池住 洋平

症例は5歳女児で、発熱、悪心、胸痛を主訴とした。砂遊びによる両手指の慢性湿疹に対して外用加療中であり、近医受診後も発熱が持続し、入院時には胸骨直上に辺縁不明瞭な発赤、腫脹を認め、CT検査で胸骨体の両側に低吸収帯を認めた。感染症の疑いで抗菌薬治療を開始し、血液培養でメチシリン耐性黄色ブドウ球菌(MRSA)が同定されたため、バンコマイシン(VCM)を併用した。その結果、解熱と胸痛の軽快が得られ、MRSAによる原発性胸骨骨髄炎と診断した。その後はCRP陰性化を確認してリネゾリド内服に変更し、VCMと併せて計6週間の抗MRSA薬による治療を行ったところ、炎症の再燃や血小板減少は認めなかった。本症例では手指の慢性湿疹が感染経路と考えられ、慢性湿疹を背景に持つ患児では薬剤耐性菌による全身性の感染症に留意する必要があると考えられた。

BACKGROUND: The immunosuppressant mizoribine (Miz) can reduce progression of childhood IgA nephropathy (IgAN). This study examined whether Miz affects CD163+ M2-type macrophages which are associated with kidney fibrosis in childhood IgAN. METHODS: A retrospective cohort of 90 children with IgAN were divided into groups treated with prednisolone (PSL) alone (P group; n = 42) or PSL plus Miz (PM group; n = 48) for a 2-year period. Normal human monocyte-derived macrophages were stimulated with dexamethasone (Dex), or Dex plus Miz, and analyzed by DNA microarray. RESULTS: Clinical and histological findings at first biopsy were equivalent between patients entering the P and PM groups. Both treatments improved proteinuria and haematuria, and maintained normal kidney function over the 2-year course. The P group exhibited increased mesangial matrix expansion, increased glomerular segmental or global sclerosis, and increased interstitial fibrosis at 2-year biopsy; however, the PM group showed no progression of kidney fibrosis. These protective effects were associated with reduced numbers of glomerular and interstitial CD163+ macrophages in the PM versus P group. In cultured human macrophages, Dex induced upregulation of cytokines and growth factors, which was prevented by Miz. Miz also inhibited Dex-induced expression of CD300E, an activating receptor which can prevent monocyte apoptosis. CD300e expression by CD163+ macrophages was evident in the P group, which was reduced by Miz treatment. CONCLUSION: Miz halted the progression of kidney fibrosis in PSL-treated pediatric IgAN. This was associated with reduced CD163+ and CD163+CD300e+ macrophage populations, plus in vitro findings that Miz can suppress steroid-induced macrophage expression of pro-fibrotic molecules. A higher resolution version of the Graphical abstract is available as Supplementary information.

Thrombotic microangiopathy (TMA) is a disease that causes organ damage due to microvascular hemolytic anemia, thrombocytopenia, and microvascular platelet thrombosis. Streptococcus pneumoniae-associated TMA (spTMA) is a rare complication of invasive pneumococcal infection. In addition, atypical hemolytic uremic syndrome (aHUS) is TMA associated with congenital or acquired dysregulation of complement activation. We report the case of a nine-month-old boy with refractory nephrotic syndrome complicated by spTMA in the setting of heterozygous complement factor-I (CFI) gene mutation and CFHR3-CFHR1 deletion. He repeatedly developed thrombocytopenia, anemia with schistocytes, hypocomplementemia, and abnormal coagulation triggered by infection, which manifested clinically with convulsions and an intraperitoneal hematoma. Eculizumab (a monoclonal humanized anti-C5 antibody) provided transient symptomatic benefit including improvement in thrombocytopenia; however, he developed unexplained cardiac arrest and was declared brain dead a few days later. In this report, we highlight the diagnostic challenges of this case and the causal relationship between spTMA and complement abnormalities and consider the contribution of heterozygous mutation of CFI and CFHR3-CFHR1 deletion.

Abstract Alport syndrome is a hereditary disorder characterized by renal impairment, hearing loss, and ocular symptoms and is caused by COL4A3, COL4A4, and COL4A5 mutations. Here, we report the case of 3-year-old boy with isolated hematuria detected in routine preventative urinary screening conducted in 3-year-old children. He carried a novel variant, NM_033380.3:c. 1032 + 1 G > A, which caused a splicing abnormality in COL4A5. He was diagnosed with X-linked Alport syndrome.

Background <p>Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery. </p>Methods <p>We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient). </p>Results <p>TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: P=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups. </p>Conclusions <p>Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation. </p>

高安動脈炎は大動脈とその主要分枝などに病変を生じる大型血管炎で、若年女性に好発する。疾患特異的なマーカーがなく、微熱や全身倦怠感が数週間〜数ヵ月続き、不明熱の鑑別の中で診断されることが多い。我々はけいれん重積で搬送された児が精査の結果、高安動脈炎による腎動脈狭窄が原因の高血圧性脳症だったことが判明した症例を経験したので報告する。症例は13歳、女児。生来健康で、既往歴、家族歴に特記すべきことなし。受診の1ヵ月ほど前から頭痛・嘔気を度々訴えていたが、登校できていた。受診前日の夜より眠れない程の強い頭痛を訴え、翌日朝に児がけいれんしているところを家族が発見し当院へ救急搬送された。けいれん重積および収縮期200mmHg以上の高血圧を認め、それぞれ抗けいれん薬および降圧薬の投与を開始した。頭部MRIの所見より高血圧性脳症と診断した。身体所見では腹部の収縮期血管雑音を認め、四肢の血圧の左右差は認めなかった。またCRPを含めた血液検査は正常であった。後に判明したRA系の亢進と、入院2日目に実施した胸腹部の造影CTで広範囲にわたる大動脈ならびに腎動脈を含む主要分枝の狭窄所見から、高血圧の原因は高安動脈炎による腎血管性高血圧と診断した。バイパス術など専門的な治療を要すると判断し入院4日目に他院に転院となった。本症例はけいれん重積で搬送され診断に至った比較的稀な例である。発熱の病歴はなく、受診時のCRPなどの炎症マーカーも陰性であり、さらにPET-CTにおいても病変部位の炎症反応を検出できず、すでに高度に狭窄した血管病変がみられた。本疾患では一般にCRPや赤沈値などの非特異的な炎症性蛋白の上昇を伴うことが多いが、慢性の経過を辿る症例では炎症所見に乏しい症例も存在する。高学年〜思春期の特に女児に原因不明の重度高血圧を認める場合は本症の可能性を考える必要がある。(著者抄録)

BACKGROUND: Several immunosuppressants have been used to treat children with steroid-dependent nephrotic syndrome (SDNS). Mizoribine (MZR) is an immunosuppressant used to maintain remission in children with SDNS, although its effectiveness for treating SDNS remains controversial. Therefore, in this study, we assessed the clinical factors associated with children having SDNS who were successfully treated with MZR. METHODS: A total of 47 children with SDNS who underwent MZR treatment were retrospectively evaluated. Clinical features including pharmacokinetics after MZR administration were compared between MZR responders and non-responders. RESULTS: The comparison of the two groups revealed no significant differences in age, body weight (BW), daily dose of MZR per BW, serum concentration 2 h after administration (C2), peak serum concentration (Cmax), and area under the concentration curve 0-4 h after administration (AUC0-4). C2/(single dose/BW), Cmax/(single dose/BW), and AUC0-4/(single dose/BW) were significantly higher in the MZR responders than in the non-responders (all p < 0.01). Receiver operating characteristic analysis revealed that the cutoff values of C2 (single dose/kg), Cmax/(single dose/BW), and AUC0-4/(single dose/BW) were 0.55, 0.58, and 1.37, respectively. CONCLUSIONS: MZR is a useful immunosuppressant for treating frequent-relapse NS in children who are susceptible to the drug. The efficacy of MZR may be associated with not only serum concentrations defined by the dosage or absorption efficiency through MZR transporters, but also the susceptibility defined by the expression level and performance of MZR transporters on the target cells.

溶連菌感染後急性糸球体腎炎(PSAGN)は、A群β溶連菌感染症後に血尿、浮腫、高血圧を三主徴として発症する小児には比較的頻度の高い腎疾患であるが、時に乏尿によりはっきりした尿所見を認めずに浮腫や高血圧のみが前面になって発症する例があり、腎外症候性急性糸球体腎炎といわれる。今回、無熱性けいれんで発症した1例を経験したので報告する。症例は10歳男児。入院1週間前より腹痛、嘔吐、下痢といった胃腸炎症状を認めていた。入院前日より頭痛があり、入院当日に急激な意識レベルの低下、両側上肢の強直性けいれんを認め当院に搬送された。来院時の血液検査・髄液検査・頭部CTでは明らかな異常所見認めず、無熱性けいれんとして精査、加療目的に入院とした。第4病日頃より強い頭痛の訴えと血圧191/103mmHgと著明高値を認め、高血圧緊急症と診断した。同日に行った頭部MRI T2強調像、FLAIR像にて後頭葉に高信号域を認め可逆性後頭葉白質脳症(PRES)と診断した。血液検査では補体価の著減を認め、さらにASLO、ASKの著増、咽頭よりA群溶連菌迅速抗原陽性を認めたことより、PSAGNとこれに伴う二次性高血圧と診断した。高血圧症に対してニカルジピン塩酸塩持続静注等の緊急治療を行い諸症状は改善した。その後の全身状態は良好で第13病日に頭部MRI再検、PRESの所見は不明瞭化していることを確認し退院とした。PSAGNの中に、本例のように臨床的に高血圧のみが前面に出現する例があり、溶連菌感染症流行期に高血圧や浮腫を呈する症例の鑑別疾患として本症があることを考慮する必要があると考えられた。(著者抄録)

レニン・アンギオテンシン・アルドステロン(RAA)系抑制薬は各種腎疾患に対し腎保護目的で使用されることがあるが、腎機能障害や高K血症に留意する必要がある。本症例はAlport症候群と診断されている14歳の男子。蛋白尿と血尿が持続しリシノプリル、カンデサルタン、エプレレノンを内服し、腎機能はeGFR=80〜100ml/min/1.73m2程度で推移していた。今回、定期受診の2週間前からめまいや頭痛を時々訴えており、体重減少、低血圧を認めた。血液検査上、腎機能の悪化、高K血症、アシドーシスを認めた。RAA系抑制薬の副作用を考えエプレレノン、リシノプリルを中止したところ、高K血症やアシドーシスは改善した。腎機能は一旦改善傾向となったが病前まで回復せず、その後腎機能障害が進行し16歳時に末期腎不全に至った。本症例の原因としてRAA系抑制薬を3剤内服していたことに加え、原疾患による腎機能障害の進行、低蛋白血症による血管内脱水が考えられた。本症例のような進行性腎炎、高度蛋白尿に対しRAA系抑制薬を多剤内服している場合はRAA系抑制薬の副作用発現のリスクが高く、腎機能・電解質などの頻回のモニタリングや低血圧症状への注意が必要である。(著者抄録)

症例は9ヵ月男児。当院初診の約3ヵ月前に熱源不明の発熱で近医に入院治療を受け、その後2ヵ月間で約1.5kgの体重減少と活気不良を認めたため精査加療目的で当科紹介受診した。初診時、脱水兆候と無呼吸発作がみられ、血液検査で著明な電解質異常と代謝性アルカローシス、高レニン・高アルドステロン血症を認めた。入院後に直ちに電解質補正を実施し徐々に全身状態、検査値とも改善した。輸液中止後も電解質が正常であることを確認して退院とした。しかし退院1ヵ月後に誘因なく同様の活気不良、電解質異常と代謝性アルカローシスを生じ、再び入院治療を行った。Bartter症候群(BS)・Gitelman症候群(GS)など遺伝性塩類喪失性尿細管機能異常症を疑い遺伝子解析を行ったところCLCNKAにヘテロでの変異を認めたが、既存の病型分類には当てはまらずBS/GSは否定的と考えられた。一方、本例は発症の約3ヵ月前に熱源不明の発熱で入院治療を行った後から体重減少を認めており、腎盂腎炎や尿細管間質性腎炎などの感染症、もしくは薬剤性による間質性腎炎に伴う広汎な尿細管障害をきっかけとする慢性的な電解質異常や哺乳不良の結果、偽性BSを呈した可能性が考えられた。(著者抄録)

症例:12歳女児。重症新生児仮死による脳性麻痺、慢性腎不全の診断で重症心身障害児として外来管理を行なっていた。入院の3日前から頻回嘔吐、喘鳴が出現し徐々に増悪、経管栄養も困難となったため当院救急外来を受診した。発熱、喘鳴、ツルゴールの低下、10%の体重減少を認め、検査にて高Na血症および右上肺野の浸潤影を認めたことから、誤嚥性肺炎、高張性脱水の診断で入院となった。高張性脱水に対し、等張液を用いた輸液を開始したところ、脱水所見は改善したものの血清Na濃度は上昇を続けた。輸液を低張Na製剤に変更した後も血清Naが上昇するため、最終的に5%グルコース液にて1日水分量を最低100ml/kgとなるよう輸液量を維持したところ、数日で血清Na濃度は改善した。高Na血症下で慢性腎不全状態としては不相応に血清K濃度が低下する傾向があったことから、アルドステロン作用の関与を疑い追加検査を行ったところ、著明な高アルドステロン血症および抗利尿ホルモン(AVP)の高値を認めた。全身状態の改善後、自宅での充分な水分管理を続けたところ、約3ヵ月後には血漿アルドステロン値およびAVPの改善がみられ、電解質の異常は認められなかった。患児は胃食道逆流により日常的に嘔吐が認められ、慢性的な水分、栄養注入量の不足状態にあったことに加え、腎不全によるAVP反応性低下による希釈尿排泄が慢性的な脱水状態を生じ、アルドステロンの過剰分泌を来したものと考えられた。このようなNa排泄障害下でのNa含有製剤による輸液が容易に高Na血症を招いたと考えられた。本例のような特殊な背景がある患児に対して輸液を行う際には、基礎疾患とそれに伴う病態を十分に把握しておくことが重要と考えられた。(著者抄録)

(目的)小児腎不全の治療目標は生命予後の改善のみならず患児を健常児と遜色なく心身ともに健やかに成長、自立させることである。腎不全患児が安心して成人を迎えるためには5〜15年以上にわたって移植腎機能が保たれる必要がある。我々が1995年から2014年までに経験した症例につき検討し、報告する。(対象と方法)1995年12月から2014年8月までに腎移植を行い、移植時に16歳以下であった26名、27症例を対象として後方視的に検討した(1例のみ期間中に2回の移植を経験)。(結果)当院での移植腎生着率は1年、5年、10年でそれぞれ96%、96%、88%であり諸家の報告と遜色のない成績であった。腎廃絶は3例に認められ、廃絶の原因は移植腎血栓症、ステロイド抵抗性拒絶反応、抗体関連型拒絶反応だった。Drug non-adherenceは拒絶反応を高率に誘発し、その後の移植腎機能悪化に関連していた。また移植腎機能悪化は、その後の成長にも悪影響を及ぼした。移植後の就職状況は、経過観察中に18歳以上となった18例(69%)中、作業所勤務やアルバイトも含めれば17例が職に就いていた。(結論)小児腎移植において服薬指導を徹底しdrug non-adherenceを防ぎ、拒絶反応を防ぐことが長期の移植腎機能温存と移植後身長の改善に寄与すると考えられた。腎移植の成功により、患児の就職状況は良好であった。(著者抄録)

Insufficient nutrition during the perinatal period causes structural alterations in humans and experimental animals, leading to increased vulnerability to diseases in later life. Japanese quail, Coturnix japonica, in which partial (8-10%) egg white was withdrawn (EwW) from eggs before incubation had lower birth weights than controls (CTs). EwW birds also had reduced hatching rates, smaller glomeruli and lower embryo weight. In EwW embryos, the surface condensate area containing mesenchymal cells was larger, suggesting that delayed but active nephrogenesis takes place. In mature EwW quail, the number of glomeruli in the cortical region (mm(2)) was significantly lower (CT 34.7 +/- 1.4, EwW 21.0 +/- 1.2); capillary loops showed focal ballooning, and mesangial areas were distinctly expanded. Immunoreactive cell junction proteins, N-cadherin and podocin, and slit diaphragms were clearly seen. With aging, the mesangial area and glomerular size continued to increase and were significantly larger in EwW quail, suggesting compensatory hypertrophy. Furthermore, apoptosis measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling analysis was higher in EwWs than in CTs on embryonic day 15 and postnatal day 4 (D4). Similarly, plasma glucocorticoid (corticosterone) was higher (P&lt;0.01) on D4 in EwW quail. These results suggest that although nephrogenic activity is high in low-nutrition quail during the perinatal period, delayed development and increased apoptosis may result in a lower number of mature nephrons. Damaged or incompletely mature mesangium may trigger glomerular injury, leading in later life to nephrosclerosis. The present study shows that birds serve as a model for fetal programming,' which appears to have evolved phylogenetically early.

Background and objectives A low total nephron number, which is associated with low birth weight (LBW), may indicate increased susceptibility to early-onset renal diseases in children. However, few studies have assessed renal biopsy findings in LBW children. We examined the relationship between LBW and glomerular density (GD) and/or glomerular volume (GV) in renal biopsy samples as a surrogate for total nephron number. Design, setting, participants, & measurements Renal biopsy findings of children of LBW were compared with those of age-matched control subjects of normalbirth weight (NBW) who were histopathologically diagnosed with FSGS or minimal change nephrotic syndrome (MCNS) from 1995 to 2011. The GD and GV were estimated on the basis of measurements obtained by computerized image analysis. Results A total of 31 subjects (mean age 11 years; eight with low birth weight FSGS [LBW-FSGS], 10 with normal birth weight FSGS [NBW-FSGS], and 13 with normal birth weight minimal change nephrotic syndrome [NBW-MCNS]) were analyzed. The mean birth weight of each group was 777 g (629-1000), 3110 g (2888-3358), and 3120 g (2748-3398), respectively (median [25th-75th percentile]). Age, body mass index, BP, and degrees of globally sclerotic glomeruli at biopsy were comparable between the groups. The GD was lower (LBW-FSGS, 1.4 +/- 0.6/mm(2); NBW-FSGS, 3.3 +/- 1.2/mm(2); and NBW-MCNS, 3.6 +/- 1.1/mm(2); P&lt;0.05) and the GV was greater (LBW-FSGS, 4.1 [3.1-5.1]X10(6) mu m(3); NBW-FSGS, 1.6 [1.5-2.1]X10(6) mu m(3); and NBW-MCNS, 1.3 [1.1-1.8] x10(6) mu m(3) [median, (25th-75th percentile)]; P&lt;0.05) in patients with LBW-FSGS than in the other patient groups. The GD showed close positive correlations with birth weight (r=0.48) and gestational age (r=0.54), independent of renal function and degree of global glomerular sclerosis. Conclusions A low GD together with marked glomerular enlargement characterizes renal biopsy samples of children born with a LBW at an early stage of gestation.

AimThis study was aimed at examining the effects of treatment with rituximab, a chimeric monoclonal antibody against the protein CD20, in a B-lymphocyte independent adriamycin-induced rat model of nephrotic syndrome. Rituximab is an emerging rescue therapy used in patients with complicated nephrotic syndrome and, therefore, we sought to elucidate the apparent B-lymphocyte independent mechanism underlying its anti-proteinuric effect. MethodsAdriamycin-induced nephropathy was established in Wistar rats by intravenously injecting 10mg/kg of adriamycin, which were then treated with rituximab or purified human IgG weekly and euthanized on day 28. Proteinuria, glomerular expression of sphingomyelin phosphodiesterase acid-like 3b protein, and podocyte-related proteins were examined using immunofluorescence staining and a reverse transcription-polymerase chain reaction. ResultsRituximab treatment of rats with adriamycin-induced nephropathy significantly reduced urinary protein excretion 14 to 28days after induction of disease, compared with those treated with purified normal human IgG. Furthermore, rituximab treatment also prevented the reduction of glomerular nephrin and podocin expression on day 28. Double-immunofluorescence staining revealed that after in vivo administration, rituximab was bound to the glomeruli, which also expressed synaptopodin or sphingomyelin phosphodiesterase, acid-like 3b. Moreover, sphingomyelin phosphodiesterase, acid-like 3b expression was significantly decreased on day 28 of adriamycin-induced nephropathy, which was also prevented by rituximab. ConclusionsThis study demonstrated that rituximab directly affected glomerular podocytes and ameliorated proteinuria in adriamycin-induced nephropathy in rats. Furthermore, protection of podocyte function by rituximab may be mediated by direct modulation of a sphingomyelin phosphodiesterase, acid-like 3b-dependent mechanism. Summary at a Glance This study demonstrated that rituximab directly affected glomerular podocytes and ameliorated proteinuria in adriamycin-induced nephropathy in rats. Furthermore, protection of podocyte function by rituximab may be mediated by direct modulation of a sphingomyelin phosphodiesterase, acid-like 3b-dependent mechanism.