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The burden of fractures, vascular pathology and mortality in chronic kidney disease‐mineral and bone disorders

Chronic kidney disease (CKD) is increasingly recognized globally as a major public health problem. The prevalence of CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73 m and/or proteinuria for at least 3 months) in Australian adults is between 11.5% and 13.4% (equivalent to 1.4–1.6 million individuals). Patients with CKD have substantial morbidity and mortality compared with individuals without CKD, with the increase in disease burden largely attributed to cardiovascular events. Considerable cardiovascular risk in the CKD population results not only from traditional cardiovascular risk factors, but also from atypical, CKD-specific cardiovascular risk factors including abnormalities of mineral and bone metabolism. Chronic kidney disease results in a cascade of changes inmineralmetabolism, including vitaminD deficiency, hypocalcaemia, hyperphosphataemia, elevated fibroblast growth factor 23 and elevated parathyroid hormone, which contributes to secondary hyperparathyroidism, renal bone disease and increased vascular pathology. These abnormalities are now commonly referred to as Chronic Kidney Disease-Mineral and Bone Disorder (CKDMBD), a term developed by the international organisation Kidney Disease Improving Global Outcomes (KDIGO) to appreciate the intimate relationship between bone disease and cardiovascular disease. CKD-MBD is a systemic disease that links disorders of mineral and bone metabolism due to CKD to either one or all of the following: abnormalities of calcium, phosphate, parathyroid hormone or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, linear growth or strength; and vascular or other soft-tissue calcification. These abnormalities begin to appear even in early stages of CKD and make a significant contribution to the pathogenesis of renal bone disease and the burden of vascular pathology, as well as to eventual morbidity and mortality largely because of fractures and cardiovascular disease. Patients with CKD, compared with the general population, have a 3–30 fold increase in mortality, depending on the agegroup examined, and cardiovascular disease accounts for over half of all deaths among patients on dialysis, with myocardial infarction, ischaemic cardiomyopathy, stroke and peripheral vascular disease making up the majority of deaths. Cardiovascular mortality in CKD is higher than would be predicted simply from concurrent risk factors such as diabetes, hypertension and elevated cholesterol levels; and interventions to modify traditional cardiovascular risk factors such as lipid levels have been disappointing. Much of the cardiovascular burden is likely to arise from problems of vascular calcification and arterial stiffness precipitated by abnormal mineral metabolism. Amediated complex of inhibitory and inducing factors are involved in the pathogenesis of vascular calcification, and in the CKD population the normal balance becomes dysregulated towards the development of accelerated and progressive disease. Vascular calcification in CKD has intimate interactions with bonemineralization and, as a result of imbalances inmineral metabolism, is associated with enhanced bone resorption. An inverse relationship between cardiovascular disease and bone mineral density has been reported in both the general population and in patients with CKD. Renal bone disease, or renal osteodystrophy, related to the metabolic and hormonal abnormalities that occur as part of CKD-MBD, is associated with high risk of fractures. Fractures are common across the spectrum of CKD and are associated with additional hospitalisation, excess morbidity and mortality. The abnormalities of CKD-MBD adversely affect the bone remodelling process in CKD resulting in impaired turnover andmineralization and deterioration in microarchitecture of the bone akin to the normal ageing process. Bone strength, a composite of bone quantity and quality, is compromised in CKD increasing the susceptibility to fragility fractures. Despite the significant burden of CKD-MBD related complications, studies of the association between biochemical markers, cardiovascular disease and bone morphology and fracture in CKD are surprisingly limited in number and size. There is a shortage of randomized trials specifically evaluating the effect of interventions on patient-centred outcomes and, furthermore, existing trials have multiple methodological limitations including small sample size and short follow-up. These issues were highlighted in the KDIGO Clinical Guidelines on CKD-MBD published in 2009. These guidelines provided a summary of the evidence base (until December 2008) and identified significant key gaps in knowledge in the area of