Oxidative Stress in Kidney Transplant Patients With Calcineurin Inhibitor–Induced Hypertension: Effect of Ramipril

Abstract

In patients with cyclosporine-induced hypertension, upregulation of the nitric oxide system and oxidative stress were shown, which could induce hypertension, remodeling, and chronic rejection by increasing nitric oxide catabolism. However, it is still debated whether cyclosporine and tacrolimus exert a different action. The aim of the current study was to compare the effects of cyclosporine and tacrolimus on markers of oxidative stress and endothelial dysfunction in kidney transplant patients with posttransplant hypertension. Monocyte p22, a NADH/NADPH system subunit, transforming growth factor-beta (TGF-beta), heme oxygenase-1 (HO-1), and endothelial NOS gene expression were measured in 16 patients. Angiotensin II is a potent stimulator of oxidative stress and angiotensin-converting enzyme inhibition may blunt this effect. Therefore, the same parameters were measured before and after 2 months of treatment with ramipril (5 mg/d). At baseline, in cyclosporine-and tacrolimus-treated patients, p22 and TGF-beta mRNA were similarly increased in comparison with normotensive healthy controls (0.90 +/- 0.05 d.u. and 0.83 +/- 0.05 in cyclosporine, 0.89 +/- 0.07 and 0.84 +/- 0.05 in tacrolimus; 0.53 +/- 0.07 and 0.75 +/- 0.03 in controls, respectively; p < 0.001). Endothelial NOS mRNA was increased in cyclosporine-and tacrolimus-treated patients in comparison with controls (0.92 +/- 0.09, 0.96 +/- 0.04, and 0.37 +/- 0.05 respectively; p < 0.001), whereas no difference was found between patients and controls in HO-1 mRNA. Ramipril reduced blood pressure (from 140 +/- 11/91 +/- 7 mm Hg to 129 +/- 6/85 +/- 5 mm Hg in cyclosporine and from 138 +/- 7/92 +/- 7 mm Hg to 127 +/- 10/82 +/- 6 mm Hg in tacrolimus group; p < 0.02 with no difference between groups). Ramipril also reduced p22 (to 0.83 +/- 0.05 in cyclosporine, p < 0.03 and to 0.81 +/- 0.08 in tacrolimus; p < 0.01) and TGF-beta mRNA (to 0.72 +/- 01 in cyclosporine, p < 0.02, and to 0.73 +/- 0.05 in tacrolimus; p < 0.01) with no difference between groups, but it did not change HO-1 and ecNOS mRNA. Cyclosporine and tacrolimus induce a comparable oxidative stress in kidney transplant patients with posttransplant hypertension. The association of ramipril normalizes blood pressure and reduces the oxidative stress induced by both drugs.

Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

“…Moreover, because oxidative stress is equally involved in the development of hypertension in other organ transplant recipients, such as kidney transplant patients, our findings may also be of importance for the prognosis of these patients. 45 …”

Changes in Oxidative Stress in Renal Graft Patients Receiving Calcineurin Inhibitors: Cyclosporine Versus Tacrolimus

“…Similar to our study, Calò and associates reported an increase in the levels of oxidative stress in 16 cyclosporine-or tacrolimus-treated allograft recipients with posttransplant hypertension. 10 In a short-term study, Vural and associates found a reduction in malondialdehyde levels in both cyclosporine-and tacrolimus-treated patients 28 days after transplant. 31 These results conflict with our results, as we demonstrated an increase in malondialdehyde levels even at 30 days after transplant.…”

“…4,8 Patients in these studies also demonstrate upregulation of the nitric oxide (NO) system, as suggested by increased endothelial nitric oxide synthase (NOS) gene expression and nitrite/nitrate levels. 9,10 In another study, the effects of cyclosporine and tacrolimus on advanced oxidation protein products and total antioxidant status were compared for 6 months and no significant differences were found. 11 Kanbay and associates also found no differences on serum uric acid levels in stable kidney transplant recipients using both calcineurin inhibitors.…”

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“…16 Tacrolimus or cyclosporine cause comparable oxidative stress at the cellular level in patients who have hypertension after kidney transplant. 43 At 6 months after the kidney transplant, patients receiving tacrolimus or cyclosporine have increased MDA levels. 17 Total cholesterol and triglycerides are higher in patients treated with cyclosporine than tacrolimus.…”