Yuji Matsumoto

A 12-year-old girl presented with steroid-resistant nephrotic syndrome and was found on kidney biopsy to have membranous nephropathy with a full-house immunofluorescence pattern. At presentation, she had marked hypercholesterolemia, with an LDL-C level of 589 mg/dL, and a family history suggestive of familial hypercholesterolemia. Multiple immunosuppressive therapies resulted in only transient or insufficient improvement in proteinuria, while conventional lipid-lowering agents failed to control hypercholesterolemia. On hospital day 98, evolocumab was initiated for refractory hypercholesterolemia. LDL-C levels declined rapidly, and proteinuria subsequently improved during the clinical course. Corticosteroids were tapered and discontinued. Evolocumab was administered for three doses, and nephrotic remission was achieved during the subsequent clinical course and maintained for nearly 1 year. This case illustrates that evolocumab may be an effective lipid-lowering option for selected pediatric patients with nephrotic syndrome complicated by severe refractory hypercholesterolemia. The subsequent improvement in proteinuria should be interpreted cautiously as a temporal association.

BACKGROUND: Tosufloxacin (TFLX), a fluoroquinolone, is widely used in Japanese children with macrolide-resistant Mycoplasma pneumoniae infection. Acute kidney injury (AKI) associated with TFLX has been reported, often with urinary drug crystals; however, its incidence and clinical characteristics remain unclear. METHODS: In this multicenter retrospective study, we included 227 children (2-15 years) who underwent blood and/or urine testing. AKI was defined according to KDIGO criteria. Kidney function and clinical characteristics were compared between patients with and without TFLX exposure at the initial visit and during follow-up. Among TFLX-treated patients, factors associated with AKI and urinary drug crystals were analyzed. RESULTS: At the initial visit, AKI was more frequent in patients already receiving TFLX than in those not treated with TFLX (10% vs. 2.0%; p = 0.018). However, when analysis was restricted to patients in whom TFLX was newly initiated at our institutions, AKI incidence was 2.6% and not significantly different from controls. Gastrointestinal symptoms were more common in the AKI group (70% vs. 11%; p < 0.0001). Urinary drug crystals were detected with similar frequencies in the AKI and non-AKI groups (63% vs. 57%), and continuation of TFLX after crystal detection did not lead to AKI progression. CONCLUSIONS: Our findings suggest an association between TFLX exposure and creatinine elevation. We also evaluated AKI incidence among patients newly initiated on TFLX. Urinary drug crystals were frequently detected; however, crystal formation alone did not fully explain AKI development. Clinicians should be aware of the potential for AKI during TFLX therapy, particularly in patients with gastrointestinal symptoms.

BACKGROUND: Cyclosporine A (CsA) is an effective steroid-sparing agent for steroid-dependent nephrotic syndrome (SDNS); however, long-term use can cause chronic kidney injury (CsA nephropathy). We previously reported that alternatively activated macrophages (M2-type) are linked to interstitial fibrosis in progressive kidney disease. This study aimed to investigate the potential involvement of M2-type macrophages in CsA nephropathy in SDNS. METHODS: Thirty-three children with SDNS treated with CsA for more than 2 years were investigated. Fourteen age-matched SDNS children without CsA served as controls. Kidney fibrosis was assessed by Masson staining. Sections were immunostained for α-SMA, type I collagen, CD68, CD163, and CCL2. Urine levels of CCL2 were measured using a cytometric bead array kit. RESULTS: The CsA-treated group showed greater interstitial fibrosis (12.2 ± 7.3 vs.7.6 ± 2.1%, p < 0.001) and increased CD163+CD68+ macrophages (10.8 vs.7.9/HPF; p < 0.001). Multivariate analysis identified CD163⁺ infiltration (β = 0.632, p < 0.0001), cumulative prednisolone (PSL) dose during CsA therapy (β = 0.015, p = 0.0031), and cumulative PSL dose from onset to biopsy (β =  - 0.005, p = 0.030) as independent predictors of fibrosis. CCN2 and CCL2 co-localized with CD163+ macrophages in CsA biopsies. Urinary CCL2/creatinine ratio was higher in the CsA group than controls at relapse (1012 ± 641.2 vs. 239.9 ± 226.9 pg/mg; p = 0.02) and at remission (202.0 ± 178.4 vs. 77.7 ± 127.3 pg/mg; p = 0.04). CONCLUSION: CD163+ M2-type macrophages may contribute to CsA-induced interstitial fibrosis. Steroid treatment during CsA treatment appears to augment CsA nephrotoxicity via pro-fibrotic pathways.