Genomic biomarkers for chronic kidney disease: the first step towards personalized medicine?

Abstract

With the prevalence of end stage renal disease steadily increasing, chronic kidney disease (CKD) represents an impending public healthcare challenge. Classical diagnostic biomarkers of CKD, including creatinine, have low sensitivity and specificity. Thus, novel diagnostic and prognostic biomarkers for patients at high risk of early-stage progression are urgently needed. Personalized medicine approaches generally stratify patients according to their biological or genomic make-up. Targeted clinical trials require more precise identification of these subgroups. The use of new biomarkers obtained via high-throughput technologies is expected in future, accompanied by vast improvements in computational power applied in genomics, proteomics, and metabolomics studies using biological fluids and renal biopsy tissue. Genomic biomarkers may not only provide additional information regarding the etiology and mechanisms underlying CKD progression, but may also enable early diagnosis and the selection of appropriate drugs, thereby personalizing therapy. This review discusses commonly used research methods in genomic medicine and summarizes currently available genomic biomarkers in inherited and acquired CKD.

Keywords

Genomics / biomarkers / chronic kidney disease / personalized medicine / end-stage renal disease / high-throughput technology

References

[1] Webster AC,Morton RL.Chronic kidney disease..Lancet2017;389:1238-52

[2] Benjamin O.End-stage renal disease.2018;Treasure Island (FL)StatPearls Publishing

[3] Biomarkers Definitions Working GroupBiomarkers and surrogate endpoints: preferred definitions and conceptual framework..Clin Pharmacol Ther2001;69:89-95

[4] Urbschat A,Haferkamp A.Biomarkers of kidney injury..Biomarkers.2011;16 Suppl 1:S22-30

[5] Wuttke M.Insights into kidney diseases from genome-wide association studies..Nat Rev Nephrol2016;12:549-62

[6] Schena FP.Biomarkers and personalized therapy in chronic kidney diseases..Expert Opin Investig Drugs2014;23:1051-4

[7] Hamburg MA.The path to personalized medicine..N Engl J Med2010;363:301-4

[8] Aronson SJ.Building the foundation for genomics in precision medicine..Nature2015;526:336-42 PMCID:PMC5669797

[9] Salzberg SL.Open questions: how many genes do we have?.BMC Biol2018;16:94 PMCID:PMC6100717

[10] Venter JC,Adams MD.The sequence of the human genome..Clin Chem2015;61:1207-8

[11] Hansen TF.Clinical implications of genetic variations in the VEGF system in relation to colorectal cancer..Pharmacogenomics2011;12:1681-93

[12] Chakravarti A.To a future of genetic medicine..Nature2001;409:822-3

[13] Klein RJ,Chew EY,Sackler RS.Complement factor H polymorphism in age-related macular degeneration..Science2005;308:385-9 PMCID:PMC1512523

[14] Nordfors L,Carrero JJ,Stenvinkel P.Genetic studies in chronic kidney disease: basic concepts..J Nephrol2012;25:141-9

[15] Gross O,Rheault MN,Savige J.Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: report from the 2015 International Workshop on Alport Syndrome..Nephrol Dial Transplant2017;32:916-24 PMCID:PMC5837236

[16] Kashtan CE,Garosi G,Massella L.Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group..Kidney Int2018;93:1045-51

[17] Watson S.Alport syndrome.2018;Treasure Island (FL)StatPearls Publishing

[18] Savige J,Gross O,Ding J.Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy..J Am Soc Nephrol2013;24:364-75

[19] Cervera-Acedo C,Huarte-Loza E,Domínguez-Garrido E.Phenotype variability in a large Spanish family with Alport syndrome associated with novel mutations in COL4A3 gene..BMC Nephrol2017;18:325 PMCID:PMC5664579

[20] Fu XJ,Eguchi A,Morisada N.X-linked Alport syndrome associated with a synonymous p.Gly292Gly mutation alters the splicing donor site of the type IV collagen alpha chain 5 gene..Clin Exp Nephrol2016;20:699-702

[21] Liu JH,Li A,Xia XY.Novel mutations in COL4A3, COL4A4, and COL4A5 in Chinese patients with Alport Syndrome..PLoS One2017;12:e0177685 PMCID:PMC5436713

[22] Weber S,Rath S,Beicht S.Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy..Pediatr Nephrol2016;31:941-55

[23] Guo L,Dong S,Yang B.Mutation analysis of COL4A3 and COL4A4 genes in a Chinese autosomal-dominant Alport syndrome family..J Genet2017;96:389-92

[24] Savige J,Tonna S,Dagher H.Thin basement membrane nephropathy..Kidney Int2003;64:1169-78

[25] Tryggvason K.Thin basement membrane nephropathy..J Am Soc Nephrol2006;17:813-22

[26] Hou P,Ding J,Zhang H.A novel mutation of COL4A3 presents a different contribution to Alport syndrome and thin basement membrane nephropathy..Am J Nephrol2007;27:538-44

[27] Xu Y,Dong H,Ma R.A novel COL4A4 mutation identified in a Chinese family with thin basement membrane nephropathy..Sci Rep2016;6:20244

[28] Baek JI,Park SH,Kim CD.Identification of novel variants in the COL4A4 gene in Korean patients with thin basement membrane nephropathy..Indian J Med Res2009;129:525-33

[29] Gale DP,Lin F,Khan N.A novel COL4A1 frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen..Nephrol Dial Transplant2016;31:1908-14 PMCID:PMC5091614

[30] Sha YK,Mei LB,Wang X.Use of targeted sequence capture and high-throughput sequencing identifies a novel PKD1 mutation involved in adult polycystic kidney disease..Gene2017;634:1-4

[31] Harris PC.Molecular diagnostics for autosomal dominant polycystic kidney disease..Nat Rev Nephrol2010;6:197-206 PMCID:PMC4050432

[32] Porath B,Cornec-Le Gall E,Heyer CM.Mutations in GANAB, encoding the glucosidase IIα subunit, cause autosomal-dominant polycystic kidney and liver disease..Am J Hum Genet2016;98:1193-1207 PMCID:PMC4908191

[33] Cornec-Le Gall E,Harris PC.Genetic complexity of autosomal dominant polycystic kidney and liver diseases..J Am Soc Nephrol2018;29:13-23 PMCID:PMC5748917

[34] Song X,Iliuta IA.Molecular diagnosis of autosomal dominant polycystic kidney disease..Expert Rev Mol Diagn2017;17:885-95

[35] Wang Z,Xiong J.A new PKD1 mutation discovered in a Chinese family with autosomal polycystic kidney disease..Kidney Blood Press Res2014;39:1-8

[36] Stanescu HC,Medlar A,Kottgen A.Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy..N Engl J Med2011;364:616-26

[37] Lv J,Zhou X,Zhou F.Interaction between PLA2R1 and HLA-DQA1 variants associates with anti-PLA2R antibodies and membranous nephropathy..J Am Soc Nephrol2013;24:1323-9 PMCID:PMC3736719

[38] Sekula P,Stanescu HC,Ekici AB.Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies..Nephrol Dial Transplant2017;32:325-32 PMCID:PMC5837679

[39] Le WB,Zhang T,Qin HZ.HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-related membranous nephropathy..J Am Soc Nephrol2017;28:1642-50 PMCID:PMC5407724

[40] Bullich G,Oliver A,Silva I.HLA-DQA1 and PLA2R1 polymorphisms and risk of idiopathic membranous nephropathy..Clin J Am Soc Nephrol2014;9:335-43 PMCID:PMC3913240

[41] Kanigicherla D,McKenzie EA,Harris S.Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy..Kidney Int2013;83:940-8

[42] Ronco P.Membranous nephropathy: a fairy tale for immunopathologists, nephrologists and patients..Mol Immunol2015;68:57-62

[43] Kiryluk K,Sanna-Cherchi S,Suzuki H.Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis..PLoS Genet2012;8:e1002765 PMCID:PMC3380840

[44] Kiryluk K.The genetics and immunobiology of IgA nephropathy..J Clin Invest2014;124:2325-32 PMCID:PMC4089454

[45] Kiryluk K,Gharavi AG.Pathogenesis of immunoglobulin A nephropathy: recent insight from genetic studies..Annu Rev Med2013;64:339-56 PMCID:PMC3921622

[46] Kiryluk K,Scolari F,Choi M.Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens..Nat Genet2014;46:1187-96 PMCID:PMC4213311

[47] Li M,Wang JQ,Tang XQ.Identification of new susceptibility loci for IgA nephropathy in Han Chinese..Nat Commun2015;6:7270 PMCID:PMC4458882

[48] Nie R,Zhang J,Wang C.The association of rs1047763 and rs1008898 of C1GALT1 with IgA nephropathy risk: a global meta-analysis..Monoclon Antib Immunodiagn Immunother2017;36:95-103

[49] Gharavi AG,Choi M,Hou P.Genome-wide association study identifies susceptibility loci for IgA nephropathy..Nat Genet2011;43:321-7 PMCID:PMC3412515

[50] Jullien P,Claisse G,Dinic M.Deletion variants of CFHR1 and CFHR3 associate with mesangial immune deposits but not with progression of IgA nephropathy..J Am Soc Nephrol2018;29:661-9 PMCID:PMC5791061

[51] Zhai YL,Zhu L,Wang SX.Rare variants in the complement factor H-related protein 5 gene contribute to genetic susceptibility to IgA nephropathy..J Am Soc Nephrol2016;27:2894-905 PMCID:PMC5004636

[52] Qi YY,Cheng FJ,Zhu L.DEFA gene variants associated with IgA nephropathy in a Chinese population..Genes Immun2015;16:231-7

[53] Feehally J,Boland A,Gut I.HLA has strongest association with IgA nephropathy in genome-wide analysis..J Am Soc Nephrol2010;21:1791-7 PMCID:PMC3013538

[54] Milillo A,Costanzi S,Martini M.A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy..Eur J Hum Genet2015;23:1673-8 PMCID:PMC4795196

[55] Gale DP,Wimbury D,Levine AP.Galactosylation of IgA1 is associated with common variation in C1GALT1..J Am Soc Nephrol2017;28:2158-66 PMCID:PMC5491291

[56] Zhong Z,Xu RC,Huang FX.Association of TNFSF13 polymorphisms with IgA nephropathy in a Chinese Han population..J Gene Med2017;

[57] Maillard N,Julian BA,Gharavi A.Current understanding of the role of complement in IgA nephropathy..J Am Soc Nephrol2015;26:1503-12 PMCID:PMC4483595

[58] Cox SN,El-Sayed Moustafa JS,Serino G.Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network..J Intern Med2017;281:189-205 PMCID:PMC5297991

[59] Xue JL,Agodoa LY,Collins AJ.Longitudinal study of racial and ethnic differences in developing end-stage renal disease among aged medicare beneficiaries..J Am Soc Nephrol2007;18:1299-306

[60] Kopp JB,Nelson GW,Freedman BI.MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis..Nat Genet2008;40:1175-84 PMCID:PMC2827354

[61] Tzur S,Shemer R,Selig S.Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene..Hum Genet2010;128:345-50 PMCID:PMC2921485

[62] Limou S,Kopp JB.APOL1 kidney risk alleles: population genetics and disease associations..Adv Chronic Kidney Dis2014;21:426-33 PMCID:PMC4157456

[63] Genovese G,Ross MD,Uzureau P.Association of trypanolytic ApoL1 variants with kidney disease in African Americans..Science2010;329:841-5 PMCID:PMC2980843

[64] Limou S,Nelson GW,Winkler CA.APOL1 toxin, innate immunity, and kidney injury..Kidney Int2015;88:28-34 PMCID:PMC4490079

[65] Parsa A,Xie D,Li M.APOL1 risk variants, race, and progression of chronic kidney disease..N Engl J Med2013;369:2183-96 PMCID:PMC3969022

[66] Larsen CP,Saeed M.Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy..J Am Soc Nephrol2013;24:722-5 PMCID:PMC3636799

[67] Lipkowitz MS,Langefeld CD,Bowden DW.Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans..Kidney Int2013;83:114-20 PMCID:PMC3484228

[68] Kopp JB,Sampath K,Genovese G.APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy..J Am Soc Nephrol2011;22:2129-37 PMCID:PMC3231787

[69] Papeta N,Patel A,Kacak N.APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy..J Am Soc Nephrol2011;22:1991-6 PMCID:PMC3231781

[70] Freedman BI,Israni AK,Julian BA.APOL1 genotype and kidney transplantation outcomes from deceased African American donors..Transplantation2016;100:194-202 PMCID:PMC4684443

[71] Lee BT,Williams TA,Bernhardy A.The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival..Am J Transplant2012;12:1924-8 PMCID:PMC3387301

[72] Chandraker A.The real world impact of APOL1 variants on kidney transplantation..Transplantation2016;100:16-7

[73] Cooper ME.Diabetes: treating diabetic nephropathy-still an unresolved issue..Nat Rev Endocrinol2012;8:515-6

[74] Sandholm N Van Zuydam N,Juliusdottir T.The genetic landscape of renal complications in type 1 diabetes..J Am Soc Nephrol2017;28:557-74 PMCID:PMC5280020

[75] Teumer A,Sorice R,Yeo NC.Genome-wide association studies identify genetic loci associated with albuminuria in diabetes..Diabetes2016;65:803-17 PMCID:PMC4764151

[76] Pezzolesi MG,Skupien J,Mychaleckyj JC.An intergenic region on chromosome 13q33.3 is associated with the susceptibility to kidney disease in type 1 and 2 diabetes..Kidney Int2011;80:105-11 PMCID:PMC3774030

[77] Sandholm N,Salem RM,Forsblom C.Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes..J Am Soc Nephrol2013;24:1537-43 PMCID:PMC3785274

[78] Iyengar SK,Freedman BI,Kretzler M.Genome-wide association and trans-ethnic meta-analysis for advanced diabetic kidney disease: family investigation of nephropathy and diabetes (FIND)..PLoS Genet2015;11:e1005352 PMCID:PMC4549309

[79] Li Q,Li H,Kang Z.Effect of AMP-activated protein kinase subunit alpha 2 (PRKAA2) genetic polymorphisms on susceptibility to type 2 diabetes mellitus and diabetic nephropathy in a Chinese population..J Diabetes2018;10:43-9

[80] Limou S,Parsa A.Lessons from CKD-related genetic association studies-moving forward..Clin J Am Soc Nephrol2018;13:140-52 PMCID:PMC5753320

[81] Joyner MJ.Seven questions for personalized medicine..JAMA2015;314:999-1000

[82] Witasp A,Carrero JJ,Lindholm B.Genetic studies in chronic kidney disease: interpretation and clinical applicability..J Nephrol2012;25:851-64

[83] Zheng M,Ni J,Li Q.Urinary podocyte-associated mRNA profile in various stages of diabetic nephropathy..PLoS One2011;6:e20431 PMCID:PMC3105067

[84] Cao YH,Zhang X,Ding LH.Urinary vimentin mRNA as a potential novel biomarker of renal fibrosis..Am J Physiol Renal Physiol2015;309:F514-22

[85] Zhou LT,Lv LL,Chen PS.Feature selection and classification of urinary mRNA microarray data by iterative random forest to diagnose renal fibrosis: a two-stage study..Sci Rep2017;7:39832 PMCID:PMC5206620

[86] Breit M.Metabolic biomarkers for chronic kidney disease..Arch Biochem Biophys2016;589:62-80

[87] Hocher B.Metabolomics for clinical use and research in chronic kidney disease..Nat Rev Nephrol2017;13:269-84

[88] Lyu LL,Liu BC.Urinary biomarkers for chronic kidney disease with a focus on gene transcript..Chin Med J (Engl)2017;130:2251-6 PMCID:PMC5598339

[89] Chen R,Li-Pook-Than J,Lam HY.Personal omics profiling reveals dynamic molecular and medical phenotypes..Cell2012;148:1293-307 PMCID:PMC3341616