Advances in Peritoneal Dialysis, Vol.
30, 2014
Ruchi Kumra,1,2 Joanne M. Bargman1,3
Diuretics are commonly prescribed to manage vari-
ous conditions in the general population. They can
continue to play a role in dialysis patients to manage
extracellular fluid volume and hypertension and to
reduce the tendency to hyperkalemia. Nevertheless,
diuretics are often stopped when patients commence
dialysis. Several studies have shown that preserved
residual renal function in dialysis patients is associ-
ated with improved patient survival. Although the as-
sociation between diuretic use and preserved residual
renal function is still controversial, the numerous
clinical benefits offered by diuretics render those
agents valuable in dialysis patients with urine output.
Loop diuretics are generally the agents of choice
in end-stage renal disease. They need to be used at
higher doses because of pharmacokinetic changes
in the context of diminishing renal clearance. Other
classes of diuretics can still be used in end-stage
renal disease, but usually in conjunction with loop
diuretics or for benefits independent of diuresis.
Complications can occur with the use of diuretics,
but are avoidable with appropriate use. Dose-related
ototoxicity, especially with concomitant use of other
ototoxic medications, can occur. Hyperkalemia is
possible with the use of potassium-sparing diuretics,
but studies suggest that these agents can be safely
administered with close monitoring.
Key words
Diuretics, hemodialysis, pharmacology, adverse
events, residual kidney function
Introduction
Diuretics are commonly prescribed in the general
population to manage various conditions such as hy-
pertension, edema, and congestive heart failure (1).
Although dialysis patients have similar conditions, the
From: 1Division of Nephrology and 2Department of
Pharmacy, University Health Network, and 3University of
Toronto, Toronto, Ontario, Canada.
A Review of Diuretic Use
in Dialysis Patients
use of diuretics declines sharply in these individuals
after they have been on dialysis for 2 years. Furthermore,
the prescribing practices of clinicians appear to vary
dramatically across dialysis facilities, with 0% 83.9%
of dialysis patients being on diuretics (2). Some studies
have shown an association between diuretic use and bet-
ter preserved residual renal function (RRF) in dialysis
patients (2), but that finding is still controversial.
In this review, we explore the mechanism of ac-
tion of diuretics and their utility in patients with a
diminished glomerular filtration rate (GFR), and we
revisit the importance of RRF. We also discuss the
clinical benefits and risks of diuretics, specifically
in the peritoneal dialysis (PD) and hemodialysis
(HD) populations.
Discussion
Mechanism of action of diuretics
Loop diuretics block the Na+K+2Cl co-transporter.
They inhibit sodium and chloride reabsorption in the
thick ascending limb of the loop of Henle and cause
increased secretion of water, potassium, sodium, and
chloride. Furosemide, bumetanide, and ethacrynic
acid are examples of this class of diuretics.
Loop diuretics are the drug of choice in patients
with end-stage renal disease (ESRD) because they
are thought to be effective to some degree at low
GFR (3). However, a reduction in GFR results in less
tubular transport of the diuretic to the lumen of the
nephron (the site of action), which limits the maxi-
mum achievable diuretic effect. In fact, in patients
with a GFR below 15mL/min, secretion of the loop
diuretic into tubular fluid is only 10% 20% of that
seen in individuals with normal renal function (4).
To overcome that difference, a sufficiently high dose
(that is, 160 200mg intravenous furosemide) might
be needed to attain effective diuresis or maximal na-
triuresis (approaching 20% of the filtered Na+ load)
(4,5). In patients with a GFR below 10mL/min and
a daily urine volume below 100mL, the effect of
diuretics might be minimal (6).
116 Diuretic Use in Dialysis
Thiazide diuretics block the Na+Cl co-trans-
porter in the distal tubule. Hydrochlorothiazide,
metolazone, indapamide, and chlorthalidone belong
to this class of diuretics. As in the case of loop di-
uretics, decreased delivery of thiazide diuretics to
the nephron lumen requires that sufficiently high
doses be given in the context of diminishing GFR.
Using hydrochlorothiazide as an example, 50
100mg daily might have to be prescribed in mild-
to-moderate renal failure and 100 200mg daily in the HD population, the CHOICE study showed that
severe renal failure (5). Still, even at those high
doses, hydrochlorothiazide, because of its low po-
tency and limited natriuresis, is not typically effec-
tive in severe renal failure (4). To achieve effective
diuresis with a thiazide diuretic in patients with a
GFR below 30mL/min, the more common approach
is to give it in combination with a loop diuretic (7,8).
The combination generates additive natriuresis in
the setting of loop diuretic resistance and can allow
for lower doses of the latter drug to be administered.
Metolazone has a long half-life and is compartmen-
talized in red blood cells. For those reasons, it can
maintain diuresis over a considerable period of time,
rendering it the thiazide of choice as an adjunct to
a loop diuretic in ESRD (4). Finally, because thiazide
diuretics lower peripheral vascular resistance inde-
pendent of natriuresis, some clinicians use them for
their antihypertensive effects in ESRD, although
that use is not routinely recommended (9).
Potassium-sparing diuretics act in the distal renal
tubule. Spironolactone, amiloride, and triamterene are
examples of this drug class. Spironolactone competes
with aldosterone for receptor sites and increases so-
dium, chloride, and water excretion while conserving
potassium. Amiloride and triamterene block epithelial
sodium channels that inhibit sodium reabsorption,
decrease the function of the NaK pump, and lead
to potassium retention. True to their name, they can
cause hyperkalemia (especially in patients with dia-
betes) and should be used with caution (7).
Other less commonly used classes of diuretics are
osmotic diuretics (mannitol) and carbonic anhydrase
inhibitors (acetazolamide).
Importance of RRF
The 2006 clinical practice guidelines for PD adequacy
from the National Kidney Foundations Kidney
Disease Outcomes Quality Initiative emphasize the
importance of monitoring and preserving residual
kidney function (10). Similarly, the clinical practice
guidelines for HD adequacy state that one should
strive to preserve residual kidney function in HD
patients (11). Both guidelines are supplemented with
good evidence and are presented as gradeA recom-
mendations. They are supported by the reanalysis
of the CANUSA PD study, which showed that, for
each additional 250 mL of urine excreted per day,
the relative risk for death declined by 36% (12). In
RRF (defined as 250mL of urine output daily) was
associated with better survival and quality of life, less
inflammation, and a significantly lower erythropoi-
etin requirement (13).
Unfortunately, longitudinal studies have shown
that RRF declines progressively with time on di-
alysis (6), and therefore any intervention that can
potentially slow RRF decline in dialysis patients is
considered advantageous.
Clinical benefits of diuretics in dialysis patients
It had been postulated that loop diuretics might po-
tentially play a role in slowing the observed decline
in RRF. Medcalf et al. showed that patients newly
started on continuous ambulatory PD, with RRF at
baseline, maintained their urine volume over 1 year
when given an oral daily dose of 250mg furosemide
(6). At the 12-month mark, a significant mean differ-
ence of 340mL in daily urine volume was observed
that was associated with a significant difference in
sodium excretion (which the authors postulated to be
the mechanism behind the greater urine volume). In
the HD population, observational studies have sug-
gested the same outcome (14). It is important to note
that Medcalf et al. showed that, although furosemide
increased urine volume, it had no effect on preserving
or slowing the decline in small-solute clearance (6).
The Dialysis Outcomes and Practice Patterns
Study postulated that the association between lower
mortality and diuretic use observed in their analysis
is one more example of the known survival benefit
conferred by RRF (2); however, there are other po-
tential explanations. One confounding explanation
for the finding is that RRF might itself be associated
with lower mortality and that patient selection bias
might be operating (in that diuretics are usually pre-
scribed to patients who have RRF). However, there
are mechanisms whereby diuretics might plausibly
affect patient survival.
Kumra and Bargman 117
electrolyte balance and volume control
The advantage conferred by preserved RRF might be
related to the urine volume excreted and maintenance
of euvolemic status (12). Based on the mechanism of
action of loop diuretics, the beneficial effects observed
in dialysis patients could be explained by the removal
of sodium and water. That removal plays a crucial
role in preventing volume overload and its sequelae
(such as left ventricular hypertrophy, congestive heart
failure, and uncontrolled hypertension). Further, RRF
allows for increased clearance of middle molecules,
lower circulating levels of inflammatory markers,
reduced blood pressure, improved hemoglobin sta-
tus and phosphorus control, reduced left ventricular
hypertrophy, and fewer comorbid conditionsall
potentially leading to improved patient survival (15).
In HD patients, it is possible that diuretic use helps
to preserve RRF and to improve survival by reducing
interdialytic fluid accumulation and thus minimizing
hypotensive episodes during dialysis, which have
been associated with greater morbidity and mortality
(2). Hyperkalemia has also been less often observed
in patients on diuretics (2).
impact on quality of life and nutrition
Patients on dialysis oftentimes have diets that restrict
sodium, potassium, phosphorus, and fluid intake.
Diuretic use might allow patients to liberalize their
diet and fluid intake, which could potentially be more
palatable for them and might increase compliance
with other therapies. In PD patients specifically, the
use of diuretics might perhaps allow for less frequent
and less hypertonic dextrose exchanges, which could
be convenient for the patient and could theoretically
diminish systemic glucose loading and perhaps pro-
tect the peritoneal membrane from damaging high
glucose concentrations. As well, PD patients with
higher RRF have been observed to have a lower risk
of peritonitis (15).
Side effects and complications of diuretics
aldosterone antagonists and hyperkalemia
Dialysis patients have an increased extracellular
fluid volume and high aldosterone levels, which can
contribute to cardiovascular risk. The potassium-
sparing diuretics spironolactone and eplerenone are
also known as aldosterone antagonists. They can
improve cardiac function and reduce left ventricular
mass in moderate-to-severe heart failure in dialysis
patients (15). However, these patients might also be
at particularly high risk for developing hyperkalemia
while on aldosterone antagonists; rates are reported
to be as high as 10%, particularly at higher doses
(16). The risk is theoretically intensified with the
concomitant use of medications such as angioten-
sin-converting enzyme inhibitors, angiotensinII
receptor blockers, trimethoprim, antifungals, and
nonsteroidal anti-inflammatory drugs, which can
also cause hyperkalemia (4,5,17).
Baker et al. reviewed the literature on the safe
use of mineralocorticoid antagonists in patients with
ESRD undergoing HD and suggested that those agents
could be safely used in HD patients because the inci-
dence of severe hyperkalemia remained low (16). It
is noteworthy, though, that most studies lacked a true
control arm and had small patient populations and rela-
tively short follow-up periods. The doses used in the
reviewed studies varied from spironolactone 12.5mg 3
times weekly to 300mg daily. Taheri et al. performed
a prospective randomized double-blind placebo-con-
trolled clinical trial evaluating the safety and efficacy
of spironolactone 25mg every other day in 18 con-
tinuous ambulatory PD patients with New York Heart
Association classIII or IV heart failure (18). Those
authors showed that potassium levels rose in both
groups, with no statistically significant difference,
and only 1 patient in the treatment group developed
hyperkalemia (defined as >5.7mmol/L potassium). It
is noteworthy that patients on angiotensin-converting
enzyme inhibitors and angiotensinII receptor blockers
were not excluded from the studies. In general, aldo-
sterone antagonists can be used in ESRD patients for
several cardiac benefits (although those benefits have
not been extrapolated to the dialysis population), but
K+ levels should be monitored frequently, especially
with concomitant use of other medications that could
exacerbate hyperkalemia.
loop diuretics and ototoxicity
Loop diuretics can cause ototoxicity, usually in pa-
tients receiving high intravenous doses while taking
other other ototoxic medications, particularly amino-
glycoside antibiotics (5). The ototoxicity is usually
transient and reversible. Limited data suggest that
the frequency of ototoxicity seems to be higher with
furosemide than with bumetanide and even higher
with ethacrynic acid (4). For that reason, ethacrynic
118 Diuretic Use in Dialysis
acid is reserved mainly for patients with an allergy to
furosemide (5). Several older studies have explored
furosemide ototoxicity, one of which found that,
among patients with severe renal failure, infusion of
furosemide at a constant rate of 25 mg/min caused
noticeable hearing loss in two thirds of patients. When
given at a rate of 15mg/min, only minor hearing loss
was reported. The authors concluded that furosemide
should be given at a rate of less than 4mg/min to avoid
hearing loss (19). Rastogi et al. found no hearing loss
among renal patients receiving daily oral doses of
furosemide up to 2g (20), although Rifkin et al. and
Gallagher et al. reported permanent hearing loss from
smaller oral doses (21,22).
Although ESRD patients require higher doses
of furosemide to attain adequate diuretic effect, it
is important to note that a ceiling effect has been
observed in loop diuretics for a dose at which the
fractional percentage of sodium excretion (the diuretic
effect) plateaus for any incremental increase in the
dose. Continuing to increase the dose of a diuretic
therefore results in no additional diuretic effect, but
theoretically exposes the patient to more side effects.
The usual maximum intravenous dose of furosemide is
80 160mg in moderate renal insufficiency and 160
200mg in severe renal insufficiency (the equivalent
oral dose is double) (5).
Summary
Diuretics are often underutilized in dialysis patients
or even stopped once patients are initiated on dialysis.
Several studies have suggested that, in ESRD patients
who continue to have RRF, many benefits accrue from
continuation of diuretics. Loop diuretics are the drugs
of choice, and they might need to be used at higher
doses to attain optimal diuresis. Some side effects can
occur, but those effects can be avoided and managed
with close patient monitoring.
Disclosures
The authors have no financial conflicts of interest
to disclose.
References
1 Yancy CW, Jessup M, Bozkurt B, et al. on behalf
of the American College of Cardiology Foundation;
American Heart Association Task Force on Practice
Guidelines. 2013 ACCF/AHA guideline for the man-
agement of heart failure: a report of the American
College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines. J Am
Coll Cardiol 2013;62:e147-239.
2 BraggGresham JL, Fissell RB, Mason NA, et al.
Diuretic use, residual renal function, and mortality
among hemodialysis patients in the Dialysis Outcomes
and Practice Pattern Study (DOPPS). Am J Kidney Dis
2007;49:42631.
3 Dussol B, MoussiFrances 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;20:34953.
4 Sica DA. Diuretic use in renal disease. Nat Rev Nephrol
2011;8:1009.
5 Brater DC. Diuretic therapy. N Engl J Med
1998;339:38795.
6 Medcalf JF, Harris KP, Walls J. Role of diuretics in the
preservation of residual renal function in patients on
continuous ambulatory peritoneal dialysis. Kidney Int
2001;59:112833.
7 Aronoff GR, Bennett WM, Berns JS, et al. Drug pre-
scribing in renal failure: dosing guidelines for adults and
children. 5th ed. Philadelphia, PA: American College of
Physicians; 2007.
8 Fliser D, Schroter M, Neubeck M, Ritz E. Coadministra-
tion of thiazides increases the efficacy of loop diuretics
even in patients with advanced renal failure. Kidney Int
1994;46:4828.
9 Chan CY, Peterson EJ, Ng TM. Thiazide diuretics as
chronic antihypertensive therapy in patients with severe
renal diseaseis there a role in the absence of diuresis?
Ann Pharmacother 2012;46:15548.
10 U.S. National Kidney Foundation (NKF), Kidney Dis-
ease Outcomes Quality Initiative (KDOQI). Clinical
practice guidelines for peritoneal dialysis adequacy,
update 2006. I.Clinical practice guidelines for peri-
toneal dialysis adequacy. Guideline 3. Preservation of
residual kidney function. In: KDOQI. 2006 Updates:
clinical practice guidelines and recommendations. New
York, NY: NKF; 2006: 1505.
11 U.S. National Kidney Foundation (NKF), Kidney Disease
Outcomes Quality Initiative (KDOQI). Clinical practice
guidelines for hemodialysis adequacy, update 2006.
I.Clinical practice guidelines for hemodialysis adequacy.
Guideline6. Preservation of residual kidney function. In:
KDOQI. 2006 Updates: clinical practice guidelines and
recommendations. New York, NY: NKF; 2006: 513.
12 Bargman JM, Thorpe KE, Churchill DN on behalf of
the CANUSA Peritoneal Dialysis Study Group. Relative
contribution of residual renal function and peritoneal
clearance to adequacy of dialysis: a reanalysis of the
CANUSA study. J Am Soc Nephrol 2001;12:215862.
Kumra and Bargman 119
13 Shafi T, Jaar BG, Plantinga LC, et al. Association of
residual urine output with mortality, quality of life,
and inflammation in incident hemodialysis patients:
the Choices for Healthy Outcomes in Caring for End-
Stage Renal Disease (CHOICE) Study. Am J Kidney
Dis 2010;56:34858.
14 van Olden RW, van Meyel JJ, Gerlag PG. Acute and
long-term effects of therapy with high-dose furose-
mide in chronic hemodialysis patients. Am J Nephrol
1992;12:3516.
15 Thomas J, Teitelbaum I. Preservation of residual
renal function in dialysis patients. Adv Perit Dial
2011;27:11217.
16 Baker WL, White WB. Safety of mineralocorticoid
receptor antagonists in patients receiving hemodialysis.
Ann Pharmacother 2012;46:88994.
17 Sanghavi S, Whiting S, Uribarri J. Potassium balance
in dialysis patients. Semin Dial 2013;26:597603.
18 Taheri S, Mortazavi M, Pourmoghadas A, Seyrafian
S, Alipour Z, Karimi S. A prospective double-blind
randomized placebo-controlled clinical trial to evalu-
ate the safety and efficacy of spironolactone in patients
with advanced congestive heart failure on continuous
ambulatory peritoneal dialysis. Saudi J Kidney Dis
Transpl 2012;23:50712.
19 Rybak LP. Furosemide ototoxicity: clinical and experi-
mental aspects. Laryngoscope 1985;95(suppl 38):114.
20 Rastogi SP, Volans G, Elliott RW, et al. High dose
frusemide in the treatment of hypertension in chronic
renal insufficiency and of terminal renal failure. Post-
grad Med J 1971;47(suppl):4553.
21 Rifkin SI, de Quesada AM, Pickering MJ, Shires DL Jr.
Deafness associated with oral furosemide. South Med
J 1978;71:868.
22 Gallagher KL, Jones JK. Furosemide-induced ototoxic-
ity. Ann Intern Med 1979;91:7445.
Corresponding author:
Joanne M. Bargman, md, Toronto General Hospital,
200Elizabeth Street, Toronto, Ontario M5G2C4
Canada.
E-mail:
joanne.bargman@uhn.ca