Satoko Tsuchida

Recurrent URAT1 gene mutations and prevalence of renal hypouricemia in Japanese

Recent identification of the urate transporter in the kidney (URAT1, encoded by SLC22A12) led to the molecular elucidation of idiopathic renal hypouricemia, which is a predisposition toward exercise-induce acute renal failure. One Japanese patient with renal hypouricemia demonstrated compound heterozygous mutations of the URAT1 gene (Q297X and IVS2+1G>A). It was suggested that these two mutations are recurrent mutations of the URAT1 gene in a Japanese population. In addition, we expect the prevalence of renal hypouricemia, 0.23%, from the analysis of serum urate levels in 1,730 Japanese children.

A case report of pediatric fulminant hepatitis treated with plasma diafiltration.

Abstract:  Plasma diafiltration (PDF) is blood purification therapy in which simple plasma exchange is performed with a membrane plasma separator while dialysate flows outside the hollow fibers. A 14‐year‐old boy with fulminant hepatitis underwent two sessions of PDF and one session of hemodiafiltration. We infused filtered replacement fluid for artificial kidneys at a dialysate flow rate of 600 mL/h and a replacement flow rate of 450 mL/h. We infused fresh frozen plasma (1200 mL) and 25% albumin solution (50 mL) intravenously over 8 h. Each PDF session lasted 8 h. The patients total bilirubin, interleukin‐18, and cystatin C levels decreased with treatment, and he recovered from hepatic failure. PDF may be an extremely useful blood purification therapy for pediatric fulminant hepatitis in terms of both medical economics and cytokine removal.

Johanson-Blizzard Syndrome: Loss of Glucagon Secretion Response to Insulin-induced Hypoglycemia

Johanson-Blizzard syndrome is a rare autosomal recessive disorder characterized by aplasia of the alae nasi, aplasia cutis, dental anomalies, postnatal growth retardation and pancreatic exocrine aplasia. Some endocrinological dysfunctions--growth hormone (GH) deficiency, hypothyroidism, and diabetes mellitus--are known to complicate this syndrome. We report here a Japanese infant with Johanson-Blizzard syndrome presenting with failure to thrive. Endocrinological examination by insulin-induced hypoglycemia showed not only the presence of GH deficiency, but also the loss of the glucagon secretion response to hypoglycemia. This complication suggests abnormal input of autonomic nerves to the islets of pancreas in Johanson-Blizzard syndrome.

Large intracardiac thrombus in a patient with steroid‐responsive nephrotic syndrome

Thromboembolic events are recognized as serious complications of nephrotic syndrome. Intracardiac thrombus formation is extremely rare, but it is the most serious thromboembolic complication of nephrotic syndrome because of its high morbidity and mortality. We herein report a case involving a 12-year-old boy with steroidresponsive nephrotic syndrome complicated by a large intracardiac thrombus that required urgent surgical intervention. A 12-year-old boy was referred to our hospital with a large thrombus in the right atrium. One month previously, he had been diagnosed with idiopathic nephrotic syndrome at a regional hospital. He began treatment with prednisolone at 80 mg daily, which resulted in steady improvement in his proteinuria. Partial remission was achieved in 10 days. Two weeks after remission, the patient developed chest pain and palpitation that occurred several times a day and spontaneously resolved within a few minutes. Echocardiographic examination showed a large thrombus in the right atrium, and the patient was referred to us for further workup. On admission, he was asymptomatic and all vital parameters were within their reference ranges. Laboratory examination revealed the following data: haemoglobin level, 160 g/L; platelet count, 149 × 10/L; urea nitrogen level, 4.8 mmol/L; creatinine level, 34.5 μmol/L; total protein level, 55 g/L; albumin level, 30 g/L; activated partial thromboplastin time, 22.1 s; prothrombin time, 8.7 s; fibrinogen level, 1.46 g/L; antithrombin III activity, > 130%; and protein C activity, > 150%. A urine dipstick test result was negative for protein. Systemic magnetic resonance imaging revealed no evidence of thromboembolism to any other site. Echocardiographic examination showed a large isolated hyperechoic mass in the right atrium. The mass measured 31 × 26 mm in diameter and traversed through the tricuspid valve in a to-and-fro motion. The patient underwent an urgent thoracotomy with excision to avoid pulmonary trunk obliteration. The excised thrombus was 31 × 25 × 20 mm (Fig. 1), and histopathological examination showed that it was mostly composed of platelets. Hypercoagulability is regarded as the factor most attributable to thromboembolic complications in patients with nephrotic syndrome. Multiple factors are associated with nephrotic syndrome; alterations in the coagulative and fibrinolytic system, platelet hyperaggregation, hyperviscosity of blood, and corticosteroid use are mainly responsible for the hypercoagulablity. Thromboembolic complications, including serious events such as intracardiac thrombus formation, can occur in patients with various types of nephrotic syndrome. Thus, clinicians should be aware of the possible risk of life-threatening thromboembolic events in patients with nephrotic syndrome.

Elevation of Serum Acid Sphingomyelinase Activity in Acute Kawasaki Disease.

Kawasaki disease (KD) is an acute systemic vasculitis that affects both small and medium-sized vessels including the coronary arteries in infants and children. Acid sphingomyelinase (ASM) is a lysosomal glycoprotein that hydrolyzes sphingomyelin to ceramide, a lipid, that functions as a second messenger in the regulation of cell functions. ASM activation has been implicated in numerous cellular stress responses and is associated with cellular ASM secretion, either through alternative trafficking of the ASM precursor protein or by means of an unidentified mechanism. Elevation of serum ASM activity has been described in several human diseases, suggesting that patients with diseases involving vascular endothelial cells may exhibit a preferential elevation of serum ASM activity. As acute KD is characterized by systemic vasculitis that could affect vascular endothelial cells, the elevation of serum ASM activity should be considered in these patients. In the present study, serum ASM activity in the sera of 15 patients with acute KD was determined both before and after treatment with infusion of high-dose intravenous immunoglobulin (IVIG), a first-line treatment for acute KD. Serum ASM activity before IVIG was significantly elevated in KD patients when compared to the control group (3.85 ± 1.46 nmol/0.1 ml/6 h vs. 1.15 ± 0.10 nmol/0.1 ml/6 h, p < 0.001), suggesting that ASM activation may be involved in the pathophysiology of this condition. Serum ASM activity before IVIG was significantly correlated with levels of C-reactive protein (p < 0.05). These results suggest the involvement of sphingolipid metabolism in the pathophysiology of KD.

Role of Plasma Exchange in the Management of Pediatric Optic Neuritis With Antibodies Against Myelin Oligodendrocyte Glycoprotein

therapy-refractory/relapsing TTP can achieve sustained remission after treatment with the monoclonal antibody rituximab (RTX) targeting mature B-lymphocytes. Observational data propose that RTX exposure during pregnancy is safe for the child (4). Of note, RTX is actively transported across the placenta and suppresses development of neonatal B-cells, yet only few infection-related complications occurred to the newborn children and B-cell counts normalized after birth. However, in these cases RTX was administered for maternal life-threatening diseases in the absence of alternative treatment options. Neither long-term outcomes nor data on the safe use of RTX during pregnancy treating relapsed TTP have been appraised so far. For autoimmune diseases, it is recommended by the European League Against Rheumatism Committee to interrupt RTX during pregnancy due to insufficient clinical evidence of safety for the fetus. Balancing risks vs. chances to prevent complications to the mother while elongating the pregnancy and protecting the fetus, we decided to continue TPE longer than any other case reported in the literature. No adverse effects of TPE were observed under close-meshed motoring by an interdisciplinary team of nephrologists, obstetricians, and neonatologists. In gestation week 35, a healthy child was born by cesarean section and TPE was discontinued. Yet, thrombocyte counts and ADAMTS13 activity dropped again and we initiated RTX (375 mg/m once per week for 4 weeks). Ultimately, thrombocyte counts stabilized and regular visits in our outpatient clinic confirm sustained remission. Based on our experience in the treatment of TTP and the existing literature, we propose that under careful monitoring daily long-term TPE is a safe option for acquired TTP during pregnancy. We strongly emphasize that therapy-refractory pregnancy-related TTP may be challenging and mandates careful monitoring and management by a multidisciplinary team with expertise in managing the TPE procedure and potential serious complications.

Biopsy-proven acute interstitial nephritis due to fosfomycin in a child

A one-year-old girl with a medical history of haemorrhagic enteritis was treated with fosfomycin, administered orally. After 5 days of treatment, the infant developed severe acute kidney injury, and was referred to our hospital for renal replacement therapy. On admission, she presented with a mild maculopapular rash on her body, and slight oedema of her face. The laboratory examination results were as follows: white blood cells 20.0 × 10/L with 0% eosinophils, urea nitrogen 52.8 mmol/L, creatinine 703.7 μmol/L, and bicarbonate 10.4 mmol/L. On the day of admission, she commenced renal replacement therapy in the form of peritoneal dialysis. The patient achieved clinical recovery, and renal function improved with eventual discontinuation of dialysis on hospital day 8. An open renal biopsy was performed on hospital day 36 to access for acute kidney injury. Histopathological examination revealed diffuse tubulitis associated with patchy inflammatory cell infiltrates including eosinophils (Fig. 1). In addition, the drug lymphocyte stimulation test for fosfomycin revealed a stimulation index of 477% (normal: under 180%). On the basis of these findings, it was suggested that fosfomycin was the offending drug for the acute interstitial nephritis (AIN). Fosfomycin has been generally recognized as a welltolerated drug, and hypersensitivity reactions are extremely rare in the clinical setting of fosfomycin use. In addition, fosfomycin has been reported to have unique immunomodulatory activities associated with high-tolerance, such as suppression of IgE-mediated histamine release from peripheral blood basophils. Recently, some cases of anaphylaxis evoked by fosfomycin have been reported. Each case demonstrated evidence of hypersensitivity on various examinations, including the challenge test, skin test and basophil activation test, although, to our knowledge, severe renal toxicity, including AIN has never been reported previously. Herein, we have presented the first biopsy-proven case of AIN caused by fosfomycin administration. Clinicians should be aware of the possibility that fosfomycin, which is generally considered to be a well-tolerated antibiotic, can cause severe AIN via an allergic mechanism.