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Abstract: SA-PO214

Severe Bone Loss Occurs in Slow but Not in Fast CKD Progression

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Tsai, Hao-Hsuan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Kentrup, Dominik, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Hunt-Tobey, Bridget, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Spindler, Jadeah Jeannine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Von Drasek, John Charles, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Alterations in mineral metabolism contribute to bone fragility and increased mortality in chronic kidney disease (CKD). The pathogenic mechanisms of CKD-associated bone disease are unclear.

Methods

We studied the Col4a3 knockout model of progressive CKD on two genetic backgrounds: the fast progressing 129X1/SvJ (129Sv-CKD) mice (lifespan: 11 weeks) and the slow progressing C57BL6/J (B6-CKD) mice (lifespan: 23 weeks) and age-matched wild-type (WT) littermates. In all mice, we assessed markers of kidney function, mineral metabolism and 3D bone microarchitecture every 2 weeks in 129Sv mice, and every 4 weeks in B6 mice.

Results

129Sv-CKD mice showed a rapid decline in kidney function from 6 to 10 weeks of age shown by a progressive increase in blood urea nitrogen (BUN) levels (p<0.05 vs. WT at 8 and 10 weeks). At 6 weeks, 129Sv-CKD mice showed mild elevations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels that severely worsened as kidney function declined (p<0.05 at 6, 8 and 10 weeks). Overt hyperphosphatemia developed only at 10 weeks (p<0.05). Starting at 8 weeks, 129Sv-CKD mice showed mild bone loss (-3% in bone mineral density (BMD), +8% in cortical bone porosity (Ct.Po)) (p<0.05). Compared to 129Sv-CKD mice, B6-CKD mice showed a delayed and slow decline in kidney function marked by rising BUN levels starting only at 12 weeks (p<0.05 vs. WT at 16, 20 and 23 weeks). Of note, BUN levels were similar in 10 week-old 129Sv-CKD and 23 week-old B6-CKD mice. In B6-CKD mice, FGF23 and PTH levels started to increase also at 12 weeks (p<0.05 vs. WT at 16, 20 and 23 weeks). Despite a severe increase in PTH levels, FGF23 increase was milder in B6-CKD than in 129Sv-CKD mice, resulting in more pronounced hyperphosphatemia (p<0.05 vs. WT at 20 and 23 weeks). In contrast with 129Sv-CKD mice, B6-CKD mice showed severe bone loss from 12 weeks of age, and reaching dramatic reductions in trabecular bone volume (-40%) and BMD (-15%), cortical thickness (-26%) and BMD (-6%), and increased Ct.Po (+60%) at 23 weeks (p<0.05 vs. WT from 12 to 23 weeks).

Conclusion

To conclude, sustained alterations in mineral metabolism and kidney function induce severe bone loss in CKD.

Funding

  • NIDDK Support