Parathyroid suppression therapy normalizes chronic kidney disease-induced elevations in cortical bone vascular perfusion: a pilot study

Abstract

Patients with chronic kidney disease (CKD) have accelerated bone loss, vascular calcification and abnormal biochemistries, together contributing to an increased risk of cardiovascular disease and fracture-associated mortality. Despite evidence of vascular pathologies and dysfunction in CKD, our group has shown that cortical bone tissue perfusion is higher in a rat model of highturnover CKD. The goal of the present study was to test the hypothesis that parathyroid hormone (PTH) suppressive interventions would normalize cortical bone vascular perfusion in the setting of CKD. In two separate experiments, 35-week old CKD animals and their normal littermates, underwent intra-cardiac fluorescent microsphere injection to assess the effect of 10 weeks of PTH suppression (Experiment 1: calcium supplementation, Experiment 2: calcimimetic treatment) on alterations in bone tissue perfusion. In Experiment 1, CKD animals had serum blood urea nitrogen (BUN) and PTH levels significantly higher than NL (+182% and +958%; p<0.05). CKD+Ca animals had BUN levels that were similar to CKD, while PTH levels were significantly lower and comparable to NL. Both femoral cortex (+220%, p=0.003) and tibial cortex (+336, p=0.005) tissue perfusion were significantly higher in CKD animals when compared to NL; perfusion was normalized to those of NL in CKD+Ca animals. MicroCT analysis of the proximal tibia cortical porosity showed a trend toward higher values in CKD (+401%; p=0.017) but not CKD+Ca (+111%; p = 0.38) compared to NL. Experiment 2, using an alternative method of PTH suppression, showed similar results as those of Experiment 1. These data demonstrate that PTH-suppression based interventions normalize cortical bone perfusion in the setting of CKD.

Inhibition of Osteoclast Differentiation by 1.25-D and the Calcimimetic KP2326 Reveals 1.25-D Resistance in Advanced CKD

“…KP‐2326 (Ac‐c(C)rrarar‐NH2) is a peptide analog of the calcimimetic etelcalcetide (Ac‐c(C)arrrar‐NH2), which are related but clearly distinct branched peptides; the lowercase letters refer to D‐amino acids and the uppercase letters refer to the natural L‐amino acids (C, Cystein; A, Alanin; R, Arginin). ( 17,18 ) In fact, both of them are pro‐drugs in the sense that the disulfide between D‐Cystein and L‐Cystein at the branch‐point must be cleaved before the main chain D‐Cystein residue (c) can bind to the CaSR Venus Flytrap (VFT) residue Cys‐482. ( 19 )…”

“…KP-2326 (Ac-c(C)rrarar-NH2) is a peptide analog of the calcimimetic etelcalcetide (Ac-c(C)arrrar-NH2), which are related but clearly distinct branched peptides; the lowercase letters refer to D-amino acids and the uppercase letters refer to the natural L-amino acids (C, Cystein; A, Alanin; R, Arginin). (17,18) In fact, both of them are pro-drugs in the sense that the disulfide between D-Cystein and L-Cystein at the branch-point must be cleaved before the main chain D-Cystein residue (c) can bind to the CaSR Venus Flytrap (VFT) residue Cys-482. (19) Osteoclast functional assays At the end of the osteoclastic differentiation protocol, the cells were harvested for real-time PCR analysis or were fixed with 4% of PFA and stained with leukocyte acid phosphatase (TRAP) staining kit according to the manufacturer's instructions (Sigma-Aldrich, St. Louis, MO, USA).…”