Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder

Abstract

Chronic kidney disease (CKD) causes dysregulation of mineral metabolism, vascular calcification and renal osteodystrophy, an entity called 'CKD-Mineral and Bone Disorder' (CKD-MBD). Here we determine whether metformin, an anti-diabetic drug, exerts favorable effects on progressive, severe CKD and concomitant mineral metabolism disturbances. Rats with CKD-MBD, induced by a 0.25% adenine diet for eight weeks, were treated with 200 mg/kg/day metformin or vehicle from one week after CKD induction onward. Severe, stable CKD along with marked hyperphosphatemia and hypocalcemia developed in these rats which led to arterial calcification and high bone turnover disease. Metformin protected from development toward severe CKD. Metformin-treated rats did not develop hyperphosphatemia or hypocalcemia and this prevented the development of vascular calcification and inhibited the progression toward high bone turnover disease. Kidneys of the metformin group showed significantly less cellular infiltration, fibrosis and inflammation. To study a possible direct effect of metformin on the development of vascular calcification, independent of its effect on renal function, metformin (200 mg/kg/day) or vehicle was dosed for ten weeks to rats with warfarin-induced vascular calcification. The drug did not reduce aorta or small vessel calcification in this animal model. Thus, metformin protected against the development of severe CKD and preserved calcium phosphorus homeostasis. As a result of its beneficial impact on renal function, associated comorbidities such as vascular calcification and high bone turnover disease were also prevented.

Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes

“…Recent experimental data in a rat model of chronic kidney disease (CKD) showed that kidneys from the metformin group exhibited significantly less cellular infiltration, fibrosis and inflammation, and that metformin protected against the development of severe renal failure (while preserving calcium phosphorus homoeostasis) and vascular calcification. Of note, these positive effects were independent of any glucose-lowering effect in this model using non-diabetic rats [31]. Overall, these preclinical data suggest that the potential benefits of metformin on renal outcomes in patients with T2DM may well extend beyond its antihyperglycaemic activity.…”

Metformin modulates immune cell infiltration into the kidney during unilateral ureteral obstruction in mice

“…; Neven et al. ). We have previously demonstrated that metformin can attenuate inflammation as well as tubular damage in a unilateral ureteral obstruction (UUO) model (Christensen et al.…”

Metformin and Its Benefits for Various Diseases

“…In recent years, many additional unexpected but effective roles of metformin were found. Studies showed that metformin exerts a strong effect on numerous cancers (6,7), cardiovascular disease (CVD) (8), liver diseases (9), obesity (10), neurodegenerative diseases (11), and renal diseases (12). Sole medication or combination therapy with other drugs has shown to be effective to treat different diseases.…”