Our purpose is to investigate the reasons why erythropoiesis remains suppressed in the majority of maintenance dialysis patients. Although a hypoproliferative anemia exists in all patients with chronic renal failure, some improve their anemia, most likely because of increased renal and/or non-renal erythropoietin (Ep) production. We propose to determine if the following factors contribute to continued erythropoietic suppression: 1) inhibitors retained in uremic sera; 2) hypertransfusion or repetitive red cell transfusions; 3) aluminum (Al) suppression of home synthesis; 4) inappropriate Ep production in the absence of all of the above three conditions. Coversely, we plan to determine if erythropoiesis is stimulated by the following factors: 1) Removal of inhibitors by dialysis (if specific erythropoietic inhibitors can be confirmed in vitro); 2) phlebotomy induced hypoxemia; 3) desferrioxamine removal of aluminum from marrow tissue; 4) human Ep-rich plasma (ERP) into very anemic dialysis patients compared with follow-up studies done when hematologically normal after kidney transplantations; and 5) the development of acquired renal cystic disease. If specific inhibitors of erythropoiesis are present in uremic sera as defined in vitro, efforts will undertaken to determine their significance in vivo by quantitative erythropoiesis and serum Ep levels in CAPD patients, hemodialysis patients using a more porous dialyzer membrane and a control group. The erythropoietic effects of hypertransfusion and phlebotomy will be studied to see if the reciprocal changes in Ep production and erythropoiesis, observed in normals, are found in uremia or whether these changes will be blunted or non-existent. If erythropoiesis is suppressed by hypertransfusion as determined by ferrokinetics, marrow morphology will be examined for macrophage-like cells, thought to be the """"""""nurse"""""""" cells to erythroid precursors. Al suppression of erythropoiesis will be ascertained by correlating marrow levels of Al, as quantitated by electron probe microanalysis, to serum Al levels, and ferrokinetics. The definitive test as to whether erythropoietic inhibitors exist will be the response in human uremia to infusions of human ERP compared to normal renal function. An indirect assessment of Ep action will be to determine if erythropoiesis and serum Ep levels improve mainly in patients developing acquired renal cystic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033488-07
Application #
3231882
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1984-05-01
Project End
1992-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Eschbach, J W; Haley, N R; Egrie, J C et al. (1992) A comparison of the responses to recombinant human erythropoietin in normal and uremic subjects. Kidney Int 42:407-16
Eschbach, J W; Aquiling, T; Haley, N R et al. (1992) The long-term effects of recombinant human erythropoietin on the cardiovascular system. Clin Nephrol 38 Suppl 1:S98-103
Adamson, J W; Eschbach, J W (1990) The use of recombinant human erythropoietin in humans. Ciba Found Symp 148:186-95;discussion 195-200
Buckner, F S; Eschbach, J W; Haley, N R et al. (1990) Hypertension following erythropoietin therapy in anemic hemodialysis patients. Am J Hypertens 3:947-55
Adamson, J W; Eschbach, J W (1990) Treatment of the anemia of chronic renal failure with recombinant human erythropoietin. Annu Rev Med 41:349-60
Adamson, J W; Eschbach, J W (1990) The use of recombinant human erythropoietin (rHuEpo) in humans. Cancer Surv 9:157-67
Eschbach, J W; Haley, N R; Adamson, J W (1990) The anemia of chronic renal failure: pathophysiology and effects of recombinant erythropoietin. Contrib Nephrol 78:24-36;discussion 37
Adamson, J W; Eschbach, J W (1990) The use of recombinant human erythropoietin [rHuEpo] in man. Prog Clin Biol Res 352:505-17
Adamson, J W; Eschbach, J W (1989) Management of the anaemia of chronic renal failure with recombinant erythropoietin. Q J Med 73:1093-101
Eschbach, J W; Haley, N R; Adamson, J W (1989) The use of recombinant erythropoietin in the treatment of the anemia of chronic renal failure. Ann N Y Acad Sci 554:225-30

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