HLA loci predisposing to immune TTP in Japanese: potential role of the shared ADAMTS13 peptide bound to different HLA-DR.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder caused by neutralizing anti-ADAMTS13 autoantibodies. In white individuals, HLA allele DRB1*11 is a predisposing factor for iTTP, whereas DRB1*04 is a protective factor. However, the role of HLA in Asians is unclear. In this study, we analyzed 10 HLA loci using next-generation sequencing in 52 Japanese patients with iTTP, and the allele frequency in the iTTP group was compared with that in a Japanese control group. We identified the following HLA alleles as predisposing factors for iTTP in the Japanese population: DRB1*08:03 (odds ratio [OR], 3.06; corrected P [Pc] = .005), DRB3/4/5*blank (OR, 2.3; Pc = .007), DQA1*01:03 (OR, 2.25; Pc = .006), and DQB1*06:01 (OR,: 2.41; Pc = .003). The estimated haplotype consisting of these 4 alleles was significantly more frequent in the iTTP group than in the control group (30.8% vs 6.0%; Pc < .001). DRB1*15:01 and DRB5*01:01 were weak protective factors for iTTP (OR, 0.23; Pc = .076; and OR, 0.23, Pc = .034, respectively). On the other hand, DRB1*11 and DRB1*04 were not associated with iTTP in the Japanese. These findings indicated that predisposing and protective factors for iTTP differ between Japanese and white individuals. HLA-DR molecules encoded by DRB1*08:03 and DRB1*11:01 have different peptide-binding motifs, but interestingly, bound to the shared ADAMTS13 peptide in an in silico prediction model.

Comprehensive coagulation and fibrinolytic potential in the acute phase of pediatric patients with idiopathic nephrotic syndrome evaluated by whole blood-based rotational thromboelastometry.

BACKGROUND: Venous thromboembolism is a rare, serious complication of idiopathic nephrotic syndrome (INS) in childhood. The mechanisms responsible for the hypercoagulable state in the acute phase of INS are poorly understood, however. This study aimed to assess overall coagulation and fibrinolytic function in pediatric patients with INS. METHODS: Global coagulation and fibrinolysis were examined in whole blood samples from 22 children with initial onset INS (initial-group), 22 children with relapsed INS (relapse-group), and 15 control pediatric patients using rotational thromboelastometry (ROTEM®). In the initial-group, blood samples were obtained before (week 0) and 1-4 weeks after initiation of corticosteroid therapy. EXTEM and FIBTEM were used to assess coagulation and fibrinolysis, respectively. Clot time (CT), clot formation time (CFT), maximum clot firmness (MCF), and α-angle were determined as coagulation parameters, and lysis index at 30 and 60 min (LI30 and LI60, respectively) were assessed as fibrinolytic parameters. RESULTS: CT was significantly shortened, and MCF and α-angle were significantly greater than controls at week 0 and week 1 both in the initial-group and the relapse-group. MCF correlated with serum albumin (r = 0.70, p < 0.001) and fibrinogen level (r = 0.68, p < 0.001). The fibrinolytic parameters (LI30 and LI60) in the initial-group were stable and higher than those in controls at all time points (p < 0.01). CONCLUSIONS: We have shown that the hypofibrinolytic defect did not improve with effective NS treatment at the early 4-week time-point. Additionally, a likely pre-thrombotic state was evident in the period before initial onset and 1 week after corticosteroid therapy in pediatric INS.

Coagulation potential in pediatric patients with immunoglobulin A nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most prevalent primary chronic glomerular disease in children. Understanding the changes in coagulability caused by IgAN is important for clarifying pathophysiology and choice of treatment. The coagulation potential in patients with IgAN remains to be investigated, however. We aimed to assess comprehensive coagulation potential in pediatric patients with IgAN and explore its relationship with pathological disease severity. METHODS: Fourteen children with IgAN diagnosed by renal biopsy, who were admitted at Nara Medical University Hospital between 2015 and 2020, were analyzed. Rotational thromboelastometry was used to evaluate coagulation potential. Values of rotational thromboelastometry parameters in patients with IgAN were compared with those in control children. RESULTS: In patients with IgAN (aged median 9.5 year), clotting time plus clot formation time (CT + CFT) was shortened (P = 0.003) and α angle was greater (P < 0.001) than those in controls, indicating a hypercoagulable state. The rate of mesangial hypercellularity of glomeruli correlated with CT + CFT, α, and maximum clot firmness (MCF) (rs = -0.79, 0.56, and 0.37). The rate of cellular/fibrocellular crescent of glomeruli correlated with CT + CFT, α, and MCF (rs = -0.41, 0.60, and 0.50). Patients with mesangial hypercellularity ≥80% of glomeruli showed reduced CT + CFT and increased α angle (P = 0.007 and 0.03). Patients with cellular/fibrocellular crescent ≥10% of glomeruli showed decreased CT + CFT and increased α angle (both P = 0.02). CONCLUSIONS: The hypercoagulable state in pediatric patients with IgAN may be associated with the pathological severity of their disease.

Lung abscess caused by Mycoplasma pneumoniae.

A 10-year-old boy with West syndrome was referred to hospital because of high fever and cough. Chest X-ray and computed tomography showed consolidation with an abscess in the right upper lobe. Laboratory data indicated cytokine storm. Various antibacterial agents and additional corticosteroid were unable to control the hypercytokinemia, which was suppressed after cyclosporine A was started. The lung abscess remained, however, and right upper lobectomy was performed. Culture from the abscess showed no growth, while polymerase chain reaction assay indicated Mycoplasma pneumoniae DNA. Serum passive agglutinin titer for M. pneumoniae was significantly elevated in the convalescent phase. These findings are strong evidence that the lung abscess was caused by M. pneumoniae infection.

Peritoneal dialysis-associated infection caused by Mycobacterium abscessus in a pediatric patient on continuous peritoneal dialysis without switching to hemodialysis.

Most peritoneal dialysis (PD)-associated infections caused by Mycobacterium abscessus (M. abscessus) require a transfer from PD to hemodialysis (HD). Here, we report a pediatric case of exit-site and tunnel infections caused by M. abscessus, for whom PD was continued with catheter replacement, debridement of the infected site, and the administration of multiple antibacterial agents. A 10-year-old boy with end-stage kidney disease secondary to juvenile nephronophthisis with NPHP1 deletion, for whom PD was initiated at the age of 9 years, was admitted to the hospital with complaints of fever, pus at the exit-site of the PD catheter, and poor PD drainage. The dialysis effluent culture results were negative; however, M. abscessus was detected in the pus at the exit-site of the PD catheter. The management of HD was expected to be challenging owing to the presence of developmental disorders. Therefore, PD was continued with the simultaneous removal of the PD catheter, reinsertion of a new catheter at a new site, and debridement of the infected site. Multiple antibacterial therapies were administered for 2 months, and the patient was eventually discharged without switching to HD. To the best of our knowledge, this is the first pediatric case of a PD-associated infection caused by M. abscessus, for whom PD was continued without switching to HD. This treatment strategy is not generally recommended but may be an option for patients without peritonitis who have difficulty switching to HD.

Pediatric mesangial proliferative glomerulonephritis has increased the platelet thrombus formation potentials under high-shear flow condition.

INTRODUCTION: Blood coagulation is associated with glomerulonephritis (GN) pathophysiology. Using whole-blood-based rotational thromboelastometry, we recently reported that the degree of hypercoagulability in pediatric patients with immunoglobulin A nephropathy (IgAN), a GN, might be associated with pathological severity. To further clarify the coagulation status of mesangial proliferative glomerulonephritis (MesPGN), we assessed the platelet thrombus formation (PTF) under high-shear flow using a microchip-based flow chamber system (T-TAS®). METHODS: Thirty-four pediatric patients definitively diagnosed with MesPGN by renal biopsy at Nara Medical University Hospital between 2015 and 2022 were enrolled, and 29 patients (case group; median age, 8.0 years) were assessed. Microchips coated with collagen (PL-chip) were used to assess PTF at high-shear in whole blood. The times to increase by 10 and 30 kPa (T10 and T30) from baseline were calculated and compared with those of the pediatric controls. Changes in the parameters during the treatment course and the relationship between pathological severity and the parameters were evaluated. RESULTS: T10 and T30 parameters in the PL-chip were significantly shorter and the area under the curves were greater in the case group than those in the control group (both p <0.05). Each parameter was enhanced during the 3-week treatment but improved after the end of treatment. No significant relationship was observed between pathological severity and these parameters. Little PTF difference was observed between IgAN and Henoch-Schönlein purpura nephritis. CONCLUSIONS: Pediatric MesPGN increased the potential for PTF under high-shear flow conditions.