cardiorenal axis disorders - to and fro

8/11/2019 CardioRenal Axis Disorders - To and Fro

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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,

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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


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


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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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


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


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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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

cardiorenal axis disorders - to and fro

Documents