U.S. patent application number 15/358779 was filed with the patent office on 2017-03-23 for prediction and recognition of acute kidney injury after surgery.
The applicant listed for this patent is Roche Diagnostics Operations, Inc.. Invention is credited to Georg Hess, Andrea Horsch, Dietmar Zdunek.
Application Number | 20170082639 15/358779 |
Document ID | / |
Family ID | 42941969 |
Filed Date | 2017-03-23 |
United States Patent
Application |
20170082639 |
Kind Code |
A1 |
Hess; Georg ; et
al. |
March 23, 2017 |
PREDICTION AND RECOGNITION OF ACUTE KIDNEY INJURY AFTER SURGERY
Abstract
Systems, kits, and methods for predicting the risk of an adverse
event related to acute kidney injury AKI as a consequence of a
surgical intervention in a subject. Embodiments of the system and
methods include means and steps for determining an amount of
liver-type fatty acid binding protein (L-FABP) in a sample, such as
a urine-sample of a subject; comparing the amounts of the L-FABP
with a reference amount, and predicting the risk of an adverse
event related to acute kidney injury as a consequence of surgical
intervention in the subject.
Inventors: |
Hess; Georg; (Mainz, DE)
; Horsch; Andrea; (Luzern, CH) ; Zdunek;
Dietmar; (Tutzing, DE) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Roche Diagnostics Operations, Inc. |
Indianapolis |
IN |
US |
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|
Family ID: |
42941969 |
Appl. No.: |
15/358779 |
Filed: |
November 22, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13713719 |
Dec 13, 2012 |
9535073 |
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15358779 |
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PCT/EP2011/059951 |
Jun 15, 2011 |
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13713719 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 2800/56 20130101;
G01N 33/6872 20130101; G01N 33/6893 20130101; G01N 2333/47
20130101; G01N 2800/347 20130101; G01N 33/74 20130101; G01N
2333/475 20130101 |
International
Class: |
G01N 33/68 20060101
G01N033/68 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 15, 2010 |
EP |
10165964.7 |
Claims
1. A method for diagnosing acute kidney injury in a subject,
comprising: determining an amount of liver-type fatty acid binding
protein, or a variant thereof, in a portion of a sample of a
subject; comparing the amount of liver-type fatty acid binding
protein, or variant thereof, determined in said step of determining
to a liver-type fatty acid binding protein reference amount; and
providing a diagnosis of acute kidney injury in the subject if the
amount of liver-type fatty acid binding protein, or the variant
thereof, determined in said step of determining is greater than the
liver-type fatty acid binding protein reference amount.
2. The method of claim 1, wherein the sample is a urine sample.
3. The method of claim 1, wherein the sample is procured from the
subject prior to a surgical intervention.
4. The method of claim 1, wherein said step of determining
comprises contacting, in vitro, the portion of the sample with an
antibody having specific binding affinity for liver-type fatty acid
binding protein, or a variant thereof.
5. The method of claim 1, wherein the liver-type fatty acid binding
protein reference amount is 10.7 .mu.g/g creatinine.
6. A method of diagnosing a subject as at increased risk of for an
adverse event related to acute kidney injury after a surgical
intervention, comprising the steps of: a) determining an amount of
liver-type fatty acid binding protein, or a variant thereof, in a
portion of a sample of a subject, the sample obtained from the
subject prior to a surgical intervention; b) comparing the amount
of liver-type fatty acid binding protein, or the variant thereof,
determined in said step of determining to a liver-type fatty acid
binding protein reference amount; and c) providing a diagnosis of
at increased risk for an adverse event related to acute kidney
injury after the surgical intervention if the amount of liver-type
fatty acid binding protein, or the variant thereof, determined in
said step of determining is greater than the liver-type fatty acid
binding protein reference amount.
7. The method of claim 6, wherein sample is a urine sample.
8. The method of claim 6, wherein said step of determining
comprises contacting, in vitro, the portion of the sample with an
antibody having specific binding affinity for liver-type fatty acid
binding protein, or a variant thereof.
9. The method of claim 6, wherein the liver-type fatty acid binding
protein reference amount is 10.7 .mu.g/g creatinine.
10. The method of claim 6 further comprising the steps of:
determining the amount of adiponectin, or a variant thereof, in a
portion of the sample of the subject; and comparing the amount of
adiponectin, or the variant thereof, to an adiponectin reference
amount, wherein said step of providing a diagnosis further
comprises providing a diagnosis of at increased risk for an adverse
event related to acute kidney injury after the surgical
intervention if the amount of adiponectin, or variant thereof, is
greater than the adiponectin reference amount.
11. The method of claim 6, wherein the adiponectin reference amount
is 15.5 .mu.g/g creatinine.
12. A device adapted for diagnosing a subject as at increased risk
of for an adverse event related to acute kidney injury after a
surgical intervention, comprising: means for determining an amount
of liver-type fatty acid binding protein, or a variant thereof, in
a sample from the subject; means for comparing the determined
amount of liver-type fatty acid binding protein, or the variant
thereof, to a liver-type fatty acid binding protein reference
amount; and means for providing a diagnosis of at increased risk
for an adverse event related to acute kidney injury after a
surgical intervention if the amount of liver-type fatty acid
binding protein, or the variant thereof, determined in the sample
of the subject is greater than the liver-type fatty acid binding
protein reference amount.
13. The device of claim 12, wherein the means for comparing
comprises executable implemented rules.
14. The device of claim 13, wherein the executable implemented
rules are executed by a processor of a computing device.
15. The device of claim 14, wherein the liver-type fatty acid
binding protein reference amount is a stored value.
16. The device of claim 12, further comprising: means for
determining an amount of adiponectin, or a variant thereof, in a
sample from the subject; and means for comparing the determined
amount of adiponectin, or the variant thereof, to an adiponectin
reference amount, wherein the means for providing a diagnosis
further comprises means for providing a diagnosis of at increased
risk for an adverse event related to acute kidney injury after the
surgical intervention if the amount of adiponectin, or variant
thereof, determined in the sample of the subject is greater than
the adiponectin reference amount.
17. The device of claim 12 further comprising means for determining
an amount of at least one of NGAL, or a variant thereof, and
albumin, or a variant thereof, in a sample from the subject.
18. The device of claim 12, wherein the means for determining are
adapted for determining an amount of liver-type fatty acid binding
protein, or a variant thereof, in a urine-sample of the
subject.
19. The device of claim 12, wherein said means for determining the
amount of liver-type fatty acid binding protein, or a variant
thereof, comprise a micro-plate optical analyzer.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/713,719, filed Dec. 13, 2012 which is a
continuation of International Application No. PCT/EP2011/059951,
filed Jun. 15, 2011 which claims the benefit of European Patent
Application No. 10165964.7, filed Jun. 15, 2010, the disclosures of
which are hereby incorporated by reference in their entirety.
BACKGROUND OF THE DISCLOSURE
[0002] Acute kidney injury represents a significant problem in
clinical medicine. Five percent of hospitalized patients and up to
30 percent of patients in intensive care units will develop acute
kidney injury ("AKI"). In AKI, serum creatinine levels rise slowly
and it may take 2-3 days before kidney injury becomes apparent, in
general indicated by an increase in creatinine of at least 0.3
mg/dl or an increase of more than 50 percent from baseline
(Devarajan, Expert Opinion Med Diagn 2008, 2: 387-398).
[0003] The pathogenesis of postoperative AM appears multifactorial,
and its association with increased morbidity and long term
mortality is well established (Brown et al Ann Thorac Surg 2008,
86: 4-11).
[0004] Coronary bypass surgery is preferentially carried out in
patients in whom percutaneous coronary intervention is not possible
due to the localization or extent of coronary atherosclerosis. This
intervention is associated with a significant risk of AKI, this
risk has been described to range between 10 and 20%, and wherein 1
to 5 percent of these individuals require dialysis (Mehta,
Circulation 2006: 114 2208-16).
[0005] AKI may be prevented in patients who are known to be at
increased risk by maintaining a careful fluid balance during
surgery and, avoiding other precipitating factors of AM, such as
discontinuation of ACE inhibitors, NSAIDs and other drugs known to
cause kidney injury before surgery, and the careful use of
diuretics, specifically loop diuretics. Details are summarized in
Brit J. of Hospital Medicine, 2008, 69, 450-454 (for details see
Tables 2 and 3).
[0006] It is important to recognize early evidence of acute kidney
injury in particular in low risk population which is frequently
subject to early discharge. Although many cases are reversible if
diagnosed and treated early, the overall survival rate remains
about 50 percent because many patients with AKI have significant
underlying disorders, e.g. sepsis, respiratory failure. Frequently
death is caused by these disorders, rather than by the renal
failure itself. In about 10 percent of the cases dialysis or
transplant is required, either as an immediate treatment or as
renal function slowly deteriorates. AM can be fully reversible if
treated appropriately and in time. As mentioned above, renal
function may also deteriorate to chronic renal failure. Treatment
may include immediate treatment of pulmonary edema and
hyperkalemia; dialysis; adjustment of drug regimen, restriction of
water, Na, and K intake, phosphate binders and Na polystyrene
sulfonate.
BRIEF SUMMARY OF THE DISCLOSURE
[0007] The instant disclosure provides methods and means for
predicting risk of an individual to suffer from AKI after a
surgical intervention, such as a cardiac intervention (including,
for example, a coronary bypass surgery). The instant disclosure
also provides means to predict the risk of an individual to suffer
from AM after a surgical intervention based on analysis of a sample
obtained before carrying out the surgical intervention.
[0008] The present disclosure relates to diagnostic methods and
means. More specifically, it relates to a method for predicting the
risk of acute kidney injury (AM) in individuals who will receive a
surgical intervention, such as a cardiac intervention, for example
coronary bypass surgery. The present disclosure, likewise, relates
to a method for predicting the risk of acute kidney injury in
individuals having undergone a surgical intervention, such as
cardiac intervention, for example coronary bypass surgery, and to a
method of diagnosing acute kidney injury in patients having
undergone a surgical intervention, such as cardiac intervention,
for example coronary bypass surgery. Moreover, the present
disclosure relates to devices, kits for carrying out said method
and a method of deciding on a suitable therapy in patients
suffering from AM after a surgical intervention.
[0009] According to some embodiments, the present disclosure
relates to a method for predicting the risk of a subject to
experience an adverse event related to acute kidney injury AKI
after a surgical intervention in a subject, based on the comparison
of the amounts of liver-type fatty acid binding protein (L-FABP) or
a variant thereof, determined in a urine sample of the subject,
also referred to as urinary liver-type fatty acid binding protein,
determined in a sample of said subject, to at least one reference
amount.
[0010] According to some embodiments, the method of the present
disclosure comprises at least one of the following steps and/or may
comprise the following steps: a) determining the amounts of
liver-type fatty acid binding protein (L-FABP) or a variant
thereof, for example urinary liver-type fatty acid binding protein
(L-FABP), in sample, such as a urine-sample of a subject; b)
comparing the amounts determined in step a) with reference amounts;
c) predicting the risk based on the comparison carried out in step
b).
[0011] In some embodiments the present disclosure provides a method
for predicting the risk of a subject to experience adverse event
related to acute kidney injury AM after a surgical intervention in
a subject, comprising the steps of: a) determining the amounts of
liver-type fatty acid binding protein (L-FABP) or a variant
thereof, for example urinary liver-type fatty acid binding protein
(L-FABP) or a variant thereof, in a sample, for example a
urine-sample of a subject; b) comparing the amounts determined in
step a) with reference amounts; and c) predicting the risk based on
the comparison carried out in step b).
[0012] In another embodiment of the present disclosure, the present
disclosure provides a method for predicting the risk of a subject
to experience adverse event related to acute kidney injury AKI
after a surgical intervention in a subject, comprising the steps
of: a) determining the amounts of liver-type fatty acid binding
protein (L-FABP) or a variant thereof, for example urinary
liver-type fatty acid binding protein (L-FABP) or a variant
thereof, in a sample, such as a urine-sample of a subject; and b)
comparing the amounts determined in step a) with reference amounts;
whereby the risk of the subject to experience adverse event related
to acute kidney injury AM after a surgical intervention is
predicted.
[0013] In some embodiments of the present disclosure, the amount of
adiponectin or a variant thereof or a variant thereof is determined
in the sample, such as the urine sample, further to the amount of
L-FABP or a variant thereof, and the risk is predicted based on the
comparison of the marker amounts with reference amounts.
[0014] In further embodiments of the present disclosure, the amount
of at least one further marker selected from albumin or a variant
thereof and neutrophil gelatinase associated lipocalin (NGAL) or a
variant thereof is measured in the urine sample, and the risk is
predicted based on the comparison of the marker amounts with
reference amounts. In such embodiments, the amount of only one
additional marker from the above-cited group (further to L-FABP or
a variant thereof) and, in some embodiments adiponectin or a
variant thereof, will be measured, or the amounts of both
additional markers further to L-FABP or a variant thereof and
adiponectin or a variant thereof.
[0015] In some embodiments, the risk is predicted prior to the
surgical intervention. The present disclosure also includes
embodiments in which the risk is predicted following surgical
intervention.
[0016] Moreover, the present disclosure relates to a method of
deciding on a suitable therapy in a subject patient as defined
beforehand, a method of monitoring the therapy, and a device and a
kit for carrying out the methods of the present disclosure.
[0017] According to some embodiments, a method of diagnosing acute
kidney injury in a subject is provided. Embodiments of the instant
method include the steps of determining an amount of liver-type
fatty acid binding protein, or a variant thereof, in a portion of a
sample of a subject, comparing the amount of liver-type fatty acid
binding protein, or variant thereof, determined in said step of
determining to a liver-type fatty acid binding protein reference
amount, and providing a diagnosis of acute kidney injury in the
subject if the amount of liver-type fatty acid binding protein, or
the variant thereof, determined in said step of determining is
greater than the liver-type fatty acid binding protein reference
amount.
[0018] According to some embodiments of the instant methods, the
step of determining comprises contacting, in vitro, the portion of
the sample with an antibody having specific binding affinity for
liver-type fatty acid binding protein, or a variant thereof. In
some such embodiments, the liver-type fatty acid binding protein
reference amount is 10.7 .mu.g/g creatinine.
[0019] Some embodiments of the disclosed methods include the sample
being a urine sample. In some further embodiments, the sample of
the subject is provided prior to a surgical intervention.
[0020] According to other embodiments of the instant disclosure, a
method of diagnosing a subject as at increased risk of for an
adverse event related to acute kidney injury after a surgical
intervention is provided. In some embodiments, the method includes
the steps of a) determining an amount of liver-type fatty acid
binding protein, or a variant thereof, in a portion of a sample of
a subject, the sample obtained from the subject prior to a surgical
intervention; b) comparing the amount of liver-type fatty acid
binding protein, or the variant thereof, determined in said step of
determining to a liver-type fatty acid binding protein reference
amount; and c) providing a diagnosis of at increased risk for an
adverse event related to acute kidney injury after the surgical
intervention if the amount of liver-type fatty acid binding
protein, or the variant thereof, determined in said step of
determining is greater than the liver-type fatty acid binding
protein reference amount.
[0021] According to yet further embodiments of the instant
disclosure, a device adapted for diagnosing a subject as at
increased risk of for an adverse event related to acute kidney
injury after a surgical intervention is provided. According to some
embodiments, the device includes means for determining an amount of
liver-type fatty acid binding protein, or a variant thereof, in a
sample from the subject; means for comparing the determined amount
of liver-type fatty acid binding protein, or the variant thereof,
to a liver-type fatty acid binding protein reference amount; and
means for providing a diagnosis of at increased risk for an adverse
event related to acute kidney injury after a surgical intervention
if the amount of liver-type fatty acid binding protein, or the
variant thereof, determined in the sample of the subject is greater
than the liver-type fatty acid binding protein reference
amount.
[0022] In some embodiments, the device includes means for
determining an amount of adiponectin, or a variant thereof, in a
sample from the subject, and means for comparing the determined
amount of adiponectin, or the variant thereof, to an adiponectin
reference amount. In such embodiments, the means for providing a
diagnosis further comprise means for providing a diagnosis of at
increased risk for an adverse event related to acute kidney injury
after the surgical intervention if the amount of adiponectin, or
variant thereof, determined in the sample of the subject is greater
than the adiponectin reference amount.
[0023] According to even more embodiments of the device, the means
for comparing comprises executable implemented rules. In some such
embodiments, the executable implemented rules are executed by a
processor of a computing device. In even further embodiments, the
liver-type fatty acid binding protein reference amount is a stored
value.
BRIEF DESCRIPTION OF THE FIGURES
[0024] The features of this disclosure, and the manner of attaining
them, will become more apparent and the disclosure itself will be
better understood by reference to the following description of
embodiments of the disclosure taken in conjunction with the
accompanying drawing.
[0025] FIG. 1 is a receiver operating characteristic ("ROC")
analysis for urinary L FABP of samples obtained from the patients
described in Example 1 before surgery in which analysis was
performed with respect to the clinical endpoint acute kidney injury
(yes or no).
[0026] FIG. 2 is a ROC analysis for urinary L FABP of samples
obtained from the patients described in Example 1 before surgery in
which analysis was performed with respect to the need for dialysis
(yes or no).
[0027] FIG. 3 is a ROC analysis for adiponectin of samples obtained
from the patients described in Example 1 before surgery in which
analysis was performed with respect to the clinical endpoint acute
kidney injury (yes or no).
[0028] FIG. 4 is a ROC analysis for adiponectin of samples obtained
from the patients described in Example 1 before surgery in which
analysis was performed with respect to the need for dialysis (yes
or no).
[0029] FIG. 5 is a ROC analysis for albumin of samples obtained
from the patients described in Example 1 before surgery in which
analysis was performed with respect to the clinical endpoint acute
kidney injury (yes or no).
[0030] FIG. 6 is a ROC analysis for albumin of samples obtained
from the patients described in Example 1 before surgery in which
analysis was performed with respect to the need for dialysis (yes
or no).
[0031] FIG. 7 is a ROC analysis for NGAL of samples obtained from
the patients described in Example 1 before surgery I which analysis
was performed with respect to the clinical endpoint acute kidney
injury (yes or no).
[0032] FIG. 8 is a ROC analysis for NGAL of samples obtained from
the patients described in Example 1 before surgery in which
analysis was performed with respect to the need for dialysis (yes
or no).
[0033] FIG. 9 is a ROC analysis for albumin of samples obtained
from the patients described in Example 1 about 6 h after surgery
termination, in which analysis was performed with respect to the
clinical endpoint acute kidney injury (yes or no).
[0034] FIG. 10 is a ROC analysis for albumin of samples obtained
from the patients described in Example 1 about 12 h after surgery
termination, in which analysis was performed with respect to the
clinical endpoint acute kidney injury (yes or no).
[0035] FIG. 11 is a ROC analysis for albumin of samples obtained
from the patients described in Example 1 about 6 h after surgery
termination, in which analysis was performed with respect to the
need for dialysis (yes or no).
[0036] FIG. 12 is a ROC analysis for albumin of samples obtained
from the patients described in Example 1 about 12 h after surgery
termination, in which analysis was performed with respect to the
need for dialysis (yes or no).
[0037] FIG. 13 is a ROC analysis for adiponectin of samples
obtained from the patients described in Example 1 about 6 h after
surgery termination, in which analysis was performed with respect
to the need for dialysis (yes or no)
[0038] FIG. 14 is a ROC analysis for adiponectin of samples
obtained from the patients described in Example 1 about 12 h after
surgery termination, in which analysis was performed with respect
to the need for dialysis (yes or no).
[0039] FIG. 15 is a ROC analysis for urinary L-FABP of samples
obtained from the patients described in Example 1 about 6 h after
surgery termination, in which analysis was performed with respect
to the need for dialysis (yes or no).
[0040] FIG. 16 is a ROC analysis for urinary L-FABP of samples
obtained from the patients described in Example 1 about 12 h after
surgery termination, in which analysis was performed with respect
to the need for dialysis (yes or no).
[0041] FIG. 17 is a ROC analysis for NGAL of samples obtained from
the patients described in Example 1 about 6 h after surgery
termination, in which analysis was performed with respect to the
need for dialysis (yes or no).
[0042] FIG. 18 is a ROC analysis for NGAL of samples obtained from
the patients described in Example 1 about 12 h after surgery
termination, in which analysis was performed with respect to the
need for dialysis (yes or no).
[0043] Corresponding reference characters indicate corresponding
parts throughout the several views. Although the drawings represent
embodiments of the present disclosure, the drawings are not
necessarily to scale and certain features may be exaggerated in
order to better illustrate and explain the present disclosure. The
exemplifications set out herein illustrate an exemplary embodiment
of the disclosure, in one form, and such exemplifications are not
to be construed as limiting the scope of the disclosure in any
manner.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0044] The embodiments disclosed herein are not intended to be
exhaustive or limit the disclosure to the precise form disclosed in
the following detailed description. Rather, the embodiments are
chosen and described so that others skilled in the art may utilize
their teachings.
[0045] Methods of the present disclosure include in vitro methods.
Moreover, they may comprise steps in addition to those explicitly
mentioned above where appropriate. For example, further steps may
relate to sample pre-treatments or evaluation of the results
obtained by the method.
[0046] The amounts of the markers determined in the context of the
present disclosure (i.e. L-FABP or a variant thereof and
optionally, adiponectin or a variant thereof and, optionally,
albumin or a variant thereof, and, optionally, NGAL or a variant
thereof may be determined in a urine sample of the respective
subject. As the case may be, the marker(s) may also be determined
in a blood, plasma or serum sample of the respective subject.
[0047] The term "adverse event related to acute kidney injury AKI"
which may be used interchangeably with the term "acute kidney
injury AM related adverse event" refers to events/complications
which are known to the person skilled in the art to occur in
individuals suffering from AM. The term may also include AKI
itself, need for dialysis and death. In the context of patients
undergoing surgery, acute kidney injury is defined as an increase
in creatinine of at least 0.3 mg/dl within 3 days. Because of the
delay in increase of creatinine this final diagnosis is frequently
made late. Early signs of impaired kidney function are the
reduction in urine volume. Intravasal hypovolemia may mimic acute
kidney injury, in this case application of fluids results in rapid
restoration of diuresis. In case oliguria proceeds to anuria (no or
little urine excretion) and depending on the duration of anuria,
intravasal volume overload occurs which may be associated with the
clinical signs of heart failure specifically in individuals with
pre-existing cardiac dysfunction. In case diuretics and fluid
restriction are ineffective, dialysis is required. There are no
clear recommendations for the initiation of dialysis, however blood
urea concentrations above 100 mg/dl, hyperkalemia or acidosis are
used for a decision to initiate dialysis. Decision making may be
supported by chest X ray, echocardiography, ultrasound and possibly
CT scan if needed.
[0048] The terms "predicting" and "predicting the risk" as used
herein refers to assessing the probability according to which a
subject will suffer from an AKI related adverse event in the
future, e.g., AKI, need for dialysis and/or death. According to
embodiments, the prediction is based on the analysis of a patient
sample prior to the surgical intervention being carried out. As
will be understood by those skilled in the art, such an assessment
is usually not intended to be correct for 100% of the subjects to
be diagnosed. The term, however, requires that a statistically
significant portion of subjects can be diagnosed to suffer from the
said disease (e.g. a cohort in a cohort study). Whether a portion
is statistically significant can be determined without further ado
by the person skilled in the art using various well known statistic
evaluation tools, e.g., determination of confidence intervals,
p-value determination, Student's t-test, Mann-Whitney test etc.
Details are found in Dowdy and Wearden, Statistics for Research,
John Wiley & Sons, New York 1983. According to embodiments of
the instant disclosure, confidence intervals are generally at least
90%, at least 95%, at least 97%, at least 98% or at least 99%.
Also, the p-values are generally 0.1, 0.05, 0.01, 0.005, or
0.0001.
[0049] In general, an adverse event as specified elsewhere in the
application occurs within 3 days, e.g. 1 day, or 2 days, or 3 days,
for example 3 days, as determined by creatinine or GFR.
[0050] "Monitoring" as used herein relates to keeping track of the
pathophysiological state of the respective individual relative to
AM related events, in particular AM itself or need for dialysis,
occurrence and/or progression of the disease or the influence of a
particular treatment on the progression of disease. Diagnosing as
used herein refers to analyzing and monitoring of the relevant
disease. In particular, diagnosing means analyzing the pathology of
specific parts of an organ (e.g. glomerules, tubules and henle
loops of the kidney) and estimating the extent of damage and repair
(e.g. in case of the tubules).
[0051] The term "subject" as used herein relates to animals, such
as mammals, and humans According to embodiments of the present
disclosure, the subject may be apparently healthy, in particular
with respect to kidney function (based on the glomerular filtration
rate (GFR) and/or serum creatinine). A GFR of .gtoreq.about 60
ml/min/1.73 m.sup.2 (i.e. filtration rate per 1.73 m.sup.2 of body
surface) is considered, within in the context of the present
disclosure, to indicate an apparently healthy subject. A serum
creatinine value of .ltoreq.1.3, preferably .ltoreq.1.2 mg/dl is
considered to indicate, within the context of the present
disclosure, an apparently healthy subject. The limit of the serum
creatinine value quoted above in general corresponds to the upper
limit of normal of the test method.
[0052] In the context of the present disclosure, the term
"apparently healthy" is known to the person skilled in the art and
refers to a subject which does not show obvious signs of an
underlying disease. The disease here is related to an impaired
kidney function, in particular in respect to GFR, for example based
on creatinine clearance, in particular its upper limit as specified
above. The subject, thus, may suffer from an impaired kidney
function as defined below, but generally does not show obvious
signs such that the impaired kidney function can be diagnosed or
assessed without detailed diagnostic examination by a physician. In
particular, the diagnosis by a specialist (e.g. a nephrologist)
would be required to diagnose impaired kidney function in the
apparently healthy subject not showing obvious symptoms of the
disease. The term "impaired kidney function" may also be referred
to as "renal disorder", in the context of the present disclosure.
One example for a renal disorder is "renal failure".
[0053] The term "kidney function" as used herein is well known to
the person skilled in the art. It may be used interchangeably with
"renal function" and relates to the capacity of the kidney for
urine production, control and elimination of body water and body
fluids, and homeostasis and filtration of electrolytes and wastes,
and, frequently, erythropoietin synthesis.
[0054] One of the first hints for impaired kidney function (renal
failure) as used in the present application is the presence of
protein in urine (micro- or macroalbuminuria).
[0055] In renal failure, kidney function is not adequate, resulting
in decreased urine production, accumulation of body water and body
fluids disturbances, and accumulation of electrolytes and wastes
which are removed by filtration in healthy kidneys. Moreover,
anemia is frequently observed as a consequence of diminished
erythropoietin synthesis.
[0056] Kidney function is evaluated using values calculated from
formulae based on results of blood and urine tests, in general GFR
(the volume of blood filtered through the kidney per minute) and/or
creatinine clearance.
[0057] GFR is one of the best overall measures of kidney function
expressed in ml/min. Normal GFR in young, healthy adults is about
120 to 130 mL/min/1.73 m.sup.2 and declines with age to about 75
mL/min/1.73 m.sup.2 at age 70. Chronic kidney disease is defined by
a GFR <60 mL/min/1.73 m.sup.2 for >3 mo. Currently considered
the gold standard for GFR measurement is inulin clearance. Inulin
is neither absorbed nor secreted by the renal tubule and therefore
it is the ideal marker for evaluation of kidney function. However,
its measurement is cumbersome and therefore it is mostly used in
research settings.
[0058] Creatinine is produced at a constant rate by muscle
metabolism and is freely filtered by the glomeruli and also is
secreted by the renal tubule. Because creatinine is secreted,
creatinine clearance (CrCl) overestimates GFR by about 10 to 20% in
people with normal kidney function and up to 50% in those with
advanced renal failure.
[0059] Because serum creatinine by itself is inadequate for
evaluation of kidney function, several formulae have been devised
to estimate CrCl using serum creatinine and other factors. The
Cockcroft and Gault formula can be used to estimate CrCl. It uses
age, lean body weight, and serum creatinine level. It is based on
the premise that daily creatinine production is 28 mg/kg/day with a
decrease of 0.2 mg/yr of age.
[0060] Acute kidney injury (AKI), as well as chronic kidney disease
(CKD) are known to the person skilled in the art and generally
recognized as referring to renal failure as determined by GFR or
creatinine clearance.
[0061] CKD is known as a loss of renal function which may worsen
over a period of months or even years. The symptoms of worsening
renal function are unspecific. In CKD glomerular filtration rate is
significantly reduced, resulting in a decreased capability of the
kidneys to excrete waste products by water and solute filtration.
Creatinine levels may be normal in the early stages of CKD. CKD is
not reversible. The severity of CKD is classified in five stages,
with stage 1 being the mildest and usually causing few symptoms.
Stage 5 constitutes a severe illness including poor life expectancy
and is also referred to as end-stage renal disease (ESRD), chronic
kidney failure (CKF) or chronic renal failure (CRF).
[0062] Acute kidney injury (AKI), previously also referred to as
acute renal failure (ARF), is a rapid loss of kidney function which
may originate from various reasons, including shock, low blood
volume, exposure to nephrotoxic compounds and urine congestion
following urethra obstruction. Contrary to CKD, AKI may be
reversible. AM is diagnosed on the basis of creatinine levels,
urinary indices like blood urea nitrogen (BUN), occurrence of
urinary sediment, but also on clinical history. A progressive daily
rise in serum creatinine is considered diagnostic of AKI.
[0063] AKI is characterized by a rapid decline in glomerular
filtration rate over hours to days, in particular of at least 0.3
mg/dl within 3 days.
[0064] AKI is heterogeneous in terms of its underlying causes,
comprising causes occurring in the setting of renal hypoperfusion
(prerenal), causes occurring in predominant compartments of the
kidney (intrinsic or renal), and causes related to urinary tract
obstruction (postrenal).
[0065] Prerenal causes of AM are those that decrease effective
blood flow to the kidney. These include systemic causes, such as
low blood volume, low blood pressure, and heart failure, as well as
local changes to the blood vessels supplying the kidney. The latter
include renal artery stenosis (narrowing of the renal artery) and
renal vein thrombosis (formation of blood clots in the renal vein).
To be more precise, prerenal causes include hypovolemia such as
severe hemorrhage, gastrointestinal fluid loss (e.g. caused by
diarrhea), renal fluid loss (e.g. caused by diuretics),
extravascular sequestration (e.g. caused by burns or severe
hypalbuminemia), or decreased intake (e.g. dehydration). Also
altered hemodynamics may be the cause of prerenal acute renal
failure, this includes low cardiac output, systemic vasodilatation,
renal vasoconstriction, impairment of renal autoregulatory
responses or hepatorenal syndrome.
[0066] Intrinsic or renal causes of AM are those occurring in the
kidney itself and include damage to the glomeruli, renal tubules,
or interstitium which are each caused by glomerulonephritis, acute
tubular necrosis (ATN), and acute interstitial nephritis (AIN),
respectively. To be more precise, intrinsic or renal causes include
renal artery obstruction, diseases of the glomeruli or vasculature,
acute tubular necrosis (which includes infections but also drugs
such as radiocontrast agents, antibiotics and chemotherapy)
interstitial nephritis and intratubular obstruction.
[0067] Postrenal causes of AM comprise urinary tract obstruction
(of the ureter, the urethra and/or the bladder neck). This may be
related to benign prostatic hyperplasia, kidney stones, or an
obstructed urinary catheter.
[0068] Early clinical sign of AKI is oliguria with a decreased
urine output of less than 400 ml/day associated with extracellular
fluid overload. Electrolyte- and acid/base abnormalities can also
be found, this in finally followed by an increase of urea and
creatinine. While postrenal causes of acute renal failure can be
diagnosed by imaging and specifically by ultrasound, prerenal and
intrinsic causes of acute renal failure cannot be diagnosed using
imaging techniques.
[0069] In the context of the present disclosure, the term "tubular
damage" refers to epithelial injury in tubule cells. The tubular
damage may be a consequence of or following an existing cardiac
dysfunction and/or a cardiovascular disease, including coronary
artery disease and heart failure. The present disclosure preferably
refers to chronic tubular damage. It is believed that in tubular
damage tubule cells become ischemic following heart failure, but it
is also believed that tubules have retained their functionality
within the kidney entirely or at least to the greatest or a great
part. This means that renal function is not impaired or only
impaired to a lesser extent, such that CKD or AKI will not be
diagnosed. In tubular damage, tubule cells may become
dysfunctional, in general by necrosis, and die. However, tubular
epithelium regeneration is possible after ischemia and even after
necrosis, referred to as "tubular repair" in the context of the
present disclosure. According to some embodiments of the present
disclosure which refer to chronic tubular injury, some embodiments
likewise refer to chronic tubular repair or tubular repair from
chronic tubular damage.
[0070] In the context of the present disclosure, the term
"glomerular damage" refers to epithelial injury in glomerule cells.
For example, the glomerular damage may be a consequence of or
following an existing cardiac dysfunction and/or a cardiovascular
disease, including coronary artery disease and heart failure. The
present disclosure also refers to chronic glomerular damage. It is
believed that in glomerular damage glomerule cells are ischemic
following heart failure, but it is also believed that glomerules
have retained their functionality within the kidney entirely or at
least to the greatest or a great part. This means that renal
function is not impaired or only impaired to a lesser extent, such
that CKD or AKI will not be diagnosed. In glomerular damage,
glomerule cells may become dysfunctional, in general by necrosis,
and die. However, glomerular epithelium regeneration is possible
after ischemia and even after necrosis, referred to as "glomerular
repair" in the context of the present disclosure. As the present
disclosure refers to chronic glomerular injury, it likewise refers
to chronic glomerular repair or glomerular repair from chronic
glomerular damage.
[0071] Renal failure occurs as CKD progresses (chronic renal
failure). Renal failure also occurs as a consequence of AKI (acute
renal failure). Severe stages of renal failure require dialysis and
may be treated by renal transplantation, as the case may be. Acute
renal failure may be reversible. AKI may also progress to
death.
[0072] In this context, the term "renal disorder" is considered to
relate, for example, to any disease, injury, or dysfunction of the
kidney or affecting the kidney, more particularly affecting the
capacity of the kidney for waste removal and/or ultrafiltration.
Examples for renal disorders include congenital disorders and
acquired disorders.
[0073] The term "liver-type fatty acid binding protein" (L-FABP,
frequently also referred to as FABP1 herein also referred to as
liver fatty acid binding protein) relates to a polypeptide being a
liver type fatty acid binding protein and to a variant thereof.
Liver-type fatty acid binding protein is an intracellular carrier
protein of free fatty acids that is expressed in the proximal
tubules of the human kidney. For a sequence of human L-FABP, see
e.g. Chan et al.: Human liver fatty acid binding protein cDNA and
amino acid sequence, Functional and evolutionary implications, J.
Biol. Chem. 260 (5), 2629-2632 (1985) or GenBank Acc. Number
M10617.1.
[0074] According to embodiments of the instant disclosure, L-FABP
is determined in a urine sample of the respective subject, and may
also be referred to, in the context of the present disclosure, as
"urinary liver-type fatty acid binding protein" or "urinary"
L-FABP.
[0075] The term "L-FABP" encompasses also variants of L-FABP, such
as of human L-FABP. Such variants have at least the same essential
biological and immunological properties as L-FABP, i.e. they bind
free fatty acids and/or cholesterol and/or retinoids, and/or are
involved in intracellular lipid transport. In particular, they
share the same essential biological and immunological properties if
they are detectable by the same specific assays referred to in this
specification, e.g., by ELISA Assays using polyclonal or monoclonal
antibodies specifically recognizing the L-FABP. Moreover, it is to
be understood that a variant as referred to in accordance with the
present disclosure shall have an amino acid sequence which differs
due to at least one amino acid substitution, deletion and/or
addition wherein the amino acid sequence of the variant is still,
in general, at least 50%, 60%, 70%, 80%, 85%, 90%, 92%, 95%, 97%,
98%, or 99% identical with the amino sequence of the human L-FABP.
How to determine the degree of identity is specified elsewhere
herein. Variants may be allelic variants or any other species
specific homologs, paralogs, or orthologs. Moreover, the variants
referred to herein include fragments of L-FABP or the
aforementioned types of variants as long as these fragments have
the essential immunological and biological properties as referred
to above. Such fragments may be, e.g., degradation products of the
L-FABP. Further included are variants which differ due to
posttranslational modifications such as phosphorylation or
myristylation. The term "L-FABP" does not include heart FABP, brain
FABP and intestine FABP.
[0076] Adiponectin is a polypeptide (one of several known
adipocytokines) secreted by the adipocyte. In the art, adiponectin
is frequently also referred to as Acrp30 and apM1. Adiponectin has
recently been shown to have various activities such as
anti-inflammatory, antiatherogenic, preventive for metabolic
syndrome, and insulin sensitizing activities. Adiponectin is
encoded by a single gene, and has 244 amino acids, its molecular
weight is approximately 30 kilodaltons. The mature human
adiponectin protein encompasses amino acids 19 to 244 of
full-length adiponectin. A globular domain is thought to encompass
amino acids 107-244 of full-length adiponectin. The sequence of the
adiponectin polypeptide is well known in the art, and, e.g.,
disclosed in WO/2008/084003.
[0077] Adiponectin is the most abundant adipokine secreted by
adipocytes. Adipocytes are endocrine secretory cells which release
free fatty acids and produce, in addition to adiponectin, several
cytokines such as tumour necrosis factor (TNF) alpha, leptin, and
interleukins.
[0078] It is generally assumed that adiponectin sensitizes the body
to insulin. Decreased adiponectin blood levels are observed in
patients with diabetes and metabolic syndrome and are thought to
play a key role in insulin resistance (see e.g. Han et al. Journal
of the American College of Cardiology, Vol. 49(5)531-8).
[0079] Adiponectin associates itself into larger structures. Three
adiponectin polypeptides bind together and form a homotrimer. These
trimers bind together to form hexamers or dodecamers. Adiponectin
is known to exist in a wide range of multimer complexes in plasma
and combines via its collagen domain to create 3 major oligomeric
forms: a low-molecular weight (LMW) trimer, a middle-molecular
weight (MMW) hexamer, and high-molecular weight (HMW) 12- to 18-mer
adiponectin (Kadowaki et al. (2006) Adiponectin and adiponectin
receptors in insulin resistance, diabetes, and the metabolic
syndrome. J Clin Invest. 116(7): 1784-1792; Rexford S. Ahima,
Obesity 2006; 14:242 S-249S). Adiponectin has been reported to have
several physiological actions, such as protective activities
against atherosclerosis, improvement of insulin sensitivity, and
prevention of hepatic fibrosis.
[0080] Adiponectin as used herein, preferably, relates to total
adiponectin, which encompasses low molecular weight adiponectin,
mid molecular weight adiponectin and high molecular weight
adiponectin. The terms high molecular weight adiponectin, low and
mid molecular weight adiponectin and total adiponectin are
understood by the skilled person. According to the instant
disclosure, adiponectin may be human adiponectin. Methods for the
determination of adiponectin are, e.g., disclosed in US
2007/0042424 A1 as well as in WO/2008/084003. The amount of
adiponectin is determined in a urine sample.
[0081] The adiponectin referred to in accordance with the present
disclosure further encompasses allelic and other variants of said
specific sequence for human adiponectin discussed above. For
example, embodiments of the instant disclosure include variant
polypeptides which are on the amino acid level, at least 50%, 60%,
70%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical, to human
adiponectin. The degree of identity between two amino acid
sequences can be determined by algorithms well known in the art.
The degree of identity may be determined by comparing two optimally
aligned sequences over a comparison window, where the fragment of
amino acid sequence in the comparison window may comprise additions
or deletions (e.g., gaps or overhangs) as compared to the reference
sequence (which does not comprise additions or deletions) for
optimal alignment. The percentage is calculated by determining the
number of positions at which the identical amino acid residue
occurs in both sequences to yield the number of matched positions,
dividing the number of matched positions by the total number of
positions in the window of comparison and multiplying the result by
100 to yield the percentage of sequence identity. Optimal alignment
of sequences for comparison may be conducted by the local homology
algorithm of Smith and Waterman Add. APL. Math. 2:482 (1981), by
the homology alignment algorithm of Needleman and Wunsch J. Mol.
Biol. 48:443 (1970), by the search for similarity method of Pearson
and Lipman Proc. Natl. Acad. Sci. (USA) 85: 2444 (1988), by
computerized implementations of these algorithms (GAP, BESTFIT,
BLAST, PASTA, and TFASTA in the Wisconsin Genetics Software
Package, Genetics Computer Group (GCG), 575 Science Dr., Madison,
Wis.), or by visual inspection. Given that two sequences have been
identified for comparison, GAP and BESTFIT may be employed to
determine their optimal alignment and, thus, the degree of
identity. For example, the default values of 5.00 for gap weight
and 0.30 for gap weight length are used. Variants referred to above
may be allelic variants or any other species specific homologs,
paralogs, or orthologs. Substantially similar and also envisaged
are proteolytic degradation products which are still recognized by
the diagnostic means or by ligands directed against the respective
full-length peptide. Also encompassed are variant polypeptides
having amino acid deletions, substitutions, and/or additions
compared to the amino acid sequence of human adiponectin as long as
the said polypeptides have adiponectin properties, in particular
insulin sensitizing properties.
[0082] The term "albumin" refers to a to a globular protein mainly
found in blood. They reach a concentration of 3.5 g/dl to 4.5 g/dl
and represent approximately 60% of the plasma proteins. Albumin
includes human albumin Mature human albumin comprises 585 amino
acids and has a molecular weight of approximately 66,470 Da. The
preproprotein has, generally, an amino acid sequence as defined by
the NCBI reference sequence NP_000468.1. Albumin plays an important
role in maintaining the colloid osmotic pressure of the blood,
transports free fatty acids, thyroid hormones, unconjugated
bilirubin and many drugs. Moreover, it buffers the pH of the
blood.
[0083] The term "albumin" encompasses also variants of albumin, for
example, of human albumin Such variants have at least the same
essential biological and immunological properties as albumin, i.e.
they maintain the colloid osmotic pressure of the blood, and/or
transport free fatty acids, and/or transport thyroid hormones,
and/or transport unconjugated bilirubin, and/or buffers the pH of
the blood. In particular, they share the same essential biological
and immunological properties if they are detectable by the same
specific assays referred to in this specification, e.g., by ELISA
Assays using polyclonal or monoclonal antibodies specifically
recognizing the albumin. Moreover, it is to be understood that a
variant as referred to in accordance with the present disclosure
shall have an amino acid sequence which differs due to at least one
amino acid substitution, deletion and/or addition wherein the amino
acid sequence of the variant is still, in general, at least 50%,
60%, 70%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical with
the amino sequence of the human albumin. How to determine the
degree of identity is specified elsewhere herein. Variants may be
allelic variants or any other species specific homologs, paralogs,
or orthologs. Moreover, the variants referred to herein include
fragments of albumin or the aforementioned types of variants as
long as these fragments have the essential immunological and
biological properties as referred to above. Such fragments may be,
e.g., degradation products of the albumin Further included are
variants which differ due to posttranslational modifications such
as phosphorylation or myristylation.
[0084] The term "neutrophil gelatinase-associated Protein" (NGAL)
refers to a protein having a molecular mass of 25 kDa in its
glycosylated form and approximately 21 kDa in its deglycosylated
form. It comprises 178 amino acids and has an amino acid sequence
as described by Kjeldsen et al. in 1993 (Journal of Biological
Chemistry, 268: 10425-10432). It is sometimes found as a
heterodimer with human neutrophil gelatinase (matrix
metalloproteinase 9). Some evidence indicates that binding of NGAL
prevents the degradation of matrix metalloproteinase 9 (Yan et al.,
2001, Journal of Biological Chemistry, 276: 37258-37265). The
expression of NGAL is known to be up-regulated in patients with
acute renal dysfunction, especially after renal ischemic injury
(Wagener et al., 2006, Anesthesiology, 105: 485-491.
[0085] The term "NGAL" encompasses also variants of NGAL, such as,
of human NGAL. Such variants have at least the same essential
biological and immunological properties as NGAL, i.e. they prevent
the degradation of matrix metalloproteinase 9. In particular, they
share the same essential biological and immunological properties if
they are detectable by the same specific assays referred to in this
specification, e.g., by ELISA Assays using polyclonal or monoclonal
antibodies specifically recognizing the NGAL. Moreover, it is to be
understood that a variant as referred to in accordance with the
present disclosure shall have an amino acid sequence which differs
due to at least one amino acid substitution, deletion and/or
addition wherein the amino acid sequence of the variant is still,
in general, at least 50%, 60%, 70%, 80%, 85%, 90%, 92%, 95%, 97%,
98%, or 99% identical with the amino sequence of the human NGAL.
How to determine the degree of identity is specified elsewhere
herein. Variants may be allelic variants or any other species
specific homologs, paralogs, or orthologs. Moreover, the variants
referred to herein include fragments of NGAL or the aforementioned
types of variants as long as these fragments have the essential
immunological and biological properties as referred to above. Such
fragments may be, e.g., degradation products of the NGAL. Further
included are variants which differ due to posttranslational
modifications such as phosphorylation or myristylation.
[0086] Determining the amount of adiponectin or a variant thereof,
L-FABP or a variant thereof, albumin or a variant thereof, NGAL or
a variant thereof or any other peptide or polypeptide referred to
in this specification relates to measuring the amount or
concentration, either semi-quantitatively or quantitatively.
Measuring can be done directly or indirectly. Direct measuring
relates to measuring the amount or concentration of the peptide or
polypeptide based on a signal which is obtained from the peptide or
polypeptide itself and the intensity of which directly correlates
with the number of molecules of the peptide present in the sample.
Such a signal--sometimes referred to herein as intensity
signal--may be obtained, e.g., by measuring an intensity value of a
specific physical or chemical property of the peptide or
polypeptide. Indirect measuring includes measuring of a signal
obtained from a secondary component (i.e. a component not being the
peptide or polypeptide itself) or a biological read out system,
e.g., measurable cellular responses, ligands, labels, or enzymatic
reaction products.
[0087] In accordance with the present disclosure, determining the
amount of a peptide or polypeptide can be achieved by all known
means for determining the amount of a peptide in a sample. Said
means comprise immunoassay devices and methods which may utilize
labelled molecules in various sandwich, competition, or other assay
formats. Said assays will develop a signal which is indicative for
the presence or absence of the peptide or polypeptide. Moreover,
the signal strength can be correlated directly or indirectly (e.g.
reverse-proportional) to the amount of polypeptide present in a
sample. Further suitable methods comprise measuring a physical or
chemical property specific for the peptide or polypeptide such as
its precise molecular mass or NMR spectrum. Said methods comprise,
for example, biosensors, optical devices coupled to immunoassays,
biochips, analytical devices such as mass-spectrometers,
NMR-analyzers, or chromatography devices. Further, methods include
micro-plate ELISA-based methods, fully-automated or robotic
immunoassays (available for example on ELECSYS.TM. analyzers), CBA
(an enzymatic Cobalt Binding Assay, available for example on
ROCHE-HITACHI.TM.analyzers), and latex agglutination assays
(available for example on ROCHE-HITACHI.TM. analyzers).
[0088] According to the instant disclosure, determining the amount
of a peptide or polypeptide may comprise the steps of (a)
contacting a cell capable of eliciting a cellular response the
intensity of which is indicative of the amount of the peptide or
polypeptide with the said peptide or polypeptide for an adequate
period of time, (b) measuring the cellular response. For measuring
cellular responses, the sample or processed sample may be added to
a cell culture and an internal or external cellular response is
measured. The cellular response may include the measurable
expression of a reporter gene or the secretion of a substance, e.g.
a peptide, polypeptide, or a small molecule. The expression or
substance shall generate an intensity signal which correlates to
the amount of the peptide or polypeptide.
[0089] Also, determining the amount of a peptide or polypeptide
comprises the step of measuring a specific intensity signal
obtainable from the peptide or polypeptide in the sample. As
described above, such a signal may be the signal intensity observed
at an m/z variable specific for the peptide or polypeptide observed
in mass spectra or a NMR spectrum specific for the peptide or
polypeptide.
[0090] Determining the amount of a peptide or polypeptide may
comprise the steps of (a) contacting the peptide with a specific
ligand, (optionally) removing non-bound ligand, (b) measuring the
amount of bound ligand. The bound ligand will generate an intensity
signal. Binding according to the present disclosure includes both
covalent and non-covalent binding. A ligand according to the
present disclosure can be any compound, e.g., a peptide,
polypeptide, nucleic acid, or small molecule, binding to the
peptide or polypeptide described herein. Exemplary ligands include
antibodies, nucleic acids, peptides or polypeptides such as
receptors or binding partners for the peptide or polypeptide and
fragments thereof comprising the binding domains for the peptides,
and aptamers, e.g. nucleic acid or peptide aptamers. Methods to
prepare such ligands are well-known in the art. For example,
identification and production of suitable antibodies or aptamers is
also offered by commercial suppliers. The person skilled in the art
is familiar with methods to develop derivatives of such ligands
with higher affinity or specificity. For example, random mutations
can be introduced into the nucleic acids, peptides or polypeptides.
These derivatives can then be tested for binding according to
screening procedures known in the art, e.g. phage display.
Antibodies as referred to herein include both polyclonal and
monoclonal antibodies, as well as fragments thereof, such as Fv,
Fab and F(ab).sub.2 fragments that are capable of binding antigen
or hapten. The present disclosure also includes single chain
antibodies and humanized hybrid antibodies wherein amino acid
sequences of a non-human donor antibody exhibiting a desired
antigen-specificity are combined with sequences of a human acceptor
antibody. The donor sequences will usually include at least the
antigen-binding amino acid residues of the donor but may comprise
other structurally and/or functionally relevant amino acid residues
of the donor antibody as well. Such hybrids can be prepared by
several methods well known in the art. Preferably, the ligand or
agent binds specifically to the peptide or polypeptide. Specific
binding according to the present disclosure means that the ligand
or agent should not bind substantially to ("cross-react" with)
another peptide, polypeptide or substance present in the sample to
be analyzed. The specifically bound peptide or polypeptide should
be bound with at least 3 times higher, and in some embodiments will
be bound with at least 10 times higher and even at least 50 times
higher affinity than any other relevant peptide or polypeptide.
Non-specific binding may be tolerable, if it can still be
distinguished and measured unequivocally, e.g. according to its
size on a Western Blot, or by its relatively higher abundance in
the sample. Binding of the ligand can be measured by any method
known in the art. Said method will be semi-quantitative or
quantitative. Suitable methods are described in the following.
[0091] According to the instant disclosure, the term "antibody"
refers to an antibody binding to a peptide selected from the group
consisting of L-FABP or a variant thereof, adiponectin or a variant
thereof, albumin or a variant thereof and NGAL or a variant
thereof.
[0092] First, binding of a ligand may be measured directly, e.g. by
NMR or surface plasmon resonance.
[0093] Second, if the ligand also serves as a substrate of an
enzymatic activity of the peptide or polypeptide of interest, an
enzymatic reaction product may be measured (e.g. the amount of a
protease can be measured by measuring the amount of cleaved
substrate, e.g. on a Western Blot). Alternatively, the ligand may
exhibit enzymatic properties itself and the "ligand/peptide or
polypeptide" complex or the ligand which was bound by the peptide
or polypeptide, respectively, may be contacted with a suitable
substrate allowing detection by the generation of an intensity
signal. For measurement of enzymatic reaction products, the amount
of substrate may be saturating. The substrate may also be labeled
with a detectable label prior to the reaction. In some embodiments,
the sample is contacted with the substrate for an adequate period
of time. An adequate period of time refers to the time necessary
for a detectable, (and in some cases measurable), amount of product
to be produced. Instead of measuring the amount of product, the
time necessary for appearance of a given (e.g. detectable) amount
of product can be measured.
[0094] Third, the ligand may be coupled covalently or
non-covalently to a label allowing detection and measurement of the
ligand. Labelling may be done by direct or indirect methods. Direct
labeling involves coupling of the label directly (covalently or
non-covalently) to the ligand. Indirect labeling involves binding
(covalently or non-covalently) of a secondary ligand to the first
ligand. The secondary ligand should specifically bind to the first
ligand. Said secondary ligand may be coupled with a suitable label
and/or be the target (receptor) of tertiary ligand binding to the
secondary ligand. The use of secondary, tertiary or even higher
order ligands is often used to increase the signal. Suitable
secondary and higher order ligands may include antibodies,
secondary antibodies, and the well-known streptavidin-biotin system
(Vector Laboratories, Inc.). The ligand or substrate may also be
"tagged" with one or more tags as known in the art. Such tags may
then be targets for higher order ligands. Suitable tags include
biotin, digoxygenin, His-Tag, Glutathion-S-Transferase, FLAG, GFP,
myc-tag, influenza A virus haemagglutinin (HA), maltose binding
protein, and the like. In the case of a peptide or polypeptide, the
tag may be at the N-terminus and/or C-terminus. Suitable labels are
any labels detectable by an appropriate detection method. Typical
labels include gold particles, latex beads, acridan ester, luminol,
ruthenium, enzymatically active labels, radioactive labels,
magnetic labels ("e.g. magnetic beads", including paramagnetic and
superparamagnetic labels), and fluorescent labels. Enzymatically
active labels include e.g. horseradish peroxidase, alkaline
phosphatase, beta-Galactosidase, Luciferase, and derivatives
thereof. Suitable substrates for detection include
di-amino-benzidine (DAB), 3,3'-5,5'-tetramethylbenzidine, NBT-BCIP
(4-nitro blue tetrazolium chloride and
5-bromo-4-chloro-3-indolyl-phosphate, available as ready-made stock
solution from Roche Diagnostics), CDP-STAR.TM. (Amersham
Biosciences), ECF.TM. (Amersham Biosciences). A suitable
enzyme-substrate combination may result in a colored reaction
product, fluorescence or chemoluminescence, which can be measured
according to methods known in the art (e.g. using a light-sensitive
film or a suitable camera system). As for measuring the enzymatic
reaction, the criteria given above apply analogously. Typical
fluorescent labels include fluorescent proteins (such as GFP and
its derivatives), Cy3, Cy5, Texas Red, Fluorescein, and the Alexa
dyes (e.g. Alexa 568). Further fluorescent labels are available
e.g. from Molecular Probes (Oregon). Also the use of quantum dots
as fluorescent labels is contemplated. Typical radioactive labels
include .sup.35S, .sup.125I, .sup.32P, .sup.33P and the like. A
radioactive label can be detected by any method known and
appropriate, e.g. a light-sensitive film or a phosphor imager.
Suitable measurement methods according the present disclosure also
include precipitation (particularly immunoprecipitation),
electrochemiluminescence (electro-generated chemiluminescence), RIA
(radioimmunoassay), ELISA (enzyme-linked immunosorbent assay),
sandwich enzyme immune tests, electrochemiluminescence sandwich
immunoassays (ECLIA), dissociation-enhanced lanthanide fluoro
immuno assay (DELFIA), scintillation proximity assay (SPA),
turbidimetry, nephelometry, latex-enhanced turbidimetry or
nephelometry, or solid phase immune tests. Further methods known in
the art (such as gel electrophoresis, 2D gel electrophoresis, SDS
polyacrylamide gel electrophoresis (SDS-PAGE), Western Blotting,
and mass spectrometry), can be used alone or in combination with
labeling or other detection methods as described above.
[0095] The amount of a peptide or polypeptide may be determined as
follows: (a) contacting a solid support comprising a ligand for the
peptide or polypeptide as specified above with a sample comprising
the peptide or polypeptide and (b) measuring the amount peptide or
polypeptide which is bound to the support. The ligand, which may be
chosen from the group consisting of nucleic acids, peptides,
polypeptides, antibodies and aptamers, may be present on a solid
support in immobilized form. Materials for manufacturing solid
supports are well known in the art and include, inter alia,
commercially available column materials, polystyrene beads, latex
beads, magnetic beads, colloid metal particles, glass and/or
silicon chips and surfaces, nitrocellulose strips, membranes,
sheets, duracytes, wells and walls of reaction trays, plastic tubes
etc. The ligand or agent may be bound to many different carriers.
Examples of well-known carriers include glass, polystyrene,
polyvinyl chloride, polypropylene, polyethylene, polycarbonate,
dextran, nylon, amyloses, natural and modified celluloses,
polyacrylamides, agaroses, and magnetite. The nature of the carrier
can be either soluble or insoluble for the purposes of the
disclosure. Suitable methods for fixing/immobilizing said ligand
are well known and include, but are not limited to ionic,
hydrophobic, covalent interactions and the like. It is also
contemplated to use "suspension arrays" as arrays according to the
present disclosure (Nolan 2002, Trends Biotechnol. 20(1):9-12). In
such suspension arrays, the carrier, e.g. a microbead or
microsphere, is present in suspension. The array consists of
different microbeads or microspheres, possibly labeled, carrying
different ligands. Methods of producing such arrays, for example
based on solid-phase chemistry and photo-labile protective groups,
are generally known (U.S. Pat. No. 5,744,305).
[0096] The term "amount" as used herein encompasses the absolute
amount of a polypeptide or peptide, the relative amount or
concentration of the said polypeptide or peptide as well as any
value or parameter which correlates thereto or can be derived there
from. Such values or parameters comprise intensity signal values
from all specific physical or chemical properties obtained from the
said peptides by direct measurements, e.g., intensity values in
mass spectra or NMR spectra. Moreover, encompassed are all values
or parameters which are obtained by indirect measurements specified
elsewhere in this description, e.g., response levels determined
from biological read out systems in response to the peptides or
intensity signals obtained from specifically bound ligands. It is
to be understood that values correlating to the aforementioned
amounts or parameters can also be obtained by all standard
mathematical operations.
[0097] The term "comparing" as used herein encompasses comparing
the amount of the peptide or polypeptide comprised by the sample to
be analyzed with an amount of a suitable reference source specified
elsewhere in this description. It is to be understood that
comparing as used herein refers to a comparison of corresponding
parameters or values, e.g., an absolute amount is compared to an
absolute reference amount while a concentration is compared to a
reference concentration or an intensity signal obtained from a test
sample is compared to the same type of intensity signal of a
reference sample or a ratio of amounts is compared to a reference
ratio of amounts. The comparison referred to in step (c) of the
method of the present disclosure may be carried out manually or
computer assisted. For a computer assisted comparison, the value of
the determined amount may be compared to values corresponding to
suitable references which are stored in a database by a computer
program. The computer program may further evaluate the result of
the comparison, i.e. automatically provide the desired assessment
in a suitable output format.
[0098] Based on the comparison of the amount(s) determined in step
a) to suitable reference amount(s), it is possible to predict the
risk of an individual to suffer from an adverse event related to
AKI. It is to be understood that amounts of L-FABP or a variant
thereof and, as the case may be, adiponectin or a variant thereof
and/or NGAL or a variant thereof and/or albumin or a variant
thereof as determined in step (a) of the methods of the presents
disclosure are compared in step (b) to reference amounts for of
L-FABP or a variant thereof and, as the case may be, adiponectin or
a variant thereof and/or NGAL or a variant thereof and/or albumin
or a variant thereof as specified elsewhere in this
application.
[0099] The term "reference amounts" as used herein in this
embodiment of the disclosure refers to amounts of the polypeptides
which allow diagnosing if an individual does not have an increased
risk of suffering from an AM related adverse event after surgery
(in general, this subject is a physiologically healthy subject), or
a subject which is not healthy and has an increased risk of
suffering from an AKI related adverse event after surgery.
[0100] Therefore, the reference amounts will in general be derived
from subjects known to be a physiologically healthy, or subjects
known to suffer from renal disorder (which may be apparently
healthy), or subjects which will be undergoing or having undergone
CABG, or subjects known to suffer from renal disorder and which
will be undergoing or having undergone CABG.
[0101] Accordingly, the term "reference amount" as used herein
either refers to an amount which allows to predict the risk of
suffering from an adverse event related to AKI in a subject, in
particular AKI itself, need for hemodialysis and/or death, and
wherein the amounts of the respective marker(s) can be determined
prior to the surgical intervention, such as the coronary artery
disease related intervention (e.g., a CABG intervention), which the
subject is to undergo. The comparison with reference amounts
permits to predict or estimate the risk of a subject/individual of
suffering from an adverse event related to AM in a subject, in
particular AKI itself, need for hemodialysis and/or death. The
individual's need for a surgical intervention may previously have
been established prior to determining the markers of the present
disclosure.
[0102] Reference amounts for L-FABP or a variant thereof and, as
the case may be, adiponectin or a variant thereof and/or NGAL or a
variant thereof and/or albumin or a variant thereof may be derived
from subjects as defined above in the present disclosure which will
be undergoing or having undergone a surgical intervention, such as
a CABG, and where the subject's outcome was determined, namely
occurrence of AKI, need for hemodialysis and/or death. The amounts
of the respective peptide serving for establishing the reference
amounts can be determined prior to the surgical intervention. In a
further embodiment of the present disclosure, the marker(s) are
determined at one or various points in time after the surgical
intervention, e g immediately when terminating intervention, or
after 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 or 24 h later.
[0103] In embodiments of the present disclosure, the amount/amounts
of the respective markers used therein (L-FABP or a variant thereof
and, as the case may be, adiponectin or a variant thereof and/or
NGAL or a variant thereof and/or albumin or a variant thereof) may
be determined by methods known to the person skilled in the
art.
[0104] In general, for determining the respective
amount(s)/amount(s) or amount ratios allowing to establish the
desired diagnosis in accordance with the respective embodiment of
the present disclosure, ("threshold", "reference amount"), the
amount(s)/amount(s) or amount ratios of the respective peptide or
peptides are determined in appropriate patient groups. According to
the diagnosis to be established, the patient group may, for
example, comprise only healthy individuals, or may comprise healthy
individuals and individuals suffering from the pathophysiological
(state which is to be determined, or may comprise only individuals
suffering from the pathophysiological state which is to be
determined, or may comprise individuals suffering from the various
pathophysiological states to be distinguished, by the respective
marker(s) using validated analytical methods. The results which are
obtained are collected and analyzed by statistical methods known to
the person skilled in the art. The obtained threshold values are
then established in accordance with the desired probability of
suffering from the disease and linked to the particular threshold
value. For example, it may be useful to choose the median value,
the 60.sup.th, 70.sup.th, 80.sup.th, 90.sup.th, 95.sup.th or even
the 99.sup.th percentile of the healthy and/or non-healthy patient
collective, in order to establish the threshold value(s), reference
value(s) or amount ratios.
[0105] A reference value of a diagnostic marker can be established,
and the amount of the marker in a patient sample can simply be
compared to the reference value. The sensitivity and specificity of
a diagnostic and/or prognostic test depends on more than just the
analytical "quality" of the test-they also depend on the definition
of what constitutes an abnormal result. In practice, Receiver
Operating Characteristic curves, or "ROC" curves, are typically
calculated by plotting the value of a variable versus its relative
frequency in "normal" and "disease" populations. For any particular
marker of the disclosure, a distribution of marker amounts for
subjects with and without a disease will likely overlap. Under such
conditions, a test does not absolutely distinguish normal from
disease with 100% accuracy, and the area of overlap indicates where
the test cannot distinguish normal from disease. A threshold is
selected, above which (or below which, depending on how a marker
changes with the disease) the test is considered to be abnormal and
below which the test is considered to be normal. The area under the
ROC curve is a measure of the probability that the perceived
measurement will allow correct identification of a condition. ROC
curves can be used even when test results don't necessarily give an
accurate number. As long as one can rank results, one can create an
ROC curve. For example, results of a test on "disease" samples
might be ranked according to degree (say 1=low, 2=normal, and
3=high). This ranking can be correlated to results in the "normal"
population, and a ROC curve created. These methods are well known
in the art. See, e.g., Hanley et al, Radiology 143: 29-36
(1982).
[0106] In certain embodiments, markers and/or marker panels are
selected to exhibit at least about 70% sensitivity, in some cases
at least about 80% sensitivity, or even at least about 85%
sensitivity, at least about 90% sensitivity, and in some cases at
least about 95% sensitivity, combined with at least about 70%
specificity, at least about 80% specificity, at least about 85%
specificity, at least about 90% specificity, and at least about 95%
specificity. In exemplary embodiments, both the sensitivity and
specificity are at least about 75% and in some cases at least about
80%, at least about 85%, at least about 90%, and even at least
about 95%. The term "about" in this context refers to +/-5% of a
given measurement.
[0107] In other embodiments, a positive likelihood ratio, negative
likelihood ratio, odds ratio, or hazard ratio is used as a measure
of a test's ability to predict risk or diagnose a disease. In the
case of a positive likelihood ratio, a value of 1 indicates that a
positive result is equally likely among subjects in both the
"diseased" and "control" groups; a value greater than 1 indicates
that a positive result is more likely in the diseased group; and a
value less than 1 indicates that a positive result is more likely
in the control group. In the case of a negative likelihood ratio, a
value of 1 indicates that a negative result is equally likely among
subjects in both the "diseased" and "control" groups; a value
greater than 1 indicates that a negative result is more likely in
the test group; and a value less than 1 indicates that a negative
result is more likely in the control group. In certain embodiments,
markers and/or marker panels may be selected to exhibit a positive
or negative likelihood ratio of at least about 1.5 or more or about
0.67 or less, and in some embodiments at least about 2 or more or
about 0.5 or less, and in other embodiments at least about 5 or
more or about 0.2 or less, at least about 10 or more or about 0.1
or less, and even at least about 20 or more or about 0.05 or less.
The term "about" in this context refers to +/-5% of a given
measurement.
[0108] In the case of an odds ratio, a value of 1 indicates that a
positive result is equally likely among subjects in both the
"diseased" and "control" groups; a value greater than 1 indicates
that a positive result is more likely in the diseased group; and a
value less than 1 indicates that a positive result is more likely
in the control group. In certain exemplary embodiments, markers
and/or marker panels may be selected to exhibit an odds ratio of at
least about 2 or more or about 0.5 or less, and in some embodiments
at least about 3 or more or about 0.33 or less, at least about 4 or
more or about 0.25 or less, at least about 5 or more or about 0.2
or less, and even in some embodiments at least about 10 or more or
about 0.1 or less. The term "about" in this context refers to +/-5%
of a given measurement.
[0109] In the case of a hazard ratio, a value of 1 indicates that
the relative risk of an endpoint (e.g., death) is equal in both the
"diseased" and "control" groups; a value greater than 1 indicates
that the risk is greater in the diseased group; and a value less
than 1 indicates that the risk is greater in the control group. In
certain exemplary embodiments, markers and/or marker panels are
selected to exhibit a hazard ratio of at least about 1.1 or more or
about 0.91 or less, and in some embodiments at least about 1.25 or
more or about 0.8 or less, at least about 1.5 or more or about 0.67
or less, at least about 2 or more or about 0.5 or less, and in some
embodiments at least about 2.5 or more or about 0.4 or less. The
term "about" in this context refers to +/-5% of a given
measurement.
[0110] While exemplary panels are described herein, one or more
markers may be replaced, added, or subtracted from these exemplary
panels while still providing clinically useful results. Panels may
comprise both specific markers of a disease (e.g., markers that are
increased or decreased in bacterial infection, but not in other
disease states) and/or non-specific markers (e.g., markers that are
increased or decreased due to inflammation, regardless of the
cause; markers that are increased or decreased due to changes in
hemostasis, regardless of the cause, etc.). While certain markers
may not individually be definitive in the methods described herein,
a particular "fingerprint" pattern of changes may, in effect, act
as a specific indicator of disease state. As discussed above, that
pattern of changes may be obtained from a single sample, or may
optionally consider temporal changes in one or more members of the
panel (or temporal changes in a panel response value).
[0111] In order to test if a chosen reference value yields a
sufficiently safe diagnosis of patients suffering from the disease
of interest, one may for example determine the efficiency (E) of
the methods of the disclosure for a given reference value using the
following formula:
E=(TP/TO).times.100,
wherein TP=true positives and TO=total number of tests=TP+FP+FN+TN,
wherein FP=false positives; FN=false negatives and TN=true
negatives. E has the following range of values: 0<E<100).
According to some embodiments, a tested reference value yields a
sufficiently safe diagnosis provided the value of E is at least
about 50, at least about 60, at least about 70, at least about 80,
at least about 90, at least about 95, and in some cases at least
about 98.
[0112] The diagnosis if individuals are healthy or suffer from a
certain pathophysiological state is made by established methods
known to the person skilled in the art. The methods differ in
respect to the individual pathophysiological state.
[0113] The algorithms to establish the desired diagnosis are laid
out in the present application, in the passages referring to the
respective embodiment, to which reference is made.
[0114] Accordingly, the present disclosure also comprises a method
of determining the threshold amount indicative for a physiological
and/or a pathological state and/or a certain pathological state,
comprising the steps of determining in appropriate patient groups
the amounts of the appropriate marker(s), collecting the data and
analyzing the data by statistical methods and establishing the
threshold values.
[0115] The term "about" as used herein refers to +/-20%, preferably
+/-10%, preferably, +/-5% of a given measurement or value.
[0116] This surprising findings presented herein are of clinical
importance as it allows to take an appropriate decision before the
intervention and the occurrence of AM. In this respect, it has to
be taken into consideration that after the occurrence of AKI
therapeutical option (options for treatment) are clearly more
limited than in cases where the risk of suffering from AKI is
recognized and its occurrence can be treated prophylactically. Such
decisions include reconsideration of the indication for surgery in
terms of improving risk benefit assessment, discontinuation of
drugs known to precipitate AKI including ACE inhibitors,
angiotensin receptor blockers and NSIADs and potentially
antibiotics and other drugs known to precipitate AKI. Furthermore
during surgery appropriate and intense balancing of fluid as well
as blood pressure is required. Thus the method of the present
disclosures targets prophylaxis of AM thus provides improved
clinical decision making.
[0117] Accordingly, the methods of the present disclosure lend
themselves in particular for adults. In exemplary embodiments, the
method of risk prediction, the method of recommending or deciding
on a suitable therapy and the method of monitoring the therapy are
applied to adults; in further embodiments, these cited methods are
not applied to children.
[0118] Surprisingly it was found that the amount of L-FABP or a
variant thereof is a good predictor for future events related to
AKI when determined before intervention is carried out. It was also
found that the amount of adiponectin when determined before
intervention may add complementary information to that provided by
L-FABP or a variant thereof. Further information may be added by
determining the amount of albumin or a variant thereof and/or NGAL
or a variant thereof before intervention.
[0119] Major surgery interventions, in particular major
cardiovascular surgery interventions, are associated with
significant mortality and morbidity, including the development of
acute kidney injury (AKI). AKI may resolve without dialysis or, if
prolonged, may require dialysis, or may even be associated with
future chronic renal disorder. Currently, risk of development of AM
or even need for dialysis cannot be predicted in patients with
normal kidney function (as assessed by creatinine levels within the
normal range of the test or a GFR above 60 ml/min) However, thanks
to the present disclosure, L-FABP can be used to identify patients
at risk even before surgery. Only a risk assessment before surgery,
for example in the course of a risk/benefit analysis, allows to
reconsider indication for surgery, discontinuation of drugs
precipitating AKI (although they may be indicated because of the
underlying disease(s)) and to take appropriate measure during
surgery (maintenance of blood pressure, avoidance of temporary
hypovolemia, and further measures known to the person skilled in
the art).
[0120] L-FABP is a urinary biomarker which is expressed in the
proximal tubule epithelial cells in the postischemic kidney. As
adiponectin appears to be an indicator of "glomerular health",
combined determination of these markers disclose relevant
information of pathogenic kidney processes.
[0121] In further embodiments of the present disclosure, albumin
and/or NGAL are determined further to L-FABP and adiponectin. NGAL
is a marker of tubular damage, albumin is a marker of glomerular
damage, permitting gathering supplementary information.
[0122] Advantageously, as described herein it has been found that
the amount of L-FABP or a variant thereof as a biomarker, in
particular the amount of L-FABP or a variant thereof present in
sample, for example a urine-sample of a subject, can predict the
risk of an individual of suffering from an adverse event related to
acute kidney injury AKI following a surgical intervention in a
reliable and efficient manner, as reflected by the high specificity
and sensitivity of the method of the present disclosure as
evidenced in the examples.
[0123] It has also been found that the amount of adiponectin or a
variant thereof as a biomarker, in particular the amount of
adiponectin or a variant thereof present in a urine-sample of a
subject predict the risk of an individual of suffering from an
adverse event related to acute kidney injury AKI following a
surgical intervention in a reliable and efficient manner L-FABP or
a variant thereof and adiponectin or a variant thereof give
complementary information in respect to the risk of an individual
to suffer from an adverse event related to acute kidney injury.
[0124] AKI may progress to a need for dialysis and even to death
(which both are considered, in the context of the present
disclosure, to be adverse events related to acute kidney injury).
In an exemplary embodiment of the present disclosure, the amounts
of L-FABP or a variant thereof and/or adiponectin or a variant
thereof, for example a combination of the two, may be used to
predict the risk of an individual to develop a need for dialysis as
a consequence of or following a surgical intervention.
[0125] A "need for dialysis" occurs in individuals suffering from
renal failure, in the context of the present disclosure acute renal
failure (AM), wherein the extent or degree of renal failure (as
determined by GFR and/or creatinine clearance) impairs renal
function such that the urine production and removal of electrolytes
and wastes (which are removed by filtration in healthy kidneys
body's) does not comply with body's needs and may seriously affect
the individual's health, in particular cause non-reversible health
impairment. An example is anemia which is frequently observed as a
consequence of diminished erythropoietin synthesis.
[0126] The term "surgical intervention" in the context of the
present disclosure refers to any kind of invasive intervention on
the body of an animal, for example a mammal such as a human, by a
surgical method (including major surgery). The surgical
intervention may be indicated because of a vascular disease, a
trauma, a bleeding disorder, a tumor, e.g. a benign or malignant
tumor, an infection or for other reasons. Surgery may be of short
or prolonged duration may be associated with pre-existing fluid or
blood loss or during the surgical procedure itself. The surgical
procedure may be carried out with or without localized or general
anaesthesia. The term may also include minimal invasive surgery,
even though the complications which are cited in the present
application for occurring after surgery are less frequently
observed after minimal invasive surgery.
[0127] The term "major surgery" as used in the context of the
present disclosure refers to any surgery that requires anesthesia
and/or respiratory assistance.
[0128] The term "surgical intervention" also includes e.g.
interventions on the extremities (legs, arms), and the head. The
term includes interventions on inner organs, (e.g. liver, kidney,
bowel, stomach, lung, without being exhaustive). The term also
includes interventions of on the heart (e.g. on the valve or any
part of the myocard), also termed cardiovascular surgery.
[0129] Patients undergoing cardiovascular surgery frequently suffer
from heart failure as a consequence of or following a
cardiovascular disease and, most importantly, pre-existing kidney
disease.
[0130] According to the instant disclosure, the term also refers to
interventions on the heart vessels (also termed cardiovascular
surgery), for example bypass grafting.
[0131] In coronary artery bypass grafting (CABG) native coronary
arteries with high-grade stenosis or occlusion not appropriate for
performing angioplasty with stenting are bypassed typically using
an artery as a pedicled graft to the left anterior descending
coronary artery. The term and its meaning are known to the person
skilled in the art.
[0132] It is known to the person skilled in the art that, in
principle, any surgical intervention may cause AM related adverse
events. It is believed that this phenomenon may be due to the
existence of non-recognized renal disorders in the respective
individuals (meaning that the individuals are apparently healthy)
which induce a higher probability to suffer from an AKI related
adverse event. In some embodiments, the non-recognized renal
disorder is present before the surgical intervention. Frequently,
the renal disorders are a consequence of ischemic and/or necrotic
processes, in general after an impaired blood supply leading to
non-compliance with the kidneys' metabolic needs. Ischemic and
necrotic processes, in turn, frequently are caused by
cardiovascular diseases, preferably coronary artery disease
(CAD).
[0133] In consequence, there is an increased probability that an
individual not showing obvious signs and symptoms of a renal
disorder, as indicated by GFR and/or creatinine values, and which
is apparently healthy in the sense of the present disclosure, will
develop an AM related adverse event undergoing cardiovascular
surgery, in particular in the context of CAD and/or heart
failure.
[0134] The term "cardiovascular disease" as used in the context of
the present disclosure is known to the person skilled in the art
and relates to any dysfunction observed in the coronary vessels and
the heart itself, and includes, in particular, coronary artery
disease CAD.
[0135] The term "cardiovascular surgery" refers to surgery carried
out in the context of cardiovascular diseases. In some embodiments
the term relates to surgery carried out in the context of CAD,
which may also be referred to as "CAD surgery".
[0136] "Coronary artery disease" (CAD) as used in the context of
the present disclosure is known to the person skilled in the art
and involves impairment of blood flow through the coronary
arteries, in many cases by arteriosclerotic processes, in general
atheromas, which may cause ischemia, angina pectoris, acute
coronary syndromes (unstable angina pectoris, myocardial infarction
MI) and sudden cardiac death. Treatment includes drugs and
procedures to reduce ischemia and restore or improve coronary blood
flow. Usually, CAD is due to deposition of atheromas in large and
medium-sized coronary arteries (atherosclerosis). Less often, CAD
is due to coronary spasm. Rare causes include coronary artery
embolism, dissection, aneurysm, and vasculitis. In the context of
the present disclosure, CAD also includes heart failure.
[0137] According to the method of the disclosure increased amounts
of L-FABP or a variant thereof in comparison to reference amounts
measured in a sample, for example a urinary sample of a subject are
indicative for a tubular damage of the kidney. Increased amounts of
NGAL or a variant thereof in comparison to reference amounts
measured in a sample of a subject are indicative for a tubular
damage of the kidney. Increased amounts of adiponectin or a variant
thereof in comparison to reference amounts are indicative for a
glomerular damage of the kidney. Increased amounts of albumin or a
variant thereof in comparison to reference amounts are indicative
for a glomerular damage of the kidney. Increased amounts of L-FABP
or a variant thereof and/or increased amounts of NGAL or a variant
thereof, in combination with increased amounts of adiponectin or a
variant thereof and/or increased amounts of albumin or a variant
thereof, in comparison to reference amounts, are indicative for a
progressive tubular and glomerular damage of the kidney.
[0138] In the context of the present disclosure, one embodiment
refers to the case that the marker amounts are determined prior to
carrying out the surgical intervention for example, such as at
least or up to about 4 weeks, at least or up to about 2 weeks prior
to the intervention, or at least or up to about 7 days, or at least
or up to about 3 days, or at least or up to about 1 day, or at
least or up to about 20 h, or at least or up to about 12 h, or at
least or up to about 6 h prior to the surgical intervention. In the
case of acute events occurring after the determination of the
amounts of the markers, the amounts may be determined again.
[0139] In exemplary embodiments of the present disclosure, the
following reference amounts for the markers are used, where the
marker amount is determined in a sample taken prior to the surgical
intervention. The amounts of each marker are normalized in respect
to creatinine ("creatinine for . . . "), in order to eliminate
inaccuracies resulting from variations in urine volume of the
respective individual.
[0140] Acute kidney injury and need for dialysis in AKI are known
complications of major surgery and specifically after cardiac
surgery and to occur within 72 hours (or 3 days) after surgery.
Calculation of the average risk of these complications is known to
the person skilled in the art. (McIlroy D. R. et al, Clin J. Am Soc
Nephrol 5: 211-219, 2010). Average risk depends among others on the
underlying disease, comorbidities and type of intervention which
form the basis for calculation of the average risk. The terms "high
risk", "higher risk", "very high risk" as used in the context of
the present disclosure relate to those cases where the risk is
increased relative to average risk. The terms "low risk", "lower
risk", "very low risk" as used in the context of the present
disclosure relate to those cases where the risk is decreased
relative to average risk.
[0141] L-FABP:
[0142] According to embodiments of the present disclosure, a
reference amount of .ltoreq.about 3.6 .mu.g/g; .ltoreq.about 3.2
.mu.g/g; and .ltoreq.about 2.9 .mu.g/g, creatinine for L-FABP or a
variant thereof, is indicative that the individual is at a low
risk; at lower risk; at a very low risk of suffering from AM (rule
out).
[0143] According to embodiments of the present disclosure, a
reference amount of .gtoreq.about 10.8 .mu.g/g; .gtoreq.about 29.5
.mu.g/g; .gtoreq.about 32.3 .mu.g/g, creatinine for L-FABP or a
variant thereof, is indicative that the individual is at a high
risk; at higher risk; at a very high risk of suffering from AM
(rule in).
[0144] According to embodiments of the present disclosure, a
reference amount of .ltoreq.about 4.2 .mu.g/g; .ltoreq.about 3.2
.mu.g/g; .ltoreq.about 2.8 .mu.g/g, creatinine for L-FABP or a
variant thereof, is indicative that the individual is at a low
risk; at lower risk; at a very low risk of suffering from need for
dialysis (rule out).
[0145] According to embodiments of the present disclosure, a
reference amount of .gtoreq.about 35.4 .mu.g/g; .gtoreq.about 36.2
.mu.g/g; .gtoreq.about 37.2 .mu.g/g, creatinine for L-FABP or a
variant thereof, is indicative that the individual is at a high
risk; at higher risk; at a very high risk of suffering from need
for dialysis (rule in).
[0146] Adiponectin:
[0147] In case additionally the amount of adiponectin or a variant
thereof is determined, the reference values indicating a risk
suffering from AKI/need for dialysis is at low risk and at high
risk of suffering from AKI/need for dialysis is the following:
[0148] According to embodiments of the present disclosure, a
reference amount of .ltoreq.about 3.6 .mu.g/g; .ltoreq.about 3.2
.mu.g/g; .ltoreq.about 2.8 .mu.g/g, creatinine for adiponectin or a
variant thereof, is indicative that the individual is at a low
risk; at lower risk; at a very low risk of suffering from AKI (rule
out).
[0149] According to embodiments of the present disclosure, a
reference amount of .gtoreq.about 15.6 .mu.g/g; .gtoreq.about 17.6
.mu.g/g; .gtoreq.about 30.0 .mu.g/g, creatinine for adiponectin or
a variant thereof, is indicative that the individual is at a high
risk; at higher risk; at a very high risk of suffering from AM
(rule in).
[0150] According to embodiments of the present disclosure, a
reference amount of .ltoreq.about 8.8 .mu.g/g; .ltoreq.about 3.2
.mu.g/g; .ltoreq.about 1.2 .mu.g/g, creatinine for adiponectin or a
variant thereof, is indicative that the individual is at a low
risk; at lower risk; at a very low risk of suffering from need for
dialysis (rule out).
[0151] According to embodiments of the present disclosure, a
reference amount of .gtoreq.about 30.4 .mu.g/g; .gtoreq.about 135.2
.mu.g/g; .gtoreq.about 171.6 .mu.g/g, creatinine for adiponectin or
a variant thereof, is indicative that the individual is at a high
risk; at higher risk; at a very high risk of suffering from need
for dialysis (rule in).
[0152] Adiponectin gives information independently from L-FABP.
[0153] Albumin:
[0154] In case additionally the amount of albumin or a variant
thereof is determined, the reference values indicating a risk
suffering from AKI/need for dialysis is at low risk and at high
risk of suffering from AKI/need for dialysis is the following:
[0155] According to embodiments of the present disclosure, a
reference amount of .ltoreq.about 6 .mu.g/g; .ltoreq.about 4
.mu.g/g; .ltoreq.about 2 .mu.g/g, creatinine for albumin or a
variant thereof, is indicative that the individual is at a low
risk; at lower risk; at a very low risk of suffering from AKI (rule
out).
[0156] According to embodiments of the present disclosure, a
reference amount of .gtoreq.about 128 .mu.g/g; .gtoreq.about 142
.mu.g/g; .gtoreq.about 160 .mu.g/g, creatinine for albumin or a
variant thereof, is indicative that the individual is at a high
risk; at higher risk; at a very high risk of suffering from AM
(rule in).
[0157] According to embodiments of the present disclosure, a
reference amount of .ltoreq.about 8 .mu.g/g; .ltoreq.about 4
.mu.g/g; .ltoreq.about 2 .mu.g/g, creatinine for albumin or a
variant thereof, is indicative that the individual is at a low
risk; at lower risk; at a very low risk of suffering from need for
dialysis (rule out).
[0158] According to embodiments of the present disclosure, a
reference amount of .gtoreq.about 54 .mu.g/g; .gtoreq.about 128
.mu.g/g; .gtoreq.about 142 .mu.g/g, creatinine for albumin or a
variant thereof, is indicative that the individual is at a high
risk; at higher risk; at a very high risk of suffering from need
for dialysis (rule in).
[0159] Albumin gives information independently from L-FABP.
[0160] NGAL:
[0161] In case additionally the amount of NGAL or a variant thereof
is determined, the reference values indicating a risk suffering
from AKI/need for dialysis is at low risk and at high risk of
suffering from AKI/need for dialysis is the following:
[0162] According to embodiments of the present disclosure, a
reference amount of .ltoreq.about 7.0 .mu.g/g; .ltoreq.about 5.5
.mu.g/g; .ltoreq.about 3.5 .mu.g/g, creatinine for NGAL or a
variant thereof, is indicative that the individual is at a low
risk; at lower risk; at a very low risk of suffering from AM (rule
out).
[0163] According to embodiments of the present disclosure, a
reference amount of .gtoreq.about 12 .mu.g/g; .gtoreq.about 13
.mu.g/g; .gtoreq.about 14 .mu.g/g, creatinine for NGAL or a variant
thereof, is indicative that the individual is at a high risk; at
higher risk; at a very high risk of suffering from AM (rule
in).
[0164] According to embodiments of the present disclosure, a
reference amount of .ltoreq.about 9.0 .mu.g/g; .ltoreq.about 7.5
.mu.g/g; .ltoreq.about 1.5 .mu.g/g, creatinine for NGAL or a
variant thereof, is indicative that the individual is at a low
risk; at lower risk; at a very low risk of suffering from need for
dialysis (rule out).
[0165] According to embodiments of the present disclosure, a
reference amount of .gtoreq.about 15.0 .mu.g/g; .gtoreq.about 20.5
.mu.g/g; .gtoreq.about 26.5 .mu.g/g, creatinine for NGAL or a
variant thereof, is indicative that the individual is at a high
risk; at higher risk; at a very high risk of suffering from need
for dialysis (rule in).
[0166] NGAL gives information independently from L-FABP.
[0167] In one embodiment of the present disclosure, one or more of
the marker L-FABP or a variant thereof, adiponectin or a variant
thereof, albumin or a variant thereof and NGAL or a variant thereof
are determined at surgery termination or following surgery
termination. By this, the risk for suffering from AM and/or need
for dialysis can be determined. The one or more markers are
determined at the end of surgery (i.e. within a few minutes up to
about 1 hour after surgery termination) and/or may be determined in
intervals thereafter, e.g. about 2 h, 4 h, 5 h, 6 h, 10 h, 12 h, 16
h, 24 h after termination of surgery.
[0168] The amounts of albumin or a variant thereof determined at or
after surgery termination permit to differentiate between
individuals at risk of future occurrence of acute kidney injury and
those not at risk, when determined immediately after surgery. Also,
the amounts of albumin or a variant thereof permit to differentiate
between individuals at risk of future need for dialysis and those
not at risk, when determined after surgery. Even though albumin or
a variant thereof amounts decrease rapidly after termination of
surgery, determining albumin or a variant thereof amounts within
about 6 to 24 h, and according to some embodiments of the instant
disclosure about 6 to 12 h after surgery termination are still able
to discriminate between patients at risk and not at risk, both for
AKI and dialysis.
[0169] When determined after surgery, for example at about 6 h
after surgery termination, a reference amount of .ltoreq.about 8
.mu.g/g, and ins some embodiments herein .ltoreq.about 5 .mu.g/g,
or .ltoreq.about 4 .mu.g/g, creatinine for albumin or a variant
thereof, is indicative that the individual is at a low risk, lower
risk, and even at a very low risk of suffering from AKI (rule
out).
[0170] When determined after surgery, for example at about 12 h
after surgery termination, a reference amount of .ltoreq.about 8
.mu.g/g, and ins some embodiments herein .ltoreq.about 4 .mu.g/g,
or .ltoreq.about 2 .mu.g/g, creatinine for albumin or a variant
thereof, is indicative that the individual is at a low risk, lower
risk, and even at a very low risk of suffering from AM (rule
out).
[0171] When determined after surgery, for example at about 6 h
after surgery termination, a reference amount of .ltoreq.about 8
.mu.g/g, and ins some embodiments herein .ltoreq.about 6 .mu.g/g,
or .ltoreq.about 4 .mu.g/g, creatinine for albumin or a variant
thereof, is indicative that the individual is at a low risk, lower
risk, and even at a very low risk of suffering from need for
dialysis (rule out).
[0172] When determined after surgery, for example at about 12 h
after surgery termination, a reference amount of .ltoreq.about 10
.mu.g/g, and in some embodiments herein .ltoreq.about 4 .mu.g/g, or
.ltoreq.about 2 .mu.g/g, creatinine for albumin or a variant
thereof, is indicative that the individual is at a low risk, lower
risk, and even at a very low risk of suffering from need for
dialysis (rule out).
[0173] The amounts of adiponectin or a variant thereof determined
at or after surgery termination permit to differentiate between
individuals at risk of future need for dialysis and those not at
risk, when determined after surgery. Even though adiponectin or a
variant thereof amounts increase rapidly after termination of
surgery, determining adiponectin amounts within about 6 to 24 h,
and in some embodiments of the instant disclosure about 6 to 12 h
after surgery termination are still able to discriminate between
patients at risk and not at risk for dialysis.
[0174] When determined after surgery, for example at about 6 h
after surgery termination, a reference amount of .ltoreq.about 65
.mu.g/g, and in some embodiments herein .ltoreq.about 48 .mu.g/g,
or .ltoreq.about 24 .mu.g/g creatinine for adiponectin or a variant
thereof, is indicative that the individual is at a low risk, lower
risk, and even at a very low risk, and even at an even lower risk
of suffering from need for dialysis (rule out).
[0175] When determined after surgery, for example at about 12 h
after surgery termination, a reference amount of .ltoreq.about 72
.mu.g/g, and in some embodiments herein .ltoreq.about 62 .mu.g/g,
or .ltoreq.about 47 .mu.g/g creatinine for adiponectin or a variant
thereof, is indicative that the individual is at a low risk, at
lower risk, and even at a very low risk, and even at an even lower
risk of suffering from need for dialysis (rule out).
[0176] The amounts of L FABP or a variant thereof determined at or
after surgery termination were lower in patients developing AKI
than in those who did not, presumably because of preexisting kidney
disease. Determining adiponectin or a variant thereof amounts not
immediately after surgery termination, but after about 6 to 24 h,
and in some embodiments herein about 6 to 12 h after surgery
termination, is able to discriminate between patients at risk and
not at risk for need of dialysis.
[0177] When determined after surgery, for example at about 6 h
after surgery termination, a reference amount of .ltoreq.about 10
.mu.g/g, and in some embodiments herein .ltoreq.about 5 .mu.g/g, or
.ltoreq.about 0 .mu.g/g, creatinine for L-FABP or a variant
thereof, is indicative that the individual is at a low risk, at
lower risk, and even at a very low risk of suffering from need for
dialysis (rule out).
[0178] When determined after surgery, for example at about 12 h
after surgery termination, a reference amount of .ltoreq.about 10
.mu.g/g, and in some embodiments herein .ltoreq.about 5 .mu.g/g, or
.ltoreq.about 2 .mu.g/g, creatinine for L-FABP or a variant
thereof, is indicative that the individual is at a low risk, at
lower risk, and even at a very low risk of suffering from need for
dialysis (rule out).
[0179] The amounts of NGAL or a variant thereof determined at or
after surgery termination permit to differentiate between
individuals at risk of future need for dialysis and those not at
risk. Determining NGAL amounts or those of a variant thereof about
6 to 24 h, and in some embodiments herein about 6 to 12 h after
surgery termination is able to discriminate between patients at
risk and not at risk for need of dialysis.
[0180] When determined after surgery, for example at about 6 h
after surgery termination, a reference amount of .ltoreq.about 20
.mu.g/g, and in some embodiments herein .ltoreq.about 15 .mu.g/g,
or .ltoreq.about 10 .mu.g/g, creatinine for NGAL or a variant
thereof, is indicative that the individual is at a low risk, at
lower risk, and even at a very low risk of suffering from need for
dialysis (rule out).
[0181] When determined after surgery, for example at about 12 h
after surgery termination, a reference amount of .ltoreq.about 30
.mu.g/g, and in some embodiments herein .ltoreq.about 20 .mu.g/g,
or .ltoreq.about 10 .mu.g/g, creatinine for NGAL or a variant
thereof, is indicative that the individual is at a low risk, at
lower risk, and even at a very low risk of suffering from need for
dialysis (rule out).
[0182] The present disclosure also relates to a method of
recommending or deciding on a suitable therapy in a subject being
at risk of experiencing an adverse event related to acute kidney
injury AKI after a surgical intervention in a subject, based on
predicting the risk of the adverse event related to AM by the
comparison of the amounts of liver-type fatty acid binding protein
(L-FABP) or a variant thereof, determined in a sample of said
subject, to at least one reference amount.
[0183] This method of the present disclosure comprises at least one
of the following steps and/or may comprise the following steps: a)
determining the amounts of liver-type fatty acid binding protein
(L-FABP) or a variant thereof, for example urinary liver-type fatty
acid binding protein (L-FABP) or a variant thereof, in a sample,
such as a urine-sample of a subject; b) comparing the amounts
determined in step a) with reference amounts; c) predicting the
risk based on the comparison carried out in step b); d)
recommending or deciding the initiation of a suitable therapy or
refraining from the suitable therapy, based on the information
obtained in step c).
[0184] The present disclosure also provides a method of
recommending or deciding on a suitable therapy in a subject being
at risk of experiencing an adverse event related to acute kidney
injury AKI after a surgical intervention in a subject, comprising
the steps of: a) determining liver-type fatty acid binding protein
(L-FABP) or a variant thereof, such as urinary liver-type fatty
acid binding protein (L-FABP) or a variant thereof, in sample, such
as a urine-sample of a subject; b) comparing the amounts determined
in step a) with reference amounts; and c) predicting the risk based
on the comparison carried out in step b) and d) recommending or
deciding the initiation of a suitable therapy or refraining from
the suitable therapy, based on the information obtained in step
c).
[0185] In another embodiment of the present disclosure, the present
disclosure provides a method of recommending or deciding on a
suitable therapy in a subject being at risk of experiencing an
adverse event related to acute kidney injury AKI after a surgical
intervention in a subject, comprising the steps of: a) determining
the amounts of liver-type fatty acid binding protein (L-FABP) or a
variant thereof, such as urinary liver-type fatty acid binding
protein (L-FABP) or a variant thereof, in a sample, for example a
urine-sample of a subject; and b) comparing the amounts determined
in step a) with reference amounts; whereby the risk of the subject
to experience adverse event related to acute kidney injury AKI
after a surgical intervention is predicted and the initiation of or
the refraining from a suitable therapy is recommended based on the
prediction.
[0186] In an exemplary embodiment of the present disclosure, the
amount of adiponectin or a variant thereof is determined in the
urine sample further to the amount of L-FABP or a variant thereof,
and the recommendation is established based on the comparison of
the marker amounts with reference amounts.
[0187] In further embodiments of the present disclosure, the amount
of at least one further marker selected from albumin or a variant
thereof and neutrophil gelatinase associated lipocalin (NGAL) or a
variant thereof is measured in the urine sample, and the
recommendation is established based on the comparison of the marker
amounts with reference amounts. In this embodiment, the amount of
only one additional marker from the above-cited group further to
L-FABP or a variant thereof and, for example adiponectin or a
variant thereof will be measured, or the amounts of both additional
markers further to L-FABP or a variant thereof and, for example,
adiponectin or a variant thereof.
[0188] In the method of recommending or deciding on a suitable
therapy as disclosed beforehand, the respective markers may be
determined prior to surgery. In a further embodiment of the present
disclosure, the marker(s) are determined after surgical
intervention has been terminated, e g immediately when terminating
intervention, or after 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 or 24 h
later.
[0189] In further embodiments of the present disclosure, suitable
therapies are the administration of pharmaceuticals and/or life
style recommendations which are effective in respect of inhibition
of further progression of kidney disease.
[0190] Advantageously, the method of the present disclosure allows
the identification of patients with an increased risk of AM prior
to the surgical intervention and/or following the surgical
intervention. From the determination of an increased risk of AKI in
a patient, known risk factors that precipitate AKI can be
controlled in a patient having an increased risk of suffering from
AKI after a surgical procedure. Control of these risk factors
includes careful fluid balance during and after surgery. If a
cardiopulmonary bypass is used during surgery, low perfusion
temperatures have to be avoided. Nephrotoxic drugs (e.g.
non-steroidal anti-inflammatory drugs and sulfonamides) have to be
avoided as well. Moreover, the administration of erythropoietin may
be indicated (Song et al., 2009, American Journal of Nephrology,
253-260). The possibility to predict the risk of acute kidney
injury after a surgical intervention in a patient prior to said
intervention and/or after said intervention obviously has
consequences for deciding whether the patient in question is
eligible for the surgical procedure in question.
[0191] The term "susceptible" as used herein means that a therapy
applied to a subject will inhibit or ameliorate the progression of
diabetes mellitus or its accompanying symptoms. It is to be
understood assessment for susceptibility for the therapy will not
be correct for all (100%) of the investigated subjects. However, it
is envisaged that at least a statistically significant portion can
be determined for which the therapy can be successfully applied.
Whether a portion is statistically significant can be determined by
techniques specified elsewhere herein.
[0192] Furthermore, the present disclosure relates to a method of
monitoring the therapy in a subject being at risk of an adverse
event related to acute kidney injury AKI as a consequence of a
surgical intervention in a subject, based on predicting the risk of
an adverse event related to AKI by the comparison of the amounts of
liver-type fatty acid binding protein (L-FABP), such as urinary
L-FABP or a variant thereof, determined in a sample of said subject
at various points in time (at least two different points in time),
to at least one reference amount.
[0193] This method of the present disclosure comprises at least one
of the following steps and/or may comprise the following steps: a)
determining the amounts of liver-type fatty acid binding protein
(L-FABP) or a variant thereof, in a sample, such as a urine-sample
of a subject at various points in time (at least two different
points in time); b) comparing the amounts determined in step a)
with reference amounts; c) predicting the risk based on the
comparison carried out in step b); d) monitoring the therapy, based
on the information obtained in step c).
[0194] The present disclosure also provides a method of monitoring
the therapy in a subject being at risk of an adverse event related
to acute kidney injury AKI as a consequence of a surgical
intervention in a subject, comprising the steps of: a) determining
the amounts of liver-type fatty acid binding protein (L-FABP) or a
variant thereof, in a urine-sample of a subject at various points
in time (at least two different points in time); b) comparing the
amounts determined in step a) with reference amounts; and c)
predicting the risk based on the comparison carried out in step b)
and d) recommending or deciding the initiation of a suitable
therapy or refraining from the suitable therapy, based on the
information obtained in step c).
[0195] In another embodiment of the present disclosure, the present
disclosure provides a method of monitoring the therapy in a subject
being at risk of an adverse event related to acute kidney injury
AKI as a consequence of a surgical intervention in a subject,
comprising the steps of: a) determining the amounts of liver-type
fatty acid binding protein (L-FABP) or a variant thereof, in a
urine-sample of a subject at various points in time (at least two
different points in time); b) comparing the amounts determined in
step a) with reference amounts; whereby the risk of the subject to
experience adverse event related to acute kidney injury AKI after a
surgical intervention is predicted and the initiation of or
refraining from a suitable therapy is recommended based on the
prediction.
[0196] In an exemplary embodiment of the present disclosure, the
amount of adiponectin or a variant thereof is determined in the
urine sample further to the amount of L-FABP or a variant thereof,
and monitoring is carried out based on the comparison of the marker
amounts with reference amounts.
[0197] In additional exemplary embodiments of the present
disclosure, the amount of at least one further marker selected from
albumin or a variant thereof and neutrophil gelatinase associated
lipocalin (NGAL) or a variant thereof is measured in the urine
sample, and monitoring is carried out based on the comparison of
the marker amounts with reference amounts. In such embodiments, the
amount of only one additional marker from the above-cited group
further to L-FABP or a variant thereof and, for example,
adiponectin or a variant thereof will be measured, or the amounts
of both additional markers further to L-FABP or a variant thereof
and, for example, adiponectin or a variant thereof.
[0198] "Monitoring" as used herein relates to keeping track of the
pathophysiological state of the respective individual relative to
AKI related events, such as AKI itself or need for dialysis,
occurrence and/or progression of the disease or the influence of a
particular treatment on the progression of disease. Monitoring
means control after about 1 day, about 2 day, about 3 days, about 5
days, about 7 day, about 10 days, about 12 days, about 14 days.
[0199] In one embodiment, the present disclosure provides a method
for diagnosing acute kidney injury AKI in a subject, comprising the
steps of: a) determining the amounts of liver-type fatty acid
binding protein (L-FABP) or a variant thereof, such as a
urine-sample of a subject; b) comparing the amounts determined in
step a) with reference amounts; and c) diagnosing AKI based on the
steps carried out in step b).
[0200] The present disclosure also provides a method for diagnosing
acute kidney injury AM in a subject, comprising the steps of: a)
determining the amounts of liver-type fatty acid binding protein
(L-FABP) or a variant thereof, such as a urine-sample of a subject;
and b) comparing the amounts determined in step a) with reference
amounts; wherein AM is diagnosed based on the steps carried out in
step b).
[0201] Moreover, the present disclosure also includes kits and
devices adapted to carry out the method of the present disclosure.
Furthermore, the present disclosure relates to a device for
predicting the risk of an adverse event related to acute kidney
injury AKI as a consequence of a surgical intervention in a
subject, comprising: a) means for determining the amounts of
liver-type fatty acid binding protein, such as urinary liver-type
fatty acid binding protein (L-FABP) or a variant thereof, and, as
the case may be, adiponectin or a variant thereof and/or NGAL or a
variant thereof and/or albumin or a variant thereof, in a sample,
for example a urine-sample of a subject; b) means for comparing the
amounts determined in step a) with reference amounts; and c)
predicting the risk based on the comparison carried out in step b),
and whereby the device is adapted for diagnosing the kidney
damage.
[0202] Moreover the present disclosure is concerned with a kit for
predicting the risk of an adverse event related to acute kidney
injury AM as a consequence of a surgical intervention in a subject,
comprising: a) means for determining the amounts of liver-type
fatty acid binding protein, for example urinary liver-type fatty
acid binding protein (L-FABP) or a variant thereof, and, as the
case may be, adiponectin or a variant thereof and/or NGAL or a
variant thereof and/or albumin or a variant thereof, in a sample,
for example a urine-sample of a subject; b) means for comparing the
amounts determined in step a) with reference amounts; and c)
predicting the risk based on the comparison carried out in step b),
and whereby the kit is adapted for diagnosing the kidney
damage.
[0203] The term "device" as used herein relates to a system of
means comprising at least the aforementioned means operatively
linked to each other as to allow predicting the risk of an adverse
event related to acute kidney injury AKI as a consequence of a
surgical intervention in a subject, and/or recommending or deciding
on a suitable therapy in a subject being at risk of an adverse
event related to acute kidney injury AM as a consequence of a
surgical intervention in a subject, and/or monitoring the therapy
in a subject being at risk of an adverse event related to acute
kidney injury AKI as a consequence of a surgical intervention in a
subject, based on predicting the risk of an adverse event related
to AKI in a subject. Exemplary means for determining the amount of
(L-FABP), and, as the case may be, adiponectin or a variant thereof
and/or NGAL or a variant thereof and/or albumin or a variant
thereof, and means for carrying out the comparison are disclosed
above in connection with the method of the disclosure. How to link
the means in an operating manner will depend on the type of means
included into the device. For example, where means for
automatically determining the amount of the peptides are applied,
the data obtained by said automatically operating means can be
processed by, e.g., a computer program in order to obtain the
desired results. According to the instant disclosure, the means may
be comprised by a single device in such a case. Said device may
accordingly include an analyzing unit for the measurement of the
amount of the peptides or polypeptides in an applied sample and a
computer unit for processing the resulting data for the evaluation.
Alternatively, where means such as test stripes are used for
determining the amount of the peptides or polypeptides, the means
for comparison may comprise control stripes or tables allocating
the determined amount to a reference amount. The test strips may be
coupled to a ligand which specifically binds to the peptides or
polypeptides referred to herein. According to the instant
disclosure, the strip or device may comprise means for detection of
the binding of said peptides or polypeptides to the said ligand.
Exemplary means for detection are disclosed in connection with
embodiments relating to the method of the disclosure above. In such
a case, the means are operatively linked in that the user of the
system brings together the result of the determination of the
amount and the diagnostic or prognostic value thereof due to the
instructions and interpretations given in a manual. The means may
appear as separate devices in such an embodiment and may be
packaged together as a kit. The person skilled in the art will
realize how to link the means. Exemplary devices are those which
can be applied without the particular knowledge of a specialized
clinician, e.g., test strips or electronic devices which merely
require loading with a sample. The results may be given as output
of raw data which need interpretation by the clinician. In some
embodiments, the output of the device is, however, processed, i.e.
evaluated, raw data the interpretation of which does not require a
clinician. Further exemplary devices comprise the analyzing
units/devices (e.g., biosensors, arrays, solid supports coupled to
ligands specifically recognizing L-FABP or a variant thereof, and,
as the case may be, adiponectin or a variant thereof and/or NGAL or
a variant thereof and/or albumin or a variant thereof, Plasmon
surface resonance devices, NMR spectrometers, mass-spectrometers
etc.) or evaluation units/devices referred to above in accordance
with the method of the disclosure.
[0204] The term "kit" as used herein refers to a collection of the
aforementioned means, provided separately or within a single
container. Optionally, the kit may additionally comprise a user's
manual for interpreting the results of any measurement(s) with
respect to predicting the risk of an adverse event related to acute
kidney injury AM as a consequence of a surgical intervention in a
subject, and/or recommending or deciding on a suitable therapy in a
subject being at risk of an adverse event related to acute kidney
injury AKI as a consequence of a surgical intervention in a
subject, and/or monitoring the therapy in a subject being at risk
of an adverse event related to acute kidney injury AKI as a
consequence of a surgical intervention in a subject, based on
predicting the risk of an adverse event related to AKI, as defined
in the present disclosure. Particularly, such manual may include
information about what determined amounts corresponds to what kind
of diagnosis. This is outlined in detail elsewhere in this
specification. Additionally, such user's manual may provide
instructions about correctly using the components of the kit for
determining the amount of the respective biomarkers.
[0205] The present disclosure also relates to the use of a kit or
device for determining the amount of L-FABP or a variant thereof,
and, as the case may be, adiponectin or a variant thereof and/or
NGAL or a variant thereof and/or albumin or a variant thereof, in a
sample of a subject, and/or the use of means for determining the
amount of L-FABP or a variant thereof, and, as the case may be,
adiponectin or a variant thereof and/or NGAL or a variant thereof
and/or albumin or a variant thereof, and/or the use of means for
comparing the amount of L-FABP or a variant thereof, and, as the
case may be, adiponectin or a variant thereof and/or NGAL or a
variant thereof and/or albumin or a variant thereof, to at least
one reference amount, for: predicting the risk of an adverse event
related to acute kidney injury AM as a consequence of a surgical
intervention in a subject, and/or recommending or deciding on a
suitable therapy in a subject being at risk of an adverse event
related to acute kidney injury AM as a consequence of a surgical
intervention in a subject, and/or monitoring the therapy in a
subject being at risk of an adverse event related to acute kidney
injury AKI as a consequence of a surgical intervention in a
subject, wherein all uses are based on predicting the risk of an
adverse event related to AM in a subject.
[0206] According to embodiments of the instant disclosure, the
prediction of the risk of an adverse event related to acute kidney
injury AM as a consequence of a surgical intervention is based on a
sample taken prior to the surgical intervention. The present
disclosure also relates to the use of: an antibody to L-FABP or a
variant thereof, and, as the case may be, an antibody to
adiponectin or a variant thereof and/or an antibody to NGAL or a
variant thereof and/or an antibody to albumin or a variant thereof,
and/or of means for determining the amount of L-FABP or a variant
thereof, and, as the case may be, means for determining the amount
adiponectin or a variant thereof and/or means for determining the
amount of NGAL or a variant thereof and/or of means for determining
the amount of albumin or a variant thereof, and/or of means for
comparing the amount of L-FABP or a variant thereof, and, as the
case may be, adiponectin or a variant thereof and/or NGAL or a
variant thereof and/or albumin or a variant thereof, to at least
one reference amount for the manufacture of a diagnostic
composition for: predicting the risk of an adverse event related to
acute kidney injury AKI as a consequence of a surgical intervention
in a subject, and/or recommending or deciding on a suitable therapy
in a subject being at risk of an adverse event related to acute
kidney injury AKI as a consequence of a surgical intervention in a
subject, and/or monitoring the therapy in a subject being at risk
of an adverse event related to acute kidney injury AKI as a
consequence of a surgical intervention in a subject, wherein all
uses are based on predicting the risk of an adverse event related
to AM in a subject.
[0207] According to some embodiments of the instant disclosure, the
prediction of the risk of an adverse event related to acute kidney
injury AM as a consequence of a surgical intervention is based on a
sample taken prior to the surgical intervention.
[0208] The present disclosure also relates to the use of: an
antibody to L-FABP or a variant thereof, and, as the case may be,
an antibody to adiponectin or a variant thereof and/or an antibody
to NGAL or a variant thereof and/or an antibody to albumin or a
variant thereof, and/or of means for determining the amount of
L-FABP or a variant thereof, and, as the case may be, of means for
determining the amount adiponectin or a variant thereof, and/or of
means for determining the amount of NGAL or a variant thereof
and/or of means for determining the amount of albumin or a variant
thereof, and/or of means for comparing the amount of L-FABP or a
variant thereof, and, as the case may be, adiponectin or a variant
thereof and/or NGAL or a variant thereof and/or albumin or a
variant thereof, to at least one reference amount for: predicting
the risk of an adverse event related to acute kidney injury AKI as
a consequence of a surgical intervention in a subject, and/or
recommending or deciding on a suitable therapy in a subject being
at risk of an adverse event related to acute kidney injury AM as a
consequence of a surgical intervention in a subject, and/or
monitoring the therapy in a subject being at risk of an adverse
event related to acute kidney injury AKI as a consequence of a
surgical intervention in a subject, wherein all uses are based on
predicting the risk of an adverse event related to AM in a
subject.
[0209] According to embodiments of the instant disclosure, the
prediction of the risk of an adverse event related to acute kidney
injury AM as a consequence of a surgical intervention is based on a
sample taken prior to the surgical intervention.
[0210] The following examples, sequence listing, and figures are
provided for the purpose of demonstrating various embodiments of
the instant disclosure and aiding in an understanding of the
present disclosure, the true scope of which is set forth in the
appended claims. These examples are not intended to, and should not
be understood as, limiting the scope or spirit of the instant
disclosure in any way. It should also be understood that
modifications can be made in the procedures set forth without
departing from the spirit of the disclosure.
Illustrative Embodiments
[0211] The following comprises a list of illustrative embodiments
according to the instant disclosure which represent various
embodiments of the instant disclosure. These illustrative
embodiments are not intended to be exhaustive or limit the
disclosure to the precise forms disclosed, but rather, these
illustrative embodiments are provided to aide in further describing
the instant disclosure so that others skilled in the art may
utilize their teachings.
1. A method for predicting the risk of a subject to experience an
adverse event related to acute kidney injury (AM) after a surgical
intervention, comprising the steps of: a) determining the amounts
of liver-type fatty acid binding protein (L-FABP) or a variant
thereof, in a sample, preferably a urine-sample, of a subject
obtained before the surgical intervention; and b) comparing the
amounts determined in step a) with reference amounts; and whereby
the risk of the subject to experience adverse event related to
acute kidney injury AM after a surgical intervention is predicted.
2. The method according to 1, wherein additionally the amount of
adiponectin or a variant thereof is determined in the sample and
the risk is predicted based on the comparison of the marker amounts
with respective reference amounts. 3. The method according to 1 or
2, wherein the amount of at least one further marker selected from
albumin or a variant thereof and neutrophil gelatinase associated
lipocalin (NGAL) or a variant thereof is measured in the sample,
and the risk is predicted based on the comparison of the marker
amounts with respective reference amounts. 4. The method according
to any of 1 to 3, wherein a reference amount of .ltoreq.about 3.6
.mu.g/g creatinine for L-FABP or a variant thereof is indicative
that the individual is at a low risk of suffering from AKI, and a
reference amount of .gtoreq.about 10.8 .mu.g/g, creatinine for
L-FABP or a variant thereof, is indicative that the individual is
at a high risk of suffering from AKI, when determined prior to
carrying out the surgical intervention. 5. The method according to
any of 1 to 4, wherein a reference amount of .ltoreq.about 4.2
.mu.g/g creatinine for L-FABP or a variant thereof, is indicative
that the individual is at a low risk of suffering from need for
dialysis, and a reference amount of .gtoreq.about 35.4 .mu.g/g
creatinine for L-FABP or a variant thereof is indicative that the
individual is at a high risk of suffering from need for dialysis,
when determined prior to carrying out the surgical intervention. 6.
The method according to any of 1 to 5, wherein a reference amount
of .ltoreq.about 3.6 .mu.g/g creatinine for adiponectin or a
variant thereof is indicative that the individual is at a low risk
of suffering from AM, and a reference amount of .gtoreq.about 15.6
.mu.g/g creatinine for adiponectin or a variant thereof is
indicative that the individual is at a high risk of suffering from
AKI, when determined prior to carrying out the surgical
intervention.
[0212] 7. The method according to any of 1 to 6, wherein a
reference amount of .ltoreq.about 8.8 .mu.g/g creatinine for
adiponectin or a variant thereof is indicative that the individual
is at a low risk of suffering from need for dialysis, and a
reference amount of .gtoreq.about 30.4 .mu.g/g creatinine for
adiponectin or a variant thereof is indicative that the individual
is at a high risk of suffering from need for dialysis, when
determined prior to carrying out the surgical intervention.
8. A method for diagnosing acute kidney injury AM in a subject,
comprising the steps of: a) determining the amounts of liver-type
fatty acid binding protein (L-FABP) or a variant thereof,
preferably a urine-sample of a subject; and b) comparing the
amounts determined in step a) with reference amounts; wherein AKI
is diagnosed based on the comparison of step b). 9. A method of
recommending a suitable therapy in a subject being at risk of
experiencing an adverse event related to acute kidney injury AKI
after a surgical intervention, comprising the steps of: a)
determining the amounts of liver-type fatty acid binding protein
(L-FABP) or a variant thereof, in a urine-sample of a subject; b)
comparing the amounts determined in step a) with reference amounts;
and whereby the risk of the subject to experience adverse event
related to acute kidney injury AKI after a surgical intervention is
predicted and the initiation of or refraining from a suitable
therapy is recommended based on the prediction. 10. A method of
monitoring the therapy in a subject being at risk of an adverse
event related to acute kidney injury AM as a consequence of a
surgical intervention in a subject, comprising the steps of: a)
determining the amounts of liver-type fatty acid binding protein
(L-FABP) or a variant thereof, in a sample, preferably a
urine-sample of a subject at various points in time (at least two
different points in time); and b) comparing the amounts determined
in step a) with reference amounts; and whereby the risk of the
subject to experience adverse event related to acute kidney injury
AKI after a surgical intervention is predicted and the initiation
of or refraining from a suitable therapy is recommended based on
the prediction. 11. Use of an anti-L-FABP antibody for predicting
the risk of a subject to experience an adverse event related to
acute kidney injury (AKI) after a surgical intervention. 12. Use of
an anti-L-FABP antibody for recommending or deciding on a suitable
therapy in a subject being at risk of experiencing an adverse event
related to acute kidney injury AM after a surgical intervention.
13. A device for predicting the risk of an adverse event related to
acute kidney injury AKI as a consequence of a surgical intervention
in a subject, comprising: a) means for determining the amounts of
liver-type fatty acid binding protein (L-FABP) or a variant
thereof, and, as the case may be, adiponectin or a variant thereof
and/or NGAL or a variant thereof and/or albumin or a variant
thereof, in a sample, preferably a urine-sample of a subject; b)
means for comparing the amounts determined in step a) with
reference amounts; and c) means for predicting the risk based on
the comparison carried out in step b), and whereby the device is
adapted for diagnosing the kidney damage. 14. A kit for predicting
the risk of an adverse event related to acute kidney injury AKI as
a consequence of a surgical intervention in a subject, comprising:
a) means for determining the amounts of liver-type fatty acid
binding protein (L-FABP) or a variant thereof, and, as the case may
be, adiponectin or a variant thereof and/or NGAL or a variant
thereof and/or albumin or a variant thereof, in a sample,
preferably a urine-sample of a subject; b) means for comparing the
amounts determined in step a) with reference amounts; and c) means
for predicting the risk based on the comparison carried out in step
b), and whereby the device is adapted for diagnosing the kidney
damage.
EXAMPLES
[0213] In the following examples, the following tests were used for
the determination of the amounts of the respective peptides:
[0214] L-FABP was determined by using the L-FABP ELISA-Kit from
CMIC Co., Ltd, Japan The test was based on an ELISA 2-step assay.
L-FABP standard or urine samples were firstly treated with
pretreatment solution as provided with the test, and transferred
into a L-FABP antibody coated microplate containing assay buffer
and incubated. During this incubation, L-FABP in the reaction
solution bound to the immobilized antibody. After washing, the
2.sup.nd Antibody-POD conjugate was added as the secondary antibody
and incubated, thereby forming sandwich of the L-FABP antigen
between the immobilized antibody and conjugate antibody. After
incubation, the plate was washed and substrate for enzyme reaction
was added, color develops according to the L-FABP antigen quantity.
The L-FABP concentration was determined based on the optical
density. The assay had a measuring range from 3 ng/ml to 400
ng/ml.
[0215] Adiponectin (multimeric) was determined by using the test
EIA from ALPCO DIAGNOSTICS.RTM. (USA), operating on the principle
of a "sandwich" format ELISA. The specific antibodies used in the
kit were anti-human adiponectin monoclonal antibodies (MoAbs)
directed to two independent epitopes. The specimens were
pre-treated as described below, and total adiponectin and
individual multimers of adiponectin were determined selectively,
directly or indirectly. Multimers of adiponectin were classified
into four fractions with this kit: [0216] 1) Total adiponectin
fraction: "Total-Ad"-assayed directly on the plate [0217] 2)
High-molecular adiponectin fraction (equivalent of
dodecamer-octodecamer): "HMW-Ad"-assayed directly on the plate
[0218] 3) Middle-molecular adiponectin fraction (equivalent of
hexamer): "MMW-Ad"-inferred value obtained by subtracting the
concentration of HMW-Ad from the combined concentration of
MMW-Ad+HMW-Ad [0219] 4) Low-molecular adiponectin fraction
(equivalent of trimer including albumin-binding adiponectin):
"LMWAd"--inferred value obtained by subtracting the combined
concentration of MMW-Ad+HMW-Ad from the total concentration of Ad.
The microtiter plate wells had been coated with an anti-human
adiponectin monoclonal antibody. Adiponectin in the standards and
pretreated specimens was captured by the antibody during the first
incubation. Afterwards, a wash step removed all unbound material.
Subsequently, an anti-human adiponectin antibody which had been
biotin-labeled was added and bound to the immobilized adiponectin
in the wells. Subsequently, an anti-human adiponectin antibody
which had been biotin-labeled was added and bound to the
immobilized adiponectin in the wells. After the second incubation
and subsequent wash step, HRP-labeled streptavidin was added. After
the third incubation and subsequent wash step, substrate solution
was added. Finally, stop reagent was added after allowing the color
to develop. The intensity of the color development was read by a
microplate reader. The absorbance value reported by the plate
reader was proportional to the concentration of adiponectin in the
sample. The test kit was effective in the range from 0.075 ng/ml to
4.8 ng/ml.
[0220] NGAL was determined by the NGAL Rapid ELISA Kit from
BIOPORTO.RTM. Diagnostics, Denmark. The assay was an ELISA
performed in microwells coated with a monoclonal antibody against
human NGAL. Bound NGAL was detected with a horseradish peroxidase
(HRP)-conjugated monoclonal antibody and the assay was developed by
incubation with a color-forming substrate. The assay used a rapid
2-step procedure:
[0221] Step 1. Aliquots of calibrators, diluted samples and any
controls were incubated with HRP-conjugated detection antibody in
the coated microwells. Only NGAL would bind to both coat and
detection antibody, while unbound materials were removed by
washing.
[0222] Step 2. A chromogenic peroxidase substrate containing
tetramethylbenzidine (TMB) was added to each test well. The HRP
linked to the bound detection antibody reacted with the substrate
to generate a colored product. The enzymatic reaction was stopped
chemically, and the color intensity was read at 450 nm in an ELISA
reader. The color intensity (absorbance) was a function of the
concentration of NGAL originally added to each well. The results
for the calibrators were used to construct a calibration curve from
which the concentrations of NGAL in the test specimens were
read.
[0223] Albumin was determined by using the COBAS.RTM. Tina-quant
Albumin test (Roche Diagnostics) by immuno-turbidometry. The test
principle was the recognition of albumin by a specific anti-albumin
antibody forming a complex with albumin, which was determined after
agglutination. The assay had a measuring range in urine between 3
ng/ml and 400 ng/ml.
[0224] The named tests were also preferably employed in the general
context of the present disclosure for the determination of the
respective peptides.
[0225] In order to optimize reference values that would predict the
likelihood of complications to occur or not to occur receiver
operating curves (ROC curves) were constructed. Complications in
the context of the current disclosure are acute kidney injury as
defined or need for dialysis. Timepoints for determination of the
likelihood of complications to occur or not to occur were
preferably pre surgery. This timepoint allows to take all
appropriate measures to avoid such complications including the
possibility not to perform the surgery as has been outlined in the
present disclosure. Post surgery or even later measures to avoid or
ameliorate such complications are much more limited, however with
regard to the risk to dialysis such information will provide
appropriate time to prepare for such a complication, e.g.
availability for dialysis equipment, transport to appropriate unit,
more intensive surveillance etc.
Example 1
[0226] A total of 126 patients (median age 63 years), creatinine
within normal range, undergoing elective coronary bypass surgery
were evaluated for the presence of kidney injury markers before,
after and 6, 12 and 24 hours after intervention.
[0227] 89 patients did not develop AKI, AKI was recognized in 37
patients as indicated by an increase in creatinine by at least 0.3
mg/dl, 12 patients developed need for dialysis and 9 died within 30
days after surgery.
[0228] The following urinary kidney markers were measured: Albumin,
adiponectin, L-FABP and NGAL. The results are presented in the ROC
curves 1-18 (see above).
[0229] The amount of L-FABP in a sample taken before surgery
predicts the need for dialysis after surgery well (see FIG. 2). A
sensitivity of approximately 60% can be reached while maintaining a
selectivity of about 80%. Thus, the need for dialysis after surgery
is correctly predicted for more than half of all patients who
finally require dialysis.
[0230] It is important to understand that acute kidney injury and
specifically acute kidney injury followed by dialysis may be caused
by a disease before the intervention or by complications of the
intervention itself. In the current study urinary L-FABP identified
a subgroup of patients at increased risk of acute kidney injury and
dialysis that was not recognized by other kidney functions tests,
e.g. based on the determination of creatinine. This identification
was possible before the intervention. Risk assessment before the
intervention allows taking preventive measures which are not
effective or less effective if taken after occurrence of the events
leading to acute kidney injury. Such measures include specifically
careful fluid balance, avoidance of nephrotoxic drugs and avoidance
of low perfusion temperatures if cardiopulmonary bypass is
used.
Example 2
[0231] A patient is scheduled to undergo cardiovascular bypass
grafting. The patient's amount of urinary L-FABP before surgery is
36.0 .mu.g/g Creatinine. Consequently, the fluid balance of the
patient is carefully monitored and low perfusion temperatures of
the cardiopulmonary bypass are avoided. The patient recovers from
surgery without signs or symptoms of kidney injury.
Example 3
[0232] A patient is scheduled to undergo cardiovascular bypass
grafting. The patient's amount of urinary L-FABP before surgery is
3.1 .mu.g/g Creatinine. Although no special preventive measures are
taken, the patient recovers from surgery without signs or symptoms
of kidney injury.
[0233] All references cited in this specification are herewith
incorporated by reference with respect to their entire disclosure
content and the disclosure content specifically mentioned in this
specification.
[0234] While this disclosure has been described as having an
exemplary design, the present disclosure may be further modified
within the spirit and scope of this disclosure. This application is
therefore intended to cover any variations, uses, or adaptations of
the disclosure using its general principles. Further, this
application is intended to cover such departures from the present
disclosure as come within the known or customary practice in the
art to which this disclosure pertains.
* * * * *