Conversion from cyclosporin A to tacrolimus is safe and decreases blood pressure, cholesterol levels and TGF-beta 1 type I receptor expression.
To determine whether conversion from cyclosporin A (CsA) to tacrolimus (TAC)-based immunosuppressive therapy is safe and might lead to improvement in the clinical side effect profile we studied 55 cardiac allograft recipients. Ten stable patients were electively converted (0.2-1.5 yr after transplantation; group I) and 45 patients were converted on indication (0.5-14 yr after transplantation; group II). We studied blood pressure, cholesterol level and renal function in all patients. To unravel the mechanisms by which CsA may exert its toxic effects and to evaluate whether conversion is associated with immune activation, we analyzed the transforming growth factor (TGF)-beta 1 system and intragraft interleukin (IL)-2 and IL-15 mRNA expression by real-time reverse transcription-polymerase chain reaction (RT-PCR) and quantitative flow cytometry in the selectively converted patients (group I). Conversion did not result in immune activation as no clinical, histological or molecular signs of immune activation (increased intragraft IL-2 and IL-15 messenger RNA (mRNA) expression) leading to rejection were found. It did not improve renal function neither in patient group I nor in patient group II. However, after conversion the blood pressure decreased (group I: systolic 154+/-16 vs 143+/-21 mmHg, p=0.03, diastolic: 99+/-11 vs 90+/-11, p=0.02 and group II: systolic 155+/-17 vs 142+/-14, p<0.001, diastolic: 99+/-11 vs 91+/-8 mmHg, p<0.001). Likewise, the cholesterol levels improved (group I: 6.6+/-0.5 vs 5.7+/-0.3 mmol/L, p=0.001 and group II: 7.1+/-1.7 vs 6.1+/-1.7 mmol/L, p=0.001). When patients were treated with TAC the ongoing rejections (n=4) resolved and gum hyperplasia disappeared (n=5). Conversion was associated with a two-fold lower TGF-beta 1 type I receptor expression on peripheral lymphocytes and monocytes (p=0.02 and p=0.002, respectively). Conversion from CsA to TAC results in improvement of blood pressure and cholesterol levels and does not induce immune activation. These beneficial effects were accompanied with lower TGF-beta 1 type I receptor expression.
Baan
C C
CC
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. baan@inw1.azr.nl
van Riemsdijk-van Overbeeke
I C
IC
Balk
A H
AH
Vantrimpont
P M
PM
Mol
W M
WM
Knoop
C J
CJ
Niesters
H G
HG
Maat
L P
LP
Weimar
W
W
D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D016207:Cytokines; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016572:Cyclosporine; D002784:Cholesterol; D016559:Tacrolimus