Shojiro Watanabe

Podocyte infolding glomerulopathy is a rare glomerular lesion characterized by microtubular structures and microspheres in the glomerular basement membrane. While most reported cases are associated with autoimmune diseases such as systemic lupus erythematosus, pediatric cases are rarely reported. The patient was a 14-year-old Japanese girl with a 1-year history of proteinuria detected during a school urinary screening program. Five months prior to admission to our department, she was hospitalized at a regional hospital for acute abdominal pain. Although her symptoms resolved spontaneously, a renal biopsy was performed due to the presence of proteinuria, leukopenia and antinuclear antibody positivity. However, the diagnoses of systemic lupus erythematosus was not established at that time owing to negative IgG, IgA, IgM, C3 and C1q on immunofluorescence, negative anti-dsDNA and anti-Smith antibody as well as normal serum C3 and C4 levels. On admission to our department, she was diagnosed with systemic lupus erythematosus and lupus enteritis based on the presence of malar rash, fever, leukopenia, and proteinuria supported by the characteristic findings on abdominal enhanced computed tomography. Reassessment of the initial renal pathology revealed microtubular structures and microspheres within the glomerular basement membrane on electron microscopy, consistent with podocyte infolding glomerulopathy. Induction therapy with methylprednisolone pulse therapy improved her systemic symptoms and proteinuria promptly. This is the first report of podocyte infolding glomerulopathy in a pediatric patient with systemic lupus erythematosus. Clinicians should be aware of this unique glomerular lesion in pediatric-onset systemic lupus erythematosus.

症例は8歳女児．嘔吐，発熱にて前医小児科を受診したところ，心雑音，心臓超音波検査にて左室壁運動の低下を指摘され，急性心筋炎が疑われたため当科に搬送された．入院時心囊液は認めず，左室駆出率低下，肺うっ血，高血圧，蛋白尿，血尿および腎機能障害から急性腎炎症候群による高血圧性急性心不全と診断した．また抗核抗体高値，anti-double-stranded DNA antibodies（抗dsDNA 抗体）高値，低補体血症，汎血球減少から全身性エリテマトーデスと診断した．利尿剤，血管拡張薬にて心機能は改善したが，ステロイドパルス療法施行後に腎機能が増悪したため持続的血液ろ過透析および血漿交換を要した．腎生検にてループス腎炎class IV，細胞性半月体を認め，入院36日目よりエンドキサンパルス療法を開始したところ，腎機能は回復し，蛋白尿も低下傾向を示した．ループス腎炎は多彩な発症様式を呈するが，急性腎炎症候群による高血圧性急性心不全にも留意が必要である．

A 16-year-old Japanese girl presented to the emergency department with a complaint of increased muscle pain in the thighs and difficulty walking. Laboratory examinations revealed elevated levels of creatine phosphokinase, severe hypokalemia (1.4 mmol/L), hyperchloremic metabolic acidosis with a normal anion gap, and a urinary pH of 7.5. The patient was thus diagnosed with hypokalemic rhabdomyolysis due to distal renal tubular acidosis. Furthermore, the patient was diagnosed with Sjögren syndrome based on a high titer of anti-SS-A antibodies, reduced tear production on the Schirmer test, decreased salivary secretion on the Saxon test, and labial salivary gland pathology. Although her muscle symptoms resolved rapidly with fluid and potassium replacement therapy, hypophosphatemia and hypouricemia persisted. The patient was subsequently diagnosed with Fanconi syndrome based on elevated urinary β₂-microglobulin and pan-aminoaciduria. Following induction therapy with prednisolone, mycophenolate mofetil was added for maintenance based on renal pathology, which successfully reduced the urinary β₂-microglobulin levels. This report describes a case of hypokalemic rhabdomyolysis due to concurrent distal and proximal renal tubular dysfunction in a patient with juvenile Sjögren syndrome. Early detection of renal tubular dysfunction is crucial to prevent life-threatening complications, such as rhabdomyolysis.

症例は8歳男児．胆道閉鎖症のため生後3か月で葛西手術，1歳7か月時に生体肝移植を施行され，肝移植後肝静脈狭窄症による門脈圧亢進症および蛋白漏出性胃腸症のため長期入院加療されていた．8歳時に高度蛋白尿および血尿が判明し腎生検を施行したところ，光顕にてメサンギウム増殖および基底膜の二重化，蛍光抗体法にてfull house pattern, 電顕にて上皮，内皮下への沈着とメサンギウム間入を認めた．抗核抗体は陰性で，発疹や発熱などの症状はなくループス腎炎は否定的であり，造影CTにて脾静脈の拡張と腹水を認めたため，肝静脈狭窄症に伴う門脈圧亢進による二次性膜性増殖性糸球体腎炎と診断した．蛋白尿はプレドニゾロンにて速やかに陰性化し，リシノプリルにて寛解を維持している．小児の肝移植後遠隔期において，免疫複合体型糸球体腎炎が発症する可能性がある．

Recent studies have revealed the importance of cell membrane stability in normal cell function. Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), a lipid modifying enzyme that converts sphingomyelin to ceramide in the cell membrane, is expressed in macrophages and regulates Toll-like receptor (TLR) 4 signaling by altering cell membrane fluidity. SMPDL3b is also expressed in human podocytes, which are involved in the pathogenesis of several glomerular diseases such as diabetic kidney disease, focal segmental glomerulosclerosis, and idiopathic nephrotic syndrome in children; however, the role of SMPDL3b in podocyte innate immunity is unclear. As podocytes are equipped with innate immune systems including TLR3, and viral infections often exacerbate proteinuria in children with idiopathic nephrotic syndrome, we hypothesized that changes in SMPDL3b expression levels could affect anti-viral responses via TLR3 signaling in podocytes, consequently impairing normal podocyte function. To examine the role of SMPDL3b in TLR3 signaling in podocytes, we treated conditionally immortalized human podocytes with polyinosinic–polycytidylic acid (poly IC), to activate TLR3 signaling. The cells were then transfected with small interfering RNA against SMPDL3b. Poly IC activated the TLR3 pathway, whereas knockdown of SMPDL3b attenuated poly IC-induced interferon-β/chemokine C–X–C ligand 10 expression in podocytes. To our knowledge, this is the first report demonstrating SMPDL3b involvement in podocyte innate immunity; these results suggest that SMPDL3b is essential for adequate anti-viral responses in podocytes, possibly by modulating lipid metabolism in the cell membrane.

Background Glomerular endothelial cells (GECs) are directly exposed to circulating viral particles in the glomerulus. Although viral infections may trigger the development of acute kidney injury (AKI) or the worsening of pre‐existing chronic kidney disease (CKD), the specific molecular mechanisms underlying antiviral reactions via the activation of endothelial Toll‐like receptor 3 (TLR3) signaling in the kidney remain to be determined. Interferon (IFN)‐induced transmembrane protein 1 (IFITM1), a member of interferon‐stimulated gene (ISG) protein family, is involved in the prevention of viral entry into cerebral vascular endothelial cells, respiratory epithelial cells, and endometrium. However, to our knowledge, the implication of IFITM1 associated with viral infections in GECs has not been investigated to date. Methods Cultured normal human GECs were treated with polyinosinic‐polycytidylic acid (poly IC), a synthesized viral double‐stranded RNA, then the expression of IFITM1 was examined by quantitative real‐time reverse transcription‐polymerase chain reaction and western blotting. To further elucidate the poly IC‐induced signaling pathway, the cells were applied to RNA interference against IFN‐β, nuclear factor (NF)‐κB p65, and IFN regulatory factor (IRF) 3. We also conducted an immunofluorescence study to examine endothelial IFITM1 expression in biopsy specimens from patients with CKD. Results We found that the activation of TLR3 induced endothelial expression of IFITM1, and that this involved IRF3 and IFN‐β, but not NF‐κB. Intense endothelial IFITM1 immunoreactivity was observed in biopsy specimens from patients with lupus nephritis (LN). Conclusion Antiviral reaction‐related endothelial expression of IFITM1 may be involved, at least in part, in the development of particularly in LN. Further detailed studies of the implication of ISGs, including IFITM1 in GECs are needed.

Aim Sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b), a regulator of the cytoskeleton, is expressed on podocytes. Recent reports present evidence that it is directly targeted by rituximab in the treatment of intractable nephrotic syndrome. However, the implications of SMPDL-3b for treatment of paediatric-onset idiopathic nephrotic syndrome (INS) remain unclear. This study aimed to investigate the level of expression of SMPDL-3b in urine, serum, and biopsy specimens and explore its implications in treatment of patients with INS. Methods Levels of urinary SMPDL-3b among 31 patients (20 in remission and 11 in relapse) with INS were analysed by dot blotting. For reference of precise quantitative analysis, we examined urinary excretion of SMPDL-3b from 10 patients with INS by liquid chromatography-tandem mass spectrometry (LC–MS/MS) in both remitted and relapsed status. The levels of serum SMPDL-3b among 20 patients (13 in remission and 7 in relapse or onset) with INS were also measured using enzyme-linked immunosorbent assay. Further, the immunoreactivity of SMPDL-3b in the biopsy specimens obtained from patients with INS was compared with those from patients with proteinuric IgA nephropathy, lupus nephritis, and non-proteinuric controls. Results Urinary excretion of SMPDL-3b in patients with INS was significantly decreased in relapse cases compared with cases of remission and other types of proteinuric glomerular disease or controls by both dot blotting and LC–MS/MS method. On the other hand, serum SMPDL-3b level in INS was not different between cases of remission and relapse. Glomerular immunoreactivity of SMPDL-3b in patient with INS in remission was almost the same level to that of control. Conclusion The expression of SMPDL-3b on podocytes is specifically decreased in paediatric-onset INS and its urinary excretion level reflects such conditions.