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Nephrol Dial Transplant (2010): Editorial Reviews

dialysis patients with chronic kidney disease. Kidney Int 2010; 77:
550556
163. Steppan CM, Bailey ST, Bhat S et al. The hormone resistin links
obesity to diabetes. Nature 2001; 409: 307312
164. Steppan CM, Lazar MA. The current biology of resistin. J Intern
Med 2004; 255: 439447

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165. Kielstein JT, Becker B, Graf S et al. Increased resistin blood levels are
not associated with insulin resistance in patients with renal disease.
Am J Kidney Dis 2003; 42: 6266

Received for publication: 12.3.10; Accepted in revised form: 13.4.10

Nephrol Dial Transplant (2010) 25: 20772089


doi: 10.1093/ndt/gfq252
Advance Access publication 20 May 2010

ADQI 7: the clinical management of the Cardio-Renal syndromes:


work group statements from the 7th ADQI consensus conference

UCL Center for Nephrology, University College London Medical School, London, UK, 2Division of Applied Cachexia Research,
Department of Cardiology, Charit-Universittsmedizin, Berlin, Germany, 3Department of Anesthesiology and Critical Care Medicine,
Hpital Lariboisire, University Paris 7 Paris Diderot, France. U942 Inserm, Paris, France, 4Department of Internal Medicine and
Metabolic Diseases, Cardiology Section, Le Scotte Hospital, Siena, Italy, 5Department of Internal Medicine, S. Bortolo Hospital,
Vicenza, Italy, 6Department of Intensive Care Medicine, Austin Hospital, Melbourne, Australia, 7Cardiac Department, Faculty of
Public Health, Medical University, Military Hospital, Wroclaw, Poland, 8Department of Cardiology, VA Medical Centre, Minneapolis,
MN, USA, 9Department of Cardiology, Ospedale San Filippo Neri, Rome, Italy, 10Division of Critical Care Medicine, University of
Alberta Hospital, Edmonton, Canada, 11Department of Nephrology, University of Colorado Health Sciences Center, Denver, CO,
USA, 12Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, Vicenza, Italy, 13Department of Cardiology,
University of Padova, Italy, 14Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland, 15Trial Coordination
Center, Department of Cardiology and Epidemiology, University Medical Center Groningen, Hanzeplein, The Netherlands, 16Division
of Nephrology, London Health Sciences Centre, University Hospital, London, Ontario, Canada, 17Department of Surgery, The George
Washington University, Washington DC, USA, 18Department of Medicine and Cardiology, San Diego VA Medical Center and University
of California, San Diego, CA, USA, 19Department of Cardiology, Mayo Clinic, Rochester, MN, USA, 20Department of Medicine,
Divisions of Cardiology, Nutrition and Preventive Medicine, William Beaumont Hospital, Royal Oak, MI, USA, 21Department of
Anesthesiology, Duke University Medical Center, Durham, NC, USA, 22R. Adams Cowley Shock Trauma Center, University of
Maryland Medical Center, Baltimore, MD, USA, 23Division of Nephrology, Mediciti Hospitals, Hyderabad, India, 24Department of
Intensive Care, San Bortolo Hospital, Vicenza, Italy and 25Department of Nuclear Medicine, San Bortolo Hospital, Vicenza, Italy
Correspondence and offprint requests to: C. Ronco; E-mail: cronco@goldnet.it

Keywords: cardio-renal; chronic kidney disease; heart failure; ischaemic


heart disease; renal failure

Introduction
Many patients with heart failure have underlying renal dysfunction, and similarly, patients with kidney failure are
prone to cardiac failure. This has led to the concept of
cardio-renal syndromes, which can be an acute or chronic
cardio-renal syndrome, when cardiac failure causes deterioration in renal function, or acute and/or chronic

Reno-Cardiac syndrome, when renal dysfunction leads to


cardiac failure. Patients who develop these syndromes
have increased risk of hospital admission and mortality.
Although there are clinical guidelines for managing both
heart failure and chronic kidney disease, there are no agreed
guidelines for managing patients with cardio-renal and/or
Reno-Cardiac syndromes, as these patients have typically been excluded from clinical trials. We have therefore
reviewed the currently available published literature to outline a consensus of current best clinical practice for these
patients.

The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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A. Davenport1, S. D. Anker2, A. Mebazaa3, A. Palazzuoli4, G. Vescovo5, R. Bellomo6,


P. Ponikowski7, I. Anand8, N. Aspromonte9, S. Bagshaw10, T. Berl11, I. Bobek12, D.N. Cruz12,
L. Daliento13, M. Haapio14, H. Hillege15, A. House16, N. Katz17, A. Maisel18, S. Mankad19,
P. McCullough20, F. Ronco13, A Shaw21, G. Sheinfeld22, S. Soni23, N. Zamperetti24, P. Zanco25, C. Ronco12
and the Acute Dialysis Quality Initiative (ADQI) consensus group

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Nephrol Dial Transplant (2010): Editorial Reviews

Table 1. Heart failure is a clinical syndrome based on the combination of symptoms and signs typical of heart failure supported by objective evidence
of a structural or functional abnormality of the heart at rest [1]
Symptoms

Signs

Evidence

Breathlessness at rest
Breathlessness on exertion
Fatigue
Tiredness
Ankle swelling

Tachycardia
Tachypnoea
Pulmonary rales
Pleural effusion
Raised jugular venous pressure
Peripheral oedema
Hepatomegaly

Cardiomegaly
Third heart sound
Cardiac murmurs
Abnormal echocardiogram
Raised natriuretic peptide concentration

Table 2. Common causes of heart failure (modified from [1])


Major causes of heart failure

Drugs

Toxins

Endocrine

Nutritional

Others

Circulatory failure

Familial/genetic
Myocarditis
Hypertrophic
Dilated cardiomyopathy
Restrictive cardiomyopathy
Arrhythmogenic right
ventricular tachycardia
induced cardiomyopathy
Cytotoxics
Beta-blockers
Calcium channel antagonists
Antiarrhythmics
Alcohol
Cocaine
Heavy metal poisoning
Herbal medications
Diabetes mellitus
Hypo- and/or hyperthyroidism
Cushings syndrome
Acromegaly
Phaeochromocytoma
Thiamine deficiency
Selenium deficiency
Obesity
Cachexia
Amyloid
Sarcoid
Haemochromatosis
Sickle cell disease
Connective tissue diseases
Chagas disease
HIV infection
Peripartum cardiomyopathy
Septicaemia
Anaemia
Shunts
Thyrotoxicosis
Tamponade
Pulmonary embolism

Cardio-Renal syndromes
The cardiorenal syndromes are a heterogenous group of
conditions, comprising both cardiac and renal dysfunction,
typically on a background of chronic disease. Cardiac failure has recently been defined by the European Society of
Cardiology (ESC) (Table 1) [1]. Heart failure can occur

Acute Cardio-Renal syndrome (acute impairment


in cardiac function causing renal dysfunction)
Acute heart failure is defined as a rapid onset or change
in signs and symptoms of heart failure, requiring urgent
therapy, and subdivided into five types based on clinical
presentation [2]: (i) acute decompensated chronic heart
failure [3], typically worsening of already treated chronic
heart failure (CHF) usually associated with normal blood
pressure and impaired left ventricular ejection fraction
(LVEF); (ii) pulmonary oedema and (iii) hypertensive
heart failure, characterized by hypertension typically with
preserved LVEF; (iv) isolated right ventricular failure; and
(v) cardiogenic shock [4].
Underlying causes of acute heart failure include ACS,
valvular heart disease, hypertension, arrhythmias, infection
and non-compliance with heart failure management [5,6].

Chronic Cardio-Renal syndrome (chronic cardiac


dysfunction causing renal dysfunction)
Coronary artery disease and hypertension are the commonest causes of chronic heart disease, followed by valvular heart disease and cardiomyopathies [1,2] (Table 2).
Ascites may complicate severe right-sided heart failure,
and the combination of increased intra-abdominal pressure
and high right-sided venous pressure may further compromise renal function [7].

Acute Reno-Cardiac syndrome (acute decline in


kidney function causing cardiac dysfunction)
Acute deterioration in kidney function is now classified according to risk, injury, failure, loss and end-stage renal disease criteria (RIFLE) [8] (Table 3) and recently modified to
define acute as deterioration 48 h time frame [9]. A sud-

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Coronary artery disease


Hypertension
Valvular heart disease
Cardiomyopathies

acutely with pulmonary oedema/congestion following


acute coronary syndrome (ACS) or sudden rise in blood
pressure, or transiently following myocarditis, myocardial
infarction or myocardial ischaemia resolved by revascularization. However, in most cases, heart failure is chronic in
nature and can be clinically classified as stable, worsening
or decompensated. Acute decompensation of chronic heart
failure remains the commonest cause of heart failure admissions to hospital.

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Table 3. RIFLE staging of acute kidney injury [10]


RIFLE stage

GFR criteria

Urine output

Risk
Injury
Failure

SCreat 1.5 or GFR >25%


SCreat 2.0 or GFR >50%
SCreat 3.0 or GFR >75% or SCreat 4 mg/dL
or absolute SCreat 0.5 mg/dL
Dialysis dependence >4 weeks
Dialysis dependence >3 months

<0.5 mL/kg/h for 6 h


<0.5 mL/kg/h for 12 h
<0.3 mL/kg/h for 24 h or anuria 12 h

Loss
End-stage kidney disease

GFR, glomerular filtration rate; SCreat, serum creatinine (mg/dL; to convert to mol/l multiply by 0.88). This was modified by the Acute Kidney Injury
Network to define the acute nature of acute kidney injury as a rise in creatinine or fall in urine output within a 48-h time frame [9].

Chronic Reno-Cardiac syndrome (chronic kidney


disease causing cardiac dysfunction)
Patients with chronic kidney disease (CKD) are predisposed to cardiac dysfunction [2]. CKD (Table 4) typically
leads to progressive sodium retention [1416] predisposing to arteriosclerosis and hypertension. Increased peripheral pulse wave velocity causes progressive cardiac
changes, including left atrial and ventricular remodelling,
left ventricular hypertrophy and increased myocardial fibrosis, potentially exacerbated by anaemia [17]. Valvular
calcification is increased in dialysis patients. Repeated intradialytic hypotension [18] with myocardial stunning may
increase myocardial fibrosis. Carnitine deficiency in longterm haemodialysis patients may reduce LVEF and high flow
arterio-venous fistulae may cause high output cardiac failure.
More haemodialysis patients die from sudden cardiac
death than myocardial infarction, assumed to be arrhythmic, due to electrolyte disturbances, underlying autonomic
neuropathy, increased sympathetic nervous system activity,
circulating catecholamines and prolonged QTc interval in
a population with increased risk of sleep apnoea [19]. Peri-

Table 4. Staging of chronic kidney disease according to estimated


glomerular filtration rate (eGFR)
Stage Description
1
2
3a
3b
4
5

Kidney damage with normal or eGFR


Kidney damage with mild eGFR
Moderate eGFR
Moderate eGFR
Severe eGFR
Kidney failure

eGFR mL/min/1.73 m2
90
6089
4559
3045
1529
<15 (or dialysis)

cardial effusions may occur in patients with CKD, causing


tamponade.
In addition, some diseases and/or toxins can directly affect both organs, either de novo or chronically, as secondary cardio-renal syndromes (Table 5) [2]. Management of
these patients may well require additional specialized treatments for the underlying pathology.
Methods
A multidisciplinary stakeholder committee was convened, and an overall
research agenda was developed by the committee as an iterative process
using a two-step modified Delphi procedure [20], briefly: a systematic
search for evidence with review and evaluation of the available literature
pre-conference, with establishment of clinical and physiological outcomes
as well as measures to be used for comparison of different treatments,
along with the description of current clinical practice and the rationale
for the use of current therapies. In addition, analysis was made of areas
in which evidence is lacking. Studies were identified via Medline and
Web of Science (which also contains abstracts of major conferences)
searches and bibliographies of review articles and participants files, using Medical Subject Headings of heart failure, cardiac failure, acute coronary syndrome, myocardial infarction and left ventricular failure, refined
with kidney disease, renal insufficiency, kidney failure, renal failure and
kidney injury. The conference was divided into breakout sessions, with
work groups addressing their assigned topic area, and plenary sessions,
where their findings were presented, debated and refined. Evidence was
classified according to levels per standard evidence-based medicine methodology. A series of summary statements were then developed and
refined and research agenda determined by identifying deficiencies in
the literature [21].

Table 5. Secondary causes of cardio-renal syndrome


Acute

Chronic

Cocaine
CCB selfpoisoning
Leptospirosis
Malaria
SLE
Scleroderma renal crisis
HUS
Liver failure
Systemic sepsis
Acute sickle cell disease
Phaeochromoctoma
Burkitts lymphoma

Amyloid
Sarcoid
TB
HIV
Hypertension
Diabetes
Liver failure
Sickle cell disease
Post bone marrow transplant
Fabrys disease

CCB, calcium channel blocker; SLE, systemic lupus erythematosis; HUS,


haemolytic uraemic syndrome.

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den reduction in kidney function can lead to sodium and


water retention. Acute kidney injury (AKI) also causes cardiac changes, due to paracrine effects [10], or the so-called
Reno-Cardiac organ cross talk [11,12]. AKI can lead to
metabolic acidosis and electrolyte abnormalities, typically
hyperkalaemia, which may precipitate cardiac arrhythmias.
Patients with critical renovascular stenosis may present
with flash pulmonary oedema resulting from acute pulmonary venous congestion in the presence of normal or
well-preserved LVEF [13].

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Nephrol Dial Transplant (2010): Editorial Reviews

Table 6. Pharmacological agents used in the management of or under investigation for the treatment of acute and chronic heart failure in patients with
the cardiorenal syndrome (CRS) and/or Reno-Cardiac syndrome (RCS)
Drug classes

Indication

Intended action and effects

Side effects and problems

Deterioration of kidney function if


already on board
Hypotension

Acute RCS

No consensus on the ideal timing for initiation.


Treatment should be continued whenever
possible in those already treated.
Treatment should be initiated before
hospital discharge
Life saving, reduce morbidity
Prevent cardiac remodelling
ARBs as an alternative only in
patients intolerant to ACEI

Chronic RCS

Nephroprotection

ACE inhibitors and ARBS


Acute CRS

Chronic CRS

RAAS antagonism
Decrease proteinuria

Monitor kidney function and electrolytes


Hypotension
Contraindicated in renal
artery stenosis
Mild transient deterioration of
kidney function
Careful monitoring in dialysis
patients (hypotension)

Beta-blockers
Acute CRS

Chronic RCS

Prevent remodelling
Cardioprotection and prevention
of tachyarrhythmias

Bradykinin reactions, bradyarrhythmias

Hypotension, bradyarrhythmias
Deterioration in heart failure
symptoms (transient)
Asthma
As above

Aldosterone antagonists
Chronic CRS
Chronic RCS

Life saving in moderate-severely symptomatic


CHF, reduce morbidity
Prevent myocardial and vascular fibrosis
Prevent myocardial and vascular fibrosis

Hyperkalaemia in patients treated


with ACEIs, ARBs, and
decreased eGFR
Monitor potassium levels

Natriuresis, reduction of fluid overload,


Na and H2O elimination
Symptomatic benefit
Loop diuretics preferred
Control of diuresis and extracellular
fluid volume
Symptoms relief

Potential hypovolemia, hypotension


and worsening of renal failure

Diuretics
Acute CRS

Chronic CRS

Acute RCS
Chronic RCS
Secondary CRS

Maintenance of non oliguric AKI


Frusemide preferred
Maintenance of diuresis in CKD 4
and 5. Control of hypertension and
fluid balance
Maintenance of diuresis and fluid balance

Volume depletion, hypotension,


worsening renal failure,
hyperuricemia, K imbalance.
Diuretic resistance
No evidence for renal protection
nor reduction of need for RRT
Potential toxic effects
Direct and cumulative toxicity with
other drugs (antibiotics,
anti-inflammatory)

Digoxin
Chronic CRS and
chronic RCS

Reduce HF hospitalizations
Improve symptoms
Mortality unchanged

Acute CRS

To reduce ventricular rate in patients with


fast atrial fibrillation

Chronic CRS

May improve survival and symptoms


when ACEIs and ARBs cannot
be given
In African-American patients reduce
mortality and morbidity and improve
quality of life

Toxicity if reduced GFR


Monitor plasma levels and adjust
dosage (when >1 pg/mL
increased risk arrhythmias)
As above

Hydralazine and nitrates


Headache, dizziness, hypotension

Continued

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Chronic CRS

In those already treated, dose may need


to be reduced temporarily; in general
should not be withdrawn unless signs
of low output
Treatment should be initiated before
hospital discharge
Life saving
Reduce morbidity

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Table 6. Continued
Drug classes
Inotropic agents
Dopamine
Dobutamine
Levosimendan
Milrinone
Enoximone
Vasopressors
Norepinephrine

Indication

Intended action and effects

Side effects and problems

Acute CRS

To increase cardiac output in low output


stage, in the presence of signs of
hypoerfusion or congestion despite the
use of vasodilators and or diuretics
Some inotropic agents may decrease
peripheral resistances

Arrhythmias

Acute CRS

Norepinephrine indicated only in cardiogenic


shock when other inotropic therapies fail
Epinephrine indicated only as rescue therapy
for cardiac arrest, not as an inotrope

Acute CRS

Indicated if organ congestion is present

Epinephrine
Vasodilators
Nitroprusside
Nitrates
Nesiritide

Increase renal and peripheral blood flow

Receptor desensitization with


prolonged use
Some may adversely affect outcome

Hypotension especially in
hypovolaemic patients
Cyanide intoxication for nitroprusside

BNP analogue vasodilator


Data on mortality uncertain

Hypotension
Can worsen kidney function,
but the data uncertain

Acute CRS

Symptoms relief, promote water elimination


and weight loss in the short term

No changes in mortality and morbidity


at 1 year with tolvaptan

Acute CRS

Relief of dyspnoea, chest pain, helps NIV

Respiratory depression

Chronic CRS and


Chronic RCS

Aimed to block endothelin II


mediated vasoconstriction

No changes in mortality
Currently licenced only for
pulmonary hypertension

Block adenosine mediated glomerular


vasoconstriction
May improve symptoms and prevent
deterioration in renal function

Weight loss?

May improve exercise capacity


in patients with anaemia
No clear impact on mortality and
morbidity in CHF
Improves survival in CKD

Possible thrombogenicity and increase


in blood pressure

Vasopressin antagonists
Morphine
Endothelin antagonists

Adenosine A1-receptor antagonists


Acute and
chronic CRS
Erythropoiesis stimulating agents
Chronic CRS

Chronic RCS

As above

Parenteral iron
Chronic CRS
Chronic RCS

Improves exercise capacity and quality of


life in iron deficient patients
No clear impact on mortality and morbidity
No clear impact on mortality and morbidity

Potential anaphylactic reaction with


iron dextran

To treat hyperuricaemia that carries an


adverse prognosis in CHF
Treat further deterioration of kidney
function due to hyperuricaemia

Haematologic and cutaneous toxicity


Precipitation of gout
As above

Warfarin is more effective than aspirin


in preventing thromboembolism
in heart failure patients in AF with
reduced LVEF
Prevention of thromboembolism

Risk of bleeding
Potential risk of vascular calcification

No clear impact on mortality


and morbidity

Allopurinol
Chronic CRS
Chronic RCS
Warfarin/antiplatelets
Chronic CRS

Chronic RCS

As above

CO, cardiac output; Na, sodium; K, potassium; H2O, water; ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin II receptor antagonist; EPO, recombinant human erythropoietin; statins, HMG CoA 3 reductase inhibitors; RRT, renal replacement therapy.

Results
The following questions were considered:
Q 1: What are the key management goals in the treatment of patients with cardio-renal syndromes?

Q 2: What is the best clinical management for


heart failure patients who develop acute cardio-renal
syndrome?
Q 3: What is the best clinical management for heart
failure patients who develop chronic cardio-renal
syndrome?

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Acute CRS

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Q 4: What is the best clinical management for renal failure patients who develop acute Reno-Cardiac syndrome?
Q 5: What is the best clinical management for renal
failure patients who develop chronic Reno-Cardiac
syndrome?
Q 6: What clinical research agenda is required to evaluate these management strategies?
A literature search was made concentrating on core management areas, both from the patients perspective in terms
of relief of symptoms, morbidity, quality of life and survival (clinical effectiveness) and for the clinician treating
the patient to improve cardiac output and renal function.

Discussion

Acute Cardio-Renal syndrome


Impaired baseline renal function in acute heart failure and
deterioration in renal function early in the course of treatment are strong adverse prognostic factors for patient survival and morbidity. Thus, renal protection is an important
pathophysiological target, and any treatment for acute
heart failure should at least have a neutral effect or preferably improve renal function [1].
Whereas there are many clinical trials on CHF, the management of acute heart failure remains essentially empiric
(level C evidence). Patients should be oxygenated to
achieve a peripheral oxygen saturation >90% (unless the
patient has severe obstructive pulmonary disease) and
may require non-invasive positive pressure ventilation
and morphine to relieve distress, anxiety or pain. Clinical
assessment should establish whether acute heart failure is
associated with signs of congestion (common) or of low
cardiac output (rare) or both. In all cases, an underlying
cause needs to be identified and treated. This is particularly important in the case of acute arrhythmias, myocardial
infarction, hypertension crisis, cardiac tamponade, aortic

dissection and pulmonary embolus, where specific therapies are required.


Vasodilators nitroglycerine, isosorbide dinitrate and nitroprusside [26,27] and loop diuretics are widely recommended for decompensated heart failure (recommendation
class 1 level B) (Table 6). Nesiritide, a recombinant B-type
natriuretic peptide, is a potent vasodilator with modest natriuretic effects (Figure 1). Initial studies reported deterioration in renal function when nesiritide was administered with
diuretics [2831].
Typically, CHF patients have underlying CKD and previously prescribed diuretics, so larger doses of loop diuretics are often required, and infusions are more potent than
simple boluses (recommendation class 1, level A) [32,33].
Loop diuretics may potentially predispose to hypokalaemia, hyponatraemia and hyperuricaemia but, importantly, hypovolaemia with increased neurohumoral
activation, worsening renal function [34,35]. Vasodilators,
including nesiritide [28], and to a lesser extent ularitide
[31], by precipitating hypotension [36], can exacerbate renal injury [30].
Both endothelin and adenosine cause renal vasoconstriction [37], so endothelin (A and also both A and B) [38]
and adenosine A1 receptor blockers have been evaluated
in clinical trials with decompensated CHF patients [39].
Currently, endothelin receptor blockers have not proved
successful in acute heart failure, and trials of adenosine
A1 receptor blockers are ongoing.
Severe heart failure causes hyponatraemia, and vasopressin receptor 2 antagonists can increase renal free-water clearance. Short-term studies reported improvement in
hyponatraemia and weight loss, without survival benefit
[4043].
Some patients fail to respond to non-invasive ventilation, vasodilators and diuretics, and selected patients may
require ultrafiltration to reduce volume overload [44].
However, ultrafiltration does not improve renal function.
If congestion coincides with hypotension, inotropic agents
should be considered [45].
Low cardiac output syndromes, such as cardiogenic
shock [6], often lead to AKI, and treatments are designed
to increase cardiac output and restore renal blood flow. A
fluid challenge, with saline, may be clinically indicated if
blood pressure and organ perfusion do not respond to inotropes (Figure 1). Although inotropes, typically dobutamine, with inotropic and chronotropic actions (stimulation
of beta1-adrenegic receptors), and dopamine (dopaminergic, alpha1 and beta-adrenergic receptor agonist), may tide
patients over acutely, these often may result in potential
midterm poorer outcome [6]. Phosphodiesterase inhibitors,
milrinone [46] and enoximone, should be used cautiously
in patients with ischaemic heart disease. Levosimendam, a
lusitropic agent that increases cardiac contractility without
affecting intracellular calcium, also reduces peripheral vascular resistance [47,48].
If the systemic blood pressure remains low, cautious introduction of norepinephrine may be considered (recommendation class IIb, level C). Elective ventilation and/or
insertion of an intra-aortic balloon pump (ABP) may be
required, as ABP or external counter-pulsation may improve renal and other organ perfusion [49]. Depending up-

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Although there are data concerning the minimum mean


systemic arterial blood pressure to maintain renal autoregulation for dogs and rats (75 and 85 mmHg, respectively)
[22], there are no human data. Low blood pressure is associated with increased mortality, and during cardiac bypass
surgery neurological damage increased with mean perfusion pressures 60 mmHg [23,24]. Cardiac perfusion relies
upon the diastolic pressure, but there is no apparent critical
threshold beyond which irreversible cardiac damage occurs.
Thus, there are no simple clinical targets in terms of cardiac
output and blood pressure for goal-directed therapy.
Similarly, there are no evidence-based clinical targets for
managing patients with both cardiac and renal disease,
whereas there are standard treatment protocols for patients
with both heart failure [25] and kidney disease. The question arises as to whether management of patients with heart
failure requires modification for those patients with kidney
failure and vice versa. Thus, the ADQI group reviewed the
currently available literature to synthesize an expert opinion consensus treatment strategy for these patient groups.

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Acute heart failure


clinical evaluation
oxygen/non-invasive ventilation
loop diuretic vasodilator
SBP 90 -100 mmHg

SBP > 100 mmHg

vasodilator
nitrate, nesiritide
levosimendan

vasodilator inotrope
dobutamine
Phospho-diesterase inhibitor
levosimendan

consider preload
reduction
fluids, inotrope,
dopamine

Poor Response
Inotrope,
vasopressor
mechanical support

Fig. 1. Algorithm for the management of acute heart failure. ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker;
nitrate, nitroglycerin or nitroprusside; phosphodiesterase inhibitor: milrinone, enoximone.

on pre-existing co-morbidity and underlying aetiology, left


ventricular assist devices [50,51] as a bridge to transplantation or cardiac surgery may be appropriate [52,53]. Patients with acute right heart failure often do not respond
to fluid challenges, typically become severely hypotensive
when intubated and may potentially benefit from lusitropic
agents [54].

Chronic Cardio-Renal syndrome


Therapeutic approaches to patients with CHF are complex
and comprise elimination and treatment of the underlying
cause or disease causing damage to the cardiovascular system and CHF progression. Increased survival remains the
major goal and key end point in clinical trials, coupled
with therapies directed towards improvement in quality
of life, provided they do not adversely affect the natural
history of CHF.
Non-pharmacological management or self-care management is an integral part of successful CHF treatment.
It contains self-care management, defined as actions
aimed to maintain physical stability, avoid behaviour that
can worsen the disease and detect early symptoms of deterioration. The following behaviours may be considered:
adherence to treatment [55], proper symptom recognition
(recommendation class 1 evidence level C), weight control, lifestyle changes including diet and nutrition, smoking
cessation, exercise training and education (recommendation class 2a level C) [5658]. These need to be clearly explained with patients and relatives. The optimal model of
outpatient review remains to be determined [59].
The following pharmacological therapies have been
proven to reduce mortality and morbidity and potentially
reduce disease progression (recommendation class 1,

grade A) angiotension converting enzyme inhibitors


(ACEIs) [1,6062], beta-blockers [1,6365], angiotensin
II receptor blockers (ARBs) [1,66] and aldosterone antagonists [1,67,68] (Table 6). They all target neuroendocrine
activation differently, and so combinations are desirable.
The optimal approach is to use ACEIs and beta-blockade
in incremental doses to which either ARBs or aldosterone
antagonists are subsequently added depending on individual responses [66]. ARBs have been shown to be non-inferior to ACEIs [6974]. The addition of an ARB to an
ACEI has been shown to improve outcomes (recommendation grade 1, level A); however, the ONTARGET trial did
not observe any additional benefit of adding an ARB in a
high-risk population compared to an ACEI alone [74,75].
Additionally, a combination of all four neuroendocrine
blockers (ACEI, ARB, -blocker and aldosterone antagonist) is not recommended. In symptomatic patients unable
to tolerate ACEIs/ARBs, a combination of hydralazine and
nitrates may be an alternative [76]. Digoxin and diuretics
which improve symptoms in CHF have no effect on mortality [77].
Implantation devices may become an alternative effective treatment for selected CHF patients. Cardiac resynchronization therapy is recommended for patients who
remain symptomatic New York Heart Association (NYHA
IIIIV) despite optimal pharmacological treatment with
poor LVEF and QRS prolongation (recommendation grade
1 level A) (Figure 2) [1,7880], and implantable cardiac
defibrillators are recommended not only for survivors of
cardiac arrest or sustained ventricular arrhythmias but also
for symptomatic CHF patients with impaired LVEF (recommendation class 1 level A) [1].
Recent studies have showed no advantages for statins in
patients with symptomatic CHF [81,82], although n-3
polyunsaturated fatty acids may be of modest benefit [83].

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Good Response
stabilize
initiate diuretic
ACEI/ARB
-blocker

SBP < 90 mmHg

2084

Nephrol Dial Transplant (2010): Editorial Reviews

Symptomatic heart failure + reduced ejection fraction


Diuretic + ACEI (or ARB)
titrate doses to clinical stability
blocker
persistent signs + symptoms
add aldosterone antagonist
or ARB

yes

no

yes

yes

persisting symptoms

QRS> 120 ms
no

yes

consider
ICD

no

no further
treatment
indicated

consider digoxin
hydralazine/nitrate
LVAD and cardiac transplantation

Fig. 2. Algorithm for the management of chronic heart failure (CHF). ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor
blocker; LVEF, left ventricular ejection fraction; CRT-D, resynchronization therapy defibrillator; CRT-P, cardiac resynchronization therapy
pacemaker; LVAD, left ventricular assist device.

In selected patients who do not respond to treatment,


mechanical assist devices and/or cardiac transplantation
may be appropriate [51,8388] depending upon other
co-morbidities.
Whereas there have been many clinical trials in the management of patients with CHF, there are very few studies
involving patients with right-sided heart failure due to pulmonary hypertension (Table 7) [89]. Treatment depends
upon whether the right ventricle is under- or over-filled
but should also be directed towards the underlying cause
[6,90]. Paracentesis should be considered for those with
ascites.
Table 7. Classification of right-sided heart failure in adults
Classification Main pathology
Type 1

Type 2
Type 3
Type 4
Type 5

Etiologies

Pulmonary artery hypertension Idiopathic


Systemic sclerosis
Portal hypertension
Left to right shunts
High output AV fistulae
HIV infection
Secondary to LV dysfunction
Secondary to hypoxaemia
COPD
Interstitial lung disease
Sleep apnoea
Secondary to thomboembolic Pulmonary emboli
disease
Miscellaneous
Sarcoid
histiocytosis
lymphangiomatosis

AV, arterio-venous; LV, left ventricule; COPD, chronic obstructive pulmonary disease.

Management of CHF patients with renal disease


(based on the current ESC guidelines)
Renal dysfunction, even mild, constitutes a risk factor for
CHF and is a strong independent predictor of increased
morbidity and mortality [1,91,92]. The prevalence of renal
dysfunction increases with CHF severity, age and other comorbidities (such as hypertension and diabetes mellitus).
Potentially reversible causes, including hypotension, dehydration, drug effects and renovascular disease should always be excluded [13]. Therapy of CHF patients with
concomitant renal impairment is not evidence-based, as
these patients were underrepresented in CHF trials [93,94].
CHF patients with renal dysfunction often have excessive salt and water retention [14] and require more intensive diuretic treatment [95]. In patients with creatinine
clearance <30 mL/min/1.73 m2, standard thiazide diuretics
may be ineffective and loop diuretics preferred, with infusions more potent than intermittent boluses (recommendation class 1 level A). [96,97]. As increasing doses of loop
diuretics are associated with worse outcome [34,98], combinations with epithelial sodium channel blockers, aldosterone antagonists or metolazone should be considered
[33,99].
Therapy with ACEIs and ARBs is usually associated
with a mild deterioration in renal function, frequently transient and reversible. Patients with CKD and renal artery
stenosis are at a higher risk. In all cases, careful monitoring is recommended. If renal function declines, other secondary causes such as excessive diuresis, persistent
hypotension and concurrent nephrotoxic therapies should
be excluded. ACEIs and ARBs cause potassium retention,

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consider
CRT-P or CRT-D

LVEF <35%

Nephrol Dial Transplant (2010): Editorial Reviews

Management of heart failure in patients with


chronic kidney disease
Correction of anaemia, aiming for a Hb >10 g/dL has been
shown to reduce left ventricular hypertrophy in CKD patients [121]. Hypertension is common in CKD [122124],
but surprisingly there is no proven association with cardiovascular outcomes for haemodialysis patients [124,125].
However, this may be due to reliance on pre- and posthaemodialysis measurements [126], as more recent studies
have shown survival benefit with lower home blood pressure recordings [127]. Interdialytic weight gains should be
minimized to prevent volume overload and heart failure
[128]. Dietary sodium restriction [100] and lower sodium
dialysates [129] reduce interdialytic weight gains, lowering
ultrafiltration requirements and reducing intradialytic hypotension [130] and repetitive ischaemic stunning to the
heart [131] and brain [132].

Repeated studies have shown that only a small proportion of CKD patients are prescribed cardioprotective
ACEIs and beta-blockers, despite these drugs having
been shown to reduce cardiovascular morbidity and mortality [25,133,134]. Although many patients with CKD
were excluded from the major trials, smaller prospective
studies reported a benefit for carvedilol [135]. The prescription of cardioprotective medications has not been
shown to increase the incidence of intradialytic hypotension [128]. However, hypotension can occur following
bradykinin generation, which may be exacerbated by
ACEIs [18].
Additional management strategies include correcting
anaemia, controlling calcium and phosphate product and
parathyroid hormone to minimize vascular calcification
[136,137] and providing adequate dialysis [138].
Pericardial tamponade occasionally occurs in uraemia
and typically responds to intensive dialysis and biochemical control but may require drainage [139].
Although arterio-venous fistulae (AVF) are the preferred access for haemodialysis [140]; high-flow fistulae
or grafts may cause significant cardiac shunting leading
to pulmonary hypertension and high output CHF [141].
Patent AVF in renal transplant patients predispose to
CHF [142]. However, central venous access catheters predispose to infections including bacterial endocarditis.
Although there is strong evidence for treatment strategies using ACEIs, beta-blockers, ARBs and aldosterone
antagonists from well-designed randomized clinical trials
in CHF, there is a paucity of equivalent evidence for patients with CKD and dialysis [143]. The limited trials
available for review are in keeping with previous results
for beta-blockers and ACEIs [134], although combinations of ACEIs, ARBs and statins have not always shown
benefit [101]. Thus, randomized clinical trials of management of CHF are required in both CKD and dialysis
patients.
Unfortunately, there is limited evidence for the management of acute heart failure, let alone for patients with
abnormal renal function. This is one area where the development of biomarkers for both acute renal and cardiac
dysfunction could aid the development of clinical trials
for patients with an acute cardio-renal syndrome to allow
clinical-goal-directed therapies to be studied.
Conflict of interest statement. None declared.

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Received for publication: 18.11.09; Accepted in revised form: 15.4.10

Post-transplant lymphoproliferative disorder in view of the new WHO


classification: a more rational approach to a protean disease?
Krzysztof Mucha1,2, Bartosz Foroncewicz1,2, Bogna Ziarkiewicz-Wrblewska3, Marek Krawczyk4,
Jan Lerut5 and Leszek Pczek1
1

Transplantation Institute, Department of Immunology, Transplantology and Internal Medicine, Warsaw Medical University, Warsaw,
Poland, 2Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland, 3Department of Pathology, Warsaw
Medical University, Warsaw, Poland, 4Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw,
Poland and 5Unit of Abdominal Transplantation, Department of Abdominal and Transplantation Surgery, Universit catholique de
Louvain-UCL, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Correspondence and offprint requests to: Krzysztof Mucha; E-mail: kjmucha@gmail.com

Abstract
Post-transplant lymphoproliferative disorders (PTLDs) are
serious, life-threatening complications of solid-organ
transplantation (SOT) and bone marrow transplantation
leading to a high mortality (3060%). PTLD represents a
heterogeneous group of lymphoproliferative diseases.
They become clinically relevant because of the expansion
of transplantation medicine together with the development
of potent immunosuppressive drugs. Although the diagnostic morphological criteria of different forms of PTLD
are commonly known, rapid and correct diagnosis is not
always easy. Because of the limited number of clinical
trials, a consensus is lacking on the optimal treatment of
PTLD. This review focuses on incidence, risk factors, clin-

ical picture of the disease and diagnostic tools including


histopathology relating to the new classification introduced in 2008 by the World Health Organisation (WHO)
and treatment of PTLD.
Keywords: EBV; histopathology; PTLD; SOT; transplantation

Introduction
The term post-transplant lymphoproliferative disorder or
disease (PTLD) was first introduced in 1984 by Starzl [1].
Today, it represents a heterogeneous group of lymphoproli-

The Author 2010. Published by Oxford University Press on behalf of the ERA-EDTA. All rights reserved. This is an Open Access article distributed under the terms of the
Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution,
and reproduction in any medium, provided the original work is properly cited.

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Nephrol Dial Transplant (2010) 25: 20892098


doi: 10.1093/ndt/gfq231
Advance Access publication 1 January 2010

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