ANCA Kidney Risk Score (AKRiS) performance in a German Cohort of Patients with Histologically Confirmed ANCA-Associated Renal Vasculitis.

BACKGROUND: Predicting the outcome of ANCA-associated vasculitis (AAV) is a difficult task. One of the most promising prognostic scores, the ANCA Renal Risk Score (ARRS), has recently been updated and renamed to ANCA Kidney Risk Score (AKRiS). We wanted to test its performance in our population. METHODS: 164 patients were included and categorized in subgroups analogous to that of both scores. Multivariable logistic regression analysis was applied to assess the risk of renal failure. Additionally, baseline data and outcome were compared between the subgroups of each score to retrieve useful clinical information. RESULTS: Stratified by AKRiS risk category, the proportions of patients who developed end-stage kidney disease (ESKD) at 36 months were 9.8%, 29.1%, 63.0%, and 83.3%, respectively (p < 0.001).Those belonging to the higher risk groups showed more pronounced proteinuria and anemia at diagnosis (p=0.001, p<0.001, respectively). Although our patients exhibited a more severe disease phenotype than those of AARS and AKRiS, both scores performed equally well: The Harrell´s C Index was similar (0.8381 vs. 0.8337). Beyond that, we found differences and similarities in the risk associations between the subgroups of both scores and disease activity or patient outcome, with some of them being described for the first time. For example, there was a higher risk of renal failure with anemia but not with C-reactive protein and the Birmingham Vasculitis Activity Score (BVAS) and an increased incidence of relapsing disease in the lower risk categories of ARRS. CONCLUSION: Here, we present the first external AKRiS validation confirming the improved ESKD prediction of the revised score in our cohort. Furthermore, we highlighted associations between risc score categories and patient mortality or vasculitis relapse.

Cardiac Surgery Associated Acute Kidney Injury (CSA-AKI).

Acute kidney injury (AKI) is a common and serious complication of cardiac surgery that has a significant impact on patient morbidity and mortality. The Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI is widely used to classify and identify AKI associated with cardiac surgery (CSA-AKI) based on changes in serum creatinine and/or urine output. There are various pre-, intra-, and postoperative risk factors for the development of CSA-AKI which should be recognized and addressed as early as possible to expedite its diagnosis, reduce its occurrence and prevent or ameliorate its devastating complications. Crucial issues are the inaccuracy of serum creatinine as a surrogate parameter of kidney function in the perioperative setting of cardiothoracic surgery and the necessity to discover more representative markers of the pathophysiology of AKI. However, except for the tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 ratio (TIMP2/IGFBP7), other diagnostic biomarkers with an acceptable sensitivity and specificity are still lacking. This article provides a comprehensive review of various aspects of CSA-AKI, including pathogenesis, risk factors, diagnosis, biomarkers, classification, prevention and treatment management.

Short-, Mid-, and Long-term Outcomes after Deceased Donor Kidney Transplantation in Patients with Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is a common complication in hospitalized patients and may occur in potential kidney donors. Observational studies have suggested that kidney transplantation in patients with AKI is feasible and safe, but no systematic evaluation has been performed. METHODS: We performed a systematic review and meta-analysis to evaluate the outcomes of kidney transplantation in patients with AKI. We searched MEDLINE, EMBASE, Cochrane, Google Scholar, and other databases for studies reporting outcomes of donor kidneys with AKI. We included single-center, multicenter, and registry-based studies and analyzed them according to the definition and severity of AKI. Endpoints were primary and delayed graft function (PNF, DGF), length of hospital stay, rejection, graft function, patient and graft survival at one, three, five, and eight to ten years after transplantation. This study was registered in PROSPERO, number CRD42021260088. RESULTS: We identified 33 single-center, 4 multicenter, and 7 registry studies with more than 100,000 patients published between 2005 and 2022. Recipients from donors with AKI had a higher risk of delayed graft function (RR 1.51, 95% CI 1.35-1.68). Graft function at discharge was worse in the AKI group (MDCrea (95%CI): 0.96 mg/dl (0.36-1.56 I2=96%), MDGFR (95%CI): -8.88 ml/min1.73 m2 (-15.32 - -2.44 I2=93%)), but improved thereafter and was similar in both groups at 3 months after transplantation (MDCrea (95%CI): -0.05 mg/dl (-0.18-0.07 I2=0%), MDGFR (95%CI): -1.83 ml/min1.73 m2 (-5.29 - 1.63 I2=91%)). PNF and patient and graft survival were simila at one, three, five, and eight to ten years after transplantation. There were no differences in rejections regardless of AKI definition and severity. CONCLUSION: Transplantation of kidneys with AKI is associated with satisfactory short- and long-term outcomes and should be pursued to increase the donor pool.

The effect of bolus advisors on glycaemic parameters in adults with diabetes on intensive insulin therapy: A systematic review with meta-analysis.

AIM: To conduct a systematic review with meta-analysis to provide a comprehensive synthesis of randomized controlled trials (RCTs) and prospective cohort studies investigating the effects of currently available bolus advisors on glycaemic parameters in adults with diabetes. MATERIALS AND METHODS: An electronic search of PubMed, Embase, CINAHL, Cochrane Library and ClinicalTrials.gov was conducted in December 2022. The risk of bias was assessed using the revised Cochrane Risk of Bias tool. (Standardized) mean difference (MD) was selected to determine the difference in continuous outcomes between the groups. A random-effects model meta-analysis and meta-regression were performed. This systematic review was registered on PROSPERO (CRD42022374588). RESULTS: A total of 18 RCTs involving 1645 adults (50% females) with a median glycated haemoglobin (HbA1c) concentration of 8.45% (7.95%-9.30%) were included. The majority of participants had type 1 diabetes (N = 1510, 92%) and were on multiple daily injections (N = 1173, 71%). Twelve of the 18 trials had low risk of bias. The meta-analysis of 10 studies with available data on HbA1c showed that the use of a bolus advisor modestly reduced HbA1c compared to standard treatment (MD -011%, 95% confidence interval -0.22 to -0.01; I2 = 0%). This effect was accompanied by small improvements in low blood glucose index and treatment satisfaction, but not with reductions in hypoglycaemic events or changes in other secondary outcomes. CONCLUSION: Use of a bolus advisor is associated with slightly better glucose control and treatment satisfaction in people with diabetes on intensive insulin treatment. Future studies should investigate whether personalizing bolus advisors using artificial intelligence technology can enhance these effects.

Unveiling peripheral neuropathy and cognitive dysfunction in diabetes: an observational and proof-of-concept study with video games and sensor-equipped insoles.

Background: Proactive screening for cognitive dysfunction (CD) and peripheral neuropathy (PNP) in elderly patients with diabetes mellitus is essential for early intervention, yet clinical examination is time-consuming and prone to bias. Objective: We aimed to investigate PNP and CD in a diabetes cohort and explore the possibility of identifying key features linked with the respective conditions by machine learning algorithms applied to data sets obtained in playful games controlled by sensor-equipped insoles. Methods: In a cohort of patients diagnosed with diabetes (n=261) aged over 50 years PNP and CD were diagnosed based on complete physical examination (neuropathy symptom and disability scores, and Montreal Cognitive Assessment). In an observational and proof-of-concept study patients performed a 15 min lasting gaming session encompassing tutorials and four video games with 5,244 predefined features. The steering of video games was solely achieved by modulating plantar pressure values, which were measured by sensor-equipped insoles in real-time. Data sets were used to identify key features indicating game performance with correlation regarding CD and PNP findings. Thereby, machine learning models (e.g. gradient boosting and lasso and elastic-net regularized generalized linear models) were set up to distinguish patients in the different groups. Results: PNP was diagnosed in 59% (n=153), CD in 34% (n=89) of participants, and 23% (n=61) suffered from both conditions. Multivariable regression analyses suggested that PNP was positively associated with CD in patients with diabetes (adjusted odds ratio = 1.95; 95% confidence interval: 1.03-3.76; P=0.04). Predictive game features were identified that significantly correlated with CD (n=59), PNP (n=40), or both (n=59). These features allowed to set up classification models that were enriched by individual risk profiles (i.e. gender, age, weight, BMI, diabetes type, and diabetes duration). The obtained models yielded good predictive performance with the area under the receiver-operating-characteristic curves reaching 0.95 for CD without PNP, 0.83 for PNP without CD, and 0.84 for CD and PNP combined. Conclusions: The video game-based assessment was able to categorize patients with CD and/or PNP with high accuracy. Future studies with larger cohorts are needed to validate these results and potentially enhance the discriminative power of video games.

Comparative Analysis of Acute Kidney Injury Models and Related Fibrogenic Responses: Convergence on Methylation Patterns Regulated by Cold Shock Protein.

BACKGROUND: Fibrosis is characterized by excessive extracellular matrix formation in solid organs, disrupting tissue architecture and function. The Y-box binding protein-1 (YB-1) regulates fibrosis-related genes (e.g., Col1a1, Mmp2, and Tgfß1) and contributes significantly to disease progression. This study aims to identify fibrogenic signatures and the underlying signaling pathways modulated by YB-1. METHODS: Transcriptomic changes associated with matrix gene patterns in human chronic kidney diseases and murine acute injury models were analyzed with a focus on known YB-1 targets. Ybx1-knockout mouse strains (Ybx1ΔRosaERT+TX and Ybx1ΔLysM) were subjected to various kidney injury models. Fibrosis patterns were characterized by histopathological staining, transcriptome analysis, qRT-PCR, methylation analysis, zymography, and Western blotting. RESULTS: Integrative transcriptomic analyses revealed that YB-1 is involved in several fibrogenic signatures related to the matrisome, the WNT, YAP/TAZ, and TGFß pathways, and regulates Klotho expression. Changes in the methylation status of the Klotho promoter by specific methyltransferases (DNMT) are linked to YB-1 expression, extending to other fibrogenic genes. Notably, kidney-resident cells play a significant role in YB-1-modulated fibrogenic signaling, whereas infiltrating myeloid immune cells have a minimal impact. CONCLUSIONS: YB-1 emerges as a master regulator of fibrogenesis, guiding DNMT1 to fibrosis-related genes. This highlights YB-1 as a potential target for epigenetic therapies interfering in this process.

Telemedical Monitoring of Plantar Temperature in Diabetic Patients at Risk of Foot Ulcers.

BACKGROUND: The worldwide prevalence of diabetic foot ulcers (DFUs) among persons with diabetes is estimated at 6.3%, with an annual incidence of 9.1 to 26.1 million persons. The early detection of asymmetrical plantar temperature elevation, followed by reduction of weight-bearing on the affected foot, may be an effective mode of prevention. METHODS: Patients with diabetes and peripheral neuropathy (DFU risk groups 2/3) were monitored for plantar abnormalities with a telemedical system consisting of sole inserts with temperature sensors and photographic documentation. An open, prospective, randomized controlled trial was performed to determine whether this system prevented DFUs. The intervention and control groups were also trained in ulcer prevention and observed in follow-up at 6-month intervals for 24 months. RESULTS: 283 patients were recruited. In 85 137 observation days, DFUs arose in five patients in the control group (n = 143) and in no patient in the intervention group (n = 140). The primary outcome measure was the hazard ratio, which was calculated to be 0.015 (95% confidence interval [0; 19,717]; p = 0.25) after adjustment for age, sex, severity of neuropathy, and risk class. There were 239 alarms and 75 instructions to reduce weight-bearing on the foot. The subjects carried out the telemedical application on about 70% of the days of observation. Quality of life improved in both groups. CONCLUSION: The tele-health system used in this trial is practical and enables the early detection of morbidity. Likely explanations for the unexpectedly low ulceration rate in this trial (and, in turn, for the lack of statistical significance) include the availability of a training program and regular follow-up examinations to patients in both arms of the trial, along with lower mobility levels due to the COVID pandemic.

Association of metabolic syndrome and chronic kidney disease.

The prevalence of kidney disease is increasing rapidly worldwide, reflecting rising rates of obesity, diabetes, and associated metabolic syndrome (MetS). Chronic kidney disease and related comorbidities such as obesity, diabetes, and hypertension place a significant financial burden on healthcare systems. Despite the widespread use of RAAS inhibitors, intensive blood pressure and glycemic control, and newer therapeutic options consisting of sodium/glucose cotransporter-2 (SGLT-2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists, a significant risk of progression to end-stage renal disease remains in the high-risk obese and diabetic population. The MetS is a cluster of cardiovascular risk factors that adversely affect the development and progression of chronic kidney failure. According to the criteria of the World Health Organization, it is defined by visceral adiposity, impaired glucose tolerance or insulin resistance, atherogenic dyslipidemia, raised blood pressure, and microalbuminuria with a albumin-to-creatinine ratio ≥30 mg/g. At molecular level MetS is marked by a proinflammatory state and increased oxidative stress leading to various pathophysiological changes causing endothelial dysfunction and a hypercoagulable state. Because the kidney is a highly vascularized organ, it is especially susceptible for those microvascular changes. Therefore, the MetS and its individual components are associated with the premature development, acceleration, and progression of chronic kidney disease. Therefore, it is becoming increasingly important to elucidate the underlying mechanisms of MetS-associated chronic kidney disease in order to develop new strategies for preventing and slowing the progression of renal disease. In this review, we will elucidate (i) the renal structural, hemodynamic, and metabolic changes that occur in obesity and obesity-related kidney injury; (ii) the clinicopathological characteristics of obesity-related kidney injury, primarily focusing on obesity-associated glomerulopathy; (iii) the potential additional factors or predisposing factors that may turn patients more susceptible to renal structural or functional compensatory failure and subsequent injury.

Glomerular-tubular crosstalk via cold shock Y-box binding protein-1 in the kidney.

Glomerular-tubular crosstalk within the kidney has been proposed, but the paracrine signals enabling this remain largely unknown. The cold-shock protein Y-box binding protein 1 (YBX1) is known to regulate inflammation and kidney diseases but its role in podocytes remains undetermined. Therefore, we analyzed mice with podocyte specific Ybx1 deletion (Ybx1ΔPod). Albuminuria was increased in unchallenged Ybx1ΔPod mice, which surprisingly was associated with reduced glomerular, but enhanced tubular damage. Tubular toll-like receptor 4 (TLR4) expression, node-like receptor protein 3 (NLRP3) inflammasome activation and kidney inflammatory cell infiltrates were all increased in Ybx1ΔPod mice. In vitro, extracellular YBX1 inhibited NLRP3 inflammasome activation in tubular cells. Co-immunoprecipitation, immunohistochemical analyses, microscale cell-free thermophoresis assays, and blunting of the YBX1-mediated TLR4-inhibition by a unique YBX1-derived decapeptide suggests a direct interaction of YBX1 and TLR4. Since YBX1 can be secreted upon post-translational acetylation, we hypothesized that YBX1 secreted from podocytes can inhibit TLR4 signaling in tubular cells. Indeed, mice expressing a non-secreted YBX1 variant specifically in podocytes (Ybx1PodK2A mice) phenocopied Ybx1ΔPod mice, demonstrating a tubular-protective effect of YBX1 secreted from podocytes. Lipopolysaccharide-induced tubular injury was aggravated in Ybx1ΔPod and Ybx1PodK2A mice, indicating a pathophysiological relevance of this glomerular-tubular crosstalk. Thus, our data show that YBX1 is physiologically secreted from podocytes, thereby negatively modulating sterile inflammation in the tubular compartment, apparently by binding to and inhibiting tubular TLR4 signaling. Hence, we have uncovered an YBX1-dependent molecular mechanism of glomerular-tubular crosstalk.

Endostatin, soluble tumour necrosis factor receptor 1 and soluble tumour necrosis factor receptor 2 cannot predict new onset of microalbuminuria in patients with type 2 diabetes.

AIMS: Inflammation and angiogenesis play an important role in the development of early diabetic kidney disease. We investigated the association of soluble Tumour Necrosis Factor Receptor 1 (sTNF-R1), sTNF-R2 and endostatin with new onset microalbuminuria in normoalbuminuric patients with diabetes mellitus type 2. METHODS: We conducted a case control study to assess serum levels of sTNF-R1, sTNF-R2 and endostatin in 169 patients with new onset microalbuminuria and in 188 matched normoalbuminuric, diabetic controls. Baseline serum samples from participants of the ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) and observational follow-up (ROADMAP-OFU) studies were used. RESULTS: Endostatin and sTNF-R1 but not sTNF-R2 were increased at baseline in patients with future microalbuminuria. In the multivariate analysis, each log2 increment in endostatin levels was associated with an increase of only 6% in the risk of development of microalbuminuria (adjusted HR (95% CI) 1.006 (1.001-1011). sTNF-R1 and sTNF-R2 levels were conversely associated with microalbuminuria, but the results did not reach statistical significance. The respective adjusted HRs (95% CI) were 1.305 (0.928-1.774) and 0.874 (0.711-1.074). CONCLUSIONS: sTNF-R1 and sTNF-R2 failed to predict the occurrence of microalbuminuria in normoalbuminuric patients with type 2 diabetes. Likewise, the utility of endostatin in predicting new onset proteinuria is limited.

Case report: Acute kidney injury as the initial manifestation of chronic lymphocytic leukemia/small lymphocytic lymphoma.

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder often diagnosed after incidental finding of leukocytosis. Renal involvement is usually clinically silent. Symptomatic renal impairment due to CLL/small lymphocytic lymphoma (SLL) cell infiltration in the kidney tissue is uncommon, and acute kidney injury (AKI) as a presenting feature is rare. In this case report, we describe the case of a patient with AKI caused by CLL/SLL infiltration as a presenting feature. Our report highlights the possibility of kidney injury as the first evident symptom of CLL/SLL. Kidney biopsy is the mainstay in these cases in order to establish a diagnosis. Treatment with zanubrutinib resulted in improved kidney function.

Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis.

The interleukin-1 gene cluster encodes cytokines, which modulate mesangial cell proliferation and matrix expansion, both constituting central factors in the development and progression of immunoglobulin A nephropathy (IgAN). A candidate-gene study was performed to examine the association of polymorphisms of the interleukin-1 gene cluster with the risk of progressive IgAN. To gain deeper insights into the involvement of interleukin genes in IgAN, a meta-analysis of genetic association studies (GAS) that examine the association between interleukin variants and IgAN was conducted. Association study: The case-control study consisted of 121 unrelated Caucasians with sporadic, histologically diagnosed IgAN and of 246 age- and sex-matched healthy controls. Persistent proteinuria (>2 g/24 h) and/or impaired kidney function (serum creatinine > 1.5 mg/dL) defined progressive (n = 67) vs. non-progressive (n = 54) IgAN cases. Genotypes were assessed for two promoter-region single-nucleotide polymorphisms, C-899T (rs1800587) in IL1A and C-511T (rs16944) in IL1B, and for one penta-allelic variable-length tandem repeat polymorphism (VNTR 86 bp intron 2) in IL1RN. The association of these variants with the susceptibility of IgAN and the development of progressive IgAN (healthy status, IgAN, progressive IgAN) was tested using the generalized odds ratio (ORG) metric. Linkage disequilibrium and haplotype analysis were also performed. Meta-analysis: We included in the meta-analysis 15 studies investigating association between 14 interleukin variants harbored in eight different genes and IgAN. The ORG was used to evaluate the association between interleukin variants and IgAN using random effects models. The present case-control study revealed association of IL1B C-511T (rs16944) with the progression of IgAN (p = 0.041; ORG = 2.11 (1.09-4.07)). On haplotype analysis, significant results were derived for the haplotypes C-C-1 (p = 0.005; OR = 0.456 (0.261~0.797)) and C-T-2 (p = 0.003; OR = 4.208 (1.545-11.50)). Regarding association and meta-analysis results, variants in IL1B (rs1143627 and rs16944), IL1RN (rs928940, rs439154, and rs315951) and IL10 (rs1800871) were associated with IgAN based on either genotype or allele counts. Genetic variants and haplotypes in the IL1B, IL1RN, and IL10 genes might contribute to an increased risk for development and progression of IgAN.

Excessive sodium chloride ingestion promotes inflammation and kidney fibrosis in aging mice.

In aging kidneys, a decline of function resulting from extracellular matrix (ECM) deposition and organ fibrosis is regarded as "physiological." Whether a direct link between high salt intake and fibrosis in aging kidney exists autonomously from arterial hypertension is unclear. This study explores kidney intrinsic changes (inflammation, ECM derangement) induced by a high-salt diet (HSD) in a murine model lacking arterial hypertension. The contribution of cold shock Y-box binding protein (YB-1) as a key orchestrator of organ fibrosis to the observed differences is determined by comparison with a knockout strain (Ybx1ΔRosaERT+TX). Comparisons of tissue from mice fed with normal-salt diet (NSD, standard chow) or high-salt diet (HSD, 4% NaCl in chow; 1% NaCl in water) for up to 16 mo revealed that with HSD tubular cell numbers decrease and tubulointerstitial scarring [periodic acid-Schiff (PAS), Masson's trichrome, Sirius red staining] prevails. In Ybx1ΔRosaERT+TX animals tubular cell damage, a loss of cell contacts with profound tubulointerstitial alterations, and tubular cell senescence was seen. A distinct tubulointerstitial distribution of fibrinogen, collagen type VI, and tenascin-C was detected under HSD, transcriptome analyses determined patterns of matrisome regulation. Temporal increase of immune cell infiltration was seen under HSD of wild type, but not Ybx1ΔRosaERT+TX animals. In vitro Ybx1ΔRosaERT+TX bone marrow-derived macrophages exhibited a defect in polarization (IL-4/IL-13) and abrogated response to sodium chloride. Taken together, HSD promotes progressive kidney fibrosis with premature cell aging, ECM deposition, and immune cell recruitment that is exacerbated in Ybx1ΔRosaERT+TX animals.NEW & NOTEWORTHY Short-term experimental studies link excessive sodium ingestion with extracellular matrix accumulation and inflammatory cell recruitment, yet long-term data are scarce. Our findings with a high-salt diet over 16 mo in aging mice pinpoints to a decisive tipping point after 12 mo with tubular stress response, skewed matrisome transcriptome, and immune cell infiltration. Cell senescence was aggravated in knockout animals for cold shock Y-box binding protein (YB-1), suggesting a novel protective protein function.

Cold Shock Domain Protein DbpA Orchestrates Tubular Cell Damage and Interstitial Fibrosis in Inflammatory Kidney Disease.

DNA-binding protein A (DbpA) belongs to the Y-box family of cold shock domain proteins that exert transcriptional and translational activities in the cell via their ability to bind and regulate mRNA. To investigate the role of DbpA in kidney disease, we utilized the murine unilateral ureter obstruction (UUO) model, which recapitulates many features of obstructive nephropathy seen in humans. We observed that DbpA protein expression is induced within the renal interstitium following disease induction. Compared with wild-type animals, obstructed kidneys from Ybx3-deficient mice are protected from tissue injury, with a significant reduction in the number of infiltrating immune cells as well as in extracellular matrix deposition. RNAseq data from UUO kidneys show that Ybx3 is expressed by activated fibroblasts, which reside within the renal interstitium. Our data support a role for DbpA in orchestrating renal fibrosis and suggest that strategies targeting DbpA may be a therapeutic option to slow disease progression.

Low levels of complement factor C3 at diagnosis can predict outcome in antineutrophil antibody associated vasculitis.

INTRODUCTION: Experimental data support the involvement of complement in the pathogenesis of antineutrophil antibody associated vasculitis, and clinical studies describe a more severe disease phenotype in patients with antineutrophil antibody associated vasculitis and complement activation. In the present study, we looked for an association between circulating serum complement factor 3 levels at diagnosis and outcomes. METHODS: One hundred sixty-four patients with antineutrophil antibody associated vasculitis who underwent kidney biopsy at our center during the last 15 years were retrospectively reviewed. Patients were categorized according to their serum complement factor 3 level at diagnosis. Patient and renal survival were compared between those above and below the median serum complement factor 3 at diagnosis. RESULTS: During the first year, 6 patients died and 53 reached end-stage renal disease. Death or end-stage renal disease at one-year were significantly more common in the low serum complement factor 3 group (44 vs. 29%, p = 0.037). In the multivariable analysis, serum complement factor 3 was the strongest negative outcome predictor (HR, 95%CI 0.118, (0.021-0.670)). The lower the serum complement factor 3 level at baseline, the higher the risk of dialysis and death. The risk was particularly high for both endpoints if the serum complement factor 3 concentration was below 0.9 g/l at baseline. CONCLUSION: Complement activation at diagnosis may identify a distinct subgroup of patients with antineutrophil antibody associated vasculitis and higher risk for poor outcomes. However, it remains to be proven whether inhibition of serum complement factor 3 is beneficial and safe in the clinical setting.

Fracture healing in a mouse model of Hajdu-Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability.

Notch signaling regulates cell fate in multiple tissues including the skeleton. Hajdu-Cheney-Syndrome (HCS), caused by gain-of-function mutations in the Notch2 gene, is a rare inherited disease featuring early-onset osteoporosis and increased risk for fractures and non-union. As the impact of Notch2 overactivation on fracture healing is unknown, we studied bone regeneration in mice harboring a human HCS mutation. HCS mice, displaying high turnover osteopenia in the non-fractured skeleton, exhibited only minor morphologic alterations in the progression of bone regeneration, evidenced by static radiological and histological outcome measurements. Histomorphometry showed increased osteoclast parameters in the callus of HCS mice, which was accompanied by an increased expression of osteoclast and osteoblast markers. These observations were accompanied by inferior biomechanical stability of healed femora in HCS mice. Together, our data demonstrate that structural indices of bone regeneration are normal in HCS mice, which, however, exhibit signs of increased callus turnover and display impaired biomechanical stability of healed fractures.

Monitoring disease activity in antineutrophil antibody-associated vasculitis.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) comprises a group of multisystem disorders with alternating periods of relapse and remission. Beyond that, a smouldering progress during apparently clinically silent phases often develops. AAVs are subgrouped in microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and renal limited vasculitis (RLV). ANCA are hallmark of this disease entity, although they are not always present. Despite the simplification of treatment, fundamental aspects concerning assessment of its efficacy and its adaptation to encountered complications or to the relapsing/remitting/subclinical disease course remain still unknown. Through the advances in pathogenesis and pathophysiology of AAV a reliable biomarker-based monitoring and treatment algorithm has not been established and disease management follows not infrequently a "trial and error" approach. Here, we overviewed the most interesting biomarkers reported so far.

Bilateral non-contiguous necrotizing fasciitis of the lower extremities.

Necrotizing fasciitis (NF) is an uncommon soft tissue infection. Multifocal-extremity NF is a rarity with high mortality rates. Herein we report a case of bilateral non-contiguous NF of the lower extremities due to Escherichia coli with a fatal outcome, stressing the necessity of rapid and aggressive intervention in suspected cases.

Validation of a risk prediction model for early chronic kidney disease in patients with type 2 diabetes: Data from the German/Austrian Diabetes Prospective Follow-up registry.

AIM: To validate a recently proposed risk prediction model for chronic kidney disease (CKD) in type 2 diabetes (T2D). MATERIALS AND METHODS: Subjects from the German/Austrian Diabetes Prospective Follow-up (DPV) registry with T2D, normoalbuminuria, an estimated glomerular filtration rate of 60 ml/min/1.73m2 or higher and aged 39-75 years were included. Prognostic factors included age, body mass index (BMI), smoking status and HbA1c. Subjects were categorized into low, moderate, high and very high-risk groups. Outcome was CKD occurrence. RESULTS: Subjects (n = 10 922) had a mean age of 61 years, diabetes duration of 6 years, BMI of 31.7 kg/m2 , HbA1c of 6.9% (52 mmol/mol); 9.1% had diabetic retinopathy and 16.3% were smokers. After the follow-up (~59 months), 37.4% subjects developed CKD. The area under the curve (AUC; unadjusted base model) was 0.58 (95% CI 0.57-0.59). After adjustment for diabetes and follow-up duration, the AUC was 0.69 (95% CI 0.68-0.70), indicating improved discrimination. After follow-up, 15.0%, 20.1%, 27.7% and 40.2% patients in the low, moderate, high and very high-risk groups, respectively, had developed CKD. Increasing risk score correlated with increasing cumulative risk of incident CKD over a median of 4.5 years of follow-up (P < .0001). CONCLUSIONS: The predictive model achieved moderate discrimination but good calibration in a German/Austrian T2D population, suggesting that the model may be relevant for determining CKD risk.