Disturbances in Bone Largely Predict Aortic Calcification in an Alternative Rat Model Developed to Study Both Vascular and Bone Pathology in Chronic Kidney Disease

Abstract

Because current rat models used to study chronic kidney disease (CKD)-related vascular calcification show consistent but excessive vascular calcification and chaotic, immeasurable, bone mineralization due to excessive bone turnover, they are not suited to study the bone-vascular axis in one and the same animal. Because vascular calcification and bone mineralization are closely related to each other, an animal model in which both pathologies can be studied concomitantly is highly needed. CKD-related vascular calcification in rats was induced by a 0.25% adenine/low vitamin K diet. To follow vascular calcification and bone pathology over time, rats were killed at weeks 4, 8, 10, 11, and 12. Both static and dynamic bone parameters were measured. Vascular calcification was quantified by histomorphometry and measurement of the arterial calcium content. Stable, severe CKD was induced along with hyperphosphatemia, hypocalcemia as well as increased serum PTH and FGF23. Calcification in the aorta and peripheral arteries was present from week 8 of CKD onward. Four and 8 weeks after CKD, static and dynamic bone parameters were measurable in all animals, thereby presenting typical features of hyperparathyroid bone disease. Multiple regression analysis showed that the eroded perimeter and mineral apposition rate in the bone were strong predictors for aortic calcification. This rat model presents a stable CKD, moderate vascular calcification, and quantifiable bone pathology after 8 weeks of CKD and is the first model that lends itself to study these main complications simultaneously in CKD in mechanistic and intervention studies.

Adenine‐induced chronic kidney disease in rats

“…In comparison, the 0.25% adenine‐induced CKD model demonstrated only moderate vascular calcification, and significant bone pathology after 8 weeks of adenine treatment. This report was the first to demonstrate these major complications in the adenine model of induced CKD …”

“…Vascular calcification and bone pathologies are two complications of CKD that have a major impact on mortality. Neven et al studied markers of CKD in the 0.75% adenine diet model, showing excessive vascular calcification with chaotic and marked bone mineralisation due to excessive bone turnover. In comparison, the 0.25% adenine‐induced CKD model demonstrated only moderate vascular calcification, and significant bone pathology after 8 weeks of adenine treatment.…”

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

“…In the present study, we observed an effect of (OEG 2 ) 2 -IP4 on bone osteoid area. However, it was seen in a CKD/VC rat model in young animals with open growth plates and rapid bone growth that presents a dramatically increased bone turnover with chaotic bone mineralization, making the rats particularly vulnerable to an imbalance between excessive osteoid deposition, subsequent mineralization, and bone resorption 74 . Therefore, this model does not accurately reflect the low to mildly increased bone metabolism in the majority of CKD patients 75 .…”

Characterization of an Animal Model to Study Risk Factors and New Therapies for the Cardiorenal Syndrome, a Major Health Issue in Our Aging Population

“…A severe CKD develops with the direct consequence of a disturbed mineral balance as reflected by the altered calcium and phosphorus levels and in association with the aberrations in hormonal levels of FGF-23 (PTH was not measured in this study but was reported earlier by our group to be increased in rats with adenine-induced CKD [1]) which in turn induced the well-known and highly undesirable complication of CKD, i.e. mineral and bone disorder (MBD) which is characterized by high turnover bone disease and pathological vessel calcification.…”

“…Therefore, we further developed and characterized our previously described model of CKD-MBD (chronic kidney disease - mineral and bone disorders) [1] and investigated whether it would be usable as a model for CRS type 4, as defined by the Ronco classification [2], i.e. CKD causing cardiac dysfunction.…”