Population pharmacokinetics of mycophenolic acid in pediatric renal transplant patients using parametric and nonparametric approaches.

International audienceMycophenolic acid (MPA) is an immunosuppressive drug widely used in the prevention of acute rejection in pediatric renal transplant recipients and is characterized by a wide inter-individual variability in its pharmacokinetics. The aim of this study was to compare population pharmacokinetic modeling of MPA in pediatric renal transplant recipients given mycophenolate mofetil, the ester prodrug of MPA, using parametric and nonparametric population methods. The data from 34 pediatric renal transplants (73 full pharmacokinetic profiles obtained on day 21, months 3, 6 and 9 post-transplant) were analyzed using both the nonlinear mixed-effect modeling (NONMEM) and nonparametric adaptive grid (NPAG) approaches, based on a two-compartment model with first order lagged time absorption and first order elimination. The predictive performance of the two models was evaluated in a separate group of 32 patients. Higher mean population parameter values and ranges of individual pharmacokinetic parameters were obtained with NPAG, especially for the elimination constant ke: mean 1.16 h(-1) (0.26-4.33 h(-1)) and 0.78 h(-1) (0.66-1.15 h(-1)) with NPAG and NONMEM, respectively. With NPAG, the skewness and kurtosis values for ke (2.03 and 7.80, respectively) were far from the theoretical values expected for normal distributions. Such a non-normal distribution could explain the high value of shrinkage (35%) obtained for this parameter with the parametric NONMEM method. Bayesian forecasting of mycophenolic acid exposure using the NPAG population pharmacokinetic parameters as priors yielded a better predictive performance, with a significantly smaller bias than with the NONMEM model (-1.68% vs -9.53%, p<0.0001). In conclusion, in the present study, NPAG was found to be the most adequate population pharmacokinetic method to describe the pharmacokinetics of MPA in pediatric renal transplant recipients

Growth promoting effects of growth hormone and IGF-I are additive in experimental uremia.

Exogenous growth hormone (GH) stimulates the endogenous production of IGF-I and improves growth in uremia. We investigated whether exogenous IGF-I is also able to improve uremic growth failure in rats and whether the growth promoting effects of GH and IGF-I are additive. In female 150 g uremic (subtotal nephrectomy, NX) Sprague-Dawley rats, both rhGH in doses from 2 X 1.25 to 2 X 10 IU/kg bid s.c. and rhIGF-I in doses from 2 X 0.5 to 2 X 4.0 mg/kg bid s.c. caused a dose-dependent increase in weight gain and length gain. However, endogenous production of GH was suppressed by both agents. Peptide hormone treatment did not affect cumulative food intake, but significantly increased food efficiency ratio (weight gain/food intake). Concomitant s.c. treatment with maximally effective doses of rhGH (12 X 5 IU/kg bid) and of rhIGF-I (2 X 2 mg/kg bid) resulted in additive growth promoting effects in NX and pair-fed control (CO) animals during the observation period of 12 days. Cumulative length gain was 3.2 +/- 0.5 cm in solvent-treated NX-animals, 4.1 +/- 0.5 cm with rhGH (+ 28% above solvent), 4.2 +/- 0.6 cm with rhIGF-I (+ 31%) and 4.9 +/- 0.5 cm with both peptides (+ 53%). The food efficiency ratio was 0.16 +/- 0.05 in solvent NX, 0.33 +/- 0.04 with rhGH (+ 106% above solvent), 0.23 +/- 0.02 with rhIGF-I (+ 44%), and 0.38 +/- 0.02 with both peptides (+ 138%). Histomorphometric analysis and measurements of length gain by fluorescence microscopy in the upper tibial metaphysis confirmed the growth promoting effects of both peptide hormones. The serum concentrations of IGF binding protein (BP)-4 (Western ligand blotting analysis) and of IGFBP-2 (immunoblot) were increased in uremic animals whereas IGFBP-3 was unchanged. Treatment with IGF-I and/or rhGH increased serum concentration of IGF-I but did not change the IGFBP pattern. rhIGF-I lowered blood glucose levels within one to two hours after injection. The effect was most pronounced during the first treatment day and declined thereafter. Concomitant treatment with rhGH attenuated the glucose lowering effect of rhIGF-I (glucose serum concentration at day one: 120 +/- 11 mg% in solvent NX, 50 +/- 21 mg% with rhIGF-I, 80 +/- 24 mg% with both peptides). It is concluded that: (i) IGF-I is able to stimulate growth in NX animals but suppresses endogenous GH production in the long run; (ii) the concomitant treatment with IGF-I and GH has additive effects on growth; and (iii) concomitant treatment with rhGH prevents hypoglycemia that is noted with rhIGF-I alone

The use of mycophenolate mofetil suspension in pediatric renal allograft recipients

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m 2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m 2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC 0–12 ) of 27.2 µg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m 2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42304/1/467-16-12-978_10160978.pd

Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis

Introduction: Nephronophthisis (NPH) comprises a group of rare disorders accounting for up to 10% of end-stage kidney disease (ESKD) in children. Prediction of kidney prognosis poses a major challenge. We assessed differences in kidney survival, impact of variant type, and the association of clinical characteristics with declining kidney function. Methods: Data was obtained from 3 independent sources, namely the network for early onset cystic kidney diseases clinical registry (n = 105), an online survey sent out to the European Reference Network for Rare Kidney Diseases (n = 60), and a literature search (n = 218). Results: A total of 383 individuals were available for analysis: 116 NPHP1, 101 NPHP3, 81 NPHP4 and 85 NPHP11/TMEM67 patients. Kidney survival differed between the 4 cohorts with a highly variable median age at onset of ESKD as follows: NPHP3, 4.0 years (interquartile range 0.3–12.0); NPHP1, 13.5 years (interquartile range 10.5–16.5); NPHP4, 16.0 years (interquartile range 11.0–25.0); and NPHP11/TMEM67, 19.0 years (interquartile range 8.7–28.0). Kidney survival was significantly associated with the underlying variant type for NPHP1, NPHP3, and NPHP4. Multivariate analysis for the NPHP1 cohort revealed growth retardation (hazard ratio 3.5) and angiotensin-converting enzyme inhibitor (ACEI) treatment (hazard ratio 2.8) as 2 independent factors associated with an earlier onset of ESKD, whereas arterial hypertension was linked to an accelerated glomerular filtration rate (GFR) decline. Conclusion: The presented data will enable clinicians to better estimate kidney prognosis of distinct patients with NPH and thereby allow personalized counseling

Миграция и эмиграция поволжских немцев

This article presents an overview of current simulation methods describing the interaction of grinding process and grinding machine structure, e.g., vibrations, deflections, or thermal deformations. Innovative process models which describe the effects of the grinding wheel–workpiece interaction inside the contact zone are shown in detail. Furthermore, simulation models representing the static and dynamic behaviour of a grinding machine and its components are discussed. Machine tool components with a high influence on the process results are modelled more detailed than those with low influence. The key issue of the paper is the coupling of process and machine tool models for predicting the interactions of process and machine. Several coupling methods are introduced and the improvements of the simulation results are documented. On the basis of the presented simulation approaches, grinding processes and machines can be designed more effectively resulting in higher workpiece quality and process stability

Tool wear in dry helical milling for hole-making in AISI H13 hardened steel

Helical milling is a hole-making process which can be applied to achieve high-quality finished boreholes in hardened steels. Due to the drilling process limitations, which are intensified when applied in hardened steels, the helical milling process can be applied on hole-making tasks in moulds and dies industry, since milling have been widely applied in moulds and dies machining to replace high-cost operations like grinding and electrical discharge machining. However, to succeed in achieving high-quality boreholes in hardened parts, which presents high added value due to previous operations, tool wear in the helical milling of hardened steels should be more investigated. In the present study, dry helical milling tool life tests were conducted in AISI H13 hardened steel parts, varying the cutting velocity. The flank wear on frontal cutting edges was progressively measured through optical microscopy, and SEM/EDS was performed in frontal and peripheral worn cutting edges. The wear occurred progressively in the flank of the frontal cutting edges with adhesion and oxidation as main wear mechanisms. In the peripheral edges, coating loss, and adhesion of workpiece material in the tool clearance surface were observed, besides fracture in the tool nose flank with the highest cutting velocity. A nested ANOVA was performed to evaluate the burr height in the borehole exit. The tool life stage was statistically significant in the burr height.publishe

Hypertension in children with chronic kidney disease: pathophysiology and management

Arterial hypertension is very common in children with all stages of chronic kidney disease (CKD). While fluid overload and activation of the renin–angiotensin system have long been recognized as crucial pathophysiological pathways, sympathetic hyperactivation, endothelial dysfunction and chronic hyperparathyroidism have more recently been identified as important factors contributing to CKD-associated hypertension. Moreover, several drugs commonly administered in CKD, such as erythropoietin, glucocorticoids and cyclosporine A, independently raise blood pressure in a dose-dependent fashion. Because of the deleterious consequences of hypertension on the progression of renal disease and cardiovascular outcomes, an active screening approach should be adapted in patients with all stages of CKD. Before one starts antihypertensive treatment, non-pharmacological options should be explored. In hemodialysis patients a low salt diet, low dialysate sodium and stricter dialysis towards dry weight can often achieve adequate blood pressure control. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are first-line therapy for patients with proteinuria, due to their additional anti-proteinuric properties. Diuretics are a useful alternative for non-proteinuric patients or as an add-on to renin–angiotensin system blockade. Multiple drug therapy is often needed to maintain blood pressure below the 90th percentile target, but adequate blood pressure control is essential for better renal and cardiovascular long-term outcomes