tacrolimus and Hyperhomocysteinemia

The effect of mycophenolate mofetil (MMF) on homocysteine (Hcy) metabolism is unknown.. This in vitro study examined whether mycophenolic acid or tacrolimus influences the formation of Hcy as determined by measuring the total Hcy (tHcy) concentrations in supernatants of human renal proximal tubule epithelial cells. Cells were incubated with and without vitamins (folate, vitamin B6 and B12) in the presence of low or high methionine concentrations at different mycophenolic acid (0, or 5, or 20 microg/mL) or tacrolimus (0, or 10, or 25 ng/mL) concentrations for 24, 48 or 72 hours. The concentration of tHcy in culture supernatants was measured by a fluorescence polarization immunoassay. The effect of MMF on tHcy plasma levels was also examined in 454 kidney graft recipients.. Comparisons of tHcy levels in culture supernatants over time by four way ANOVA showed that methionine concentration (P < 0.00001), time (P < 0.00001), vitamins (P = 0.002728), and mycophenolic acid concentration (P = 0.000095) were all significant predictors of tHcy concentrations. This was due to significantly lower tHcy levels with using mycophenolic acid at a high concentration versus control at the 48- and 72-hour time points. By contrast, tacrolimus showed no effect in vitro. Among the kidney graft recipients, male patients on MMF therapy showed lower plasma tHcy concentrations as compared to those on azathioprine (P = 0.03).. Our study suggests a tHcy lowering effect of MMF in male transplant recipients, which improves the cardiovascular disease risk profile, whereas tacrolimus showed no effect.

Topics: Adult; Cells, Cultured; Enzyme Inhibitors; Female; Graft Rejection; Homocysteine; Humans; Hyperhomocysteinemia; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules, Proximal; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

Cardiovascular disease (CVD) accounts for 35% to 50% of deaths among renal transplant recipients. Beside the atherogenic risk factors related to hemodialysis, renal function, and use of immunosuppressive agents, other relevant risk factors for CVD include acute rejection episodes, microalbuminuria (muAlb), diabetes, arterial hypertension, lipid disorders, inflammatory triggers, hyperhomocysteinemia, anemia, erythrocytosis, obesity, and hyperuricemia. We studied the prevalence of risk factors and the impact of various drugs on CVD among 103 renal transplant recipients with measured glomerular filtration rates showing values >45 mL/min. We measured uric acid, triglycerides (TG), low-density lipoprotein (LDL)/high-density lipoprotein (HDL) LDL/HDL ratio, homocysteine (HOMO), insulin resistance, muAlb, C-reactive protein (CRP), and fibrinogen. Subsequently, patients were divided into 8 groups based on the immunosuppressive protocol to evaluate its impact on CVD risk factors. Insulin resistance and hyperhomocysteinemia were present in >2/3 of patients. Considering the impact of protocols, the combination of cyclosporine (CsA) + everolimus (EVL) resulted in the most favorable profile in terms of reduction of hyperuricemia, hyperlipidemia, and hyperhomocysteinemia. Insulin resistance tended to be more frequent among patients treated with protocols including calcineurin inhibitors (CNI) and steroids. The prevalence of hyperhomocyteinemia was similar among patients on CsA and on tacrolimus (Tac). Sirolimus (SRL) was associated with higher levels of HOMO. The combination of CNI and proliferative signal inhibitors (PSI) seemed to be the most promising one to reduce the impact of CVD risk factors. The reduction in CVD morbidity can improve expectancy and quality of life, as well as graft function and survival among renal transplant patients.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Humans; Hyperhomocysteinemia; Hyperlipidemias; Hyperuricemia; Immunosuppressive Agents; Kidney Transplantation; Lipoproteins, HDL; Middle Aged; Risk Factors; Sirolimus; Tacrolimus; Transplant Recipients

Hyperhomocysteinemia, an independent risk cardiovascular factor, has been reported in renal transplanted patients (RTP). The aim of the present study was to evaluate homocysteine levels in RTP treated with cyclosporine or tacrolimus, and the changes observed in the two groups of patients after treatment with folic acid. Forty-two RTP with stable function (21 treated with cyclosporine and 21 with tacrolimus, matched by gender and age) were studied. Forty healthy control subjects were matched by age and gender with the patients. In RTP, homocysteine was increased compared with the controls (16.4 +/-5.2 vs 8.0 +/- 1.8 micromol/L; p < 0.001), but there was no difference in vitamin B12 and folic acid levels. Thirty-three patients and one control showed hyperhomocysteinemia (78.5 vs 2.5%; p < 0.001). Homocysteine correlated negatively with creatinine clearance in the patients (p = 0.04), but no correlation was found with vitamin B12, folic acid and lipoproteins. By univariate analysis, patients treated with cyclosporine had higher homocysteine than those treated with tacrolimus (p = 0.03), but multivariate analysis did not confirm these results. In 21 patients with hyperhomocysteinemia and folate levels similar to those of the controls, folic acid (5 mg/d for 3 months) was administered. Homocysteine decreased significantly (19.1 +/- 4.8 vs 13.2 +/- 3.4 micromol/L; p < 0.001), with a median reduction of 31% and with no differences observed in patients treated with either cyclosporine or tacrolimus. We concluded that hyperhomocysteinemia is very frequent in RTP, but homocysteine levels are not different in patients treated with cyclosporine or tacrolimus. Folic acid therapy produces a significant decrease in homocysteine concentrations, in the absence of clear folate deficiency, without differences in relation to immunosuppressant therapy.

Topics: Analysis of Variance; Case-Control Studies; Cholesterol; Creatinine; Cyclosporine; Female; Folic Acid; Hematinics; Homocysteine; Humans; Hyperhomocysteinemia; Immunosuppressive Agents; Kidney Transplantation; Linear Models; Male; Middle Aged; Multivariate Analysis; Risk Factors; Tacrolimus; Triglycerides; Vitamin B 12