Exploring the potential effect of paricalcitol on markers of inflammation in de novo renal transplant recipients

Hege Kampen Pihlstrøm, Thor Ueland, Annika E Michelsen, Pål Aukrust, Franscesca Gatti, Clara Hammarström, Monika Kasprzycka, Junbai Wang, Guttorm Haraldsen, Geir Mjøen, Dag Olav Dahle, Karsten Midtvedt, Ivar Anders Eide, Anders Hartmann, Hallvard Holdaas, Hege Kampen Pihlstrøm, Thor Ueland, Annika E Michelsen, Pål Aukrust, Franscesca Gatti, Clara Hammarström, Monika Kasprzycka, Junbai Wang, Guttorm Haraldsen, Geir Mjøen, Dag Olav Dahle, Karsten Midtvedt, Ivar Anders Eide, Anders Hartmann, Hallvard Holdaas

Abstract

Following a successful renal transplantation circulating markers of inflammation may remain elevated, and systemic inflammation is associated with worse clinical outcome in renal transplant recipients (RTRs). Vitamin D-receptor (VDR) activation is postulated to modulate inflammation and endothelial function. We aimed to explore if a synthetic vitamin D, paricalcitol, could influence systemic inflammation and immune activation in RTRs. Newly transplanted RTRs were included in an open-label randomized controlled trial on the effect of paricalcitol on top of standard care over the first post-transplant year. Fourteen pre-defined circulating biomarkers reflecting leukocyte activation, endothelial activation, fibrosis and general inflammatory burden were analyzed in 74 RTRs at 8 weeks (baseline) and 1 year post-engraftment. Mean changes in plasma biomarker concentrations were compared by t-test. The expression of genes coding for the same biomarkers were investigated in 1-year surveillance graft biopsies (n = 60). In patients treated with paricalcitol circulating osteoprotegerin levels increased by 0.19 ng/ml, compared with a 0.05 ng/ml increase in controls (p = 0.030). In graft tissue, a 21% higher median gene expression level of TNFRSF11B coding for osteoprotegerin was found in paricalcitol-treated patients compared with controls (p = 0.026). Paricalcitol treatment did not significantly affect the blood- or tissue levels of any other investigated inflammatory marker. In RTRs, paricalcitol treatment might increase both circulating and tissue levels of osteoprotegerin, a modulator of calcification, but potential anti-inflammatory treatment effects in RTRs are likely very modest. [NCT01694160 (2012/107D)]; [www.clinicaltrials.gov].

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Changes in levels of osteoprotegerin…
Fig 1. Changes in levels of osteoprotegerin across the study period.
Osteoprotegerin change (ng/nl) in patients treated with paricalcitol vs patients receiving no extra treatment; median (horizontal line), interquartile range (blue box), outlier (°).
Fig 2. Heat map of inflammatory marker…
Fig 2. Heat map of inflammatory marker gene expression levels in graft tissue.
The expression of 15 genes coding for 13 inflammatory biomarkers in 30 treated patients (to the left) vs 30 patients in the control group (to the right). Darker color indicates higher expression levels. Z-scores of duplicated genes in the array are averaged. Genes coding for proteins with different nomenclature: ACVR1/ACVR1B/ ACVR1C, activin A receptor subunits; ANGPT2, angiopoietin-2; COL18A1, endostatin; LCN2, neutrophil gelatinase-associated lipocalin (NGAL); LGALS3, galectin-3; TNFRSF11B, osteoprotegerin; TNFRSF1A, soluble tumor necrosis factor receptor-1 (sTNFr1).

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