SUCCESSFUL USE OF LDL APHERESIS IN CYCLOSPORINE-RESISTANT NEPHROTIC SYNDROME: A CASE REPORT WITH MECHANISTIC INSIGHTS

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Abstract Title *

SUCCESSFUL USE OF LDL APHERESIS IN CYCLOSPORINE-RESISTANT NEPHROTIC SYNDROME: A CASE REPORT WITH MECHANISTIC INSIGHTS

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Co-author 1

Tomohide R. Sato satou_tomohide@kurume-u.ac.jp Kurume University Division of nephrology, department of Medicine Kurume Japan *

Co-author 2

Chinami Hori hori_chinami@kurume-u.ac.jp Kurume University Division of nephrology, department of Medicine Kurume Japan -

Co-author 3

Yuusei Wada wada_yuusei@kurume-u.ac.jp Kurume University Division of nephrology, department of Medicine Kurume Japan -

Co-author 4

Nakano Kaoru nakano_kaoru@med.kurume-u.ac.jp Kurume University Division of nephrology, department of Medicine Kurume Japan -

Co-author 5

Gou Kodama kodama_gou@med.kurume-u.ac.jp Kurume University Division of nephrology, department of Medicine Kurume Japan -

Co-author 6

Kensei Taguchi taguchi_kensei@med.kurume-u.ac.jp Kurume University Division of nephrology, department of Medicine Kurume Japan -

Co-author 7

Ryo Shibata ryo0513@kurume-u.ac.jp Kurume University Division of nephrology, department of Medicine Kurume Japan -

Co-author 8

Kei Fukami fukami@kurume-u.ac.jp Kurume University Division of nephrology, department of Medicine Kurume Japan -

Co-author 9

Co-author 10

Co-author 11

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

A man in his seventies with a three-year history of type 2 diabetes mellitus developed bilateral lower limb edema. Laboratory testing revealed significant proteinuria, leading to a diagnosis of nephrotic syndrome. Renal biopsy demonstrated the coexistence of diabetic kidney disease and membranous glomerulonephritis. Despite initial immunosuppressive therapy with prednisolone and cyclosporine (CyA), the patient showed no clinical improvement, indicating CyA resistance.

Methods

Given the CyA resistance, LDL apheresis therapy was initiated. A total of 12 sessions were performed. Clinical parameters including serum albumin, LDL cholesterol, and urine protein-to-creatinine ratio were monitored throughout the course. To investigate the pharmacokinetic mechanism underlying the observed clinical effects, we developed a mechanistic mathematical model incorporating CyA binding to LDL, passive diffusion, and LDL receptor (LDLR)-mediated uptake. Parameter sweeps were conducted to evaluate the effects of CyA-LDL binding affinity, LDLR saturation threshold, receptor activity, and passive uptake rate.

Results

Following LDL apheresis, the patient’s LDL cholesterol levels markedly decreased, serum albumin levels improved, and urinary protein excretion declined. Model simulations revealed that the impact of circulating LDL on intracellular CyA uptake is not linear, but highly dependent on the interplay of key parameters. Model simulations revealed counterintuitive behaviors, including scenarios where lowering LDL levels leads to increased CyA uptake. This outcome aligns with clinical observations of enhanced CyA efficacy following LDL apheresis, and these findings suggest a mechanistic basis for the improved CyA efficacy observed after LDL apheresis.

Conclusion

We present a case of CyA-resistant nephrotic syndrome successfully treated with LDL apheresis. The combined clinical and model-based findings suggest that LDL apheresis may exert therapeutic benefits beyond lipid lowering, potentially by modulating CyA pharmacokinetics and enhancing its intracellular delivery. This highlights the broader potential of LDL apheresis as an adjunctive therapy in resistant forms of nephrotic syndrome.

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