Decreased TAX1BP1 participates in systemic lupus erythematosus by regulating monocyte/macrophage function.

Systemic lupus erythematosus (SLE) involves disorders of innate and adaptive immune pathways. Tax1-binding protein 1 (TAX1BP1) modulates the production of antibodies in B cells and the T-cell cycle by regulating the NF-κB signaling pathway. However, the potential association of TAX1BP1 with SLE and its role in monocytes/macrophages have not been fully elucidated. In this study, we utilized whole-exome sequencing (WES) in combination with Sanger sequencing and identified 16 gene mutations, including in TAX1BP1, in an SLE family. TAX1BP1 protein expression with western blotting detection was reduced in SLE patients and correlated with disease activity negatively. Furthermore, RNA sequencing and 4D Label-Free Phosphoproteomic analysis were employed to characterize the transcriptome and phosphoproteome profiles in THP-1 and THP-1-differentiated M1 macrophages with TAX1BP1 knockdown. Silencing of TAX1BP1 in THP-1 and THP-1-differentiated M1 macrophages led to an increase in cluster of differentiation 80 (CD80) expression and differential changes in CD14 and CD16 expression, as assessed by flow cytometry. Additionally, western blot analysis showed that knockdown of TAX1BP1 led to a reduction in TRAF6 and p-p65 in THP-1-differentiated macrophages, with or without lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α stimulation. Taken together, our findings suggest that TAX1BP1 participates in SLE activity by regulating antigen presentation in monocytes and inflammatory responses in M1 macrophages.

First reported case of ANCA-associated vasculitis induced by oxaliplatin, capecitabine, and trastuzumab.

A 68-year-old male, who was undergoing XELOX plus trastuzumab therapy for gastric cancer, developed proteinuria, hematuria, and progressive increase in creatinine after 3 months. Subsequently, the patient also experienced hemoptysis, nasal bleeding. Chest CT examination shown pulmonary hemorrhage. The MRI of the nasopharynx ruled out nasopharyngeal cancer recurrence. The MPO and PR3 were elevated, and renal biopsy confirmed ANCA-related vasculitis, which affected the lungs, kidneys, and nasopharynx. Based on the review of the patient''s medical history and medication, it is believed that ANCA-related vasculitis was caused by XELOX plus trastuzumab chemotherapy, but it is difficult to confirm which specific drug caused it. After stopping XELOX plus trastuzumab chemotherapy, glucocorticoids and cyclophosphamide was given, the patient''s pulmonary hemorrhage and nasal bleeding stopped, and the lung lesions were absorbed. The renal function also improved. The patient later experienced pulmonary infection again, and tNGS indicated Legionella pneumophila and pulmonary tuberculosis infection. Despite anti-infection treatment, steroid dose was rapidly reduced. Ultimately, the patient gave up on treatment and eventually died.

Tacrolimus Monotherapy after Intravenous Methylprednisolone in Adults with Minimal Change Nephrotic Syndrome.

Glucocorticoid treatment is the first choice therapy for adults with minimal change nephrotic syndrome; however, this therapy associates with many adverse effects. Tacrolimus may be an alternative to conventional glucocorticoid therapy. To investigate this possibility, we conducted a prospective, randomized, controlled trial (WHO International Clinical Trials Registry Platform: ChiCTR-TRC-11001454) in eight renal units across China. We randomized enrolled patients with adult-onset minimal change nephrotic syndrome (n=119) to receive glucocorticoid therapy or tacrolimus after intravenous methylprednisolone (0.8 mg/kg per day) for 10 days. Patients received a conventional glucocorticoid regimen or tacrolimus monotherapy, starting with 0.05 mg/kg per day (target trough whole-blood level of 4-8 ng/ml) for 16-20 weeks and subsequently tapering over approximately 18 weeks. Remission occurred in 51 of 53 (96.2%; all complete remission) glucocorticoid-treated patients and 55 of 56 (98.3%; 52 complete and three partial remission) tacrolimus-treated patients (P=0.61 for remission; P=0.68 for complete remission). The groups had similar mean time to remission (P=0.55). Relapse occurred in 49.0% and 45.5% of the glucocorticoid- and tacrolimus-treated patients, respectively (P=0.71), with similar time to relapse (P=0.86). Seven (13.7%) glucocorticoid-treated and four (7.3%) tacrolimus-treated patients suffered frequent relapse (P=0.28); five glucocorticoid-treated and two tacrolimus-treated patients became drug dependent (P=0.26). Adverse events occurred more frequently in the glucocorticoid group (128 versus 81 in the tacrolimus group). Seven adverse events in the glucocorticoid group and two adverse events in the tacrolimus group were serious. Consequently, tacrolimus monotherapy after short-term intravenous methylprednisolone is noninferior to conventional glucocorticoid treatment for adult-onset minimal change nephrotic syndrome in this cohort.

Diagnostic value of serum procalcitonin for acute pyelonephritis in infants and children with urinary tract infections: an updated meta-analysis.

PURPOSE: The aims were to assess (1) the diagnostic value of serum procalcitonin (PCT) for acute pyelonephritis (APN) in infants and children with urinary tract infections (UTIs) and (2) to compare the performance of two commonly used cutoff values. METHODS: A meta-analysis of serum PCT in the diagnosis of APN among pediatrics with lower UTIs was conducted. The process of search strategy, publications selection and data analysis was in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines. RESULTS: Eighteen high-quality studies with a total of 831 APN patients and 651 individuals with lower UTIs were analyzed. The overall performance of serum PCT ≥ 0.5 ng/mL was as follows: pooled sensitivity of 0.86 (95 % CI 0.73-0.93), pooled specificity of 0.76 (95 % CI 0.66-0.83), DOR of 18.90 (95 % CI 6.78-52.71) and AUROC of 0.86 (95 % CI 0.83-0.89), with significant heterogeneity. However, use of 1.0 ng/mL as a cutoff value produced an improved specificity of 0.91 (95 % CI 0.86-0.94), a DOR of 55.06 (95 % CI 22.57-115.48) and an AUROC of 0.94 (95 % CI 0.92-0.96), without obvious heterogeneity. CONCLUSION: In pediatrics with UTIs, the cutoff value of serum PCT, 1.0 ng/mL, has a preferable diagnostic performance compared with 0.5 ng/mL for APN. Additional prospective studies that propose an appropriate cutoff value and validate the performance of PCT for young with APN are needed in the future.

Membranous nephropathy and thymoma in a patient with ankylosing spondylitis: A case report.

RATIONALE: We report a rare case with ankylosing spondylitis (AS), thymoma, and membranous glomerulonephritis. The pathogenic mechanisms of these 3 diseases may be associated with each other. Here, we discuss the course of diagnosis and treatment. PATIENT CONCERNS: A 64-year-old woman with bilateral pain of the sacroiliac joints for 10 years and anasarca for 10 days. DIAGNOSES: A diagnosis of AS by HLA-B27 and pelvic X-ray tests, thymoma based on computed tomography and pathological diagnosis, and membranous glomerulonephritis based on renal biopsy. INTERVENTIONS: We administered methylprednisolone 500 mg/d for 3 consecutive days, followed by methylprednisolone 40 mg oral QD, for a month. OUTCOMES: The patient was followed up once a month. In the sixth month, the patient's serum creatinine had decreased to 0.96 mg/dL, urine microalbumin/creatinine decreased to 173.3 mg/g, and albumin had risen to 33.1 g/L. Pain and morning stiffness were relieved, and the Bath Ankylosing Spondylitis Disease Activity Index score dropped to 4.0. LESSONS: Although the causal relationship between AS, thymoma, and membranous nephropathy in this patient still needs to be established, the pathogenesis between the 3 diseases may have some association. In clinical practice, patients with AS need to be screened for tumors and renal complications.

Nocturnal and Circadian Rhythm of Blood Pressure Is Associated with Renal Structure Damage and Function in Patients with IgAN.

BACKGROUND AND AIMS: Abnormal circadian rhythm of blood pressure (BP) is closely related to target organ damage in hypertension. However, the association between abnormal circadian rhythm of BP and renal injury is not clear. We investigated whether renal injury is associated with nocturnal BP and circadian rhythm of BP in Chinese IgAN patients. METHODS: Clinic and 24 h ambulatory BP monitoring data were obtained from 330 Chinese IgAN patients with mean 24 h BP < 130/80 and mean daytime BP < 135/85 mmHg. Renal histopathological injury was determined according to the Oxford classification of IgAN. RESULTS: Among the 330 IgAN subjects, 35.8% suffered from nocturnal hypertension, 61.5% had abnormal circadian BP, and 27% had nocturnal hypertension with a nondipping pattern. Compared with nocturnal normotensive patients, patients with nocturnal hypertension had significantly higher levels of blood cystatin C, blood uric acid, and lower estimated glomerular filtration rate (eGFR), and significantly a higher mean renal tissue injury score. The nondipping hypertensive group had significantly higher nocturnal diastolic and systolic BP, blood uric acid, and glomerulosclerosis rates, whereas eGFR was lower. In nondipping hypertensive patients, urinary sodium excretion and renal tissue injury scores were significantly higher than dipping patients. Nocturnal hypertension and abnormal circadian BP correlated with renal tissue injury, renal interstitial fibrosis, and aortic arch atherosclerosis. CONCLUSION: Abnormal circadian rhythm of BP and nocturnal hypertension are common clinical manifestations in Chinese IgAN patients with normal mean 24 h BP. Abnormal circadian BP and nocturnal hypertension may accelerate IgAN progression by inducing renal dysfunction and histopathological damage.

Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling.

Premature senescence is a key process in the progression of diabetic nephropathy (DN). In our study, we hypothesized that receptors for advanced glycation end-products (RAGE) mediate endoplasmic reticulum (ER) stress to induce premature senescence via p21 signaling activation in diabetic nephropathy. Here, we demonstrated that elevated expression of RAGE, ER stress marker glucose-regulated protein 78 (GRP78), and cell-cycle regulator p21 was all positively correlated with enhanced senescence-associated-ß-galactosidase (SA-ß-gal) activity in DN patients. In addition, the fraction of SA-ß-gal or cells in the G0G1 phase were enhanced in cultured mouse proximal tubular epithelial cells (PTECs) and the expression of RAGE, GRP78 and p21 was up-regulated by advanced glycation end-products (AGEs) in a dose- and time-dependent manner. Interestingly, ER stress inducers or RAGE overexpression mimicked AGEs induced-premature senescence, and this was significantly suppressed by p21 gene silencing. However, RAGE blocking successfully attenuated AGEs-induced ER stress and p21 expression, as well as premature senescence. Moreover, ER stress inducers directly caused p21 activation, premature senescence, and also enhanced RAGE expression by positive feedback. These observations suggest that RAGE promotes premature senescence of PTECs by activation of ER stress-dependent p21 signaling.