A New Murine Model of Chronic Kidney Disease-Mineral and Bone Disorder

Abstract

Chronic kidney disease (CKD) is associated with mineral and bone disorder (MBD), which is the main cause of the extensively increased cardiovascular mortality in the CKD population. We now aimed to establish a new murine experimental CKD-MBD model. Dilute brown non-Agouti (DBA/2) mice were fed with high-phosphate diet for 4 (HPD4) or 7 (HPD7) days, then with standard chow diet (SCD) and subsequently followed until day 84. They were compared to DBA/2 mice maintained on SCD during the whole study period. Both 4 and 7 days HPD-fed mice developed phosphate nephropathy with tubular atrophy, interstitial fibrosis, decreased glomerular filtration rate, and increased serum urea levels. The abdominal aorta of HPD-treated mice showed signs of media calcification. Histomorphometric analysis of HPD-treated mice showed decreased bone volume/tissue volume, low mineral apposition rate, and low bone formation rate as compared to SCD-fed mice, despite increased parathyroid hormone levels. Overall, the observed phenotype was more pronounced in the HPD7 group. In summary, we established a new, noninvasive, and therefore easy to perform reproducible CKD-MBD model, which showed media calcification, secondary hyperparathyroidism, and low-turnover bone disease.

Mouse Models of Mineral Bone Disorders Associated with Chronic Kidney Disease

“…Frausher et al reported that Brown agouti/2 (DBA/2) mice fed with a high phosphate diet develop progressive calcifications and CKD [ 55 ]. Some authors used both groups of mice with surgically induced CKD and adenine-induced CKD [ 46 , 64 ], with the degree of CKD being higher in the latter in one study [ 46 ].…”

“…Phosphate-enriched diets (HP diet) have been used to enhance the severity of SHPT in many CKD–MBD mouse studies [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 , 56 , 57 , 58 , 64 ], see Table 1 . An increase in vascular disease has been observed in mice with CKD and HP diet [ 18 ], accompanied by a similar increase in bone alterations [ 37 , 38 , 44 ].…”

“…An increase in vascular disease has been observed in mice with CKD and HP diet [ 18 ], accompanied by a similar increase in bone alterations [ 37 , 38 , 44 ]. The recommended minimal standard dietary phosphate content is 0.3% phosphate together with 0.5% calcium [ 70 ], while in CKD–MBD studies, diets usually contained 0.5 to 0.9% phosphate per kg diet [ 20 , 21 , 27 , 28 , 29 , 34 , 35 , 36 , 37 , 38 , 40 , 42 , 44 , 48 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 64 , 65 , 68 ] or even up to 1.2% [ 67 ]. Phosphate-enriched diets contained 0.9 to 2% of phosphate [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 , 56 , 57 , 58 , 64 ].…”

“…The recommended minimal standard dietary phosphate content is 0.3% phosphate together with 0.5% calcium [ 70 ], while in CKD–MBD studies, diets usually contained 0.5 to 0.9% phosphate per kg diet [ 20 , 21 , 27 , 28 , 29 , 34 , 35 , 36 , 37 , 38 , 40 , 42 , 44 , 48 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 64 , 65 , 68 ] or even up to 1.2% [ 67 ]. Phosphate-enriched diets contained 0.9 to 2% of phosphate [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 , 56 , 57 , 58 , 64 ]. These diets were administered over periods ranging from 4 days to 18 weeks [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 ,…”

Editorial: Management of osteoporosis in patients with chronic kidney disease

“…Postulating a hypothesis and testing it in suitable model is a fundamental step in understanding complex challenging medical problems as CKD-MBD. Traditionally, murine models were used for this purpose ( 13 ), however, extrapolating evidence from mouse to human pathophysiology has demonstrated multiple pitfalls. Mice show considerable genetic diversities in bone diseases.…”