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WO2012146645A1 - Diagnostic de blessure du rein suite à une intervention chirurgicale - Google Patents

Diagnostic de blessure du rein suite à une intervention chirurgicale Download PDF

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Publication number
WO2012146645A1
WO2012146645A1 PCT/EP2012/057619 EP2012057619W WO2012146645A1 WO 2012146645 A1 WO2012146645 A1 WO 2012146645A1 EP 2012057619 W EP2012057619 W EP 2012057619W WO 2012146645 A1 WO2012146645 A1 WO 2012146645A1
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WO
WIPO (PCT)
Prior art keywords
sample
amount
sflt
subject
surgery
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2012/057619
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English (en)
Inventor
Georg Hess
Dietmar Zdunek
Andrea Horsch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Roche Diagnostics GmbH filed Critical F Hoffmann La Roche AG
Publication of WO2012146645A1 publication Critical patent/WO2012146645A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy

Definitions

  • the present invention relates to the field of laboratory diagnostics. Specifically, means and methods for diagnosing acute kidney injury associated with a major surgery based on the bio marker sFlt-1 are disclosed.
  • Patients with advanced coronary artery disease may suffer from stable and/or unstable angina. This is caused by advanced coronary artery disease which can be classified into 1 , 2 or 3 vessel disease depending on the number of affected coronary arteries.
  • PCI percutaneous cardiovasacular intervention
  • CABG coronary artery bypass graft surgery
  • PCI percutaneous cardiovasacular intervention
  • CABG coronary artery bypass graft surgery
  • Coronary bypass surgery is, however associated with a significant risk of complications.
  • the incidence of acute kidney injury (AKI) after coronary bypass surgery ranges from 10 to 20 % (Mehta et al, Circulation 2006, 114: 2208 - 2216).
  • One to 5 percent of these individuals require postoperative dialysis.
  • the pathogenesis of postoperative AKI is multifactorial and its association with increased morbidity and long term mortality after cardiac surgery is well established. (Brown et al, Annals of Thoracic Surgery 2008, 86: 4 - 11 : Kourliouros et al, European Journal of Cardiothoracic Surgery 2009, in press).
  • AKI may be prevented in risk patients.
  • Prevention includes careful fluid balance during and after surgery, avoidance of low cardiopulmonary bypass /CPB) perfusion temperatures (Kourliouros et al), avoidance or discontinuation of potentially nephrotoxic drugs prior to surgery or application of drugs such as erythropoietin after surgery (Song et al American Journal of Nephrology 2009, 30: 253 - 260).
  • CPB cardiopulmonary bypass /CPB
  • Soluble fms-like thyrosine kinase- 1 (sFlT-1 or sVEGFR-1) is a splice variant of VEGF receptor 1 (FLT-1) which is produced by a variety of tissues. It is a thyrosine kinase protein that disables proteins that cause blood vessel growth.
  • Ataga et al. (Eur J Haematol. 2010 Sep;85(3):257-63) discloses that in sickle cell disease patients, sFlt-1 serum levels correlate with the magnitude of albuminuria which in turn indicates the degree of renal impairment.
  • Marco et al. J Am Soc Nephrol 20: 2235-2245 discloses that increased sFlt-1 (serum) levels are associated with impairment of renal function in an animal model of chronic kidney disease. It also discloses that sFlt-1 levels rise early in chronic kidney disease patients and that sFlt-1 possesses antiangiogenic effects which may contribute to the impairment of renal function.
  • the biomarker sFlt-1 is frequently measured in combination with the biomarker P1GF (Placental Growth Factor) in order for assessing preeclampsia.
  • P1GF Percental Growth Factor
  • the ratio of sFlt-1 to P1GF has been shown to be a reliable tool for predicting preeclampsia. Studies show that the determination of the ratio is a much better predictor of preeclampsia than the determination of sFlt-1 or P1GF alone (Hirashima C, et al. Establishing Reference Values for Both Total Soluble Fms-Like Tyrosine Kinase 1 and Free Placental Growth Factor in Pregnant Women. Hypertens Res 2005;28:727-732).
  • the present invention relates to a method for diagnosing acute kidney injury associated with major surgery in a subject, said method comprising the steps of
  • acute kidney injury is diagnosed by carrying out the further step of d) diagnosing acute kidney injury based on the result of the comparison carried out in step c).
  • the method of the present invention preferably, is an ex vivo or in vitro method. Moreover, it may comprise steps in addition to those explicitly mentioned above. For example, further steps may relate to sample pre-treatments or evaluation of the results obtained by the method.
  • the method may be carried out manually or assisted by automation. Prefera- bly, step (a), (b) and/or (c) may in total or in part be assisted by automation, e.g., by a suitable robotic and sensory equipment for the determination in step (a), or (b), or a computer- implemented comparison and/or diagnosis based on said comparison in step (b).
  • the subject shall not exhibit an acute coronary sy drome (ACS) at the time at which the sample(s) as referred to herein is (are) obtained. Moreover, the subject, preferably, is not pregnant.
  • ACS acute coronary sy drome
  • the risk subject suffers from cardiovascular atherosclerosis that requires treat- ment by coronary artery bypass surgery (CABP).
  • CABP coronary artery bypass surgery
  • a subject suffering from cardiovascular artherosclerosis accompanying diseases preferably diabetes and cardiovascular disease
  • the risk of the patient to suffer from acute kidney injury increases.
  • Diabetes is, preferably, type 1 or, more preferably, type 2 diabetes.
  • the subject to be tested in the context of the present invention may exhibit a pre-existing disorder of the renal tubules (for an explanation of this term, see below) before the major surgery. However, it is preferred that the subject does not exhibit a pre-existing disorder of the renal tubules. It has been shown in the context of the present invention that patients with AKI associated with major surgery without pre-existing disorders of the renal tubules had the highest levels of sFlt-1.
  • CABP acute kidney injury
  • AKI acute kidney injury
  • said AKI is post-renal, intrinsic and, more preferably, pre-renal.
  • the endpoint acute kidney injury within said window will become apparent, e.g. by an increase of the serum creatinine as defined elsewhere in this specification.
  • AKI is char- acterized by an increase of serum creatinine of at least 0.3 mg/dl within 48 hours after surgery or by an increase of at least 50 % from baseline (preferably within 48 hours after surgery). Methods and criteria to diagnose AKI have been described in Mehta et al. (2007) Critical Care (London, England) 11 (2): R31. doi: 10.1186/cc5713. PMC 2206446. PMID 17331245).
  • AKI may lead to various complications such metabolic acidosis, high potassium levels, uremia, changes in body fluid balance. Said changes in fluid balance may result in heart failure (or may worsen heart failure). Moreover, it may effect other organ systems. In se- vere cases of acute kidney injury, renal replacement therapy (including e.g. hemodialysis or renal transplantation) may be required. Early detection of AKI is of high importance, since it allows for an early treatment, thereby minimizing the risks associated with kidney injury. In particular, early recognition of AKI allows for taking measures to avoid necessi- ty of dialysis or complications that might be associated with fluid retention and volume overload such as heart failure.
  • sFlt-1 allows for an early assessment of AKI, i.e. even before AKI can be diagnosed via the de- termination of the aforementioned increase of serum creatinine. Accordingly, sFlt-1 is an earlier marker for AKI than creatinine. Thus, by determining the amount of sFlt-1 an in- crase of creatinine can be predicted. Preferably, an increase of serum creatinine of at least 0.3 mg/dl or by an increase of at least 50 % within 48 hours after surgery can be predicted. Accordingly, the term "diagnosis of AKI" as used herein, preferably, also refers to the pre- diction of an increase of serum creatinine of at least 0.3 mg/dl or by an increase of at least 50 % within 48 hours after surgery.
  • the first sample is, preferably, obtained prior to major surgery, i.e. before the subject undergoes the surgical procedure. More preferably, the sample has been obtained not more than two weeks, not more than one week, or, more preferably, not more than 3 days, and even more preferably, not more than one day before said surgery. It is particularly contemplated that the first sample has been obtained not more than 6 hours, not more than 3 hours, not more than 2 hours, and, more preferably, 1 hour before the major surgery.
  • the "second sample” is, preferably, understood as a sample which is obtained in order to reflect a change of the amount of the sFlt-1 as compared to the amount of the respective marker in the first sample.
  • the second sample shall be obtained after the first sample.
  • the second sample is not obtained too early after the first sample (in order to observe a sufficiently significant change to allow for monitoring).
  • the second sample has been obtained during or after a major surgery. It is particularly contemplated that the second sample has been obtained after the surgical procedure has been completed, preferably, within a time period of not later than 1, 2 or 3 days after surgery. It is more preferred that the second sample has been obtained immediately or not later than 1 day after completion of the surgery.
  • the sample has been obtained immediately after surgery.
  • the sample is preferably obtained within a period of 0 to 6 hours, 0 to 3 hours, 0 to 2 hours, or 0 to 1 hour after the surgery (or more precisely after completion of the surgery).
  • the second sample has been obtained at the end of surgery.
  • the time "X hours after surgery" is calculated from the time point when the respiration support (e.g.
  • 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 invention (Nolan 2002, Trends Biotech- no 1. 20(1):9-12).
  • the carrier e.g. a microbead or microsphere
  • 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 (US 5,744,305).
  • nephrotoxic medication in particular of NSIADs (nonsteroidal anti-inflammatory drugs) , COX 2 inhibitors, ACE inhibitors and Angiotensin II receptor blockers shall be avoided once the diagnosis has been made.
  • NSIADs nonsteroidal anti-inflammatory drugs
  • COX 2 inhibitors COX 2 inhibitors
  • ACE inhibitors ACE inhibitors
  • Angiotensin II receptor blockers shall be avoided once the diagnosis has been made.
  • blood pressure lowering medicaments shall be administered.
  • careful fluid balance is important in subject for which the diagnosis of AKI has been established.
  • the method of the present invention preferably, is an ex vivo or in vitro method. Moreover, it may comprise steps in addition to those explicitly mentioned above. For example, further steps may relate to sample pre-treatments or evaluation of the results obtained by the method.
  • the method may be carried out manually or assisted by automation.
  • step (a) and/or (b) may in total or in part be assisted by automation, e.g., by a suitable robotic and sensory equipment for the determination in step (a) or a computer-implemented comparison and/or diagnosis based on said comparison in step (b).
  • the subject according to the present invention preferably, has undergone or shall undergo a major surgery at the time at which the sample as referred to in the context of the aforementioned method is obtained.
  • 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 re- suit of the comparison, i.e. automatically provide the desired assessment in a suitable output format.
  • the reference amount is to be chosen so that either a difference or a similarity in the compared amounts allows for diagnosing AKI, and, thus, for identifying those test subjects which suffer from AKI associated with major surgery (rule-in) or not (rule out).
  • ischemic complications in the kidney refers to a condition of the kidney characterized by a reduced delivery of oxygen (undersupply) to kidney tissue, preferably, the renal tubules.
  • tissue is affected by ischemia, if the amount of oxygen that is supplied to said tissue is not sufficient in order to cover the need of the cells comprised by said tissue, and, thus, to meet the rate of mitochondrial oxidation in said cells.
  • AKI may occur.
  • the ischemic complications shall be caused by the major surgery.
  • the "disorder of the renal tubules" is well understood by the skilled person.
  • sFlt-1, Troponin T (hsTNT), GDF-15 and NT-proBNP were determined with sandwich immunoassays using analyzers from Elecsys or COBAS e-series.
  • the assays comprise two monoclonal antibodies specific for the respective peptide. The first of these iv biotinylated and the second one in labelled with a Tris(2,2'-bibyridyl)ruthemium (Il)-complex. In a first incubation step both antibodies are incubated with the sample.
  • Table 4 GDF15 levels in patients with and without AKI at various time points

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Endocrinology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
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  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention concerne le domaine des diagnostics en laboratoire. Plus précisément, l'invention concerne des moyens et des procédés permettant de diagnostiquer une blessure aiguë du rein associée à une intervention chirurgicale majeure sur la base du biomarqueur sFLt-1. De plus, la présente invention concerne des moyens et des procédés permettant d'effectuer le suivi d'une intervention chirurgicale majeure.
PCT/EP2012/057619 2011-04-27 2012-04-26 Diagnostic de blessure du rein suite à une intervention chirurgicale Ceased WO2012146645A1 (fr)

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EP11163951 2011-04-27
EP11163951.4 2011-04-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020064995A1 (fr) * 2018-09-28 2020-04-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de biomarqueurs représentant des voies cardiaques, vasculaires et inflammatoires permettant la prédiction d'une lésion rénale aiguë chez des patients atteints de diabète de type 2

Citations (6)

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WO1999006445A1 (fr) 1997-07-31 1999-02-11 The Johns Hopkins University School Of Medicine Facteur de differenciation en cours de croissance 15
EP1016596A1 (fr) 1998-12-28 2000-07-05 ITW Litec France, société par actions simplifiée Profilé en U pliable
WO2000070051A1 (fr) 1999-05-17 2000-11-23 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Und Zum Vertrieb Von Pharmaka Mbh PROPRIETES NEUROPROTECTRICES DU GDF-15, UN NOUVEAU MEMBRE DE LA SUPERFAMILLE DE TGF-$g(b)
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US5744305A (en) 1989-06-07 1998-04-28 Affymetrix, Inc. Arrays of materials attached to a substrate
WO1999006445A1 (fr) 1997-07-31 1999-02-11 The Johns Hopkins University School Of Medicine Facteur de differenciation en cours de croissance 15
EP1016596A1 (fr) 1998-12-28 2000-07-05 ITW Litec France, société par actions simplifiée Profilé en U pliable
WO2000070051A1 (fr) 1999-05-17 2000-11-23 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Und Zum Vertrieb Von Pharmaka Mbh PROPRIETES NEUROPROTECTRICES DU GDF-15, UN NOUVEAU MEMBRE DE LA SUPERFAMILLE DE TGF-$g(b)
WO2005113585A2 (fr) 2004-05-20 2005-12-01 Acceleron Pharma Inc. Superfamille des polypeptides tgf-beta modifiés et procédés atenants
WO2009141357A1 (fr) * 2008-05-20 2009-11-26 Roche Diagnostics Gmbh Facteur gdf-15 utilisé comme biomarqueur dans le diabète de type 1

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020064995A1 (fr) * 2018-09-28 2020-04-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de biomarqueurs représentant des voies cardiaques, vasculaires et inflammatoires permettant la prédiction d'une lésion rénale aiguë chez des patients atteints de diabète de type 2

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