A pathogenic role for secretory IgA in IgA nephropathy

IgA nephropathy (IgAN) is characterized by deposits of IgA in the renal mesangium. It is thought that deposits of IgA mainly involve high molecular weight (HMW) IgA1. However, there is limited information on the exact composition of HMW IgA in these deposits. In this study, we investigated the presence of secretory IgA (SIgA) in human serum and in the glomerular deposits of a patient with IgAN. Furthermore, we analyzed the interaction of SIgA with mesangial cells. With enzyme-linked immunosorbent assay, SIgA concentrations in the serum of IgAN patients and healthy controls were measured. Both patients and controls had circulating SIgA that was restricted to the HMW fractions. Patients tended to have higher levels of SIgA, but this difference was not significant. However, in patients with IgAN, high serum SIgA concentrations were associated with hematuria. Binding of size-fractionated purified serum IgA and SIgA to mesangial cells was investigated with flow cytometry. These studies showed stronger binding of SIgA to primary mesangial cells compared to binding of serum IgA. Importantly, after isolation and elution of glomeruli from a nephrectomized transplanted kidney from a patient with recurrent IgAN, we demonstrated a 120-fold accumulation of SIgA compared to IgA1 in the eluate. In conclusion, we have demonstrated that SIgA strongly binds to human mesangial cells, and is present in significant amounts in serum. Furthermore, we showed that SIgA is accumulated in the glomeruli of an IgAN patient. These data suggest an important role for SIgA in the pathogenesis of IgAN

Decision making around living and deceased donor kidney transplantation: a qualitative study exploring the importance of expected relationship changes

Transplant surger

Model-informed precision dosing to optimise immunosuppressive therapy in renal transplantation

Immunosuppressive therapy is pivotal for sustained allograft and patient survival after renal transplantation. However, optimally balanced immunosuppressive therapy is challenged by between-patient and within-patient pharmacokinetic (PK) variability. This could warrant the application of personalised dosing strategies to optimise individual patient outcomes. Pharmacometrics, the science that investigates the xenobiotic-biotic interplay using computer-aided mathematical modelling, provides options to describe and quantify this PK variability and enables identification of patient characteristics affecting immunosuppressant PK and treatment outcomes. Here, we review and critically appraise the available pharmacometric model-informed dosing solutions for the typical immunosuppressants in modern renal transplantation, to guide their initial and subsequent dosing.Nephrolog

Age and gender differences in symptom experience and health-related quality of life in kidney transplant recipients: a cross-sectional study

Background Health-related quality of life (HRQOL) is an increasingly important patient-reported outcome in kidney transplant recipients (KTRs). This study explored relationships between symptom prevalence and burden with HRQOL, and age and gender differences in symptom experience. Methods Eligible Dutch KTRs transplanted in Leiden University Medical Center were invited for this cross-sectional study. HRQOL, and occurrence and burden of 62 symptoms were measured using validated questionnaires. Univariate and multivariate regression analysis were used for investigating the associations of symptom experience with mental and physical HRQOL, and differences in symptom experience between genders and KTRs of diverse age groups. Results A total of 631 KTRs were analyzed; the mean (standard deviation) age was 61.3 (11.3) years, and 62% were male. The median (interquartile range) number of symptoms was 14 (7-22), with a burden of 20 (8-37; range 0-244). Per extra symptom, physical and mental HRQOL decreased [-0.41 (-0.50; -0.31) and -0.51 (-0.59; -0.42), respectively, P 50-65 >= 65 years) feelings of depression and both female and younger KTRs reported higher symptom prevalence concerning changes in physical appearance. Conclusion KRTs' symptom experience differed depending on gender and age, highlighting the need to develop tailored treatment strategies to reduce symptom experience and subsequently improve HRQOL.Nephrolog

Tacrolimus and mycophenolic acid exposure are associated with biopsy-proven acute rejection: a study to provide evidence for longer-term target ranges

Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the association of measurements at 1 year and repeated measurements of real-world Tac-trough levels (C-0) and abbreviated area under the curve from zero to 12 hours (AUC(0-12h)) of Tac and MPA with biopsy-proven acute rejection (BPAR) between years 1 and 3 post-transplant in 968 kidney transplant recipients (KTRs). Thirty-five (3.6%) out of 968 KTRs experienced BPAR. Both Tac-AUC(0-12h) (hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.30-0.50, P < 0.001), Tac-C-0 (HR: 0.46, 95% CI: 0.38-0.57, P < 0.001) and MPA-AUC(0-12h) at 1 year (HR: 0.80, 95% CI: 0.68-0.94, P = 0.006), as well as repeated measurements of Tac-C-0 (HR: 0.70, 95% credibility interval (CrI): 0.61-0.82, P < 0.001), and of MPA-AUC(0-12h) (HR: 0.75, 95% CrI: 0.62-0.93, P < 0.001) were associated with BPAR. In our population, the recommended target range for Tac-AUC(0-12h) at 1 year would be 75-95 ng*hour/mL and a Tac-C-0 5-7 ng/mL. The Tac-AUC(0-12h) predicted BPAR better than Tac-C-0 and identified KTRs with over- or underexposure despite supposedly adequate Tac-C-0. We did not find evidence to recommend another target than the consensus range of 30-60 mg*hour/L for MPA-AUC(0-12h) after the first year of transplantation. To our knowledge, this is a first study on the simultaneous exposure of Tac and MPA at year 1 and subsequent BPAR up to year 3, which may help define the therapeutic target window for the longer term.Personalised Therapeutic

Applicability and reproducibility of the CPAT-grading system for pancreas allograft thrombosis

Purpose: : Although pancreas allograft thrombosis (PAT) incidence has progressively decreased, it remains the most common cause of early graft failure. Currently, there is no consensus on documentation of PAT, which has resulted in a great variability in reporting. The Cambridge Pancreas Allograft Thrombosis (CPAT) grading system has recently been developed for classification of PAT. In this study we aimed to assess the applicability and validate the reproducibility of the CPAT grading system.Methods: : This study is a retrospective cohort study. Selected for this study were all 177 pancreas transplantations performed at our center between January 1 st, 2008 and September 1 st, 2018 were included.Results: : A total of 318 Computed Tomography (CT) images was reevaluated according the CPAT system by two local radiologists. Inter-rater agreement expressed in Cohen's kappa was 0.403 for arterial and 0.537 for venous thrombosis. Inter-rater agreement, expressed in the Fleiss' kappa, within clinically relevant thrombosis categories was 0.626 for Grade 2 and 0.781 for Grade 3 venous thrombosis.Conclusions: : Although not perfect, we believe that implementation of the CPAT system would improve current documentation on PAT. However, it is questionable whether identification of a small Grade 1 thrombosis would be relevant in clinical practice.Furthermore, a good quality CT scan, including adequate phasing, is essential to accurately identify potential thrombus and extend after pancreas transplantation.Cardiovascular Aspects of Radiolog

Phase Transformation for the Large-Scale Synthesis and Assembly via Welding of Metal Silicide Nanowires for Thermoelectric Applications

Solid-state thermoelectrics that convert thermal energy into electricity have the potential to increase the efficiencies of existing process and systems (e.g., automobiles). The large-scale deployment of thermoelectrics for terrestrial use requires the following: a) enhancing their efficiencies beyond that are currently possible, and b) their fabrication from non-toxic, inexpensive, earth-abundant elements. Recent studies have determined that nanostructuring of earth-abundant materials, such as magnesium silicide (Mg2Si), is a possible pathway for accomplishing this task. Contextually, the overall aim of this dissertation is to engineer highly efficient Mg2Si nanowire-based thermoelectrics. This was achieved through the design of strategies for (1) the large-scale synthesis of a form of nanostructured Mg2Si, nanowires of Mg2Si, and (2) the interface-engineered assembly of the synthesized nanowires into welded nanowire networks that do not have any insulating MgO at the nanowire interfaces. Together, these strategies are intended to offer the ability to control thermal and electrical transport through Mg2Si. For the large-scale synthesis of Mg2Si nanowires, a phase transformation strategy that converts pre-synthesized silicon nanowires into Mg2Si nanowires was engineered. Experimentation performed indicated that 20 to 300 nm-thick, 5 to 20 µm-long silicon nanowires obtained by electroless etching can be phase transformed into polycrystalline Mg2Si nanowires by reacting them with magnesium supplied via the vapor phase. To prevent the formation of multiple nuclei within each silicon nanowire during the phase transformation process and the formation of polycrystalline Mg2Si nanowires, a solid-state phase transformation process was engineered. Here, the solid-state reaction of sharp-tipped silicon nanowires with magnesium foils was employed for obtaining single-crystalline Mg2Si nanowires. To assemble the nanowires, the solid-state phase transformation strategy was extended and the phase transformation of silica nanoparticle coated silicon nanowires was employed. This procedure led to the formation of welded Mg2Si nanowire networks, where both the nanowires and the bridges connecting the nanowires were composed of Mg2Si. Thermoelectric performance evaluation of these networks and microcrystalline Mg2Si devices proved our hypothesis and indicated a 2-fold increase in the power factors. The high power factor of 0.972 x 10^-3 Wm^-1K^-2 achieved at 875 K is twice that reported in the literature for undoped Mg2Si

Pancreas Transplantation With Grafts From Donors Deceased After Circulatory Death: 5 Years Single-Center Experience

Transplant surger

A Self-management Approach for Dietary Sodium Restriction in Patients With CKD:A Randomized Controlled Trial

Health and self-regulatio