IgG N-glycans are associated with prevalent and incident complications of type 2 diabetes.

AIMS/HYPOTHESIS: Inflammation is important in the development of type 2 diabetes complications. The N-glycosylation of IgG influences its role in inflammation. To date, the association of plasma IgG N-glycosylation with type 2 diabetes complications has not been extensively investigated. We hypothesised that N-glycosylation of IgG may be related to the development of complications of type 2 diabetes. METHODS: In three independent type 2 diabetes cohorts, plasma IgG N-glycosylation was measured using ultra performance liquid chromatography (DiaGene n = 1815, GenodiabMar n = 640) and mass spectrometry (Hoorn Diabetes Care Study n = 1266). We investigated the associations of IgG N-glycosylation (fucosylation, galactosylation, sialylation and bisection) with incident and prevalent nephropathy, retinopathy and macrovascular disease using Cox- and logistic regression, followed by meta-analyses. The models were adjusted for age and sex and additionally for clinical risk factors. RESULTS: IgG galactosylation was negatively associated with prevalent and incident nephropathy and macrovascular disease after adjustment for clinical risk factors. Sialylation was negatively associated with incident diabetic nephropathy after adjustment for clinical risk factors. For incident retinopathy, similar associations were found for galactosylation, adjusted for age and sex. CONCLUSIONS: We showed that IgG N-glycosylation, particularly galactosylation and to a lesser extent sialylation, is associated with a higher prevalence and future development of macro- and microvascular complications of diabetes. These findings indicate the predictive potential of IgG N-glycosylation in diabetes complications and should be analysed further in additional large cohorts to obtain the power to solidify these conclusions.

Anti-myeloperoxidase and proteinase 3 antibodies for nephritis flare prediction in anti-neutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: The value of myeloperoxidase (MPO) and proteinase 3 (PR3) antibody titres in the assessment of renal disease activity and flare prediction in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is not well known. METHODS: We performed a retrospective study including 113 AVV patients with renal biopsy-proven pauci-immune necrotizing glomerulonephritis from seven Spanish hospitals. The main inclusion criteria were assessment of MPO antibodies using multiplex flow immunoassay and PR3 antibody measurements using immunoassay chemiluminescence with an identical range of values for all participating centres. RESULTS: Serum MPO antibodies 3 ± 1.2 months before relapse were higher in patients who relapsed [19.2 ± 12.2 versus 3.2 ± 5.1 antibody index (AI); P < 0.001]. The discrimination value of MPO antibodies 3 months before renal relapse had an area under the receiver operating characteristics curve (AUC) of 0.82 [95% confidence interval (CI) 0.73-0.92; P < 0.001]. ΔMPO antibodies (change in antibodies titration 6 months before relapse) were higher in patients who relapsed (8.3 ± 12 versus 0.9 ± 3.1 AI; P = 0.001). The discrimination value of ΔMPO had an AUC of 0.76 (95% CI 0.63-0.88; P < 0.001). The positive predictive value of renal relapse in PR3 patients is 100% and the negative predictive value of renal relapse in patients with PR3-positive titres is 57.1%. Serum PR3 antibodies were higher in patients who relapsed 2.8 ± 1.4 months before relapse (58.6 ± 24.6 versus 2.0 ± 0.6 AI; P < 0.001). CONCLUSIONS: MPO level monitoring using multiplex flow immunoassay and PR3 measurements using immunoassay chemiluminescence are useful and sensitive tools for the prediction of renal relapse in the follow-up of AAV patients with renal disease and relevant surrogate markers of renal disease activity.

Composition of the immunoglobulin G glycome associates with the severity of COVID-19.

A large variation in the severity of disease symptoms is one of the key open questions in coronavirus disease 2019 (COVID-19) pandemics. The fact that only a small subset of people infected with severe acute respiratory syndrome coronavirus 2 develops severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the immunoglobulin G (IgG) glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of interindividual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing.

ctDNA from body fluids is an adequate source for EGFR biomarker testing in advanced lung adenocarcinoma.

OBJECTIVES: Epidermal growth factor receptor (EGFR) biomarker testing using blood-based liquid biopsies remains challenging due to the low concentration of circulating tumor DNA (ctDNA) in certain plasma samples. The aim of this study is to evaluate the usefulness for EGFR biomarker testing of ctDNA from pleural effusions, cerebrospinal fluids, ascites and pericardial effusions obtained during the clinical management of lung adenocarcinoma patients. METHODS: For comparison purposes, 23 paired plasma and body fluid samples were collected from 17 patients with EGFR-positive lung adenocarcinoma. After circulating free DNA (cfDNA) isolation, samples were evaluated for the initial EGFR-sensitizing mutation and the p.T790M resistance mutation by array-based digital PCR (dPCR). RESULTS: Body fluids had more cfDNA than plasma samples (1.90 vs. 0.36 ng/µL; p=0.0130), and more samples tested positive for EGFR mutations (21 vs. 16 samples), with a total of 28 vs. 22 variants detected. Furthermore, mutant allele frequencies (MAFs) observed in body fluids were significantly higher than those assessed in the paired plasma samples for EGFR-sensitizing mutations (median MAFs = 15.8 vs. 0.8%; p=0.0004) as well as for the p.T790M resistance mutation (median MAFs = 8.69 vs. 0.16%; p=0.0390). Importantly, two patients who had progressed on first-generation EGFR-tyrosine kinase inhibitors with a dubious result for p.T790M plasma (MAFs = 0.11%) had an indisputably positive result in their respective body fluid samples (MAFs = 10.25 and 9.66%). CONCLUSIONS: ctDNA derived from body fluids is an informative source for EGFR biomarker testing, with greater sensitivity than plasma samples.

Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes.

Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of Adam17 in endothelial cells and to analyse the effects on different renal structures. Endothelial Adam17 knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Results showed that obese mice presented higher blood glucose levels, dysregulated glucose homeostasis, and higher body weight compared to control mice. In addition, obese wild-type mice presented an increased albumin-to-creatinine ratio; greater glomerular size and mesangial matrix expansion; and tubular fibrosis with increased galectin-3 expression. Adam17 deletion decreased the albumin-to-creatinine ratio, glomerular mesangial index, and tubular galectin-3 expression. Moreover, macrophage infiltration in the glomeruli of obese Adam17 knockout mice was reduced as compared to obese wild-type mice. In conclusion, the expression of ADAM17 in endothelial cells impacted renal inflammation, modulating the renal function and histology in an obese pre-diabetic mouse model.

Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes.

Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.

COVID-19 in elderly kidney transplant recipients.

The SARS-Cov-2 infection disease (COVID-19) pandemic has posed at risk the kidney transplant (KT) population, particularly the elderly recipients. From March 12 until April 4, 2020, we diagnosed COVID-19 in 16 of our 324 KT patients aged ≥65 years old (4.9%). Many of them had had contact with healthcare facilities in the month prior to infection. Median time of symptom onset to admission was 7 days. All presented with fever and all but one with pneumonia. Up to 33% showed renal graft dysfunction. At infection diagnosis, mTOR inhibitors or mycophenolate were withdrawn. Tacrolimus was withdrawn in 70%. The main treatment combination was hydroxychloroquine and azithromycin. A subset of patients was treated with anti-retroviral and tocilizumab. Short-term fatality rate was 50% at a median time since admission of 3 days. Those who died were more frequently obese, frail, and had underlying heart disease. Although a higher respiratory rate was observed at admission in nonsurvivors, symptoms at presentation were similar between both groups. Patients who died were more anemic, lymphopenic, and showed higher D-dimer, C-reactive protein, and IL-6 at their first tests. COVID-19 is frequent among the elderly KT population and associates a very early and high mortality rate.

Atherosclerosis in Chronic Kidney Disease: More, Less, or Just Different?

Patients with chronic kidney disease (CKD) are at an increased risk of premature mortality, mainly from cardiovascular causes. The association between CKD on hemodialysis and accelerated atherosclerosis was described >40 years ago. However, more recently, it has been suggested that the increase in atherosclerosis risk is actually observed in early CKD stages, remaining stable thereafter. In this regard, interventions targeting the pathogenesis of atherosclerosis, such as statins, successful in the general population, have failed to benefit patients with very advanced CKD. This raises the issue of the relative contribution of atherosclerosis versus other forms of cardiovascular injury such as arteriosclerosis or myocardial injury to the increased cardiovascular risk in CKD. In this review, the pathophysiogical contributors to atherosclerosis in CKD that are shared with the general population, or specific to CKD, are discussed. The NEFRONA study (Observatorio Nacional de Atherosclerosis en NEFrologia) prospectively assessed the prevalence and progression of subclinical atherosclerosis (plaque in vascular ultrasound), confirming an increased prevalence of atherosclerosis in patients with moderate CKD. However, the adjusted odds ratio for subclinical atherosclerosis increased with CKD stage, suggesting a contribution of CKD itself to subclinical atherosclerosis. Progression of atherosclerosis was closely related to CKD progression as well as to the baseline presence of atheroma plaque, and to higher phosphate, uric acid, and ferritin and lower 25(OH) vitamin D levels. These insights may help design future clinical trials of stratified personalized medicine targeting atherosclerosis in patients with CKD. Future primary prevention trials should enroll patients with evidence of subclinical atherosclerosis and should provide a comprehensive control of all known risk factors in addition to testing any additional intervention or placebo.

Next-generation sequencing for tumor mutation quantification using liquid biopsies.

Background Non-small cell lung cancer (NSCLC) patients benefit from targeted therapies both in first- and second-line treatment. Nevertheless, molecular profiling of lung cancer tumors after first disease progression is seldom performed. The analysis of circulating tumor DNA (ctDNA) enables not only non-invasive biomarker testing but also monitoring tumor response to treatment. Digital PCR (dPCR), although a robust approach, only enables the analysis of a limited number of mutations. Next-generation sequencing (NGS), on the other hand, enables the analysis of significantly greater numbers of mutations. Methods A total of 54 circulating free DNA (cfDNA) samples from 52 NSCLC patients and two healthy donors were analyzed by NGS using the Oncomine™ Lung cfDNA Assay kit and dPCR. Results Lin's concordance correlation coefficient and Pearson's correlation coefficient between mutant allele frequencies (MAFs) assessed by NGS and dPCR revealed a positive and linear relationship between the two data sets (ρc = 0.986; 95% confidence interval [CI] = 0.975-0.991; r = 0.987; p < 0.0001, respectively), indicating an excellent concordance between both measurements. Similarly, the agreement between NGS and dPCR for the detection of the resistance mutation p.T790M was almost perfect (K = 0.81; 95% CI = 0.62-0.99), with an excellent correlation in terms of MAFs (ρc = 0.991; 95% CI = 0.981-0.992 and Pearson's r = 0.998; p < 0.0001). Importantly, cfDNA sequencing was successful using as low as 10 ng cfDNA input. Conclusions MAFs assessed by NGS were highly correlated with MAFs assessed by dPCR, demonstrating that NGS is a robust technique for ctDNA quantification using clinical samples, thereby allowing for dynamic genomic surveillance in the era of precision medicine.

Risk Factors Associated with Major Complications after Ultrasound-Guided Percutaneous Renal Biopsy of Native Kidneys.

INTRODUCTION: Percutaneous renal biopsy (PRB) of native kidneys is an important tool for diagnosis and management of renal disease. In this study, we analyzed the success, safety, and risk complications of PRB in our center. METHODS: A retrospective review of ultrasound-guided PRB done at our institution from January 1998 to December 2017 was performed. Clinical and laboratory data were collected for 661 PRBs. Statistical analysis was performed using the Mann-Whitney U test for continuous variable and chi-square test for categorical variables. Multivariate analysis using logistic regression was performed to assess factors associated with increased risk of complications after PRB. RESULTS: The median age was 56 (42-68) years old, the majority were male (64%) and white (82%). Ten glomeruli were present in 63.5% of PRBs. Overall, the rate of complications was 16.6%, where 15.1% of them were minor complications and 1.5% were major complications. Perinephritic hematoma accounted for the minor complication that occurred most frequently, whereas the need of a blood transfusion was the prevalent for major complications. By multivariate analysis, increased activated partial thromboplastin time (aPTT; OR 1.11, 95% CI 1.035-1.180) and prebiopsy lower hemoglobin (Hgb; OR 1.61, 95% CI 1.086-2.304) were identified as independent risk factors for major complications. In addition, older patients (OR 1.057, 95% CI 1.001-1.117) were identified as an independent risk factor for blood transfusion requirement. CONCLUSION: The current risk of complications after native PRB is low. Major complications are most common in case of increased aPTT and decreased Hgb baseline level.

COVID-19 in Grade 4-5 Chronic Kidney Disease Patients.

INTRODUCTION: Chronic kidney disease (CKD) increases the risk of mortality during coronavirus disease 2019 (COVID-19) episodes, and some reports have underlined the high incidence and severity of this infection in dialysis patients. Information on COVID-19 in nondialysis CKD patients is not available yet. CASE REPORTS: Here we present 7 patients with grade 4-5 CKD who developed symptomatic COVID-19; they comprise 2.6% of our 267 advanced CKD patients. The estimated GFR was between 12 and 20 mL/min during the month prior to COVID-19. The 3 major symptoms were fever, cough, and dyspnea, and 5 patients showed bilateral pneumonia. Hydroxychloroquine, azithromycin, ceftriaxone, and steroids were the most frequently prescribed drugs. Two patients needed noninvasive mechanical ventilation. All patients showed minimal to moderate kidney function deterioration during admission, with an eGFR decline below 5 mL/min in 6 cases. No patient required acute dialysis. Six patients were discharged alive and remained dialysis free athe t the time of reporting, and one 76-year-old patient died. CONCLUSIONS: COVID-19 affects grade 4-5 CKD patients, but prognosis may be acceptable if prompt supportive measures are applied. These findings should be confirmed in larger cohorts, and further observations will be needed to understand the full spectrum of clinical features and the optimal approach to COVID-19 in patients with advanced CKD.

Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease.

Male sex predisposes to many kidney diseases. Considering that androgens exert deleterious effects in a variety of cell types within the kidney, we hypothesized that dihydrotestosterone (DHT) would alter the biology of the renal tubular cell by inducing changes in the proteome. We employed stable isotope labeling with amino acids (SILAC) in an indirect spike-in fashion to accurately quantify the proteome in DHT- and 17ß-estradiol (EST)-treated human proximal tubular epithelial cells (PTEC). Of the 5043 quantified proteins, 76 were differentially regulated. Biological processes related to energy metabolism were significantly enriched among DHT-regulated proteins. SILAC ratios of 3 candidates representing glycolysis, N-acetylglucosamine metabolism and fatty acid ß-oxidation, namely glucose-6-phosphate isomerase (GPI), glucosamine-6-phosphate-N-acetyltransferase 1 (GNPNAT1), and mitochondrial trifunctional protein subunit alpha (HADHA), were verified in vitro. In vivo, renal GPI and HADHA protein expression was significantly increased in males. Furthermore, male sex was associated with significantly higher GPI, GNPNAT1, and HADHA kidney protein expression in two different murine models of diabetes. Enrichment analysis revealed a link between our DHT-regulated proteins and oxidative stress within the diabetic kidney. This finding was validated in vivo, as we observed increased oxidative stress levels in control and diabetic male kidneys, compared with females. This in depth quantitative proteomics study of human primary PTEC response to sex hormone administration suggests that male sex hormone stimulation results in perturbed energy metabolism in kidney cells, and that this perturbation results in increased oxidative stress in the renal cortex. The proteome-level changes associated with androgens may play a crucial role in the development of structural and functional changes in the diseased kidney. With our findings, we propose a possible link between diabetic and non-diabetic kidney disease progression and male sex hormone levels. Data are available via ProteomeXchange (https://www.ebi.ac.uk/pride/archive/) with identifier PXD003811.

Impact of Recurrent Acute Kidney Injury on Patient Outcomes.

BACKGROUND/AIMS: Recurrent acute kidney injury (AKI) is common among patients after a first hospitalized AKI. However, little is known about the prognosis of recurrent AKI episodes in chronic kidney disease (CKD) development, cardiovascular events and mortality. METHODS: A retrospective study included patients admitted to our Hospital from 2000 to 2010. AKI was defined according to the Acute Dialysis Quality Initiative criteria. In the follow-up period after the first AKI episode, clinical, laboratory data and the number of repeated AKI episodes, etiology and severity were recorded. RESULTS: Among the 359 AKI survivor patients included, 250 new AKI episodes were observed in 122 patients (34%). Variables independently associated to new episodes were: type 2 DM [OR 1.2, 95%CI 1.2-3.8, p=0.001], ischemic heart disease [OR 1.9; 95%CI 1.1-3.6, p=0.012], and SCr at the first AKI event>2,6 mg/dl [OR 1.2; 95%CI 1.03-1.42, p=0.02]. Development of CKD during four years follow-up was more frequent in patients with recurrent AKI, HR [2.2 (95% CI: 1.09-4.3, p=0.003)] and 44% of recurrent AKI patients who developed CKD occurred during the first 6 months after the initial event. Cardiovascular events were more frequent among patients with recurrent AKI patients than in those with one AKI episode (47.2% vs 24%, p=0.001). Mortality at 4 years was higher in the patient subgroup with several episodes of AKI as compared with those with a single episode [HR: 4.5 (95% CI 2.7-7.5) p<0.001]. CONCLUSION: Episodes of recurrent AKI have a high potential to be associated with relevant complications such as cardiovascular events, mortality and CKD development.

Membrane Attack Complex and Factor H in Humans with Acute Kidney Injury.

BACKGROUND AND AIMS: Complement system seems to play an important role in the pathogenesis of Acute Kidney Injury (AKI). The aim of this study was to investigate the role of complement system in the pathogenesis of human AKI. For this purpose, we studied Membrane Attack Complex (MAC) and factor H in plasma and kidney tissue in AKI. METHODS: Plasmatic concentrations of MAC and Factor H were studied in patients with hospital-acquired AKI and their respective controls. MAC and Factor H expression and localization within the kidney were studied by immunohistochemistry in kidney tissue samples from autopsies. Demographical, past medical, and laboratory data in patients on admission and 3 years after discharge were recorded. RESULTS: Plasmatic MAC concentrations were significantly higher in AKI-patients (5848±3604 vs 3703±1483 mAU/mL, p< 0.01), mainly in the severe cases, as measured by the need of renal replacement therapy, non-recovery of renal function, RIFLE classification and CKD development. MAC deposition was observed in tubular epithelial cell basal membranes, showing a larger number of tubules with MAC deposition, larger perimeter of affected tubules and greater intensity of MAC immunostaining in AKI patients. Factor H concentrations were higher in AKI patients (0.86±0.05 vs 0.60±0.04 mg/mL, p=0.007), showing a strong positive association with plasmatic MAC (r=0.7, p< 0.01)). Factor H immunostaining showed a tubular cytoplasmic pattern, with significant variations in the staining intensity, associated with the severity of histologic damage. CONCLUSION: Our data confirm that complement system is involved in human AKI, through the lytic action of MAC in tubular epithelial cells. These results suggest that complement system activation in AKI could be related with CKD development.

Treatment for hepatitis C virus-associated mixed cryoglobulinaemia.

BACKGROUND: Hepatitis C virus (HCV)-associated mixed cryoglobulinaemia is the manifestation of an inflammation of small and medium-sized vessels produced by a pathogenic IgM with rheumatoid factor activity generated by an expansion of B-cells. The immune complexes formed precipitate mainly in the skin, joints, kidneys or peripheral nerve fibres. Current therapeutic approaches are aimed at elimination of HCV infection, removal of cryoglobulins and also of the B-cell clonal expansions. The optimal treatment for it has not been established. OBJECTIVES: This review aims to look at the benefits and harms of the currently available treatment options to treat the HCV-associated mixed cryoglobulinaemia with active manifestations of vasculitis (cutaneous or glomerulonephritis). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 30 November 2017 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs looking at interventions directed at treatment of HCV-associated cryoglobulinaemic vasculitis (immunosuppressive medications and plasma exchange therapy) have been included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the retrieved titles and abstracts. Authors of included studies were contacted to obtain missing information. Statistical analyses were performed using random effects models and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI). The planned primary outcomes were kidney disease, skin vasculitis, musculoskeletal symptoms, peripheral joint arthralgia, peripheral neuropathies, liver involvement, interstitial lung involvement, widespread vasculitis and death. Other planned outcomes were: therapy duration, laboratory findings, adverse effects, antiviral therapy failure, B-cell lymphoma, endocrine disorders and costs of treatment. MAIN RESULTS: Ten studies were included in the review (394 participants). None of them evaluated direct-acting antivirals. Seven studies were single-centre studies and three were multicentre. The duration of the studies varied from six to 36 months. The risk of bias was generally unclear or low. Three different interventions were examined: use of rituximab (3 studies, 118 participants); interferon (IFN) (IFN compared to other strategies (5 studies, 223 participants); six IFN months versus one year (1 study, 36 participants), and immunoadsorption apheresis versus only immunosuppressive therapy (1 study, 17 participants).The use of rituximab may slightly improve skin vasculitis (2 studies, 78 participants: RR 0.57, 95% CI 0.28 to 1.16; moderate certainty evidence) and made little of no difference to kidney disease (moderate certainty evidence). In terms of laboratory data, the effect of rituximab was uncertain for cryocrit (MD -2.01%, 95% CI -10.29% to 6.27%, low certainty evidence) and HCV replication. Rituximab may slightly increase infusion reactions compared to immunosuppressive medication (3 studies, 118 participants: RR 4.33, 95%CI 0.76 to 24.75, moderate certainty evidence) however discontinuations of the treatment due to adverse reactions were similar (3 studies, 118 participants: RR 0.97, 95% CI 0.22 to 4.36, moderate certainty evidence).Effects of lFN on clinical symptoms were evaluated only in narrative results. When laboratory parameters were assessed, IFN made little or no difference in levels of alanine transaminase (ALT) at six months (2 studies, 39 participants: MD -5.89 UI/L, 95%CI -55.77 to 43.99); rheumatoid factor activity at six months (1 study, 13 participants: MD 97.00 UI/mL, 95%CI -187.37 to 381.37), or C4 levels at 18 months (2 studies, 49 participants: MD -0.04 mg/dL, 95%CI -2.74 to 2.67). On the other hand, at 18 months IFN may probably decrease ALT (2 studies, 39 participants: MD -28.28 UI/L, 95%CI -48.03 to -8.54) and Ig M (-595.75 mg/dL, 95%CI -877.2 to -314.3), but all with low certainty evidence. One study reported infusion reactions may be higher in IFN group compared to immunosuppressive therapy (RR 27.82, 95%CI 1.72 to 449.18), and IFN may lead to higher discontinuations of the treatment due to adverse reactions (4 studies, 148 participants: RR 2.32, 95%CI 0.91 to 5.90) with low certainty evidence. Interferon therapy probably improved skin vasculitis (3 studies, 95 participants: RR 0.60, 95% CI 0.36 to 1.00) and proteinuria (2 studies, 49 participants: MD -1.98 g/24 h, 95% CI -2.89 to -1.07), without changing serum creatinine at 18 months (2 studies, 49 participants: MD -30.32 µmol/L, 95%CI -80.59 to 19.95).Six months versus one year treatment with IFN resulted in differences terms of the maintenance of the response, 89% of patients in the six months group presented a relapse and only 11% maintained a long-term response at one year, while in the one year group only 78% relapsed and long-term response was observed in 22%. The one-year therapy was linked to a higher number of side-effects (severe enough to cause the discontinuation of treatment in two cases) than the six-month schedule.One study reported immunoadsorption apheresis had uncertain effects on skin vasculitis (RR 0.44, 95% CI 0.05 to 4.02), peripheral neuropathies (RR 2.70, 95%CI 0.13 to 58.24), and peripheral joint arthralgia (RR 2.70, 95%CI 0.13 to 58.24), cryocrit (MD 0.01%, 95%CI -1.86 to 1.88) at six months, and no infusion reactions were reported. However when clinical scores were evaluated, they reported changes were more favourable in immunoadsorption apheresis with higher remission of severe clinical complications (80% versus 33%, P = 0.05) compared to immunosuppressive treatment alone.In terms of death, it was not possible to present a pooled intervention effect estimate because most of the studies reported no deaths, or did not report death as an outcome. AUTHORS' CONCLUSIONS: To treat HCV-associated mixed cryoglobulinaemia, it may be beneficial to eliminate HCV infection by using antiviral treatment and to stop the immune response by using rituximab. For skin vasculitis and for some laboratory findings, it may be appropriate to combine antiviral treatment with deletion of B-cell clonal expansions by using of rituximab. The applicability of evidence reviewed here is limited by the absence of any studies with direct-acting antivirals, which are urgently needed to guide therapy.

Short- and long-term outcomes after non-severe acute kidney injury.

BACKGROUND: Severe acute kidney injury (AKI) is associated with chronic kidney disease (CKD), cardiovascular events and increased mortality. However, little is known about the prognosis in hospitalized population suffering from non-severe AKI episodes. The aim of this study is to determine the impact of non-severe AKI episodes in cardiovascular events, mortality and CKD, on short and long term. METHODS: Retrospective cohort study to 360 patients who met the criteria for diagnosis of AKI according ADQI guidelines with full recovery of renal function after the AKI episode, admitted between January 2000 and December 2010 in our hospital. Follow-up was 4 years after the diagnosis of AKI. Covariates included demographic variables, baseline creatinine and diagnosis of comorbidities. RESULTS: 360 AKI survivor patients were included. Twenty five of them (6.7%) had developed CKD after 1-year follow-up. Hypertension (OR 1.62; 95% CI 1.2-2.6, p < 0.05) and serum creatinine >2.6 mg/dL in AKI (OR 1.7; 95% CI 1.2-3.7, p < 0.05) were independent risk factors. After 4-year follow-up, 40 patients (18.3%) had developed CKD; age >66 years was an independent risk factor (OR 1.03, 95% CI 1.03-1.06, p < 0.05). Mortality rate at 4 years was 25.3% and was significantly higher in CKD patients (OR 4.3, 95% CI 1.13-4.90, p < 0.05) and patients >66 years (OR 1.12, 95% CI 1.02-1.06, p < 0.05). The incidence of cardiovascular events also was higher in CKD patients than in non-CKD patients (62.7 vs. 21.7%, p < 0.05). CONCLUSION: Even after fully recovered non-severe AKI episodes, some patients develop CKD and those have an increase in the incidence of cardiovascular events and long-term mortality.

Effects of statins on the immunoglobulin G glycome.

BACKGROUND: Statins are among the most widely prescribed medications worldwide and usually many individuals involved in clinical and population studies are on statin therapy. Immunoglobulin G (IgG) glycosylation has been associated with numerous cardiometabolic risk factors. METHODS: The aim of this study was to investigate the possible association of statin use with N-glycosylation of IgG. The association was analyzed in two large population cohorts (TwinsUK and KORA) using hydrophilic interaction liquid chromatography (HILIC-UPLC) in the TwinsUK cohort and reverse phase liquid chromatography coupled with electrospray mass spectrometry (LC-ESI-MS) in the KORA cohort. Afterwards we investigated the same association for only one statin (rosuvastatin) in a subset of individuals from the randomized double-blind placebo-controlled JUPITER study using LC-ESI-MS for IgG glycome and HILIC-UPLC for total plasma N-glycome. RESULTS: In the TwinsUK population, the use of statins was associated with higher levels of core-fucosylated biantennary glycan structure with bisecting N-acetylglucosamine (FA2B) and lower levels of core-fucosylated biantennary digalactosylated monosialylated glycan structure (FA2G2S1). The association between statin use and FA2B was replicated in the KORA cohort. In the JUPITER trial we found no statistically significant differences between the randomly allocated placebo and rosuvastatin groups. CONCLUSIONS: In the TwinsUK and KORA cohorts, statin use was associated with a small increase of pro-inflammatory IgG glycan, although this finding was not confirmed in a subset of participants from the JUPITER trial. GENERAL SIGNIFICANCE: Even if the association between IgG N-glycome and statins exists, it is not large enough to pose a problem for glycomic studies.

Glycosylation Profile of IgG in Moderate Kidney Dysfunction.

Glycans constitute the most abundant and diverse form of the post-translational modifications, and animal studies have suggested the involvement of IgG glycosylation in mechanisms of renal damage. Here, we explored the associations between IgG glycans and renal function in 3274 individuals from the TwinsUK registry. We analyzed the correlation between renal function measured as eGFR and 76 N-glycan traits using linear regressions adjusted for covariates and multiple testing in the larger population. We replicated our results in 31 monozygotic twin pairs discordant for renal function. Results from both analyses were then meta-analyzed. Fourteen glycan traits were associated with renal function in the discovery sample (P<6.5×10(-4)) and remained significant after validation. Those glycan traits belong to three main glycosylation features: galactosylation, sialylation, and level of bisecting N-acetylglucosamine of the IgG glycans. These results show the role of IgG glycosylation in kidney function and provide novel insight into the pathophysiology of CKD and potential diagnostic and therapeutic targets.

A Metabolome-Wide Association Study of Kidney Function and Disease in the General Population.

Small molecules are extensively metabolized and cleared by the kidney. Changes in serum metabolite concentrations may result from impaired kidney function and can be used to estimate filtration (e.g., the established marker creatinine) or may precede and potentially contribute to CKD development. Here, we applied a nontargeted metabolomics approach using gas and liquid chromatography coupled to mass spectrometry to quantify 493 small molecules in human serum. The associations of these molecules with GFR estimated on the basis of creatinine (eGFRcr) and cystatin C levels were assessed in ≤1735 participants in the KORA F4 study, followed by replication in 1164 individuals in the TwinsUK registry. After correction for multiple testing, 54 replicated metabolites significantly associated with eGFRcr, and six of these showed pairwise correlation (r≥0.50) with established kidney function measures: C-mannosyltryptophan, pseudouridine, N-acetylalanine, erythronate, myo-inositol, and N-acetylcarnosine. Higher C-mannosyltryptophan, pseudouridine, and O-sulfo-L-tyrosine concentrations associated with incident CKD (eGFRcr <60 ml/min per 1.73 m(2)) in the KORA F4 study. In contrast with serum creatinine, C-mannosyltryptophan and pseudouridine concentrations showed little dependence on sex. Furthermore, correlation with measured GFR in 200 participants in the AASK study was 0.78 for both C-mannosyltryptophan and pseudouridine concentration, and highly significant associations of both metabolites with incident ESRD disappeared upon adjustment for measured GFR. Thus, these molecules may be alternative or complementary markers of kidney function. In conclusion, our study provides a comprehensive list of kidney function-associated metabolites and highlights potential novel filtration markers that may help to improve the estimation of GFR.

Characterization and rapid control of a vancomycin-resistant Enterococcus faecium (VREF) outbreak in a renal transplant unit in Spain: The environment matters.

OBJECTIVE: To describe a clonal outbreak due to vancomycin-resistant Enterococcus faecium (VREF) in the nephrology and renal transplant unit of a tertiary teaching hospital in Barcelona, Spain, and to highlight how active patient and environment surveillance cultures, as well as prompt and directed intervention strategies, mainly environmental, helped to successfully bring it under control. PATIENTS AND METHODS: A study was conducted on patients admitted to the nephrology ward with any culture positive for VREF over a 6-month period (August 2012-January 2013). Based on the identification of a clonal link between the isolates, weekly rectal screening using swabs was implemented for all patients, as well as environmental cultures and cleaning of medical equipment and the ward. VREF isolates were identified by MicroScan and confirmed by Etest. Bacterial identification was confirmed by MALDI-TOF MS. The presence of van genes, and esp and hyl virulence genes was determined using PCR. The clonal relationship between the isolates was studied first with DiversiLab (bioMérieux), and then by PFGE-Smal and MLST. A two-tier sequence of infection control measures was implemented. RESULTS: During the study period, VREF was isolated from 13 patients. All cases were colonized with no criteria for infection. VREF isolates were also extensively recovered from the environment and medical equipment. Isolates carried the vanA gene, and were multidrug-resistant, including high-level resistance (MIC >16mg/L) to vancomycin and teicoplanin. Molecular analysis showed that all VREF isolates belonged to sequence type 17 (ST17) carrying hyl virulence genes. After implementing infection control measures in a two-tier sequence, and reinforcing particularly environmental and medical equipment cleaning, no further cases were detected in the follow-up year. CONCLUSION: A clonal outbreak of VREF-ST17 involving only colonization is reported. The prompt implementation of aggressive infection control measures in patients and the environment was effective in controlling the outbreak and avoided the potential emergence of infection among patients.