Urokinase prophylactic anticoagulation in children with nephrotic syndrome: a multicenter retrospective cohort study.

OBJECTIVE: To analyze the clinical effect of urokinase on the prevention of thrombosis in children with primary nephrotic syndrome. METHODS: A total of 370 children diagnosed with primary nephrotic syndrome (PNS) in the Children's Hospital of Soochow University and Zibo Maternal and Child Health Hospital from January 2018 to December 2022 were selected as the research objects. The patients were divided into a urokinase adjuvant therapy group and non-urokinase adjuvant therapy group according to the application of drugs. The clinical data of the children were collected, including sex, age, drug application, bleeding during treatment, and telephone follow-up, to record whether thromboembolism occurred in the acute stage and remission stage. The clinical pattern of PNS, renal biopsy, histopathological type, and related laboratory indexes before and after treatment were recorded. RESULTS: A total of 313 patients were treated with urokinase and 57 patients were not. More thrombotic events was observed in non-urokinase group compared to the urokinase group(2 versus 0 episodes, p = 0.02). The thrombotic events observed included one patient had pulmonary embolism combined with right ventricular thrombosis, and another had intracranial venous thrombosis. More minor bleeding events occurred in urokinase group compared to the non-urokinase group(7 versus 1 episodes, p = 1.0). No major bleeding events occurred in either group. CONCLUSION: The rational prophylactic use of urokinase anticoagulation in children with PNS can prevent the formation of thromboembolism and has good safety.

Reduction of renal interstitial fibrosis by targeting Tie2 in vascular endothelial cells.

BACKGROUND: Tie2, a functional angiopoietin receptor, is expressed in vascular endothelial cells and plays an important role in angiogenesis and vascular stability. This study aimed to evaluate the effects of an agonistic Tie2 signal on renal interstitial fibrosis (RIF) and elucidate the underlying mechanisms. METHODS: We established an in vivo mouse model of folic acid-induced nephropathy (FAN) and an in vitro model of lipopolysaccharide-stimulated endothelial cell injury, then an agonistic Tie2 monoclonal antibody (Tie2 mAb) was used to intervent these processes. The degree of tubulointerstitial lesions and related molecular mechanisms were determined by histological assessment, immunohistochemistry, western blotting, and qPCR. RESULTS: Tie2 mAb attenuated RIF and reduced the level of fibroblast-specific protein 1 (FSP1). Further, it suppressed vascular cell adhesion molecule-1 (VCAM-1) and increased CD31 density in FAN. In the in vitro model, Tie2 mAb was found to decrease the expression of VCAM-1, Bax, and α-smooth muscle actin (α-SMA). CONCLUSIONS: The present findings indicate that the agonistic Tie2 mAb exerted vascular protective effects and ameliorated RIF via inhibition of vascular inflammation, apoptosis, and fibrosis. Therefore, Tie2 may be a potential target for the treatment of this disease. IMPACT: This is the first report to confirm that an agonistic Tie2 monoclonal antibody can reduce renal interstitial fibrosis in folic acid-induced nephropathy in mice. This mechanism possibly involves vascular protective effects brought about by inhibition of vascular inflammation, apoptosis and fibrosis. Our data show that Tie2 signal may be a novel, endothelium-specific target for the treatment of tubulointerstitial fibrosis.

Sintilimab treatment for chronic active Epstein-Barr virus infection and Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children.

BACKGROUND: Chronic active Epstein-Barr virus infection (CAEBV) and Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) are rare but life-threatening progressive diseases triggered by EBV infection. Glucocorticoid/immunosuppressants treatment is temporarily effective; however, most patients relapse and/or progress. Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy; however, there are risks of transplantation-associated complications. Currently there is no standard treatment for CAEBV and EBV-HLH. Programmed death protein 1 (PD-1) inhibitors have achieved a high response in many EBV-related diseases. Sintilimab (a recombinant human IgG4 monoclonal antibody against PD-1) disrupts the interaction between PD-1 and its ligand, leading to T cell reinvigoration. METHODS: A retrospective analysis was performed on three children with CAEBV or EBV-HLH in the Children's Hospital of Soochow University between 12 December 2020 and 28 November 2022. The efficacy of sintilimab was evaluated. RESULTS: Three patients, including two males and one female, were analyzed. Among them, two children were diagnosed with CAEBV with intermittent fever for more than four years, and one child was diagnosed with EBV-HLH. After sintilimab treatment and a mean follow-up of 17.1 months (range 10.0-23.3 months), patients 1 and 3 achieved a complete clinical response and patient 2 achieved a partial clinical response. All three children showed a > 50% decrease in EBV-DNA load in both blood and plasma. EBV-DNA copies in sorted T, B, and NK cells were also markedly decreased after sintilimab treatment. CONCLUSION: Our data supported the efficacy of PD-1 targeted therapy in certain patients with CAEBV and EBV-HLH, and suggested that sintilimab could provide a cure for these diseases, without HSCT. More prospective studies and longer follow-up are needed to confirm these conclusions.

Clinical features and management of atypical hemolytic uremic syndrome patient with DGKE gene variants: a case report.

Background: Atypical hemolytic uremic syndrome (aHUS) with diacylglycerol kinase epsilon (DGKE) gene variant is a rare variant of thrombotic microangiopathy (TMA). The information on the clinical features, management and long-term outcomes of DGKE-aHUS patients have not yet been fully elucidated. The aim of this study was to report a novel variant of the DGKE gene in a Chinese population with aHUS. Case presentation: The present work reports a 7-month-old boy with aHUS, possibly triggered by gastrointestinal infection, without complement activation, with little response to plasma therapy and nephroprotective measures. The patient died during the 8th week of his hospital stay. The causes of death were intracranial hemorrhage and multiorgan dysfunction. Comprehensive WES of peripheral blood-derived DNA revealed two heterozygous variations in the DGKE exon region: NM_003647.2, c.610dup, p.Thr204Asnfs*4 and deletion of exons 4-6. Conclusions: This case suggest that atypical HUS with DGKE gene variant has a poor prognosis with a high mortality rate, which typically manifests in the first year of life and presents as a systemic disease with early-onset HUS with rapidly worsening renal function and chronic proteinuria. There is no specific treatment for DGKE-aHUS. There have an uncertain benefit of plasma therapy for DGKE-aHUS patients. The literature demonstrated that anti-complement therapy showed benefits for DGKE-aHUS with complement activation and autoantibodies during the overt TMA presentation but did not prevent TMA relapses. Early diagnosis and treatment may prevent complications and improve prognosis.

The role of PD-1 signaling in health and immune-related diseases.

Programmed cell death 1 receptor (PD-1) and its ligands constitute an inhibitory pathway to mediate the mechanism of immune tolerance and provide immune homeostasis. Significantly, the binding partners of PD-1 and its associated ligands are diverse, which facilitates immunosuppression in cooperation with other immune checkpoint proteins. Accumulating evidence has demonstrated the important immunosuppressive role of the PD-1 axis in the tumor microenvironment and in autoimmune diseases. In addition, PD-1 blockades have been approved to treat various cancers, including solid tumors and hematological malignancies. Here, we provide a comprehensive review of the PD-1 pathway, focusing on the structure and expression of PD-1, programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2); the diverse biological functions of PD-1 signaling in health and immune-related diseases (including tumor immunity, autoimmunity, infectious immunity, transplantation immunity, allergy and immune privilege); and immune-related adverse events related to PD-1 and PD-L1 inhibitors.

Incidence of thromboembolism in children with primary nephrotic syndrome: a systematic review and metaanalysis.

OBJECTIVE: To estimate the incidence of thromboembolism in children with primary nephrotic syndrome with Meta-analysis. METHODS: Relevant studies published from January 1, 1980 to December 31, 2021 were retrieved from Pubmed, Web of science, Cochrane library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database(VIP) and Wangfang Database. Quality evaluation of the literatures included was conducted according to Agency for Healthcare Research and Quality(AHRQ) assessment tool, followed by data extraction and Meta-analysis with software RevMan 5.3. RESULTS: A total of seven studies involving 3675 subjects were included. The overall prevalence was 4.9% with 95% CI of 2.83 to 7.05.However, a significant heterogeneity (P < 0.001) was observed with I2 = 89%. The prevalence of venous thromboembolism was 3.3% with 95% CI of 1.7 to 4.9. The prevalence of arterial thromboembolism was 0.5% with 95% CI of 0.2 to 1.4. CONCLUSION: Children with nephrotic syndrome are prone to thromboembolism, and it may lead to disability or death, therefore prevention measures is critical to decreasing the prevalence of thromboembolism.

Pathological evaluation of renal complications in children following allogeneic hematopoietic stem cell transplantation: a retrospective cohort study.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematologic malignancies and non-malignant disorders, such as aplastic anemia, fanconi anemia, and certain immune deficiencies. Post-transplantation kidney injury is a common complication and involves a wide spectrum of structural abnormalities, including glomerular (MSPGN, mesangial proliferative glomerulonephritis; FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; MCD, minimal change disease), vascular (TMA, thrombotic microangiopathy), and/or tubulointerstitial (TIN, tubulointerstitial nephritis; ATI, acute tubular injury). Renal biopsy is the gold-standard examination for defining multiple etiologies of kidney impairment. Although kidney injury following HSCT has been studied, little is known about the effects of allo-HSCT on renal pathology in pediatric patients. METHODS: We retrospectively analyzed renal biopsy specimens from children with kidney injury after allo-HSCT and correlated results with clinical data in the last 10 years. RESULTS: Among 25 children (18 males and 7 females), three patients had proteinuria indicating nephrotic syndrome (24-hour urinary total protein/weight > 50 mg/kg/d), nine patients had severely reduced estimated glomerular filtration rate (eGFR < 30 ml/min/1.73 m2) and four patients received kidney replacement therapy (KRT). The main pathologies identified from kidney biopsies were MSPGN (n = 12), FSGS (n = 12), MPGN (n = 5), TMA (n = 4), MCD (n = 3), diffuse glomerular fibrosis (DGF, n = 2), ATI and TIN, in isolation or combined with other pathologies. The median follow-up time was 16.5 (0.5 ~ 68.0) months. Three patients died of recurrent malignancy and/or severe infection, one child developed to end-stage renal disease (ESRD), six patients (24%) had elevated serum creatinine (SCr > 100µmol/l) and nine patients (36%) still had proteinuria. CONCLUSIONS: This study evaluates histomorphologic findings from kidney biopsies of pediatric recipients following allo-HSCT. Detailed evaluation of renal biopsy samples is helpful to elucidate the nature of renal insult, and may potentially identify treatable disease processes.

Clinical characteristics and outcomes of chronic nonbacterial osteomyelitis in children: a multicenter case series.

OBJECTIVE: The aim of this study was to evaluate demographic, clinical, laboratory, imaging, histopathology characteristics, and treatment responses of children with Chronic nonbacterial osteomyelitis (CNO). METHODS: Retrospective multi-center case series study of pediatric patients diagnosed with CNO treated at five tertiary centers in south China. RESULTS: Totally there were 18 patients diagnosed as CNO between 2014 and 2020. The median age of onset was 9.2 years (range 3.7-13.1) and 55.6% were female. Median delay in diagnosis was 10.9 months (range 1.0-72.0). The most frequent presenting symptoms were bone pain (100%) and fever (44.4%). Most patients had more than one lesion (median of 5, range 1-7). Most frequently affected bones were tibiofibula (88.9%) and femur (77.8%). The MRI characteristics mainly presented as bone edema and hyperintensity in bone marrow. Bone biopsy was conducted in 11 patients (61.1%) with inflammatory cells infiltration manifested as chronic osteomyelitis, and none showed bacterial infection or tumor. In treatment, non-steroid anti-inflamatory drugs (NSAIDs) is used as the first-line drug followed by steriods, methotexate (MTX), salazosulfadimidine (SASP), Bisphosphonates and TNF-α inhibitor. Two refractory cases received combination therapy with Bisphosphonates and TNF-α inhibitor, and achieved good therapeutic effect. CONCLUSIONS: The present study described a multicenter series of CNO from south China and highlighted the clinical features, laboratory tests, imaging characteristics and treatment outcomes. Increasing awareness of this disease is important to decrease time to diagnosis, improve access to treatment, and reduce complications.

Acute pancreatitis and macrophage activation syndrome in pediatric systemic lupus erythematosus: case-based review.

Pancreatitis is uncommon in systemic lupus erythematosus (SLE) and is rarely reported in children, possibly being related to macrophage activation syndrome (MAS). The incidence of MAS in children with lupus pancreatitis is unknown, as is their prognosis. In this case-based review, we report a pediatric patient with SLE complicated with pancreatitis and MAS, and performed a literature review. We report an 11-year-old girl with SLE and MAS who developed pancreatitis on the second day of methylprednisolone pulse therapy (500 mg/day). We continued methylprednisolone pulse therapy, and performed three rounds of DNA-immunoadsorption and three rounds of hemoperfusion. A second course of methylprednisolone pulse therapy was initiated 9 days later. The patient received a monthly cyclophosphamide pulse therapy (10 mg/kg/day, 2 consecutive days every month) for 6 months, after which she was treated with mycophenolate mofetil 20 mg/kg/day. The condition of the patient gradually improved, her blood amylase and lipase decreased. She was in a stable condition during 13-month follow-up period. Review of the literature of pediatric patients with SLE and pancreatitis showed that there are 127 cases that have been reported in the past 30 years, 40 cases were excluded in our study because of inadequate information. Of the 87 patients included in our literature review, the mortality rate was 33.33%, and 52.86% of the patients with pancreatitis had MAS at the same time. Pancreatitis is uncommon in SLE, but must be suspected if a patient with SLE develops digestive symptoms. Patients with SLE with pancreatitis have a high incidence of MAS and high mortality rate; however, early recognition and effective treatment can relieve the disease symptoms.