No gender-associated differences of cyclosporine pharmacokinetics in stable renal transplant patients treated with diltiazem.

Cytochrome-P450 enzymes metabolize cyclosporine both in the liver and in the intestinal wall. Diltiazem, by competitive inhibition of these enzymes, may increase the absorption and the bioavailability of cyclosporine. Some evidence points to a higher activity of some specific enzymes in women, such as CYP3A, that may influence differences in cyclosporine pharmacokinetics. We examined possible gender-associated differences in pharmacokinetic profiles of cyclosporine in 19 stable renal transplant recipients cotreated with diltiazem. Ten women and nine men, chronically using diltiazem associated with cyclosporine, azathioprine, and prednisone were randomly assigned to an 8-week period of continued controlled treatment with diltiazem (10 patients) or a wash-out period discontinuing diltiazem (nine patients). At the end of this period, the time-concentration curves of cyclosporine in the first 4 hours were performed after a single dose of cyclosporine. Thereafter, a cross-over between groups was performed, and time-concentration curves repeated. A specific RIA was used to measure cyclosporine concentrations. Comparisons between male and female patients in doses of cyclosporine and other pharmacokinetics parameters (C(0), C(2), AUC(0-4)), with or without diltiazem, did not show any difference related to gender. The association of diltiazem allowed a similar degree of reduction in Neoral dosage in male and female patients (21%). No changes in serum creatinine, blood urea nitrogen, potassium, uric acid, or blood pressure, or other adverse event were observed during the study. In these groups of patients, gender was not an important factor to be considered when diltiazem is added to cyclosporine therapy.

Correlation Between C2 and AUC(0-4) in Renal Transplant Patients Treated With Diltiazem.

BACKGROUND: The area-under-the-curve (AUC) of cyclosporine (CsA) reflects exposure to the drug, but this monitoring strategy is time-consuming and not cost-effective. Recently, it has been suggested that the concentration at 2 hours after dosing (C2) shows the best correlation with AUC. The C2 has been replacing the trough measurement (C0) to monitor CsA therapy, but in patients receiving diltiazem there is not much information about this issue. We investigated the correlations between C2 and C0 with absorption AUC over the first 4 hours (AUC(0-4)) in renal stable transplant patients receiving CsA therapy with or without diltiazem. PATIENTS AND METHODS: Ten patients (five men) of ages 23 to 68 years and 6 to 84 months after transplantation, were randomly assigned to an 8-week initial period of either diltiazem washout or controlled treatment with diltiazem. Time-concentration curves of cyclosporine were performed at the end of this period using a specific RIA measurement of blood samples. Thereafter, a crossover of the groups was performed and after another 8 weeks, a second curve was obtained. Drugs that change the pharmacokinetics of cyclosporine or diltiazem were not allowed. RESULTS: The cyclosporine daily dose was lower with diltiazem (173 +/- 4 mg vs 213 +/- 4 mg, P = .002), but despite a dose reduction of only 19% +/- 1.5%, there was a trend to a larger AUC/dose (28 +/- 5 ng x h/mL x mg vs 17 +/- 2 ng x h/mL x mg, P = .1) and a trend to an increased C2 when treatment included diltiazem (1035 +/- 156 ng/mL vs 652 +/- 126 ng/mL, P = NS). Moreover, we confirmed that C2 showed the best correlation with AUC(0-4), (r = 0.7, P = .04), a correlation that improved with diltiazem (r = 0.9, P < .002). CONCLUSION: C2 is the point that correlates best with AUC(0-4) with or without diltiazem. C2 in the presence of diltiazem was associated with a stronger, more significant correlation with AUC(0-4).

Valsartan-induced hematocrit changes in renal transplant patients.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARB) are frequently prescribed for renal transplant patients. The main reasons for their use are that their antihypertensive and antifibrogenic effects may prevent chronic renal allograft dysfunction, potentially improving transplant survival. Furthermore, ACE and ARB have been used to reduce the hematocrit in patients with posttransplant erythrocytosis. We evaluated the effects of the ARB valsartan on the evolution of hematocrit in stable renal transplant patients treated with cyclosporine (CsA), azathioprine (Aza), and prednisone. PATIENTS AND METHODS: Twenty-six stable renal transplant patients treated with valsartan 80 mg/d orally were followed for 6 months. Evaluations were performed prior to as well as at 3 and 6 months following the initiation of valsartan. RESULTS: The hematocrit levels decreased significantly at 3 months (46.1 +/- 7.3 vs 39.9 +/- 5.8 ; P < .0001) in patients with a normal hematocrit, namely a level over 38%, with no further reduction at 6 months. In recipients with an hematocrit less than 38%, there was no significant reduction, either at 3 or 6 months follow-up. Valsartan was well tolerated without significant side effects. CONCLUSION: We postulate that inhibition of the proerythropoietic effects of angiotensin II and/or the reduction in hypoxia within the renal tubulointerstitium as well as the vasodilator effects on the efferent arterioles, represent possible mechanisms for the reduction and stabilization of the hematocrit in stable renal transplant patients.

Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy.

UNLABELLED: Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy. BACKGROUND: Proteinuria plays a central role in the progression of glomerular disease, and there is growing evidence suggesting that it may determine tubular cell activation with release of chemokines and fibrogenic factors, leading to interstitial inflammatory reaction. However, most studies on this subject have been performed in experimental models, and the experience in human kidney biopsies has been scarce. We analyzed the tissue sections of patients with idiopathic membranous nephropathy (IMN), a noninflammatory glomerular disease that may follow a progressive disease with heavy persistent proteinuria, interstitial cell infiltration, and decline of renal function. METHODS: Paraffin-embedded biopsy specimens from 25 patients with IMN (13 progressive and 12 nonprogressive) were retrospectively studied by immunohistochemistry [monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted chemokine (RANTES), osteopontin (OPN), platelet-derived growth factor-BB (PD-GF-BB)] and in situ hybridization [MCP-1, RANTES, PDGF-BB, transforming growth factor-beta1 (TGF-beta1)]. Moreover, we studied the presence of myofibroblasts, which were identified by the expression of alpha-smooth muscle actin (alpha-SMA), the monocytes/macrophages (CD68-positive cells), and T-cell infiltration (CD4+ and CD8+ cells). All of the patients were nephrotic and without treatment at time of the biopsy. RESULTS: A strong up-regulation of MCP-1, RANTES, and OPN expression was observed, mainly in tubular epithelial cells, with a significant major intensity in the progressive IMN patients. A strong correlation between the mRNA expression and the corresponding protein was noted. The presence of these chemokines and OPN was associated with interstitial cell infiltration. TGF-beta and PDGF were also up-regulated, mainly in tubular epithelial cells, with a stronger expression in the progressive IMN, and an association with the presence of myofibroblasts was found. CONCLUSIONS: Patients with severe proteinuria and progressive IMN have an overexpression in tubular epithelial cells of the chemokines MCP-1, RANTES, and OPN and the profibrogenic cytokines PDGF-BB and TGF-beta. Because this up-regulation was associated with an interstitial accumulation of mononuclear cells and an increase in myofibroblastic activity, it is suggested that those mediators are potential predictors of progression in IMN. Finally, based on experimental data and the findings of this article, we speculate that severe proteinuria is the main factor responsible for the up-regulation of these factors in tubular epithelial cells.