U.S. patent application number 12/076410 was filed with the patent office on 2009-09-24 for method for the early identification and prediction of kidney injury.
This patent application is currently assigned to BIOTRIN INTELLECTUAL PROPERTIES LIMITED. Invention is credited to Cormac Gerald Kilty, Jay Lawrence Koyner, Claire Victoria McGrath, Patrick Thomas Murray, Kerstin Schuster.
Application Number | 20090239242 12/076410 |
Document ID | / |
Family ID | 39691082 |
Filed Date | 2009-09-24 |
United States Patent
Application |
20090239242 |
Kind Code |
A1 |
Kilty; Cormac Gerald ; et
al. |
September 24, 2009 |
Method for the early identification and prediction of kidney
injury
Abstract
A method for the early identification and prediction of elevated
blood creatinine levels resulting from a reduction in kidney
function in a subject, comprises contacting a urine sample from the
subject with a capture molecule for a biomarker specific for the
distal region of the renal tubule and which biomarker is released
from said region when there is damage to said region indicative and
predictive of elevated blood creatinine levels resulting from a
reduction in kidney function. The method can be used to detect
Acute Kidney Injury (AKI) caused by many conditions or diseases or
through the administration of drugs. The method can indicate and/or
predict a reduction in kidney function significantly earlier than
the current standard creatinine test. Methods for predicting a need
for renal replacement therapy (RRT) are also disclosed.
Inventors: |
Kilty; Cormac Gerald;
(Sandycove, IE) ; Koyner; Jay Lawrence; (Chicago,
IL) ; McGrath; Claire Victoria; (Dun Laoghaire,
IE) ; Murray; Patrick Thomas; (Chicago, IL) ;
Schuster; Kerstin; (Blackrock, IE) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
BIOTRIN INTELLECTUAL PROPERTIES
LIMITED
|
Family ID: |
39691082 |
Appl. No.: |
12/076410 |
Filed: |
March 18, 2008 |
Current U.S.
Class: |
435/7.4 ;
435/193; 435/7.9; 436/501 |
Current CPC
Class: |
G01N 2333/91177
20130101; G01N 33/6893 20130101; G01N 2800/347 20130101 |
Class at
Publication: |
435/7.4 ;
436/501; 435/193; 435/7.9 |
International
Class: |
G01N 33/573 20060101
G01N033/573; G01N 33/53 20060101 G01N033/53; C12N 9/10 20060101
C12N009/10 |
Claims
1. A method for the early identification and prediction of elevated
blood creatinine levels resulting from a reduction in kidney
function in a subject, which method comprises contacting a urine
sample from the subject with a capture molecule for a biomarker
specific for the distal region of the renal tubule and which
biomarker is released from said region when there is damage to said
region indicative and predictive of elevated blood creatinine
levels resulting from a reduction in kidney function.
2. A method according to claim 1, wherein the reduction in kidney
function is caused by Acute Kidney Injury (AKI).
3. A method according to claim 2, wherein the AKI is caused by a
condition or disease selected from age, burns, pre-existing chronic
kidney disease, reduced effective arterial volume, volume
depletion, nephrotic syndrome, congestive heart failure, cirrhosis,
sepsis, type I diabetes, type II diabetes, obesity, inflammation,
surgery, solid organ transplant, allogenic bone marrow transplant,
mechanical ventilation and/or trauma.
4. A method according to claim 2, wherein the AKI is caused by
administration of a drug to the subject.
5. A method according to claim 4, wherein the drug is selected from
aminoglycosides, non-steroidal anti-inflammatory drugs and
radiocontrast drugs.
6. A method according to claim 2, wherein the AKI is caused by
renal ischemia in a patient undergoing cardiothoracic (CT)
surgery.
7. A method according to claim 6, wherein the biomarker is
detectable as early as intraoperatively, allowing for immediate
corrective medical intervention.
8. A method according to claim 6, wherein the biomarker is
detectable in the recovery stage post CT surgery, allowing for
immediate corrective medical intervention.
9. A method according to claim 8, wherein the biomarker is
detectable prior to transfer of the patient to the Intensive Care
Unit (ICU).
10. A method according to claim 1, wherein the biomarker is pi
glutathione S transferase (.pi.GST).
11. A method according to claim 1, wherein the biomarker is
detected by immunoassay.
12. A method according to claim 11, wherein the capture molecule is
an antibody to .pi.GST.
13. A method according to claim 10, wherein the biomarker is
detected enzymatically.
14. A method according to claim 1, wherein the biomarker is
detected by a point-of-care assay.
15. .pi.GST for use as a biomarker for the early identification and
prediction of elevated blood creatinine levels resulting from a
reduction in kidney function.
16. A method for predicting a need for renal replacement therapy
(RRT) in a patient comprising: determining a concentration of
glutathione S transferase (GST) in a first urine sample from the
patient; and wherein a need for RRT is predicted when the GST
concentration is determined to be elevated in comparison to a
patient without kidney injury.
17. A method according to claim 16, further comprising contacting a
urine sample from the patient with a capture molecule for a GST
isozyme.
18. A method according to claim 16, wherein the GST is .pi.GST.
19. A method according to claim 16, wherein the GST is detected by
immunoassay.
20. A method according to claim 19, wherein the capture molecule is
an antibody to .pi.GST.
21. A method according to claim 16, wherein the GST is detected
enzymatically.
22. A method according to claim 16, wherein the GST is detected by
a point-of-care assay.
23. A method for predicting a need for RRT in a patient comprising:
determining a concentration of GST in two urine samples taken at
least 24 hours apart from the patient; and wherein a need for RRT
is predicted when the GST concentration is determined to be
elevated in the two urine samples.
24. A method according to claim 16, wherein the elevated GST
concentration in urine is .gtoreq.30 ng/ml.
25. A method according to claim 16, wherein the elevated GST
concentration in urine is .gtoreq.60 ng/ml.
26. A method according to claim 16, wherein the elevated GST
concentration in urine is .gtoreq.70 ng/ml.
27. A method according to claim 16, wherein the elevated GST
concentration in urine is .gtoreq.80 ng/ml.
28. A method according to claim 16, wherein the elevated GST
concentration in urine is .gtoreq.90 ng/ml or more.
29. A method according to claim 16, wherein the GST is a .pi.GST
isozyme.
30. A method according to claim 16, wherein the patient is affected
by an age-related condition, burns, pre-existing chronic kidney
disease, reduced effective arterial volume, volume depletion,
nephrotic syndrome, congestive heart failure, cirrhosis, sepsis,
type I diabetes, type II diabetes, obesity, inflammation, surgery,
being a solid organ transplant recipient, being an allogenic bone
marrow transplant recipient, mechanical ventilation and/or trauma
or has taken or has been administered an antibiotic, drug and/or
toxin.
31. A method according to claim 16, further comprising detecting
for the presence of risk factors for RRT in the patient wherein the
risk factor is selected from the group consisting of elevated serum
creatinine concentration, type I diabetes, type II diabetes,
hypertension, dyslipidemia, hyperglycaemia, proteinuria and
hypoalbuminemia.
Description
TECHNICAL FIELD
[0001] This invention relates to the early identification and
prediction of kidney damage, including early identification and
prediction of elevated blood creatinine levels resulting from a
reduction in kidney function in a subject and, in particular, to
biomarkers for the detection thereof.
BACKGROUND ART
[0002] There are many causes of a reduction in kidney function and
it is essential that corrective action is taken as early as
possible by appropriate medical intervention so as to minimise as
far as possible the deleterious consequences, which include total
renal failure and a need for dialysis and ultimately kidney
transplant. For example, an abrupt reduction in kidney function
occurs frequently following cardiothoracic (CT) surgery. Thus,
Acute Kidney Injury (AKI) is common following CT surgery occurring
in 7-42% of patients (Mora Mangano, C. et al (1998) Ann Intern Med
128:194-203; and Tuttle, K. R. et al (2003) Amer J. Kid Dis
41:76-83.) Small changes in serum creatinine have been shown to
correlate with increased morbidity and mortality, following CT
surgery (Lassnigg, A. et al (2004) J. Am Soc Nephrol 15;
1597-1605)
[0003] Measurement of creatinine is the standard test in the clinic
for measuring kidney function. If kidney function is abnormal,
creatinine levels will increase in the blood due to decreased
excretion of creatinine in the urine. Creatinine levels vary
according to a person's age, size and muscle mass. In acute
conditions build up of creatinine in the blood may take up to 24-72
hours to occur.
[0004] Patients who develop severe AKI requiring Renal Replacement
Therapy (RRT), after CT surgery have a greatly increased
in-hospital mortality (63%) compared to those with non-dialyzed AKI
(19%), or stable renal function (0.9%) (Mora Mangano, C. et al
(1998) supra).
[0005] Koyner, J. L. et al (poster presentation at American Society
of Nephrology, Renal Week 2007, Oct. 31-Nov. 5, 2007, Moscone
Center, San Francisco, Calif.) have investigated urinary Cystatin C
(CyC) and Neutrophil Gelatinase--Associated Lipocalin (NGAL) in
patients with AKI following adult cardiac surgery. Koyner, J L et
al found that urinary CyC excretion increases in the early
post-operative period following adult CT surgery and concluded that
urinary CyC may be a useful early biomarker for the development of
AKI as it appears to correlate with the severity of AKI and thus
the future need of RRT. Similarly, Koyner, J L et al found that
urinary NGAL in the early post-operative period appears to predict
the development of AKI and correlate strongly with the future need
of RRT.
[0006] U.S. Publication 2004/0219603 discloses that urinary NGAL
measured within two hours of cardiac surgery was predictive of
Acute Renal Failure (ARF) as reflected by serum creatinine peak,
which occurs several hours or even days later.
[0007] Koyner J. L. et al (2007) (supra) show that for both CyC and
NGAL the main increase occurs in the ICU (Intensive Care Unit)
phase post CT surgery.
[0008] Eijkenboom, J. J. A. et al (2005) Intensive Care Med
31:664-667 show that an increase in Glutathione S-Transferase
(GST), excretion following cardiac surgery was not correlated with
changes in plasma creatinine and is not associated with clinically
relevant renal injury.
[0009] Davis, C. L. et al (1999) J Am Soc Nephrol 10: 2396-2402
disclose that urinary GST excretion increased in most patients
after CPB, however, this increase was not associated with the
development of clinically apparent ARF.
[0010] There is a need for a biomarker which predicts elevated
blood creatinine levels resulting from an abrupt reduction in
kidney function and thus the development of AKI at the earliest
stage post CT surgery, ideally at zero hours in the recovery room
and prior to transfer to ICU or earlier, namely intraoperatively,
so as to enable corrective action to be taken as soon as possible
for those patients who develop AKI with the attendant
consequences.
[0011] Currently no drug therapy is available for counteracting the
effects of a reduction in kidney function as seen, for example in
post CT surgery. Accordingly, the surgeon and other attending
medical professionals will endeavour to reduce the effects of renal
ischemia or other causative effect by managing fluid levels and
other physiological parameters. However, as indicated above,
frequently, if such measures do not prove successful, the patient
will require RRT, namely dialysis.
DISCLOSURE OF THE INVENTION
[0012] Accordingly, the invention provides in a first aspect a
method for the early identification and prediction of elevated
blood creatinine levels resulting from a reduction in kidney
function in a subject, which method comprises contacting a urine
sample from the subject with a capture molecule for a biomarker
specific for the distal region of the renal tubule and which
biomarker is released from said region when there is damage to said
region indicative and predictive of elevated blood creatinine
levels resulting from a reduction in kidney function.
[0013] The method according to the invention, provides a means of
detecting damage to, and predicting the extent of damage to, the
kidney within two hours or less of the damage occurring with the
attendant advantages for the patient.
[0014] By "capture molecule" herein is meant any molecule or
portion thereof which binds reversibly or irreversibly to said
biomarker, so that said biomarker can be detected in the urine
sample.
[0015] According to one embodiment of the invention, the reduction
in kidney function is caused by Acute Kidney Injury (AKI).
[0016] According to a further embodiment of the invention, the AKI
is caused by a condition or disease selected from age, burns,
pre-existing chronic kidney disease, reduced effective arterial
volume, volume depletion, nephrotic syndrome, congestive heart
failure, cirrhosis, sepsis, type I diabetes, type II diabetes,
obesity, inflammation, surgery, solid organ transplant, allogenic
bone marrow transplant, mechanical ventilation and/or trauma.
[0017] According to a still further embodiment of the invention,
the AKI is caused by administration of a drug to the subject,
including antibiotics.
[0018] Preferably, the drug is selected from aminoglycosides,
non-steroidal anti-inflammatory drugs and radiocontrast drugs.
[0019] It will be appreciated that the AKI may be caused by a
toxin.
[0020] According to a further embodiment of the invention, the AKI
is caused by renal ischemia in a patient undergoing cardiothoracic
(CT) surgery.
[0021] Preferably, the biomarker is detectable as early as
intraoperatively, allowing for immediate corrective medical
intervention.
[0022] The method according to the invention, by providing a means
of detecting damage to, and predicting the extent of damage to, the
kidney as early as intraoperatively represents a very significant
advance in the management and treatment of patients undergoing CT
surgery.
[0023] According to one embodiment of the invention, the biomarker
is detectable in the recovery stage post CT surgery, allowing for
immediate corrective medical intervention.
[0024] The method according to the invention, by providing a means
of detecting damage to, and predicting the extent of damage to, the
kidney in the recovery stage post CT surgery, allows for the
appropriate medical intervention to be taken, dependent on the
level of the biomarker detected during the recovery stage or
earlier, namely intraoperatively.
[0025] Thus, the method according to the invention can indicate
and/or predict a reduction in kidney function significantly earlier
than the current standard creatinine test or other current methods
hereinabove mentioned.
[0026] Preferably, the biomarker is detectable prior to transfer of
the patient to the Intensive Care Unit (ICU).
[0027] When the abrupt reduction in kidney function is caused by
AKI, the reduction in kidney function can be reversed by managing
fluid levels and other physiological parameters.
[0028] The abrupt reduction in kidney function may result in a
requirement for Renal Replacement Therapy (RRT).
[0029] In such a situation, the RRT will generally involve putting
the patient on dialysis supplemented, as required, by managing
fluid levels and other physiological parameters.
[0030] Thus, it will be appreciated that use of the method
according to the invention can result in a significant reduction of
the deleterious side effects of renal ischemia in a patient
undergoing CT surgery.
[0031] Preferably, the biomarker is pi glutathione S transferase
(.pi.GST), also referred to hereinafter as pi GST.
[0032] According to one embodiment, the biomarker is detected by
immunoassay.
[0033] When the biomarker is .pi.GST, the capture molecule is
preferably an antibody to .pi.GST. The antibody may be a monoclonal
or a polyclonal antibody which binds to .pi.GST.
[0034] For example, the biomarker .pi.GST can be detected using an
enzyme immunoassay, more particularly an Enzyme Linked
Immunosorbent Assay (ELISA). In this regard, the .pi.GST can be
assayed using a commercially available kit marketed by Biotrin
International Limited, Dublin, Ireland as PI GST EIA, (Catalogue
No. BIO 85) which is a 96 well EIA assay format kit. However, any
other conventional assay for detecting .pi.GST can be used.
[0035] It will be appreciated that when the biomarker is .pi.GST,
an enzyme, then the capture molecule therefor can also be a
substrate or co-factor therefor.
[0036] Accordingly, according to a further embodiment of the
invention, the biomarker can be detected enzymatically.
[0037] According to one embodiment of the invention the biomarker
is detected by a point-of-care assay.
[0038] A point-of-care assay will typically be performed on a urine
sample of less than 500 .mu.l, typically 10 .mu.l or less. In a
point-of-care assay in accordance with the invention, the capture
medium will be suitably a dip-stick or like device having the
capture molecule affixed thereto.
[0039] The invention also provides .pi.GST for use as a biomarker
for the early identification and prediction of elevated blood
creatinine levels resulting from a reduction in kidney
function.
[0040] According to a further aspect of the invention, there is
provided a method for predicting a need for renal replacement
therapy (RRT) in a patient comprising:
[0041] determining a concentration of glutathione S transferase
(GST) in a first urine sample from the patient; and
[0042] wherein a need for RRT is predicted when the GST
concentration is determined to be elevated in comparison to a
patient without kidney injury.
[0043] Without being bound by any theoretical explanation of the
invention, it is believed that elevated urinary GST concentrations
can be used to differentiate between patients with less severe
acute kidney injury not likely to require RRT and those for whom
RRT, for example peritoneal dialysis, hemofiltration, renal
transplantation and the like, will be required.
[0044] According to this aspect of the invention, the method may
further comprise contacting a urine sample from the patient with a
capture molecule for a GST isozyme.
[0045] According to one embodiment of the invention, the GST is
.pi.GST.
[0046] The GST can be detected by immunoassay and the capture
molecule can be an antibody to .pi.GST.
[0047] Alternatively, the GST can be detected enzymatically as in
the case of the method hereinabove described.
[0048] Furthermore, the GST can be detected by a point-of-care
assay, as hereinbefore described.
[0049] Elevated urinary GST concentrations can persist for days in
a patient in need of RRT.
[0050] According to a still further aspect of the invention there
is provided a method for predicting a need for RRT in a patient
comprising;
[0051] determining a concentration of GST in two urine samples
taken at least 24 hours apart from the patient; and
[0052] wherein a need for RRT is predicted when the GST
concentration is determined to be elevated in the two urine
samples.
[0053] The elevated GST concentration in the urine can, for
example, be .gtoreq.30 ng/ml, .gtoreq.60 ng/ml, .gtoreq.70 ng/ml,
.gtoreq.80 ng/ml, .gtoreq. or 90 ng/ml or more.
[0054] According to this embodiment of the invention, the GST is
preferably a .pi.GST isozyme.
[0055] The cause of the underlying renal dysfunction in the patient
for whom RRT is predicted can, for example, be such that the
patient is affected by an age-related condition, burns,
pre-existing chronic kidney disease, reduced effective arterial
volume, volume depletion, nephrotic syndrome, congestive heart
failure, cirrhosis, sepsis, type I diabetes, type II diabetes,
obesity, inflammation, surgery, being a solid organ transplant
recipient, being an allogenic bone marrow transplant recipient,
mechanical ventilation and/or trauma or has taken or has been
administered an antibiotic, drug and/or toxin.
[0056] The method according to this aspect of the invention can
further comprises detecting for the presence of risk factors for
RRT in the patient wherein the risk factor is selected from the
group consisting of elevated serum creatinine concentration, type I
diabetes, type II diabetes, hypertension, dyslipidemia,
hyperglycaemia, proteinuria and hypoalbuminemia.
[0057] The invention will be described herein with reference to one
cause of a reduction in kidney function, namely that which
frequently occurs in a patient undergoing CT surgery.
[0058] Preferably, the biomarker is detected earlier than 2 hours
post CT surgery or earlier than two hours post Cardio-Pulmonary
Bypass (CPB).
[0059] Further, preferably, the biomarker is detected at zero hours
post CT surgery or CPB.
[0060] It will be appreciated that individuals have different
urinary biomarker reference baseline levels. Therefore,
post-operative or post-treatment results should be considered in
relation to the patient's pre-operative or pre-treatment reference
baseline biomarker level, as appropriate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0061] FIG. 1 is a graph of % change in Serum Creatinine (SCr)
concentration from baseline versus time as described in Example
1;
[0062] FIG. 2. is a graph of absolute change in SCr concentration
(mg/dl) from baseline versus time as described in Example 1;
[0063] FIG. 3. is a graph of .pi.GST concentration (ng/ml) versus
time as described in Example 1;
[0064] FIG. 4. is a graph of .pi.GST concentration (ng/ml) versus
time as described in Example 2;
[0065] FIG. 5. is a graph of SCr concentration as % of baseline
value versus time as described in Example 2; and
[0066] FIG. 6. is a graph of absolute change in SCr concentration
from baseline (mg/dl) versus time as described in Example 2.
MODES FOR CARRYING OUT THE INVENTION
[0067] The invention will be further illustrated by the following
Examples
Example 1
Use of .pi.GST as a Biomarker for AKI in Patients Undergoing CT
Surgery
[0068] A retrospective study of 68 patients who had undergone
elective CT surgery at the University of Chicago Hospital was
carried out.
[0069] The patients were screened and approached for enrollment.
The patients were excluded if they met any of the following
criteria:
Pre-existing End Stage Renal Disease (ESRD) (on RRT) or Renal
Transplant.
[0070] Age <18 years old. Use of radiocontrast within 24 hours
of surgery. Change in thyroid hormone replacement dose in the last
2 weeks Change in thyroid chronic corticosteroids dose in the last
2 weeks Unstable renal function (.DELTA. Serum Creatinine
.gtoreq.0.2 mg/dl in the last 2 months of Oliguria defined as
<400 ml/day).
[0071] Urine and blood samples were collected and stored.
[0072] The urine samples were tested for the presence of .pi.GST
using the aforementioned .pi.GST EIA available from Biotrin
International Limited (Catalogue Number BIO85).
[0073] Serum Creatinine (SCr) was measured using the Jaffe Method
in a manner known per se on a Beckman Unicel DxC 600 autoanalyser
(Beckman Coulter, Fullerton, Calif., USA).
[0074] AKI was determined by change in SCr as defined as:
[0075] An abrupt (within 48 hours) reduction in kidney function
currently defined as
[0076] 1) absolute increase in serum creatinine of more than or
equal to 0.3 mg/dl (.gtoreq.26.4 .mu.mol/l); or
[0077] 2) a percentage increase in serum creatinine of more than or
equal to 50% (1.5-fold from baseline).
[0078] This definition is consistent with the usual definition
used, for example, by Mehta, R. L., et al (2007) Critical Care; 11:
R31
[0079] The results are shown in Table 1 and FIGS. 1-3
TABLE-US-00001 TABLE 1 Future Development of AKI (as defined above)
by Day 2 post surgery AUC* for ROC** Curves &
Sensitivity/Specificity at indicated time points. AUC Sensitivity
Specificity Urinary Pi GST Post Op 0.679 63.6% 72.2% % SCr Post Op
0.5 0.0% 100.0% % SCr ICU Admit 0.5 0.0% 100.0% % SCr 6 hr post ICU
0.56 12.0% 100.0% % SCr Post Op Day 1 0.72 44.0% 100.0% .DELTA.SCr
Post Op 0.545 9.1% 100.0% .DELTA.SCr ICU Admit 0.538 7.7% 100.0%
.DELTA.SCr 6 hr post ICU 0.76 52.0% 100.0% .DELTA.SCr Post Op Day 1
0.84 68.0% 100.0% *Area under Curve. *Receiver Operating
Characteristic.
[0080] FIG. 1. shows the percentage change in SCr from
pre-operative baseline values for non-AKI patients (- -) and AKI
patients (-.box-solid.-). As shown in FIG. 1, the percentage change
in SCr does not increase until after the patients have been
admitted to ICU. However, as AKI is defined as an increase in SCr
of 1.5 fold from baseline, detection of AKI by SCr does not occur
until Day 2.
[0081] FIG. 2. shows the change in absolute value of SCr from
pre-operative baseline values for non-AKI patients (- -) and AKI
patients (-.box-solid.-). As shown in FIG. 2, a significant
increase in SCr concentration does not occur until 6 hours post ICU
in AKI patients. As the definition of AKI is an absolute increase
in SCr of more than or equal to 0.3 mg/dl, AKI would not be
diagnosed until after 6 h Post ICU.
[0082] FIG. 3. shows urinary .pi.GST levels following CT surgery
for non-AKI patients (- -) and AKI patients (-.box-solid.-). As
shown in FIG. 3, a significant increase in .pi.GST concentration is
observed in Post Op. This indicated that patients could be
diagnosed with AKI before they are admitted to ICU. Although an
increase in .pi.GST is observed in non-AKI patients, it is
significantly lower than AKI patient .pi.GST levels, allowing
diagnosis of AKI.
[0083] Significantly elevated levels of .pi.GST are detected
post-op, namely at zero hours.
[0084] Analysis of the data shows that .pi.GST is a good early
indicator of patients that will develop AKI by day 2 post
surgery.
Example 2
Use of .pi.GST as a Biomarker for a Requirement for RRT Patients
Undergoing CT Surgery
[0085] A study was carried out on the 68 patients, the subject of
Example 1, using the same methodology for the detection of SCr and
.pi.GST.
[0086] Seven patients out of the 68 patients tested required RRT.
The results are shown in Table 2.
TABLE-US-00002 TABLE 2 Baseline Creatinine Hours in Creatinine at
RRT ICU prior (mg/dL) (mg/dL) to RRT Indication 1 5.03 5.4 25.3
Refractory Hyperkalemia (6.0), Oliguria 2 1.49 3.48 51.2 Anuria,
Elevated creatinine, Shock 1.36 post-op 3 1.3 1.42 21.6 Volume
overload, Hypoxia, Oliguria, Hemodynamic instability *AKI not
diagnosed using current SCr measures* 4 1.2 3.79 26.8 Lactic
Acidosis Oliguria, Shock, Elevated creatinine 5 0.99 1.28 3 Lactic
Acidosis Anuria, Shock, *AKI not diagnosed using current SCr
measures* 6 1.19 1.74 5.3 Anuria, Shock (3 pressors), Volume
overload. Acidosis 7 1.66 2.8 81 Volume overload, pulmonary edema.
Shock
[0087] The time point at which patients requiring RRT would be
first diagnosed is shown in Table 3.
TABLE-US-00003 TABLE 3 SCr increase .gtoreq. 150% SCr increase
.gtoreq. 0.3 mg/dL Pi GST > 90 ng/ml Admit Admit Admit Post- to
6 hr post Post- to 6 hr post Post- to 6 hr post op ICU ICU Day 1
Day 2 op ICU ICU Day 1 Day 2 op ICU ICU Day 1 Day 2 1 Pos Pos 2 Pos
Pos Pos 3 Pos 4 Pos Pos Pos 5 Pos * Pos 6 Pos Pos Pos 7 Pos * No
sample available for testing
[0088] Table 4 shows the sensitivity and specificity of .pi.GST to
detect RRT as summarised therein.
TABLE-US-00004 TABLE 4 Time Cut off point No RRT RRT As determined
by Pi GST concentration # patients/group 90 ng/ml Post-op No AKI 43
1 AKI 9 3 Sensitivity: 83% Specificity: 83% As determined by % SCr
increase # patients/group 50% Post-op No AKI 49 5 AKI 0 0
Sensitivity: 0% Specificity: 100% # patients/group 50% Admit to No
AKI 60 7 ICU AKI 0 0 Sensitivity: 0% Specificity: 100% #
patients/group 50% 6 hr post No AKI 56 5 ICU admit AKI 2 1
Sensitivity: 17% Specificity: 97% # patients/group 50% Day 1 No AKI
51 4 AKI 8 3 Sensitivity: 43% Specificity: 86% # patients/group 50%
Day 2 No AKI 55 4 AKI 4 3 Sensitivity: 43% Specificity: 93% As
determined by increase of 0.3 mg/dl in SCr # patients/group 0.3
mg/dl Post-op No AKI 47 5 AKI 2 0 Sensitivity: 0% Specificity: 96%
# patients/group 0.3 mg/dl Admit to No AKI 58 5 ICU AKI 2 2
Sensitivity: 29% Specificity: 97% # patients/group 0.3 mg/dl 6 hr
post No AKI 47 3 ICU admit AKI 11 3 Sensitivity: 50% Specificity:
81% # patients/group 0.3 mg/dl Day 1 No AKI 41 3 AKI 18 4
Sensitivity: 57% Specificity: 69% # patients/group 0.3 mg/dl Day 2
No AKI 45 3 AKI 14 4 Sensitivity: 57% Specificity: 76%
[0089] The results are also depicted in FIGS. 4-6.
[0090] FIG. 4. shows the variation in urinary .pi.GST post CT
surgery for non-RRT patients (- -) and RRT patients
(-.box-solid.-). It will be noted that the .pi.GST level of RRT
Patients is significantly higher than non-RRT Patients at the Post
Op time point. FIG. 4 shows a concentration of 135 ng/ml is
reached, which is considerably higher than AKI patients shown in
FIG. 3 (75 ng/ml). This indicates severe AKI and that RRT is
required.
[0091] FIG. 5. depicts the variation in percentage SCr from
baseline post CT surgery for non-RRT patients (- -) and RRT
patients (-.box-solid.-). FIG. 5 shows that the percentage change
of SCr above baseline is not significantly elevated above 1.5 fold
increase (AKI) until Day 2. This indicates that the earliest
diagnosis that RRT is required using this technique would be two
days following surgery.
[0092] FIG. 6. shows the variation in SCr from baseline post CT
surgery for non-RRT patients (- -) and RRT patients (- -). It will
be noted from FIG. 6 that the absolute change in SCr peaked at Day
2, post surgery. At 6 h post ICU a level of 0.3 mg/dl was reached
which indicates AKI. Higher concentrations of SCr were measured at
Day 1 and Day 2 indicating severe AKI and a need for RRT. Using
this method, RRT would not begin until one day after surgery.
[0093] From FIG. 3 and FIG. 4 a relationship is evident between the
concentration of .pi.GST and the damage incurred to the patients'
kidneys. A .pi.GST concentration of 300%-500% relative to baseline
indicates AKI. However, a .pi.GST concentration greater than 500%
indicates severe AKI and a requirement for RRT.
[0094] The results show that .pi.GST is a very good early indicator
of patients that will require RRT undergoing and post CT surgery. *
* * * *
[0095] The above Examples show that .pi.GST can be used to detect
elevated blood creatinine, AKI and a requirement for RRT earlier
than with current biomarkers used to detect an abrupt reduction in
kidney function due to renal ischemia intraoperatively or post CT
surgery, with the attendant advantages.
* * * * *