Download PDF
J Pediatr Genet 2016; 05(01): 061-068
DOI: 10.1055/s-0035-1557112
Review Article
Georg Thieme Verlag KG Stuttgart · New York

AKI and Genetics: Evolving Concepts in the Genetics of Acute Kidney Injury: Implications for Pediatric AKI

Kathy Lee-Son
1   Division of Pediatric Nephrology, Dialysis, and Transplantation, University of Iowa Children's Hospital, Iowa City, Iowa, United States
,
Jennifer G. Jetton
1   Division of Pediatric Nephrology, Dialysis, and Transplantation, University of Iowa Children's Hospital, Iowa City, Iowa, United States
› Author Affiliations
Further Information

Publication History

15 April 2015

21 May 2015

Publication Date:
13 August 2015 (online)

    Permissions and Reprints

Abstract

In spite of recent advances in the field of acute kidney injury (AKI) research, morbidity and mortality remain high for AKI sufferers. The study of genetic influences in AKI pathways is an evolving field with potential for improving outcomes through the identification of risk and protective factors at the individual level that may in turn allow for the development of rational therapeutic interventions. Studies of single nucleotide polymorphisms, individual susceptibility to nephrotoxic medications, and epigenetic factors comprise a growing body of research in this area. While promising, this field is still only emerging, with a small number of studies in humans and very little data in pediatric patients.

Keywords

acute kidney injury - genetics - epigenetics - nephrotoxins - sepsis - ischemia–reperfusion
 

  • References

  • 1 Susantitaphong P, Cruz DN, Cerda J , et al; Acute Kidney Injury Advisory Group of the American Society of Nephrology. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol 2013; 8 (9) 1482-1493
    CrossrefPubMedGoogle Scholar
  • 2 Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 2007; 71 (10) 1028-1035
    CrossrefPubMedGoogle Scholar
  • 3 Alkandari O, Eddington KA, Hyder A , et al. Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study. Crit Care 2011; 15 (3) R146
    CrossrefPubMedGoogle Scholar
  • 4 Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL. 3-5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 2006; 69 (1) 184-189
    CrossrefPubMedGoogle Scholar
  • 5 Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 2012; 81 (5) 442-448
    CrossrefPubMedGoogle Scholar
  • 6 Mehta RL, Kellum JA, Shah SV , et al; Acute Kidney Injury Network Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11 (2) R31
    CrossrefPubMedGoogle Scholar
  • 7 Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P ; Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8 (4) R204-R212
    CrossrefPubMedGoogle Scholar
  • 8 Kellum JA, Lameire N ; KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care 2013; 17 (1) 204
    CrossrefPubMedGoogle Scholar
  • 9 Bomsztyk K, Denisenko O. Epigenetic alterations in acute kidney injury. Semin Nephrol 2013; 33 (4) 327-340
    CrossrefPubMedGoogle Scholar
  • 10 Cardinal-Fernández P, Ferruelo A, Martín-Pellicer A, Nin N, Esteban A, Lorente JA. Genetic determinants of acute renal damage risk and prognosis: a systematic review [in Spanish]. Med Intensiva 2012; 36 (9) 626-633
    CrossrefPubMedGoogle Scholar
  • 11 Lu JC, Coca SG, Patel UD, Cantley L, Parikh CR ; Translational Research Investigating Biomarkers and Endpoints for Acute Kidney Injury (TRIBE-AKI) Consortium. Searching for genes that matter in acute kidney injury: a systematic review. Clin J Am Soc Nephrol 2009; 4 (6) 1020-1031
    CrossrefPubMedGoogle Scholar
  • 12 Selewski DT, Jordan BK, Askenazi DJ, Dechert RE, Sarkar S. Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia. J Pediatr 2013; 162 (4) 725-729.e1
    CrossrefPubMedGoogle Scholar
  • 13 Kaur S, Jain S, Saha A , et al. Evaluation of glomerular and tubular renal function in neonates with birth asphyxia. Ann Trop Paediatr 2011; 31 (2) 129-134
    CrossrefPubMedGoogle Scholar
  • 14 Fekete A, Treszl A, Tóth-Heyn P , et al. Association between heat shock protein 72 gene polymorphism and acute renal failure in premature neonates. Pediatr Res 2003; 54 (4) 452-455
    CrossrefPubMedGoogle Scholar
  • 15 Sharfuddin AA, Molitoris BA. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 2011; 7 (4) 189-200
    PubMedGoogle Scholar
  • 16 Bányász I, Bokodi G, Vásárhelyi B , et al. Genetic polymorphisms for vascular endothelial growth factor in perinatal complications. Eur Cytokine Netw 2006; 17 (4) 266-270
    PubMedGoogle Scholar
  • 17 Gerber HP, Dixit V, Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 1998; 273 (21) 13313-13316
    CrossrefPubMedGoogle Scholar
  • 18 Basile DP, Friedrich JL, Spahic J , et al. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am J Physiol Renal Physiol 2011; 300 (3) F721-F733
    CrossrefPubMedGoogle Scholar
  • 19 Nobilis A, Kocsis I, Tóth-Heyn P , et al. Variance of ACE and AT1 receptor gene does not influence the risk of neonatal acute renal failure. Pediatr Nephrol 2001; 16 (12) 1063-1066
    CrossrefPubMedGoogle Scholar
  • 20 Chevalier RL. Developmental renal physiology of the low birth weight pre-term newborn. J Urol 1996; 156 (2, Pt 2): 714-719
    CrossrefPubMedGoogle Scholar
  • 21 Bagshaw SM, Uchino S, Bellomo R , et al; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol 2007; 2 (3) 431-439
    CrossrefPubMedGoogle Scholar
  • 22 Blatt NB, Srinivasan S, Mottes T, Shanley MM, Shanley TP. Biology of sepsis: its relevance to pediatric nephrology. Pediatr Nephrol 2014; 29 (12) 2273-2287
    CrossrefPubMedGoogle Scholar
  • 23 Mathur NB, Agarwal HS, Maria A. Acute renal failure in neonatal sepsis. Indian J Pediatr 2006; 73 (6) 499-502
    CrossrefPubMedGoogle Scholar
  • 24 Gomez H, Ince C, De Backer D , et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock 2014; 41 (1) 3-11
    PubMedGoogle Scholar
  • 25 Treszl A, Tóth-Heyn P, Kocsis I , et al. Interleukin genetic variants and the risk of renal failure in infants with infection. Pediatr Nephrol 2002; 17 (9) 713-717
    CrossrefPubMedGoogle Scholar
  • 26 Henao-Martínez AF, Agler AH, LaFlamme D, Schwartz DA, Yang IV. Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea bacteremia. Infect Genet Evol 2013; 16: 386-391
    CrossrefPubMedGoogle Scholar
  • 27 Cardinal-Fernández P, Ferruelo A, El-Assar M , et al. Genetic predisposition to acute kidney injury induced by severe sepsis. J Crit Care 2013; 28 (4) 365-370
    CrossrefPubMedGoogle Scholar
  • 28 Frank AJ, Sheu CC, Zhao Y , et al. BCL2 genetic variants are associated with acute kidney injury in septic shock*. Crit Care Med 2012; 40 (7) 2116-2123
    CrossrefPubMedGoogle Scholar
  • 29 Blinder JJ, Goldstein SL, Lee VV , et al. Congenital heart surgery in infants: effects of acute kidney injury on outcomes. J Thorac Cardiovasc Surg 2012; 143 (2) 368-374
    CrossrefPubMedGoogle Scholar
  • 30 Popov AF, Schulz EG, Schmitto JD , et al. Relation between renal dysfunction requiring renal replacement therapy and promoter polymorphism of the erythropoietin gene in cardiac surgery. Artif Organs 2010; 34 (11) 961-968
    CrossrefPubMedGoogle Scholar
  • 31 Moore E, Bellomo R. Erythropoietin (EPO) in acute kidney injury. Ann Intensive Care 2011; 1 (1) 3
    CrossrefPubMedGoogle Scholar
  • 32 Song YR, Lee T, You SJ , et al. Prevention of acute kidney injury by erythropoietin in patients undergoing coronary artery bypass grafting: a pilot study. Am J Nephrol 2009; 30 (3) 253-260
    CrossrefPubMedGoogle Scholar
  • 33 Endre ZH, Walker RJ, Pickering JW , et al. Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). Kidney Int 2010; 77 (11) 1020-1030
    CrossrefPubMedGoogle Scholar
  • 34 Perianayagam MC, Tighiouart H, Liangos O , et al. Polymorphisms in the myeloperoxidase gene locus are associated with acute kidney injury-related outcomes. Kidney Int 2012; 82 (8) 909-919
    CrossrefPubMedGoogle Scholar
  • 35 Basile DP, Dwinell MR, Wang SJ , et al. Chromosome substitution modulates resistance to ischemia reperfusion injury in Brown Norway rats. Kidney Int 2013; 83 (2) 242-250
    CrossrefPubMedGoogle Scholar
  • 36 Basile DP, Donohoe D, Cao X, Van Why SK. Resistance to ischemic acute renal failure in the Brown Norway rat: a new model to study cytoprotection. Kidney Int 2004; 65 (6) 2201-2211
    CrossrefPubMedGoogle Scholar
  • 37 Rhone ET, Carmody JB, Swanson JR, Charlton JR. Nephrotoxic medication exposure in very low birth weight infants. J Matern Fetal Neonatal Med 2014; 27 (14) 1485-1490
    CrossrefPubMedGoogle Scholar
  • 38 McWilliam SJ, Antoine DJ, Sabbisetti V , et al. Mechanism-based urinary biomarkers to identify the potential for aminoglycoside-induced nephrotoxicity in premature neonates: a proof-of-concept study. PLoS ONE 2012; 7 (8) e43809
    CrossrefPubMedGoogle Scholar
  • 39 Menon S, Kirkendall ES, Nguyen H, Goldstein SL. Acute kidney injury associated with high nephrotoxic medication exposure leads to chronic kidney disease after 6 months. J Pediatr 2014; 165 (3) 522-527.e2
    CrossrefPubMedGoogle Scholar
  • 40 Moffett BS, Goldstein SL. Acute kidney injury and increasing nephrotoxic-medication exposure in noncritically-ill children. Clin J Am Soc Nephrol 2011; 6 (4) 856-863
    CrossrefPubMedGoogle Scholar
  • 41 Goldstein SL, Kirkendall E, Nguyen H , et al. Electronic health record identification of nephrotoxin exposure and associated acute kidney injury. Pediatrics 2013; 132 (3) e756-e767
    CrossrefPubMedGoogle Scholar
  • 42 Zappitelli M, Moffett BS, Hyder A, Goldstein SL. Acute kidney injury in non-critically ill children treated with aminoglycoside antibiotics in a tertiary healthcare centre: a retrospective cohort study. Nephrol Dial Transplant 2011; 26 (1) 144-150
    CrossrefPubMedGoogle Scholar
  • 43 Schmitz C, Hilpert J, Jacobsen C , et al. Megalin deficiency offers protection from renal aminoglycoside accumulation. J Biol Chem 2002; 277 (1) 618-622
    CrossrefPubMedGoogle Scholar
  • 44 Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther 2009; 86 (4) 396-402
    CrossrefPubMedGoogle Scholar
  • 45 Kikuchi R, Kusuhara H, Hattori N , et al. Regulation of the expression of human organic anion transporter 3 by hepatocyte nuclear factor 1alpha/beta and DNA methylation. Mol Pharmacol 2006; 70 (3) 887-896
    CrossrefPubMedGoogle Scholar
  • 46 Kikuchi R, Kusuhara H, Hattori N , et al. Regulation of tissue-specific expression of the human and mouse urate transporter 1 gene by hepatocyte nuclear factor 1 alpha/beta and DNA methylation. Mol Pharmacol 2007; 72 (6) 1619-1625
    CrossrefPubMedGoogle Scholar
  • 47 Nakamura T, Yonezawa A, Hashimoto S, Katsura T, Inui K. Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem Pharmacol 2010; 80 (11) 1762-1767
    CrossrefPubMedGoogle Scholar
  • 48 Kusaka J, Koga H, Hagiwara S, Hasegawa A, Kudo K, Noguchi T. Age-dependent responses to renal ischemia-reperfusion injury. J Surg Res 2012; 172 (1) 153-158
    CrossrefPubMedGoogle Scholar
  • 49 Anderson S, Eldadah B, Halter JB , et al. Acute kidney injury in older adults. J Am Soc Nephrol 2011; 22 (1) 28-38
    CrossrefPubMedGoogle Scholar
  • 50 Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 2011; 11 (10) 726-734
    CrossrefPubMedGoogle Scholar
  • 51 Calvanese V, Lara E, Kahn A, Fraga MF. The role of epigenetics in aging and age-related diseases. Ageing Res Rev 2009; 8 (4) 268-276
    CrossrefPubMedGoogle Scholar
  • 52 Brooks WH, Le Dantec C, Pers JO, Youinou P, Renaudineau Y. Epigenetics and autoimmunity. J Autoimmun 2010; 34 (3) J207-J219
    CrossrefPubMedGoogle Scholar
  • 53 Ordovás JM, Smith CE. Epigenetics and cardiovascular disease. Nat Rev Cardiol 2010; 7 (9) 510-519
    CrossrefPubMedGoogle Scholar
  • 54 Ballestar E. Epigenetics lessons from twins: prospects for autoimmune disease. Clin Rev Allergy Immunol 2010; 39 (1) 30-41
    CrossrefPubMedGoogle Scholar
  • 55 Petronis A. Epigenetics and twins: three variations on the theme. Trends Genet 2006; 22 (7) 347-350
    CrossrefPubMedGoogle Scholar
  • 56 Fan H, Yang HC, You L, Wang YY, He WJ, Hao CM. The histone deacetylase, SIRT1, contributes to the resistance of young mice to ischemia/reperfusion-induced acute kidney injury. Kidney Int 2013; 83 (3) 404-413
    CrossrefPubMedGoogle Scholar
  • 57 Simmons Jr GE, Pruitt WM, Pruitt K. Diverse roles of SIRT1 in cancer biology and lipid metabolism. Int J Mol Sci 2015; 16 (1) 950-965
    CrossrefPubMedGoogle Scholar
  • 58 Hasegawa K, Wakino S, Yoshioka K , et al. Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem 2010; 285 (17) 13045-13056
    CrossrefPubMedGoogle Scholar
  • 59 He W, Wang Y, Zhang MZ , et al. Sirt1 activation protects the mouse renal medulla from oxidative injury. J Clin Invest 2010; 120 (4) 1056-1068
    CrossrefPubMedGoogle Scholar
  • 60 Heard E, Martienssen RA. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 2014; 157 (1) 95-109
    CrossrefPubMedGoogle Scholar
  • 61 Hui-Stickle S, Brewer ED, Goldstein SL. Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis 2005; 45 (1) 96-101
    CrossrefPubMedGoogle Scholar
  • 62 Isbir SC, Ak K, Tekeli A, Civelek A, Atalan N, Arsan S. Coronary artery bypass grafting in idiopathic myelofibrosis: a case report. Heart Surg Forum 2007; 10 (1) E55-E56
    CrossrefPubMedGoogle Scholar
  • 63 Chew ST, Newman MF, White WD , et al. Preliminary report on the association of apolipoprotein E polymorphisms, with postoperative peak serum creatinine concentrations in cardiac surgical patients. Anesthesiology 2000; 93 (2) 325-331
    CrossrefPubMedGoogle Scholar
  • 64 Stafford-Smith M, Podgoreanu M, Swaminathan M , et al; Perioperative Genetics and Safety Outcomes Study (PEGASUS) Investigative Team. Association of genetic polymorphisms with risk of renal injury after coronary bypass graft surgery. Am J Kidney Dis 2005; 45 (3) 519-530
    CrossrefPubMedGoogle Scholar
  • 65 Isbir SC, Tekeli A, Ergen A , et al. Genetic polymorphisms contribute to acute kidney injury after coronary artery bypass grafting. Heart Surg Forum 2007; 10 (6) E439-E444
    CrossrefPubMedGoogle Scholar
  • 66 Perianayagam MC, Liangos O, Kolyada AY , et al. NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure. J Am Soc Nephrol 2007; 18 (1) 255-263
    CrossrefPubMedGoogle Scholar
  • 67 Haase-Fielitz A, Haase M, Bellomo R , et al. Decreased catecholamine degradation associates with shock and kidney injury after cardiac surgery. J Am Soc Nephrol 2009; 20 (6) 1393-1403
    CrossrefPubMedGoogle Scholar
  • 68 Popov AF, Hinz J, Schulz EG , et al. The eNOS 786C/T polymorphism in cardiac surgical patients with cardiopulmonary bypass is associated with renal dysfunction. Eur J Cardiothorac Surg 2009; 36 (4) 651-656
    CrossrefPubMedGoogle Scholar
  • 69 Kolyada AY, Tighiouart H, Perianayagam MC, Liangos O, Madias NE, Jaber BL. A genetic variant of hypoxia-inducible factor-1alpha is associated with adverse outcomes in acute kidney injury. Kidney Int 2009; 75 (12) 1322-1329
    CrossrefPubMedGoogle Scholar
  • 70 Jaber BL, Pereira BJ, Bonventre JV, Balakrishnan VS. Polymorphism of host response genes: implications in the pathogenesis and treatment of acute renal failure. Kidney Int 2005; 67 (1) 14-33
    CrossrefPubMedGoogle Scholar
  • 71 Alam A, O'Connor DT, Perianayagam MC , et al. Phenylethanolamine N-methyltransferase gene polymorphisms and adverse outcomes in acute kidney injury. Nephron Clin Pract 2010; 114 (4) c253-c259
    CrossrefPubMedGoogle Scholar
  • 72 Chen H, Huang S, Han X , et al. Salt-inducible kinase 3 is a novel mitotic regulator and a target for enhancing antimitotic therapeutic-mediated cell death. Cell Death Dis 2014; 5: e1177
    CrossrefPubMedGoogle Scholar
  • 73 Li HF, Cheng CF, Liao WJ, Lin H, Yang RB. ATF3-mediated epigenetic regulation protects against acute kidney injury. J Am Soc Nephrol 2010; 21 (6) 1003-1013
    CrossrefPubMedGoogle Scholar
  • 74 Marumo T, Hishikawa K, Yoshikawa M, Fujita T. Epigenetic regulation of BMP7 in the regenerative response to ischemia. J Am Soc Nephrol 2008; 19 (7) 1311-1320
    CrossrefPubMedGoogle Scholar
  • 75 Kim J, Zarjou A, Traylor AM , et al. In vivo regulation of the heme oxygenase-1 gene in humanized transgenic mice. Kidney Int 2012; 82 (3) 278-291
    CrossrefPubMedGoogle Scholar