金井 孝裕

RATIONALE: Vacuolated podocytes are the most common form of renal damage in Fabry disease, but other types of renal damage have been reported, such as membranous nephropathy (MN) or IgM nephropathy. Enzyme replacement therapy (ERT) is effective at preventing renal damage, but the nephropathies require appropriate treatment to prevent renal damage. PATIENT CONCERNS: A 22-year-old male with Fabry disease presented with proteinuria during ERT with agalsidase-β and carbamazepine. He had received the treatment for 10 years and maintained normal plasma globotryaosylceramide levels. DIAGNOSIS: Renal biopsy revealed MN without vacuolated podocytes. Immunofluorescent staining of the IgG subclass revealed granular patterns of IgG1, G2, G4, and C3 deposition in the glomerular basement membrane. INTERVENTIONS: The carbamazepine dose was reduced from 600 mg/day to 200 mg/day (serum concentration 10.0-11.0-4.0-5.0 μg/mL). OUTCOMES: After reducing the carbamazepine dose, proteinuria was negative, and the patient has had a normal urinalysis for 17 months. Plasma globotryaosylceramide levels have also remained normal. LESSONS: This report is a reminder of the co-existence of MN without vacuolated podocytes in Fabry disease during ERT with agalsidase-β and carbamazepine.Physicians should be aware of this form of renal damage in Fabry disease, even during treatment.

AIM: Glucocorticoids (GC) are essential medicines for idiopathic steroid-sensitive nephrotic syndrome (ISSNS) and IgA nephropathy (IgAN), with good clinical results. However, they cause bone fragility. The aim of this study was to elucidate GC effects on bone strength assessed as bone mineral density (BMD) and bone quality, using bone turnover markers (BTM), in children with ISSNS or IgAN. METHODS: Eleven children with ISSNS and 13 with IgAN were included. All the patients received GC treatment according to each protocol. The BMD and BTM-serum alkaline phosphatase (S-ALP), tartrate-resistant acid phosphatase 5b (S-TRACP-5b), and undercarboxylated osteocalcin (S-ucOC)-were measured from the initiation of steroid treatment (STx) to the end of STx in both groups. RESULTS: In ISSNS, S-ALP and S-ucOC levels were decreased significantly at 1 month. BMD and S-TRACP-5b levels showed no significant change through this observation period. In IgAN, BMD and S-ALP levels were decreased significantly at 1 and 3 months, respectively, and recovered to baseline at 10 months after the initiation of GC dosage reduction. S-TRACP-5b levels were decreased significantly at 3 months and remained lower than at baseline through the observation period. In both groups, S-ucOC levels did not directly reflect bone strength. CONCLUSION: This study clarified the following three points regarding GC effects on bone strength in children with ISSNS or IgAN: first, S-ALP is a more sensitive bone quality marker than S-TRACP-5b; second, BMD loss was observed only when both S-ALP and S-TRACP-5b levels decreased, and third, S-ucOC levels do not directly reflect bone strength.

In individuals treated with immunosuppressive therapies, the varicella-zoster virus (VZV) infection can become disseminated and lead to a life-threatening condition. There is currently no established treatment strategy for this life-threatening condition. Here, we describe a case where plasma exchange (PE) with a high dose of acyclovir (ACV) ameliorated the severe effects, including VZV-hemophagocytic lymphohistiocytosis (VZV-HLH) and disseminated intravascular coagulation (DIC), in a 9-year-old girl with steroid-dependent nephrotic syndrome. This 9-year-old girl experienced frequent relapse steroid-dependent nephrotic syndrome. She had been treated with steroids, tacrolimus, mizoribine, and rituximab. She had not previously received a varicella vaccine. She was admitted with only one vesicular rash. At admission, a serum test revealed 1.6 × 106 copies/mL of VZV DNA. The patient rapidly developed VZV-HLH and DIC. A combination of a high dose of ACV, immunoglobulin, and steroid pulse therapy could not improve these severe complications. Therefore, PE was applied. PE with a high dose of ACV successfully reduced serum VZV DNA from 7.5 × 106 to 2.8 × 104 copies/mL. This reduction in the VZV DNA copy number suggested that the combination of PE and a high dose of ACV was effective in treating a disseminated VZV infection. To the best of our knowledge, this is the first report showing that PE with a high dose of ACV ameliorated the severe complications of disseminated VZV by reducing the VZV DNA copy number.

BACKGROUND: We previously reported that the top-down approach (TDA) for infants with febrile urinary tract infections (fUTI) could prevent recurrent fUTI (r-fUTI) but produced a high number of false-positives on acute-phase 99m Tc dimercaptosuccinic acid (DMSA) renal scintigraphy. Therefore we compared the ultrasonography-oriented approach (USOA) with TDA from the viewpoint of prevention of r-fUTI. METHODS: The TDA was applied between July 2010 and February 2014 and the USOA was applied between March 2014 and April 2017 in infants with first fUTI. In the USOA group, voiding cystourethrography (VCUG) was performed in the case of abnormality on acute-phase renal bladder ultrasonography (RBUS) or on chronic- phase DMSA, which were performed in all cases. The frequency of r-fUTI was compared between the TDA group and USOA group retrospectively. RESULTS: Seventy-four infants (52 male) and 79 infants (60 male) received TDA or USOA, respectively. No significant differences were found between the TDA and USOA groups in male : female ratio, age in months at initial onset of fUTI, observation period, or number of cases of r-fUTI (TDA group, n = 4; USOA group, n = 5). Seventy-four DMSA scintigraphy and 25 VCUG were carried out in the USOA group, and 111 DMSA scintigraphy and 34 VCUG in the TDA group. CONCLUSIONS: Both USOA and TDA were valid for prevention of r-fUTI, but USOA was superior to TDA with regard to the reduced number of patients undergoing VCUG and DMSA.

BACKGROUND: C1q nephropathy (C1qN) was first described as glomerular disease characterized by predominant meangial C1q deposits in patients with proteinuria and no evidence of systemic lupus erythematosus. Several studies, however, revealed the clinical heterogeneity of C1qN, showing some cases with normal urinalysis. To confirm the existence of cases with predominant mesangial C1q deposits and negative or mild proteinuria and/or hematuria, we investigated renal graft biopsy specimens showing negative to mild proteinuria (less than or equal to 1+ by dip stick test) and/or hematuria. METHODS: Eligible participants were kidney transplant cases who corresponded to the criteria for C1qN and were followed more than 10 years. Their medical records were reviewed to determine the age at detection of predominant mesangial C1q deposits, gender, original renal disease and reason for renal graft biopsy, blood pressure, degree of proteinuria and hematuria, and serum creatinine levels. RESULTS: From 414 cases in adults and children, five pediatric patients (the male to female ratio, 1:1.5) were eligible. At the time when predominant mesangial C1q deposits were detected, 2 cases presented with mild proteinuria without hematuria, but the other 3 cases showed normal urinalysis. Light microscopy revealed minor glomerular abnormality in all the cases. Immunofluorescent study showed predominant mesangial C1q deposits with IgG, IgM and C3 in all cases. All selected specimens presented electron dense-depos in the mesangium. Ten years later from the detection, 2 cases continued to be normal urinalysis and 3 cases had mild proteinuria without hematuria. During this follow-up period, no cases presented with persistent proteinuria and/or hematuria greater than or equal to 2+ by dip stick test. And no cases developed systemic lupus erythematosus. Follow-up renal graft biopsies were performed once in 2 cases 8 years later from the detection. They showed minor glomerular abnormalities. C1q deposit disappeared in one case. In another case, immunofluorescent study was not examined. CONCLUSIONS: This long-term observational study on transplanted kidneys confirms the existence of cases with predominant but silent C1q deposits in the mesangium who have negative or mild proteinuria.

Background: Acute-phase technetium-99 m dimercaptosuccinic acid (DMSA) scintigraphy is recommended for initial imaging in children with febrile urinary tract infection (fUTI). Recently, the importance of identifying patients at risk of recurrent fUTI (r-fUTI) has been emphasized. To clarify the effectiveness of DMSA scintigraphy for predicting r-fUTI in infants, we investigated the relationship between defects on DMSA scintigraphy and r-fUTI. Methods: Seventy-nine consecutive infants (male: female, 60:19) with fUTI were enrolled in this study. DMSA scintigraphy was performed in the acute phase, and patients with defect underwent voiding cystourethrography and chronic-phase (6 months later) DMSA scintigraphy. Patients were followed on continuous antibiotic prophylaxis (CAP). Results: Defects on acute-phase DMSA scintigraphy were observed in 32 children (40.5%) of 79. The mean follow-up observation period was 17.0 +/- 10.1 months. Four patients had r-fUTI (5%). Two of them had defects on DMSA scintigraphy in both the acute phase and chronic phase, and had bilateral vesicoureteral reflux (VUR) grade IV. Two others had r-fUTI without defects on DMSA and did not have VUR. Twelve patients had defect on chronic-phase DMSA scintigraphy and four of them had no VUR. Conclusions: The top-down approach is a possible method for predicting r-fUTI in infants and does not miss clinically significant VUR. Also, given that the prevalence of r-fUTI was 5% regardless of the presence of defects on acute-phase DMSA, then, in conjunction with genital hygiene and CAP, acute-phase DMSA might be unnecessary if chronic-phase DMSA is performed for all patients to detect renal scar.

Background: We evaluated the effect of glucocorticoids (GCs) on bone strength via bone mineral density (BMD) scores and serum alkaline phosphatase (S-ALP) levels in children with idiopathic steroid-sensitive nephrotic syndrome (ISSNS) or IgA nephropathy (IgAN). Methods: Sixteen children with ISSNS and 13 with IgAN were eligible for this study. The BMD and S-ALP levels were measured before the initiation of steroid treatment (STx), one month after initiation of STx and one month after terminating STx (Phases 0, 1 and 2). For IgAN, scores and levels were measured before the initiation of STx (Phase 0) and 1, 3, 6, and 12 months after the initiation of STx (Phases 1, 2, 3, and 4). Results: In ISSNS, the BMD and S-ALP levels were significantly lower in Phase 1 than in Phase 0 however, scores and levels returned to baseline in Phase 2. In IgAN, BMD was significantly lower in Phase 2 than in Phase 0 while S-ALP levels were significantly lower in Phases 1, 2, and 3 compared to Phase 0. No significant difference was observed between Phase 0 and Phase 4. Conclusions: In ISSNS, bone strength recovered one month after terminating STx. In IgAN, bone strength recovered 10 months after tapering of STx.

Various humoral factors have been proposed as causal agents of idiopathic steroid-sensitive nephrotic syndrome (ISSNS), resulting in varying data. We used mass spectrometry (MS) to analyze serum proteins in a search for proteins that might be involved in ISSNS pathophysiology. Serial serum samples were obtained from 33 children with ISSNS. Samples were collected during Phase A1 [the acute phase prior to steroid treatment (STx)], Phase A2 (remission with STx), and Phase A3 (remission without any medication). We also included age- and sex-matched two control groups comprising children with normal urinalysis (Group B) and children with a nephrotic syndrome other than ISSNS (Group C). The urinary protein/urinary creatinine (UP/UCr) ratios were not statistically different between Phase A1 and Group C. Samples were analyzed using surface-enhanced laser desorption/ionization time of flight MS. A total of 207 peptide ion peaks were detected in the range of m/z 2000-10000. Four peptide ions (m/z 6444, 6626, 8695, and 8915) were detected at significant elevation during Phase A1 compared with Phase A2, Phase A3, and Group C. The intensities of m/z 6444 and 8695 were higher in Phase A3 than in Group B. There were significant correlations between the intensities of m/z 6626, 8695, and 8915 and UP/UCr levels. The m/z 8695 was identified as apolipoprotein AII. Apolipoprotein AII was detected as a protein associated with the UP/UCr levels in pediatric ISSNS. Our findings present an interesting starting point for further investigation into the pathophysiology of ISSNS.

UNLABELLED: In Fabry disease, globotriaocylceramid (GL3) starts to accumulate in kidney cells in utero, and continues to accumulate throughout childhood and adulthood with progressive tissue damage, which may lead to renal failure. MATERIAL AND METHODS: Eight children with classical Fabry disease, median age 12 (range 4-16 years) had a renal biopsy performed before the initiation of enzyme replacement therapy (ERT). All patients were normalbuminuric and had normal GFR. Three patients were re-biopsied after three or five years. RESULTS: In all patients, significant GL3-accumulation was found in several types of kidney cells with high amounts of GL3 in the podocytes. Segmental podocyte foot process effacement was shown in all but two patients; no effacement was seen neither in the youngest male patient at 4 years of age nor in a male aged 12. A 12-year-old female patient had normal podocyte foot processes before the start of ERT, but de novo foot process flattening and unchanged high score of podocyte GL3 accumulation were seen in the re-biopsy after three years of ERT (agalsidase alpha 0.2 mg/kg/every other week). Two boys showed worsening of podocyte effacement in kidney biopsy after five years of agalsidase alpha 0.2 mg/kg/eow. CONCLUSIONS: Podocyte foot process effacement was found in the majority of eight young classical Fabry patients of both genders after the age of 11 years, without clinical signs of Fabry nephropathy. Kidney biopsies are essential in the early diagnosis of nephropathy and in the evaluation of the response to enzyme replacement therapy of early Fabry nephropathy.

症例は4歳男児で、発熱、黄疸、腎機能障害を主訴に、精査加療目的で当科紹介転院となった。検査所見では溶血性貧血、血小板の軽度減少、FDPおよびD-dimerの著明高値、腎機能障害、肉眼的血尿、尿潜血3+、β2MG高値を認めた。直接クームス試験は抗C3d血清で陽性、間接クームス試験は陰性で、寒冷凝集素価は256倍であった。以上より、急性腎障害を合併した低力価寒冷凝集素症と診断し、保温と寒冷刺激回避で対応し、水溶性プレドニンの静注を3日間行い、漸減中止した。さらに輸血、ハプトグロビンの静注、輸液、フロセミド静注、炭酸水素ナトリウム静注などの保存的治療を行ったところ軽快が得られ、腎機能も正常化し、転院20日目に退院となった。

It has been established that enhanced computed tomography (CT) and 99mTc-dimercaptosuccinic acid renal scintigraphy (99mTc-DMSA scintigraphy) used in conjunction with single-photon emission CT is a useful tool for the diagnosis of acute pyelonephritis (APN). The utility of non-enhanced magnetic resonance imaging (MRI), however, has not been investigated extensively for the diagnosis of APN or renal abscess in children. We describe the case of a 23-month-old boy with suspected APN who received non-enhanced MRI. Whole body diffusion-weighted imaging (DWI) was used, and a background body-signal suppression sequence was applied. High-intensity focal lesions were identified on DWI and low-intensity lesions on the apparent diffusion coefficient map in the acute phase. This case suggested that non-enhanced MRI could be a useful tool for the diagnosis of APN in children, because it can avoid the risks of not only radiation exposure but also nephrogenic systemic fibrosis associated with gadolinium-based contrast agents, especially in infants.

Tubulointerstitial nephritis and uveitis (TINU) syndrome, which was first described in 1975, has been reported in more than 130 patients, mostly in adolescent or young women. Although data concerning the etiologic background of this inflammatory disease are limited, several humoral factors, including cytokines, have been reported in association with the disease. Here, we report a case of TINU in a 14-year-old girl, whose renal and ophthalmological improvement was associated with the decrease of serum levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-8 (IL-8). This suggests the presence of T-cell-mediated immunity in this unique syndrome.

Signal transducer and activator of transcription (STAT) comprises a family of universal transcription factors that help cells sense and respond to environmental signals. STAT5 refers to two highly related proteins, STAT5A and STAT5B, with critical function: their complete deficiency is lethal in mice; in humans, STAT5B deficiency alone leads to endocrine and immunological problems, while STAT5A deficiency has not been reported. STAT5A and STAT5B show peptide sequence similarities greater than 90%, but subtle structural differences suggest possible non-redundant roles in gene regulation. However, these roles remain unclear in humans. We applied chromatin immunoprecipitation followed by DNA sequencing using human CD4(+) T cells to detect candidate genes regulated by STAT5A and/or STAT5B, and quantitative-PCR in STAT5A or STAT5B knock-down (KD) human CD4(+) T cells to validate the findings. Our data show STAT5A and STAT5B play redundant roles in cell proliferation and apoptosis via SGK1 interaction. Interestingly, we found a novel, unique role for STAT5A in binding to genes involved in neural development and function (NDRG1, DNAJC6, and SSH2), while STAT5B appears to play a distinct role in T cell development and function via DOCK8, SNX9, FOXP3 and IL2RA binding. Our results also suggest that one or more co-activators for STAT5A and/or STAT5B may play important roles in establishing different binding abilities and gene regulation behaviors. The new identification of these genes regulated by STAT5A and/or STAT5B has major implications for understanding the pathophysiology of cancer progression, neural disorders, and immune abnormalities.

1ヵ月男児。3日前から哺乳後の嘔吐が頻回になった。40℃の発熱があり、受診時に膿尿・細菌尿を認め、急性腎盂腎炎の診断で入院した。白血球増多はなかったが、他系統の血球減少があり、CRP値が高値であることと合わせ、重症感染症を疑った。また、血清Cr値は上昇しており、腎機能障害を認めた。尿中のβ2-ミクログロブリン値は著明に上昇していた。急性腎盂腎炎に対してセフォチアム塩酸塩の点滴静注を開始した。48時間後にも解熱せず、全身状態の改善もみられなかった。血液培養で大腸菌を検出した。菌血症の合併と診断し、メロペネム水和物に変更した。23時間で解熱し、入院9日目にはCRP値も陰性化した。DMSAシンチを施行し、瀰漫性の近位尿細管障害を疑った。急性腎盂腎炎発症から7ヵ月後のDMSAシンチの再検査では膀胱内の異常集積を認めなかった。

The signal transducer and activator of transcription (STAT) 5b is a universal transcription factor that plays key biological roles in allergic diseases, immunodeficiencies, autoimmunities, cancers, hematological diseases, growth disorders, and lung diseases. The identification of distinct pathological manifestations of STAT5b deficiency in humans has highlighted the critical role of the STAT5b pathway. Proper gene transcription at IL-2R alpha, FOXP3, Bcl-2, and growth hormone (GH) associated loci are thought to be associated with normal STAT5b transcriptional activity.These genes are thought to play important roles in allergy/autoimmunity, immunodeficiency, cancer/anemia, and growth, respectively. The STAT5A and STAT5B genes are collocated on 17q11. Although these two monomeric proteins exhibit peptide sequence similarities of >90%, it is known through observations of STAT5b deficient subjects that STAT5a and STAT5b are not fully redundant in humans. Patients with STAT5b deficiency have decreased numbers of regulatory CD4(+)CD25(high) T cell (Treg) despite their STAT5a levels being normal. Prior studies on STAT5b deficient subjects have revealed immunological aberrations associated with the following disease phenotype: modest lymphopenia and decreased populations of Treg, gamma-delta Tcells, and natural killer INK) cells. Most subjects with STAT5b deficiency show severe eczema, and autoimmune disease (juvenile idiopathic arthritis, autoimmune thyroiditis, idiopathic thrombocytic purpura) which are thought to be associated with Treg dysfunction. We will review the likely pathophysiological mechanisms associated with STAT5b deficiency.

Background: Several cytokines have a pathological association with idiopathic steroid-sensitive nephrotic syndrome (ISSNS) in inducing proteinuria or regulating T cells. Because interleukin (IL)-7 plays important roles in regulating T-cell proliferation and sustaining naive or memory T cells, IL-7 is one of the candidate cytokines in the pathogenesis of ISSNS. Very little is known, however, about the association of IL-7 with ISSNS. To clarify the IL-7 dynamics in children with ISSNS, serum IL-7 level was investigated, from the nephrotic phase before steroid treatment (STx; group A1) to the remission phase with STx (group A2) and without STx (group A3). Methods: Eighteen children with ISSNS were included in the present study. A total of 25 paired samples were analyzed for groups A1 and A2, and a total of 10 paired samples for groups A1, A2, and A3 due to recurrence. Two control groups ( with normal urinalysis, group B; or with nephrotic syndrome other than ISSNS, group C), matched for age and gender, were also included. Serum cytokine level was measured on bead-based assay. Results: Each serum IL-7 level in groups A1 and A3 was higher than each serum IL-7 level of groups C and B, respectively. The group A2 serum IL-7 level was higher than that of group A1. There was no statistical significance of serum IL-7 level between group A1 and group A3. Conclusion: Serum IL-7 level was elevated in children with ISSNS regardless of the status of the disease. This brings us one step closer to a better understanding of the pathophysiology of ISSNS in children.

Various studies reported a higher incidence of allergic disorders, with an overreactivity of type 2 helper T-cell (Th2) immune mechanisms, in children with idiopathic steroid-sensitive nephrotic syndrome (ISSNS). However, Th2 predominance in ISSNS has not been definitively identified. To determine whether Th2 was predominant in children with ISSNS, we used paired samples to measure the type 1 helper T-cell (Th1)/Th2 ratios and serum cytokine levels secreted by Th1 and Th2. We measured the Th1/Th2 ratios and levels of Th1- or Th2-secreted cytokines in paired samples. Fourteen children met the inclusion criteria: (1) ISSNS; (2) selectivity index < 0.1; (3) sera obtained in at least two disease phases; (4) no infection; (5) no immunosuppressants. Two control groups (group B, normal urinalysis; group C, nephrotic syndrome other than ISSNS) were included for cytokine level comparisons. Th1 and Th2 numbers were counted by three-color flow cytometry. Cytokine levels were measured by bead-based assay. The Th1/Th2 ratio was lower in group A-1 [nephrotic-phase before steroid treatment (STx)] than in groups A-2 (remission-phase with STx) and A-3 (remission-phase without STx). Th2-secreted interleukin-5 (IL-5) levels were higher in group A-1 than in groups A-2 and A-3. There were no differences in IL-5 levels between groups A-1 and C and between groups A-3 and B. Our results suggest that Th2 played a predominant role both in the Th1/Th2 ratio and in the serum IL-5 level in children with ISSNS in the nephrotic phase.

An anomalous tapeworm with abnormal segmentation was obtained from a 6-year-old boy in Japan. The tapeworm consisted of proglottids with slanted anterior and posterior margins of proglottids and 4-6 sets of reproductive organs arranged between the margins. The morphology of the tapeworm did not correspond to any of the described cestodes. However, molecular identification based on nuclear and mitochondrial genes clearly showed the tapeworm was Diphyllobothrium nihonkaiense. (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Background: The cytokines associated with idiopathic steroid-sensitive nephrotic syndrome (ISSNS) have not been identified definitively, because previous studies had variable sampling and population heterogeneity. To clarify the cytokines involved, serum cytokine levels were measured using uniform sampling in a homogeneous population. Methods: Five children meeting the following criteria were included: (i) ISSNS; (ii) selectivity index < 0.1; (iii) paired sera obtained in the nephrotic phase before steroid treatment (STx; group A) and in the remission phase under STx (group B); (iv) no infection; and (v) no immunosuppressant. Control groups were as follows: group C, four children with ISSNS in the remission phase without STx; group D, five with normal urinalysis; group E, five with symptomatic secondary nephrotic syndrome before STx. Cytokine levels were measured using bead-based assay. Results: Serum macrophage inflammatory protein-1 beta (MIP-1 beta) levels were higher in group B compared to group A, and group C was lower than groups A and B. Serum interleukin-8 (IL-8) levels were higher in group A than in groups B and C, and groups B and C did not differ. With regard to both cytokine levels, there were no differences between groups C and D, and groups A and E. Conclusion: Serum MIP-1 beta and IL-8 are associated with the clinical status of ISSNS in children. A relationship between MIP-1 beta and ISSNS has not been previously reported. The mechanism by which MIP-1 beta and IL-8 affect ISSNS is unclear. Nevertheless, the present findings are an interesting starting point for further investigations into the pathophysiology of ISSNS in children.