CONVERSION FROM CYCLOSPORINE-A TO AZATHIOPRINE TREATMENT IMPROVES LDLOXIDATION IN KIDNEY-TRANSPLANT RECIPIENTS

The use of the immunosuppressant cyclosporine A (CsA) after transplant ation has been associated with less favorable plasma lipid profiles, w hich may contribute to the high incidence of cardiovascular morbidity and mortality in transplant recipients. Recent studies have suggested that oxidative modification of LDL plays an important role in the init iation and progression of atherosclerosis. It has also been demonstrat ed that CsA may facilitate lipid peroxidation in vitro and in vivo. Th erefore, we determined several parameters of LDL oxidizability in rena l transplant recipients who were switched from CsA to azathioprine (AZ A)-based immunosuppressive treatment. The susceptibility of LDL to in vitro oxidation, LDL particle size, plasma titers of Ige and IgM antib odies against oxidized LDL and plasma LDL subclass patterns in 19 rena l transplant recipients were determined during CsA treatment and 16 we eks after these patients were converted to AZA treatment. In addition, mean arterial pressure was recorded, and glomerular filtration rate a nd renal blood flow were estimated from the clearance of radiolabeled thalamate and hippurate. After conversion, the plasma concentrations o f total cholesterol, LDL cholesterol and triglyceride decreased, while plasma HDL cholesterol did not change. During CsA therapy plasma LDL was significantly more susceptible to in vitro oxidation than during A ZA, as reflected by a longer lag phase during in vitro oxidation (98.9 +/- 24.3 vs. 114.7 +/- 17.3 min, P = 0.031). In addition, the LDL siz e increased (236.5 +/- 7.3 vs. 240.7 +/- 6.8 nm, P = 0.00001) and the titers of IgM- and IgG-autoantibodies against oxidized LDL decreased s ignificantly after patients were converted from CsA to AZA. The more a therogenic LDL subclass pattern B was present in 13 out of 19 patients during CsA. In five patients, pattern B changed into pattern A after conversion. The subclass B pattern was maintained in eight patients an d subclass A pattern in six patients, In all patients the lag lime of ill vitro LDL oxidation increased, although the biggest changes were f ound in those patients In whom the LDL subclass changed from pattern B to pattern A. Mean arterial pressure decreased and renal function imp roved significantly after conversion. No correlation between parameter s of lipid peroxidation and changes in blood pressure or renal functio n upon conversion, underlying renal disease, lime since transplantatio n, or antihypertensive treatment was found. Our study demonstrates tha t treatment with CsA increases the susceptibility of LDL to in vitro o xidation, and also enhances the oxidation of LDL in viva. In addition, conversion to AZA results in a more favorable lipid profile, which in combination with a lower arterial pressure and better renal function may decrease the risk for atherosclerosis. These factors may account f or the cardiovascular complications during CsA treatment after organ t ransplantation: and also when CsA is used for other diseases.