Impact of gastric acid suppressants on cytochrome P450 3A4 and P-glycoprotein: Consequences for FK506 assimilation

Impact of gastric acid suppressants on cytochrome P450 3A4 and P-glycoprotein: Consequences for FK506 assimilation.BackgroundCytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) are important determinants of the oral bioavailability and clearance of tacrolimus. Cimetidine and omeprazole are known modulators of several CYPs in vitro. In the present study, the impact of cimetidine and omeprazole on tacrolimus exposure and on CYP3A4/PGP activity in vivo was examined.MethodsIn a cohort of 48 renal transplant recipients who switched standard ulcer prophylaxis with 400 mg of cimetidine daily to 20 mg of omeprazole, dose/weight normalized trough levels of tacrolimus during a 5-day interval before and after switch were compared and further studied using multivariate analysis. In a cohort of 6 healthy volunteers, the effect of a 5-day course of ranitidine, cimetidine, and omeprazole on overall CYP, CYP3A4, and PGP activity in vivo was assessed with the 13C-aminopyrin breath test and the combined per oral and intravenous 14C-erythromycin breath and urine test.ResultsDose/weight normalized trough levels of tacrolimus decreased significantly (-15%) after switch from cimetidine to omeprazole. In healthy volunteers, a significant increase of intestinal CYP3A4 activity was observed after omeprazole, whereas no change was noted after cimetidine/ranitidine. Overall CYP activity was significantly decreased after cimetidine and remained unchanged after omeprazole/ranitidine. No effects on PGP or hepatic CYP3A4 were seen.ConclusionSwitching treatment with cimetidine to omeprazole in renal transplant recipients is associated with a decrease of dose/weight normalized trough levels of tacrolimus. Studies in healthy volunteers suggest that this may be explained by an increase of intestinal CYP3A4 activity

A new single nephron model of focal and segmental glomerulosclerosis in the Munich-Wistar rat

A new single nephron model of focal and segmental glomerulosclerosis in the Munich-Wistar rat. The hypothesis that damage to the visceral epithelial cell plays a central role in the pathogenesis of focal and segmental glomerulosclerosis was tested by injecting saponin solutions of increasing concentration (0.1, 0.3, 0.6 and 1.0 mg/ml) in Bowman's space of superficial glomeruli in the Munich-Wistar rat. The microinjections were performed both with and without intermittent clamping of the renal vessels during two minutes. After 8 to 14 days the injected glomeruli were examined by light microscopy. The injected glomeruli were classified as, normal (NL), showing visceral epithelial cell damage (VECD), showing focal and segmental glomerulosclerosis (FSGS) or showing global sclerosis (GS). Swelling and intracellular vacuolation of the visceral epithelial cells (VEC) were considered as VECD. FSGS-lesions were seen most frequently in the glomeruli injected with 10 nl of a saponin solution with a concentration higher than 0.3 mg/ml. In view of the light microscopic lesions four glomeruli in a 0 mg/ml, the 0.1 mg/ml and the 0.6 mg/ml saponin groups were examined after 40 minutes with transmission electron microscopy (TEM) to evaluate the selectivity of the lesions. In the 0 and 0.1 mg/ml group only occasional limited fusion of the foot processes of the podocytes was seen. In the 0.6 mg/ml group segmental lysis of the VEC without ultrastructural damage to the capillary basement membrane or the endothelial and mesangial cells was seen. It is concluded that it is possible to induce direct segmental lysis of the visceral epithelial cells in a single glomerulus, and that this damage to the visceral epithelial cells is related to the development of focal and segmental glomerulosclerosis

Bradykinin is a mediator of anaphylactoid reactions during hemodialysis with AN69 membranes

Bradykinin is a mediator of anaphylactoid reactions during hemodialysis with AN69 membranes. Anaphylactoid reactions (AR) are the most feared complications of hemodialysis. Recently, a high incidence of AR has been reported during dialysis with AN69 membranes in patients treated with ACE inhibitors. Plasma levels of C3a, histamine and bradykinin were measured in 12 patients at the onset of AR during dialysis with AN69. We also investigated bradykinin generation in 10 symptom-free patients dialyzed with four different membranes. None of the 12 patients studied during AR displayed excessive complement activation or histamine release. In contrast, high bradykinin plasma levels (2392 53 fmol/ml; mean sem) were observed in all nine patients of whom bradykinin was measured. One patient developed two consecutive episodes of hypersensitivity on AN69 membranes even without taking ACE inhibitors. Bradykinin levels were high in both episodes (5280 and 10467.7 fmol/ml). Furthermore, this patient showed no symptoms and normal bradykinin levels (123.4 fmol/ml) when dialyzed with other membranes. The role of the membrane type in the AR is further substantiated by the observation that AN69 also provoked a significantly higher bradykinin generation (327.6 18 fmol/ml; mean SEM) during symptom-free sessions compared to other membranes like CuprophanR (5.1 7.3), HemophanR (17.2 6.3) and PolysulfoneR (39.7 6.6). Our findings strongly suggest that bradykinin is the principal mediator of AR during hemodialysis with AN69 membranes. To our knowledge it is the first time that data support the hypothesis of a more general role of bradykinin in shock-like symptoms. Furthermore, bradykinin generation must be regarded as a new marker of biocompatibility of extracorporeal treatments

Mycophenolate mofetil in IgA nephropathy: Results of a 3-year prospective placebo-controlled randomized study

Mycophenolate mofetil in IgA nephropathy: Results of a 3-year prospective placebo-controlled randomized study.BackgroundBecause humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy (IgAN), a prospective placebo-controlled randomized study was started in patients with IgAN using mycophenolate mofetil (MMF).MethodsA total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2g per day (N = 21) or placebo (N = 13). After 36months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis.ResultsTherapy had to be stopped prematurely in five patients. Two patients (MMF group) evolved to end-stage renal disease (ESRD). There was no difference between groups in the percentage of patients with a decrease of 25% or more in the inulin clearance or with a serum creatinine increase of 50% or more over 3years. There was also no significant difference between groups in annualized rate of change of serum creatinine, computed by linear regression analysis. No significant difference was noted between groups for inulin clearance, serum creatinine, proteinuria, blood pressure, or other parameters of renal function. Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group. As a function of time, a significant decline in both groups was noted of proteinuria, parenchymal thickness of the kidneys and C3d.ConclusionIn patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results

Reduced exposure to calcineurin inhibitors in renal transplantation

Background: immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens. Methods: we randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival. Results: the mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%). Conclusions: a regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction

Fundus Changes in Membranoproliferative Glomerulonephritis Type-ii - a Fluorescein Angiographic Study of 23 Patients

A total of 23 patients aged between 11 and 64 years who had biopsy-proven membranoproliferative glomerulonephritis type II (dense deposit disease) were studied using fluorescein angiography of the retina. With the exception of two adolescents, all patients exhibited small subretinal nodules that were similar to basal laminar drusen. Subjects with a long history of renal disease displayed more numerous and larger nodules as well as atrophic changes. Four subjects presented with subretinal neovascular membranes

SERUM CONCENTRATIONS OF p-CRESYL SULFATE AND INDOXYL SULFATE, BUT NOT INFLAMMATORY MARKERS, INCREASE IN INCIDENT PERITONEAL DIALYSIS PATIENTS IN PARALLEL WITH LOSS OF RESIDUAL RENAL FUNCTION

UNLABELLED: BACKGROUND: High serum concentrations of the protein-bound uremic retention solutes p-cresyl sulfate (PCS) and indoxyl sulfate (IndS) and inflammation are associated with increased cardiovascular morbidity and mortality in chronic kidney disease. Renal clearance contributes to up to 80% of the total clearance of PCS and IndS in peritoneal dialysis (PD) patients. Cross-sectional studies evaluating the impact of residual renal function (RRF) on serum concentrations of PCS, IndS, and circulating inflammatory markers have yielded conflicting results. ♢ METHODS: To clarify this issue, we carried out a prospective observational cohort study in incident PD patients (n = 35; 19 men; mean age: 55 ± 17 years). Midday blood samples were collected and analyzed for total serum PCS, IndS, C-reactive protein, and high-sensitivity interleukin 6. Peritoneal and renal clearances were calculated from urine and dialysate collections, and RRF was calculated as the mean of renal urea nitrogen and creatinine clearances. Patients were assessed 1, 6, 12, and 24 months after PD start. Differences between time points were analyzed using linear mixed models (LMMs). ♢ RESULTS: Residual renal function declined significantly over time (LMM p < 0.0001). Peritoneal clearances of both toxins tended to increase, but did not compensate for the declining renal clearances. Serum concentrations of PCS and IndS increased significantly over time (LMM p = 0.01; p = 0.0009). In contrast, total mass removal of both toxins remained stable. Circulating inflammatory markers did not change over time. ♢ CONCLUSIONS: Our data indicate that serum concentrations of PCS and IndS, but not inflammatory markers, increase in incident PD patients in parallel with loss of RRF.status: publishe

The Economic Implications of Non-Adherence after Renal Transplantation

Background: The economic impact of therapeutic non-adherence in chronic diseases has rarely been examined using qualitative standards for economic evaluation. This study illustrates the impact of non-adherence on the cost utility of renal transplantation versus haemodialysis from the societal perspective and examines the scope for adherence-enhancing interventions. Methods: Long-term costs and outcomes in adherent and non-adherent renal transplant patients were simulated in a Markov model. The cost (euros, year 2000 values) and outcome data that were imputed in the model were derived from a prospective study in renal transplantation candidates performed in 2002. Probabilities of adverse events, graft rejection, graft loss and death in adherent and non-adherent renal transplant patients were derived from literature. Results: Compared with dialysis, renal transplantation offers a better outcome in both adherent and non-adherent patients. Lifetime costs after transplantation in the adherent patient group are higher than lifetime dialysis costs and lifetime costs in the non-adherent patient group, mainly because adherent patients live longer after transplantation. Long-term outcomes after transplantation are better for adherent than for non-adherent patients. The mean cost per QALY gained in adherent patients relative to non-adherent patients was Conclusion: Compared with established healthcare interventions, such as haemodialysis, renal transplantation can be considered a cost-effective therapy for patients with end-stage renal disease, even if patients are non-adherent after transplantation. The low incremental cost per QALY calculated in this model for adherent renal transplant patients, suggests there may be scopeCost-utility, Dialysis, Immunosuppressants, Patient-compliance, Renal-failure, Renal-transplant-rejection