Background In peritoneal dialysis, the high glucose load absorbed from dialysis fluid contributes to several metabolic abnormalities, including insulin resistance. We evaluate the efficacy of a ...peritoneal dialysis solution containing l -carnitine as an additive to improve insulin sensitivity. Study Design Multicenter parallel randomized controlled trial. Setting & Participants Nondiabetic uremic patients on continuous ambulatory peritoneal dialysis enrolled in 8 peritoneal dialysis centers. Intervention Patients were randomly assigned to receive peritoneal dialysis diurnal exchanges with either a standard glucose-based solution (1.5% or 2.5% according to the patient's need) or a glucose-based solution (identical glucose amount) enriched with l -carnitine (0.1%, weight/volume; 2 g/bag) for 4 months, the nocturnal exchange with icodextrin being unmodified. Outcomes & Measurements The primary outcome was insulin sensitivity, measured by the magnitude of change from baseline in glucose infusion rate (in milligrams per kilogram of body weight per minute) during a euglycemic hyperinsulinemic clamp. Secondary outcomes were safety and tolerability, body fluid management, peritoneal dialysis efficiency parameters, and biochemistry tests. Results 35 patients were randomly assigned, whereas 27 patients (standard solution, n=12; experimental solution, n = 15) were analyzed. Adverse events were not attributable to treatment. Glucose infusion rates in the l -carnitine–treated group increased from 3.8 ± 2.0 (SD) mg/kg/min at baseline to 5.0 ± 2.2 mg/kg/min at day 120 ( P = 0.03) compared with 4.8 ± 2.4 mg/kg/min at baseline and 4.7 ± 2.4 mg/kg/min at day 120 observed in the control group ( P = 0.8). The difference in glucose infusion rates between groups was 1.3 (95% CI, 0.0-2.6) mg/kg/min. In patients treated with l -carnitine–containing solution, urine volume did not change significantly ( P = 0.1) compared to a significant diuresis reduction found in the other group ( P = 0.02). For peritoneal function, no differences were observed during the observation period. Limitations Small sample size. Conclusions The use of l -carnitine in dialysis solutions may represent a new approach to improving insulin sensitivity in nondiabetic peritoneal dialysis patients.
...in some patients, the occurrence of AE attacks with a clinical onset after the third to fourth decade of life is not associated to C1 inh alteration and absence of other clinical accompanying ...conditions or drugs (idiopathic AE IAE). Edema persisted to minimal degree to the left cheek and disappeared completely 9 hours after the icatibant administration; at this time, pain and local discomfort had also completely resolved (Fig). ...compared with the usual spontaneous resolution of AE attacks in this patient that invariably required a mean time of 36 hours, treatment with 1 injection (30 mg) of icatibant was able to induce a relief of AE signs as early as 45 minutes and a complete resolution in 9 hours.
Background Fetuin A, a circulating inhibitor of ectopic calcification, is downregulated in hemodialysis and has been shown to predict cardiovascular mortality in this setting. The association of ...altered calcium-phosphorus with serum fetuin A levels is still a matter of debate. Although carotid intima-media thickness (cIMT) is a strong predictor of major cardiovascular events, its association with serum fetuin A levels is poorly defined. Study Design Cohort study. Participants & Settings 174 uremic patients on long-term hemodialysis therapy enrolled in 4 university hospitals. Predictors Serum fetuin A levels at the beginning of the study (T0) and after 12 months (T12). Outcomes Progression of atherosclerosis assessed by means of cIMT measurements at 24 months (T24); cardiovascular morbidity and mortality at 36 months. Results Serum fetuin A concentrations at T0 and T12 were 282.3 ± 79.4 and 290.0 ± 92.2 μg/mL, respectively. Mean T0 and T24 cIMT values were 1.02 ± 0.2 and 1.06 ± 0.2 mm, respectively ( P < 0.001). Fatal and nonfatal cardiovascular disease occurred in 36 and 86 patients by 36 months, respectively. In multivariate logistic regression, higher calcium-phosphorus product was associated with lower serum fetuin A level (odds ratio, 0.96; 95% confidence interval CI, 0.93 to 1.00; P = 0.02). Multiple regression analysis showed that T0 serum fetuin A level was associated with T24 cIMT ( P = 0.01) after adjustments for age, cholesterol level, high-sensitivity C-reactive protein level, previous cardiovascular events, and T0 cIMT. In a multivariate Cox regression analysis, cardiovascular mortality was independently associated with a 1-tertile lower T0 serum fetuin A level, and a 1-tertile higher T0 cIMT value was independently associated with greater cardiovascular mortality (hazard ratio, 0.45; 95% CI, 0.15 to 0.65; P = 0.007 and hazard ratio, 10.00; 95% CI, 3.16 to 31.73; P < 0.001, respectively) after adjustment for age and previous cardiovascular events. Limitation Length of follow-up. Conclusion Calcium-phosphorus product in hemodialysis patients inversely correlated with serum fetuin A level, which, in turn, was associated inversely with progression of atherosclerotic lesions and cardiovascular mortality in this study population.
Background Inhibition of P70S6 kinase (P70S6K ) phosphorylation in activated T cells is 1 of the major mechanisms by which rapamycin exerts its immunosuppressive action. Study Design Observational ...cohort study. Settings & Participants 2 different groups of kidney transplant recipients at a single center: 30 transplant recipients converted from mycophenolic acid and low-dose prednisone plus cyclosporine A to mycophenolic acid and low-dose prednisone plus rapamycin therapy for chronic allograft nephropathy (group 1) and 16 recipients of suboptimal organs converted from tacrolimus plus rapamycin to rapamycin therapy alone after 3 months (group 2). Predictor Exposure to rapamycin therapy and rapamycin trough levels. Outcomes & Measurements Basal and stimulated phosphorylation of P70S6K was measured by using Western blotting in patients’ peripheral-blood mononuclear cells before and 6 to 11 months after conversion to rapamycin-based therapy. Kinase activation was attained in vivo by means of intravenous insulin injection. Results The potency of rapamycin inhibition of P70S6K phosphorylation varied among patients (RAPA blood concentration required to achieve 50% inhibition of P70S6K activation for mitogen-activated kinase, 3.14 to 12.14 ng/mL) and failed to correlate with drug trough levels. The combination of tacrolimus and rapamycin limited the inhibitory effect of the latter drug on P70S6K activation. Limitations Need for additional studies exploring the relationship between P70S6K activity and kidney graft outcome. Exclusion of patients with diabetes. Conclusions Long-term rapamycin treatment inhibits P70S6K phosphorylation in peripheral-blood mononuclear cells without significant correlation with rapamycin trough levels. By measuring in vivo the biological action of rapamycin, the assay may provide potentially relevant information for the clinical management of rapamycin-treated patients.
Background The clinical challenge for the application of rapamycin and its derivatives as anticancer drugs is the ability to prospectively identify which tumors will be sensitive to mammalian target ...of rapamycin (mTOR) inhibition. The present study is designed to explore mTOR signaling in peripheral-blood mononuclear cells (PBMCs) from renal transplant recipients with Kaposi sarcoma and ascertain whether it would reflect deregulation of the AKT-mTOR pathway in skin cancer tissue and might help identify which patients would benefit from rapamycin treatment, as well as to monitor their clinical response. Methods We measured basal and in vivo stimulated AKT and P70 S6 kinase (P70S6K ) phosphorylation in PBMCs from 37 cyclosporine A–treated patients, 10 of whom had Kaposi sarcoma, before and 6 months after conversion to rapamycin therapy. Results Patients with Kaposi sarcoma showed markedly increased basal P70S6K activation and depressed phosphorylation of AKT. Long-term treatment with rapamycin was associated with marked inhibition of basal and stimulated phosphorylation of both AKT and P70S6K , in parallel with regression of the dermal neoplasm. Conclusion Overactivation of basal P70S6K in PBMCs from renal transplant recipients appears to be associated with the presence of Kaposi sarcoma dermal lesions; conversely, kinase inhibition is linked to regression of skin cancer lesions. Thus, monitoring P70S6K phosphorylation can help predict and monitor the biological effectiveness of rapamycin in renal transplant recipients with Kaposi sarcoma and possibly adjust the biologically active doses of the mTOR inhibitor.
