WO2014142649A1 - Biomarqueurs pour diagnostic et pronostic améliorés de l'insuffisance rénale chronique - Google Patents

Biomarqueurs pour diagnostic et pronostic améliorés de l'insuffisance rénale chronique Download PDF

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WO2014142649A1
WO2014142649A1 PCT/NL2013/050191 NL2013050191W WO2014142649A1 WO 2014142649 A1 WO2014142649 A1 WO 2014142649A1 NL 2013050191 W NL2013050191 W NL 2013050191W WO 2014142649 A1 WO2014142649 A1 WO 2014142649A1
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subject
expression level
endostatin
biomarkers
kidney disease
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PCT/NL2013/050191
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English (en)
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Hiddo J. LAMBERS-HEERSPINK
Dick De Zeeuw
Roelf Datema
Wolfgang Woloszczuk
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Biomarker Design Forschungsgesellschaft Mbh
Rijksuniversiteit Groningen
Academisch Ziekenhuis Groningen
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Priority to PCT/NL2013/050191 priority Critical patent/WO2014142649A1/fr
Publication of WO2014142649A1 publication Critical patent/WO2014142649A1/fr

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    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N31/00—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods
    • G01N31/22—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators
    • G01N31/228—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators for peroxides

Definitions

  • the present invention relates to (a profile of) peripheral-blood biomarkers and methods of use thereof for screening, prevention, diagnosis, therapy-monitoring, and prognosis of kidney disease in patients with diabetes mellitus.
  • CKD Chronic Kidney Disease
  • GFR glomerular filtration rate
  • UAE urinary albumin excretion
  • CKD affects about 50 million people around the world, and its prevalence is rapidly increasing especially due to the increase of diabetes, one of the main causes of CKD.
  • Diabetes, especially type-2 diabetes is a globally rising health problem due to population growth, aging, urbanization, obesity, and physical inactivity. According to the diabetes atlas of the International Diabetes Federation, 366 million people were affected with diabetes in 2011, and diabetes prevalence is expected to rise to 552 million by 2030.
  • Diabetic nephropathy (or kidney disease) is histopathologically characterized by several changes in the kidney, such as nodular glomerulosclerosis, mesangial expansion, basement membrane thickening and interstitial fibrosis.
  • diabetic nephropathy is usually a constellation of persistent albuminuria, elevated arterial blood pressure and decline in glomerular filtartion rate.
  • Albuminuria is one of the first asymptomatic clinical manifestations of microvascular damage in diabetes and quantification of albuminuria in diabetic patients can be used to identify those who are at risk for long-term complications.
  • Increased urinary albumin excretion is often considered a sign of endothelial dysfunction representing dysfunctional filtration capability of the kidney. It has been shown that the presence of albuminuria is associated with progressive renal function loss and an increased risk of cardiovascular disease.
  • a reduction in the estimated glomerular filtration rate is also associated with renal and cardiovascular disease in individuals with diabetes, and can be used to identify individuals at risk of long-term complications.
  • About 35% of diabetic patients have progressive renal function loss (defined by a GFR ⁇ 60 ml/min or presence of microalbuminuria) which eventually culminates in End Stage Renal Disease (ESRD).
  • ESRD End Stage Renal Disease
  • Reduction in GFR is the consequence of severely compromised kidney function and substantial loss and destruction of the glomeruli.
  • GFR is usually estimated by formulae based on serum creatinine concentration such in the Modification of Diet in Renal Disease (MDRD) equation.
  • MDRD Modification of Diet in Renal Disease
  • albuminuria a reduction in eGFR is associated with a higher risk to develop end-stage renal or cardiovascular disease. The finding that albuminuria and eGFR are independent additive risk markers was confirmed in a large meta-analysis.
  • the present invention relates to the identification of novel biomarkers for correlating their expression patterns as predictors of the risk or presence of kidney disease in a subject.
  • the biomarkers also find use in monitoring the progression of kidney disease or risk thereof in subjects.
  • the invention provides expression patterns that are able to identify subjects, such those with type 1 or type 2 diabetes, at risk for developing or suffering from kidney disease.
  • the present invention also relates to novel methods for treating subjects identified as at risk for developing or suffering from kidney disease comprising administering one or more therapeutic agents to delay the onset of or treat the kidney disease.
  • the present invention provides an objective means for identifying subjects, such as those with type 1 or type 2 diabetes mellitus, who are at risk for or are suffering from kidney disease by assaying for the expression level of one or more of the biomarkers described herein. Expression of these biomarkers thus provides an objective means to determine kidney disease risk with significant accuracy. These biomarkers may be used alone to determine kidney disease risk or may be used in combination with other objective or subjective criteria. The biomarkers described herein are identified as correlating with kidney disease in patients with type 2 diabetes mellitus such that their expression levels are relevant to determining appropriate treatment protocols.
  • the biomarkers described herein may be used singly with significant accuracy or in any combination, such as in the format of a ratio of expression levels, to increase the ability to accurately correlate an expression profile with a risk of kidney disease.
  • the ability to identify patients at risk for or suffering from kidney disease is conferred by the identification of an expression level of the biomarkers and not by the methodology used to determine such expression level.
  • the assay may utilize any feature of a biomarker described herein as long as the assay provides a qualitative or preferably a quantitative expression of the protein (or gene).
  • a biomarker can be measured or detected by a variety of methods, including, but not limited to immunohistochemistry (IHC), immunoassays, protein arrays, reverse protein arrays, nucleic acid arrays, mass spectroscopy, polymerase chain reaction (PCR) and the like.
  • IHC immunohistochemistry
  • PCR polymerase chain reaction
  • a method for determining if a subject is at risk to develop or is suffering from kidney disease comprising the steps of (a) determining the expression level of one or more biomarkers in one or more samples from the subject; (b) comparing the expression level determined in step (a) to a control expression level; and (c) correlating a higher relative expression level of the one or more biomarkers in the subject with the presence or risk of kidney disease in the subject.
  • the subject has been diagnosed with or is suspected of having type 1 or type 2 diabetes mellitus.
  • the test samples include but are not limited to blood, plasma, serum, and urine.
  • the method further comprises (d) managing subject treatment based on determination of risk, wherein the subject is administered one or more therapeutic agents to treat or prevent kidney disease if the subject is identified as having a risk of kidney disease.
  • additional objective criteria such as estimated glomerular filtration rate (eGFR) and/or proteinuria (e.g. albuminuria) are assessed in combination with the biomarkers to determine a subject's risk of kidney disease.
  • eGFR estimated glomerular filtration rate
  • proteinuria e.g. albuminuria
  • the expression level of one or more biomarkers in a subject is determined at multiple time points as a means of monitoring the progression of kidney disease or risk thereof in a subject.
  • additional objective criteria such as estimated glomerular filtration rate (eGFR) and/or proteinuria (e.g. albuminuria) are also measured at the multiple time points.
  • eGFR estimated glomerular filtration rate
  • proteinuria e.g. albuminuria
  • An increase in expression level of the one or more biomarkers and/or a decrease in the eGFR and/or an increase in proteinuria in the subject over time correlates with the progression of risk or disease in the subject.
  • a method for monitoring the effectiveness of kidney disease treatment in a subject is provided.
  • a method of preventing or treating kidney disease in a subject comprising (a) determining the expression level of one or more biomarkers in one or more samples from the subject; (b) comparing the expression level determined in step (a) to a control expression level and (c) administering the subject a therapeutic agent if the expression level of the one or more biomarkers is elevated relative to the control.
  • Preferred therapeutic agents are those which reduce blood pressure in the subject.
  • a diagnostic kit for determining the risk of development of kidney disease in a subject comprising (a) two or more antibodies against any two or more biomarkers and optionally (b) instructions for using the antibodies.
  • FIG. 1 Receiver operating characteristics (ROC) curves for eGFR plus diabetes duration (continuous lines) and for serum levels of TNF-RII plus eGFR plus diabetes duration (dashed line).
  • FIG. Receiver operating characteristcs (ROC) curves for eGFR plus diabetes duration (continuous lines) and for serum levels of endostatin plus eGFR plus diabetes duration (dashed line).
  • FIG. 3 Receiver operating characteristcs (ROC) curves for eGFR plus diabetes duration (continuous lines) and for serum levels of TNF-RII plus endostatin plus NTproCNP plus podocin, plus FGF-23 plus galectin-3 plus eGFR plus diabetes duration (dashed line).
  • ROC Receiver operating characteristcs
  • an antigen is a molecule capable of being bound by an antibody or T-cell receptor.
  • An antigen is additionally capable of inducing a humoral immune response and/or cellular immune response leading to the production of B- and/or T- lymphocytes.
  • the structural aspect of an antigen e.g., three dimensional conformation or modification (e.g., phosphorylation) that gives rise to a biological response is referred to herein as an "antigenic determinant" or "epitope.”
  • B-lymphocytes respond to foreign antigenic determinants via antibody production, whereas T-lymphocytes are the mediator of cellular immunity.
  • antigenic determinants or epitopes are those parts of an antigen that are recognized by antibodies, or in the context of an MHC, by T-cell receptors.
  • An antigenic determinant need not be a contiguous sequence or segment of protein and may include various sequences that are not immediately adjacent to one another.
  • antibody or "immunoglobulin” is used to include intact antibodies and binding fragments/segments thereof. Typically, fragments compete with the intact antibody from which they were derived for specific binding to an antigen. Fragments include separate heavy chains, light chains Fab, Fab', F(ab')2, Fabc, and Fv. Fragments/segments are produced by recombinant DNA techniques, or by enzymatic or chemical separation of intact immunoglobulins.
  • the term “antibody” also includes one or more immunoglobulin chains that are chemically conjugated to, or expressed as, fusion proteins with other proteins.
  • antibody also includes a bispecific antibody. A bispecific or bifunctional antibody is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments.
  • Biomarker refers to a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention without necessarily being causally related to the clinical endpoint. Biomarkers can be used as diagnostic tools, staging tools, prognostic tools or tools for prediction or monitoring of clinical response to an intervention. Biomarkers of the present invention are useful for assessing overall renal risk in patients with diabetes (e.g. type 2 diabetes). Protein biomakers include fragments thereof (preferably at least 10, 15, 20 25, 40, 50, 60, 70, 80, 90, 100, 120, 150, 180, 200, or at least 250 amino acids in length), and in particular, immunologically detectable fragments which may or may not possess a functional activity of the full length native protein.
  • control or "control expression level” as used herein refers to a baseline level of one or more biomarkers of the invention as determined from one, or preferably an average obtained from more than one, "normal” or “healthy” subjects believed not to or confirmed by diagnosis not to have kidney disease. Once a level has become established for a standard population, results from test samples can be directly compared with the predetermined control.
  • a baseline may be obtained from at least one subject and preferably is obtained from an average of subjects, wherein the subject or subjects have no prior history of kidney disease.
  • a level of a biomarker of the invention such as endostatin in a serum sample from a patient may be compared to the serum level of the same biomarker in an undiseased subject or an average serum level of more than one undiseased subject.
  • "normal" or “healthy” subject(s) are those with excretion of less than about 30 mg of albumin per 24 hour period (normoalbuminuria).
  • control refers to a baseline level of one or more biomarkers of the invention as determined from an average value in subjects with type 2 diabetes believed not to or confirmed by diagnosis not to have kidney disease.
  • a level of a biomarker such as endostatin in a serum sample from a patient may be compared to an average serum level obtained from multiple type 2 diabetics with normoalbuminuria.
  • the level of one or more biomarkers of the invention in a test sample to be measured is of the same type (obtained from the same biological source) and is processed in the same way as what is used for determination of the baseline control level. For example, if a level of endostatin in a patient is determined by measuring the level of endostatin in serum, the baseline level of endostatin is determined by measuring the level of endostatin in serum from e.g. subjects with normoalbuminuria.
  • a "high" expression level or an “increase” in the measured level of a biomarker relative to a predetermined control means that the amount or concentration of biomarker in a test sample is sufficiently greater in the test sample relative to the predetermined control level of biomarker.
  • an increase in the level of a biomarker relative to a predetermined control may be any increase which is detectable by ELISA or other suitable assay such as without limitation, at least about a 1%, about a 5%, about a 10%, about a 15%, about a 20%, about a 30%, about a 40%, about a 50%, about a 60%, about a 70%, about an 80%, about a 90%, about a 100% or about a 110% elevation or more relative to the predetermined control.
  • the increase in biomarker level is statistically significant.
  • a "high" expression level of biomarker in a test sample compared to control may refer to a detection level of an antibody above a predetermined threshold wherein the control level is below the predetermined threshold.
  • normal in the context of a diagnosis or prognosis refers to an individual or group of individuals who have not shown any symptoms of renal disease and are not known to suffer from the disorder.
  • Normal according to the invention also refers to samples isolated from normal individuals.
  • Normal according to the invention also refers to an expression level of one or more biomarkers that is in the reference range.
  • the present inventors have discovered novel biomarkers and combinations thereof which improve diagnostic accuracy and are predictive of the risk that a subject will experience progressive renal function decline.
  • the biomarkers and combinations thereof provide superior discriminatory power as compared to the traditional markers eGFR, albuminuria and duration of diabetes mellitus, for predicting whether a subject will experience progressive renal function decline.
  • These novel biomarkers and- combinations thereof can be used alone to provide an improved ability to predict whether a subject having or suspected of having diabetes mellitus (type 1 or 2) is at risk for developing or is suffering from kidney disease (or to monitor the development of kidney disease in this patient group) as compared to conventional markers such as eGFR, albuminuria and duration of diabetes mellitus, or can be superposed on top of one or more of these conventional markers.
  • albuminuria levels have been categorized into normoalbuminuria (urinary albumin excretion of less than 30 mg over a 24 hour period), microalbuminuria (urinary albumin excretion of between 30 and 300 mg over a 24 hour period) and macroalbuminuria (urinary albumin excretion of at least 300 mg over a 24 hour period).
  • normoalbuminuria urinary albumin excretion of less than 30 mg over a 24 hour period
  • microalbuminuria urinary albumin excretion of between 30 and 300 mg over a 24 hour period
  • macroalbuminuria urinary albumin excretion of at least 300 mg over a 24 hour period
  • the amount of albumin a sample is compared to the concentration of creatinine in order to control for variations in urine concentration.
  • normoalbuminuria may be defined as a urinary albumin/creatinine ratio (ACR) less than 30 mg albumin per gram creatinine
  • microalbuminuria may be defined as an ACR between 30 and 300 mg albumin/g creatinine
  • macroalbuminuria may be defined as an ACR of at least 300 mg albumin/g creatinine.
  • a transition in albuminuria class e.g. normoalbuminuria to microalbuminuria or from microalbuminuria to macroalbuminuria from baseline is an indicator of nephropathy onset or progression.
  • Onset of nephropathy can be defined as the development of microalbuminuria in previously normoalbuminuric patients (early nephropathy). Progression of nephropathy can be defined as the transition from normo- or micro- to macroalbuminuria, a change in the extent of albuminuria or a doubling of serum creatinine levels in micro- and macroalbuminuric patients (late nephropathy).
  • the glomerular filtration rate (GFR) describes the flow rate of fluid filtered through the kidney. GFR is an important indicator of excretory function of the kidneys and as such serves as a prognostic marker for kidney disease. Subjects with normal kidney function typically exhibit GFR above 90mL/min/1.73m 2 . A progressive decline in the estimated GFR (eGFR) relative to a previous measurement can be used as an indicator of kidney disease.
  • Biomarkers that may be measured or detected include, without limitation, proteins and nucleic acids. Proteins that can be used as biomarkers of kidney disease include, but are not limited to podocin, endostatin, galectin-3, T F-RII, aZGPl, FGF-23 and NTproC P and fragments thereof. The sequences of the biomarker proteins of the invention and their encoding nucleic acids are known in the art and have been deposited in gene databases such as GenBank.
  • the amino acid sequence of human podocin (also known as nephrosis 2, idiopathic, steroid resistant (NPHS2)) is set forth in GenBank Accession No. CAB83216.1 and the encoding DNA is set forth in GenBank Accession No. AJ279254.1.
  • the podocin to be quantified has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%>, at least 99% or 100%> identity with the amino acid sequence set forth in GenBank Accession No. CAB83216.1.
  • the amino acid sequence of human endostatin (the C-terminal fragment (amino acids 1572-1754) of collagen alpha- 1 (XVIII)) is set forth in GenBank Accession No. AAF01310 and the encoding DNA is set forth in GenBank Accession No. AF 184060.1.
  • the endostatin to be quantified has at least 80%>, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity with the amino acid sequence set forth in GenBank Accession No. AAF01310.
  • the amino acid sequence of human galectin-3 (also known as lectin, galactoside- binding, soluble 3 (LGALS3) is set forth in GenBank Accession No. BAA22164.1 and the encoding DNA is set forth in GenBank Accession No. AB006780.1.
  • the galectin-3 to be quantified has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%), at least 98%, at least 99% or 100% identity with the amino acid sequence set forth in GenBank Accession No. BAA22164.1.
  • TNF-RII also known as tumor necrosis factor receptor superfamily, member lb (TNFRSF1B)
  • TNFRSF1B tumor necrosis factor receptor superfamily, member lb
  • the encoding DNA is set forth in GenBank Accession No. BC052977.1.
  • the TNF-RII to be quantified has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity with the amino acid sequence set forth in GenBank Accession No. AAH52977.1.
  • the amino acid sequence of human aZGPl (also known as alpha-2-glycoprotein 1, zinc-binding (AZGPl)) is set forth in GenBank Accession No. AAH33830.1 and the encoding DNA is set forth in GenBank Accession No. BC033830.1.
  • the aZGPl to be quantified has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity with the amino acid sequence set forth in GenBank Accession No. AAH33830.1.
  • the amino acid sequence of human FGF-23 (fibroblast growth factor 23 precursor) is set forth in NCBI Reference Sequence No. NP_005238.1 and the encoding DNA is set forth in GenBank Accession No. NM_005247.2.
  • the FGF-23 to be quantified has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%), at least 99% or 100% identity with the amino acid sequence set forth in NCBI Reference Sequence No. NP_005238.1.
  • Preferred binding molecules e.g. antibodies
  • for detecting FGF-23 in a sample bind specifically to the C-terminal portion of FGF-23 (amino acids 181-251 of NP 005238.1) and therefore recognize both the active and inactive forms of FGF-23.
  • NTproCNP is the N terminal propeptide of C-type natriuretic peptide (CNP). It is a cleavage product of proCNP, is produced in equimolar amounts with CNP, and is measurable in plasma.
  • the amino acid sequence of human CNP precursor protein (preproCNP) is set forth at Accession Number NP_077720. A 23 amino acid signal peptide is removed converting it into proCNP (amino acid residues 24-126 of Accession Number NP_077720).
  • NTproCNP comprises amino acid residues 24-73 of Accession Number NP_077720.
  • the NTproCNP to be quantified has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity with amino acid residues 24-73 of Accession Number NP_077720.
  • the present invention provides a method for determining if a subject is at risk to develop or is suffering from kidney disease comprising the steps of (a) determining the expression level of one or more biomarkers selected from the group consisting of podocin, endostatin, galectin-3, TNF-RII, aZGPl, FGF-23 and NTproCNP in one or more blood, serum, plasma or urine samples from the subject; (b) comparing the expression level determined in step (a) to a control expression level; (c) correlating a higher relative expression level of the one or more biomarkers in the subject with the presence or risk of kidney disease in the subject and optionally (d) managing subject treatment based on determination of risk, wherein the subject is administered one or more therapeutic agents to treat or prevent kidney disease or a condition related thereto if the subject is identified as having a risk of kidney disease.
  • the subject may be a human or an animal, but is preferably a human. More preferably, the subject is a human that has been diagnosed with or is suspected
  • the present invention provides a method of preventing or treating kidney disease in a subject having or suspected of having diabetes mellitus comprising (a) determining the expression level of one or more biomarkers selected from the group consisting of podocin, endostatin, galectin-3, TNF-RII, aZGPl, FGF-23 and NTproCNP in one or more blood, serum, plasma or urine samples from the subject; (b) comparing the expression level determined in step (a) to a control expression level and (c) administering the subject a therapeutic agent for the treatment of kidney disease if the expression level of the one or more biomarkers is elevated relative to the control.
  • Preferred therapeutic agents are those which reduce blood pressure in the subject.
  • the present invention provides a method for monitoring the progression of kidney disease in a patient having or suspected of having kidney disease comprising the steps of (a) determining, at a first time point, the expression level of one or more biomarkers selected from the group consisting of podocin, endostatin, galectin- 3, T F-RII, aZGPl, FGF-23 and NTproC P in one or more blood, serum, plasma or urine samples from the subject; (b) determining, at a second time point, the expression level of one or more biomarkers selected from the group consisting of podocin, endostatin, galectin-3, TNF-RII, aZGPl, FGF-23 and NTproCNP in one or more blood, serum, plasma or urine samples from the subject and (c) comparing the expression level determined in step (a) to the expression level determined in step (b) wherein an increase in the expression level of one or more of the biomarkers indicates progression of kidney disease in the subject.
  • the present invention provides a method for monitoring the effectiveness of kidney disease treatment in a subject with an agent comprising the steps of (a) determining the expression level of one or more biomarkers selected from the group consisting of podocin, endostatin, galectin-3, TNF-RII, aZGPl, FGF-23 and NTproCNP in one or more blood, serum, plasma or urine samples obtained from the subject prior to administration of the agent; (b) determining the expression level of one or more biomarkers selected from the group consisting of podocin, endostatin, galectin- 3, TNF-RII, aZGPl, FGF-23 and NTproCNP in one or more blood, serum, plasma or urine samples obtained from the subject post-administration of the agent (c) comparing the expression level determined in step (a) to the expression level determined in step (b) and (c) altering the administration of the agent to the subject accordingly.
  • Biomarkers of kidney disease may be used alone or in any combination according to the methods described herein.
  • the expression of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or all 7 biomarkers selected from the group consisting of podocin, endostatin, galectin-3, TNF-RII, aZGPl, FGF-23 and NTproCNP is measured in one or more test samples from a patient. Elevated expression of any (and preferably of the majority or all) of these biomarkers relative to a control expression level correlates with an increased risk that the patient will develop or is suffering from kidney disease.
  • step (a) of the above described methods comprises determining the expression level of two or more biomarkers selected from the group consisting of podocin, endostatin, galectin-3, TNF-RII, aZGPl, FGF-23 and NTproCNP in one or more blood, serum, plasma or urine samples from the subject, wherein the two or more biomarkers include endostatin and/or TNF-RII.
  • the expression levels of one or more biomarkers selected from the group consisting of podocin, galectin-3, TNF-RII, aZGPl, FGF-23 and NTproCNP according to the methods of the invention is determined in one or more blood, serum or plasma samples from the subject.
  • the expression level of endostatin is determined in one or more blood, serum, plasma or urine samples from the subject.
  • the expression level of endostatin is determined in or more blood, serum, or plasma samples from the subject and in one or more urine samples from the subject.
  • additional biomarkers selected from the group consisting of FGF-23, podocin and galectin-3 are measured in one or more test samples from a subject.
  • the expression level is determined in a blood, serum or plasma sample from the subject.
  • the expression levels of at least endostatin and FGF-23 and/or podocin are measured in one or more test samples from a subject.
  • the expression of endostatin and FGF-23 may be measured; alternatively, the expression of endostatin and podocin may be measured; alternatively, the expression of endostatin and FGF-23 and podocin may be measured in one or more test samples from a subject.
  • FGF-23 and podocin are preferably measured in one or more blood, serum or plasma samples from the subject.
  • Endostatin is preferably measured in one or more blood, plasma, serum and/or urine samples from the subject.
  • the expression levels of at least endostatin and TNF-RII are measured in one or more test samples from a subject.
  • TNF-RII is preferably measured in one or more blood, plasma or serum samples from the subject but may also be measured in one or more urine samples from the subject.
  • Endostatin is preferably measured in one or more blood, plasma, serum and/or urine samples from the subject.
  • the expression levels of endostatin and TNF-RII and at least one (i.e. one, two or three) biomarkers selected from FGF-23 and/or galectin-3 and/or podocin are preferably measured in one or more blood, plasma or serum samples from the subject.
  • the expression level of NTproCNP preferably in a blood, serum or plasma sample from the subject, is additionally determined in combination with the expression level of any biomarker or combination of biomarkers heretofore described.
  • the expression level of NTproCNP, TNF-RII, galectin-3 and endostatin can be measured.
  • the expression level of NTproCNP, endostatin, TNF-RII, FGF-23, galectin-3 and podocin is measured in one or more samples from the subject.
  • the expression levels of endostatin, NTproCNP, TNF-RII, FGF-23, galectin-3 and podocin are measured in one or more blood, serum or plasma samples from the subject and the expression level of endostatin is optionally also measured in one or more urine samples from the subject.
  • the expression level of endostatin in a urine sample from the subject is additionally determined in combination with the expression level of any biomarker or combination of biomarkers heretofore described.
  • the expression level of aZGPl preferably in a blood, serum or plasma sample from the subject, is additionally determined in combination with the expression level of any biomarker or combination of biomarkers heretofore described.
  • Subjects identified as at risk for or suffering from kidney disease can be administered one or more therapeutic agents to prevent (or slow the onset of) or treat kidney disease.
  • Preferred therapeutic agents include agents which reduce blood pressure in the subject.
  • Therapeutic agents that prevent or treat kidney disease include without limitation, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta blockers, calcium channel blockers and diuretics.
  • ACE angiotensin-converting enzyme
  • ARB angiotensin receptor blockers
  • beta blockers calcium channel blockers and diuretics.
  • ACE inhibitors include, without limitation, enalapril (Vasotec/Renitec), ramipril (Altace), quinapril (Accupril), perindopril (Coversyl), lisinopril (Listril), benazepril (Lotensin), imidapril (Tanatril), zofenopril (Zofecard), tandolapril (Mavik), and fosinopril (Fosinopril).
  • ARBs include, without limitation, losartan (Cozaar), EXP 3174, candesartan (Altacand), valsartan (Diovan), irbesartan (Avapro), telmisartan (Micardis), eprosartan (Teveten), olmesartan (Benicar), and azilsartan (Edarbi).
  • beta blockers include, without limitation, alprenolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisprolol, celiprolol, esmolol, metoprolol, nebivolol, butaxamine, ICI-118,551 and SR 59230A.
  • Calcium channel blockers include, without limitation, amlodipine (Norvasc), aranidipine (Sapresta), azelnidipine (Calblock), barnidipine (HypoCa), benidipine (Coniel), cilnidipine (Atelec), clevidipine (Cleviprex), isradipine (DynaCirc), efonidipine (Landel), felodipine (Plendil), lacidipine (Lacipil), lercanidipine (Zanidip), manidipine (Calslot), nicardipine (Cardene), nifedipine (Procardia), nilvadipine (Nivadil), nimodipine (Nimotop), nisoldipine (Baymycard), nitrendipine (Cardif) and pranidipine (Acalas).
  • Diuretics include, without limitation, methyclothiazide, hydroflumethiazide, metolazone, chlorothiazide, hydrochlorothiazide, quinethazone, chlorthalidone, trichlormethiazide, bendroflumethiazide, polythiazide, spironolactone, triamteren, amiloride, bumetanide, torsemide, ethacrynic acid, and furosemide.
  • Preferred diuretics include furosemide, hydrocholorothiazide, spironolactone, and metolazone.
  • Determination of the expression level of one or more biomarkers of the invention in any combination hereintofore described may be combined with other criteria in order to determine if a subject is at risk to develop or is suffering from kidney disease or to monitor the progression of the risk of or development of kidney disease in a subject.
  • expression level of one or more biomarkers of the invention in a subject may evaluated along with the eGFR in the subject in order to determine whether the subject is at risk to develop or is suffering from kidney disease.
  • a subject at risk to develop or suffering from kidney disease may be identified by comparing the expression level of one or more biomarkers of the invention in a sample from the subject to a control expression level and measuring the eGFR of the subject, whereby an elevated expression level of the one or biomarkers compared to control and an eGFR below 90mL/min/1.73m 2 or below 60ml/min/1.73m 2 , indicates that the subject is at risk to develop or is suffering from kidney disease.
  • the degree of albuminuria may be assessed in the subject.
  • a subject at risk to develop or suffering from kidney disease may be identified by comparing the expression level of one or more biomarkers of the invention in a sample from the subject to a control expression level and measuring albuminuria in the subject whereby an elevated expression level of the one or more biomarkers compared to control and excretion of at least 30 mg of albumin in the urine per gram creatinine or 30 mg of albumin per 24 hour period indicates that the subject is at risk to develop or is suffering from kidney disease.
  • an increase in the expression of one or more biomarkers of the invention in samples from a subject and a decrease in the eGFR and/or an increase in albuminuria in a subject indicates progression of the risk of or development of kidney disease in the subject.
  • Also provided by the present invention is a method of screening for candidate agents for the treatment of kidney disease by assaying prospective candidate agents for activity in modulating one or more biomarkers of the invention (e.g. in any combination heretofore described).
  • the method comprises administering the prospective agent to a non-human animal and measuring modulation of one or more biomarkers of the invention (i.e. the expression level of the one or more biomarkers is determined prior to administering the agent and at least once and preferably multiple times thereafter.
  • a candidate agent is identified as effective in treating kidney disease if the administration of the agent reduces the expression level of the one or more biomarkers relative to baseline.
  • kits for determining the risk of development of kidney disease in a subject having or suspected of having diabetes comprising (a) two or more binding molecules that specifically bind to two or more biomarkers selected from the group consisting of: podocin, endostatin, galectin-3, TNF- RII, aZGPl, FGF-23 and NTproC P or any combination thereof heretofore described and optionally (b) instructions for using the binding molecules.
  • the binding molecules are antibodies.
  • the diagnostic kit includes two or more antibodies against at least two, at least three, at least four, at least five or all six of the following biomarkers: endostatin, T F-RII, FGF-23, podocin, galectin-3 and NTproCNP.
  • the diagnostic kit includes antibodies against at least TNF-RII and endostatin.
  • Samples can be obtained from a patient from, without limitation, blood, plasma, serum, urine, lymph, synovial fluid, and tissue biopsy, but are preferably obtained from blood, plasma, serum or urine. Standard procedures that are known in the art for obtaining such samples are used.
  • the sample is a blood, serum, plasma or urine sample and the level of one or more biomarkers described herein is determined by enzyme linked immunosorbent assay (ELISA).
  • ELISA enzyme linked immunosorbent assay
  • the sample may be obtained from any patient that would benefit from a determination of kidney disease risk such as a patient with type 1 or type 2 diabetes mellitus and/or a patient with high blood pressure and/or a patient with heart disease and/or a patient over 60 years of age.
  • the patient has or is suspected of having type 2 diabetes mellitus.
  • the risk that a subject will develop kidney disease or has kidney disease is determined by measuring one or more biomarkers of the invention.
  • Assessment of expression levels of the biomarkers discussed above may be direct, as in the use of immunohistochemistry (IHC) (including semi-quantitative or quantitative IHC) or other antibody-based assays (Western blot, fluorescent immunoassay (FIA), fluorescence in situ hybridization (FISH), radioimmunoassay (RIA), radioimmunoprecipitation (RIP), enzyme-linked immunosorbent assay (ELISA), immunoassay, immunoradiometric assay, fluoroimmunoassay, chemiluminescent assay, bioluminescent assay, gel electrophoresis, flow cytometry), or indirect by quantitating the transcripts for these genes (e.g.
  • the invention encompasses polynucleotides and polypeptides (e.g. antibodies) which can be used to detect and monitor expression level of one or biomarkers.
  • RNA refers to a measurable quantity of a given nucleic acid as determined by hybridization or measurements such as RT PCR and which corresponds directly with the extent to which the gene is expressed.
  • the level of expression of a nucleic acid is determined by methods well known in the art.
  • the level of expression of nucleic acids is determined by microarray analysis, whereby the level of expression is measured using hybridization analysis with labeled (e.g. luminescent, fluorescent, radioactive, chemical or physical label) nucleic acids corresponding to RNA isolated from one or more individuals.
  • labeled e.g. luminescent, fluorescent, radioactive, chemical or physical label
  • Quantifying the amount of a protein biomarker of the invention is preferably carried out using a molecule that specifically binds to the protein including without limitation, an antibody specific for the protein or any other molecule which is known in the art to specifically bind to the protein.
  • Antibodies are particularly preferred binding molecules.
  • Antibodies can be used in the present invention to characterize the protein content of target cells through techniques such as immunohistochemistry, ELISAs and Western blotting. This may provide a screen e.g. for the presence or absence of a subject at risk for developing kidney disease and/or a need for treating the subject accordingly.
  • antibodies against the antigen to be detected are immobilized onto a selected surface, preferably a surface exhibiting a protein affinity such as the wells of a polystyrene microtiter plate. After washing to remove incompletely adsorbed material, it is desirable to bind or coat the assay plate wells with a non-specific protein that is known to be antigenically neutral with regard to the test antisera such as bovine serum albumin (BSA), casein or solutions of powdered milk.
  • BSA bovine serum albumin
  • the immobilizing surface After binding of antibody to the well, coating with a non-reactive material to reduce background, and washing to remove unbound material, the immobilizing surface is contacted with the sample to be tested in conditions conducive to immune complex (antigen/antibody) formation.
  • the occurrence and even amount of immunocomplex formation may be determined by subjecting the same to a second antibody having specificity for an antigen that differs from that recognized by the first antibody.
  • Appropriate conditions preferably include diluting the sample with diluents such as BSA, bovine gamma globulin (BGG) and phosphate buffered saline (PBS)/Tween®. These added agents also tend to assist in reduction of nonspecific background.
  • BSA bovine gamma globulin
  • PBS phosphate buffered saline
  • the layered antisera is then allowed to incubate for from about 2 to about 4 hours, at temperatures preferably on the order of about 25° to 27° C. Following incubation, the antisera-contacted surface is washed so as to remove non- immunocomplexed material.
  • a preferred washing procedure includes washing with a solution such as PBS/Tween®, or borate buffer.
  • the second antibody will preferably have an associated enzyme, or detectable moiety, that can be detected, e.g., will generate a color development upon incubating with an appropriate chromogenic substrate.
  • an associated enzyme or detectable moiety
  • the second antibody-bound surface with a urease or peroxidase-conjugated anti-human IgG for a period of time and under conditions which favor the development of immunocomplex formation (e.g. incubation for 2 hours at room temperature in a PBS-containing solution such as PBS/Tween®).
  • the amount of label is quantified by incubation with a chromogenic substrate such as urea and bromocresol purple or 2,2'-azino-di-(3-ethyl- benzthiazoline)-6-sulfonic acid (ABTS) and H 2 0 2 , in the case of peroxidase as the enzyme label. Quantitation is then achieved by measuring the degree of color generation, e.g. using a visible spectrum spectrophotometer.
  • a chromogenic substrate such as urea and bromocresol purple or 2,2'-azino-di-(3-ethyl- benzthiazoline)-6-sulfonic acid (ABTS) and H 2 0 2 , in the case of peroxidase as the enzyme label.
  • Quantitation is then achieved by measuring the degree of color generation, e.g. using a visible spectrum spectrophotometer.
  • the preceding format may be altered by first binding the sample to the assay plate, then contacting the sample with a primary antibody, followed by detecting bound primary antibody using a labeled second antibody with specificity for the primary antibody.
  • Antibodies can also find use in immunoblots or Western blot analysis.
  • the antibodies may be used as high affinity primary reagents for the identification of proteins immobilized onto a solid support matrix, such as nitrocellulose, nylon or combinations thereof. In conjunction with immunoprecipitation, followed by gel electrophoresis, these may be used as a single step reagent for use in detecting antigens against which secondary reagents used in the detection of the antigen cause an adverse background.
  • Immunologically-based detection methods for use in conjunction with Western blotting include enzymatically-, radiolabel-, or fluorescently-tagged secondary antibodies against the antigen of interest are considered to be of particular use in this regard.
  • ROC Receiver Operating Characteristics
  • a ROC curve is a plot of the true positive rate against the false positive rate for that test.
  • subjects can be assessed using a perfectly accurate or "standard” method that is independent of the test in question to determine whether the subjects are truly positive or negative for the disease.
  • the glomerular filtration rate or albuminuria is a standard for the presence of kidney disease.
  • the subjects can also be tested using the test in question and, for varying cut points, the subjects are reported as being positive or negative according to the test.
  • the true positive rate and the false positive rate are determined for each cut point, and each pair of x-y values is plotted as a single point on the x-y diagram.
  • the "curve" connecting those points is the ROC curve.
  • the total area under the curve (“AUC") is the indicator that allows representation of the sensitivity and specificity of a test over the entire range of cut points with a single value.
  • the AUC of the ROC curve provides a measure of accuracy of the biomarker (or biomarker panel) to discriminate subjects who will develop the event of interest versus those who will not develop the event of interest.
  • the maximum AUC is one (a perfect test) and the minimum area is one half (e.g. the area where there is no discrimination of normal versus disease). The closer the AUC is to one, the better is the discriminatory ability of the test.
  • a "high degree of diagnostic accuracy” means a test or assay wherein the AUC (area under the ROC curve for the test) is at least 0.80, preferably at least 0.85, and more preferably at least 0.90.
  • a risk prediction model complementary to the area under the ROC curve uses the integrated discrimination improvement (IDI).
  • IDI integrated discrimination improvement
  • the added value of a biomarker to an existing test is quantified and used to assess improvements in diagnostic accuracy
  • Pencina MJ D'Agostino RB Sr, D'Agostino RB Jr, Vasan RS; Clin J Am Soc Nephrol. 2012 Aug;7(8): 1355-64, New metrics for assessing diagnostic potential of candidate biomarkers, Pickering JW, Endre ZH).
  • rIDI [(ISnew - ISold) - (IPnew - IPold)]/ (IPnew - IPold).
  • Microalbuminuria (Univariate Analysis) To identify biomarkers associated with renal disease progression, serum and urine samples of a cohort of type-2 diabetic subjects were tested for biomarkers using ELISA tests. The seventy-four study participants with type-2 diabetes comprised 29 cases (macroalbuminuria > 300 mg/day) and 45 controls (normoalbuminuria ⁇ 30 mg/day) from an outpatient diabetes clinic in The Netherlands in 2009. Average age of the cohort as 63.2 ⁇ 9.2 years and 52.7% were male. By definition, urinary albumin concentration was higher in cases than controls being 723.0 [239.0, 1056.0] mg/L in cases versus 4.0 [3.0, 10.0] in controls.
  • Serum and first-morning void urine samples were collected. All samples were stored at -80°C and did not undergo freeze-thaw cycles before ELISA analysis. The following parameters were assayed for by ELISA: NTproCNP (in serum and urine), TNF-RII (in serum and urine), aZGPl (in serum), sclerostin (GenBank Accession No. AAK13454.1) (in serum and urine), nephrin (GenBank Accession No. AAG17141.1) (in serum), neuropilin (GenBank Accession No.
  • AAC51759.1 (in serum), podocin (in serum), FGF-23 (active and inactive forms in serum and urine), endostatin (in serum and urine), and galectin-3 (in serum).
  • ELISA tests were performed as described by the manufacturers. NTproCNP- and sclerostin ELISAS were from Biomedica, Vienna Austria. ELISAs for endostatin and FGF-23 were from Biomarker Design Anlagensgesellschaft mbH, Vienna, Austria. The TNF-RII ELISA was from R&D Systems, Minneapolis, MN, USA. The ELISA tests for aZGPl, nephrin, neuropilin, and podocin were obtained from USCN, Wuhan, China. The galectin-3 ELISA was obtained from BG medicine Inc., Waltham, MA, USA.
  • ELISA biomarkers The association between the ELISA results for biomarkers ("ELISA biomarkers") and macroalbuminuna was assessed by logistic regression in a crude model (univariate) and then adjusted for eGFR and diabetes duration (multivariate), as these two parameters were different between cases and controls.
  • Macroalbuminuna is defined here as a urinary albumin to creatinine ratio >300 mg per gram creatinine (300 mg/g).
  • the improvement in discrimination of the "ELISA biomarkers" for macroalbuminuria on top of eGFR and diabetes duration was assessed by measuring the increment of the Area under the Receiver Operating Characteristics Curve (ROC).
  • IDI integrated discrimination improvement
  • NTproCNP (pmol/L) 6.6 [2.6, 6.3] 3.1 [2.3, 3.3] 0.0011
  • IDI values were high for TNFRII (0.19) and endostatin (0.22), p ⁇ 0.001, and less than 0.1 for NTproCNP, podocin, FGF23, or galectin-3.
  • TNFRII- or endostatin assays to the eGFR and diabetes duration improved diagnostic accuracy in predicting albuminuria with an IDI of about 0.2 and a relative IDI >80%. Improvements of 0.25 or more (IDI>0.25) were observed by inclusion of results from the serum assays by ELISA of certain additional biomarkers.
  • a panel of biomarkers containing at least endostatin or TNF-RII is a preferred panel of biomarkers to obtain improved diagnostic accuracy in predicting nephropathy.
  • Further preferred panels contain endostatin and TNF-RII.
  • Preferred panels can also contain in addition to endostatin and TNF-RII the biomarkers FGF-23 and/or podocin and/or galectin-3.
  • the biomarker panel of six serum biomarkers is thus able to discriminate the outcome 137%) above the control model.
  • the IDI value for the full panel of serum markers (0.33) is statistically different not only from the IDI for eGFR and diabetes-duration, but also eGFR and diabetes duration plus endostatin and TNFRII (0.25). This shows that assaying by ELISA for the full complement of markers can offer advantages over assaying for endostatin and TNFRII only.
  • Inclusion into the serum-panel results of results from urine measurements of endostatin (adjusted for urinary creatinine) further yields statistically significant improvements (Table 5). Hence, to obtain improved accuracy in predicting nephropathies it is useful to include urinary levels of endostatin.
  • Table 5 Discriminative ability of serum and urine biomarkers in type-2 diabetic patients to predict nephropathies
  • a panel of biomarkers containing at least endostatin or TNFRII is a preferred panel of biomarkers to obtain improved diagnostic accuracy in predicting nephropathy.
  • Further preferred panels contain endostatin and TNFRII.
  • Preferred panels can also contain in addition to endostatin and TNFRII the biomarkers NTproCNP, and/or FGF23 and/or podocin and/or galectin-3.
  • the ELISA markers were tested on top of traditional risk markers for renal disease progression including age, gender, baseline eGFR, and log transformed urinary albumin/creatinine ratio.
  • serum TNF-RII or urinary endostatin were individually added to the reference risk-prediction model consisting of age, gender, baseline eGFR, and albuminuria the total explained variance in eGFR decline over time (R 2 ) increased from 0.41 to 0.47 and from 0.41 to 0.43, respectively.
  • the total explained variation was further increased when using test results from both endostatin and TNFRII: the R 2 of the model consisting of both serum TNF RII and urinary endostatin was 0.49.
  • a preferred biomarker panel to predict progression of disease includes endostatin and/or TNFRII. Hence, either urinary or serum endostatin levels can be assayed for to improve prediction of future outcomes.
  • assaying for endostatin plus TNFRII strongly improved predictability and diagnostic accuracy for both disease development and its progression, and are preferred components of a test kit for the same.
  • Further additions of biomarkers of the invention to a panel consisting of endostatin and/or TNFRII have utility, in particular when assaying for disease progression.

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Abstract

L'invention concerne des biomarqueurs utiles pour le pronostic, la sélection et la surveillance de l'insuffisance rénale ou du risque associé. En particulier, des protéines dont les profils d'expression sont fortement prédictifs du risque de développement ou de la présence d'une insuffisance rénale sont identifiées. Un procédé destiné à identifier un sujet qui présente un risque ou qui souffre d'insuffisance rénale, et éventuellement à gérer le traitement du sujet en conséquence à l'aide des biomarqueurs, est également décrit.
PCT/NL2013/050191 2013-03-15 2013-03-15 Biomarqueurs pour diagnostic et pronostic améliorés de l'insuffisance rénale chronique WO2014142649A1 (fr)

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WO2016046636A3 (fr) * 2014-09-05 2016-06-30 American University Of Beirut Détermination du risque de développement d'une maladie cardiovasculaire par mesure des teneurs urinaires en arn messager de podocine et de néphrine
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PL422611A1 (pl) * 2017-08-22 2019-02-25 Uniwersytet Jagielloński Sposób wykrywania uszkodzenia nerek pojawiającego się u chorych z cukrzycą
CN117711619A (zh) * 2023-12-15 2024-03-15 南方医科大学南方医院 一种糖尿病患者慢性肾脏病发生风险预测系统及存储介质

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