Hemodialysis, peritoneal dialysis or renal transplantation are lifesaving therapies for patients with end-stage renal disease (ESRD). Despite many technical advances, these patients still confront substantial short and long-term dialysis-related morbidity which interfere with their ability to function productively in society. inflammatory cytokines (IL-1beta and TNFalpha) stimulated by the dialysis procedure have been postulated to mediate a portion of these complications. Recently, naturally occurring specific inhibitors of IL-1beta and TNFalpha have been identified. We hypothesize that the balance of pro- and anti-inflammatory cytokines is an important determinant of morbidity in this patient population. The initial experiments will address the effect of artificial membranes on the transcription and translation of both IL-1beta and TNFalpha, and their respective inhibitors IL-1 receptor antagonist (IL-lra) and TNFalpha binding protein (TNF BP). Subsequently, the onset, duration, and magnitude of inhibitory cytokine production will be assessed using an in vitro model of dialysis. The impact of different membranes and reuse of membranes will be examined. we will also develop a new model of in vitro dialysis which will evaluate the role of the endothelium in cytokine production, by incorporating an endothelial cell-lined cartridge into the dialysis circuit. Further, clinical studies will attempt to correlate the balance of pro- and anti-inflammatory cytokines with dialysis-related symptoms and adequacy of dialysis. These studies will form the basis of trials of IL-lra infusion in patients. Phase 1 will determine the safety of IL-lra infusion in this patient population. Phase 2 will assess the effect of IL-lra on cytokine profiles and other clinical effects. Phase 3 will evaluate the efficacy of IL-lra in reducing the frequency and severity of dialysis-induced hypotension. In summary, the role of inhibitory cytokines in dialysis related symptoms and their potential therapeutic role will be the focus of these studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK045609-01
Application #
3247097
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1992-09-30
Project End
1996-09-29
Budget Start
1992-09-30
Budget End
1993-09-29
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Rao, Madhumathi; Li, Lijun; Tighiouart, Hocine et al. (2008) Plasma adiponectin levels and clinical outcomes among haemodialysis patients. Nephrol Dial Transplant 23:2619-28
Rao, Madhumathi; Jaber, Bertrand L; Balakrishnan, Vaidyanathapuram S (2006) Inflammatory biomarkers and cardiovascular risk: association or cause and effect? Semin Dial 19:129-35
Rao, Madhumathi; Guo, Daqing; Perianayagam, Mary C et al. (2005) Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 45:324-33
Jaber, Bertrand L; Rao, Madhumathi; Guo, Daqing et al. (2004) Cytokine gene promoter polymorphisms and mortality in acute renal failure. Cytokine 25:212-9
Balakrishnan, Vaidyanathapuram S; Guo, Daqing; Rao, Madhumathi et al. (2004) Cytokine gene polymorphisms in hemodialysis patients: association with comorbidity, functionality, and serum albumin. Kidney Int 65:1449-60
Rao, Madhumathi; Guo, Daqing; Jaber, Bertrand L et al. (2004) Dialyzer membrane type and reuse practice influence polymorphonuclear leukocyte function in hemodialysis patients. Kidney Int 65:682-91
Rao, Madhumathi; Guo, Daqing; Jaber, Bertrand L et al. (2004) Transforming growth factor-beta 1 gene polymorphisms and cardiovascular disease in hemodialysis patients. Kidney Int 66:419-27
Balakrishnan, Vaidyanathapuram S; Blumberg, Jeffrey; Pereira, Brian J G et al. (2003) Antioxidant and oxidative stress indices in dialysis-dependent acute renal failure. Blood Purif 21:213-9
Perianayagam, Mary C; Jaber, Bertrand L; Guo, Daqing et al. (2002) Defective interleukin-10 synthesis by peripheral blood mononuclear cells among hemodialysis patients. Blood Purif 20:543-50
Jaber, Bertrand L; King, Andrew J; Cendoroglo, Miguel et al. (2002) Correlates of urea kinetic modeling during hemodialysis in patients with acute renal failure. Blood Purif 20:154-60

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