Genetic Considerations in Pediatric Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) in children is an irreversible process that, in some cases, may lead to end-stage renal disease. The majority of children with CKD have a congenital disorder of the kidney or urological tract arising from birth. There is strong evidence for both a genetic and epigenetic component to progression of CKD. Utilization of gene-mapping strategies, ranging from genome-wide association studies to single-nucleotide polymorphism analysis, serves to identify potential genetic variants that may lend to disease variation. Genome-wide association studies evaluating population-based data have identified different loci associated with CKD progression. Analysis of single-nucleotide polymorphisms on an individual level suggests that secondary systemic sequelae of CKD are closely related to dysfunction of the cardiovascular-inflammatory axis and may lead to advanced cardiovascular disease through abnormal vascular calcification and activation of the renin–angiotensin system. Similarly, genetic variants affecting cytokine control, fibrosis, and parenchymal development may modulate CKD through development and acceleration of renal interstitial fibrosis. Epigenetic studies evaluate modification of the genome through DNA methylation, histone modification, or RNA interference, which may be directly influenced by external or environmental factors directing genomic expression. Lastly, improved understanding of the genetic and epigenetic contribution to CKD progression may allow providers to identify a population at accelerated risk for disease progression and apply novel therapies targeted at the genetic mechanism of disease.

Keywords

pediatric chronic kidney disease - epigenetic modifications - single-nucleotide polymorphisms

• References

• 1 Levey AS, Eckardt KU, Tsukamoto Y , et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005; 67 (6) 2089-2100
• 2 System U. USRDS 2011 Annual Report: Atlas of Chronic Kidney Disease and End-stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2011
• 3 Dressler GR, Woolf AS. Pax2 in development and renal disease. Int J Dev Biol 1999; 43 (5) 463-468
• 4 Vehaskari VM. Genetics and CKD. Adv Chronic Kidney Dis 2011; 18 (5) 317-323
• 5 Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 2010; 21 (11) 1819-1834
• 6 Satko SG, Sedor JR, Iyengar SK, Freedman BI. Familial clustering of chronic kidney disease. Semin Dial 2007; 20 (3) 229-236
• 7 Cargill M, Altshuler D, Ireland J , et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 1999; 22 (3) 231-238
• 8 Freedman BI, Volkova NV, Satko SG , et al. Population-based screening for family history of end-stage renal disease among incident dialysis patients. Am J Nephrol 2005; 25 (6) 529-535
• 9 Lei HH, Perneger TV, Klag MJ, Whelton PK, Coresh J. Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol 1998; 9 (7) 1270-1276
• 10 Axelsson J, Devuyst O, Nordfors L, Heimbürger O, Stenvinkel P, Lindholm B. Place of genotyping and phenotyping in understanding and potentially modifying outcomes in peritoneal dialysis patients. Kidney Int Suppl 2006; 103 (103) S138-S145
• 11 Luttropp K, Stenvinkel P, Carrero JJ, Pecoits-Filho R, Lindholm B, Nordfors L. Understanding the role of genetic polymorphisms in chronic kidney disease. Pediatr Nephrol 2008; 23 (11) 1941-1949
• 12 Drawz PE, Sedor JR. The genetics of common kidney disease: a pathway toward clinical relevance. Nat Rev Nephrol 2011; 7 (8) 458-468
• 13 Reeders ST, Breuning MH, Davies KE , et al. A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 1985; 317 (6037) 542-544
• 14 Smyth LJ, Duffy S, Maxwell AP, McKnight AJ. Genetic and epigenetic factors influencing chronic kidney disease. Am J Physiol Renal Physiol 2014; 307 (7) F757-F776
• 15 Wise LH, Lanchbury JS, Lewis CM. Meta-analysis of genome searches. Ann Hum Genet 1999; 63 (Pt 3): 263-272
• 16 Rao M, Mottl AK, Cole SA , et al. Meta-analysis of genome-wide linkage scans for renal function traits. Nephrol Dial Transplant 2012; 27 (2) 647-656
• 17 Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science 2008; 322 (5903) 881-888
• 18 O'Seaghdha CM, Fox CS. Genetics of chronic kidney disease. Nephron Clin Pract 2011; 118 (1) c55-c63
• 19 Tampe B, Zeisberg M. Contribution of genetics and epigenetics to progression of kidney fibrosis. Nephrol Dial Transplant 2014; 29 (Suppl. 04) iv72-iv79
• 20 Köttgen A, Glazer NL, Dehghan A , et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 2009; 41 (6) 712-717
• 21 Köttgen A, Hwang SJ, Larson MG , et al. Uromodulin levels associate with a common UMOD variant and risk for incident CKD. J Am Soc Nephrol 2010; 21 (2) 337-344
• 22 Hart TC, Gorry MC, Hart PS , et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 2002; 39 (12) 882-892
• 23 Rampoldi L, Caridi G, Santon D , et al. Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Hum Mol Genet 2003; 12 (24) 3369-3384
• 24 Köttgen A, Pattaro C, Böger CA , et al. New loci associated with kidney function and chronic kidney disease. Nat Genet 2010; 42 (5) 376-384
• 25 Kao WH, Klag MJ, Meoni LA , et al; Family Investigation of Nephropathy and Diabetes Research Group. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008; 40 (10) 1185-1192
• 26 Genovese G, Friedman DJ, Ross MD , et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010; 329 (5993) 841-845
• 27 Freedman BI, Kopp JB, Langefeld CD , et al. The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans. J Am Soc Nephrol 2010; 21 (9) 1422-1426
• 28 Bostrom MA, Freedman BI. The spectrum of MYH9-associated nephropathy. Clin J Am Soc Nephrol 2010; 5 (6) 1107-1113
• 29 Liu CT, Garnaas MK, Tin A , et al; CKDGen Consortium. Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. PLoS Genet 2011; 7 (9) e1002264
• 30 Groothoff JW, Gruppen MP, Offringa M , et al. Mortality and causes of death of end-stage renal disease in children: a Dutch cohort study. Kidney Int 2002; 61 (2) 621-629
• 31 McDonald SP, Craig JC ; Australian and New Zealand Paediatric Nephrology Association. Long-term survival of children with end-stage renal disease. N Engl J Med 2004; 350 (26) 2654-2662
• 32 Samuel SM, Tonelli MA, Foster BJ , et al; Pediatric Renal Outcomes Canada Group. Survival in pediatric dialysis and transplant patients. Clin J Am Soc Nephrol 2011; 6 (5) 1094-1099
• 33 Ketteler M, Bongartz P, Westenfeld R , et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 2003; 361 (9360) 827-833
• 34 Lebreton JP, Joisel F, Raoult JP, Lannuzel B, Rogez JP, Humbert G. Serum concentration of human alpha 2 HS glycoprotein during the inflammatory process: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant. J Clin Invest 1979; 64 (4) 1118-1129
• 35 Schinke T, Amendt C, Trindl A, Pöschke O, Müller-Esterl W, Jahnen-Dechent W. The serum protein alpha2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. A possible role in mineralization and calcium homeostasis. J Biol Chem 1996; 271 (34) 20789-20796
• 36 Stenvinkel P, Wang K, Qureshi AR , et al. Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin. Kidney Int 2005; 67 (6) 2383-2392
• 37 Ziolkowska H, Brzewski M, Roszkowska-Blaim M. Determinants of the intima-media thickness in children and adolescents with chronic kidney disease. Pediatr Nephrol 2008; 23 (5) 805-811
• 38 Weiner DE, Tabatabai S, Tighiouart H , et al. Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis 2006; 48 (3) 392-401
• 39 Baudin B. Polymorphism in angiotensin II receptor genes and hypertension. Exp Physiol 2005; 90 (3) 277-282
• 40 Caulfield M, Lavender P, Farrall M , et al. Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med 1994; 330 (23) 1629-1633
• 41 Wang AY, Chan JC, Wang M , et al. Cardiac hypertrophy and remodeling in relation to ACE and angiotensinogen genes genotypes in Chinese dialysis patients. Kidney Int 2003; 63 (5) 1899-1907
• 42 Bantis C, Ivens K, Kreusser W , et al. Influence of genetic polymorphisms of the renin-angiotensin system on IgA nephropathy. Am J Nephrol 2004; 24 (2) 258-267
• 43 Osono E, Kurihara S, Hayama N , et al. Insertion/deletion polymorphism in intron 16 of the ACE gene and left ventricular hypertrophy in patients with end-stage renal disease. Am J Kidney Dis 1998; 32 (5) 725-730
• 44 Elshamaa MF, Sabry SM, Bazaraa HM , et al. Genetic polymorphism of ACE and the angiotensin II type1 receptor genes in children with chronic kidney disease. J Inflamm (Lond) 2011; 8 (1) 20
• 45 Hohenfellner K, Wingen AM, Nauroth O, Wühl E, Mehls O, Schaefer F. Impact of ACE I/D gene polymorphism on congenital renal malformations. Pediatr Nephrol 2001; 16 (4) 356-361
• 46 Papp F, Friedman AL, Bereczki C , et al. Renin-angiotensin gene polymorphism in children with uremia and essential hypertension. Pediatr Nephrol 2003; 18 (2) 150-154
• 47 Haszon I, Friedman AL, Papp F , et al. ACE gene polymorphism and renal scarring in primary vesicoureteric reflux. Pediatr Nephrol 2002; 17 (12) 1027-1031
• 48 Brock III JW, Adams M, Hunley T, Wada A, Trusler L, Kon V. Potential risk factors associated with progressive renal damage in childhood urological diseases: the role of angiotensin-converting enzyme gene polymorphism. J Urol 1997; 158 (3 Pt 2): 1308-1311
• 49 al-Eisa A, Haider MZ, Srivastva BS. Angiotensin-converting enzyme gene insertion/deletion polymorphism and renal damage in childhood uropathies. Pediatr Int 2000; 42 (4) 348-353
• 50 Zaffanello M, Tardivo S, Cataldi L, Fanos V, Biban P, Malerba G. Genetic susceptibility to renal scar formation after urinary tract infection: a systematic review and meta-analysis of candidate gene polymorphisms. Pediatr Nephrol 2011; 26 (7) 1017-1029
• 51 Perna A, Ruggenenti P, Testa A , et al. ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies1. Kidney Int 2000; 57 (1) 274-281
• 52 Ruggenenti P, Perna A, Zoccali C , et al. Chronic proteinuric nephropathies. II. Outcomes and response to treatment in a prospective cohort of 352 patients: differences between women and men in relation to the ACE gene polymorphism. Gruppo Italiano di Studi Epidemologici in Nefrologia (Gisen). J Am Soc Nephrol 2000; 11 (1) 88-96
• 53 Braliou GG, Grigoriadou AM, Kontou PI, Bagos PG. The role of genetic polymorphisms of the Renin-Angiotensin System in renal diseases: A meta-analysis. Comput Struct Biotechnol J 2014; 10 (16) 1-7
• 54 Yoneda A, Cascio S, Green A, Barton D, Puri P. Angiotensin II type 2 receptor gene is not responsible for familial vesicoureteral reflux. J Urol 2002; 168 (3) 1138-1141
• 55 Hohenfellner K, Hunley TE, Schloemer C , et al. Angiotensin type 2 receptor is important in the normal development of the ureter. Pediatr Nephrol 1999; 13 (3) 187-191
• 56 Hohenfellner K, Hunley TE, Yerkes E, Habermehl P, Hohenfellner R, Kon V. Angiotensin II, type 2 receptor in the development of vesico-ureteric reflux. BJU Int 1999; 83 (3) 318-322
• 57 Rao M, Jaber BL, Balakrishnan VS ; DialGene Consortium Gene polymorphism association studies in dialysis: cardiovascular disease. Semin Dial 2005; 18 (3) 217-225
• 58 Zychma MJ, Gumprecht J, Grzeszczak W, Zukowska-Szczechowska E ; End-Stage Renal Disease Study Group Methylenetetrahydrofolate reductase gene C677T polymorphism, plasma homocysteine and folate in end-stage renal disease dialysis and non-dialysis patients. Nephron 2002; 92 (1) 235-239
• 59 Merouani A, Lambert M, Delvin EE, Genest Jr J, Robitaille P, Rozen R. Plasma homocysteine concentration in children with chronic renal failure. Pediatr Nephrol 2001; 16 (10) 805-811
• 60 McCarthy AM, Lindgren S, Mengeling MA, Tsalikian E, Engvall JC. Effects of diabetes on learning in children. Pediatrics 2002; 109 (1) E9
• 61 Girndt M, Heine GH, Köhler H ; DialGene Consortium Gene polymorphism association studies in dialysis: anemia and host immunity. Semin Dial 2006; 19 (3) 227-231
• 62 Fuller R, Nopoulos P, Arndt S, O'Leary D, Ho BC, Andreasen NC. Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance. Am J Psychiatry 2002; 159 (7) 1183-1189
• 63 Blackman JA, Lindgren SD, Bretthauer J. The validity of continuing developmental follow-up of high-risk infants to age 5 years. Am J Dis Child 1992; 146 (1) 70-75
• 64 Moser JJ, Veale PM, McAllister DL, Archer DP. A systematic review and quantitative analysis of neurocognitive outcomes in children with four chronic illnesses. Paediatr Anaesth 2013; 23 (11) 1084-1096
• 65 Balakrishnan VS, Guo D, Rao M , et al; HEMO Study Group Cytokine gene polymorphisms in hemodialysis patients: association with comorbidity, functionality, and serum albumin. Kidney Int 2004; 65 (4) 1449-1460
• 66 Girndt M, Kaul H, Sester U , et al. Anti-inflammatory interleukin-10 genotype protects dialysis patients from cardiovascular events. Kidney Int 2002; 62 (3) 949-955
• 67 August P, Suthanthiran M. Transforming growth factor beta signaling, vascular remodeling, and hypertension. N Engl J Med 2006; 354 (25) 2721-2723
• 68 Yamamoto T, Noble NA, Miller DE, Border WA. Sustained expression of TGF-beta 1 underlies development of progressive kidney fibrosis. Kidney Int 1994; 45 (3) 916-927
• 69 Li B, Khanna A, Sharma V, Singh T, Suthanthiran M, August P. TGF-beta1 DNA polymorphisms, protein levels, and blood pressure. Hypertension 1999; 33 (1, Pt 2): 271-275
• 70 Schultz JelJ, Witt SA, Glascock BJ , et al. TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 2002; 109 (6) 787-796
• 71 Zoja C, Corna D, Camozzi D , et al. How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol 2002; 13 (12) 2898-2908
• 72 Grainger DJ, Heathcote K, Chiano M , et al. Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 1999; 8 (1) 93-97
• 73 Hussein A, Askar E, Elsaeid M, Schaefer F. Functional polymorphisms in transforming growth factor-beta-1 (TGFbeta-1) and vascular endothelial growth factor (VEGF) genes modify risk of renal parenchymal scarring following childhood urinary tract infection. Nephrol Dial Transplant 2010; 25 (3) 779-785
• 74 Dwivedi RS, Herman JG, McCaffrey TA, Raj DS. Beyond genetics: epigenetic code in chronic kidney disease. Kidney Int 2011; 79 (1) 23-32
• 75 Jang H, Serra C. Nutrition, epigenetics, and diseases. Clin Nurs Res 2014; 3 (1) 1-8
• 76 Woroniecki R, Gaikwad AB, Susztak K. Fetal environment, epigenetics, and pediatric renal disease. Pediatr Nephrol 2011; 26 (5) 705-711
• 77 Hostetter TH, Rennke HG, Brenner BM. Compensatory renal hemodynamic injury: a final common pathway of residual nephron destruction. Am J Kidney Dis 1982; 1 (5) 310-314
• 78 Ingrosso D, Cimmino A, Perna AF , et al. Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 2003; 361 (9370) 1693-1699
• 79 Bechtel W, McGoohan S, Zeisberg EM , et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 2010; 16 (5) 544-550
• 80 Ko YA, Mohtat D, Suzuki M , et al. Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development. Genome Biol 2013; 14 (10) R108
• 81 Witasp A, Ekström TJ, Schalling M, Lindholm B, Stenvinkel P, Nordfors L. How can genetics and epigenetics help the nephrologist improve the diagnosis and treatment of chronic kidney disease patients?. Nephrol Dial Transplant 2014; 29 (5) 972-980
• 82 Reddy MA, Natarajan R. Epigenetics in diabetic kidney disease. J Am Soc Nephrol 2011; 22 (12) 2182-2185
• 83 Reddy MA, Sumanth P, Lanting L , et al. Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int 2014; 85 (2) 362-373
• 84 Sun G, Reddy MA, Yuan H, Lanting L, Kato M, Natarajan R. Epigenetic histone methylation modulates fibrotic gene expression. J Am Soc Nephrol 2010; 21 (12) 2069-2080
• 85 Liu N, He S, Ma L , et al. Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling. PLoS ONE 2013; 8 (1) e54001
• 86 Wing MR, Ramezani A, Gill HS, Devaney JM, Raj DS. Epigenetics of progression of chronic kidney disease: fact or fantasy?. Semin Nephrol 2013; 33 (4) 363-374
• 87 Chau BN, Xin C, Hartner J , et al. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med 2012; 4 (121) 121ra18
• 88 Chung AC, Huang XR, Meng X, Lan HY. miR-192 mediates TGF-beta/Smad3-driven renal fibrosis. J Am Soc Nephrol 2010; 21 (8) 1317-1325
• 89 Wang G, Kwan BC, Lai FM , et al. Intrarenal expression of miRNAs in patients with hypertensive nephrosclerosis. Am J Hypertens 2010; 23 (1) 78-84