Section 1.

DEFINITION AND CLASSIFICATION OF

ACUTE KIDNEY INJURY
Authors: Zoltan Endre, Robyn Langham

GUIDELINES
a. We recommend using the KDIGO definition to define and to stage
functional change in AKI (Table 2). (refer to KDIGO guideline)

b. We recommend that all causes of AKI including contrast-induced-AKI

be defined using the same criteria as other causes of AKI. (1D)

c. We recommend that the cause of AKI be defined as soon as possible

after diagnosis of AKI (1D)

UNGRADED SUGGESTIONS FOR CLINICAL CARE

Biomarkers of kidney cellular damage should be incorporated into the

AKI definition when sufficient cut-offs are available for each biomarker
in the context of renal injury. (Ungraded)

Functional parameters in addition to structural parameters (determined

by elevated biomarkers of structural damage) should be considered in
determining the diagnosis, prognosis and outcome of AKI. (Ungraded)

IMPLEMENTATION AND AUDIT

Individual Units should consider an audit of definitions used to diagnose acute
kidney injury (AKI) in separate clinical contexts and review against patient
outcomes in those contexts.

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 BACKGROUND

The following background is based on that provided in the KDIGO guideline

and edited to reflect the review conducted for the adaptation.

Functional AKI is defined as any of the following:

Fig 1: KDIGO guidelines regarding the definition of AKI. (Kidney International

Supplements (2012) 2; 19)

Fig 2. KDIGO staging of AKI. (Kidney International Supplements (2012) 2; 19)

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Fig 3. KDIGO stage-based management of AKI diagram (Kidney International
Supplements (2012) 2; 25).

Acute kidney injury (AKI), formerly known as acute renal failure (ARF), is
common, especially in hospitalised patients and is independently and strongly
associated with morbidity and mortality. AKI is not a single disease, but a
complex clinical syndrome that may arise in response to many etiologies, such
as circulatory shock, sepsis and nephrotoxins [1]. The underlying
pathophysiology of AKI is incompletely understood [2]. Early detection and
treatment of AKI may improve outcomes. The KDIGO consensus definition of
AKI combines two similar definitions based on SCr and urine output [3,4].

AKI is a subset of acute kidney disease (AKD) and can occur in the presence
or absence of other acute or chronic kidney disease (Figure 4 and Table 3).

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Fig 4. Overview of AKI, CKD and AKD. (Kidney International Supplements
(2012) 2; 20

Fig 5. Table of definitions of AKI, CKD and AKD (Kidney International

Supplements (2012); 2:33)

SEARCH STRATEGY
The search strategy was an update of that used by KDIGO (refer to Table 21
in the Appendix of the KDIGO guideline) (Kidney International Supplements 2
(2012); 2: 102-113). Additional key papers have been identified by the authors
that were published after the KHA-CARI update search.

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Databases searched: Medline, Central, Cochrane database of systematic
reviews

Date of searches: June 2012

ADEQUACY OF KDIGO SEARCH STRATEGY

The search strategy and evidence provided by KDIGO was comprehensive
and included some important randomised controlled trials (RCTs). A number
of systematic reviews and RCTs have subsequently been identified in the
updated search by KHA-CARI and included in this update.

APPLICABILITY OF KDIGO RECOMMENDATIONS AND

SUGGESTIONS

The KDIGO recommendations are applicable to the Australian and New

Zealand settings.

OVERVIEW OF THE EVIDENCE

The following provides an overview of the evidence as identified in the KDIGO
guidelines and the update searches conducted by KHA-CARI as part of the
adaptation process.

Definition
The conceptual model of AKI (Figure 6) is analogous to the conceptual model
of CKD and is also applicable to AKD [1,4]. The criteria for the diagnosis of
AKI and stage of severity are currently based on changes in kidney function. It
is widely recognized that GFR is the most useful overall index of kidney
function in health and disease, and changes in SCr and/or urine output are
surrogates for change in GFR. In clinical practice, an abrupt decline in GFR is
assessed from an increase in SCr or oliguria. Changes in SCr are inevitably
delayed after any step change in GFR and this will delay detection of AKI [4,
5]. Nevertheless, the current international and interdisciplinary consensus is
based on two successive consensus definitions. The modified RIFLE criteria
proposed by ADQI [6] and the AKIN [7] which better account for small
absolute changes in SCr not captured by RIFLE, comparison of both criteria
demonstrate only small differences [3]. Epidemiological studies in over
500,000 subjects collectively support the validity of both criteria to identify
groups of hospitalized patients with increased risk of death and/or need for
RRT. However application of both RIFLE and AKIN criteria to a single large
multicentre cohort of 14,536 patients with sepsis in the SAPS 3 database
highlighted differences in the patients captured by the two criteria [8]. In
particular AKIN captured mostly (90.7%) Stage 1 AKI missed by RIFLE and, in
cases missed by AKIN and identified by RIFLE, 30% were RIFLE-I and 18%
RIFLE-F. These AKIN-missed cases had a hospital mortality that was similar

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to cases identified by both criteria (37% for I and 41% for F). Similarly, the
RIFLE missed cases that were identified as stage 1 AKI by AKIN, had double
the hospital mortality rate (25%) of patients with no evidence of AKI by either
criteria (13%). A further large retrospective single centre observational study
of 4,836 consecutive patients undergoing cardiac surgery with
cardiopulmonary bypass similarly demonstrated excellent association to
outcome variables with worse outcome by increased severity of AKI
regardless of whether AKIN or RIFLE classification was used [9]. However,
potential misclassification of AKI was higher in AKIN (in stage 1/RIFLE class
R, because of the larger number of patients who developed a greater than 0.3
mg/dl increase within a 48-hour diagnostic window after cardiopulmonary
bypass surgery. Such patients were not misclassified by RIFLE since the
increases in creatinine are referred to the baseline (pre-bypass) value. The
authors noted that application of AKIN criteria in patients undergoing cardiac
surgery without correction of serum creatinine for fluid balance may lead to
over-diagnosis of AKI. These data provide a strong rationale for use of both
criteria to identify patients with functional AKI but also the caveat discussed
below that serum creatinine values should be corrected for fluid balance.

Fig 6. Conceptual Model, figure modified after reference 4.

SCr and urine output can only indirectly reflect that kidney damage has
occurred.

The availability of new biomarkers of “kidney damage” provides a new

opportunity to identify patients with AKI in addition to SCr and urine output
criteria. A large number of renal cellular damage markers have been identified
over the last decade, many using genomic or proteomic strategies. The
urinary biomarkers can be categorized [5] as filtered proteins increased due to
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glomerular injury, such as albumin and protein, pre-formed markers released
from damaged cells, such as the tubular enzymes gamma glutamyl
transpeptidase and alpha- and pi-glutathione S-transferase, and biomarkers
induced or up-regulated in response to cellular or tissue injury, including
urinary neutrophil gelatinase-associated lipocalin NGAL, kidney injury
molecule 1 (KIM-1), interleukin 18 (IL-18), cystatin C and liver-type fatty acid
binding protein (L-FABP). Some have been commercialized and two, cystatin
C and NGAL, are now available in many routine hospital laboratory
biochemistry platforms.

At present all damage biomarkers remain research tools. In homogeneous

populations, such as after cardiopulmonary bypass surgery, damage
biomarkers have usually been found to be more sensitive, and detect AKI
earlier than change in renal function based on SCr [10-15]. In heterogeneous
populations, such as the critically ill and in the emergency department,
individual biomarker performance is reduced unless there is awareness of
baseline renal function, duration and cause of renal injury [14].

Some biomarkers can be used as markers of change in GFR, such as serum

cystatin C, while others reflect tubular injury, such as urinary NGAL, KIM-1, IL-
18 and L-FABP. Many urinary markers have been validated by the Food and
Drug Administration and European Medicines Agency as damage markers for
preclinical drug development and for use in phase 1 or 2 clinical trials [16, 17]
but none have been validated for routine clinical use. Some change with
recovery or treatment [18, 19], which suggests utility in monitoring outcome
after intervention. Since some of the biomarkers are site and mechanism
specific, they will increase our understanding of AKI pathogenesis and may
even facilitate specific intervention. Most importantly, patients with increased
damage biomarkers but no increase in creatinine may have an increased risk
of dialysis or death similar to patients with an increase in creatinine without an
increase in damage biomarkers. This points to the existence of new category
of AKI, namely patients who are biomarker-positive, and creatinine-negative.

Two large studies demonstrated that biomarker detection of renal injury in

patients prior to a rise in creatinine can predict the same or worse outcomes in
terms of need for dialysis and of mortality. A review of 10 large observational
studies amalgamated to 2322 critically ill patients with predominantly
cardiorenal syndrome monitored prospectively using plasma or urinary NGAL
observed that the cohort of biomarker-positive, creatinine-negative patients
were at a similar increased risk of dialysis and death to the creatinine-positive,
biomarker negative group [20]. Similarly, a multicentre prospective cohort
study of 1,635 unselected emergency department patients revealed that, a
substantial subpopulation with increased urinary biomarkers (NGAL or KIM-1)
but low SCr at hospital admission were at increased risk of dialysis or death in
hospital. In the latter study, of the 5 urinary biomarkers assessed at the time of
admission (NGAL, KIM-1, L-FABP, IL-18 and cystatin C), NGAL was most
useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) in diagnosis and
prediction of the severity and duration of AKI [21]. In related observations, two
studies of critically ill patients with apparent pre-renal AKI, defined as transient
AKI (less than 48 hours) with preserved tubular function, detected urinary
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biomarkers at concentrations intermediate between patients without AKI and
those where AKI became established for more than 48 hours [22, 23]. These
latter observations suggested that what has been described as “pre-renal AKI”
is simply the mild end of a continuum of renal injury, rather than a reversible
functional form of AKI without cellular damage.

As a consequence of these observations, the ADQI group at a meeting in

Dublin in September 2011, recommended the addition of biomarker estimation
to the definition, staging and differential diagnosis of AKI to complement the
KDIGO (RIFLE/AKIN) criteria [24]. The group also recommended that the
pathophysiological terms “functional change” and “kidney damage” be used in
preference to the anatomical classification using the terms pre-renal, renal and
post-renal AKI. Future revisions of the definition of AKI will need to include
both biomarkers of function and damage, leading to three categories of AKI,
namely functional, damage and combined functional and damage AKI. There
are currently insufficient quantitative biomarkers data for AKI staging and
biomarker guided interventions have not yet been shown to be of benefit [25].

However functional and damage markers will be combined in the future. Such
combinations are likely to enhance diagnosis [26]. For example, a number of
studies have highlighted that “old” biomarkers detected by urine microscopy
are of significant value in the early differential diagnosis of AKI [26-
28].Combining the high specificity of epithelial cell casts with the high
sensitivity of urinary NGAL led to improved predictive performance in AKI
diagnosis [29, 30]. Further large scale studies are required to determine
context specific biomarker thresholds in AKI of different aetiologies.

While serum creatinine and urinary volume currently remain the clinical
pointers to AKI diagnosis, we consider that using the term “functional AKI” to
distinguish AKI defined only by change in creatinine or urine volume, from
“structural AKI” defined, in the future, by the presence of elevated biomarkers
of structural damage.

A number of additional concerns remain concerning definitions of functional

AKI, with respect to baseline function and the effect of fluid loading. Firstly,
creatinine-based definitions rely on knowing the baseline creatinine and
approximately 50% of admissions do not have one [25]. Consequently a
number of strategies have been proposed including back calculation of SCr
using the MDRD formula and assuming a 75% GFR [31]. This performs well
when near-normal baseline kidney function is present [32], but leads to
consistent errors [32, 33] especially in patients with pre-existing CKD [33].
These errors are best overcome by using a hierarchical approach favouring a
measured creatinine in the 3 months prior to admission, the lowest observed
creatinine at or after discharge and creatinine on-admission (in that
order)[34]. While this is fine for post-hoc analysis, it is of no benefit in patient
management, where either the back-calculation method or on admission
values must be used despite the inherent problems. While this will be solved
to some extent by use of the damage biomarkers, some of these are
increased in CKD (e.g. KIM-1, NGAL) and some conditions may differentially
increase others (e.g. NGAL in sepsis) leading to higher baseline and
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diagnostic threshold biomarker values. An analysis of nadir-to-peak creatinine
increments stratified by baseline eGFR in 29,645 adults in a single centre
found that a greater absolute increase in creatinine was required to have an
equivalent risk of in-hospital mortality as eGFR decreased [35]. The validation
of novel direct methods of measuring true GFR in close to real-time fashion
[22] will likely supersede calculation of eGFR and provide additional ways of
identifying or excluding AKI in the future. However, even future definitions of
functional AKI will still need to consider the patient‟s baseline GFR.

Secondly, large volume resuscitation is common in critically ill patients. While

many negative consequences of fluid overload are well known [36], the
significant dilution of serum creatinine can delay or obscure diagnosis of AKI.
In a study of 253 patients recruited from a prospective observational study of
critically-ill patients with AKI, 64 (25%) were recognized late (by more than 24
hours) when the serum creatinine value was not adjusted for fluid loading [37].
In contrast, as discussed earlier, dilution of serum creatinine after
cardiopulmonary bypass can lead to misclassification of patients as having
AKI when the AKIN criteria are used [9]. It is therefore important that serum
creatinine values, and by inference the concentrations of other biomarkers,
are corrected for fluid balance when patients receive large volumes of
intravenous fluid after resuscitation, cardiopulmonary bypass and other
relevant clinical scenarios.

Staging
For staging purposes, patients should be staged according to the criteria that
give them the highest stage. Thus when creatinine and urine output map to
different stages, the patient is staged according to the highest (worst) stage.
The changes in GFR that were published with the original RIFLE criteria do
not correspond precisely to changes in SCr [38]. As SCr is measured and
GFR can only be estimated, creatinine criteria should be used along with urine
output for the diagnosis (and staging) of functional AKI. One additional change
in the criteria was made for simplicity. For patients automatically qualifying as
Stage 3 by an increase in SCr to 354 mol/l (4.0mg/dl), these patients must
first satisfy the creatinine-based change specified in the definition of functional
AKI (either an increase of at least 26.5 mol/l [0.3mg/dl] within a 48-hour time
window or an increase of 1.5 times baseline).

We note and support the KDIGO recommendation to modify these criteria for
paediatric patients. The pediatric-modified RIFLE (pRIFLE) AKI criteria [6]
were developed using a change in estimated creatinine clearance (eCrCl)
based on the Schwartz formula. In pRIFLE, patients automatically reach Stage
3 if they develop an eCrCl <35 ml/min per 1.73 m 2. However, with this
automatic pRIFLE threshold, the SCr change-based AKI definition
(recommendation 2.1.1) is applicable to pediatric patients, including an
increase of 26.5 mmol/l (0.3 mg/dl) in SCr.

The use of urine output criteria for diagnosis and staging is less well validated
and in individual patients the need for clinical judgment regarding the effects of

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drugs (e.g. angiotensin-converting enzyme inhibitors), fluid balance, and other
factors must be included. For very obese patients, urine output criteria for AKI
may include some patients with normal urine output. However, these
recommendations serve as the starting point for further evaluation for a group
of patients recognized to be at increased risk.

Importantly, it is axiomatic that patients always be managed according to the

cause of their disease. Thus it is important to determine the cause as soon as
possible whenever AKI is diagnosed. In particular, patients with decreased
kidney perfusion, rapidly progressive glomerulonephritis, vasculitis, interstitial
nephritis, thrombotic microangiopathy, and urinary tract obstruction require
immediate diagnosis and specific therapeutic intervention, in addition to the
general recommendations for AKI management (Figure 1 and in the remainder
of this guideline). It is therefore always necessary to search for the underlying
cause of AKI.

Finally, we recognize that the definition of AKI will continue to evolve. The use
of functional and damage biomarkers will facilitate identification of functional
and/or structural AKI. The validation of novel measurements of GFR in near
real-time will provide additional ways of identifying or excluding functional AKI
and allowance for fluid balance will reduce misclassification by these groups of
biomarkers. These refinements will need to be incorporated progressively into
the definition of AKI.

Risk factors for AKI

Numerous risk factors for AKI have been identified, including dehydration or
volume depletion, advanced age
, female gender
, black race, CKD, other
chronic diseases (heart, lung, liver), diabetes mellitus, cancer
 and anaemia.
In the KDIGO guidelines these are summarised in Table 6 as exposures and
susceptibilities [39]. A more thorough understanding of risk factors will help to
achieve better prevention and prognosis. Newly identified risk factors for AKI
are hypoalbuminaemia, burns and inflammation as measured by C-reactive
protein in the setting of coronary artery stenting:

A meta-analysis of observational studies of hypoalbuminaemia has

identified this as an independent risk factor for AKI and post-AKI death
[40]. Although the link has not been shown to be causal, further
controlled-clinical trials are required to clarify the risk.
A meta-analysis examining AKI in severe burn patients found a 25%
incidence of AKI and associated it with increased mortality [41].
Two retrospective studies have found that elevated preprocedural
levels of C-reactive protein (CRP) before percutaneous coronary
intervention is associated with an increased risk of CI-AKI [42, 43].

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WHAT DO THE OTHER GUIDELINES SAY?
Kidney Disease Outcomes Quality Initiative (2013): [44]

2.1.1- AKI is defined as any of the following (Not Graded):

Increase in SCr by 0.3 mg/dL ( 26.5 mol/L) within 48 hours; or
Increase in SCr to 1.5 times baseline, which is known or presumed
to have occurred within the prior 7 days; or
Urine volume < 0.5 mL/kg/h for 6 hours.

2.1.2- AKI is staged for severity according to the following criteria. (Not
Graded)
Stage 1: Increase in SCr by 1.5-1.9 times baseline; OR
Increase in sSCr by ( 0.3 mg/dL ( 26.5 mol/L); OR
Urine output < 0.5 mL/kg/h for 6-12 hours

Stage 2: Increase in SCr by 2.0-2.9 times baseline; OR Urine output < 0.5
mL/kg/h for _12 hours

Stage 3: Increase in SCr by 3.0 times baseline; OR

Increase in SCr to 4.0 mg/dL (353.6 mol/L); OR
Initiation of renal replacement therapy; OR
In patients < 18 years, decrease in eGFR to 35 mL/min/1.73 m2; OR
Urine output < 0.3 mL/kg/h for 24 hours; OR Anuria for 12 hours

2.1.3: The cause of AKI should be determined whenever possible. ( Not

Graded)

2.2.1: We recommend that patients be stratified for risk of AKI according to

their susceptibilities and exposures. (1B)

2.2.2: Manage patients according to their susceptibilities and exposures to

reduce the risk of AKI (see relevant guideline sections).
(Not Graded)

2.2.3: Test patients at increased risk for AKI with measurements of SCr and
urine output to detect AKI. (Not Graded). Individualize frequency and duration
of monitoring based on patient risk and clinical course. (Not Graded)

2.3.1: Evaluate patients with AKI promptly to determine the cause, with
special attention to reversible causes. (Not Graded)

2.3.2: Monitor patients with AKI with measurements of SCr and urine output to
stage the severity, according to Recommendation

2.1.2. (Not Graded)

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2.3.3: Manage patients with AKI according to the stage (Fig 2) and cause.
(Not Graded)

2.3.4: Evaluate patients 3 months after AKI for resolution, new onset, or
worsening of pre-existing CKD. (Not Graded)
If patients have CKD, manage these patients as detailed in the KDOQI
CKD Guideline (Guidelines 7-15). (Not Graded)
If patients do not have CKD, consider them to be at increased risk for
CKD and care for them as detailed in the KDOQI CKD Guideline 3 for
patients at increased risk for CKD. (Not Graded)

UK Renal Association (2011): [45]

1.1- We recommend that the international Kidney Disease: Improving Global

Outcomes (KDIGO) definition of acute kidney injury (AKI) should be
adopted. (Not Graded)

1.2- We recommend that the international Kidney Disease: Improving Global

Outcomes (KDIGO) Staging classification* of acute kidney injury (AKI)
should be adopted. (Not Graded)

1.3- We recommend that serum creatinine and urine output remain the best
biomarkers for AKI. Serum creatinine should be measured using the
enzymatic technique. (1B)

Canadian Society of Nephrology (2013): [46]

The Canadian Society of Nephrology (CSN) commentary on KDIGO Clinical

Practice Guideline for Acute Kidney Injury, states that the KDIGO definition of
AKI should be limited to research purposes of this time. CSN states

„When diagnosing and managing AKI, clinicians should consider other factors
in addition to SCr level and urine output, such as trends in renal function,
cause of AKI, concurrent diseases and comorbid conditions, as well as fluid
balance and acid-base and/or electrolyte complications‟.

European Renal Best Practice Guidelines (2012): [47]

1.1.1 We recommend using a uniform definition of AKI, based on urinary

output and on changes in serum creatinine (SCr) level. It is important
that both criteria are taken into account. (1C)

1.1.2 We recommend diagnosing and indicating the severity of AKI

according to the criteria in the table below: (ungraded statement)

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Table 1. European Renal Best Practice Guidelines: Acute Kidney Injury
Stages

Stage 1: one of the following:

• Serum creatinine increased 1.5–1.9 times
baseline
• Serum creatinine increase >0.3mg/dl (26.5
μmol/l)
• Urinary output < 0.5ml/kg/h during a 6 hour
block
Stage 2: one of the following
• Serum creatinine increase 2.0–2.9 times
baseline
• Urinary output <0.5ml/kg/h during two 6 hour
blocks
Stage 3: one of the following:
• Serum creatinine increase >3 times baseline
• Serum creatinine increases to >4.0mg/dl (353
μmol/l)
• Initiation of renal replacement therapy
• Urinary output <0.3ml/kg/h during

1.1.2a We recommend using the first documented serum creatinine value of

the episode as „baseline‟, rather than historical creatinines or a
calculated value based on a presumed glomerular filtration rate (GFR)
of 75 mL/ min. (1C)

1.1.2b We suggest using „shift-based‟ calculation of the urinary output

criteria, especially in patients without a bladder catheter (1C). We
recommend to use the ideal weight rather than the true weight in
calculating the diuresis in mL/min/kg. (Ungraded statement)

1.1.3 The cause of AKI should be determined whenever possible. As a

minimal work-up, the presence of hypovolaemia, post-renal causes,
low cardiac output, use of nephrotoxic agents, acute glomerulonephritis
and renal micro-angiopathy as underlying contributors to AKI should be
evaluated. (Ungraded statement)

SUGGESTIONS FOR FUTURE RESEARCH

The role of biomarkers other than SCr in the early diagnosis, differential
diagnosis, and prognosis of AKI patients should be explored in all contexts of
risk. Some important areas in which to focus include:

Early detection where the gold standard is AKI by clinical diagnosis

after the fact and the biomarker is compared to existing markers (SCr
and urine output) at the time of presentation.

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 Prognosis where a biomarker is used to predict risk for AKI or risk for
progression of AKI.
Prognosis where a biomarker is used to predict recovery after AKI vs.
death or need for acute or long-term RRT.
The influence of urinary output criteria on AKI staging needs to be
further investigated, including how urine volume criteria should be
applied (e.g., average vs. persistent reduction for the period specified).
The influence of fluid balance, percent volume overload, diuretic use,
and differing weights (actual, ideal body weight, lean body mass) on all
functional and structural biomarkers should be considered.
The influence of SCr or eGFR criteria on AKI staging needs to be
further investigated. The use of different relative and absolute SCr
increments or eGFR decrements at different time points and with
differently ascertained baseline values requires further exploration and
validation in various populations.
The development of real-time measures of GFR and the potential for
using biomarkers to assess outcome should be explored.

CONFLICT OF INTEREST
Z Endre has received an Honorarium from Novartis Transplant Advisory
Board (2012, 2013), financial support for travel from Alere (2010) and Novartis
(2011) and Accommodation Amgen (2013). Research funding has been
provided by Alere, Argutis, Abbot (2007-2010) for provision of assay kits.

R.G. Langham has received honorarium and travel support from Amgen
(2010-2013), consulting fees from Astra Zeneca (2013), travel support to
travel to a European nephrology meeting from Novartis (2012) and
honorarium for Advisory Board role from MSD (2011).

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