Applications of LDL-apheresis in nephrology

Abstract

LDL-apheresis (LA) was originally used for familial hyperlipidemia, and then in Japan extended to use for the treatment of patients with peripheral arterial disease (PAD) and nephrotic syndrome due to steroid-resistant focal glomerular sclerosis (FGS). The reason why this treatment is applicable for these disorders is due to the fact that LA exerts its favorable effects beyond the lipid-lowering effect. The main underlying mechanisms, for example, in the case of LA application in patients with PAD are: (1) improvement of hemorheology, (2) improvement of endothelial dysfunction, (3) elevations of serum levels of NO and bradykinin, (4) increase in serum levels of vascular endothelial growth factor, and (5) reduction of adhesion molecules on monocytes. Furthermore, we have reported that LA could have anti-inflammatory effects because LA reduces serum levels of P-selectin, which is known to play an important role in the development of atherosclerosis as well as a reduction of serum C-reactive protein levels as standard biomarker of atherosclerosis. Massive proteinuria is also an important challenge in nephrology. The possible mechanisms besides removal of toxic lipids are the reduction of the vasoconstrictive prostanoid and thromboxane A2 (TXA2) and an improvement in macrophage function evidenced by a significant amelioration of interleukin-8 production by lipopolysaccharide-stimulated peripheral blood mononuclear cells. It is intriguing to note that in terms of pharmacodynamics, LA improves steroid and cyclosporine uptake into lymphocytes. Although there are no randomized controlled trials, it is clear that LA has various effects beyond lowering lipids. Making the device more concise and changing it into a whole blood adsorption type, we need to collect more clinical cases and to study the underlying mechanisms further.

Low-density lipoprotein apheresis in a pediatric patient with refractory nephrotic syndrome due to focal segmental glomerulosclerosis

“…Hattori et al [8] reported that LDL-A and prednisolone therapy provided complete remission in 5 of 11 pediatric patients with steroidresistant primary FSGS (median age at disease onset, 12 years; range, 7 to 14 years). Although the mechanism of the benefi cial effects of LDL-A in patients with NS is unclear, some experiments have revealed that a reduction in oxidized LDL reduced infl ammatory cytokines and chemokines and suppressed macrophage invasion into glomeruli or interstitium [7,11]. It was also reported that the adsorption of unknown factors by dextran sulfate alleviated the hypercoagulability and renal vasoconstriction [7,11].…”

“…Although the mechanism of the benefi cial effects of LDL-A in patients with NS is unclear, some experiments have revealed that a reduction in oxidized LDL reduced infl ammatory cytokines and chemokines and suppressed macrophage invasion into glomeruli or interstitium [7,11]. It was also reported that the adsorption of unknown factors by dextran sulfate alleviated the hypercoagulability and renal vasoconstriction [7,11]. Another possible mechanism is the enhancement of corticosteroid or CyA response by changing drug interactions after lipid removal [6,8,11].…”

5th Asian PAD Workshop

“…It is intriguing to note that in terms of pharmacodynamics, LDLA improves steroid and cyclosporine uptake into lymphocytes. 18) Moreover, in patients with peripheral arterial occlusive disease, serum levels in VEGF statistically increased after 10 sessions of LDLA, and further increased up 3 months after a completion of this intervention. After 10-times therapy, IGF-I significantly decreased (p<0.05), but increased over the basal value 3 months after this therapy.…”

“…The main underlying mechanisms, for example, in the case of LDLA application in patients with PAD are: (1) improvement of hemorheology, (2) improvement of endothelial dysfunction, (3) elevations of serum levels of NO and bradykinin, (4) increase in serum levels of vascular endothelial growth factor, and (5) reduction of adhesion molecules on monocytes. 18) Massive proteinuria is also an important challenge in nephrology. The possible mechanisms besides removal of toxic lipids are the reduction of the vasoconstrictive prostanoid and TXA 2 and an improvement in macrophage function evidenced by a significant amelioration of interleukin-8 production by LPS-stimulated peripheral blood mononuclear cells.…”

Evaluation of vascular quality of life questionnaire in dialysis patients with peripheral arterial disease treated by low-density lipoprotein apheresis

“…However, the obstruction or improvement of peripheral circulation is not always parallel to patients' symptom [5,6]. Kobayshi summarized the several mechanisms of LDL-A [7]: (1) direct effect of lowered lipids or reduction of lipid toxicity; (2) improvement of hemorpheology by removing fibrinogen; (3) vasodilatory effects by an increase in VEGF/NO/bradykinin production/endothelium-derived vasodilatory factors or IGF-I or a decrease in thromboxane A2 [8,9]; (4) reduction of circulating vascular permeability factors; (5) anti-inflammatory effects-reduction of oxidized LDL, P-selectin, CRP, and ICAM-1 [10,11]; (6) improvement of endothelial dysfunction [12]; and (7) enhancement of corticosteroids or cyclosporine response by changing drug interactions following lipid removal. However, the point is that we have not found a definite quantitative marker to suggest the long-term and prolonged therapeutic effects of LDL-A treatment on PAD in dialysis patients.…”