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bioRxiv · 10.64898/2026.02.19.706923

Mathematical Modeling of AA Amyloidosis: Coupling SAA-HDL Binding Dynamics with Path-Dependent Renal Aging

Kuznetsov, A. V.
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Abstract

AA amyloidosis is a severe complication of chronic inflammatory diseases characterized by fibrillar protein deposition in the kidneys, leading to progressive organ failure. This study presents a mathematical model that couples SAA-HDL binding dynamics with renal amyloid aggregation kinetics to investigate the pathogenesis of AA amyloidosis. Under normal physiological conditions, Serum Amyloid A (SAA) circulates predominantly bound to high-density lipoprotein (HDL), which acts as a chaperone-like carrier that can reduce SAA misfolding. However, during chronic inflammation, SAA production exceeds HDL binding capacity, resulting in an increased concentration of free SAA available for renal filtration. The model calculates free SAA concentration from reversible binding equilibrium and incorporates renal filtration, mesangial accumulation, and conversion to amyloid fibrils through primary nucleation and autocatalytic growth mechanisms. A central contribution of this work is the quantification of accumulated nephrotoxicity associated with AA oligomers, which may contribute to cumulative cytotoxic damage to mesangial and tubular cells over time. Because oligomers are continuously generated during ongoing aggregation, their toxic burden integrates across the entire duration of the disease. Combined nephrotoxic damage, encompassing oligomer-associated cellular injury and fibril-associated disruption of renal architecture, therefore reflects not merely the current disease state but the full inflammatory trajectory of the patient. This cumulative damage defines renal biological age, a measure of functional deterioration, a portion of which, attributable to accumulated nephrotoxicity, is assumed to be irreversible. Renal biological age is also path-dependent: two patients with identical present-day SAA levels may carry different renal damage burdens depending on the duration, timing, and severity of their prior inflammatory episodes. Sensitivity analysis reveals that HDL concentration and SAA cleavage rate are critical determinants of amyloid burden.

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Kuznetsov, A. V.. 2026-02-20. Mathematical Modeling of AA Amyloidosis: Coupling SAA-HDL Binding Dynamics with Path-Dependent Renal Aging. https://doi.org/10.64898/2026.02.19.706923

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