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WO2008129265A1 - Diagnostic et traitement de la néphropathie diabétique mettant en œuvre la protéine ccl18 - Google Patents

Diagnostic et traitement de la néphropathie diabétique mettant en œuvre la protéine ccl18 Download PDF

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Publication number
WO2008129265A1
WO2008129265A1 PCT/GB2008/001368 GB2008001368W WO2008129265A1 WO 2008129265 A1 WO2008129265 A1 WO 2008129265A1 GB 2008001368 W GB2008001368 W GB 2008001368W WO 2008129265 A1 WO2008129265 A1 WO 2008129265A1
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ccll
diabetic nephropathy
patient
antagonist
sample
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PCT/GB2008/001368
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English (en)
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Frederick Wai Keung Tam
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Imperial Innovations Limited
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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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • 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
    • G01N2800/345—Urinary calculi

Definitions

  • the current invention relates to the diagnosis and treatment of diabetic nephropathy.
  • Diabetes is the most common cause of end stage renal failure in the developed world, and inflammation and fibrosis are important mechanisms in the progression of this disorder.
  • Fibrosis of renal tissues is a critical event in the progression of renal failure from a variety of causes ranging from diabetic nephropathy, hypertensive nephropathy to immune mediatied nephritis. With deposition of extracellular matrix and loss of normal renal tissue, the renal structure is replaced by scar tissue. These processes result in irreversible loss of renal function. Severe renal fibrosis is frequently the final step of progression to end stage renal failure.
  • MCP-I monocyte chemoatractant protein- 1
  • CTGF connective tissue growth factor
  • CCLl 8 is synthesized by monocytes/macrophages and dendritic cells, is known to stimulate collagen production in pulmonary fibroblasts and is reported to cause fibrosis independent of TGF- ⁇ (Luzina et al. (2006) J. Cell Physiol 206: 221- 228).
  • the potential role of CCLl 8 in the progression of renal diseases has not previously been investigated. In diabetic nephropathy, an increased number of macrophages are found (ref: Nguyen D et al Nephrology 11:226-231, 2006), but the number were far less than in glomerulonephritis.
  • CCLl 8 As CCLl 8 is produced by macrophages in fibrotic lung diseases, it will be logical to predict that CCLl 8 will have a more important role in the pathogenesis of glomerulonephritis than that of diabetic nephropathy (ref. Ferrario et al Kidney International 28:513-9, 1985). To our surprise, we found that urinary CCLl 8 correlated with the severity of diabetic nephropathy, but not with non-diabetic renal disease in our research project. A role for CCLl 8 in diabetic nephropathy was unexpected.
  • a first aspect of the invention provides a method for aiding in the assessment of diabetic nephropathy in a patient, the method comprising the step of determining the level of CCLl 8 protein and/or nucleic acid in a sample from the patient.
  • CCLl 8 is described in, for example, Schutyser et al. (2005) J. Leukoc. Biol. 78:14-26. It is preferred that the sample is a urine sample but the sample may also be, for example, a blood serum sample or a blood plasma sample. In the blood, there are peripheral blood monocytes, so measurement of mRNA for CCLl 8 may provide indications of synthesis of CCLl 8. Alternatively, detection of CCLl 8 protein by immunohistochemistry and mRNA by in situ hybridisation and RT-PCR from renal biopsied material may also be useful.
  • studying of DNA polymorphism may provide additional information about individual patients who are genetically prone to produce too much or too little CCLl 8.
  • Using urine samples may be more convenient and may also be particularly informative, as the urine may accurately reflect renal conditions.
  • the method may be used for assessing the likely progression of diabetic nephropathy in the patient.
  • the method may also be useful for aiding in the diagnosis of diabetic nephropathy in a patient.
  • the method may also or alternatively be useful for aiding in the assessment of the likelihood or likely severity or likely progression of diabetic nephropathy in a patient.
  • the method may be useful for assessing and/or predicting the development of fibrosis in the patient.
  • CCLl 8 may also be used as a surrogate marker for the development of fibrosis in diabetic nephropathy.
  • the screening of diabetic patients for changes in CCLl 8 protein and/or mRNA levels may be useful for diagnosing those patients that may have or may develop diabetic nephropathy.
  • fibrosis is meant the damage to organs or tissues caused by the thickening and scarring of connective tissue. Production of collagen and extracellular matrix are the key components of the fibrous tissue.
  • diabetic nephropathy is meant the complex and often progressive injury of the kidney due to the direct effect of diabetes mellitus. The typical features of diabetic nephropathy include deposition of extracellular matrix, resulting in thickening of glomerular basement membrane, glomerulosclerosis and tubulo- intersitial fibrosis. The natural history of diabetic nephropathy is variable and a significant proportion of the diabetic patients progressed to renal failure.
  • the response of the patient to treatment for diabetic nephropathy may be assessed using the method of the current invention.
  • the method may be useful in predicting future response of the patient to treatment for diabetic nephropathy.
  • the method of the current invention may also be used for assessing the likely progression of response of the patient to treatment for diabetic nephropathy. It may also be useful in prognosis or aiding prognosis. Measurement of CCLl 8 is considered to be most useful in assessing the macroalbuminuric subgroup of diabetic nephropathy patients.
  • the method of the current invention may comprise the steps of (i) obtaining a sample containing nucleic acid and/or protein from the patient; and (ii) determining whether the sample contains a level of CCLl 8 nucleic acid or protein associated with the development, progression or regression (after appropriate treatment) of diabetic nephropathy.
  • determining whether the sample contains a level of CCLl 8 nucleic acid or protein associated with diabetic nephropathy may in itself be diagnostic (or prognostic) of diabetic nephropathy or it may be used by the clinician as an aid in reaching a diagnosis or prognosis.
  • measurement of CCLl 8 levels may be performed or considered alongside other measurements or factors, for example, determining the level of albumin and/or creatinine and/or assessing the estimated glomerular filtration rate (eGFR) and/or HbAIc, in the sample from the patient and/or measuring the patient's blood pressure. Simultaneous measurement of other cytokines and growth factors is considered to be helpful. For example, urinary connective tissue growth factor/creatinine ratio and monocyte chemoattractant protein- 1 /creatinine ratio are prognostic for progression of early and late stages of diabetic nephropathy respectively.
  • eGFR estimated glomerular filtration rate
  • HbAIc estimated glomerular filtration rate
  • determining whether the sample contains a level of CCLl 8 nucleic acid or protein associated with diabetic nephropathy may in itself be diagnostic (or prognostic) of diabetic nephropathy or it may be used by the clinician as an aid in reaching a diagnosis or prognosis.
  • the clinician may wish to take in to account these or other factors, such as presence of reduced perfusion of the kidneys due to renovascular diseases, including renal artery stenosis, as well as consider the level of CCLl 8, before making a diagnosis.
  • Measurement of CCLl 8 levels may provide more detailed information on the severity of individual disease mechanisms.
  • CCLl 8 determination of the level of CCLl 8 in the sample will be useful to the clinician in determining how to manage diabetic nephropathy in the patient. For example, since our research has indicated that elevated levels of CCLl 8 are associated with diabetic nephropathy, the clinician may use the information concerning the levels of CCLl 8 to facilitate decision making regarding treatment of the patient. Because CCLl 8 is known to cause fibrosis directly, monitoring of CCLl 8 will provide direct information of ongoing renal fibrosis in the patient. Based on the CCLl 8 measurement, the use of inhibitors of renin angiotensin system and any new anti-fibrotic medication may be added or optimised.
  • the level of CCL 18 which is indicative of diabetic nephropathy may be defined as the increased level present in samples from diabetic patients with diabetic nephropathy as shown by macroalbuminuria (spot urinary albumin/creatinine ratio more than 25 mg/mmol or timed urine collection albuminuria of more than 300 mg per day) or the presence of deposition of extracellular matrix, resulting in thickening of glomerular basement membrane, glomerulosclerosis and tubulo- intersitial fibrosis.
  • the level of said CCLl 8 protein may be, for example, at least 2 standard deviation higher in a sample from a patient with diabetic nephropathy than the control healthy volunteers.
  • the level of mRNA encoding CCLl 8 may be, for example, at least 2 standard deviation higher in a sample from a patient with diabetic nephropathy.
  • the level of CCLl 8 in a sample from the patient may be determined using any suitable protein detection or quantitation method, for example using methods employing antibodies specific for CCLl 8.
  • immunoassay techniques preferably quantitative techniques, may be used, for example an antibody array or captured ELISA technique, for example as described in the Examples.
  • Preferred embodiments relating to methods for detecting CCLl 8 protein include enzyme linked immunosorbent assays (ELISA), radioimmunoassay (RIA), immunoradiometric assays (IRMA) and immunoenzymatic assays (IEMA), including sandwich assays using monoclonal and/or polyclonal antibodies. Exemplary sandwich assays are described by David et al in US Patent Nos.
  • antibody-like molecules may be used in the method of the invention including, for example, antibody fragments or derivatives which retain their antigen-binding sites, synthetic antibody-like molecules such as single-chain Fv fragments (ScFv) and domain antibodies (dAbs), and other molecules with antibody-like antigen binding motifs.
  • synthetic antibody-like molecules such as single-chain Fv fragments (ScFv) and domain antibodies (dAbs)
  • dAbs domain antibodies
  • Bioassays may alternatively be used for measuring CCLl 8 activity.
  • CCLl 8 stimulates fibroblasts to produce collagen in vitro. See, for example, Luzina LG. et al. PKCalpha mediates CCL18-stimulated collagen production in pulmonary fibroblast. Am J Respir Cell MoI Biol 35:298-305, 2006.
  • the sample contains nucleic acid, such as mRNA, and the level of CCL 18 is measured by contacting said nucleic acid with a nucleic acid which hybridises selectively to CCL 18 nucleic acid.
  • nucleic acid has sufficient nucleotide sequence similarity with the said human nucleic acid that it can hybridise under moderately or highly stringent conditions.
  • stringency of nucleic acid hybridisation depends on factors such as length of nucleic acid over which hybridisation occurs, degree of identity of the hybridizing sequences and on factors such as temperature, ionic strength and GC or AT content of the sequence.
  • any nucleic acid that is capable of selectively hybridising as said is useful in the practice of the invention.
  • Nucleic acids which can selectively hybridise to the said human nucleic acid include nucleic acids which have > 95 % sequence identity, preferably those with > 98 %, more preferably those with > 99 % sequence identity, over at least a portion of the nucleic acid with the said human nucleic acid.
  • human genes usually contain introns such that, for example, a mRNA or cDNA derived from a gene would not match perfectly along its entire length with the said human genomic DNA but would nevertheless be a nucleic acid capable of selectively hybridising to the said human DNA.
  • the invention specifically includes nucleic acids which selectively hybridise to CCLl 8 mRNA or cDNA but may not hybridise to a CCLl 8 gene.
  • nucleic acids which span the intron-exon boundaries of the CCLl 8 gene may not be able to selectively hybridise to the CCLl 8 mRNA or cDNA.
  • Typical moderately or highly stringent hybridisation conditions which lead to selective hybridisation are known in the art, for example those described in Molecular Cloning, a laboratoiy manual, 2nd edition, Sambrook et al (eds), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA, incorporated herein by reference.
  • SSC saline Na + citrate
  • SDS dodecyl sulphate
  • the hybridisation is performed at 68 °C.
  • the nylon membrane, with the nucleic acid immobilised may be washed at 68 °C in 1 x SSC or, for high stringency, 0.1 x SSC.
  • 20 x SSC may be prepared in the following way. Dissolve 175.3 g of NaCl and 88.2 g OfNa + citrate in 800 ml of H 2 O. Adjust the pH to 7.0 with a few drops of a 10 N solution of NaOH. Adjust the volume to 1 litre with H 2 O. Dispense into aliquots. Sterilise by autoclaving.
  • An example of a typical hybridisation solution when a nucleic acid is immobilised on a nylon membrane and the probe is an oligonucleotide of between 15 and 50 bases is:
  • TMACl trimethylammonium chloride 0.01 M Na + phosphate
  • the optimal temperature for hybridisation is usually chosen to be 5 0 C below the
  • T for the given chain length.
  • T 1 is the irreversible melting temperature of the hybrid formed between the probe and its target sequence. Jacobs et al (1988) Nucl. Acids Res. 16: 4637 discusses the determination of TjS.
  • the recommended hybridisation temperature for 17-mers in 3 M TMACl is 48-50 °C; for 19-mers, it is 55-57 °C; and for 20-mers, it is 58-66 °C.
  • nucleic acid which selectively hybridises is also included nucleic acids which will amplify DNA from the said CCLl 8 mRNA by any of the well known amplification systems such as those described in more detail below, in particular the polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • Suitable conditions for PCR amplification include amplification in a suitable 1 x amplification buffer:
  • 10 x amplification buffer is 500 mM KCl; 100 mM Tris.Cl (pH 8.3 at room temperature); 15 mM MgCl 2 ; 0.1 % gelatin.
  • a suitable denaturing agent or procedure (such as heating to 95 °C) is used in order to separate the strands of double-stranded DNA.
  • the annealing part of the amplification is between 37 0 C and 60 °C, preferably 50 °C.
  • nucleic acid which is useful in the methods of the invention may be any nucleic acid which is useful in the methods of the invention.
  • RNA or DNA DNA is preferred, for example if assessing the patient for CCLl 8 polymorphisms. If assessing expression levels then mRNA may be preferred.
  • nucleic acid that is useful in the methods of the invention may be double-stranded or single-stranded, single-stranded nucleic acid is preferred under some circumstances such as in nucleic acid amplification reactions.
  • the nucleic acid that is useful in the methods of the invention may be any suitable size. However, for certain diagnostic, probing or amplifying purposes, it is preferred if the nucleic acid has fewer than 10 000, more preferably fewer than 1000, more preferably still from 10 to 100, and in further preference from 15 to 30 base pairs (if the nucleic acid is double-stranded) or bases (if the nucleic acid is single stranded). As is described more fully below, single-stranded DNA primers, suitable for use in a polymerase chain reaction, are particularly preferred.
  • the nucleic acid for use in the methods of the invention is a nucleic acid capable of hybridising to the CCL 18 mRNA. Fragments of the CCLl 8 gene and cDNAs derivable from the mRNA encoded by the CCLl 8 gene are also preferred nucleic acids for use in the methods of the invention.
  • the nucleic acid for use in the methods of the invention is an oligonucleotide primer which can be used to amplify a portion of the CCLl 8 nucleic acid, particularly CCLl 8 mRNA.
  • a further aspect of the invention provides a method for assessing a diabetic nephropathy treatment regime, the method comprising the step of determining the level of CCLl 8 protein or nucleic acid in a sample from patients receiving the treatment regime.
  • the sample type is typically of the type discussed hereinbefore in relation to the first aspect of the invention, for example, a urine sample from the patient.
  • the method may, for example, be used to provide information on the likelihood of the development of fibrosis in the patient.
  • levels of CCL 18 may be used as surrogate markers in clinical trials of proposed treatments for diabetic nephropathy.
  • Measurement of CCLl 8 may provide the overall assessment of how various factors affect the treatment of and progression of diabetic nephropathy.
  • a further aspect of the invention provides a method for identifying a compound useful in diabetic nephropathy, for example in treating or preventing diabetic nephropathy, the method comprising the steps of a) determining whether a test compound is capable of suppressing production of, or activity of, CCLl 8 in body tissue or cells (for example leucocytes, dendritic cells or fibroblasts) from healthy volunteers or a patient with diabetes mellitus and b) selecting a compound which is capable of suppressing production of, or activity of, CCL 18 in body tissue or a cell sample from health volunteers or a patient with diabetes mellitus.
  • Both healthy subjects and diabetic patients may be able to produce CCLl 8 in response to pathological stimuli.
  • Other organ tissues may be more accessible for testing than the kidney.
  • cells such as circulating leucocytes, fibroblast from the skin may be used.
  • the method may comprise the step of determining whether a test compound is capable of suppressing production of, or activity of, CCL 18 in a sample, for example a urine sample from a patient, as discussed hereinbefore.
  • a further aspect of the invention provides an antagonist of CCL 18 protein and/or nucleic acid for the treatment of diabetic nephropathy.
  • the antagonist of CCLl 8 protein may comprise, for example, an antibody directed towards CCLl 8 protein.
  • the antibody directed towards CCLl 8 protein may be a monoclonal antibody but may also be a polyclonal serum extracted from an appropriately immunised animal (such as a mouse, a rabbit, a goat or a horse). Alternatively, individual populations of antibodies directed to, for example, one epitope or a family of epitopes may be purified from said serum and used in this aspect of the invention.
  • the antagonist may also comprise fragments of antibody or derivatives which retain their antigen-binding sites, synthetic antibody-like molecules such as single-chain Fv fragments (ScFv) and domain antibodies (dAbs), and other molecules with antibody-like antigen binding motifs.
  • the antagonist may be a peptide inhibitor, such as mutated sequence of CCLl 8 or low molecular weight inhibitor of CCLl 8 receptor and its downstream pathway.
  • the antagonist of CCL 18 nucleic acid may comprise, for example, a short interfering RNA molecule directed towards CCLl 8 mRNA. Such molecules will hybridise selectively to CCLl 8 mRNA in vivo and lead to destruction of said mRNA and a reduction in the expression of CCL 18 protein.
  • a further aspect of the invention provides the use of an antagonist of CCLl 8 protein and/or nucleic acid in the manufacture of a medicament for the treatment of diabetic nephropathy.
  • the antagonist may comprise any one of the entities described in the preceding aspect of the invention or any other appropriate compound.
  • a yet further aspect of the invention provides a method of treating a patient with diabetic nephropathy, the method comprising the step of administering to the patient an effective amount of an antagonist of CCLl 8.
  • antagonist of CCLl 8 is meant a compound which suppresses production of, or activity of CCLl 8, for example as determined by a method according to the aspect of the invention described hereinbefore for the provision of a method for identifying a compound useful in diabetic nephropathy.
  • CCL 18 The ability of CCL 18 to induce collagen synthesis depends on activation of protein kinase C alpha, ERK2, phosphorylation of transcription factor SpI and basal expression of Smad3 in lung fibroblast in cell culture study. See: Luzina et al. (2006) Am J. Resp. Cell MoI Biology 35: 298-305; and Luzina et al. (2006) J. Cell Physiol. 206: 221-228. Therefore, it is likely that inhibition of these pathways may inhibit production of CCLl 8 in diabetic nephropathy patients.
  • the patient is typically a human.
  • CCL 18 has not been identified in rodents yet, so an animal model may not be suitable.
  • An in vitro model may be most appropriate. Examples are:
  • peripheral blood leucocytes fibroblast cell line, dendritic cells.
  • Urinary CCL18 in non-diabetic renal diseases A small amount of urinary CCL 18 levels (expressed as CCL18/creatinine ratio) was detected in some patients with non-diabetic renal diseases. Most of these were within normal range. There were no significant differences in urinary CCL18/creatinine between non- diabetic renal diseases with different degree of albuminuria. In our study of normal volunteers, urinary CCL18/creatinine ratio range from undetectable to 4.05 ng/mmol.
  • Figure 4 Relationship between urinary CCL18 and albuminuria in non- diabetic renal diseases. There was no significant correlation between urinary , CCL18/creatinine ratio and albumin/creatinine ratio in diabetic patients.
  • FIG. 1 Subgroup analysis of diabetic macroalbuminuric patients: relationship between CCL18 and urinary albumin/creatinine ratio. Data are presented as scattered plot with median values.
  • Figure 6. Subgroup analysis of diabetic macroalbuminuric patients: relationship between CCL18 and renal function. Data are presented as scattered plot with median values.
  • Example 1 Novel cytokine present in urine of diabetic patients may be involved in the regulation of inflammation and fibrosis in diabetic nephropathy.
  • Matched antibody pairs specific for human CCLl 8 and recombinant human CCLl 8 were purchase from R & D Systems, UK.
  • the ELISA was set up and optimized following the general guidelines by the manufacturer.
  • the sensitivity of the ELISA was 7.8 pg/ml.
  • Renal fibrosis is a common pathological process in a wide range of renal diseases.
  • macrophage is known to be an important source of CCLl 8.
  • CCLl 8 is a selective pro-fibrotic mediator in diabetic nephropathy.
  • eGFR estimated glomerular filtration rate
  • Example 2 Subgroup analysis: CCL18 in the diabetic macro albuminuric subgroup.
  • urinary CCL 18 provided extra information about ongoing fibrotic process. Patients with similar urinary albumin/creatinine ratio may have either undetectable urinary CCLl 8 or high CCLl 8. Therefore, direct measurement of urinary CCLl 8 provides extra clinical information beyond current standard medical test of diabetic nephropathy.
  • urinary CCLl 8 is associated with impaired renal function in patients with diabetic nephropathy.
  • urinary CCLl 8 provided extra information about ongoing flbrotic process. Patients with similar GFR may have either undetectable urinary CCLl 8 or high CCLl 8 ( Figure 6). Therefore, direct measurement of urinary CCLl 8 provides extra clinical information beyond current standard medical test of diabetic nephropathy.
  • the main principle is to intervene on a fibrotic mechanism in diabetic nephropathy before irreversible renal fibrosis happens.
  • CCLl 8 level in the urine, blood or renal biopsies are assessed.
  • CCL 18 level the dose of rennin/angiotensin antagonist or other antifibrotic therapy will be increased, even if other clinical parameters are within target. In this way, the patients at risk of progressive renal fibrosis will receive more vigorous therapy.
  • Cell lines or primary culture of cells may be used to identify drugs/chemicals which can inhibit the synthesis of CCLl 8, or the downstream effect of CCLl 8.

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Abstract

La présente invention concerne un procédé permettant de contribuer à l'évaluation de la néphropathie diabétique chez un patient et consistant à déterminer le niveau de la protéine CCL18 et/ou d'acide nucléique dans un spécimen prélevé chez le patient. Le procédé peut être utilisé pour évaluer la progression probable de la néphropathie diabétique chez le patient ou pour évaluer la progression probable de la réaction du patient au traitement de la néphropathie diabétique.
PCT/GB2008/001368 2007-04-21 2008-04-18 Diagnostic et traitement de la néphropathie diabétique mettant en œuvre la protéine ccl18 WO2008129265A1 (fr)

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CN113151446A (zh) * 2021-04-26 2021-07-23 东南大学 尿液外泌体中CCL21的mRNA的检测方法、试剂盒及应用

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