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`Hepatology
`
`Working Party proposal for a revised classification
`system of renal dysfunction in patients with cirrhosis
`Florence Wong,1 Mitra K Nadim,2 John A Kellum,3 Francesco Salerno,4
`Rinaldo Bellomo,5 Alexander Gerbes,6 Paolo Angeli,7 Richard Moreau,8
`Andrew Davenport,9 Rajiv Jalan,10 Claudio Ronco,11 Yuri Genyk,12 Vicente Arroyo13
`
`1Department of Medicine,
`University of Toronto, Toronto,
`Canada
`2Division of Nephrology,
`University of Southern
`California, Los Angeles,
`California, USA
`3Department of Critical Care
`Medicine, University of
`Pittsburgh, Pittsburgh, USA
`4Policlinico IRCCS San Donato
`and Dipartimento di Scienze
`Medico-Chirurgiche, Universita`
`di Milano, Milano, Italy
`5Department of Intensive Care,
`Austin Health, Melbourne,
`Victoria, Australia
`6Liver Center Munich, Klinikum
`Mu¨nchen-Grosshadern,
`Ludwig-Maximilians-Universita¨t
`Mu¨nchen, Mu¨nchen, Germany
`7Department of Clinical and
`Experimental Medicine,
`University of Padova, Padova,
`Italy
`8Centre de Recherche
`Biome´dicale Bichat-Beaujon,
`Service d’He´patologie, Hoˆpital
`Beaujon, Clichy, France
`9Centre for Nephrology,
`University College London
`Medical School, London, UK
`10Institute of Hepatology,
`University College London
`Medical School, London, UK
`11Division of Nephrology,
`Dialysis and Transplantation,
`San Bortolo Hospital, Vicenza,
`Italy
`12Division of Multiorgan
`Abdominal Transplantation,
`University of Southern
`California, Los Angeles,
`California, USA
`13Liver Unit, Institute of
`Digestive and Metabolic
`Diseases, Hospital Clinic,
`University of Barcelona, Spain
`
`Correspondence to
`Florence Wong, 9N/983,
`Department of Medicine,
`Toronto General Hospital,
`University of Toronto, 200
`Elizabeth Street, Toronto,
`Ontario M5G2C4, Canada;
`florence.wong@utoronto.ca
`
`Revised 22 January 2011
`Accepted 24 January 2011
`Published Online First
`15 February 2011
`
`ABSTRACT
`Objectives To propose an improvement on the current
`classification of renal dysfunction in cirrhosis. Clinicians
`caring for patients with cirrhosis recognize that the
`development of renal dysfunction is associated with
`significant morbidity and mortality. While most cases of
`renal dysfunction in cirrhosis are functional in nature,
`developed as a result of changes in haemodynamics,
`cardiac function, and renal auto-regulation, there is an
`increasing number of patients with cirrhosis and structural
`changes in their kidney as a cause of renal dysfunction.
`Therefore, there is a need for a newer classification to
`include both functional and structural renal diseases.
`Design A working party consisting of specialists from
`multiple disciplines conducted literature search and
`developed summary statements, incorporating the renal
`dysfunction classification used in nephrology. These
`were discussed and revised to produce this proposal.
`Setting Multi-disciplinary international meeting.
`Patients None.
`Interventions Literature search using keywords of
`cirrhosis, renal dysfunction, acute kidney injury (AKI),
`chronic kidney injury (CKD), and hepatorenal syndrome.
`Results Acute kidney injury will include all causes of
`acute deterioration of renal function as indicated by an
`increase in serum creatinine of >50% from baseline, or
`a rise in serum creatinine of $26.4mol/L ($0.3mg/dL) in
`<48hours. Chronic renal disease will be defined as an
`estimated glomerular filtration rate (GFR) of <60ml/min
`calculated using the Modification of Diet in Renal Disease
`6 (MDRD6) formula, recognising that the MDRD6 formula
`is not perfect for the cirrhotic patients and this may
`change as improved means of estimating GFR becomes
`available. Acute on chronic kidney disease will be defined
`as AKI superimposed on existing chronic renal disease
`using the above definitions for AKI and CKD.
`Conclusions Accepting this new classification will allow
`studies into the epidemiology, incidence, prevalence,
`natural history and the development of new treatments
`for these subtypes of renal dysfunction in cirrhosis.
`
`Acute kidney injury (AKI) is common in patients
`with cirrhosis and ascites, occurring in up to 19% of
`cirrhotic patients admitted to hospital. In addition,
`chronic kidney disease (CKD) occurs in approxi-
`mately 1% of all patients with cirrhosis.1
`The combination of
`liver disease and renal
`dysfunction can occur as a result of systemic
`conditions that affect both the liver and the kidney
`simultaneously. However,
`renal
`dysfunction
`complicating primary disorders of the liver are
`much more common. These may include structural
`
`Significance of this study
`
`What is already known about this subject?
`< Hepatorenal syndrome is a severe complication
`of advanced cirrhosis with a poor prognosis if
`left untreated.
`< The diagnosis of hepatorenal syndrome requires
`the patient fulfilling a set of diagnostic criteria.
`< Once a diagnosis of hepatorenal syndrome is
`made, treatments are available and these are
`effective in up to 40% of patients.
`
`What are the new findings?
`< A proposal to broaden the diagnosis of renal
`dysfunction in cirrhosis to include cases of
`acute and chronic renal failure not meeting the
`diagnostic criteria of hepatorenal syndrome
`types 1 and 2, respectively.
`< Acute kidney injury will
`include all causes of
`acute deterioration of renal function as indicated
`by an increase in serum creatinine of >50%
`from baseline or a rise in serum creatinine of
`$26.4 mmol/l ($0.3 mg/dl) in <48 h.
`< Chronic renal disease will be defined as an
`estimated glomerular filtration rate of <60 ml/
`min for more than 3 months calculated using the
`Modification of Diet in Renal Disease 6 formula.
`< Acute on chronic kidney disease will be defined
`as an acute kidney injury superimposed on
`existing chronic renal disease using the above
`definitions for acute kidney injury and chronic
`kidney disease.
`
`How might it impact on clinical practice in the
`foreseeable future?
`< The recognition of cases of renal dysfunction
`outside the traditional definition of hepatorenal
`syndrome will allow patients with lesser
`degrees of renal dysfunction to receive treat-
`ment.
`< The acceptance of these broadened definitions
`of renal dysfunction in cirrhosis will help to
`design studies to assess the pathophysiology,
`and thence to devise treatment strategies for
`these patients.
`< A better classification system may also secure
`more correct diagnoses leading to earlier and
`better treatment.
`< This potentially could have a positive impact on
`patient outcome, as patients will be treated
`earlier in the natural history of renal dysfunction.
`
`702
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`renal diseases such as IgA nephropathy, membranous nephrop-
`athy and cryoglobulinaemia, or
`renal dysfunction without
`significant histopathological
`changes
`such as hepatorenal
`syndrome (HRS). These episodes of renal dysfunction may occur
`acutely and are associated with significant morbidity and
`mortality. With improved understanding of renal complications in
`cirrhosis and the advent of treatment options, there is now
`a greater need to diagnose renal dysfunction in cirrhosis accurately.
`The Acute Dialysis Quality Initiative (ADQI) is an ongoing
`process that seeks to produce evidence-based recommendations
`for the prevention and management of AKI.2 As AKI has not
`been formally defined in patients with cirrhosis, members of the
`ADQI and the International Ascites Club (IAC)
`formed
`a Working Group in March 2010 to discuss the definition of renal
`dysfunction (both acute and chronic) in patients with cirrhosis.
`Members of the Working Group included specialists who are
`experts in the pathophysiology and management of renal
`dysfunction in cirrhosis and were selected from the membership
`of the ADQI and IAC. They conducted a literature search and
`developed summary statements which were discussed and
`revised at the meeting. The participants of the joint ADQIeIAC
`meeting are shown in appendix 1. The final summary statements
`and directions for future research are the basis for this paper.
`
`HISTORICAL PERSPECTIVE
`The clinical entity we now know as HRS was originally
`described by Flint in 1963.3 In 1959, Papper et al reported intense
`renal vasoconstriction in an otherwise normal kidney in such
`patients, paving the way for the understanding of the patho-
`genesis of HRS.4 Epstein et al later confirmed renal vasocon-
`striction using renal angiography in a patient with cirrhosis
`dying from renal failure and demonstrated post-mortem filling
`of all renal vessels to the periphery of the cortex, thus estab-
`lishing the ‘functional nature’ of HRS.5
`Rodes et al next identified three different outcome patterns in
`cirrhotic patients with renal dysfunction6:
`(1) a rapidly
`progressive course with a history of a complication closely
`related to the onset of renal failure (this group was later classi-
`fied as type 1 HRS); (2) patients with stable renal dysfunction
`during hospitalisation but no obvious cause for renal failure
`(type 2 HRS); and (3) patients with an initial similar course as
`those in group 2 until some complication occurred that hastened
`the course of renal failure. The outcome was worst for patients
`in the first group and best for patients in the second group.
`
`DEFINITION OF HEPATORENAL SYNDROME
`In 1979, a group of international investigators defined HRS as
`a progressive form of renal dysfunction that occurred in cirrhosis
`and other severe parenchymal liver diseases,7 with features of
`prerenal renal failure (low urine sodium concentration and
`hyperosmolar urine) but without any improvement following
`volume expansion. However, they recognised that some cases do
`progress to acute tubular necrosis. Despite setting guidelines,
`there continued to be confusion over what truly constituted
`HRS. This led to an editorial in the Lancet8 suggesting the term
`‘hepatic nephropathy’ to distinguish functional renal failure
`from any combination of renal failure occurring with liver
`failure, such as paracetamol overdose causing combined liver and
`renal failure.
`In 1996, the IAC defined HRS as a syndrome that occurs in
`patients with cirrhosis, portal hypertension and advanced liver
`failure, characterised by impaired renal function with marked
`abnormalities in the arterial circulation and activity of endoge-
`
`Hepatology
`
`nous vasoactive systems.9 Clinically, HRS was divided into two
`types: type 1 or acute HRS was characterised by a rapidly
`progressive reduction of renal function as defined by a doubling
`of the initial serum creatinine to >220 mmol/l (2.5 mg/dl) or
`a 50% reduction in the initial 24 h creatinine clearance to
`<20 ml/min in <2 weeks; type 2 or chronic HRS was defined as
`moderate renal failure that progressed gradually over weeks to
`133e220 mmol/l
`months with
`a
`serum creatinine
`of
`(1.5e2.5 mg/dl).
`The IAC updated the definition and diagnostic criteria for
`HRS in 2005 (box 1).10 This came about because of an improved
`understanding of the pathophysiology of HRS, the recognition
`that it frequently follows bacterial infections (especially spon-
`taneous bacterial peritonitis), the development of effective
`treatments and improved survival for patients with HRS, espe-
`cially type 1. HRS is therefore no longer necessarily a fatal
`condition without liver transplantation.
`
`PATHOPHYSIOLOGY OF HEPATORENAL SYNDROME
`The following is a summary of the current understanding of the
`pathophysiology of HRS (figure 1).
`
`Portal hypertension as the initiator of haemodynamic changes
`The development of cirrhosis is associated with distortion,
`compression and even obliteration of the liver vasculature. In
`addition, there is decreased intrahepatic production of vasodi-
`lators and activated hypercontractile stellate cells.11 This overall
`inflowdor portal hyper-
`increased resistance
`to portal
`tension12dwill increase the shear stress on the splanchnic vessel
`walls leading to increased production of various vasodilators
`such as nitric oxide, causing splanchnic vasodilation.13 Several
`other
`factors
`including
`increased bacterial
`translocation,
`increased mesenteric angiogenesis and hyporesponsiveness of the
`splanchnic vessels to vasoconstrictors also contribute to the
`splanchnic vasodilation.14 The end result is a pooling of blood in
`the splanchnic vascular bed, akin to a splanchnic steal
`syndrome.15 The shunting of blood and excess vasodilators from
`the splanchnic to the systemic circulation following the opening
`of portal-systemic shunts related to increased portal pressure
`also leads to systemic arterial vasodilation.16 The combined effect
`causes a relative inadequacy of the systemic circulation, the
`so-called ‘reduction in the effective arterial blood volume’,
`thereby triggering a hyperdynamic circulation in these patients.17 18
`Independent of these haemodynamic changes, portal hyper-
`tension per se can lead to renal vasoconstriction via increased
`
`Box 1 International Ascites Club (IAC) proposed
`diagnostic criteria for hepatorenal syndrome10
`
`< Cirrhosis with ascites
`< Serum creatinine >133 mmol/l (1.5 mg/dl)
`< No improvement in serum creatinine (decrease to a level of
`#133 mmol/l or 1.5 mg/dl) after at least 2 days of diuretic
`withdrawal and volume expansion with albumin. The
`recommended dose of albumin is 1 g/kg body weight/day
`up to a maximum of 100 g/day
`< Absence of shock
`< No current or recent treatment with nephrotoxic drugs
`< Absence of parenchymal kidney disease as indicated by
`proteinuria >500 mg/day, microhaematuria (>50 red blood
`cells/high power field) and/or abnormal renal ultrasonography
`
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`Hepatology
`
`Figure 1 Pathophysiology of
`hepatorenal syndrome:
`acute
`precipitating event. HRS, hepatorenal
`syndrome.
`
`sympathetic nervous activity. For example, the elimination of
`portal hypertension with the insertion of a transjugular intra-
`hepatic portosystemic shunt (TIPS) is able to improve renal
`blood flow19 associated with a reduction in sympathetic nervous
`activity.20 The infusion of glutamine which increases hepatic
`sinusoidal pressure, mimicking portal hypertension, reduces the
`glomerular filtration rate (GFR).21 Finally, lumbar sympathetic
`blockade in patients with HRS increases renal blood flow,
`suggesting that the renal sympathetic activity is implicated in
`the efferent arm of this hepatorenal reflex.22
`
`Excess renal vasoconstriction
`in the
`A reduced effective arterial blood volume results
`compensatory activation of various vasoconstrictor systems. In
`response, renal blood flow decreases with consequent reduction
`in GFR. Normally,
`the kidneys maintain blood flow by
`increasing production of renal vasodilators such as prostaglan-
`
`dins and kallikrein. However, in patients with cirrhosis there is
`an overall reduction in renal vasodilator production,15 23 thereby
`favouring renal vasoconstriction.24 This renal hypoperfusion
`further increases the production of various intrarenal vasocon-
`strictors including angiotensin II and endothelin, causing further
`deterioration of renal haemodynamics and renal function, occa-
`sionally with glomerular ischaemia and mesangial constriction.25
`
`Abnormal renal autoregulation
`Renal autoregulation is the process whereby regulatory mecha-
`nisms ensure that the kidneys receive a relatively constant blood
`supply regardless of fluctuations in blood pressure. Below a crit-
`ical threshold of 65 mm Hg, renal blood flow decreases in
`proportion to renal perfusion pressure which,
`in turn,
`is
`dependent on mean arterial pressure. In cirrhosis, there is
`a progressive rightward shift of the renal autoregulation curve as
`liver disease progressesdthat is, for every given renal perfusion
`
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`pressure, there is a gradual reduction of renal blood flow as liver
`disease advances.26 The patient with cirrhosis is therefore poised
`to develop renal failure simply because of the presence of
`advanced cirrhosis.
`
`Abnormal cardiocirculatory function
`The high cardiac output state of the hyperdynamic circulation
`in decompensated cirrhosis means that there is limited cardiac
`reserve in these patients, and further reductions in systemic
`vascular resistance cannot be met with further increases in
`cardiac output. Failure to maintain blood pressure further
`compromises renal perfusion. In cirrhotic patients with ascites
`and spontaneous bacterial peritonitis, and therefore further
`arterial vasodilation as a result of the infection, those who went
`on to develop HRS at infection resolution had significantly
`lower cardiac output compared with baseline and also compared
`with those who did not develop HRS. A relative inability to
`increase cardiac output during stress, a condition known as
`cirrhotic cardiomyopathy,27 28 may therefore be a risk factor for
`the development of HRS.29 Indeed, a relative low cardiac output
`and high plasma renin activity were significant predictors for the
`development of HRS in cirrhosis with ascites.30 The fact that
`blockage of a TIPS shunt with an angioplasty balloon instantly
`reduces renal blood flow, which reverses upon deflation of the
`balloon, confirms that a reduction or increase in venous return
`and hence cardiac output has a direct bearing on renal haemo-
`dynamics.31 Recently, the relationship between cardiac systolic
`dysfunction and the risk of developing renal dysfunction in
`cirrhosis was also confirmed, as well as the negative impact of
`cardiac dysfunction on patient survival.32
`All the above factors contribute to the gradual deterioration in
`renal function as cirrhosis advances. Any event that causes an
`abrupt deterioration in haemodynamics can lead to a rapid
`decline in renal function, precipitating type 1 HRS (figure 1).
`
`CURRENT DIAGNOSTIC CRITERIA FOR HEPATORENAL
`SYNDROME: ADVANTAGES AND DISADVANTAGES
`The most recent diagnostic criteria for HRS clearly delineated
`which patients should be regarded as having HRS and therefore
`receive specific treatment. However, the rigid cut-off value of
`a serum creatinine level of 133 mmol/l (1.5 mg/dl) may limit
`treatment to patients with the most severe degree of renal
`dysfunction. The changes that predispose to the development of
`HRS are not an ‘all-or-none’ phenomenon, but rather evolve
`progressively with the natural history of cirrhosis (figure 2). It is
`unclear whether patients who have milder degrees of renal
`dysfunction will also experience adverse outcomes. If so, they
`should also be offered treatment early rather than waiting until
`the diagnostic criteria of HRS are reached. Additionally, serum
`
`Figure 2 Natural history of cirrhosis:
`acute precipitating event. AKI,
`acute kidney injury; GFR, glomerular filtration rate.
`
`Hepatology
`
`creatinine is notoriously inaccurate in the diagnosis of renal
`dysfunction in cirrhosis.33 Although serum creatinine reflects
`renal function in patients with compensated cirrhosis fairly
`accurately, patients with decompensated cirrhosis often have
`low serum creatinine levels relative to their GFR owing to
`reduced production of creatinine from creatine in the liver and
`significant muscle wasting.34 Thus, serum creatinine in patients
`with decompensated cirrhosis can still be within the normal
`range despite significant renal dysfunction.35
`The use of creatinine clearance in cirrhosis to assess renal
`function is also unreliable because of the falsely low serum
`creatinine in these patients coupled with a relatively increased
`renal tubular creatinine secretion compared with filtered creati-
`nine. Furthermore, it requires a 24-h urine collection which is
`often incomplete. Formulae such as the CockcrofteGault and
`Modification of Diet in Renal Disease (MDRD)dwhich are
`based on serum creatinine concentrationsdwill also over-
`estimate the GFR in cirrhosis.36 37 Clearance techniques using
`exogenous markers such as inulin or iothalamate provide a more
`accurate measurement of GFR but are labour-intensive and
`expensive.38 The use of a one-sample 51Cr-EDTA clearance
`technique is much simpler. However, this method tends to
`overestimate true renal function in patients with both volume
`overload and ascites due to redistribution of tracer into the
`ascitic and interstitial fluid. These problems in the estimation of
`GFR are compounded by correcting for body surface area.39
`Other biological markers such as cystatin C40 and neutrophil
`gelatinase associated lipocalin (NGAL),41 although promising,
`have not been validated in patients with advanced liver disease.
`Therefore, until better measurements of GFR can be found and
`validated, serum creatinine measurement remains the most
`widely used method for estimating renal function in clinical
`practice in patients with cirrhosis.42
`Recognising the inadequacy of serum creatinine as an index of
`renal function in cirrhosis, patients with milder degrees of renal
`dysfunction may not be diagnosed until advanced renal failure
`sets in. The ADQIeIAC Working Group therefore proposes the
`following definitions for the diagnosis of renal dysfunction in
`cirrhosis in order to help identify patients with milder renal
`dysfunction for possible treatment. Since no studies have
`been performed in cirrhosis using these proposed definitions,
`they can best be regarded as expert opinions or level D evidence,
`but they represent an important first step in the process of
`standardising nomenclature and definitions in patients with
`cirrhosis and renal dysfunction. It is planned that this empirical
`proposed classification will be validated in prospective trials.
`
`DEFINITION OF ACUTE KIDNEY INJURY IN CIRRHOSIS
`In 2004 the ADQI Working Group developed a consensus defi-
`nition and classification for AKI known as the RIFLE criteria
`(R: renal risk, I: injury, F: failure, L: loss of kidney function, E: end-
`stage renal disease) which stratified acute renal dysfunction into
`grades of increasing severity based on changes in serum creatinine
`and/or urine output (figure 3).43 To date, the RIFLE criteria have
`been validated in over 500 000 patients with AKI44 45 and have
`been shown to predict clinical outcomes with a progressive
`increase in mortality with worsening RIFLE class.46 The Acute
`Kidney Injury Network (AKIN), an independent collaborative
`network consisting of
`experts
`from ADQI and several
`nephrology and intensive care medicine societies, broadened the
`definition of AKI to include an absolute increase in serum
`creatinine of $26 mmol/l ($0.3 mg/dl) when documented to
`occur within 48 h,47 since smaller increases in serum creatinine
`than those considered in the RIFLE classification have been
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`Hepatology
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`Figure 3
`The RIFLE (R: renal risk, I: injury, F: failure, L: loss of kidney
`function, E: end-stage renal disease) diagnostic criteria.43 ARF, acute
`renal failure; GFR, glomerular filtration rate; UO, urine output.
`
`shown to be associated with an adverse outcome.48 Once
`established, a staging system then defines the severity of the AKI
`(table 1).
`The spectrum of kidney disease in cirrhosis includes acute and
`chronic conditions. Nephrologists distinguish acute and chronic
`renal disease by an artificial timeline of 3 months. Using the
`RIFLE/AKIN criteria for AKI, only a few patients with cirrhosis
`and acute kidney dysfunction will meet the criteria for type 1
`HRS and therefore the remainder will have to be regarded as
`having AKI, be it structural or functional. Similarly, some
`patients with cirrhosis will have CKD such as diabetic
`nephropathy or mild renal dysfunction not reaching a serum
`creatinine of 133 mmol/l (1.5 mg/dl), and therefore not meeting
`the criteria for a diagnosis of type 2 HRS. HRS therefore only
`describes a portion of cirrhotic patients with renal dysfunction.
`The ADQIeIAC proposed that the term ‘hepatorenal disorders’
`(HRD) be used to describe all concurrent kidney dysfunction in
`patients with advanced liver diseasedwhether functional or
`structural in naturedwhich fulfils the diagnostic criteria of AKI
`or CKD or HRS (figure 4). Such a definition is not meant to
`replace the current definition of HRS, but rather to be inclusive
`of all patients with renal dysfunction so that a proper classifi-
`cation of renal dysfunction and appropriate studies can be
`conducted to define their prognosis and to devise treatment
`options.
`Using the creatinine criteria for AKI in patients with cirrhosis
`will certainly identify many patients with acute renal dysfunc-
`tion and normal serum creatinine but low GFR. The urine
`output criteria for AKI may not be applicable in cirrhosis since
`patients with refractory ascites may maintain a urine output of
`<0.5 ml/kg/h even in the absence of AKI. The final consensus
`proposal of the Working Party was to accept the definition of
`AKI in cirrhosis as an increase in serum creatinine of >50%
`from baseline or a rise in serum creatinine of $26.4 mmol/l
`($0.3 mg/dl) in <48 h, irrespective of whether the cause of the
`acute deterioration in renal function is related to a functional or
`structural disorder (table 2). Type 1 HRS can be regarded as
`
`a specific form of AKI. It was further agreed that these empirical
`new diagnostic criteria of AKI for cirrhosis will be validated to
`determine whether these smaller increases in serum creatinine
`are associated with poor outcomes. Two studies involving crit-
`ically ill patients with cirrhosis admitted into an intensive care
`unit already showed that the RIFLE criteria for AKI was a good
`predictor of hospital survival.49 50
`Once confirmed, the serum creatinine threshold for the diag-
`nosis of type 1 HRS may need to be revised to a lower target
`value. This has the potential to allow patients with a smaller rise
`in creatinine to benefit from treatments currently reserved for
`patients with classical HRS. This new classification will also
`allow studies of the epidemiology, incidence, prevalence and
`natural history of various subtypes of AKI in cirrhosis, thereby
`allowing the development of potential preventive and treatment
`strategies.
`
`DEFINITION OF CHRONIC KIDNEY DISEASE IN CIRRHOSIS
`Patients with chronic renal impairment related to cirrhosis may
`not fit the definition and staging of CKD (table 3) as set out by
`the practice guidelines from the Kidney Disease Outcomes
`Quality Initiatives (K/DOQI) Workgroup,51 since it requires
`a GFR of <60 ml/min/1.73 m2 for >3 months, irrespective of
`the presence or absence of structural kidney damage. As
`mentioned above, estimation of GFR in cirrhosis using various
`formulae is problematic and actual measurement of GFR using
`iothalamate or inulin clearance techniques are cumbersome and
`essentially only performed for research purposes. Therefore, the
`application of the definition of CKD in cirrhosis is challenging.
`When the serum creatinine reaches the threshold of 133 mmol/l
`(1.5 mg/dl), the patient is said to have type 2 HRS.
`The prognosis of patients with cirrhosis and CKDdwhether
`type 2 HRS or structural renal diseasedis worse than the
`corresponding stage of CKD in non-cirrhotic patients because of
`coexisting liver disease. Therefore, unlike non-cirrhotic patients,
`these patients usually do not survive long enough for the CKD
`to slowly deteriorate, nor will their CKD typically decline to the
`point of requiring dialysis unless AKI supervenes. Nevertheless,
`to be useful, a HRD classification system must include all
`potential scenarios where CKD and advanced liver disease
`coexist, either as independent entities or as the result of complex
`organ interactions. For example, a patient with cirrhosis due to
`non-alcoholic steatohepatitis may also have CKD on the basis of
`diabetes. Similarly, a patient with cirrhosis and ascites and mild
`renal dysfunction below the level defined by type 2 HRS may
`develop other forms of CKD such as IgA nephropathy related to
`his alcoholic liver disease. Finally, patients in both of these
`examples are likely to be at increased risk for AKI with various
`precipitants such as radiocontrast dye or sepsis.
`Further research is required to understand the clinical signifi-
`cance of reaching K/DOQI criteria for CKD in a patient with
`cirrhosis. Nevertheless, the Working Group proposed the defi-
`nition of CKD as an estimated GFR of <60 ml/min calculated
`
`Table 1
`The Acute Kidney Injury Network (AKIN) criteria for the definition and classification of AKI
`(modified RIFLE criteria)43 47
`AKI stage
`Serum creatinine criteria
`
`Urine output criteria
`
`1 (Risk)
`
`2 (Injury)
`3 (Failure)
`
`Increase in serum creatinine of $26.4 mmol/l ($0.3 mg/dl) within
`48 h or an increase of $150e200% (1.5e2-fold) from baseline
`Increase in serum creatinine to 200e299% (>2e3-fold) from baseline
`Increase in serum creatinine to $300% (>3-fold) from baseline or serum
`creatinine of $354 mmol/l ($4.0 mg/dl) with an acute increase of
`$44 mmol/l ($0.5 mg/dl) or initiation of renal replacement therapy
`
`<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 for 12 h
`
`706
`
`Gut 2011;60:702e709. doi:10.1136/gut.2010.236133
`
`Page 5 of 9
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`MALLINCKRODT PHARMACEUTICALS IRELAND LIMITED
`Exhibit 1014
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`Downloaded from http://gut.bmj.com/ group.bmj.com on July 25, 2017 - Published by
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`Hepatology
`
`Table 3 Definition and stages of chronic kidney disease based on
`kidney disease outcomes quality initiatives (K/DOQI) guidelines51
`GFR (ml/min/1.73 m2)
`Stage
`Description
`
`I
`
`II
`
`III
`IV
`V
`
`Kidney damage with normal or
`increased GFR
`Kidney damage with mildly
`decreased GFR
`Moderately decreased GFR
`Severely decreased GFR
`Kidney failure
`
`$90
`
`60e89
`
`30e59
`15e29
`<15 (or dialysis)
`
`Chronic kidney disease is defined as either kidney damage or glomerular filtration rate (GFR)
`<60 ml/min/1.73 m2 for >3 months. Kidney damage is defined as pathological
`abnormalities or markers of damage including abnormalities in blood or urine tests or
`imaging studies.
`
`formulate a specific equation for the calculation of GFR with an
`acceptable accuracy for patients with advanced cirrhosis and to
`determine what threshold represents an increased risk in this
`population. The use of imaging criteria or histology to diagnose
`CKD was not considered by the group, as chronic renal damage
`may well precede the appearance of small sized kidneys on
`imaging and renal biopsy in patients with cirrhosis and coagu-
`loapthy is associated with an increased risk of bleeding.
`Furthermore,
`large volume ascites may preclude this tech-
`nique.42
`
`DEFINITION OF ACUTE-ON-CHRONIC KIDNEY DISEASE IN
`CIRRHOSIS
`Finally, it is important to recognise that AKI may also occur in
`patients with cirrhosis and pre-existing renal dysfunction. The
`clinician should not have any problem identifying the precipi-
`tation of type 1 HRS with spontaneous bacterial peritonitis in
`a patient with type 2 HRS as the definitions of types 1 and 2
`HRS are well established. However, type 1 HRS may also
`superimpose on CKD that does not fulfil type 2 HRS criteria,
`either because the renal dysfunction is not severe enough or
`because it is due to other forms of kidney disease (eg, diabetic
`nephropathy). Under the current diagnostic criteria for HRS, this
`scenario poses a diagnostic dilemma as the classical definition of
`HRS does not permit the presence of any evidence of structural
`renal damage. This may have potential clinical implications as
`therapeutic interventions, such as a TIPS shunt, may not be
`inserted into patients with mixed HRD when such interventions
`are actually beneficial.53 54 We recognise that acute-on-chronic
`renal failure does occur in cirrhosis, although much work is
`needed to understand this entity better, particularly when forms
`of HRD are mixed (eg, AKI superimposed on CKD in a patient
`with advanced liver disease). The Working Group agreed that, at
`present, an empirical definition of acute-on-chronic kidney
`disease as an increase in serum creatinine of >50% from baseline
`or a rise in serum creatinine of $26.4 mmol/l ($0.3 mg/dl) in
`<48 h in a patient with cirrhosis whose baseline GFR is <60 ml/
`min calculated with the MDRD6 formula for >3 months will be
`adopted. Once again, both the acute deterioration in renal
`function and the background chronic renal dysfunction can be
`functional or structural in nature (table 2).
`
`SUMMARY
`Renal complications are common in cirrhosis, especially in
`patients with refractory ascites, and they can negatively impact
`survival. The IAC has set out clear diagnostic