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Understanding the role of genetic polymorphisms in chronic kidney disease

Pediatric Nephrology volume 23, pages 1941–1949 (2008)Cite this article

Abstract

Although no valid studies clearly indicate increasing or decreasing numbers of incident paediatric patients, the prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) is growing worldwide. This is mainly due to improved access to renal replacement therapy (RRT), increased survival after dialysis and kidney transplantation and an increase in diagnosis and referral of these patients. Although the increase in CKD prevalence is mainly caused by environmental factors, genetic factors may also influence the incidence and/or the progression of CKD and its complications. As CKD patients might be more sensitive to genetic effects due to the exposure to a uraemic milieu, this makes studies of genetic factors especially interesting in this population. The goal of identifying genetic factors that contribute to the outcome of CKD is to gain further understanding of the disease pathogenesis and underlying causes and, possibly, to use this knowledge to predict disease or its complications and to identify a risk population. Therefore, genetic screening of paediatric CKD patients may enhance the impact of preventive measures that could have a positive effect on outcome. Furthermore, by identifying patients’ genetic backgrounds, it is possible that a more individualised therapy could be designed.

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References

  1. Satko SG, Sedor JR, Iyengar SK, Freedman BI (2007) Familial clustering of chronic kidney disease. Semin Dial 20:229–236

    PubMed  Google Scholar 

  2. Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 22:231–238

    CAS  PubMed  Google Scholar 

  3. Axelsson J, Devuyst O, Nordfors L, Heimbürger O, Stenvinkel P, Lindholm B (2006) Place of genotyping and phenotyping in understanding and potentially modifying outcomes in peritoneal dialysis patients. Kidney Int 70:S138–S145

    Google Scholar 

  4. Zoccali C, Testa A, Spoto B, Tripepi G, Mallamaci F (2006) Mendelian randomization: A new approach to studying epidemiology in ESRD. Am J Kidney Dis 47:332–341

    PubMed  Google Scholar 

  5. Mitsnefes MM (2005) Cardiovascular disease in children with chronic kidney disease. Adv Chronic Kidney Dis 12:397–405

    PubMed  Google Scholar 

  6. Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, Mehls O, Schaefer F (2002) Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106:100–105

    PubMed  Google Scholar 

  7. Stenvinkel P, Alvestrand A (2002) Inflammation in end-stage renal disease: sources, consequences and therapy. Semin Dial 15:330–338

    Google Scholar 

  8. Stenvinkel P, Wang K, Qureshi AR, Axelsson J, Pecoits-Filho R, Gao P, Barany P, Lindholm B, Jogestrand T, Heimbürger O, Holmes C, Schalling M, Nordfors L (2005) Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin. Kidney Int 67:2383–2392

    CAS  PubMed  Google Scholar 

  9. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB (2000) Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478–1483

    CAS  PubMed  Google Scholar 

  10. Rao M, Jaber BL, Balakrishnan VS (2005) Gene polymorphism association studies in dialysis: Cardiovascular disease. Semin Dial 18:217–225

    PubMed  Google Scholar 

  11. Pecoits-Filho R, Stenvinkel P, Marchlewska A, Heimbürger O, Barany P, Hoff CM, Holmes CJ, Suliman M, Lindholm B, Schalling M, Nordfors L (2003) A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients. Kidney Int 84:S172–S176

    CAS  Google Scholar 

  12. Buraczynska K, Koziol-Montewka M, Majdan M, Ksiazek A (2003) Polymorphisms of tumor necrosis factor and myeloperoxidase genes in patients with chronic renal failure on peritoneal dialysis. Mol Diagn 7:175–180

    PubMed  Google Scholar 

  13. Weiner DE, Tabatabai S, Tighiouart H, Elsayed E, Bansal N, Griffith J, Salem DN, Levey AS, Sarnak MJ (2006) Cardiovascular outcomes and all-cause mortality: Exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis 48:392–401

    PubMed  Google Scholar 

  14. Kagami S, Border WA, Miller DE, Noble NA (1994) Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest 93:2431–2437

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gumprecht J, Zychma MJ, Grzeszczak W, Zukowska-Szczechowska E (2000) Angiotensin I-converting enzyme gene insertion/deletion and angiotensinogen M235T polymorphisms: risk of chronic renal failure. Kidney Int 58:513–519

    CAS  PubMed  Google Scholar 

  16. Perez-Oller L, Torra R, Badenas C, Mila M, Darnell A (1999) Influence of the ACE gene polymorphism in the progression of renal failure in autosomal dominant polycystic kidney disease. Am J Kidney Dis 34:273–278

    CAS  PubMed  Google Scholar 

  17. Hohenfellner K, Wingen A-M, Nauroth O, Wühl E, Mehls O, Schaefer F (2001) Impact of ACE I/D gene polymorphism on congenital renal malformations. Pediatr Nephrol 16:356–361

    CAS  PubMed  Google Scholar 

  18. Woo K-T, Lau Y-K, Zhao Y, Liu F-E, Tan H-B, Tan E-K, Stephanie F-C, Chan C-M, Wong K-S (2007) Disease progression, response to ACEI/ATRA therapy and influence of ACE gene in IgA nephritis. Cell Mol Immunol 4:227–232

    CAS  PubMed  Google Scholar 

  19. Wang AY, Chan JC, Wang M, Poon E, Lui SF, Li PK, Sanderson J (2003) Cardiac hypertrophy and remodeling in relation to ACE and angiotensinogen genes genotypes in Chinese dialysis patients. Kidney Int 63:1899–1907

    CAS  PubMed  Google Scholar 

  20. Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Bohm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J (2003) Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:327–333

    Google Scholar 

  21. Lehtinen AB, Burdon KP, Lewis JP, Langefeld CD, Ziegler JT, Rich SS, Register TC, Carr JJ, Freedman BI, Bowden DW (2007) Association of a2-Heremans-Schmid glycoprotein polymorphisms with subclinical atherosclerosis. J Clin Endocrinol Metab 92:345–352

    CAS  PubMed  Google Scholar 

  22. Zychma MJ, Gumprecht J, Grzeszczak W, Zukowska-Szczechowska E (2002) Methylenetetrahydrofolate reductase gene C677T polymorphism, plasma homocysteine and folate in end-stage renal disease dialysis and non-dialysis patients. Nephron 92:235–239

    CAS  PubMed  Google Scholar 

  23. Ksiazek P, Bednarek-Skublewska A, Buraczynska M (2004) The C677T methylenetetrahydrofolate reductase gene mutation and nephropathy in type 2 diabetes mellitus. Med Sci Monit 10:BR47–BR51

    CAS  PubMed  Google Scholar 

  24. Maruyama Y, Nordfors L, Stenvinkel P, Heimburger O, Barany P, Pecoits-Filho R, Axelsson J, Hoff CM, Holmes CJ, Schalling M, Lindholm B (2005) Interleukin-1 gene cluster polymorphisms are associated with nutritional status and inflammation in patients with end-stage renal disease. Blood Purif 23:384–393

    CAS  PubMed  Google Scholar 

  25. Abrahamian H, Endler G, Exner M, Mauler H, Raith M, Endler L, Rumpold H, Gerdov M, Mannhalter C, Prager R, Irsigler K, Wagner OF (2007) Association of low-grade inflammation with nephropathy in type 2 diabetic patients: role of elevated CRP-levels and 2 different gene-polymorphisms of proinflammatory cytokines. Exp Clin Endocrinol Diabetes 115:38–41

    CAS  PubMed  Google Scholar 

  26. Pecoits-Filho R, Barany P, Lindholm B, Heimbürger O, Stenvinkel P (2002) Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment. Nephrol Dial Transplant 17:1684–1688

    CAS  PubMed  Google Scholar 

  27. Honda H, Qureshi AR, Heimbürger O, Barany P, Wang K, Pecoits-Filho R, Stenvinkel P, Lindholm B (2006) Serum albumin, C-reactive protein, interleukin 6, and fetuin A as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. Am J Kidney Dis 47:139–148

    CAS  PubMed  Google Scholar 

  28. Balakrishnan VS, Guo D, Rao M, Jaber BL, Tighiouart H, Freeman RL, Huang C, King AJ, Pereira BJ (2004) Cytokine gene polymorphisms in hemodialysis patients: association with comorbidity, functionality, and serum albumin. Kidney Int 65:1449–1460

    CAS  PubMed  Google Scholar 

  29. Bennermo M, Held C, Stemme S, Ericsson CG, Silveira A, Green F, Tornvall P (2004) Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases? Clin Chem 50:2136–2140

    CAS  PubMed  Google Scholar 

  30. Liu Y, Berthier-Schaad Y, Fallin MD, Fink NE, Tracy RP, Klag MJ, Smith MW, Coresh J (2006) IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort. J Am Soc Nephrol 17:863–870

    CAS  PubMed  Google Scholar 

  31. Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits-Filho R, Riella M, Heimbürger O, Cederholm T, Girndt M (2005) Interleukin-10, IL-6 and TNF-a: Important factors in the altered cytokine network of end-stage renal disease - the good, the bad and the ugly. Kidney Int 47:1216–1233

    Google Scholar 

  32. Girndt M, Kaul H, Sester U, Ulrich C, Sester M, Georg T, Kohler H (2002) Anti-inflammatory interleukin-10 genotype protects dialysis patients from cardiovascular events. Kidney Int 62:949–955

    CAS  PubMed  Google Scholar 

  33. Tintut Y, Patel J, Parhami F, Demer LL (2000) Tumor necrosis factor-a promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation 102:2636–2642

    CAS  PubMed  Google Scholar 

  34. Jaber BL, Rao M, Guo D, Balakrishnan VS, Perianayagam MC, Freeman RB, Pereira BJ (2004) Cytokine gene promoter polymorphisms and mortality in acute renal failure. Cytokine 25:212–219

    CAS  PubMed  Google Scholar 

  35. Pankow JS, Folsom AR, Cushman M, Borecki IB, Hopkins PN, Eckfeldt JH, Tracy RP (2001) Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis 154:681–689

    CAS  PubMed  Google Scholar 

  36. Casas JP, Shah T, Cooper J, Hawe E, McMahon AD, Gaffney D, Packard CJ, O’Reilly DS, Juhan-Vague I, Yudkin JS, Tremoli E, Margaglione M, Di Minno G, Hamsten A, Kooistra T, Stephens JW, Hurel SJ, Livingstone S, Colhoun HM, Miller GJ, Bautista LE, Meade T, Sattar N, Humphries SE, Hingorani AD (2006) Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol 35:922–931

    PubMed  Google Scholar 

  37. Zhang L, Kao L, Berthier-Schaad Y, Plantinga L, Fink N, Smith MW, Coresh J (2007) C-reactive protein haplotype predicts serum C-reactive protein levels but not cardiovascular disease risk in a dialysis cohort. Am J Kidney Dis 49:118–126

    CAS  PubMed  Google Scholar 

  38. Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day INM, Palmer LJ, Hettersley AT, Ebrahim S, Lowe GDO, Rumley A, Smith GD (2005) C-reactive protein and its role in metabolic syndrome: mendelian randomisation study. Lancet 366:1954–1959

    CAS  PubMed  Google Scholar 

  39. Böger CA, Fischereder M, Deinzer M, Aslanidis C, Schmitz G, Stubanus M, Banas B, Krüger B, Riegger GAJ, Krämer BK (2005) RANTES gene polymorphisms predict all-cause and cardiac mortality in type 2 diabetes mellitus hemodialysis patients. Atherosclerosis 183:121–129

    PubMed  Google Scholar 

  40. Nakajima K, Tanaka Y, Nomiyama T, Ogihara T, Ikeda F, Kanno R, Iwashita N, Sakai K, Watada H, Onuma T, Kawamori R (2003) RANTES promoter genotype is associated with diabetic nephropathy in type 2 diabetic subjects. Diabetes Care 26:892–898

    CAS  PubMed  Google Scholar 

  41. An P, Nelson GW, Wang L, Donfield S, Goedert JJ, Phair J, Vlahov D, Buchbinder S, Farrar WL, Modi W, O’Brien SJ, Winkler CA (2002) Modulating influence on HIV/AIDS by interacting RANTES gene variants. Proc Natl Acad Sci U S A 99:10002–10007

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kato S, Lindholm B, Axelsson J, Qureshi RA, Barany P, Heimbürger O, Gustafsson J, Stenvinkel P, Nordfors L (2007) Association between oestrogen receptor alpha gene polymorphism and mortality in female end-stage renal disease patients. Nephrol Dial Transplant 22:2571–2577

    CAS  PubMed  Google Scholar 

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Acknowledgements

GENECURE (grant LSHM-CT-2006-037697), the Swedish Heart and Lung Foundation (PS) and Martins Rinds Foundation (PS) funded the present studies. JJC is supported by the ERA-EDTA.

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Affiliations

  1. Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, L8:00 CMM, 171 76, Stockholm, Sweden

    Karin Luttropp & Louise Nordfors

  2. Department of Renal Medicine (Baxter Novum), K56 Karolinska University Hospital Huddinge, Karolinska Institutet, 141 86, Stockholm, Sweden

    Peter Stenvinkel, Juan Jesús Carrero, Roberto Pecoits-Filho & Bengt Lindholm

Authors
  1. Karin Luttropp
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  2. Peter Stenvinkel
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  3. Juan Jesús Carrero
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  4. Roberto Pecoits-Filho
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  5. Bengt Lindholm
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  6. Louise Nordfors
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Correspondence to Peter Stenvinkel.

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Luttropp, K., Stenvinkel, P., Carrero, J.J. et al. Understanding the role of genetic polymorphisms in chronic kidney disease. Pediatr Nephrol 23, 1941–1949 (2008). https://doi.org/10.1007/s00467-008-0788-z

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  • DOI: https://doi.org/10.1007/s00467-008-0788-z

Keywords

  • Chronic kidney disease
  • Paediatrics
  • Cardiovascular disease
  • Inflammation
  • Single nucleotide polymorphisms