Review Article| Volume 159, ISSUE 4, P290-302, April 2012

Download started.


Genomic biomarkers for chronic kidney disease

  • Wenjun Ju
    Reprint requests: Wenjun Ju, University of Michigan, 1560A MSRB II, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0680.
    Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich

    Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Mich
    Search for articles by this author
  • Shahaan Smith
    Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich
    Search for articles by this author
  • Matthias Kretzler
    Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich

    Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Mich
    Search for articles by this author
Published:February 10, 2012DOI:
      Chronic kidney disease (CKD) remains a major challenge in nephrology and for public health care, affecting 14% to 15% of the adult US population and consuming significant health care resources. In the next 20 years, the number of patients with end stage renal disease is projected to increase by 50%. Ideal biomarkers that allow early identification of CKD patients at high risk of progression are urgently needed for early and targeted treatment to improve patient care. Recent success of integrating molecular approaches for personalized management of neoplastic diseases, including diagnosis, staging, prognosis, treatment selection, and monitoring, has strongly encouraged kidney researchers to pursue molecular definitions of patients with kidney disease. Challenges for molecular marker identification in CKD are a high degree of cellular heterogeneity of the kidney and the paucity of human tissue availability for molecular studies. Despite these limitations, potential molecular biomarker candidates have been uncovered at multiple levels along the genome––phenome continuum. Here we will review the identification and validation of potential genomic biomarker candidates of CKD and CKD progression in clinical studies. The challenges in predicting CKD progression, as well as the promises and opportunities resulting from a molecular definition of CKD will be discussed.


      CKD (chronic kidney disease), ADPKD (autosomal dominant polycystic kidney disease), FFPE (formalin-fixed, paraffin-embedded), GFR (glomerular filtration rate), GWAS (genome-wide-association studies), KDOQI (Kidney Disease Outcomes Quality Initiative), NF-кB (nuclear factor-кB), qRT-PCR (quantitative real time PCR), PBMC (peripheral blood mononuclear cell), SNPs (single nucleotide polymorphisms)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework.
        Clin Pharmacol Ther. 2001; : 6989-6995
      2. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.
        Am J Kidney Dis. 2002; 39: S1-266
        • Levey A.S.
        • Perrone R.D.
        • Madias N.E.
        Serum creatinine and renal function.
        Annu Rev Med. 1988; 39: 465-490
        • Kronenberg F.
        Emerging risk factors and markers of chronic kidney disease progression.
        Nat Rev Nephrol. 2009; 5: 677-689
        • O’Seaghdha C.M.
        • Fox C.S.
        Genetics of chronic kidney disease.
        Nephron Clin Pract. 2011; 118: c55-c63
        • Smith M.W.
        • O’Brien S.J.
        Mapping by admixture linkage disequilibrium: advances, limitations and guidelines.
        Nat Rev Genet. 2005; 6: 623-632
        • Kopp J.B.
        • Smith M.W.
        • Nelson G.W.
        • et al.
        MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis.
        Nat Genet. 2008; 40: 1175-1184
        • O’Seaghdha C.M.
        • Parekh R.S.
        • Hwang S.J.
        • et al.
        The MYH9/APOL1 region and chronic kidney disease in European-Americans.
        Hum Mol Genet. 2011; 20: 2450-2456
        • Tzur S.
        • Rosset S.
        • Shemer R.
        • et al.
        Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene.
        Hum Genet. 2010; 128: 345-350
        • Genovese G.
        • Friedman D.J.
        • Ross M.D.
        • et al.
        Association of trypanolytic ApoL1 variants with kidney disease in African Americans.
        Science. 2010; 329: 841-845
        • Keller B.J.
        • Martini S.
        • Sedor J.R.
        • Kretzler M.
        A systems view of genetics in chronic kidney disease.
        Kidney Int. 2012; 81: 14-21
        • Kottgen A.
        • Pattaro C.
        • Boger C.A.
        • et al.
        New loci associated with kidney function and chronic kidney disease.
        Nat Genet. 2010; 42: 376-384
        • Wheeler H.E.
        • Metter E.J.
        • Tanaka T.
        • et al.
        Sequential use of transcriptional profiling, expression quantitative trait mapping, and gene association implicates MMP20 in human kidney aging.
        PLoS Genet. 2009; 5: e1000685
        • Keller B.
        • Martini S.
        • Sedor J.
        • Kretzler M.
        Linking variants from genome-wide association analysis to function via transcriptional network analysis.
        Semin Nephrol. 2010; 30: 177-184
        • Woroniecka K.I.
        • Park A.S.
        • Mohtat D.
        • Thomas D.B.
        • Pullman J.M.
        • Susztak K.
        Transcriptome analysis of human diabetic kidney disease.
        Diabetes. 2011; 60: 2354-2369
        • Schmid H.
        • Boucherot A.
        • Yasuda Y.
        • et al.
        Modular activation of nuclear factor-κB transcriptional programs in human diabetic nephropathy.
        Diabetes. 2006; 55: 2993-3003
        • Neusser M.A.
        • Lindenmeyer M.T.
        • Moll A.G.
        • et al.
        Human nephrosclerosis triggers a hypoxia-related glomerulopathy.
        Am J Pathol. 2010; 176: 594-607
        • Lindenmeyer M.T.
        • Kretzler M.
        • Boucherot A.
        • et al.
        Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy.
        J Am Soc Nephrol. 2007; 18: 1765-1776
        • Ju W.
        • Eichinger F.
        • Bitzer M.
        • et al.
        Renal gene and protein expression signatures for prediction of kidney disease progression.
        Am J Pathol. 2009; 174: 2073-2085
        • Peterson K.S.
        • Huang J.F.
        • Zhu J.
        • et al.
        Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli.
        J Clin Invest. 2004; 113: 1722-1733
        • Hodgin J.B.
        • Borczuk A.C.
        • Nasr S.H.
        • et al.
        A molecular profile of focal segmental glomerulosclerosis from formalin-fixed, paraffin-embedded tissue.
        Am J Pathol. 2010; 177: 1674-1686
        • Bennett M.R.
        • Czech K.A.
        • Arend L.J.
        • Witte D.P.
        • Devarajan P.
        • Potter S.S.
        Laser capture microdissection-microarray analysis of focal segmental glomerulosclerosis glomeruli.
        Nephron Exp Nephrol. 2007; 107: e30-e40
        • Baelde H.J.
        • Eikmans M.
        • Doran P.P.
        • Lappin D.W.
        • de Heer E.
        • Bruijn J.A.
        Gene expression profiling in glomeruli from human kidneys with diabetic nephropathy.
        Am J Kidney Dis. 2004; 43: 636-650
        • Baker M.
        In biomarkers we trust?.
        Nat Biotechnol. 2005; 23: 297-304
        • Whelton A.
        • Hamilton C.W.
        Nonsteroidal anti-inflammatory drugs: effects on kidney function.
        J Clin Pharmacol. 1991; 31: 588-598
        • Stosic Z.
        • Sedlak V.
        • Felle D.
        • Curic S.
        • Ubavic M.
        • Vodopivec S.
        [Anti-proteinuria effects of nonsteroidal anti-inflammatory drugs in patients with nephrotic syndrome: an illusion or a read improvement?].
        Med Pregl. 1995; 48: 155-158
        • Henger A.
        • Kretzler M.
        • Doran P.
        • et al.
        Gene expression fingerprints in human tubulointerstitial inflammation and fibrosis as prognostic markers of disease progression.
        Kidney Int. 2004; 65: 904-917
        • Masuda N.
        • Ohnishi T.
        • Kawamoto S.
        • Monden M.
        • Okubo K.
        Analysis of chemical modification of RNA from formalin-fixed samples and optimization of molecular biology applications for such samples.
        Nucleic Acids Res. 1999; 27: 4436-4443
        • Coudry R.A.
        • Meireles S.I.
        • Stoyanova R.
        • et al.
        Successful application of microarray technology to microdissected formalin-fixed, paraffin-embedded tissue.
        J Mol Diagn. 2007; 9: 70-79
        • Cohen C.D.
        • Grone H.J.
        • Grone E.F.
        • Nelson P.J.
        • Schlondorff D.
        • Kretzler M.
        Laser microdissection and gene expression analysis on formaldehyde-fixed archival tissue.
        Kidney Int. 2002; 61: 125-132
        • Schmid H.
        • Henger A.
        • Cohen C.D.
        • et al.
        Gene expression profiles of podocyte-associated molecules as diagnostic markers in acquired proteinuric diseases.
        J Am Soc Nephrol. 2003; 14: 2958-2966
        • Wang G.
        • Kwan B.C.
        • Lai F.M.
        • et al.
        Intrarenal expression of microRNAs in patients with IgA nephropathy.
        Lab Invest. 2010; 90: 98-103
        • Wang G.
        • Kwan B.C.
        • Lai F.M.
        • et al.
        Intrarenal expression of miRNAs in patients with hypertensive nephrosclerosis.
        Am J Hypertens. 2010; 23: 78-84
        • Dai Y.
        • Sui W.
        • Lan H.
        • Yan Q.
        • Huang H.
        • Huang Y.
        Comprehensive analysis of microRNA expression patterns in renal biopsies of lupus nephritis patients.
        Rheumatol Int. 2009; 29: 749-754
        • Taal M.W.
        • Brenner B.M.
        Predicting initiation and progression of chronic kidney disease: developing renal risk scores.
        Kidney Int. 2006; 70: 1694-1705
        • Bottinger E.P.
        TGF-β in renal injury and disease.
        Semin Nephrol. 2007; 27: 309-320
        • Suthanthiran M.
        • Khanna A.
        • Cukran D.
        • et al.
        Transforming growth factor-β 1 hyperexpression in African American end-stage renal disease patients.
        Kidney Int. 1998; 53: 639-644
        • Yang C.W.
        • Hsueh S.
        • Wu M.S.
        • et al.
        Glomerular transforming growth factor-β1 mRNA as a marker of glomerulosclerosis-application in renal biopsies.
        Nephron. 1997; 77: 290-297
        • Eikmans M.
        • Baelde H.J.
        • Hagen E.C.
        • et al.
        Renal mRNA levels as prognostic tools in kidney diseases.
        J Am Soc Nephrol. 2003; 14: 899-907
        • Yamaguchi Y.
        • Iwano M.
        • Suzuki D.
        • et al.
        Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy.
        Am J Kidney Dis. 2009; 54: 653-664
        • Samejima K.I.
        • Nakatani K.
        • Suzuki D.
        • et al.
        Clinical Significance of Fibroblast-Specific Protein-1 Expression on Podocytes in Patients with Focal Segmental Glomerulosclerosis.
        Nephron Clin Pract. 2011; 120: 1-7
        • Alcorta D.
        • Preston G.
        • Munger W.
        • et al.
        Microarray studies of gene expression in circulating leukocytes in kidney diseases.
        Exp Nephrol. 2002; 10: 139-149
        • Preston G.A.
        • Waga I.
        • Alcorta D.A.
        • et al.
        Gene expression profiles of circulating leukocytes correlate with renal disease activity in IgA nephropathy.
        Kidney Int. 2004; 65: 420-430
        • Cox S.N.
        • Sallustio F.
        • Serino G.
        • et al.
        Altered modulation of WNT-β-catenin and PI3K/Akt pathways in IgA nephropathy.
        Kidney Int. 2010; 78: 396-407
        • Alcorta D.A.
        • Barnes D.A.
        • Dooley M.A.
        • et al.
        Leukocyte gene expression signatures in antineutrophil cytoplasmic autoantibody and lupus glomerulonephritis.
        Kidney Int. 2007; 72: 853-864
        • Linder G.C.
        • Lundsgaard C.
        • Van Slyke D.D.
        The concentration of the plasma proteins in nephritis.
        J Exp Med. 1924; 39: 887-920
        • Delanghe J.R.
        • Kouri T.T.
        • Huber A.R.
        • et al.
        The role of automated urine particle flow cytometry in clinical practice.
        Clin Chim Acta. 2000; 301: 1-18
        • Vogelmann S.U.
        • Nelson W.J.
        • Myers B.D.
        • Lemley K.V.
        Urinary excretion of viable podocytes in health and renal disease.
        Am J Physiol Renal Physiol. 2003; 285: F40-F48
        • Hara M.
        • Yanagihara T.
        • Takada T.
        • et al.
        Urinary excretion of podocytes reflects disease activity in children with glomerulonephritis.
        Am J Nephrol. 1998; 18: 35-41
        • Hara M.
        • Yanagihara T.
        • Itoh M.
        • Matsuno M.
        • Kihara I.
        Immunohistochemical and urinary markers of podocyte injury.
        Pediatr Nephrol. 1998; 12: 43-48
        • Nakamura T.
        • Ushiyama C.
        • Suzuki S.
        • et al.
        Urinary podocytes for the assessment of disease activity in lupus nephritis.
        Am J Med Sci. 2000; 320: 112-116
        • Nakamura T.
        • Ushiyama C.
        • Suzuki S.
        • et al.
        Urinary excretion of podocytes in patients with diabetic nephropathy.
        Nephrol Dial Transplant. 2000; 15: 1379-1383
        • Li B.
        • Hartono C.
        • Ding R.
        • et al.
        Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine.
        N Engl J Med. 2001; 344: 947-954
        • Szeto C.C.
        • Chow K.M.
        • Lai K.B.
        • et al.
        mRNA expression of target genes in the urinary sediment as a noninvasive prognostic indicator of CKD.
        Am J Kidney Dis. 2006; 47: 578-586
        • Szeto C.C.
        • Chan R.W.
        • Lai K.B.
        • et al.
        Messenger RNA expression of target genes in the urinary sediment of patients with chronic kidney diseases.
        Nephrol Dial Transplant. 2005; 20: 105-113
        • Kwan B.C.
        • Tam L.S.
        • Lai K.B.
        • et al.
        The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus.
        Rheumatology (Oxford). 2009; 48: 1491-1497
        • Zheng M.
        • Lv L.L.
        • Ni J.
        • et al.
        Urinary podocyte-associated mRNA profile in various stages of diabetic nephropathy.
        PLoS One. 2011; 6: e20431
        • Wang G.
        • Lai F.M.
        • Lai K.B.
        • Chow K.M.
        • Li K.T.
        • Szeto C.C.
        Messenger RNA expression of podocyte-associated molecules in the urinary sediment of patients with diabetic nephropathy.
        Nephron Clin Pract. 2007; 106: c169-c179
        • Szeto C.C.
        • Lai K.B.
        • Chow K.M.
        • et al.
        Messenger RNA expression of glomerular podocyte markers in the urinary sediment of acquired proteinuric diseases.
        Clin Chim Acta. 2005; 361: 182-190
        • Navarro-Munoz M.
        • Ibernon M.
        • Perez V.
        • et al.
        Messenger RNA expression of B7-1 and NPHS1 in urinary sediment could be useful to differentiate between minimal change disease and focal segmental glomerulosclerosis in adult patients.
        Nephrol Dial Transplant. 2011; 26: 3914-3923
        • Wang G.
        • Lai F.M.
        • Tam L.S.
        • et al.
        Urinary FOXP3 mRNA in patients with lupus nephritis–relation with disease activity and treatment response.
        Rheumatology (Oxford). 2009; 48: 755-760
        • Tsugawa K.
        • Oki E.
        • Suzuki K.
        • Imaizumi T.
        • Ito E.
        • Tanaka H.
        Expression of mRNA for functional molecules in urinary sediment in glomerulonephritis.
        Pediatr Nephrol. 2008; 23: 395-401
        • Zheng M.
        • Lv L.L.
        • Cao Y.H.
        • et al.
        Urinary mRNA markers of epithelial-mesenchymal transition correlate with progression of diabetic nephropathy.
        Clin Endocrinol (Oxford). 2011;
        • Sato Y.
        • Wharram B.L.
        • Lee S.K.
        • et al.
        Urine podocyte mRNAs mark progression of renal disease.
        J Am Soc Nephrol. 2009; 20: 1041-1052
        • Moon P.G.
        • You S.
        • Lee J.E.
        • Hwang D.
        • Baek M.C.
        Urinary exosomes and proteomics.
        Mass Spectrom Rev. 2011; 30: 1185-1202
        • Sika M.
        • Lewis J.
        • Douglas J.
        • et al.
        Baseline characteristics of participants in the African American Study of Kidney Disease and Hypertension (AASK) Clinical Trial and Cohort Study.
        Am J Kidney Dis. 2007; 50: 78-89.e1
        • Lash J.P.
        • Go A.S.
        • Appel L.J.
        • et al.
        Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function.
        Clin J Am Soc Nephrol. 2009; 4: 1302-1311
        • Mueller P.W.
        • Rogus J.J.
        • Cleary P.A.
        • et al.
        Genetics of Kidneys in Diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes.
        J Am Soc Nephrol. 2006; 17: 1782-1790
        • Fliser D.
        • Kollerits B.
        • Neyer U.
        • et al.
        Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study.
        J Am Soc Nephrol. 2007; 18: 2600-2608
        • Imai E.
        • Matsuo S.
        • Makino H.
        • et al.
        Chronic Kidney Disease Japan Cohort (CKD-JAC) study: design and methods.
        Hypertens Res. 2008; 31: 1101-1107
        • Eckardt K.U.
        • Barthlein B.
        • Baid-Agrawal S.
        • et al.
        The German Chronic Kidney Disease (GCKD) study: design and methods.
        Nephrol Dial Transplant. 2011; ([Epub ahead of print].)
        • Furth S.L.
        • Cole S.R.
        • Moxey-Mims M.
        • et al.
        Design and methods of the Chronic Kidney Disease in Children (CKiD) prospective cohort study.
        Clin J Am Soc Nephrol. 2006; 1: 1006-1015