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Editors
Nephrology Section
Chief EditorAss. Prof. Dr Ahmed Fathy EL Koraie
Internal Medicine & Nephrology - Faculty of MedicineAlex Univ
Head of Nephrology DepartmentKidney & Urology Center
AlexandriaEGY
Founder & Chairman of Junior Nephrology Club
Co-Editor & ReviewerDr Mohammed Abdel Gawad
Nephrology Specialist & Head of Medical Development Department
Kidney & Urology CenterAlexandriaEGY
Founder & Chairman of NephroTube
Email: [email protected]
g
Urology Section
Chief EditorProf. Dr Wael Sameh
Professor of Urology
Faculty of MedicineAlex UnivFellow of Moffitt Cancer Center
University of South Florida (USF) - USA;
Journal Coordinators
Dr Mohammed EssamNephrology Specialist & Head of quality assurance department at KUC
Deputy Director of KUC
Kidney & Urology Center
AlexandriaEGYEmail: [email protected]
Dr Kareem EL Fass PharmD,BPharmHead of Clinical Pharmacy Department
Kidney & Urology Center
AlexandriaEGY
Email: [email protected]
Journal Secretary: Dr Mohammed Abdel Gawad
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Preface
In Kidney AdvancesJournal (KAJ),we try to offer a material and data for nephrologists,
internists, and urologists that cover aspects of the clinical work of nephrology andurology. KAJ is a monthly journal that will be focusing mainly on one specific topic
regarding nephrology and another topic regarding urology. We try to make a panoramic
view to make all the data about these specific topics available to readers. You will find
too an extra-ordinary article in each volume which is handling articles related to quality,
guidance for how to audit your work and for best performance.
We thank our professors and mentors, who devoted their own time to educate us. We
thank all our colleagues who have given us inspiration and supported us. We thank all of
our patients, who have been truly instrumental in our learning and devotion to medicine.
We thank everyone who is reading this journal and sharing his valuable opinion with us.
Notice
Knowledge and best practice in Nephrology and Urology are constantly changing.
Practitioners must always rely on their own experience and they have always to reflect ontheir medical practice. To the fullest extent of the law, neither the publisher nor the
authors or editors assume any liability for any injury and/or damage to persons or
property as a matter of products liability, negligence, nor otherwise, or from any use or
operation of any methods, products, instructions, or ideas contained in the material
herein. Always update yourself.
Thank You
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ikid d (F P l U O l )
Contents & ContributorDownload your free soft copy from www.kidneyadvances.com
DiseasesCardioRenal Axis
Nephrology SectionTopic Contributor Page
RENOCARDIAC VERSUS
CARDIORENAL SYNDROME
CHANGING PARADIGM
Ass. Prof. Dr Ahmed Fathy EL KoraieInternal Medicine & Nephrology - Faculty of Medicine
Alex Univ
Head of Nephrology DepartmentKidney & Urology
Center - AlexandriaEGY
Founder & Chairman of Junior Nephrology Club
2
REFRACTORY EDEMA WITHCONGESTIVE HEART FAILURE
STEPWISE APPROACHES -
NEPHROLOGY PERSPECTIVES
Dr Mohammed Abdel Gawad
Nephrology Specialist & Head of Medical
Development Department
Kidney & Urology CenterAlexandriaEGY
Founder & Chairman of NephroTube
11
ULTRAFILTRATION VERSUS
DIURETICS IN ACUTE
DECOMPENSATED HEART FALIURE
(ADHF)
Dr Mohammed EssamHead of quality assurance&Nephrology Specialist
Deputy Director of KUCdepartment at KUC
Kidney & Urology CenterAlexandriaEGY
24
INOTROPES IN CARDIORENAL
SYNDROME (CRS),
IS THERE A ROOM?
Dr Alyaa El GhitaniClinical pharmacistKidney & Urology Center
Head of internal medicine clinical pharmacy
department at main university hospital
AlexandriaEGY
29
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Kidney Advances, Volume 5, June 2014 Cardio-Renal Axis Disorders
2kid d (F P l U O l )
RENOCARDIAC VERSUS CARDIORENAL SYNDROME
CHANGING PARADIGM
Ahmed F. EL Koraie
With the advance in our knowledge and
understanding of the physiological changes
that are responsible for the maintenance of
blood volume, vascular tone, and
hemodynamic stability and how much they
depend on a set of elegant interactions
between the heart and kidney, it is now widely
accepted that severe dysfunction in either of
these organs seldom occurs in isolation.
However, there is still huge debate not only tothe pathophysiologic mechanisms of the
cardiorenal syndrome but even to its true
definition.
The process itself remains enigmatic; our
understanding of the complex physiological,
biochemical, and hormonal derangements that
encompass the CRS is woefully deficient and
may lead to improper medical management of
patients.
The definition is now changing from the
simple notion of being a state in which therapyto relieve heart failure symptoms is limited by
further worsening renal function, to a more
complicated process that address the complex
and bidirectional nature of pathophysiological
interactions between the failing heart and
kidneys. That is, each dysfunctional organ has
the ability to initiate and perpetuate disease in
the other organ through common
hemodynamic, neurohormonal, and
immunologic/biochemical feedback pathways.
(1)
Renocardiac versus Cardiorenal
syndrome: what is the
difference?Epidemiological observations that correlates
cardiovascular morbidity and mortality and
decreased kidney function are now well
established. This relationship exists regardless
of whether the initial event is cardiac diseaseor renal parenchymal disease. The
cardiovascular mortality of patients with
congestive heart failure whose serum
creatinine level is only moderately elevated
[0.3 mg/dl] has been shown to be increased. (2)
Although the mechanisms underlying this
cardiorenal syndromehave not been clearly
elucidated, nevertheless, increased cardiac
preload and cardiac dilatation are known to be
associated with enhanced ventricular wall
stress, cardiac remodeling, increased leftventricular mass index and higher mortality.(3)
In this context, as the kidney is the primary
regulator of sodium and water excretion, even
a modest decrease in normal renal function in
patients with congestive heart failure could
contribute to increased cardiac preload,
cardiac dilatation, left ventricular hypertrophy
and increased mortality. This sequence of
events can, therefore, justifiably be termed
'cardiorenal syndrome'. (4)
In contrast to cardiorenal syndrome, shouldthe enhancement of cardiovascular death
initiated by kidney disease be termed
'renocardiac syndrome'? Again renal
parenchymal disease is associated with an
increase in the risk of cardiovascular death.
Slight elevation of serum creatinine
concentration by as little as (0.3 mg/dl) can
increase this risk. In fact, 90% of patients with
chronic kidney disease will die of
cardiovascular complications before they
progress to end-stage renal disease. Theprocesses underlying the increase in
cardiovascular mortality initiated by primary
kidney disease are not well defined, but there
are several potential mechanisms. These
include, but are not limited to, uncontrolled
hypertension, phosphate retention, secondary
hyperparathyroidism, myocardial and vascular
calcification, inflammation and oxidant
injury.(5) Lastly, it should be acknowledged
that there is overlap between these two
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syndromes; diabetes and hypertension can
initiate both cardiac and renal pathology.
Collectively some authors proposed
modification for the definition of CRS to
stress the bidirectional nature of the heart-
kidney interaction. Where they divide CRSinto five subtypes: type I, acute CRS; type II,
chronic CRS; type III, acute renocardiac
syndrome; type IV, chronic renocardiac
syndrome; and type V, secondary CRS,
meaning systemic diseases such as diabetes,
sepsis and amyloidosis causing simultaneous
cardiac and renal dysfunction.(6)
Cardiorenal syndrome (3)
Renocardiac syndrome. (5)
Renocardiac versus Cardiorenal
syndrome: what marker to use?The puzzle in understanding the
pathophysiology of CRS is far complicated. A
reduced cardiac output (CO) in CHF resultingin decreased renal perfusion could be an easy
explanation for the worsening renal function.
Interestingly, worsening renal function has
been demonstrated in patients with ADHF
even though left ventricular EF is preserved. (7)
This decline in renal function, despite a
presumed preservation of blood flow to the
kidneys, has led to the search for other
mechanisms of CRS, including the role of the
RAAS, various chemicals (nitric oxide [NO],
prostaglandins, natriuretic peptides,endothelins, etc), oxidative stress and
sympathetic overactivity. Thus CO is not a
reliable indicator to assess the severity of
CRS. More often, CO will be normal in cases
of CRS. So that, the presence of low filling
pressures, a low cardiac index or even reduced
renal perfusion is not necessary to identify
CRS.(8)
On the other hand, while making a diagnosis
of CRS, it should be kept in mind that there is
weak correlation between serum creatinineand GFR. Relative to a decline in EF, a fall in
GFR is more important regarding the
prognosis in heart failure patients. In such a
setting measurements of serum creatinine
alone could also be misleading in terms of
prognosis. Approximately two-thirds of
patients admitted for acute exacerbations of
CHF have decreased GFR or creatinine
clearance, despite many of them having
relatively normal levels of serum creatinine.
Thus, estimation of GFR should be a part of
the initial evaluation because GFR provides a
general sense of prognosis. Moreover, GFR is
helpful in the evaluation for planning a
management strategy (use of ACE inhibitors,
ARBs and radiocontrasts for diagnostic tests,
etc). (9)
MyocardialD sfunction Left Ventricular
Hypertrophy
Vascularand
MyocardialCalcification
PhosphateRetention
Renal Insufficiency
Sodium
RetentionInflammation
Oxidative Stress
H ertension
INCREASED CARDIOVASCULARMORBIDITY AND MORTALITY
Atherosclerosi
INCREASED CARDIOVASCULAR
MORBIDITY AND MORTALITY
Anemia
Increased
ParathyroidHormone
Chronic Cardiac
Failure
IncreasedCardiac Fillin
ArterialUnderfilling
Sodium & Water
Retention
Sympathetic and
RAAS Activity
Resistanceto
Natriuretic
Failure toEscape fromAldosterone
Proximal TubuleSodium and Water
Reabsorption
Decreased Distal Naand Water Delivery
CardiacDilatation
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Renocardiac vs cardio renal
prognosisImpact of Renal Disease on Clinical
Outcomes in Patients with HF
As mentioned earlier, renal dysfunction is oneof the most important independent risk factors
for poor outcomes and all-cause mortality in
patients with HF. Baseline glomerular
filtration rate (GFR) appears to be a stronger
predictor of mortality in patients with HF than
left ventricular ejection fraction or NYHA
functional class. Both elevated serum
creatinine on admission and worsening
creatinine during hospitalization predict
prolonged hospitalization, rehospitalization,
and death.(10)HF Outcomes in Patients with Renal
DiseasePatients with chronic renal insufficiency are at
strikingly higher risk for myocardial
infarction, HF with systolic dysfunction, HF
with preserved left ventricular ejection
fraction, and death resulting from cardiac
causes compared with individuals with normal
GFR.(11) In a meta-analysis individuals with
primary renal disease were more likely to die
of cardiovascular causes than renal failureitself.(12) In a multicenter cohort study of 432
patients, 31% planning to initiate hemodialysis
had HF symptoms, and 33% of such patients
had estimated left ventricular ejection fraction
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by RAAS elaboration in HF are a maladaptive
response to altered hemodynamics,
sympathetic signaling, and progressive renal
dysfunction. Thus the benefits of angiotensin-
converting enzyme (ACE) inhibition and
aldosterone antagonism through blockade ofthe intracardiac RAAS, reduction in
adrenergic tone, improvement in endothelial
function, and prevention of myocardial
fibrosis are well described in cardiac failure;
RAAS inhibition has been a main focus of
therapy in HF for the last 2 decades and has
led to improved outcomes for many patients.
Unfortunately, little is known about the long-
term benefits or adverse effects of RAAS
inhibition on kidney function in HF.(4)
Although ACE inhibitors and angiotensinreceptor blockers have important
renoprotective effects in hypertensive patients
with nondiabetic renal disease and individuals
with diabetic nephropathy, it is not clearly
established,(20) whether there is a
renoprotective role of ACE inhibitors and
angiotensin receptor blockers in systolic HF
that is independent of direct preservation of
ventricular function has not been
established.(21) Furthermore ACE inhibitors
and angiotensin receptor blockers cause dose-
dependent increases in angiotensin II (AT-II).
Significantly, AT-II directly contributes to
kidney damage. AT-II upregulates the
cytokines transforming growth factor-, tumor
necrosis factor-, nuclear factor-B, and
interleukin-6 and stimulates fibroblasts,
resulting in cell growth, inflammation, and
fibrotic damage in the renal parenchyma.(22)
Renocardiac vs cardiorenalimplication to treatmentFactors Influencing Medication Use
The commencement of renal impairment in
HF patients usually warrant unjustified
reduction or holding of the mainstay for
therapy of cardiac failure; diuretics and RAAS
blockade, under the notion of preventing
further deterioration in renal function. Such
patients are frequently discharged from the
hospital with inadequate resolution ofsymptoms and thus have high short-term
rehospitalization rates. Recognition that
elevated serum creatinine portends worse
outcomes in HF prompts physicians to be
concerned about the renal effects of these
agents. However, mean serum creatinine
increased even though outcomes were better inthe Cooperative North Scandinavian Enalapril
Survival Study (CONSENSUS).(23) With
diuresis, serum creatinine is more likely to
increase in patients receiving ACE inhibition
and in those with the lowest blood
pressures.(24) These data suggest that some
increase in creatinine should be tolerated with
the use of ACE inhibition, and other
interventions (such as decreased diuresis)
might be needed to accomplish this. The
advantage of ACE inhibitors in delayingprogression and death in HF is undeniable,
and their use should be encouraged unless
detrimental effects are clearly proven.(4)
Fluid Removal and Renal EffectsAlthough diuretics are commonly used in HF
and appear necessary, their possible adverse
effects are just starting to be explored, and
better knowledge of how to use them is
essential. Worsening serum creatinine,
azotemia, and metabolic contraction alkalosis
often limit conventional diuresis in patients
with HF. Both clinical and experimental
studies highlighted their detrimental effects to
the heart as well as the kidney. (25,26)
Nevertheless, they will remain the mainstay of
treatment until other interventions are proven
to be safer and more effective.
On the other hand continuous venovenous
ultrafiltration is emerging as a possible
alternative to pharmacological diuresis in
these scenarios and may offer greater ease andefficacy of volume and sodium reduction
without further compromising renal function
Although routine use of ultrafiltration has not
been shown to lead to better renal outcomes, if
the ultrafiltration rate does not exceed the
interstitium to intravascular refill rate (15
mL/min), it is possible that the more steady
fluid removal will prevent renal dysfunction.
(27,28)
Results of Nesiritide, ( a synthetic drug form
of human B-type natriuretic peptide) on bothfluid status and renal function in patients with
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HF have been disappointing. Although
nesiritide does have natriuretic effects and
improves GFR in normal individuals, the
effects in patients with HF are more
questionable.(29) Indeed, a meta-analysis
suggested that it might worsen renalfunction.(30) Therefore, the Acute Study of
Clinical Effectiveness in Decompensated
Heart Failure (ASCEND-HF) was designed as
a prospective, multicenter, double-blind,
randomized trial to examine the use of
nesiritide in this common, morbid, and often
lethal clinical condition. Two coprimary end
points, dyspnea and 30-day hospital
readmission or death, were chosen to examine
symptomatic response and objective
outcomes, respectively. Preliminary reportsfrom ASCEND-HF investigators suggest no
significant improvement in symptoms or
clinical outcomes, although no adverse effect
on mortality or renal function was noted. (31)
InotropesTo date no inotrope has proven to be
successful in reversing the CRS, albeit
inotropic therapy will continue to be used in
patients with worsening renal function
presumed to be secondary to decreased cardiac
output. Considering the multiple causes of
CRS in patients with HF, it is not surprising
that the data for inotropes as treatment are
mixed. It is true that dobutamine and
milrinone have been shown to increase cardiac
index and renal blood flow in most studies,
(32) However, the clinical consequences are
not clear, with urine output and outcomes not
having shown improvement in many
studies.(33,34) The routine use of inotropes to
permit more effective diuresis and treatment inpatients with HF was rejected in the OPTIME
study.(35) Again inspite of multiple studies
with dopamine and fenoldopam, no clinical
benefit has been demonstrated.(36-38)
Renocardiac vs cardiorenal
laboratory perspectivesRenal labs:Blood Urea Nitrogen (BUN); As BUN
depends on both cardiac and kidney function,since it takes into account cardiac output and
is a marker of neurohormonal activation. This
may be the explanation why BUN was found
to correlate with 60-d mortality more than
either serum creatinine or eGFR. In the
ADHERE registry, using admission BUN of
more than 43 mg/dl, this was found to be thebest identifier of in-hospital mortality in
patients with ADHF (39). Lower systolic BP
and higher serum creatinine were the second
and third best identifiers, respectively. The
same finding was observed in a retrospective
analysis of OPTIME-CHF. (35) In their
analysis, the highest BUN quartile was
associated with lowest BP, lowest plasma
sodium concentration, highest jugular venous
pressure (JVP) (41), and, therefore, worse
outcome. Trying to explain this finding, thelow cardiac output leads to significant
neurohumoral activation, including the
nonosmotic release of AVP that in turn results
in enhanced reabsorption of urea through urea
transporters in the collecting duct (42).
Moreover, in ADHF increased plasma AVP is
associated with activation of RAAS and SNS,
known predictors of mortality.
Hyponatremia; Hyponatremia is common in
patients with ADHF. Vasopressin stimulation
of the V1 and V2 receptors not only worsen
the signs, symptoms, and LV function of
patients with acute HF but also causes water
retention and hyponatremia, through
stimulation of the V2 receptors on the
collecting duct principal cells by vasopressin.
Blocking the V2 receptor vasopressin corrects
hyponatremia in HF and improves dyspnea.
However, there are no data that correction of
hyponatremia leads to better survival outcomein patients with ADHF (4346).
Lee et al. (47) demonstrated that hyponatremia
has associated with higher mortality in chronic
HF patients. Again the analysis of
OPTIMIZE- HF registry, showed that 19.7%
of patients were admitted with hyponatremia
(Na ` 135 mmol/L). Interestingly, lower
serum sodium concentration was associated
with higher mortality during hospitalization
and Post discharge and a higher risk of
readmission within 6 months.(48,49)
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Cardiac labs:B Type Natriuretic Peptide (BNP); There are
two major natriuretic peptides produced by the
heart: ANP in the atria and BNP in the
ventricles (50). In HF, congestion causes
cardiac chamber stretch and this leads torelease of these hormones. Patients with HF
who presented with BNP level of _480 pg/ml
had a 51% chance of death, hospital
readmission, or emergency room visit in 6 mo,
as opposed to 2.5% in HF patients who had a
BNP level of _230 pg/ml. (51)
Troponin; Cardiac-specific troponins I and T
are highly sensitive and specific markers of
myocardial injury. Approximately 40% of
patients who are admitted to the hospital withADHF have plasma elevations in troponin that
are not associated with any EKG changes or
findings of acute ischemia (52). In the
(EFFECT) study, (53) and an analysis of the
ADHERE (54) registry, there was a strong
association between elevated troponin, either
I or T subtypes, and mortality in patients with
no other evidence of acute ischemia on
presentation. Patients with positive troponin
had lower systolic BP on admission, a lower
ejection fraction, and higher in-hospital
mortality.
Anemia:Anemia is a common finding in patients with
HF, regardless of the presence of kidney
parenchymal disease. Whereas the mechanism
of anemia in CHF is almost certainly
multifactorial. Congestion with renal sodium
and water retention will lead to hemodilution,
relative erythropoietin deficiency may ensuewith renal impairment. Inflammation and
increased cytokine production occur with HF
and can suppress erythrocytosis by the bone
marrow, Nutritional and vitamin deficiency is
also common in patients with HF and may
contribute to anemia. (55, 56) On the other
hand correction of anemia and the target Hb in
those patients revealed contradicting results.
One analysis of the database of the Study of
LV Dysfunction (SOLVD) by Al-Ahmad et al.
showed that for every decrease in Haematocritof 1% the mortality rate increases by 2.7%
(57). Moreover, a number of small studies in
chronic heart failure patients have shown
significant improvement in outcomes by
increasing hemoglobin level up to 12 to 13
g/dl (58). Whereas, the Correction of
Hemoglobin and Outcomes In RenalInsufficiency (CHOIR) study (59) in CKD
patients with anemia receiving alfa poetic led
to increased hospital admission due to CHF
exacerbation, rate of death and cardiovascular
events.
Initiated in 2006,( RED-HF) trial had
randomized 2278 anemic patients with
symptomatic left ventricular systolic
dysfunction to either darbepoetin alfa or
placebo. The aim in the treatment group was a
target hemoglobin of at least 13.0 g/dL. Theprimary end point was a composite of time to
death from any cause or first hospital
admission for worsening HF in subjects with
heart failure and anemia. The rates of the
primary end point were no different between
groups (hazard ratio 1.01, 95% CI 0.90
1.13). The trial's failure echoes that of
the Trial to Reduce Cardiovascular Events
With Aranesp Therapy(TREAT) in 2009,
reported by heartwire, which showed no
benefit of darbepoetin alfa on death, CV
events, CV death, or renal events in diabetic
patients with chronic kidney disease and
anemia.(60)
Collectively the to and fro relationship
between the heart and the kidney in all aspects
form pathophysiology down to the
management does implicate the concept of
renocardiac &/or cardiorenal syndrome
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37. Ungar A, Fumagalli S, Marini M, Di Serio C,Tarantini F, Boncinelli L, Baldereschi G, Valoti P, La
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38. de Fijter CW, Comans EF, de Vries PM, Oe PL,
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stratification for inhospital mortality in acutely
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40. Drazner MH, Rame JE, Stevenson LW, Dries DL:Prognostic importance of elevated jugular venous
pressure and a third heart sound in patients with heart
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41. Gheorghiade M, Abraham WT, Albert NM, GattisStough W, Greenberg BH, OConnor CM, She L,
Yancy CW, Young J, Fonarow GC; OPTIMIZE-HF
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outcomes in patients hospitalized for heart failure: An
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28: 980988, 2007
42. Schrier RW: Blood urea nitrogen and serumcreatinine. Not married in heart failure. Cir Heart Fail 1:
25, 200843. Schrier RW, Gross P, Gheorghiade M, Berl T,
Verbalis JG, Czerwiec FS, Orlandi C; SALT
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V2-receptor antagonist, for hyponatremia. N Engl J
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44. Gheorghiade M, Gattis WA, OConnor CM, AdamsJr KF, Elkayam U, Alejandro Barbagelata A, Ghali JK,
Benza RL, McGrew FA, Klapholz M, Ouyang J, Cesare
Orlandi C Effects of tolvaptan, a vasopressin antagonist,
in patients hospitalized with worsening heart failure: A
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Grinfeld L, Maggioni AP, Swedberg K, Udelson JE,
Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C;
Efficacy of Vasopressin Antagonism in Heart Failure
Outcome Study With Tolvaptan (EVEREST)
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46. Gheorghiade M, Konstam MA, Burnett JC Jr.,
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Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C;
Efficacy of Vasopressin Antagonism in Heart FailureOutcome Study With Tolvaptan (EVEREST)
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an oral vasopressin antagonist, in patients hospitalized
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serum sodium concentration and its modification by
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Stough W, Pina IL, Felker GM, Adams KF Jr, Califf
RM, Gheorghiade M; OPTIME-CHF Investigators:
Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening
heart failure: Results from the Outcomes of a
Prospective Trial of Intravenous Milrinone for
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study. Circulation 111: 24542460, 2005
49. Gheorghiade M, Rossi JS, Cotts W, Shin DD,
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50. Nakagawa O, Ogawa Y, Itoh H, Suga S, KomatsuY, KishimotoI, Nishino K, Yoshimasa T, Nakao K:
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turnover of brain natriuretic peptide in cardiac
hypertrophy: Evidence for BNP as an emergency
cardiac hormone against ventricular overload. J Clin
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52. Perna ER, Macn SM, Parras JI, Pantich R, Faras
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53. You JJ, Austin PC, Alter DA, Ko DT, Tu JV:
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Investigators: Cardiac troponin and outcome in acute
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55. Fishbane S: Anemia and cardiovascular risk in the
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56. Rauchhaus M, Doehner W, Francis DP, Davos C,
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G, Baruch R, Schwartz D, Yachnin T, Steinbruch S,Shapira I, Laniado S, Iaina A: The effect of correction
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59. Singh AK, Szczech L, Tang KL, Barnhart H, SappS, Wolfson M, Reddan D; CHOIR Investigators:
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REFRACTORY EDEMA WITH CONGESTIVE HEART FAILURE
STEPWISE APPROACHES - NEPHROLOGY PERSPECTIVES
Mohammed A. Gawad
INTRODUCTIONGeneralized edema occurs secondary to many
clinical disorders, as heart failure, liver
cirrhosis, nephrotic syndrome, and renal
failure. The usual management of edema is the
using of diuretics with other lines of
precautions and steps of treatment specific for
each clinical disorder. In general, failure to
decrease the extracellular fluid volume despite
liberal use of diuretics often is termed diureticresistance. The scope of this article is to discuss
the cause of refractory edema to usual
management with diuretics in patients with
chronic congestive heart failure (CHF) and
how to deal with it.
MECHANISM OF DEVELOPMENT
OF REFRACTORY EDEMAMany factors are involved in the development
of refractory edema, and the decreased
response to the usual diuretic regimen. First
factor is high salt intake which prevents net
fluid loss even with adequate therapeutic doses
of diuretics.(1)
Second factor that may contribute to refractory
edema is decreased loop diuretic secretion. An
important step in the mechanism of action of
loop diuretics is that they enter the tubular
lumen by secretion in the proximal tubule, notby glomerular filtration. After that loop
diuretics inhibit the Na-K-2Cl carrier in the
luminal membrane of the thick ascending limb
of the loop of Henle, which will reduce NaCl
reabsorption Fig-1. Diuretic efficacy is directly
related to urinary excretion rates, rather than to
plasma drug concentrations.(2) In case of CHF,
renal perfusion and tubular blood supply is
decreased due to decreased cardiac output,
which decrease the delivery of diuretics to their
site of action causing insignificant effect. It isalso well known that
loop diuretics are highly (95 percent) protein
bound, which keeps the diuretic within the
intravascular space, which will ensure good
delivery of the diuretic to the kidney.
Hypoalbuminemia may occur in CHF if
albumin is filtered in the urine secondary to
high venous pressure. Secondary to this
hypoalbuminemia; the degree of diuretic -
protein binding is reduced, which will result ina larger extravascular space of distribution of
the diuretic with a slower rate of delivery to the
kidney, and then reduced diuresis. In addition,
the filtered albumin in the urine secondary to
high venous pressure may bind loop diuretics
in the tubular lumen and interfere with its
action.(3)
Figure-1 Site of action of different diuretics
The third and one of the important causes of
diuretic resistance is the use of nonsteroidal
anti-inflammatory drugs, which reduce the
synthesis of prostaglandins, which will affect
diuretic responsiveness.(4)
The fourth factor is that some patients with
diuretic resistance have decreased natriuresis,
despite adequate urinary delivery of thediuretic. This problem is often due to increased
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tubular sodium reabsorption in nephron
segments other than the loop of Henle with the
chronic use of diuretics (the diuretic braking
phenomenon).(5,6) Increased tubular sodium
reabsorption associated with the diuretic
braking phenomenon may occur at differentsegments of the nephron:
In the proximal tubule, secondary to the
activation of angiotensin II and
Norepinephrine. The neurohumoral activation
occurs secondary to the heart failure itself and
also may occur as a consequence of diuretic-
induced water and salt loss.(7)In the distal tubule, a flow-dependent hypertrophycan occur with chronic loop diuretic therapy, which
increases sodium reabsorption secondary to the
increased activity of the sodium chloridecotransporter in the luminal membrane of the
distal tubule cells and its hypertrophy.(8,9)
In the collecting tubules, due to increased
mineralocorticoid activity that occurs also
secondary to neurohumoral activation as that
affect sodium reabsorption in PCT.(4)
The fifth factor causing refractory edema is
inadequate diuretic dose or frequency, and the
non compliance of the patient for his prescribed
doses.(3)
The final and one of the most important factors
is that in patients with CHF there may be
decreased intestinal perfusion, reduced
intestinal motility, and also intestinal mucosal
edema, which will reduce the diuretic
absorption, and hence diuretic delivery to the
kidney and diuretic excretion rate.(10)
All these factors must be excluded during the
stepwise approach of management of refractory
edema in patients with CHF.
STEPWISE APPROACHES FOR
MANAGEMENT OF REFRACTORY
EDEMA WITH CHFStepwise approaches for management of
refractory edema with CHF are summarized in
Fig-2, Fig-5 and Fig-6.
It is important to know that these approaches
are based on our clinical experience and cases
in Kidney and Urology Center (KUC) -
Alexandria - Egypt. No available enough data
about target fluid loss or monitoring of
overloaded resistant patients. Any physiciancan change any of the steps in our approach
according the clinical situation and the need of
the patient. The following approach is just only
a skeleton that we will go around.
Pre-Diuresis Precautions (Fig-2)
It is important to ensure dietary sodium
restriction, as increased sodium intake will
cause refractory edema (refer to mechanism of
development of refractory edema above). To
estimate salt intake in CHF patients with
refractory edema, a 24-hour urine should be
collected. A value above 100 mEq per day
indicates that noncompliance with sodium
restriction.(6) The 2010 Heart Failure Society
of America (HFSA) guidelines on acute
decompensated HF (ADHF) recommend a
sodium intake of less than 2 g/day. They even
recommend greater sodium restriction in
patients with recurrent or refractory volume
overload. Water restriction may also beimportant.(11)
Also stop all nonsteroidal anti-inflammatory
drugs the patient uses, as they are of the
important factors causing refractory edema
(refer to mechanism of development of
refractory edema above).(4)
An important precaution is to exclude
concomitant aminoglycosides use, as this may
increase the incidence of ototoxicity with thehigh doses of loop diuretics use (12) (refer to
monitoring side effects and toxicity
ototoxicity below).
Pre-Diuresis Lab and Imaging (Fig-2)
Pre-Diuresis Lab: Serum Albumin,
urea/BUN, creatinine, Na, K, Ca, Mg, uric
acid, Hb, Ht%, and other lab investigations (as
indicated).
Pre-diuresis Imaging:chest X-ray, ultrasound
abdomen and pelvis, ECHO.
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The idea behind the pre-diuresis investigations
is to have a baseline for all the parameters of
the patient assessment that will be needed later
to follow the response or to detect the side
effects of the diuretics.
Figure-2 Pre-diuresis precautions, Lab & imaging
investigations (refer to the paragraph for details)
Posture dur ing Diuresis (F ig-5, 6)
Patients with CHF cannot increase cardiac
output in upright position; subsequently renal
perfusion and urinary diuretic delivery will
decrease. In addition, renal salt and waterreabsorption increase. The efficacy of
assuming a supine position was evaluated in a
randomized trial. The supine position was
associated with significantly higher mean
creatinine clearance and diuretic response. The
upright position was associated with significant
increases in plasma norepinephrine, renin, and
aldosterone; which is theoretically
reasonable.(13)
Furosemide-Albumin I nfusion (Fi g-5, 6)As mentioned some patients with
hypoalbuminemia may be resistant to the usual
diuretic therapy (refer to mechanism of
development of refractory edema above).
Theoretically, infusion of the furosemide-
albumin complex can increase diuretic delivery
to the kidney by keeping furosemide within the
vascular space.(14) However, subsequent
studies found that the use of mixture of loop
diuretic and albumin in hypoalbuminemic
patients (secondary to cirrhosis or nephrotic
syndrome), with mean plasma albumin
3.0 g/dL, produced only a modest increase in
sodium excretion compared with furosemide
alone without an increase in the rate of
furosemide excretion.(15,16) But the
significance of infusion of loop diuretic plus
albumin may appear in patients with refractoryedema and severe hypoalbuminemia (plasma
albumin less than 2.0 g/dL). However, the
evidence supporting this is weak as this has not
been studied yet.
I ntermi ttent I ntravenous (I V) Bolus
versus Continuous IV I nfusion
Diuretic Therapy
The efficacy of a continuous IV infusion
compared with intermittent IV bolus therapyhas been evaluated in randomized trials, andthey appear to have similar efficacy. But a
continuous intravenous infusion is safer, less
ototoxicity (tinnitus and hearing loss) than
bolus injections of loop diuretics (refer to
monitoring side effects and toxicity
ototoxicity below).(17-19)
Also continuous IV infusion is able to maintain
an effective stable rate of drug excretion and
therefore a maintained inhibition of sodium
chloride reabsorption in the loop of Henlethrough the duration of therapy. In contrast,
intermittent IV bolus therapy will lead to
initially higher rate of diuretic excretion,
followed thereafter by lower rates; as a result,
sodium excretion is at maximal levels for the
first two hours but then gradually falls.(19)
(Fig-3)
Figure-3: Diuresis peak following IV bolus and IV
continuous infusion of loop diuretic
Pre-Diuresis Precautions:
- Ensure dietary sodium restriction
- Stop NSAIDs
- Exclude aminoglycosides
Pre-Diuresis Lab: Serum Albumin, Urea/BUN,
Creatinine, Na, K, Ca, Mg, Uric acid , Hb, Ht%
Other lab Ix (as indicated)
Pre-diuresis Imaging: CXR, USS Abdomen &
Pelvis, ECHO.
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Single and Maximum Effective IV
Dose of L oop Diuretics
Before discussing the stepwise bolus and
continuous infusion approaches, we have to
know first the concepts of single and maximum
IV effective dose of loop diuretics.
Single IV Effective Dose of Loop Diuretics
Diuretics have a dose-response curve (Fig-4),
as there will be no natriuresis seen until a
threshold rate of drug excretion in urine is
attained. For example, if a patient does not
respond, i.e. no diuresis, to 40 mg
of furosemide, the dose may not have exceeded
the threshold of the single effective dose, so
this single dose (40 mg) should be increased to60 or 80 mg, rather than giving it twice a day.
Once a single effective dose has been
determined, i.e. there is a response of diuresis,
it should be administered multiple times per
day, with a frequency which is individualized
according to the diuretic needs of the
patient.(19-21) So simply, single effective dose
is the least dose that will cause response i.e.
diuresis.
Figure-4: Dose response curve of furosemide
Maximum IV Effective Dose of Loop
Diuretics
The maximum IV effective dose is the dose at
which loop sodium chloride transport is
completely inhibited. So administering higher
doses will produce little or no further diuresis,
a plateau is reached (Fig-4), but it may increase
the risk of toxicity and side effects. MaximumIV effective dose differs according the cause of
edema and renal function of the patient. In CHFpatients with normal or near normal estimatedglomerular filtration rate (eGFR), the maximumeffective IV dose is 40 to 80 mg of furosemide, 1 to2 mg of bumetanide, and 20 to 40 mg
of torsemide.(3) In chronic kidney disease, the
maximum IV effective dose varies with the
severity of the kidney disease (eGFR). In
moderate chronic kidney disease; maximum IV
effective dose is 80 mg of furosemide, 2 to 3
mg ofbumetanide, and 20 to 50 mg
oftorsemide.In severe chronic kidney disease;
it is 200 mg offurosemide, 8 to 10 mg
ofbumetanide, and 50 to 100 mg
oftorsemide.(21) The 2013 American College
of Cardiology/American Heart Association
(ACC/AHA) guideline on heart failurerecommended maximum IV effective dose of
furosemide (160 to 200 mg), bumetanide (4 and 8
mg), and torsemide (100 to 200 mg) for
patients with severe heart failure and a
substantially reduced GFR. This recommendation
differs in the dose of bumetanide and torsemide
than other literature.(22)
The rate of IV bolus administration is
important to be slow to decrease the incidence
of side effects. A bolus dose of about 20 to 40mg of furosemide is better to administered over
5 minutes, while a bolus dose of 60 to 120 mg
is better to administered over 20 minutes, and
finally a bolus dose of 160 to 200 mg
of furosemide is better to be given over 40 to
50 minutes.
I ntermi ttent I V Bolus Diur etic Therapy
Stepwise Regimen (Fig-5)
Start IV bolus loop diuretic targeting to reachthe single effective dose (mentioned above).
The usual initial intravenous bolus dose
of furosemide is 20 to 40 mg. Next action
depends on the response of the patient:
If good diuretic response, continue the samedose with follow up (refer to monitoring responseand side effects of IV diuretic therapy below). If little or no response to the initial bolus dose,
the dose should be doubled at two-hour intervals asneeded up to the maximum recommended doses(discussed above).(19,20,23)
http://www-uptodate-com.ezproxy.rush.edu/contents/bumetanide-drug-information?source=see_linkhttp://www-uptodate-com.ezproxy.rush.edu/contents/torsemide-drug-information?source=see_linkhttp://www-uptodate-com.ezproxy.rush.edu/contents/furosemide-frusemide-drug-information?source=see_linkhttp://www-uptodate-com.ezproxy.rush.edu/contents/bumetanide-drug-information?source=see_linkhttp://www-uptodate-com.ezproxy.rush.edu/contents/torsemide-drug-information?source=see_linkhttp://www-uptodate-com.ezproxy.rush.edu/contents/torsemide-drug-information?source=see_linkhttp://www-uptodate-com.ezproxy.rush.edu/contents/bumetanide-drug-information?source=see_linkhttp://www-uptodate-com.ezproxy.rush.edu/contents/furosemide-frusemide-drug-information?source=see_linkhttp://www-uptodate-com.ezproxy.rush.edu/contents/torsemide-drug-information?source=see_linkhttp://www-uptodate-com.ezproxy.rush.edu/contents/bumetanide-drug-information?source=see_link -
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If partial diuretic response to once daily
single effective or maximum bolus dose,
different strategies can be done to increase the
response, for example the loop diuretic dose
can be repeated twice or even three times a day
(8), and also adding a thiazide diuretic can adda lot of benefit (refer to when to add thiazides
below).
Continuous IV Infusion Diuretic
Therapy Stepwise Regimen (F ig-6)
Loading Bolus Dose:
Use of a continuous IV infusion requires the
patient to be responsive to loop diuretics. Thus,
a continuous IV infusion should notbe tried in
CHF patients who have not responded torepeated bolus doses up to the maximum bolus
doses (discussed above). IV bolus therapy will
lead to initially higher rate of diuretic
excretion, which will lead to high initial rates
of urinary diuretic and sodium excretion.(24)
(Fig-3)
Continues IV Infusion Therapy:
If there is a good response to the initial loading
bolus dose, then it must be followed by the
continuous IV infusion, which dose is
dependent on the renal function of the patient.
A start of continues infusion dose of
approximately 5 mg/h is reasonable in patients
with normal or near normal renal function
(eGFR >75 mL/min) and of approximately
20 mg/h in patients with impaired kidney
function (estimated GFR < 30 mL/min).(25)
Maximum I nfusion Dose
Higher infusion rates of up to 240 mg/h (4mg/min) are reported, but the risk of
ototoxicity and other side effects is high and
the use of this high infusion rate must be
weighed against alternative strategies such as
the addition of a thiazide diuretic or fluid
removal via ultrafiltration. This high infusion
rate is not recommended.(3,12) Acute andChronic kidney diseases also increase the risk ofototoxicity. Permanent deafness has been reportedin patients with acute kidney injury receiving
furosemide continuous IV infusion dose of 80 to160 mg/h.(26) (refer to monitoring side effects and
toxicityototoxicity below).
Furosemide
IV
Torsemide
IV / PO
Bumetanide
IV / PO
20 mg 10 mg 1 mg
40 mg 20 mg 2 mg
Table 1 equivalent doses of other loop diuretics tofurosemide dose
I f I V F urosemide is Ineff ective, Can I
Switch to Equivalent IV Dose of
Bumetanide or Torsemide?
If the patient is resistant to IV furosemide, it is
not likely to respond to an equivalent
intravenous dose of any other loop diuretic as
bumetanide or torsemide.(3)
When to Add Thiazide Diuretic?(Tabel-2)
One mechanism for overcoming diuretic
resistance is by sequential nephron blockade.
Sequential nephron blockade means the
concurrent use of diuretics acting upon
different segments of the nephron; therefore
producing an additive or synergistic diuretic
response.(27) (Fig-1)
As mentioned above, long term administration of
a loop diuretic will increase the distal sodium
delivery, a flow-dependent hypertrophy in distalconvoluted tubule can, which increases sodium
reabsorption secondary to the increased activity
of the sodium chloride cotransporter in the
luminal membrane of the distal tubule cells and
its hypertrophy.(8,9) Therefore adding thiazidediuretic (in patient with known long term use ofloop diuretics) will block the distal reabsorption of
sodium, leading to a better diuretic effect. Alsothiazides will add benefit if added to cases withpartial diuretic response to the single
effective/maximum bolus dose, or cases with partialdiuretic response to continuous IV infusion diuretic
therapy.(28) (Fig 5,6)The timing of combination therapy depends
upon the route by which the diuretics are given.
Loop and thiazides diuretics can be
administered at the same time if given by the
same route i.e. intravenous or oral. If, however,
a thiazide diuretic is given orally, so the
thiazide diuretic should precede the loop
diuretic by 2-5 hours, since the peak effect of
the thiazide is 4-6 hours after ingestion.(29)
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Pre-Diuresis Precautions,
Pre-Diuresis Lab and Pre-diuresis Imaging
(refer to Fig-2 and related paragraph, discussed before)
Albumin infusion
in case of hypoalbuminemia (
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Pre-Diuresis Precautions,
Pre-Diuresis Lab and Pre-diuresis Imaging
(refer to Fig-2 and related paragraph, discussed before)
Albumin infusion
in case of hypoalbuminemia (75 mL/min)
Continuous Furosemide infusion, 5 mg/h (orequivelant)
Follow Up UOP after 2 hrs:
Minimumal required UOP: 0.5-1 ml/kg/h, which can beincreased according clinical situation
Adequate UOP
Assess UOP every 2hrs
Increase ordecrease infusionrate according to
monitoringparameters**
Convert to oraltherapy *****
Inadequate or NoUOP
a second bolus is given followed by
a higher infusion rate of 10 mg/h
+ Thiazide Initial dose
Follow Up UOP after 2 hrs:
Minimal required UOP: 0.5-1 ml/kg/h, which can beincreased according to clinical situation
If inadequate or No UOP:
a second bolus is given followed by
a higher infusion rate of 20 mg/h
+ Thiazide maximum dose
Follow Up UOP after 2 hrs:
Minimal required UOP: 0.5-1 ml/kg/h, which can beincreased according to clinical situation
No UOP
UF
Inadequate UOP
Impaired renal function
(eGFR
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Chlorothiazide Edema:
Oral, I.V.: 500-1000 mg once or twice daily; intermittent
treatment (eg, therapy on alternative days) may be appropriate
for some patients
CrCl
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When to Add Spironolactone? (Table-3)
Utilization of spironolactone may be more
effective when circulating aldosterone
concentrations are increased (which is usually
the case in more advanced CHF, such as New
York Heart Association classes III and IV).(30)The associated reduction in collecting tubule
sodium reabsorption and potassium secretionenhanced by spironolactone (Fig-1) can bothincrease the diuresis and minimize the degree ofpotassium wasting. Therefore, it may be highlysuggested to start spironolactone in patients who
have developed low or low-normal serumpotassium with loop diuretic therapy alone. It is
also reasonable to start a spironolactone before theaddition of a thiazide diuretic, as combination
therapy of loop diuretics and thiazides can lead to amarked diuresis and hypokalemia.(29)
Normal
GFR
Edema:Oral: 25-200 mg daily in 1-
2 divided doses
Hypokalemia:Oral: 25-100 mg
once daily
Abnormal
GFR
Heart failure (Yancy, 2013):
eGFR 50 mL/minute/1.73 m2:
o Initial dose: 12.5-25 mg once daily;
o Maintenance dose (after 4 weeks
of treatment with potassium 5mEq/L): 25 mg once or twice daily
eGFR 30-49 mL/minute/1.73 m2:
o Initial dose: 12.5 mg once daily or
every other day;
o Maintenance dose (after 4 weeks
of treatment with potassium 5
mEq/L): 12.5-25 mg once daily
eGFR
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these cases. In my own opinion, HSS may be of
high value if the treated patient is already
hyponatremic, or having a low border line
blood pressure which may exacerbate the
depletion of the intravascular effective
circulating volume with the used aggressivediuresis.
Moni tori ng Response and Side Effects
of IV Diuretic Therapy (Table-4)
Lab: Na, K (daily)
Urea/BUN, Creatinine (daily)
Hb, Ht% (daily)
ABG (daily)
Ca, Mg
Uric Acid
Serum Albumin
Other lab Ix (as indicated)
Radiology
(as
needed):
CXR
USS Abdomen & Pelvis
ECHO
Clinical: Weight measurement: should be
performed at the same time each
day, usually in the morning, prior to
eating and after voiding.
Signs of hypovolemia (not lessthan 4 times/day):
o Weakness
o Hypotension
o orthostatic hypotension
o cool extremities
o + elevated serum creatinine
o + rapidly elevated Ht%
Signs of ototoxicity(not less than
4 times/day):
o decreased hearing
o tinnitus
o deafness: transient (most lasting
30 minutes to 24 hours) or
permanent deafness
Table 4 Monitoring Response and Side Effects of IV
Diuretic Therapy
Ef fect on Renal F unction
The blood urea nitrogen (BUN) and serum
creatinine often rise during diuretic treatment
of HF and careful monitoring is recommended.Heart Failure Society of America 2010
Comprehensive Heart Failure Practice
Guidelines for management of patients with HF
with elevated or rising BUN and/or serum
creatinine include the following:
Other potential causes of kidney injury (eg,
use of nephrotoxic medications, urinaryobstruction) should be evaluated and
addressed.
Patients with severe symptoms or signs of
congestion, particularly pulmonary edema,
require continued fluid removal independent of
changes in GFR. In the presence of elevated
central venous pressure, renal function may
improve with diuresis.
If the BUN rises and the serum creatinine is
stable or increases minimally, and the patient is
still fluid overloaded, the diuresis can becontinued to achieve the goal of eliminating
clinical evidence of fluid retention with careful
monitoring of renal function.
If increases in serum creatinine appear to
reflect intravascular volume depletion, then
reduction in or temporary discontinuation of
diuretic and/or angiotensin converting enzyme
(ACE) inhibitor/angiotensin II receptor blocker
therapy should be considered. Adjunctive
inotropic therapy may be required.(11)
As stated in the American College
of Cardiology/American Heart Association HF
guideline, adverse effects must be monitored
closely:
Electrolyte imbalances (particularly
hypokalemia, hypomagnesemia, and metabolic
alkalosis) that develop during diuresis should
be promptly treated while the diuresis is
continued.
If hypotension or worsening renal function
develops before the goals of treatment areachieved, the diuresis may be slowed. Diuresis
should be maintained until fluid retention is
eliminated even if this results in asymptomatic
mild to moderate decreases in blood pressure or
renal function. Excessive concern about
hypotension and azotemia can lead to
underutilization of diuretics and persistent
volume overload. Persistent volume overload
contributes to continued symptoms, may
reduce the efficacy of drug therapy for HF,
and, persistent volume overload may beassociated with increased mortality.(25)
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OtotoxicityMonitory the evidence of toxicity during the
therapy period is mandatory. Decreased
hearing , tinnitus, or deafness transient (most
lasting 30 minutes to 24 hours) or permanent
deafness.(38) As mentioned above the mechanismof action of loop diuretics is mediated by a Na-K-2Cl cotransporter inhibition at the ascending loopof Henle. A secretory isoform of this cotransporteris present in the inner ear and plays an important
role in the composition of endolymph. It wasapproved that inactivation of this transporter inmouse led to reduced endolymph secretion,structural damage to the inner ear, and
deafness.(39)
The following are the factors which may
increase the risk of ototoxicity in CHF patientsreceiving loop diuretics:
Patients who are treated with high IV dose
of bolus therapy are at high risk of developing
ototoxicity. Bolus IV furosemide doses of 160
to 200 mg (and the equivalent doses of
bumetanide and torsemide) can cause transient
tinnitus. This effect can be minimized by
giving the dose more slowly as mentioned
above in bolus IV therapy.(38)
Although the risk of ototoxicity may be
reduced by a continuous infusion rather thanbolus therapy.(24,38) But continuous diuretic
infusion can also cause ototoxicity especially
with rates above 4 mg/min.(3,12)
Risk of ototoxicity is increased if the
patient is already taking other ototoxins such as
aminoglycoside antibiotic.(12)
Acute and Chronic kidney diseases also
increase the risk of ototoxicity. Permanent
deafness has been reported in patients with
acute kidney injury receiving furosemide
continuous IV infusion dose of 80 to160 mg/h.(26)
Switching from IV to Oral Loop
Diuretics (Table-5)When to
start?
It depends on the clinical
decision of the treating
physician.
Dosage The oral dose
of Furosemide is approximately
twice the intravenous dose. The oral dose of Torsemide &
Bumetanide is the same as the
intravenous dose.
Important
Considerations
In our mind it is important to
try at least one to two days on
oral therapy will the patient still
in hospital. This facilitates theadjustment of the oral dose to
avoid over or under diuresis.
No special recommendations.
But mainly the dose of diuretic
should be adjusted once the
patients dry body weight is
attained to the minimum dose
required to maintain dry body
weight.
Table5 Switching from IV to Oral Loop Diuretics
The decision of replacing IV diuretic therapy
by the oral one depends on the clinical situation
and the clinician sense. No special
recommendations for when to switch from IV
to oral loop diuretics. When converting to oral
therapy, the dose should usually be doubled for
oral furosemide, a twofold higher dose than the
intravenous dose is a reasonable starting point
as its mean bioavailability is only about 50%,
with substantialinterpatient and intrapatientvariability (range 10 to 100 percent). Further
dose adjustments may be needed according to
the patient response, the dose of diuretic should
be adjusted once the patients dry body weight
is attained to the minimum dose required to
maintain dry body weight. In contrast, the
intravenous and oral doses are similar in
patients treated with bumetanide or torsemide,
which have higher rates of oral bioavailability
(70 to 95 percent and 80 to 90 percent,
respectively), but also with further doseadjustments may be needed according to the
patient response.(3,25,40)
Can We Use Dopamine to Enhance
Diuresis?There is no strong evidence conformation
about the significant benefit and effect from
intravenous dopamine (natriuretic and renal
vasodilator activity), few data and reports are
available on this subject.(41)
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REFRENCES1. The physiologic basis of diuretic synergism: its role
in treating diuretic resistance. Ellison DH. Ann Intern
Med. 1991;114(10):886.
2. Opie LH. Diuretics. In: Opie LH, Kaplan NM, Pool-
Wilson P, eds.Drugs for the Heart.5th edition. Diuretic
therapy.
3. Diuretic therapy. Brater DC. N Engl J Med.
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4. Diuretic drugs and the treatment of edema: from
clinic to bench and back again. Ellison DH. Am J
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5. Mechanism of impaired natriuretic response to
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CS, Unwin RJ Kidney Int. 1989;36(4):682.
6. The physiologic basis of diuretic synergism: its role
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7.
Na,K-ATPase in isolated nephron segments in rats
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Popovtzer MM. Circ Res. 1991;68(4):1051
8. A volume-independent component to postdiuretic
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9. Loop diuretic infusion increases thiazide-sensitive
Na(+)/Cl(-)-cotransporter abundance: role ofaldosterone. Abdallah JG, Schrier RW, Edelstein C,
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Diuretic treatment and diuretic resistance in heartfailure.. Krmer BK, Schweda F, Riegger GA. Am J
Med. 1999;106(1):9011. HFSA 2010 Comprehensive Heart Failure Practice
Guideline. Heart Failure Society of America, Lindenfeld
J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA,
Givertz MM, Katz SD, Klapholz M, Moser DK, Rogers
JG, Starling RC, Stevenson WG, Tang WH, Teerlink JR,
Walsh MN. J Card Fail. 2010;16(6):e1.
12. Furosemide-induced ototoxicity. Gallagher KL,
Jones JK. Ann Intern Med. 1979;91(5):744.
13. Diuretic treatment in decompensated cirrhosis and
congestive heart failure: effect of posture. Ring-Larsen
H, Henriksen JH, Wilken C, Clausen J, Pals H,Christensen NJ. Br Med J (Clin Res Ed).
1986;292(6532):1351.
14. Mechanism of furosemide resistance in
analbuminemic rats and hypoalbuminemic patients.Inoue
M, Okajima K, Itoh K, Ando Y, Watanabe N, Yasaka T,
Nagase S, Morino Y Kidney Int. 1987;32(2):198.15. Coadministration of albumin and furosemide in
patients with the nephrotic syndrome. Fliser D,
Zurbrggen I, Mutschler E, Bischoff I, Nussberger J,
Franek E, Ritz E. Kidney Int. 1999;55(2):629
16. Effects of albumin/furosemide mixtures on
responses to furosemide in hypoalbuminemic patients.
Chalasani N, Gorski JC, Horlander JC Sr, Craven R,Hoen H, Maya J, Brater DC. J Am Soc Nephrol.
2001;12(5):1010.
17. Continuous infusion versus bolus injection of loop
diuretics in congestive heart failure. Salvador DR, Rey
NR, Ramos GC, Punzalan FE. Cochrane Database Syst
Rev. 2005; :CD003178.
18. Diuretic strategies in patients with acute
decompensated heart failure. 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, NHLBI
Heart Failure Clinical Research Network. N Engl J Med.
2011;364(9):797
19. Loop diuretics for chronic renal insufficiency: a
continuous infusion is more efficacious than bolustherapy. Rudy DW, Voelker JR, Greene PK, Esparza FA,
Brater DC. Ann Intern Med. 1991;115(5):360.
20. Bumetanide and furosemide in heart failure. D
Craig Brater, Bart Day, Ann Burdette and
Shirley Anderson. Kidney Int 26: 183-189;doi:10.1038/ki.1984.15321. Brater DC, Voelker JR. Use of diuretics in patients
with renal disease. In: Pharmacotherapy of Renal
Disease and Hypertension (Contemporary Issues in
Nephrology), Bennett WM, McCarron DA (Eds),
Churchill Livingstone, New York 1987. Vol 17.
22. 2013 ACCF/AHA guideline for the management of
heart failure: a report of the American College of
Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. Yancy CW, Jessup
M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH,
Fonarow GC, Geraci SA, Horwich T, Januzzi JL,
Johnson MR, Kasper EK, Levy WC, Masoudi FA,McBride PE, McMurray JJ, Mitchell JE, Peterson PN,
Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ,
Wilkoff BL, American College of Cardiology
Foundation, American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol. 2013Oct;62(16):e147-239. Epub 2013 Jun 5.
23. Brater DC, Voelker JR. Use of diuretics in patients
with renal disease. In: Pharmacotherapy of Renal
Disease and Hypertension (Contemporary Issues in
Nephrology), Bennett WM, McCarron DA (Eds),
Churchill Livingstone, New York 1987. Vol 17.
24. Diuretic efficacy of high dose furosemide in severe
heart failure: bolus injection versus continuous infusion.Dormans TP, van Meyel JJ, Gerlag PG, Tan Y, Russel
FG, Smits P. J Am Coll Cardiol. 1996;28(2):376
25. 2009 focused update incorporated into the
ACC/AHA 2005 Guidelines for the Diagnosis and
Management of Heart Failure in Adults: a report of the
American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines:
developed in collaboration with the International Society
for Heart and Lung Transplantation. Hunt SA, AbrahamWT, Chin MH, Feldman AM, Francis GS, Ganiats TG,
Jessup M, Konstam MA, Mancini DM, Michl K, Oates
JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW.
Circulation. 2009;119(14):e391
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26. High dose frusemide in acute renal failure: a
controlled trial. Brown CB, Ogg CS, Cameron JS. Clin
Nephrol. 1981;15(2):90
27. Knauf H, Mutschler E. Functional state of the
nephron and diuretic dose-response-rationale for low-
dose combination therapy. Cardiology.1994;84(suppl
2):18-26.28. Diuretic effectiveness of hydrochlorothiazide and
furosemide alone and in combination in chronic renalfailure. Kauf H, Mutschler E. J Cardiovasc
Pharmacol.1995;26:394-400
29. Coadministration of thiazides increases the efficacy
of loop diuretics even in patients with advanced renal
failure. Fliser D, Schrter M, Neubeck M, Ritz E.
Kidney Int. 1994;46(2):482.30. The effects of spironolactone on morbidity and
mortality in patients with severe heart failure. Pitt B,
Zannad F, Remme WJ, et al. N Engl J
Med.1999;341:709-716.
31.
Executive summary of the guidelines on thediagnosis and treatment of acute heart failure: the TaskForce on Acute Heart Failure of the European Society of
Cardiology. Nieminen MS, Bohm M, Cowie MR, et al.
Eur Heart J. 2005;26:384-416.
32. Tolerability and efficacy of high-dose furosemide
and small-volume hypertonic saline solution in
refractory congestive heart failure. Paterna S, Parrinello
G, Amato P, et al. Adv Ther. 1999;16:219-28.
33. Effects of high-dose furosemide and small-volume
hypertonic saline solution infusion in comparison with a
high dose of furosemide as a bolus, in refractory
congestive heart failure. Paterna S, Di Pasquale P,
Parrinello G, et al. Eur J Heart Fail. 2000;2:305-13.34. Effects of high-dose furosemide and small-volume
hypertonic saline solution infusion in comparison with a
high dose of furosemide as bolus in refractory congestive
heart failure: long-term effects. Licata G, Di Pasquale P,
Parrinello G, et al. Am Heart J. 2003;145:459-66.
35. Changes in brain natriuretic peptide levels and
bioelectrical impedance measurements after treatment
with high-dose furosemide and hypertonic saline
solution versus high-dose furosemide alone in refractory
congestive heart failure: a double-blind study. Paterna S,
Di Pasquale P, Parrinello G, et al. J Am Coll Cardiol.
2005;45:1997-2003.36. Quantification of pro-B-type natriuretic peptide and
its products in human plasma by use of an analysisindependent of precursor processing. Goetze JP, Kastrup
J, Pedersen F, Rehfeld JF. Clin Chem. 2002;48:1035-42.
37. Changes in natriuretic peptide and cytokine plasma
levels in patients with heart failure, after treatment with
high dose of furosemide plus hypertonic saline solution
(HSS) and after a saline loading. Tuttolomondo A, PintoA, Di Raimondo D, et al. Nutr Metab Cardiovasc Dis.
2011;21:372-9.
38. Continuous infusion versus bolus injection of loop
diuretics in congestive heart failure. Salvador DR, Rey
NR, Ramos GC, Punzalan FE. Cochrane Database SystRev. 200439. Deafness and imbalance associated with inactivation
of the secretory Na-K-2Cl co-transporter. Delpire E, Lu
J, England R, Dull C, Thorne T. Nat Genet.
1999;22(2):192.
40. A comprehensive review of the loop diuretics:
should furosemide be first line? Wargo KA, Banta WM.
Ann Pharmacother. 2009;43(11):1836
41. Dopamine does not enhance furosemide-induced
natriuresis in patients with congestive heart failure.
Vargo DL, Brater DC, Rudy DW, Swan SK. J Am Soc
Nephrol. 1996;7(7):1032
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24 www.kidney advances.com (For Personal Use Only)
ULTRAFILTRATION VERSUS DIURETICS IN ACUTE
DECOMPENSATED HEART FALIURE (ADHF)
Mohammed Essam
Introduction:Heart Failure (HF) is a major public healthproblem with increasing prevalence owing to
the substantial rise in population aged over 65
years of age. Fluid overload and congestion are
major characteristics of HF and among the mostimportant targets of treatment. Acute
Cardiorenal syndrome (type 1) is worsening of
renal function in acute decompensated heartfailure (ADHF). This article will discuss the
benefits and drawbacks of ultrafiltration (UF)
therapy versus diuretic based therapeuticregimens in ADHF through currently available
studies in this field.
Reduced GFR and prognosis of HF:A reduced glomerular filtration rate (GFR) is
generally associated with a worse prognosis inpatients with heart failure (HF), whether present
at baselineor developing during therapy for HF.
The prevalence of moderate to severe reductionsin glomerular filtration rate (GFR less than
60 mL/min per 1.73m2) in patients with HF has
ranged from 30 to 60 percent in large clinicalstudies.
(1,2) This observation is important
clinically because the baseline GFR is a
predictor of mortality in both a