Mechanisms of vascular calcification in CKD—evidence for premature ageing?

Abstract

Ageing is a potent, independent risk factor for cardiovascular disease. Calcification of the vascular smooth muscle cell (VSMC) layer of the vessel media is a hallmark of vascular ageing. Young patients with chronic kidney disease (CKD) exhibit an extremely high cardiovascular mortality, equivalent to that seen in octogenarians in the general population. Even children on dialysis develop accelerated medial vascular calcification and arterial stiffening, leading to the suggestion that patients with CKD exhibit a 'premature ageing' phenotype. It is now well documented that uraemic toxins, particularly those associated with dysregulated mineral metabolism, can drive VSMC damage and phenotypic changes that promote vascular calcification; epidemiological data suggest that some of these same risk factors associate with cardiovascular mortality in the aged general population. Importantly, emerging evidence suggests that uraemic toxins may promote DNA damage, a key factor driving cellular ageing, and moreover, that these ageing mechanisms may reiterate some of those seen in patients with genetically induced progeric syndromes caused by nuclear lamina disruption. This new knowledge should pave the way for the development of novel therapies that target tissue-specific ageing mechanisms to treat vascular decline in CKD.

Key Points

  • Vascular calcification is an age-associated pathology that is accelerated in patients with chronic kidney disease (CKD) and associated with increased mortality

  • Vascular calcification is a cell-mediated process driven by vascular smooth muscle cell (VSMC) death and maladaptation

  • Emerging evidence suggests that defects in the nuclear lamina occur during VSMC ageing and in CKD, causing accelerated DNA damage and premature senescence

  • Senescent VSMCs develop a secretory phenotype and release factors that drive VSMC osteogenic differentiation both locally and potentially at remote sites

  • DNA damage may also link the parallel decline of the vasculature–kidney–bone axis in CKD

  • Prelamin A accumulation and/or DNA damage signalling pathways may represent novel therapeutic targets for vascular calcification in CKD

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Figure 1: Mechanisms leading to VSMC phenotypic change and calcification in response to dysregulated mineral metabolism in chronic kidney disease.
Figure 2: DNA damage drives the SASP in VSMCs.
Figure 3: Prelamin A accumulation promotes vascular ageing and dysfunction.
Figure 4: Tissue ageing is driven by DNA damage and inflammatory mediators released from senescent tissues.

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Acknowledgements

The author's work is supported by the British Heart Foundation.

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Shanahan, C. Mechanisms of vascular calcification in CKD—evidence for premature ageing?. Nat Rev Nephrol 9, 661–670 (2013). https://doi.org/10.1038/nrneph.2013.176

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