Bone and mineral disorders in chronic kidney disease: implications for cardiovascular health and ageing in the general population

Summary

The patient with chronic kidney disease (CKD) represents an extreme model for arteriosclerosis, vascular calcification, and bone disorders, all of which are also associated with ageing in the general population. These pathological features are also relevant to other common chronic health disorders such as diabetes, and chronic inflammatory and cardiovascular diseases. Although management and interventions for these major risk factors are now incorporated into most public health guidelines (eg, smoking cessation and control of bodyweight and blood pressure, as well as glucose and cholesterol concentrations), some residual cardiovascular risk is not reduced by implementation of these interventions. CKD should be regarded as an atypical disease in which both traditional and novel cardiovascular risk factors have effects on outcomes. But CKD can also be viewed conceptually as an accelerator of traditional cardiovascular risk factors. Findings from research into mineral bone disorder associated with CKD (CKD–MBD) could help the medical community to better understand the vascular actions of certain molecules, such as phosphates, fibroblast growth factor 23, parathyroid hormone, sclerostin, or vitamin D and their relevance to the management of different pathologies in the general population. Importantly, these components, which are recognised in nephrology, could help to explain residual risk of cardiovascular events in the general population. Thus, achieving a better understanding of CKD–MBDs could provide substantial insight into future treatments for arteriosclerosis and osteoporosis, which are strongly associated with ageing and morbidity in the general population.

Introduction

Chronic kidney disease (CKD) is a systemic condition affecting about 10% of the general population, although estimates of CKD prevalence vary widely, both within and between countries.¹ Mineral and bone disorders are common in patients with CKD and contribute to the large burden of cardiovascular and bone diseases characteristic of CKD. Although end-stage renal disease requiring dialysis is well recognised, it is also rare and unique in terms of its physiological disturbances. Much more common are the less severe forms of CKD (eg, stages 3b–4)¹ that already show distinct features and characteristics such as hyperphosphataemia, hyperparathyroidism, increased fibroblast growth factor 23 (FGF23) concentration, klotho deficiency, or vitamin D concentration abnormalities.

The kidneys are the major source of the anti-ageing protein klotho, and CKD is a state of klotho deficiency.² In fact, patients with renal disease show decreased klotho expression as early as CKD stage 1³—klotho deficiency being one of the first mineral and bone disorders that occur in the setting of CKD. As CKD progresses, klotho concentrations continue to decline, causing FGF23 resistance and therefore leading to large increases in serum concentrations of FGF23 and parathyroid hormone, as well as decreases in serum vitamin D concentration.³ Many of these changes predispose patients to develop vascular calcifications and their sequelae. Increasing evidence is indicating that klotho deficiency could contribute to salt-sensitive hypertension,⁴ aberrant cardiac remodelling,⁵ vascular calcification,² bone loss,⁶ neurodegenerative diseases,⁷ and renal fibrosis.⁵ Thus, CKD can be considered a state of premature ageing and a model for similar processes associated with ageing in the general population.

Collectively, these alterations have been termed CKD–mineral and bone disorders (CKD–MBDs). The additional health risks imposed by CKD–MBDs on CKD risk factors such as systemic hypertension, hypercholesterolaemia, left ventricular hypertrophy, coronary heart disease, and diabetes, could provide an opportunity for improved risk management beyond controlling traditional factors. In this Review we will discuss how several components considered to be CKD-specific risk factors could also contribute to the cardiovascular and ageing risk profiles in the general population.⁸ We will also summarise key elements of the CKD-derived pro-ageing process that could be of relevance for clinical practice in general internal medicine; discuss phosphate exposure, FGF23 elevation and klotho deficiency, and bone disease; and review their potential contribution to all-cause or cardiovascular mortality in patients with CKD and the general population.