Interaction of the endothelin system and calcineurin inhibitors after kidney transplantation.
Plasma endothelin (ET)-1 concentrations have been shown to be elevated in patients receiving calcineurin-inhibitors (CI). We investigated urinary and plasma ET-1 (uET-1, pET-1), BigET-1 (uBigET-1, pBigET-1) concentrations, and plasma soluble endothelin-converting enzyme (ECE) concentrations in 381 adult caucasian kidney allograft recipients with graft survival of more than 2 years from the outpatients department of our clinic. Blood and urine probes were always drawn immediately before morning dosage of immunosuppressants. Mean of urinary protein excretion (meanProt) and mean of serum creatinine (meanCrea) were calculated from all available measurements in the most recent year. uET-1 and uBigET-1 were adjusted for urinary protein excretion by calculating uET-1/meanProt and uBigET-1/meanProt. Patients (n=310) were on a cyclosporine A or FK506 (CI-group) based immunosuppression protocol, and 71 patients were immunosuppressed without use of CI (nonCI group). Time since transplantation was similar in both groups (mean+/-S.D.; CI-group: 7.55+/-2.50; nonCI-group: 7.74+/-3.06 years, P=0.240) as well as meanCrea (mean+/-S.D.; CI-group: 1.97+/-1.34; nonCI-group: 1.77+/-1.29 mg/dl, P=0.326). pET-1 was significantly higher in the CI-group, compared with nonCI (mean+/-S.D.; 0.87+/-1.4 versus 0.56+/-0.76 fmol/ml, P=0.011). pBigET-1 was similar (mean+/-S.D.; 0.85+/-1.41 versus 0.70+/-1.21 fmol/ml, P=0.33). ECE concentrations were higher in the CI group (mean+/-S.D.; 14.30+/-18.02 versus 9.23+/-7.42 ng/ml, P=0.001). uET-1/meanProt and uBigET-1/meanProt concentration were similar in the CI-group compared with the nonCI-group (mean+/-S.D.; uET-1/meanProt: 15+/-24 versus 21+/-40 pmol/g, P=0.139; uBigET-1/meanProt: 34+/-55 versus 19+/-23pmol/g, P=0.248). pET-1 elevation in patients receiving CI might be more likely to be due to elevated conversion of pBig-ET-1 by more ECE, and not to higher concentrations of pBigET-1.
Department of Nephrology, University Hospital Charité, Humboldt University of Berlin, D-10098 Berlin, Germany.
Torsten
T
Slowinski
Thomas
T
Subkowski
Petra
P
Diehr
Daniela
D
Bachert
Lutz
L
Fritsche
Hans-H
HH
Neumayer
Berthold
B
Hocher
D000328:Adult; D016282:Aspartic Acid Endopeptidases / Q000097:blood; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use; D019332:Endothelin-1 / Q000097:blood* / Q000652:urine; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000097:blood / Q000652:urine; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000097:blood / Q000652:urine; D016030:Kidney Transplantation; D008297:Male; D008666:Metalloendopeptidases; D011498:Protein Precursors / Q000097:blood / Q000652:urine; D016559:Tacrolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous
D065095:Calcineurin Inhibitors; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011498:Protein Precursors; D016572:Cyclosporine; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D016559:Tacrolimus