Cyclosporine Increases Endothelin-1 Plasma Levels in Renal Transplant Recipients R.L. Cauduro, C. Costa, F. Lhulier, R.G. Garcia, R.D. Cabral, L.E. Gonc ¸ alves, and R.C. Manfro ABSTRACT Endothelin-1 (ET-1) has been associated with the development of hypertension in cyclosporine-treated renal transplant recipients. To clarify this association, this observa- tional study compared ET-1 levels in 33 patients taking cyclosporine therapy versus 10 controls. Three hours after cyclosporine administration, ET-1 levels were higher than in the controls, namely 1.81 + 0.99 versus 1.17 + 0.46 pg/mL (P  .04). These results suggest a role of ET-1 in the pathogenesis of post–renal transplantation hypertension in cyclosporine-treated recipients. E NDOTHELIN (ET) is a potent vasoconstrictive and mitogenic peptide that exists as 3 isoforms (ET-1, ET- 2, and ET-3). ET-1 is predominantly produced in humans and mediates the majority of physiological and pathogenic actions of these substances; it interacts with 2 specific receptors (ETA and ETB). 1 Cyclosporine immunosuppres- sion for organ transplantation has been associated with hypertension and acute or chronic nephropathy. The role of ET-1 in the pathogenesis of hypertension in cyclosporine- treated renal transplant recipients remains controversial. The objective of this study was to evaluate ET-1 plasma levels in cyclosporine-treated renal transplant recipients. PATIENTS AND METHODS Forty-three patients were included in this study if they: (1) were at least 1 year after kidney transplantation; (2) displayed stable renal function in the last 3 months; and (3) had a serum creatinine level 2.0 mg/dL and a 24 hour urinary protein excretion 1.0 g. Ten patients were receiving azathioprine and prednisone as their im- munosuppressive regimen (AZA group), and 33 were receiving cyclosporine and prednisone with or without azathioprine (CyA group). Patients were admitted to the research facility in the morning, 10 to 12 hours after CyA administration. They were allowed to rest seated for 10 minutes before blood was drawn for a baseline measurement of ET-1, serum creatinine, cyclosporine, and lipid and electrolyte levels. Blood pressure was recorded twice at this time. Additional blood samples for ET-1 levels were drawn at 3 and 4 hours after the patient ingested the usual CyA dose. AZA patients also had blood drawn at the corresponding times. ET-1 plasma levels were determined using a quantitative immu- noassay technique (R&D Systems). Whole blood CyA levels were measured using a monoclonal antibody technique. Chemical anal- yses of the blood were performed using standard laboratory techniques. Results are presented as mean values  standard deviations. Statistical analyses were performed using are unpaired t test and ANOVA values of P  .05 were considered statistically significant. RESULTS The main characteristics of the groups are shown in Table 1. Patients receiving CyA showed higher serum levels of creatinine and cholesterol. They also had higher systolic and diastolic blood pressure values. As shown in Fig 1, the From the Renal Division, Hospital de Clı´nicas de Porto Alegre and Post-Graduation in Medical Sciences, Nephrology Program, Rio Grande do Sul Federal University, Porto Alegre, Brazil. Address reprint requests to R.C. Manfro, Hospital de Clinicas de Porto Alegre, Division of Nephrology, Rug, Ramiro Barcelos 2350, Room 2030, Porto Alegre, R.S. 90035003, Brazil. Table 1. Patient Characteristics All (43) AZA Group (10) CyA Group (33) P Male/female 24/19 6/4 18/15 .95 Race (W/NW) 38/5 8/2 30/3 .70 HBP (Y/N) 26/17 5/5 21/12 .91 Age (ys) 42.1  10.5 40  6 42  11 .58 Posttransplantation months 65.0  41.0 133  60 44  29 .0001 SBP (mm Hg) 136.2  17.4 122  16 140  15 .005 DBP (mm Hg) 83.8  9.0 75  8 86  7 .01 Creatinine (mg/dL) 1.2  0.28 0.97  0.13 1.29  0.27 .0001 Proteinuria (g/24 h) 0.27  0.26 27  23 27  27 .63 Cholesterol (mg/dL) 209  50 174  32 219  51 .018 Triglycerides (mg/dL) 166  117 97  24 185  125 .05 Cyclosporine (mg/dL) 187  51 - 187  51 Abbreviations: W, white; NW, not white; HBP, high blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure. 0041-1345/04/$–see front matter © 2004 by Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2004.04.007 360 Park Avenue South, New York, NY 10010-1710 880 Transplantation Proceedings, 36, 880 – 881 (2004)