, CKD causes only a
albumin could also bind furosemide after it had been rightward shift in the dose-response curve. This

Table 2. Pharmacokinetics of Loop Diuretics

Elimination Half-Life, h

Bioavailability, % Oral Dose Absorbed Healthy Kidney Disease Liver Disease Heart Failure

Furosemide 50 (range, 10-100) 1.5-2 2.8 2.5 2.7

Bumetanide 80-100 1 1.6 2.3 1.3
Torsemide 80-100 3-4 4-5 8 6
Data from Shankar and Brater.7

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 Hoorn and Ellison

implies that the maximal response is preserved when

expressed as fractional sodium excretion, but it is
important to emphasize that maximal absolute in-
crease in sodium excretion is reduced in CKD.
In addition to pharmacokinetic effects, compensa-
tory upregulation of sodium transporters not blocked
by the diuretic also contributes to diuretic resistance.
Why does this occur? Several systemic and more
local mechanisms have been implicated. For example,
the systemic renin-angiotensin system (RAS) is acti-
vated in heart failure and liver cirrhosis18 and also
becomes activated by loop diuretic treatment.19,20 In
patients with CKD, plasma aldosterone levels may be
elevated even in the presence of normal plasma renin
activity and normal serum potassium concentra-
tions.21 Elevated plasma levels of both angiotensin II Figure 3. Schematic of proposed mechanism by which
and aldosterone can activate sodium transporters in luminal plasmin in nephrotic patients activates the epithelial so-
the distal nephron, including the Na1/Cl2 cotrans-
dium channel (ENaC) in the collecting duct. eNaC comprises 3
subunits, a, b, and g, each with extracellular loops, as shown.
porter and ENaC.20,22 Angiotensin II also stimulates Plasmin, derived from filtered plasminogen in nephrotic patients,
proximal tubular sodium reabsorption, which will cleaves eNaC extracellular loops (g subunit shown here).
Plasmin may also activate prostasin, which can also cleave
reduce distal sodium delivery and contribute to ENaC. Notches in plasmin and prostasin indicate active enzy-
diuretic resistance. It is also becoming increasingly matic activity. When cleaved, ENaC is activated, increasing so-
clear that the systemic and the intrarenal RAS may dium reabsorption. Epithelial cells are shown schematically,
separating tubular fluid (lumen) from peritubular capillary.
operate independently.22 In several disorders,
including CKD, the intrarenal RAS may be activated,
resulting in increased angiotensin II production in the prostasin and subsequent cleavage of the g subunit of
kidney.23 Although convincing evidence is lacking, it ENaC.30 Subsequent studies have indicated that this
has been proposed that in such circumstances, intra- mechanism could also play a role in sodium retention
tubular angiotensin II can activate sodium transporters associated with preeclampsia, resistant hypertension,
through apical angiotensin type 1 receptors.24 A heart failure, and diabetic nephropathy.31-34 Of in-
recent study showed that additional processes, terest, a recent study analyzed whether this mecha-
including distal nephron remodeling and paracrine nism could also play a role in patients with CKD who
signaling, are also likely involved in the compensa- did not have nephrotic-range proteinuria.35 To this
tory response to diuretics.25 In a mouse model of end, the authors performed a cross-sectional study in
genetic Na1/Cl2 cotransporter inhibition (mimicking 171 outpatients with CKD (different cause and stages
long-term treatment with thiazide diuretics), a jagged and varying degrees of proteinuria) and 2 control
1-NOTCH interaction was shown to expand and groups including healthy volunteers and patients with
remodel the cortical connecting tubule to favor salt nephrotic syndrome. The investigators found that
reabsorption pathways.26 Similarly, via paracrine proteinuria was the strongest independent predictor
signaling, a-ketoglutarate secretion was observed to for hypervolemia, as assessed by bioimpedance
increase the activity of ENaC and the chloride/iodide spectroscopy. Plasminuria was found in 44% of pa-
exchanger pendrin in mice with Na1/Cl2 cotrans- tients with CKD (vs 100% in patients with nephrotic
porter inhibition. These data suggest that Na1/Cl2 syndrome) and predicted hypervolemia similar to
cotransporter inhibition by thiazide diuretics can proteinuria. In our patient, the prompt decrease in
cause similar compensatory mechanisms downstream body weight after starting treatment with the ENaC
that will limit the maximal natriuretic effect.25 blocker triamterene (in combination with loop di-
In patients with nephrotic syndrome, sodium uretics and rituximab) suggests that increased ENaC
retention does not seem to be mediated by RAS but activity may have contributed to salt and water
rather by an “intrarenal defect.”27,28 Clues to what this retention (Fig 1). Moreover, the observation that the
intrarenal defect might be have recently become marked diuresis preceded the decrease in serum
clearer. Namely, plasmin in nephrotic urine was creatinine level suggests that intrarenal edema may
shown to activate the sodium transporter ENaC have compromised glomerular hemodynamics
(Fig 3).29 It was postulated that tubular urokinase- (“nephrosarca”), as noted previously.36
type plasminogen activator converts filtered plas- How do these pathophysiologic mechanisms
minogen to plasmin.29 Plasmin may activate ENaC translate into practical strategies to overcome diuretic
either directly or indirectly through interaction with resistance? An algorithm to guide management is

4 Am J Kidney Dis. 2016;-(-):---

Treatment of Diuretic Resistance

provided in Fig 4.37 First, the possibility of non- increasing the dose of oral diuretic or by admitting
adherence or the use of nonsteroidal anti- patients for intravenous loop diuretic treatment (as in
inflammatory drugs should be ruled out (Box 1). In our case). The type of loop diuretic that is prescribed
addition, dietary counseling may be indicated to help for oral administration may be relevant, as illustrated
institute a low-sodium diet. If the patient remains by an open-label randomized trial showing fewer
resistant to diuretics, the potential pharmacokinetic readmissions for heart failure with torsemide than
causes of diuretic resistance should be addressed by with furosemide.38 When loop diuretics are given

SELECT TARGET DRY WEIGHT

SELECT DIURETIC
SELECT DOSE

ADEQUATE RESPONSE? Yes CONTINUE INDEFINITELY

INDEFINATELY
No

Check for:
Noncompliance CORRECT IDENTIFIED
Blood volume Yes PROBLEM AND REASSESS
depletion
of NSAIDs

Diuretic Resistance No
No Persists
Yes

Dietary
Measure 24 hour urinary Na excretion >100 mmol/day
Counseling

<100 mmol/day Yes

Diuretic Resistance
Persists
DOUBLE DAILY DOSE (to
maximum) OR INCREASE Yes
FREQUENCY

Response? Yes CONTINUE INDEFINITELY

No

ADD DCT, PT, OR CCD

DIURETIC

Response? MAINTAIN* UNTIL

Yes TARGET
RESPONSE ACHIEVED
No

INTRAVENOUS OR
CONTINUOUS INFUSION

Figure 4. Stepwise approach to assess and manage diuretic resistance. *Consider reducing the dose or frequency of distal con-
voluted tubule (DCT) diuretic when control of edema has been achieved. Abbreviations: CCD, cortical collecting duct; NSAIDs, nonste-
roidal anti-inflammatory drugs; PT, proximal tubule. Adapted from Brady and Wilcox37 with permission of Elsevier.

Am J Kidney Dis. 2016;-(-):--- 5

 Hoorn and Ellison

intravenously to patients with acute decompensated acetazolamide inhibits pendrin.46 Because pendrin is
heart failure, varying the dose or the mode of increasingly recognized as an important sodium
administration (bolus vs continuous) has been re- reabsorption route47,48 and there are no specific in-
ported by Felker et al39 to have little impact on hibitors for pendrin, acetazolamide may be consid-
symptoms or kidney function. However, the patients ered as a second diuretic in edematous disorders. In
enrolled in that study were not characteristic of those mice, both the coadministration of hydrochlorothia-
with true diuretic resistance because they responded zide and acetazolamide and the double genetic
to loop diuretics at traditional doses. A previous knockout of the Na1/Cl2 cotransporter and pendrin
smaller study suggested greater urinary volume and have been reported to result in severe salt
sodium excretion and less ototoxicity with continuous wasting.46,49 Future studies in patients are necessary
than with bolus furosemide infusion.40 to analyze whether the proposed efficacy of ami-
The key strategy to overcome diuretic resistance in loride and acetazolamide can be confirmed clinically.
many patients is combining 2 types of diuretics If so, this would mean an unexpected reappraisal of
(diuretic synergism).1 Because loop diuretics are the these old diuretics. The key teaching points of this
first drug of choice in edematous disorders, this im- review are summarized in Box 2.
plies adding a diuretic that targets another tubular
ACKNOWLEDGEMENTS
segment.1 Especially for patients with liver cirrhosis
and ascites, the specific combination of furosemide Support: Dr Hoorn is supported by the Dutch Kidney Foun-
dation (KSP-14OK19). Dr Ellison is supported by National In-
and spironolactone is supported by data.41,42 For the stitutes of Health DK051496 and Department of Veterans Affairs
other edematous disorders, the evidence for specific 1I0BX002228.
combinations of diuretics is less obvious, and usually Financial Disclosure: The authors declare that they have no
a thiazide diuretic is recommended as a second relevant financial interests.
diuretic (as was done in our case).1 Because kidney Peer Review: Evaluated by 2 external peer reviewers, the
Feature Editor, the Education Editor, and the Editor-in-Chief.
function is often reduced in edematous disorders,
another recommendation is to titrate the thiazide REFERENCES
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