Diosmin, a citrus fruit-derived phlebotonic bioflavonoid protects rats from chronic kidney disease-induced loss of bone mass and strength without deteriorating the renal function.

Kidney Disease Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline has recommended treatment decisions for patients with chronic kidney disease (CKD) with osteoporosis and/or high risk of fracture. Bisphosphonates, the first-line anti-osteoporosis drugs have the concern of worsening kidney functions. Moreover, despite impaired bone formation in CKD patients, teriparatide, the formation-stimulating drug is not recommended. Thus, there is an urgent need for safe and effective treatment of osteoporosis in CKD patients. Here, in CKD rats, we tested the osteoprotective effect of diosmin, a citrus-derived bioflavonoid used as a phlebotonic in chronic venous insufficiency and has a renoprotective effect. CKD was developed by 5/6th nephrectomy and diosmin at the human equivalent dose (100 mg kg-1) did not advance renal failure but reduced blood pressure to the level of sham control. Fibroblast growth factor-23 and parathyroid hormone were increased in CKD and diosmin suppressed both. CKD reduced bone mass and deteriorated the microarchitecture of trabecular bones, and diosmin maintained both to control levels. Bone formation and strength were impaired in the CKD and diosmin maintained these levels to control levels. Nanoindentation of bone showed that diosmin significantly increased tissue hardness over the control. Diosmetin, the metabolic surrogate of diosmin had comparable pharmacokinetic profiles between the control and CKD groups. Furthermore, diosmetin (50 mg kg-1) protected against CKD-induced bone loss. These data suggest that diosmin and its metabolic surrogate, diosmetin protect against CKD-induced osteopenia. Since diosmin has no renal adverse effect and protected bone mass and strength in CKD rats, we propose assessing its anti-osteoporosis effect in CKD patients.

Modulation of matrix metalloproteinase activity by EDTA prevents posterior capsular opacification.

PURPOSE: To evaluate the effect of ethylenediaminetetraacetic acid (EDTA) on posterior capsular opacification (PCO) of rabbits and to assess its effect on intraocular tissues. METHODS: Modulation of matrix metalloproteinase (MMP) activity in the aqueous following cataract surgery in rabbits and its prevention by different doses of EDTA was determined by zymography. For evaluation of PCO, lensectomized rabbits were intracamerally injected with single dose of either 5 mg EDTA or normal saline. After one month, the degree of PCO was determined by slitlamp biomicroscopy, Miyake-Apple view, and histology of the lens capsule. The effect of EDTA on intra ocular pressure (IOP), corneal endothelial cells, and the retina was evaluated by tonometry, specular microscopy and scanning electron microscopy, and electroretinography. The concentration of EDTA in the aqueous was determined by high performance liquid chromatography (HPLC) at different time points. RESULTS: The MMP activity was significantly increased in the aqueous of the operated eyes, and EDTA reduced the degree of increase in a dose-dependent manner. EDTA treatment significantly reduced the degree of PCO (p<0.05). Histopathology of the lens capsule showed a reduction in the number of proliferating and migrating cells as well as MMP2 expression in the EDTA-treated eyes. EDTA treatment did not change the IOP; density, morphology and ultrastructure of the corneal endothelial cells; and electroretinography (ERG). EDTA was detectable in the aqueous humor up to 72 h following a single intracameral injection. CONCLUSIONS: EDTA reduces the degree of PCO by suppressing the MMP activity and it is not toxic to intra ocular structures at the concentration used.