Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content.

Megalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of the megalin gene in cystinotic mice, a model of nephropathic cystinosis, essentially blocks renal cystine accumulation and partially preserves kidney tissue integrity. Here, we examined whether inhibition of the megalin pathway in adult cystinotic mice by dietary supplementation (5x-fold vs control regular diet) with the dibasic amino-acids (dAAs), lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys. Using surface plasmon resonance, we first showed that both dAAs compete for protein ligand binding to immobilized megalin in a concentration-dependent manner, with identical inhibition curves by L- and D-stereoisomers. In cystinotic mice, 2-month diets with 5x-L-lysine and 5x-L-arginine were overall well tolerated, while 5x-D-lysine induced strong polyuria but no weight loss. All diets induced a marked increase of dAA urinary excretion, most prominent under 5x-D-lysine, without sign of kidney insufficiency. Renal cystine accumulation was slowed down approx. twofold by L-dAAs, and totally suppressed by D-lysine. We conclude that prolonged dietary manipulation of the megalin pathway in kidneys is feasible, tolerable and can be effective in vivo.

Fibroid management in premenopausal women.

Uterine fibroids are the most common tumors affecting premenopausal women, responsible for bleeding, pain, and reduced quality of life. When symptomatic, their management mainly involves surgery, which is all too often radical (hysterectomy). While surgical options sparing the uterus (hysteroscopic and laparoscopic myomectomy) and other non-surgical approaches do indeed exist, drug-based therapies are associated with lower costs and morbidity rates. Since progesterone is required for fibroid growth, gonadotropin agonists have been used to control bleeding and decrease fibroid volume, but they only represent a temporary remedy due to adverse events. Ulipristal acetate (UPA), a selective progesterone receptor modulator, is indicated for fibroid management. It is safe, provides fast control of bleeding, and causes sustained fibroid volume reduction in the vast majority of cases (80%). Indeed, UPA-treated fibroids shrink by a combination of inhibition of cell proliferation, stimulation of cell death, and fibrosis resorption. In the case of symptom recurrence, repeated intermittent 3-month courses of daily UPA considerably maximize the impact of treatment, sometimes resulting in complete disappearance of treated fibroids. Despite the therapeutic dose of UPA being very well tolerated, patients with liver anomalies or disorders should be excluded at screening according to European Medicines Agency-Pharmacovigilance Risk Assessment Committee (PRAC) recommendations. We therefore propose new algorithms for fibroid management in premenopausal women with symptomatic fibroids, depending on their localization, the patient's wishes, and clinical response, while monitoring liver enzymes and bilirubin, as recommended by the PRAC, in order to minimize the risks of possible liver toxicity.