Osteoporosis Therapy With Denosumab in Organ Transplant Recipients.

OBJECTIVE: Osteoporosis and fragility fractures represent serious complications for the solid organ transplant population. The recommended osteoporosis therapy for organ recipients involves supplementation with calcium and vitamin D and bisphosphonate administration. However, these options can prove limited for patients with impaired renal function. An alternative therapy option is offered by denosumab, a monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand. PATIENTS AND METHODS: We evaluated 63 patients with osteoporosis (23 males and 40 females, age 56.4 ± 13.1 years) following solid organ transplantation (15 diabetic patients after simultaneous transplantation of the kidney and pancreas, 34 patients after kidney transplantation, and 14 patients with liver grafts). Osteoporosis was diagnosed according to standard DEXA examination using the Lunar Prodigy apparatus. Transplanted patients with impaired renal function were treated for osteoporosis of the lumbar spine (L-spine) and/or proximal femur with calcium and vitamin D supplementation and 60 mg of denosumab every 6 months between the years 2012 and 2017. The mean duration of the therapy was 1.65 ± 0.7 years. RESULTS: After denosumab therapy, L-spine T-scores improved across the whole group, ranging from -2.7 ± 0.09 to -1.8 ± 1.0 (p < 0.001). T-score values for the proximal femur increased from -2.5 ± 0.8 to -2.0 ± 0.7 after the therapy (p < 0.01). We observed only a mild, statistically insignificant improvement in distal forearm T-scores. The mean increase in L-spine bone mineral density (BMD) was 11.5 ± 6.2% in subjects with osteoporosis at this site and 10.4 ± 6.1% in the case of all patients. BMD of the proximal femur increased by 10.4 ± 8.3% in patients with osteoporosis and by 7.5 ± 7.3% in all patients. Denosumab therapy decreased the prevalence of osteoporosis in the L-spine from 75 to 27% (p < 0.001) and proximal femur osteoporosis from 54 to 36% (p < 0.05). Denosumab therapy reduced elevated levels of osteocalcin and beta-crosslaps (ßCTX) in comparison with baseline levels (p < 0.001) across the whole group of graft recipients. CONCLUSION: Denosumab therapy was well-tolerated and improved bone density in our group of solid organ transplant recipients. The indications are that denosumab could be a viable therapeutic option for transplanted patients with osteoporosis, especially in those with renal function impairment or bisphosphonate intolerance.

Molecular patterns of diffuse and nodular parathyroid hyperplasia in long-term hemodialysis.

Secondary hyperparathyroidism is a well-known complication of end-stage renal disease (ESRD). Both nodular and diffuse parathyroid hyperplasia occur in ESRD patients. However, their distinct molecular mechanisms remain poorly understood. Parathyroid tissue obtained from ESRD patients who had undergone parathyroidectomy was used for Illumina transcriptome screening and subsequently for discriminatory gene analysis, pathway mapping, and gene annotation enrichment analysis. Results were further validated using quantitative RT-PCR on the independent larger cohort. Microarray screening proved homogeneity of gene transcripts in hemodialysis patients compared with the transplant cohort and primary hyperparathyroidism; therefore, further experiments were performed in hemodialysis patients only. Enrichment analysis conducted on 485 differentially expressed genes between nodular and diffuse parathyroid hyperplasia revealed highly significant differences in Gene Ontology terms and the Kyoto Encyclopedia of Genes and Genomes database in ribosome structure (P = 3.70 × 10-18). Next, quantitative RT-PCR validation of the top differently expressed genes from microarray analysis proved higher expression of RAN guanine nucleotide release factor (RANGRF; P < 0.001), calcyclin-binding protein (CACYBP; P < 0.05), and exocyst complex component 8 (EXOC8; P < 0.05) and lower expression of peptidylprolyl cis/trans-isomerase and NIMA-interacting 1 (PIN1; P < 0.01) mRNA in nodular hyperplasia. Multivariate analysis revealed higher RANGRF and lower PIN1 expression along with parathyroid weight to be associated with nodular hyperplasia. In conclusion, our study suggests the RANGRF transcript, which controls RNA metabolism, to be likely involved in pathways associated with the switch to nodular parathyroid growth. This transcript, along with PIN1 transcript, which influences parathyroid hormone secretion, may represent new therapeutical targets to cure secondary hyperparathyroidism.

Biphasic response in number of stem cells and endothelial progenitor cells after left ventricular assist device implantation: A 6month follow-up.

BACKGROUND: Continuous blood flow could have deleterious effects on endothelium and vascular health. This could have serious consequences in patients with heart failure treated with continuous flow left ventricular assist devices (LVAD). Therefore, we studied effect of LVAD on three circulating vascular biomarkers: stem cells (SC), endothelial progenitor cells (EPC) and microparticles (MP). METHODS: In 23 patients (5 women) with end-stage heart failure, SC, EPC and MP were measured before, and 3 and 6months after implantation of LVAD (HeartMate II). SC were defined using determination of surface antigen expression as mononuclear CD34+/CD45low+ cells and EPC as mononuclear CD34+/CD45low+/KDR+ cells. MP concentrations were determined by ELISA method. RESULTS: Three months after LVAD implantation numbers of SC and EPC significantly decreased (p=0.01 and p=0.001, respectively). On the contrary, between 3rd and 6th month after implantation they significantly increased (p=0.006 and p=0.003, respectively).MP did not change significantly during the study despite exerting similar trend as SC and EPC. CONCLUSIONS: Observed biphasic changes of SC and EPC might reflect two processes. First, shortly after LVAD implantation, improved tissue perfusion could lead to decrease in ischemic stimuli and ensuing decrease of SC and EPC. Second, continuous flow between 3rd and 6th month produced by LVAD could lead to increase of SC and EPC through activation of endothelium. This explanation could be supported also by similar trend in the changes of concentrations of MP.

The impact of left ventricle assist device on circulating endothelial microparticles - pilot study.

OBJECTIVES: Recent technological breakthroughs in the design of reliable systems for long term non-pulsatile mechanical heart support offer the possibility to study the effect of continuous blood flow in the vascular system. Generally, it is assumed that the absence of physiological pulsatile flow leads to prothrombogenic and proatherogenic changes. We investigated the change in the circulating endothelial microparticle concentration as a marker of endothelial damage in patients implanted with a continuous-flow left ventricle assist device (LVAD). METHODS: Endothelial microparticles were measured in 8 males (mean age 54.1±11.5 years) with terminal heart failure before and 3 months after implantation of an LVAD. The group consisted of 3 patients with dilated cardiomyopathy, 3 patients with ischemic cardiomyopathy, 1 patient with both conditions and 1 patient with congenital valvular disease. The concentration of endothelial microparticles was determined by ELISA Zymutest MP activity test. RESULTS: We did not observe a significant change in the concentration of circulating endothelial microparticles measured before and 3 months after implantation (p=0.669). High inter-individual variability in response to implantation was found. However, no association between a change in endothelial microparticle concentration and heart failure aetiology or a significant clinical complication attributed to LVAD implantation was observed. CONCLUSION: Results from this preliminary pilot study do not indicate that LVADs contribute to short-term vascular damage as defined by an increase in circulating endothelial microparticles.