Background In bicarbonate-based hemodialysis, dialysate total calcium (tCa) concentration may have effects on mineral metabolism. Study Design Randomized crossover trial of 3 dialysate tCa ...concentrations (2.5, 2.75, and 3.0 mEq/L). Setting & Participants 22 stable anuric uremic patients underwent three 4-hour bicarbonate hemodialysis sessions with the 3 different dialysate tCa concentrations using a single-pass batch dialysis system. Outcomes Hourly measurements of plasma water ionized calcium (iCa) and plasma parathyroid hormone (PTH) concentrations. tCa mass balances were measured from the dialysate side. Results Hourly plasma water iCa concentrations were higher with a dialysate tCa concentration of 3.0 compared with 2.75 and 2.5 mEq/L ( P < 0.05), as were iCa concentrations at the end of dialysis sessions (2.66 ± 0.1, 2.56 ± 0.12, and 2.4 ± 0.08 mEq/L, respectively; P < 0.001). Mean tCa mass balance values (diffusion gradient from the dialysate to the patient) were positive with all dialysate tCa concentrations and increased progressively with dialysate tCa concentration (75 ± 122, 182 ± 125, and 293 ± 228 mg, respectively; P < 0.001). Plasma PTH levels increased during dialysis using dialysate tCa concentration of 2.5 mEq/L (mean increase, 225 ± 312 pg/mL) and decreased with dialysate tCa concentrations of 2.75 and 3.0 mEq/L (mean decreases, 68 ± 325 and 99 ± 432 pg/mL, respectively). Limitations Small sample size and lack of measurement of total-body calcium mass balances. Conclusions A dialysate tCa concentration of 2.75 mEq/L might be preferable to 2.5 or 3.0 mEq/L because it is associated with mildly positive tCa mass balance values, plasma water iCa levels in the reference range, and stable PTH levels during dialysis.
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.
