Ken Saida

Rituximab-associated agranulocytosis in children with refractory idiopathic nephrotic syndrome: case series and review of literature

BACKGROUND Agranulocytosis has been reported as a delayed-onset complication of rituximab treatment. However, the exact incidence and risk factors of this complication in patients with nephrotic syndrome remain unknown. METHODS Records of 213 rituximab treatments for 114 patients with refractory nephrotic syndrome between February 2006 and April 2013 were reviewed to identify episodes of agranulocytosis (defined as an absolute neutrophil count of <500 mm(3)). RESULTS Eleven episodes of agranulocytosis were detected in 11 patients. Median time of onset of agranulocytosis was 66 days (range, 54-161 days) after rituximab treatment. Nine patients experienced acute infections and received antibiotics. All but one patient received granulocyte colony-stimulating factor. Agranulocytosis resolved in all cases within a median of 3 days. The incidence of agranulocytosis was 9.6% in total patients and 5.2% in all treatments. Median age of the 11 patients who developed agranulocytosis was 6.4 years at the first rituximab treatment, significantly younger than the median age of the 103 patients who did not (median, 12.5 years; P = 0.0009). Five patients received re-treatment with rituximab. No recurrence of agranulocytosis was observed in any patient. CONCLUSIONS It is important to pay extra attention to this clinically serious delayed-onset complication as it may be accompanied by life-threatening infections such as sepsis. Further clinical studies are needed to clarify its pathogenesis.

Successful unrelated cord blood transplantation using a reduced-intensity conditioning regimen in a 6-month-old infant with congenital neutropenia complicated by severe pneumonia

Here we report the first successful unrelated cord blood transplantation (CBT) using reduced-intensity conditioning for the treatment of congenital neutropenia in a 6-month-old infant with complications of severe pneumonia probably due to Staphylococcus aureus infection. Because the patient showed no response to treatment with granulocyte colony-stimulating factor and had a cytogenetic aberration, unrelated CBT with an HLA-DRB1 genotypic mismatch was performed. The number of infused cells was 15x107/kg.The preparative regimen was fludarabine, cyclophosphamide, and 6 Gy of total body irradiation. Teicoplanin was administered for bacterial pneumonia. Neutrophil engraftment was achieved on day 41 and was followed by clinical improvement. The patient gradually caught up on growth and development after the CBT. Unrelated CBT using a reduced-intensity conditioning regimen may be an effective treatment for congenital neutropenia.

Lamellar ichthyosis in a collodion baby caused by CYP4F22 mutations in a non-consanguineous family outside the Mediterranean.

[3] Negi M, Tsuboi R, Matsui T, Ogawa H. Isolation and characterization from Candida albicans: substrate specificity. J Invest Dermatol 1984;83:32–6. [4] Tsuboi R, Kurita Y, Negi M, Ogawa H. A specific inhibitor of keratinolytic proteinase from Candida albicans could inhibit the cell growth of C. albicans. J Invest Dermatol 1985;85:438–40. [5] Aoki W, Kitahara N, Miura N, Morisaka H, Yamamoto Y, Kuroda K, et al. Comprehensive characterization of secreted aspartic proteases encoded by a virulence gene family in Candida albicans. J Biochem 2011;150:431–8. [6] Hornbach A, Heyken A, Schild L, Hube B, Löffler J, Kurzai O. The glycosylphosphatidylinositol-anchored protease Sap9 modulates the interaction of Candida albicans with human neutrophils. Infect Immun 2009;77:5216–24. [7] Hube B, Monod M, Schofield DA, Brown AJ, Gow NA. Expression of seven members of the gene family encoding secretory aspartyl proteinases in Candida albicans. Mol Microbiol 1994;14:87–99. Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China Laboratory for Biochemistry, Juntendo University School of Health Care and Nursing, Urayasu, Japan; Department of Dermatology, Tokyo Medical University, Tokyo, Japan; Department of Dermatology, Juntendo University School of Medicine, Tokyo, Japan

The First Nationwide Survey and Genetic Analyses of Bardet-Biedl Syndrome in Japan

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod-cone dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-19. In Western countries, this disease is often reported, but remains undiagnosed in many patients until later in life, while only a few patients with no mutations identified have been reported in Japan. We thus conducted the first nationwide survey of BBS in Japan by sending questionnaires to 2,166 clinical departments with board-certified specialists and found 7 patients with clinically definite BBS. We performed exome analyses combined with analyses of mRNA and protein in these patients. We identified 2 novel mutations in the BBS5 gene (p.R89X and IVS7-27 T>G) in 2 sibling patients. The latter mutation that resided far from the authentic splicing site was associated with skipping of exon 8. We also found 3 previously reported mutations in the BBS2 (p.R413X and p.R480X) and BBS7 (p.C243Y) genes in 2 patients. To our knowledge, a nationwide survey of BBS has not been reported in any other country. In addition, this is the first study to identify genetic alterations in Japanese patients with BBS. Our results indicate that BBS in Japan is genetically heterogeneous and at least partly shares genetic features with BBS in other countries.

Diversity of renal phenotypes in patients with WDR19 mutations: Two case reports

WDR19 has been reported as a causative gene of nephronophthisis‐related ciliopathies. Patients with WDR19 mutations can show various extrarenal manifestations such as skeletal disorders, Caroli disease, and retinal dystrophy, and typically display nephronophthisis as a renal phenotype. However, there is limited information on the renal phenotypes of patients with WDR19 mutations. We report two Japanese infants with Sensenbrenner syndrome caused by WDR19 mutations who demonstrated different features in renal ultrasound and histopathological results, despite several common extrarenal manifestations. Patient 1 had normal sized and hyperechogenic kidneys with several small cysts and histopathological findings compatible with infantile nephronophthisis. Renal ultrasound of Patient 2 showed enlarged kidneys with diffuse microcysts resembling those of autosomal recessive polycystic kidney disease. Her renal histopathology revealed dysplastic kidney with diffuse glomerular cysts. Genetic testing identified compound heterozygous mutations in WDR19 in both patients (Patient 1: c.953delA, c.3533G > A, Patient 2: c.2645 + 1G > T, c.3533G > A). Our patients suggest that WDR19 mutations can cause dysplastic kidney in addition to nephronophthisis pathologically. In addition, differences in pathology of the kidneys from WDR19 mutations may result in heterogeneous features in renal ultrasound findings. Renal phenotypes from WDR19 mutations may thus be more diverse than previously reported. Extrarenal manifestations and genetic testing can therefore help to diagnosis this disease more precisely.

Ampicillin- and ampicillin/sulbactam-resistant Escherichia coli infection in a neonatal intensive care unit in Japan.

The incidence of ampicillin (ABPC)‐resistant Escherichia coli (E. coli) infection in very low‐birthweight infants has been increasing. The rate of ABPC/sulbactam (ABPC/SBT)‐resistant E. coli in this population, however, is currently unknown. We encountered two cases of severe infection due to resistant E. coli and retrospectively studied the prevalence of ABPC‐ and ABPC/SBT‐resistant E. coli in regular surveillance cultures obtained from all neonatal intensive care unit (NICU) patients between 2000 and 2013. The overall prevalence of ABPC‐resistant E. coli was 39% (47/120), accounting for 63% of cases (32/51) between 2007 and 2013, compared with 22% (15/69) between 2000 and 2006. The prevalence of ABPC/SBT resistance was 17% (20/120), which was similar in both periods (16%, 8/51 vs 17%, 12/69). According to these results, not only ABPC, but also ABPC/SBT‐resistant E. coli must be considered in the NICU.

A case of Bardet-Biedl syndrome complicated with intracranial hypertension in a Japanese child.

Bardet-Biedl syndrome (BBS) is a rare heterogeneous autosomal recessive disorder characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity, hypogonadism, learning disability, and renal anomaly that are caused by ciliary dysfunction. 16 genes have been associated with the BBS phenotype. Although recent pathophysiological studies using animal models have shown that ciliary dysfunction may induce hydrocephalus, there have been no reports of BBS with intracranial hypertension. We here describe a 9-year-old Japanese girl who was diagnosed as having BBS and later received renal transplantation due to chronic renal failure. She also exhibited intracranial hypertension, including papilledema and increased intrathecal pressure (260-300 mmH2O), but her brain magnetic resonance imaging was normal. No genetic abnormalities were detected by DNA chip analysis or exome sequencing. Her papilledema improved following administration of acetazolamide. This is the first report of a case of BBS complicated with intracranial hypertension and its treatment.

Right-to-left shunting in the ductus arteriosus is induced readily by intense crying and rapid postural change in neonates with meconium-stained amniotic fluid.

Objective: To investigate postnatal changes in the direction of blood flow through the ductus arteriosus in neonates with meconium-stained amniotic fluid, we measured preductal and postductal oxygen saturation in normal neonates, neonates with meconium-stained amniotic fluid, and a neonate with persistent pulmonary hypertension of the newborn. Design: Prospective, observational case series report. Setting: A single, tertiary neonatal intensive care unit. Patients: Twelve normal neonates, seven neonates with meconium-stained amniotic fluid, and a neonate with persistent pulmonary hypertension of the newborn. Interventions: SpO2 is simultaneously monitored in the right upper and lower limbs after birth. Measurements and Main Results: Compared with normal neonates, three neonates with meconium-stained amniotic fluid required longer than +2 SD of the mean time for the postductal SpO2 to reach 90% and/or 95%. In a neonate with meconium-stained amniotic fluid, intense crying triggered frequent decreases to <70% in the postductal SpO2 from 25 mins after birth, while the preductal SpO2 remained at 95% or above. When the other newborn with meconium-stained amniotic fluid was held in the fathers arms after 98 mins, the postductal SpO2 decreased rapidly to <80%, while the preductal SpO2 remained at 95%. Thus, 5% or greater difference between the preductal and postductal SpO2 was observed from 25 mins after birth until 120 mins in all neonates with meconium-stained amniotic fluid, whereas the difference disappeared after 25 mins in 12 normal neonates. In a neonate with persistent pulmonary hypertension of the newborn who required vigorous resuscitation, 5% or greater difference between the preductal and postductal SpO2 levels was observed until 6 hrs after birth. Conclusions: Right-to-left shunting in the ductus arteriosus may be induced readily by intense crying and rapid postural change in infants with meconium-stained amniotic fluid. It is important to monitor SpO2 at both pre- and postductal regions until 120 mins after birth in neonates with meconium-stained amniotic fluid and to subject these infants to minimal manipulations.

Azathioprine-induced agranulocytosis and severe alopecia after kidney transplantation associated with a NUDT15 polymorphism: A Case Report

BACKGROUND Azathioprine (AZA) is the drug recommended for the continuation of immunosuppressive treatment after renal transplant in women during pregnancy. CASE REPORT A 37-year-old Japanese female developed agranulocytosis and severe alopecia after initiation of AZA (50 mg), used as an alternative to mycophenolate mofetil (MMF, 1000 mg) therapy in anticipation of a planned pregnancy. Within 4 days of the initiation of AZA therapy, the patient developed a high fever, leucopenia, and cranial alopecia. Genetic testing revealed a homozygous polymorphism of NUDT15 (rs116855232, NM_018283.3:c.415C>T: p.Arg139Cys), which has previously been identified as a risk factor for AZA-related complications in patients with inflammatory bowel disease. CONCLUSION Genetic screening for NUDT15 could contribute to the prevention of serious adverse reactions to AZA and provide the opportunity for personalized medicine. Identification of a safe alternative to MMF during pregnancy after a renal transplant is a problem to be resolved in the future.

Coagulopathy as a complication of kidney biopsies in paediatric systemic lupus erythematosus patients with antiphospholipid syndrome

Children with systemic lupus erythematosus (SLE) generally undergo a pretreatment kidney biopsy. However, some of these patients, especially those with antiphospholipid syndrome (APS), may experience serious coagulopathic complications. We report herein two cases of paediatric SLE with APS in which, despite normal blood test results, the disparate coagulopathic complications of haemorrhage and embolism developed following a kidney biopsy. Case 1 was, an 8‐year‐old male in whom, primary APS was initially diagnosed. Fourteen months later SLE was diagnosed. Based on a percutaneous kidney biopsy, International Society of Nephrology and the Renal Pathology Society (ISN/RPS) class III‐A lupus nephritis was histologically diagnosed. On post‐biopsy Day 9, a giant haematoma in the fascia of the left kidney developed and was accompanied by changes in the vital signs. Case 2, a 13‐year‐old male, initially received the diagnosis of SLE with APS and underwent two courses of pulse methylprednisolone therapy. His coagulation abnormalities improved, and a percutaneous needle kidney biopsy was performed, leading to the histological diagnosis of ISN/RPS class III‐A lupus nephritis. Furthermore, thrombotic microangiopathy was also detected in the renal histopathology. On post biopsy Day 6, the patient experienced right leg pain. A contrast CT and lower extremity ultrasonography detected a massive deep vein thrombosis and partial left pulmonary artery thrombosis. A kidney biopsy in children with SLE and APS can cause lethal coagulopathic complications, and the risks to such patients should be weighed carefully before the procedure is performed.