Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy.

Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology. Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P < 0.05). Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted.

Rare genetic variants in Shiga toxin-associated haemolytic uraemic syndrome: genetic analysis prior to transplantation is essential.

We present a case of haemolytic uraemic syndrome (HUS) in a 16-year-old female with serological evidence of acute Escherichia coli O157:H7 infection. She progressed to established renal failure and received a deceased donor kidney transplant. Shiga toxin-associated HUS (STEC-HUS) does not recur following renal transplantation, but unexpectedly this patient did experience rapid and severe HUS recurrence. She responded to treatment with the terminal complement inhibitor eculizumab and subsequent genetic analysis revealed a rare variant in a complement gene. This highlights the importance of genetic analysis in patients with STEC-HUS prior to renal transplantation so that management can be individualized.

Inhibition of Escherichia coli O157:H7 and Clostridium sporogenes in spinach packaged in modified atmospheres after treatment combined with chlorine and lactic acid bacteria.

UNLABELLED: Implementation of modified atmospheric packaging (MAP) into retail produce is a less commonly practiced method due to differences among commodities and the potential growth of anaerobes. Pathogens including Escherichia coli O157:H7 have been responsible for spinach outbreaks across the United States. In this study, hurdles, including those currently used with produce safety, such as MAP and chlorine, were combined with lactic acid bacteria (LAB) to inhibit pathogens. Spinach was coinoculated with E. coli O157:H7 and Clostridium sporogenes, a surrogate for C. botulinum, and treated with water or a hurdle that included water, chlorine, and LAB. Spinach from treatments were packaged in air (traditional), oxygen (80% O2, 20% CO2), or nitrogen (80% N2, 20% CO2) and stored in a retail display case for 9 d at 4 to 7 °C. The hurdle inhibited E. coli O157:H7 and C. sporogenes compared to controls with reductions of 1.43 and 1.10 log (P < 0.05), respectively. The nitrogen atmosphere was outperformed by air and oxygen in the reduction of E. coli O157:H7 (P < 0.05) with a decrease of 0.26 and 0.15 logs. There were no significant differences among the 3 atmospheres on C. sporogenes survival. Relative to these hurdles, we also chose to evaluate the potential benefits of LAB in pathogen control. The survival of LAB in interventions demonstrates implementation of LAB into produce could control pathogens, without damaging produce or altering organoleptic properties. PRACTICAL APPLICATION: The goal of our work was to identify methods that could reduce food-borne pathogens in packaged spinach products. Using current industry techniques in combination with unique methods, such as the use of beneficial bacteria, our research identified whether harmful microorganisms could be eliminated. Our data demonstrate that specific packaging conditions with beneficial bacteria can help eliminate or reduce the survival of E. coli O157:H7 and C. sporogenes (a model for C. botulinum) in produce.

Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.

Nutritional screening in patients on hemodialysis: is subjective global assessment an appropriate tool?

OBJECTIVE: Malnutrition is common in patients with chronic renal failure and should be screened for systematically. Subjective global assessment (SGA) is frequently used, but it is time-consuming. The aim of this study was to assess the sensitivity of SGA as a screening tool for malnutrition compared with the measurement of body mass index (BMI) and serum albumin combined with a history of unintentional weight loss. DESIGN: This was a cross-sectional study. SETTING: The study was undertaken in two hospital hemodialysis units. PATIENTS AND INTERVENTION: A total of 141 patients on hemodialysis were studied. Nutritional assessment was undertaken with a seven-point SGA, measurement of height, weight and serum albumin, and a record of unintentional weight loss. OUTCOMES: Patients were considered to be at risk of malnutrition if any of the following three criteria were met: a serum albumin less than 35 g/L, a BMI less than 18.5, and unintentional weight loss of edema free weight greater than 10% in the past 6 months. A diagnosis of malnutrition was made if the SGA score was between 1 and 5. RESULTS: A total of 41 patients had either a serum albumin less than 35 g/L or a BMI less than 18.5 or unintentional weight loss of edema free weight of more than 10% in the past 6 months. Of these 41 patients, 29 had a serum albumin less than 35 g/L, 9 had a BMI less than 18.5, and 15 had unintentional loss of edema free weight greater than 10% in the past 6 months. Thirteen patients were judged by SGA to be mild to moderately malnourished. All 13 were identified by serum albumin, BMI, or weight loss. CONCLUSIONS: In this study, measurement of SGA did not diagnose malnutrition in any patients in whom this had not already been potentially identified by measurement of serum albumin, BMI, and a history of weight loss. SGA did not therefore increase the sensitivity of nutritional screening in this cohort.

Telomere shortening and haemodialysis.

BACKGROUND: Increased oxidative stress is a well described feature of haemodialysis (HD). This is secondary to an increase in the production of reactive oxygen species and impaired antioxidant mechanisms. Telomeres are the specialized ends of eukaryotic chromosomes and consist of tandemly repeated DNA sequences. Telomeres shorten with each cell division and it is well known that telomere length in peripheral blood mononuclear cells (PBMCs) decreases with age. Telomere shortening rate is increased by oxidative stress. In this study we have examined a possible relationship between oxidative stress and telomere shortening in haemodialysis. METHODS: 20 control subjects, 20 non-diabetic and 18 diabetic HD patients were studied. Peripheral blood mononuclear cell telomere length, plasma malondialdehyde plus 4-hydroxyalkenal (MDA+4-HAE) concentration (a marker of oxidative stress) and C-reactive protein (CRP) concentration were measured. RESULTS: MDA+4-HAE and CRP were significantly higher in the HD patients (CRP, controls 7.5 +/- 1.5, HD patients 16.4 +/- 3.1 mg/l, p < 0.05). There was no difference in mean telomere length between the HD patients and controls (control, 8,283 +/- 179 bp; non-diabetic HD, 7,966 +/- 160 bp; diabetic HD, 8,033 +/- 197 bp) but age adjusted residual telomere length was inversely associated with the length of time on dialysis (r = -0.35, p = 0.03). CONCLUSION: These results suggest that length of time on dialysis is independently associated with increased telomere shortening in HD patients. We hypothesise that this reflects cumulative DNA exposure to oxidative stress.