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

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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 9 Bomsztyk K, Denisenko O. Epigenetic alterations in acute kidney injury. Semin Nephrol 2013; 33 (4) 327-340
• 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
• 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
• 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
• 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
• 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
• 15 Sharfuddin AA, Molitoris BA. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 2011; 7 (4) 189-200
• 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
• 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
• 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
• 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
• 20 Chevalier RL. Developmental renal physiology of the low birth weight pre-term newborn. J Urol 1996; 156 (2, Pt 2): 714-719
• 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
• 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
• 23 Mathur NB, Agarwal HS, Maria A. Acute renal failure in neonatal sepsis. Indian J Pediatr 2006; 73 (6) 499-502
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 31 Moore E, Bellomo R. Erythropoietin (EPO) in acute kidney injury. Ann Intensive Care 2011; 1 (1) 3
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 49 Anderson S, Eldadah B, Halter JB , et al. Acute kidney injury in older adults. J Am Soc Nephrol 2011; 22 (1) 28-38
• 50 Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 2011; 11 (10) 726-734
• 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
• 52 Brooks WH, Le Dantec C, Pers JO, Youinou P, Renaudineau Y. Epigenetics and autoimmunity. J Autoimmun 2010; 34 (3) J207-J219
• 53 Ordovás JM, Smith CE. Epigenetics and cardiovascular disease. Nat Rev Cardiol 2010; 7 (9) 510-519
• 54 Ballestar E. Epigenetics lessons from twins: prospects for autoimmune disease. Clin Rev Allergy Immunol 2010; 39 (1) 30-41
• 55 Petronis A. Epigenetics and twins: three variations on the theme. Trends Genet 2006; 22 (7) 347-350
• 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
• 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
• 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
• 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
• 60 Heard E, Martienssen RA. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 2014; 157 (1) 95-109
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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