Renal damage and old age: risk factors for thrombosis in patients with ANCA-associated vasculitis.

INTRODUCTION: Thrombosis in ANCA-associated vasculitis (AAV) was prevalent and has been neglected in Chinese patients. This study tried to describe the clinical characteristics, identify the risk factors, and investigate the causal relationship between AAV and venous thromboembolism (VTE) by two-sample Mendelian randomization (MR) analysis. METHODS: In this retrospective, observational study, we included all hospitalized AAV patients from Jan 2013 to Apr 2022 in Peking Union Medical College Hospital. We collected their clinical data for multivariate regression analysis to determine the risk factors for thrombosis. The nomogram was constructed by applying these risk factors to predict thrombosis in AAV patients. As for MR analysis, we selected single nucleotide polymorphisms (SNPs) related to AAV from published genome-wide association studies and extracted the outcome data containing deep vein thrombosis (DVT) and pulmonary embolism (PE) from the UK biobank. RESULTS: 1203 primary AAV patients were enrolled, and thrombosis occurred in 11.3%. Multivariate regression suggested that older than 65 years, EGPA, neurological involvement, lung involvement, significantly elevated serum creatinine (> 500µmol/L), and elevated D-dimer were associated with thrombosis in AAV patients. The model demonstrated satisfied discrimination with an AUC of 0.769 (95% CI, 0.726-0.812). MR analysis showed that EGPA could increase the risk of developing DVT and PE (OR = 1.0038, 95%CI = 1.0035-1.0041, P = 0.009). CONCLUSION: Thrombosis was not rare in Chinese patients with AAV. Renal damage and old age emerged as critical risk factors for thrombosis. EGPA might have a potential causal relationship with DVT and PE.

Roxadustat and Oral Iron Absorption in Chinese Patients with Anemia of Chronic Kidney Disease: A Randomized, Open-Label, Phase 4 Study (ALTAI).

INTRODUCTION: Anemia of chronic kidney disease (CKD) has a high incidence and is associated with many disease conditions. Iron dysmetabolism is an important contributor to anemia in CKD patients. METHODS: ALTAI, a randomized, active-controlled, phase 4 trial, investigated the efficacy of roxadustat versus recombinant human erythropoietin (rHuEPO) on gastrointestinal iron absorption in patients with anemia of CKD (stage 4/5). The primary endpoint was change from baseline to day 15 in gastrointestinal iron absorption (serum iron area under the concentration-time curve; AUC0-3h) following single-dose oral iron. RESULTS: Twenty-five patients with a mean age of 55.1 years were randomized 1:1 to roxadustat (n = 13) or rHuEPO (n = 12). Baseline iron profiles were similar between treatment groups. Change from baseline to day 15 in serum iron AUC0-3h was not statistically significantly different between the roxadustat and rHuEPO groups. Mean (SD) change from baseline in serum iron AUC0-3h was 11.3 (28.2) g × 3 h/dl in the roxadustat group and - 0.3 (9.7) g × 3 h/dl in the rHuEPO group. Roxadustat treatment was associated with decreased hepcidin and also increased transferrin, soluble transferrin receptor, and total iron-binding capacity (TIBC), with nominal significance. The proportion of patients experiencing one or more adverse events was 38.5% when treated with roxadustat and 16.7% with rHuEPO. CONCLUSIONS: The study showed no significant difference between roxadustat and rHuEPO in iron absorption but was underpowered because of recruitment challenges. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04655027.

Strategies for high cell density cultivation of Akkermansia muciniphila and its potential metabolism.

IMPORTANCE: Currently, there is significant interest in Akkermansia muciniphila as a promising next-generation probiotic, making it a hot topic in scientific research. However, to achieve efficient industrial production, there is an urgent need to develop an in vitro culture method to achieve high biomass using low-cost carbon sources such as glucose. This study aims to explore the high-density fermentation strategy of A. muciniphila by optimizing the culture process. This study also employs techniques such as LC-MS and RNA-Seq to explain the possible regulatory mechanism of high-density cell growth and increased cell surface hydrophobicity facilitating cell colonization of the gut in vitro culture. Overall, this research sheds light on the potential of A. muciniphila as a probiotic and provides valuable insights for future industrial production.

High-Throughput Experimentation and Machine Learning-Assisted Optimization of Iridium-Catalyzed Cross-Dimerization of Sulfoxonium Ylides.

A novel and convenient approach that combines high-throughput experimentation (HTE) with machine learning (ML) technologies to achieve the first selective cross-dimerization of sulfoxonium ylides via iridium catalysis is presented. A variety of valuable amide-, ketone-, ester-, and N-heterocycle-substituted unsymmetrical E-alkenes are synthesized in good yields with high stereoselectivities. This mild method avoids the use of diazo compounds and is characterized by simple operation, high step-economy, and excellent chemoselectivity and functional group compatibility. The combined experimental and computational studies identify an amide-sulfoxonium ylide as a carbene precursor. Furthermore, a comprehensive exploration of the reaction space is also performed (600 reactions) and a machine learning model for reaction yield prediction has been constructed.

Renal Outcomes in Older Adults with Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis: A New Prediction Model.

INTRODUCTION: Older patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) commonly experience renal impairment and poor prognoses. This study aimed to establish a risk-scoring system for predicting composite renal outcomes in older patients with AAV. METHODS: This retrospective observational study included all patients with AAV hospitalized in a single-center tertiary hospital in China between January 2013 and April 2022. Patients aged ≥65 years were defined as older adults and short-term composite renal outcomes included a ≥25% reduction in estimated glomerular filtration rate (eGFR) (for AKI), renal replacement therapy, provision of renal replacement therapy (long-term dialysis, kidney transplant, or sustained eGFR <15 mL/min/1.73 m), or all-cause mortality. Patients were randomly divided into development and validation cohorts (2:1). Logistic regression analysis was performed in the development cohort to analyze risk factors. The scoring system was established accordingly and further validated in the validation cohort. RESULTS: 1,203 patients were enrolled in the study, among whom the older adult group accounted for 36% with a mean age of 71. The older adult group had a worse prognosis, a higher mortality rate, a higher rate of end-stage renal disease, and worsening renal function. Logistic regression showed that age >75 years, chronic heart disease, and elevated serum creatinine and D-dimer values were risk factors for poor prognosis in patients with AAV. The development and validation cohorts in patients with AAV produced area under the curve values of 0.82 (0.78-0.86) and 0.83 (0.77-0.89), respectively. CONCLUSION: We established a risk-scoring system based on baseline clinical characteristics to predict composite renal outcomes in patients with AAV. Our results suggest that more attention should be paid to older patients with severe renal impairment and active inflammation.

7-Guanidinyl Coumarins: Synthesis, Photophysical Properties, and Application to Exploit the Pd-Catalyzed Release of Guanidines.

Molecular manipulation of guanidino-containing biomolecules in a cellular environment is fundamental to exploiting protein function and drug release, but currently, there is a lack of suitable methods for reaction screening and monitoring. To exploit the potential of the fluorescent method in this respect, herein, we evaluated a novel array of 7-guanidinyl coumarins by incorporating different substituted guanidino moieties into a coumarin scaffold. These compounds were prepared by guanidinylation reagent S-methylisothiourea or TFA-protected pyrazole-carboxamidine. Examination of their photophysical properties revealed that the fluorescence emission of alkyloxycarbonyl-substituted guanidinyl coumarin was significantly enhanced as compared with the unsubstituted analogue. This dramatic fluorescence difference enabled preliminary exploitation of the Pd-catalyzed release of allyloxycarbonyl (Alloc)-caged guanidinyl coumarin-6 in living cells.

Clinical characteristics and primary outcomes of patients with ANCA-associated vasculitis and central diabetes insipidus.

Introduction: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by systemic small-vessel vasculitis and may rarely present as central diabetes insipidus (CDI). In this study, we aimed to determine the clinical characteristics and prognosis of patients with AAV-associated CDI. Methods: This was a nested case-control study where AAV patients with CDI at the Peking Union Medical College Hospital were followed from January 2012 to April 2022. Case-control matching with AAV patients without CDI was performed (1:5), and participants were matched by age, sex, and AAV classification. We collected clinical data every 3-6 months and conducted a literature review using PubMed to identify relevant articles published from 1983-2022. Results: Among 1203 hospitalized AAV patients, 16 patients with CDI were included (1.3%). The average age was 49 years, and men accounted for 56.3%. Granulomatosis with polyangiitis (GPA) accounted for 87.5% of patients. AAV patients with CDI had more ear, nose, and throat (ENT) (81.3%) involvement and less renal impairment than those in the control group (P<0.05). After a mean follow-up of four years, 50% of patients were in remission from AAV, 37.5% relapsed, and 12.5% died. Our literature review suggested that patients in Asian countries tend to be older men and have higher myeloperoxidase (MPO-ANCA) positivity than those in Western countries. Furthermore, proteinase 3 (PR3-ANCA) positivity may predict disease recurrence. Discussion: AAV patients with CDI had more ENT involvement and a higher eGFR. MPO-ANCA positivity is more commonly observed in Asian countries than Western countries, and PR3-ANCA positivity may predict recurrence.

Boron-Assisted Selective Citrulline Modification under Mild Conditions.

Protein citrullination is one type of protein post-translational modification. Previous methods entail the use of a strongly acidic condition (pH <1), which impedes its exploration under physiological and pathological conditions. Here, we developed a biocompatible method based on o-boron-assisted citrulline modification. We demonstrated that this method enables selective and mainly irreversible modification of citrulline residues under neutral conditions. We expect that it will provide a valuable tool for the study of protein citrullination.

Interstitial nephritis without glomerulonephritis in ANCA-associated vasculitis: a case series and literature review.

The typical nephrological presentation of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is rapidly progressive glomerulonephritis. AAV-associated interstitial nephritis without apparent glomerular lesions was rare. We reported three local cases of AAV-associated interstitial nephritis without glomerulonephritis confirmed by renal biopsy. Then, a literature search was conducted in PubMed using free text words and MeSH terms related to "AAV and interstitial nephritis". Fifteen cases were included, and their demographics, clinical manifestations, laboratory data, renal pathological features, and treatment response were summarized. AAV-associated interstitial nephritis usually affects elderly patients. The common symptoms include fever, arthralgias, and edema. These patients were mostly MPO-ANCA positive. Pathological lesions in the kidney showed diffuse infiltration of inflammatory cells, edema, tubulitis, and fibrosis in the interstitial area. Various immunosuppressive treatments, including glucocorticoids, immunosuppressants, and rituximab, were used, and most of the patients achieved clinical remission. AAV-associated interstitial nephritis is rare but shows a characteristic clinical phenotype, serological results, and pathogenic lesions. Immunosuppressive therapy showed good efficacy in these patients.

Regioselective Access to 2-Iminoimidazolidines via AgF-Mediated Cascade Reactions.

A convergent access to substituted 2-iminoimidazolidines from aromatic amines and N-propargyl S-methylthiourea is developed via Ag(I)-mediated cascade guanylation-cyclization reactions. This method features high regioselectivity, excellent efficiency, and mild reaction conditions. Subsequent deprotection of the Boc (tert-butyloxycarbonyl) group under acidic conditions provides expedient access to aryl 2-aminoimidazole derivatives in a convenient manner.

Anti-neutrophil cytoplasmic antibody associated vasculitis in patients with rheumatoid arthritis.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may coexist with rheumatoid arthritis (RA). However, it is unclear whether the manifestations of AAV with and without coexisting RA are similar. This observational study aimed to investigate the clinicopathological manifestations of AAV with coexisting RA and to explore potential predictors for identifying AAV superimposed on RA. METHODS: Patients with both AAV and RA were identified by searching our hospital database and the literature. Data including age, sex, clinical manifestation, laboratory tests, renal pathology, and therapeutic regimens were retrieved. To assess the difference in clinical features and renal pathology between AAV patients with and without RA, we conducted 1:4 matched case-control studies. RESULTS: A total of 47 patients were identified, 15 from our hospital and 32 from the literature, and 33 (70.2%) were women. AAV was diagnosed later than RA in 83.0% of the patients and manifested as microscopic polyangiitis (MPA) in 78.7% of the patients. The kidney was the most frequently involved extra-articular organ (74.5%), followed by the lung (51.1%), and skin (8.5%). Patients with both AAV and RA were more likely to be asymptomatic (26.7% vs 3.3%, p = 0.013) than those with isolated AAV. However, they did not differ in other clinicopathological features. In RA patients, those with ANCA associated glomerulonephritis, were more likely to have decreased renal function at renal biopsy as opposed to those with primary glomerulonephritis. CONCLUSIONS: AAV can coexist with RA. In this coexistence, AAV usually develops after RA, is more likely to be asymptomatic, and manifests predominately as MPA with renal involvement. Thus, we should remain vigilant to superimposed AAV on RA.

Ag(I)-Catalyzed rapid access to 2-amino-4-methylenethiazolines with potential applications in bioconjugation chemistry.

An Ag(i)-catalyzed tandem addition-cyclization of isothiocyanate and propargylamine was successfully applied to the synthesis of 2-amino-4-methylenethiazolines. This route features an unprecedented fast reaction rate with full conversion reached within 10 min at room temperature for aromatic isothiocyanates and excellent chemoselectivity for exocyclic products. The application of this strategy is further highlighted by the accelerated bioconjugation of propargylamine with fluorescein isothiocyanate (FITC) under Ag(i)-catalysis.

Serum TNF-α Level Is Associated with Disease Severity in Adult Patients with Immunoglobulin A Vasculitis Nephritis.

BACKGROUND: Tumor necrosis factor-α (TNF-α) is a proinflammatory factor involved in the pathogenesis of immunoglobulin A vasculitis (IgAV). The association between serum TNF-α and disease severity in adult patients with IgAV nephritis (IgAV-N) has been inadequately evaluated. METHODS: Serum TNF-α was measured by chemiluminescence immunoassay in 53 renal biopsy-proved IgAV-N patients, 53 healthy controls, and 53 IgA nephropathy (IgAN) patients. The correlations of clinicopathologic parameters of IgAV-N patients with serum TNF-α were analyzed. RESULTS: In this cross-sectional study, the median age of IgAV-N patients was 29 (25-37) years, and 67.9% were female. Serum TNF-α was significantly higher in the IgAV-N group than in the healthy group [7.4 (5.7-9.4) pg/mL vs. 5.9 (5.0, 7.1) pg/mL, P = 0.001], but comparable with sex, age, and estimated glomerular filtration rate (eGFR) grade-matched IgAN patients. Serum creatinine (P = 0.006) and serum cystatin C (P = 0.001) were positively correlated with serum TNF-α level, while albumin (P = 0.014) and eGFR (P = 0.021) were negatively correlated with serum TNF-α level. Multivariate linear regression analysis revealed that eGFR (P = 0.007) was an independent clinical predictor of serum TNF-α. Patients with higher pathological classification grade also had higher serum TNF-α. CONCLUSIONS: Serum TNF-α is associated with renal function and the pathological classification of adult patients with IgAV-N. TNF-α is a potential biomarker for the assessment of IgAV-N severity.

Aldol sensor-inspired fluorescent probes for measuring protein citrullination.

Protein citrullination is an important posttranslational modification on an arginine residue. However, high quality fluorescent probes for measuring the citrullination level and capturing citrullinated proteins are quite limited. Inspired by the similarity between acid-promoted citrulline-labeling reaction and aldol reaction, here we present "turn-on" and "turn-off" fluorescent probes for measuring citrulline levels based on the scaffold of aldol sensors. Further application of the modified probe showed great potential to simultaneously monitor and capture citrullinated peptides.

Dehydration-associated chronic kidney disease: a novel case of kidney failure in China.

BACKGROUND: Mesoamerican nephropathy (MeN) is a pattern of chronic kidney disease (CKD) prevalent among Central American men who work in agriculture, and its underlying cause has not been elucidated. Currently, experts hypothesize that MeN is related to repeated episodes of occupational heat stress leading to water loss and hence it is also called dehydration-associated CKD. CASE PRESENTATION: We report a case of a 40-year-old man, whose first admission to Peking Union Medical College Hospital was due to acute kidney injury (AKI). The clinical and pathological processes were consistent with acute tubular necrosis (ATN). However, after full recovery, CKD developed 1 year later. The second renal biopsy showed characteristics of ischemic renal disease but there was no evidence of vascular disease. It is worth noting that the patient had been taking part in long-distance running without drinking adequate water for years, which would have markedly decrease his renal blood flow. Thus, this patient may have developed chronic dehydration-associated kidney disease sharing the similar etiology of MeN. CONCLUSIONS: We report here a case of dehydration-associated CKD in a Chinese patient which shared similar etiology to MeN. Even in non-agricultural areas, this etiology of CKD should be noted to obtain a relevant history and prompt diagnosis.

[Comparative study of percutaneous bridging plate and retrograde suprapubic intramedullary screw fixation for anterior pelvic ring fracture].

OBJECTIVE: To compare the effect of percutaneous bridging plate and retrograde suprapubic intramedullary screw in the treatment of anterior ring fracture of pelvis. METHODS: From January 2013 to June 2017, 40 patients with unstable pelvic fractures involving anterior ring were analyzed retrospectively. According to the fixation method, they were divided into two groups, there were 20 patients in percutaneous bridging plate group (plate group) including 9 males and 11 females; according to tile classification, fractures were classified as type B1 in 1 case, type B2 in 14, type B3 in 2, type C1 in 2 and type C2 in 1. There were 20 cases in retrograde suprapubic intramedullary screw group (screw group) including 10 males and 10 females; according to tile classification, there were 1 case of type B1, 12 cases of type B2, 3 cases of type B3, 3 cases of type C1 and 1 case of type C2. The incision length, operation time, times of fluoroscopy, intraoperative bleeding volume, postoperative Matta score, postoperative complications and the last follow-up Majeed function score of the two groups were compared and analyzed. RESULTS: Both groups were followed up for 8 to 15 (12.25±2.24) months in the plate group and 6 to 18 (12.4±2.6) months in the screw group, there was no significant difference between the two groups. The incision length of screw group was (3.85±0.75) cm shorter than that of steel plate group (7.05±1.39) cm; the operation time of screw group was (27.70±5.36) min longer than that of steel plate group (15.10±2.07) min; the fluoroscopy times of screw group was (6.00±1.83) more than that of steel plate group (3.75±1.33) . The bleeding volume was (22.50±10.82) ml in of screw group, (25.00±9.93) ml in steel plate group, there was no significant difference between the two groups (P>0.05) . There was no significant difference in Matta evaluation and Majeed functional score in the last follow-up. One case of superficial skin infection occurred in screw group, one case of superficial skin infection and one case of transient paralysis of lateral femoral cutaneous nerve occurred in steel plate group. CONCLUSION: Percutaneous bridging plate and retrograde suprapubic intramedullary screw fixation of pelvic anterior ring fracture have the same effect. The operation time of the percutaneous plate group was shorter, the times of intraoperative fluoroscopy was less, and the learning curve was shorter, but the variation of the lateral femoral cutaneous nerve should be noted during the operation.

Serum Soluble CD89-IgA Complexes Are Elevated in IgA Nephropathy without Immunosuppressant History.

PURPOSE: CD89 (FcαRI), the receptor of IgA, can shed from cells to form complexes with IgA in serum and is supposed to participate in the pathogenesis of IgA nephropathy (IgAN). There are contradictory results on their utility in clinical practice. This study is aimed at investigating whether sCD89-IgA complexes can help in the diagnosis or evaluation of the disease. METHODS: A sandwich ELISA was established using anti-CD89 as a capture antibody and HRP-conjugated anti-IgA as a detection antibody. This method was used to measure serum levels of sCD89-IgA complexes in IgAN patients without immunosuppressant history and healthy subjects. Correlations between serum levels of sCD89-IgA complexes and disease severity were analyzed. RESULTS: Serum sCD89-IgA complexes increased with age (P < 0.001). IgAN patients had higher sCD89-IgA complex levels compared with age- and gender-matched normal healthy individuals (P < 0.001). IgAN patients had higher sCD89-IgA complex levels compared with age- and gender-matched normal healthy individuals (P < 0.001). IgAN patients had higher sCD89-IgA complex levels compared with age- and gender-matched normal healthy individuals (. CONCLUSIONS: Serum sCD89-IgA complexes can guide diagnosis of IgAN in patients without immunosuppressant history, but provide limited help in clinicopathologic prediction.

Underlying IgM heavy chain amyloidosis in treatment-refractory IgA nephropathy: A case report.

BACKGROUND: Monoclonal immunoglobulin can cause renal damage, with a wide spectrum of pathological changes and clinical manifestations without hematological evidence of malignancy. These disorders can be missed, especially when combined with other kidney diseases. CASE SUMMARY: A 61-year-old woman presented with moderate proteinuria with normal renal function. She was diagnosed with IgA nephropathy combined with monoclonal gammopathy of undetermined significance after the first renal biopsy. Although having received immunosuppressive treatment for 3 years, the patient developed nephrotic syndrome. Repeated renal biopsy and laser microdissection/mass spectrometry analysis confirmed heavy chain amyloidosis. After nine cycles of bortezomib, cyclophosphamide and dexamethasone, she achieved very good partial hematological and kidney responses. CONCLUSION: Renal injury should be monitored closely in monoclonal gammopathy patients without obvious hematological malignancy, especially in patients with other pre-existing renal diseases.

Pharmacokinetics, tissue distribution and excretion of ACT001 in Sprague-Dawley rats and metabolism of ACT001.

This study investigated pharmacokinetics, tissue distribution and excretion of ACT001 in Sprague-Dawley rats. Stability study and metabolism study of ACT001 are conducted. The absolute bioavailability of ACT001 is 50.82%. ACT001 has no accumulation effect and displayed wide tissue distribution. ACT001 can be rapidly distributed to tissues after oral administration and can diffuse through the blood-brain barrier. The total cumulative excretion of ACT001 in feces, urine and bile were found to be 0.05, 3.42 and 0.012%, respectively. UPLC/ESI-QTOF-MS coupled with MetaboLynx XS software was utilized to detect the metabolites of ACT001 in vitro. Five metabolites (M1, M2, M3, M4 and M5) were detected. M2 wasn't discovered in human liver microsome samples and bile samples. M1 and M2 weren't discovered in rat plasma and human plasma. M3, M4 and M5 weren't discovered in bile samples. M5 is an active metabolite named micheliolide (MCL). There is no significant difference in half-life, type of identified metabolites and the amount of each metabolites between using rat plasma and human plasma. Owing to the species differences of hepatomicrosome enzymes, significant differences were shown in half-life, type of identified metabolites and the amount of each metabolites between using rat liver microsome and human liver microsome.