Acute Kidney Injury in Different Anticoagulation Strategies: A Large-Scale Pharmacoepidemiologic Study Using Real-World Data.

PURPOSE: Acute kidney injury (AKI) following anticoagulant application has received growing attention as a significant emerging complication of anticoagulation. Nevertheless, there remains a lack of real-world studies to compare the incidence, clinical features, and prognosis of AKI across different anticoagulant regimens. METHODS: Disproportionality analysis and Bayesian analysis were used to identify suspected AKI cases after different anticoagulant use within the Food and Drug Administration's Adverse Event Reporting System from January 2004 to March 2023. The time to onset, fatality, and hospitalization rates of anticoagulant-associated AKI were also investigated. RESULTS: We identified 9313 anticoagulant-associated AKIs, which appeared to influence mostly patients over 65 years old (65.37%). Lepirudin displayed a stronger AKI association than others, based on the highest reporting odds ratio (ROR = 6.66, 95% CI = 3.97-11.18), proportional reporting ratio (PRR = 6.08, χ2 = 69.12), and empirical Bayes geometric mean (EBGM = 6.08, the lower 90% one-sided CI = 3.95). Warfarin showed the slightest association with AKI in oral anticoagulants, lower than any direct oral anticoagulants excluding apixaban. Edoxaban exhibited the highest potential renal risk among direct oral anticoagulants, with an ROR of 3.32 (95% CI = 2.95-3.72). The median time to AKI onset was 36 (IQR 7-205) days following the initiation of anticoagulation therapy, and most AKI cases occurred within the first month. CONCLUSION: Particular attention should be directed toward monitoring renal function in individuals receiving anticoagulants, including warfarin and direct oral anticoagulants, as well as other anticoagulant agents. This diligence is particularly imperative within the first month after anticoagulant administration for individuals with a tendency for AKI.

New-onset metabolic syndrome is associated with accelerated renal function decline partially through elevated uric acid: an epidemiological cohort study.

Background: The burden of metabolic syndrome (MetS) continues to rise globally and is associated with complications of multiple organ systems. We aimed to identify the association between changes in MetS status and accelerated renal function progression through a regional epidemiological survey in China, thus discovering influence factors with treatable potential. Methods: This study was a population-based survey conducted in 2008 and 2014, assessing a representative sample of 5,225 individuals from rural areas of China. They were divided into four subgroups according to their MetS status in 2008 and 2014 (Never, Previously abnormal, New-onset, and Consistent). Multivariate logistic regression and stratification analysis evaluated the relationship between clinical factors and renal function decline under different MetS statuses. Smooth curve fitting further addressed the role of serum uric acid, illustrating the vital turning point of uric acid levels in the background of renal function deterioration. Results: Of all groups of MetS states, the new-onset MetS showed the most significant eGFR decline, with a 6.66 ± 8.21 mL/min/1.73 m2 decrease over 6 years. The population with newly-onset MetS showed a considerable risk increase in delta eGFR with a beta coefficient of 1.66 (95%CI=1.09-2.23) after necessary correction. In searching for the drivers, the strength of the association was significantly reduced after additional adjustment for uric acid levels (ß=0.91, 95%CI=0.35-1.45). Regarding the turning point, uric acid levels exceeding 426 µmol/L were more significantly associated with the stepped-up deterioration of kidney function for those with new-onset MetS. Conclusion: Metabolic syndrome demonstrated a solid correlation with the progression of renal function, particularly in those with newly-onset MetS status. In addition to the diagnostic components of MetS, hyperuricemia could be used as a marker to identify the high risk of accelerating eGFR decline early. Furthermore, we suggested a potential renal benefit for the newly-onset MetS population when maintaining their serum uric acid level below the criteria for asymptomatic hyperuricemia.

Malignancy-associated membranous nephropathy: focus on diagnosis and treatment.

BACKGROUND: The clinicopathological features of malignancy-associated membranous nephropathy have been described previously, but information about diagnosis and treatment remains limited. METHODS: Patients with malignancy-associated membranous nephropathy in a tertiary hospital in China between June 2012 and October 2021 were retrospectively reviewed. RESULTS: Forty-two patients with malignancy-associated membranous nephropathy were identified. Compared to patients with idiopathic membranous nephropathy, patients with malignancy-associated membranous nephropathy were older and less frequently showed glomerular phospholipase A2 receptor staining (37.9% vs 85.0%) and IgG4 predominant deposition (66.7% vs 95.0%). At diagnosis of membranous nephropathy, the malignancy was unknown in 67% (28/42) of patients and was detected only by tumor screening. Among the 19 patients with concurrent diagnosis of cancer and biopsy-proven membranous nephropathy, 15 received anticancer treatment alone initially. Six of the 10 patients who attained cancer remission achieved remission of membranous nephropathy, while none of the 5 patients without remission of cancer did, suggesting a causal relationship between the two diseases. Some patients with persistent or relapsing membranous nephropathy following cancer remission achieved remission of membranous nephropathy after immunosuppressive therapy. Over a median follow-up of 24 months, 25% (10/40) of patients died, mainly due to neoplasia. CONCLUSIONS: Tumor screening is important in patients with membranous nephropathy, especially in elderly patients and patients with negative phospholipase A2 receptor or non-IgG4 predominant deposition. Remission of membranous nephropathy can be observed following remission of cancer in some cases. Immunosuppressive therapy may be considered if membranous nephropathy does not remit after remission of cancer.

Characteristics and Diagnostic Challenge of Antineutrophil Cytoplasmic Antibody Positive Infective Endocarditis.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA) has been reported in patients with infective endocarditis. Whether ANCA is associated with certain characteristics of infective endocarditis is unclear. The principal aim of this study is to investigate the clinical implications of ANCA in infective endocarditis and highlight the diagnostic challenge in ANCA-positive patients with infective endocarditis. METHODS: A retrospective study was conducted in a tertiary hospital in China from August 2012 to December 2021. Patients with a diagnosis of infective endocarditis and available ANCA results were included in the study. The clinical and pathological characteristics were compared between ANCA-positive and ANCA-negative patients. RESULTS: A total of 237 patients were included. Forty three (18.1%) were ANCA-positive, predominantly c-ANCA/anti-PR3. Compared to ANCA-negative patients, ANCA-positive patients had longer disease duration (P = .004), more frequent purpura (P = .015), macrohematuria (P = .002), proteinuria (P = .043), acute kidney injury (P = .004), and rapidly progressive glomerulonephritis (P = .010). Histologic findings of 8 patients with infective endocarditis-associated glomerulonephritis were reviewed. Two ANCA-positive patients with infective endocarditis presented with pauci-immune necrotizing and crescentic glomerulonephritis. A total of 18.6% of ANCA-positive patients with infective endocarditis were misdiagnosed as ANCA-associated vasculitis. CONCLUSIONS: ANCA is detected in a substantial proportion of patients with infective endocarditis. The presence of ANCA in infective endocarditis is associated with longer disease duration, more frequent purpura, and kidney involvement. ANCA-positive infective endocarditis may mimic ANCA-associated vasculitis, and the differential diagnosis is challenging. Whether ANCA is pathogenic in infective endocarditis-associated small vessel vasculitis requires further study.

Vasculitis Secondary to Pulmonary Bacterial Infection: A Case Report.

Vasculitides are a heterogeneous group of primary disorders which may occur secondary to a variety of conditions. Among them, vasculitis caused by bacterial infection is rare. Here, we present images of CT scans and histology from a 22-year-old young Chinese man with vasculitis secondary to bacterial infection, which is a difficult disease to diagnose. This patient had been diagnosed with antineutrophil-cytoplasmic-antibody-negative vasculitis with pulmonary and renal involvement and was treated with glucocorticoids combined with immunosuppressive agents. However, during his follow up we found that multiple patchy shadows and cavities in both lungs and renal lesions had fluctuated, and the improvement of chest imaging was always related to antibiotic treatment. In addition, renal histology showed capillary loop necrosis and extensive crescent formation, and electron microscopy revealed scattered subepithelial hump-like deposits, which favored the diagnosis of infection over idiopathic vasculitis. Therefore, vasculitis secondary to infection was confirmed. The subsequent therapy response supported our diagnosis. This case is important; since vasculitis secondary to infection is uncommon, our case provides a model for the diagnosis of vasculitis secondary to infection.

Endocarditis-associated rapidly progressive glomerulonephritis mimicking vasculitis: a diagnostic and treatment challenge.

BACKGROUND: Infective endocarditis (IE)-associated rapidly progressive glomerulonephritis (RPGN) is rarely reported. Sporadic case reports have noted the diagnostic and therapeutic challenge in IE-associated glomerulonephritis because it may masquerade as idiopathic vasculitis. METHODS: Patients with clinical diagnosis of IE-related RPGN in a tertiary hospital in China between January 2004 and May 2021 were identified and retrospectively reviewed. RESULTS: Twenty-four patients with IE-associated RPGN were identified. All patients presented with fever and multiorgan system involvement on top of heart and kidneys, spleen (79%, 19/24), skin (63%, 15/24), lung (33%, 8/24) and nervous system (17%, 4/24). Six of the 24 patients (25%) were initially suspected to have ANCA-associated or IgA vasculitis. Forty-five percent of patients are seropositive for ANCA. Renal histology showed mesangial and/or endocapillary hypercellularity with extensive crescents in most patients. C3-dominant deposition was the predominant pattern on immunofluorescence and pauci-immune necrotising crescentic glomerulonephritis was observed in one case. All patients received antibiotics with or without surgery. Six patients received immunosuppressive therapy before antibiotics due to misdiagnosis and seven patients received immunosuppressive therapy after antibiotics due to persistence of renal failure. Three of the 24 patients died due to severe infection. All the surviving patients had partial or complete recovery of renal function. CONCLUSION: IE-associated RPGN is rare and the differential diagnosis from idiopathic vasculitis can be challenging due to overlaps in clinical manifestations, ANCA positivity and absence of typical presentations of IE. The prognosis is generally good if antibiotics and surgery are not delayed. The decision on introducing immunoruppressive treatment should be made carefully on a case by case basis when kidney function does not improve appropriately after proper anti-infective therapy.Key messagesInfective endocarditis associated RPGN is rare and differentiating it from idiopathic vasculitis can be challenging due to overlap in clinical manifestations, ANCA positivity and occasional absence of typical manifestations of infective endocarditis.Kidney function usually responds to antibiotic therapy alone.Immunosuppressive therapy may be beneficial in carefully selected patients whose kidney function does not improve with antibiotics alone.

Infective Endocarditis-Associated Purpura and Glomerulonephritis Mimicking IgA Vasculitis: A Diagnostic Pitfall.

BACKGROUND: Purpura and glomerulonephritis are typical presentations in IgA vasculitis. Infective endocarditis mimicking IgA vasculitis by presenting with glomerulonephritis and purpura is rarely reported. METHODS: We searched for cases with infective endocarditis-associated purpura and glomerulonephritis in a tertiary hospital in China and retrospectively reviewed their clinicopathological features. Differential diagnosis and treatment in patients with infective endocarditis-associated purpura and glomerulonephritis were discussed. RESULTS: A total of 20 cases with infective endocarditis-associated purpura and glomerulonephritis were identified among 548 cases with infective endocarditis in our center during an 8-year period: 7 of the 20 cases (35%) were initially misdiagnosed as IgA vasculitis and 10 cases (50%) presented with left-sided endocarditis caused by Streptococcus viridans. Fever (100%, 20 out of 20), prior valvular deformities (80%, 16 out of 20), cardiac murmur (95%, 19 out of 20), splenomegaly (84%, 16 out of 19), embolism (55%, 11 out of 20), and hypocomplementemia (76%, 13 out of 17) were present in most patients. Crescents and mesangial hypercellularity with or without endothelial hypercellularity were the primary findings on light microscopy, with C3-dominant deposition on immunofluorescence. But IgA-dominant staining was also observed (40%, 2 out of 5). In patients with rapidly progressive glomerulonephritis, patients with complete recovery of renal function had shorter disease duration and higher ratio (67% vs 20%) of immunosuppressive therapy compared with patients with partial recovery. CONCLUSIONS: Infective endocarditis-associated glomerulonephritis and purpura can closely mimic IgA vasculitis. Differential diagnosis is challenging, particularly when typical presentations of infective endocarditis are absent. In adults with presentations like IgA vasculitis, infective endocarditis should be evaluated through comprehensive clinical and pathological investigations. Immunosuppressive therapy can be considered in patients with severe glomerulonephritis who do not improve after proper anti-infective therapy.

Alteration of methylation status in the ATXN3 gene promoter region is linked to the SCA3/MJD.

DNA methylation has been acknowledged as one of the key epigenetic mechanisms involved in the regulation of gene expression and genomic functions. Alteration of the DNA methylation level has been linked to modification of the disease progression and instability regulation of certain disease-causing repeats in neurodegenerative diseases. In this study, blood samples collected from spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) patients versus control were used to explore the potential link of DNA methylation levels at ATXN3 gene promoter to the pathogenesis of SCA3/MJD. We found that the methylation levels in the ATXN3 promoter were significantly higher in SCA3/MJD patients relative to the controls. Furthermore, higher methylation levels were detected in the SCA3/MJD patients with earlier age at onset and the families with an intergenerational CAG repeats instability. In addition, the first CpG island of the ATXN3 promoter served as the main regulation region of DNA methylation. These findings suggested that an epigenetic change may contribute to the pathogenesis of the SCA3/MJD and provide potential therapeutic targets for CAG repeats-based diseases.

Hypomethylation of SNCA in blood of patients with sporadic Parkinson's disease.

SNCA is a pathogenic gene identified in rare familial PD, and over-expression of SNCA was suggested in the pathogenesis of familial and sporadic PD. Rep1 polymorphism of SNCA was associated with susceptibility to sporadic PD and SNCA expression in intro and in vivo. Hypomethylation in SNCA intron-1 was associated with increased SNCA expression and was observed in postmortem brains of patients with sporadic PD. We studied the methylation status of SNCA intron-1, SNCA mRNA levels and Rep1 genotypes in PBMCs of 100 sporadic PD patients and 95 controls and explored the relationship between DNA methylation, mRNA expression and Rep1 genotypes. Hypomethylation of SNCA intron-1 was detected in PBMCs of PD patients, and DNA methylation levels were associated with Rep1 polymorphism. The shorter allele was associated with higher level of SNCA intron-1 methylation, and genotypes carrying the shorter allele showed significantly higher methylation level of SNCA intron-1 than genotypes carrying the longer allele. However, SNCA mRNA levels were not associated with disease status, Rep1 polymorphism or DNA methylation of SNCA intron-1 in our study.

DNA methylation as a biomarker for neuropsychiatric diseases.

ABSTRACT DNA methylation, which has been investigated extensively recently, has been studied in various human diseases, including cancer, and the analysis of DNA methylation has provided useful biomarkers for diagnosing cancer, monitoring treatment, and predicting the prognosis of cancer. Recently, aberrant DNA methylation has been reported in various neuropsychiatric diseases in both postmortem brains and peripheral blood cells. This review summarizes the current evidence on aberrant DNA methylation in peripheral blood cells from patients with neurodevelopmental, neurodegenerative, and psychiatric disorders, and we propose that DNA methylation could be a novel biomarker for these disorders.

Mutation analysis of microRNA-7 gene in Chinese patients with Parkinson's disease.

OBJECTIVE: To investigate the mutation of small sequence changes in microRNA-7 gene in Chinese patients with Parkinson's disease (PD). METHODS: We analyzed miR-7 variants in 225 PD patients from Chinese Han group by DNA sequence. RESULTS: None of the patients had miR-7 variants. CONCLUSION: MiR-7 variation is not associated with PD in Chinese patients.

Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias.

Paroxysmal kinesigenic dyskinesias is a paroxysmal movement disorder characterized by recurrent, brief attacks of abnormal involuntary movements induced by sudden voluntary movements. Although several loci, including the pericentromeric region of chromosome 16, have been linked to paroxysmal kinesigenic dyskinesias, the causative gene has not yet been identified. Here, we identified proline-rich transmembrane protein 2 (PRRT2) as a causative gene of paroxysmal kinesigenic dyskinesias by using a combination of exome sequencing and linkage analysis. Genetic linkage mapping with 11 markers that encompassed the pericentromeric of chromosome 16 was performed in 27 members of two families with autosomal dominant paroxysmal kinesigenic dyskinesias. Then, the whole-exome sequencing was performed in three patients from these two families. By combining the defined linkage region (16p12.1-q12.1) and the results of exome sequencing, we identified an insertion mutation c.649_650InsC (p.P217fsX7) in one family and a nonsense mutation c.487C>T (p.Q163X) in another family. To confirm our findings, we sequenced the exons and flanking introns of PRRT2 in another three families with paroxysmal kinesigenic dyskinesias. The c.649_650InsC (p.P217fsX7) mutation was identified in two of these families, whereas a missense mutation, c.796C>T (R266W), was identified in another family with paroxysmal kinesigenic dyskinesias. All of these mutations completely co-segregated with the phenotype in each family. None of these mutations was identified in 500 normal unaffected individuals of matched geographical ancestry. Thus, we have identified PRRT2 as the first causative gene of paroxysmal kinesigenic dyskinesias, warranting further investigations to understand the pathogenesis of this disorder.