Kidney Week

Abstract: FR-PO799

Role of LDL-Scavenger Receptor CD36-Positive Macrophages in Refractory Nephrotic Syndrome with Hyperlipidemia under High-Dosage Steroid Treatment

Session Information

• Glomerular Diseases: Inflammation and Immunology
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Ikezumi, Yohei, Fujita Health University School of Medicine Department of Pediatrics, Toyoake, Japan

Yohei Ikezumi, MD, PhD

• Kondo, Tomomi, Fujita Health University School of Medicine Department of Pediatrics, Toyoake, Japan

Tomomi Kondo, MD

• Ando, Takuma, Fujita Health University School of Medicine Department of Pediatrics, Toyoake, Japan

Takuma Ando, MD

• Matsumoto, Yuji, Fujita Health University School of Medicine Department of Pediatrics, Toyoake, Japan

Yuji Matsumoto, MD, PhD

• Nikolic-Paterson, David J., Monash University Department of Medicine, Clayton, Victoria, Australia

David J. Nikolic-Paterson, PhD, FASN

• Kumagai, Naonori, Fujita Health University School of Medicine Department of Pediatrics, Toyoake, Japan

Naonori Kumagai, MD, PhD

Background

Most cases of pediatric nephrotic syndrome (NS) are steroid-sensitive (SSNS); however, about 10% of cases are steroid-resistant (SRNS), and some patients develop SRNS during treatment. We have previously reported that chronic lesions, including matrix expansion and fibrosis, seen during steroid therapy are associated with increasing numbers of macrophages (MQ). This study examined expression of the LDL-scavenger receptor (CD36) in MQ in pediatric SRNS.

Methods

Renal biopsies and clinicopathological findings from 25 children with SSNS and 18 children with SRNS were compared. The number of glomerular CD36⁺CD68⁺ MQ was assessed by immunofluorescence staining. Urine levels of CCL2 were measured by ELISA. Cultured human monocyte-derived MQ were stimulated with dexamethasone (Dex) and/or oxidized LDL (oxLDL) for 48hr and RNA levels compared to control cells.

Results

Children with SRNS has significantly lower serum albumin levels, higher serum levels of total cholesterol and LDL cholesterol, higher proteinuria and were on higher doses of Prednisolone at time of biopsy (all P<0.01 vs SSNS). Combined stimulation of cultured MQ with Dex plus ox-LDL induced up-regulation of mRNA levels of CD36, cytokines and growth factors associated with inflammation and fibrosis (CCL2, IL25, NOS2, FGF1, FGF2, CTGF), and extracellular matrix proteins (COL1A2, COL4A1, COL4A2, COL13A1). Immunostaining showed a 3-fold increase in the number of glomerular CD36⁺CD68⁺ MQ in SRNS vs SSNS (2.3 vs 0.8, P<0.001), and revealed expression of FGF1, AGT and CCL2 in biopsies from SRNS patients which co-localized with glomerular CD36⁺CD68⁺ MQ. In addition, the urine CCL2/creatinine ratio was increased 5-fold in SRNS vs SSNS patients (986.2 vs 200.8, P=0.012).

Conclusion

The significant hyperlipidemia seen in steroid-treated pediatric SRNS was associated with a substantial increase in the number of glomerular CD36⁺CD68⁺ MQ. In vitro studies support a direct link between steroids and ox-LDL in stimulating MQ expression of CD36 and of the genes involved in both inflammation and fibrosis. Thus, cholesterol processing CD36⁺CD68⁺ MQ may contribute to resistance to treatment in SRNS through the production of pro-fibrotic and pro-inflammatory factors.

Funding

• Government Support – Non-U.S.