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Fibrinogen-like 2 (FGL2) was recently found to be associated with fibrosis in a mouse model of kidney damage and was proposed as a potential therapeutic target in chronic kidney disease (CKD). We assessed the association of renal FGL2 mRNA expression with the disease outcome in two independent CKD cohorts (NEPTUNE and Innsbruck CKD cohort) using Kaplan Meier survival analysis. The regulation of FGL2 in kidney biopsies of CKD patients as compared to healthy controls was further assessed in 13 human CKD transcriptomics datasets. The FGL2 protein expression in human renal tissue sections was determined via immunohistochemistry. The regulators of FGL2 mRNA expression in renal tissue were identified in the co-expression and upstream regulator analysis of FGL2-positive renal cells via the use of single-cell RNA sequencing data from the kidney precision medicine project (KPMP). Higher renal FGL2 mRNA expression was positively associated with kidney fibrosis and negatively associated with eGFR. Renal FGL2 mRNA expression was upregulated in CKD as compared with healthy controls and associated with CKD progression in the Innsbruck CKD cohort (p-value = 0.0036) and NEPTUNE cohort (p-value = 0.0048). The highest abundance of FGL2 protein in renal tissue was detected in the thick ascending limb of the loop of Henle and macula densa, proximal tubular cells, as well as in glomerular endothelial cells. The upstream regulator analysis identified TNF, IL1B, IFNG, NFKB1, and SP1 as factors potentially inducing FGL2-co-expressed genes, whereas factors counterbalancing FGL2-co-expressed genes included GLI1, HNF1B, or PPARGC1A. In conclusion, renal FGL2 mRNA expression is elevated in human CKD, and higher FGL2 levels are associated with fibrosis and worse outcomes. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a systemic inflammatory disease that is characterized by non-caseating epithelioid-cell granulomas upon histology. However, similar histological findings may also be seen with certain infections. Thus, differentiation from infection is pivotal to ensure appropriate treatment. Here, we present a case of a disseminated infection with Mycobacterium genavense owing to an interleukin 12 receptor subunit beta 1 (IL-12Rβ1) associated immunodeficiency in a previously healthy female who was initially misdiagnosed with sarcoidosis. M. genavense is a nontuberculous mycobacterium which can cause lymphadenopathy, gastrointestinal and bone marrow infiltration in immunocompromised patients. With this case report we aim to highlight that an infection with M. genavense on the ground of a genetic defect of mycobacterial immune control may represent a rare differential diagnosis of sarcoidosis.Case Presentation: A 31-year-old female was referred to our hospital with progressive lymphadenopathy, hepatosplenomegaly, pancytopenia and systemic inflammation. She had previously been evaluated for generalized lymphadenopathy in another hospital. At that time, lymph node biopsies had revealed sarcoid-like lesions and a systemic corticosteroid treatment was initiated based on a putative diagnosis of sarcoidosis. When her condition worsened, she was transferred to our university clinic, where the diagnosis of disseminated M. genavense infection owing to an inborn interferonopathy was made. Her family history revealed that her brother had also suffered from IL-12Rβ1 deficiency and had died from a systemic infection with M. genavense at the age of 21. The patient received antimycobacterial treatment combined with subcutaneous type I interferon, which eventually led to a gradual improvement over the next months.Conclusions: Differentiating between sarcoidosis and sarcoid-like lesions secondary to infections may be challenging, especially when pathogens are difficult to detect or not expected in an apparently immunocompetent patient. Patients with IL-12Rβ1-associated immunodeficiency may be asymptomatic until adulthood, and disseminated M. genavense infection on the grounds of an IL-12Rβ1-associated immunodeficiency may represent a rare differential diagnosis of sarcoidosis. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes and its complications represent a huge burden to public health. With this prospective, observational cohort study, we aimed to estimate and to compare the incidence rate (IR) of renal and cardiovascular outcomes and all-cause mortality in patients with type 2 diabetes in different European countries. Methods: The renal endpoint was a composite of a sustained decline in estimated GFR of at least 40%, a sustained increase in albuminuria of at least 30% including a transition in albuminuria class, progression to kidney failure with replacement therapy, or death from renal causes. The cardiovascular endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results: 3,131 participants from four European countries (Austria, Hungary, The Netherlands, and Scotland) with a median follow-up time of 4.4 years were included. IRs were adjusted for several risk factors including sex, age, estimated GFR, albuminuria, HbA1c, blood pressure, and duration of type 2 diabetes. Across countries, the adjusted IR for the renal endpoint was significantly higher in Hungary and Austria, and the adjusted IR for the cardiovascular endpoint was significantly higher in Scotland and Austria. All-cause mortality was significantly higher in Scotland compared to all other countries. Conclusion: Our findings show how the longitudinal outcome of patients with type 2 diabetes varies significantly across European countries even after accounting for the distribution of underlying risk factors. [ABSTRACT FROM AUTHOR]

Cardiovascular and renal complications are a major burden for individuals with type 2 diabetes mellitus (T2DM). Besides lifestyle interventions, current guidelines recommend combination drug therapy to prevent or delay the incidence and progression of comorbidities. However, non-adherence to pharmacotherapy is common in chronic conditions such as T2DM and a barrier to successful disease management. Numerous studies have associated medication non-adherence with worse outcome as well as higher health care costs. This narrative review provides (i) an overview on adherence measures used within and outside research settings, (ii) an estimate on the prevalence of non-adherence to antidiabetic and cardiovascular drugs in T2DM, and (iii) specifically focuses on the association of non-adherence to these drugs with renal and cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Background/Objectives: Anemia is a frequent multifactorial co-morbidity in end-stage kidney disease (ESKD) associated with morbidity and poor QoL. Apart from insufficient erythropoietin formation, iron deficiency (ID) contributes to anemia development. Identifying patients in need of iron supplementation with current ID definitions is difficult since no good biomarker is available to detect actual iron needs. Therefore, new diagnostic tools to guide therapy are needed. Methods: We performed a prospective cohort study analyzing tissue iron content with MRI-based R2*-relaxometry in 20 anemic ESKD patients and linked it with iron biomarkers in comparison to 20 otherwise healthy individuals. Results: ESKD patients had significantly higher liver (90.1 s−1 vs. 36.1 s−1, p < 0.001) and spleen R2* values (119.8 s−1 vs. 19.3 s−1, p < 0.001) compared to otherwise healthy individuals, while their pancreas and heart R2* values did not significantly differ. Out of the 20 ESKD patients, 17 had elevated spleen and 12 had elevated liver R2* values. KDIGO guidelines (focusing on serum iron parameters) would recommend iron supplementation in seven patients with elevated spleen and four patients with elevated liver R2* values. Conclusions: These findings highlight that liver and especially spleen iron concentrations are significantly higher in ESKD patients compared to controls. Tissue iron overload diverged from classical iron parameters suggesting need of iron supplementation. Measurement of MRI-guided tissue iron distribution might help guide treatment of anemic ESKD patients. [ABSTRACT FROM AUTHOR]

Mass spectral library annotation of liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS) data is a reliable approach for fast identification of organic contaminants and toxicants in complex environmental and biological matrices. While determining the exposure of humans or mammals, it is indispensable to include phase I and phase II metabolites (conjugates) along with the parent compounds, but often, tandem mass spectra for these are unavailable. In this study, we present and evaluate a strategy for annotating glucuronide conjugates in LC-HRMS/MS scans by applying a neutral loss search for detection, then truncating the spectra which we refer to as in silico deconjugation, and finally searching these against mass spectral libraries of the aglycones. The workflow was tested on a dataset of in vitro–generated glucuronides of reference standard mixtures and a dataset of 51 authentic urine samples collected from patients with known medication status, acquired on different instrumentations. A total number of 75 different glucuronidated molecular structures were identified by in silico deconjugation and spectral library annotation. We also identified specific molecular structures (sulfonamides, ether bonds, di-glucuronides), which resulted in slightly different fragmentation patterns between the glucuronide and the unconjugated compound. This led to a decreased spectral matching score and in some cases to a false-negative identification. Still, by applying this method, we revealed a reliable annotation of most common glucuronides, leading to a new strategy reducing the need for deconjugation steps or for recording many reference glucuronide spectra for screening approaches. [ABSTRACT FROM AUTHOR]

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis. [ABSTRACT FROM AUTHOR]

Studies reporting on biomarkers aiming to predict adverse renal outcomes in patients with type 2 diabetes and kidney disease (DKD) conventionally define a surrogate endpoint either as a percentage of decrease of eGFR (e.g. ≥ 30%) or an absolute decline (e.g. ≥ 5 ml/min/year). The application of those study results in clinical practise however relies on the assumption of a linear and intra-individually stable progression of DKD. We studied 860 patients of the PROVALID study and 178 of an independent population with a relatively preserved eGFR at baseline and at least 5 years of follow up. Individuals with a detrimental prognosis were identified using various thresholds of a percentage or absolute decline of eGFR after each year of follow up. Next, we determined how many of the patients met the same criteria at other points in time. Interindividual eGFR decline was highly variable but in addition intra-individual eGFR trajectories also were frequently non-linear. For example, of all subjects reaching an endpoint defined as a decrease of eGFR by ≥ 30% between baseline and 3 years of follow up, only 60.3 and 45.2% lost at least the same amount between baseline and year 4 or 5. The results were similar when only patients on stable medication or subpopulations based on baseline eGFR or albuminuria status were analyzed or an eGFR decline of ≥ 5 ml/min/1.73m2/year was used. Identification of reliable biomarkers predicting adverse prognosis is a strong clinical need given the large interindividual variability of DKD progression. However, it is conceptually challenging in early DKD because of non-linear intra-individual eGFR trajectories. As a result, the performance of a prognostic biomarker may be accurate after a specific time of follow-up in a single population only. [ABSTRACT FROM AUTHOR]

Background and objectives: Renal transplantation is the preferred form of renal replacement therapy for the majority of patients with end stage renal disease (ESRD). The Internet is a key tool for people seeking healthcare-related information. This current work explored the interest in kidney transplantation based on Internet search queries using Google TrendsTM. Design, setting, participants, and measurements: We performed a Google TrendsTM search with the search term "kidney transplantation" between 2004 (year of inception) and 2018. We retrieved and analyzed data on the worldwide trend as well as data from the United Network for Organ Sharing (UNOS), the Organización Nacional de Trasplantes (ONT), the Eurotransplant area, and the National Health Service (NHS) Transplant Register. Google TrendsTM indices were investigated and compared to the numbers of performed kidney transplants, which were extracted from the respective official websites of UNOS, ONT, Eurotransplant, and the NHS. Results: During an investigational period of 15 years, there was a significant decrease of the worldwide Google TrendsTM index from 76.3 to 25.4, corresponding to an absolute reduction of −50.9% and a relative reduction by −66.7%. The trend was even more pronounced for the UNOS area (−75.2%), while in the same time period the number of transplanted kidneys in the UNOS area increased by 21.9%. Events of public interest had an impact on the search queries in the year of occurrence, as shown by an increase in the Google TrendsTM index by 39.2% in the year 2005 in Austria when a person of public interest received his second live donor kidney transplant. Conclusions: This study indicates a decreased public interest in kidney transplantation. There is a clear need to raise public awareness, since transplantation represents the best form of renal replacement therapy for patients with ESRD. Information should be provided on social media, with a special focus on readability and equitable access, as well as on web pages. [ABSTRACT FROM AUTHOR]