Acute renal failure (ARF) is a serious complication in hospitalized patients, with an incidence of 5-10%, and mortality exceeding 50% among those who require dialysis. Pro- and anti-inflammatory cytokines play a pivotal role in the host inflammatory responses that mediate the severity of ARF. Yet, the importance of susceptibility genetic factors such as cytokine gene polymorphisms has remained largely unexplored. The principal investigator (PI) has designed a rigorous training program that will provide him with the necessary skills, experience, and opportunities to develop into an independent investigator in the field of inflammatory genetic markers and epidemiology of acute renal failure. He will obtain a Masters of Science in Clinical Care Research, participate in projects utilizing a broad range of study designs for clinical research, and carry out an original research project from its inception to completion. His mentors have extensive experience in clinical and laboratory investigation of ARF and clinical care research in Nephrology. Single nucleotide polymorphisms (SNP) in the promoter region of the human tumor necrosis factor-alpha (TNF-alpha) (position -308), interleukin-6 (IL-6) (position -174) and interleukin-10 (IL-10) (position -1082) genes affect transcriptional activity and have functional relevance. These genetically determined differences might influence variations in host inflammatory responses to stressful stimuli. The hypotheses to be investigated are that SNP involving these cytokines predetermine the severity of ARF, and are independent risk factors for adverse clinical outcomes.
The specific aims are to: 1) characterize the frequency of these pro- (TNF-alpha and IL-6) and anti-inflammatory (IL-10) cytokine gene polymorphisms in a cohort of patients with ARF; 2) Examine their relationship to leukocyte production and plasma levels of cytokines as well as clinical and laboratory variables; and 3) Evaluate whether these genetic markers individually or in combinations, predict adverse clinical outcomes, mainly dialysis requirement and mortality. The research project is achievable and promises to provide new insights into the importance of genetic markers as novel susceptibility factors for severity of disease in ARF. The results may help identify target patients who may benefit from anti-cytokine therapies. The PI has assembled a team of scientists to assist in the conduct of the project, and convened and internal and external scientific advisory committee to monitor his progress. The proposed training program and research project will prepare him for a career as an independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK065102-05
Application #
7111075
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2003-09-15
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
5
Fiscal Year
2006
Total Cost
$125,334
Indirect Cost
Name
St. Elizabeth's Medical Center of Boston
Department
Type
DUNS #
073797292
City
Boston
State
MA
Country
United States
Zip Code
01235
Susantitaphong, Paweena; Perianayagam, Mary C; Tighiouart, Hocine et al. (2013) Tumor necrosis factor alpha promoter polymorphism and severity of acute kidney injury. Nephron Clin Pract 123:67-73
Liangos, Orfeas; Domhan, Sophie; Schwager, Christian et al. (2010) Whole blood transcriptomics in cardiac surgery identifies a gene regulatory network connecting ischemia reperfusion with systemic inflammation. PLoS One 5:e13658
Wald, Ron; Liangos, Orfeas; Perianayagam, Mary C et al. (2010) Plasma cystatin C and acute kidney injury after cardiopulmonary bypass. Clin J Am Soc Nephrol 5:1373-9
Wald, Ron; Jaber, Bertrand L; Price, Lori Lyn et al. (2010) Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med 170:294-302
Alam, Ahsan; O'Connor, Daniel T; Perianayagam, Mary C et al. (2010) Phenylethanolamine N-methyltransferase gene polymorphisms and adverse outcomes in acute kidney injury. Nephron Clin Pract 114:c253-9
Kolyada, Alexey Y; Tighiouart, Hocine; Perianayagam, Mary C et al. (2009) A genetic variant of hypoxia-inducible factor-1alpha is associated with adverse outcomes in acute kidney injury. Kidney Int 75:1322-9
Perianayagam, Mary C; Seabra, Victor F; Tighiouart, Hocine et al. (2009) Serum cystatin C for prediction of dialysis requirement or death in acute kidney injury: a comparative study. Am J Kidney Dis 54:1025-33
Upadhyay, Ashish; Jaber, Bertrand L; Madias, Nicolaos E (2009) Epidemiology of hyponatremia. Semin Nephrol 29:227-38
Liangos, Orfeas; Tighiouart, Hocine; Perianayagam, Mary C et al. (2009) Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass. Biomarkers 14:423-31
Liangos, Orfeas; Kolyada, Alexey; Tighiouart, Hocine et al. (2009) Interleukin-8 and acute kidney injury following cardiopulmonary bypass: a prospective cohort study. Nephron Clin Pract 113:c148-54

Showing the most recent 10 out of 30 publications