Researchers examined previous studies on chronic kidney disease and contributing factors, exploring how they might affect bone loss and heart disease.
In addition to reducing the body’s ability to remove waste, controlling fluid levels, and managing blood pressure, chronic kidney disease (CKD) also impacts a number of processes related to aging and cardiovascular disease. Exploring how the biological changes associated with chronic kidney disease promote age-related disorders and cardiovascular dysfunction could lead to an improved understanding of these conditions in the general population and how to treat them effectively.
In a recent review published in the Lancet Diabetes & Endocrinology, researchers summarized, compared, and contrasted the findings of studies on chronic kidney disease, aging, bone disorders, and cardiovascular disease. They particularly focused on structural and functional changes in the blood vessels, bones, and kidneys, and changes in the levels of phosphate and certain proteins in the blood.
Blood Vessels, Bones, and Kidneys
The elasticity of blood vessels, the density of bone, and kidney function all decrease with age. As these decreases are also common in chronic kidney disease, in many cases occurring with greater severity or earlier in life, it has been suggested that the processes which underlie chronic kidney disease’s signs and symptoms may also be at work in the population at large and there is evidence that they may be interconnected.
Previous studies have found that the accumulation of calcium (found in rich amounts in the bones) in the largest artery of the body is directly proportional to the degree of bone loss in post-menopausal women. Patients with the accelerated aging disorder progeria tend to have both atherosclerosis (arteries narrowed and hardened by deposits of fat and calcium) and osteoporosis (loss of bone density and strength).In patients with high levels of phosphates (of which bone is also rich) in their blood cardiovascular disease-related death occurs earlier for those with chronic kidney disease than for those without.The calcification of blood vessel walls and the deterioration of the cells within them that normally occur with age also happen earlier in chronic kidney disease patients.
Both osteoporosis and CKD-related bone disorders negatively affect the composition, integrity, and the renewal of bone, and increase the likelihood of fractures and death. There have also been links found between the kidneys’ reduced ability to manage levels of calcium, phosphate, and magnesium in chronic kidney disease and the progression of bone disease, vessel calcification, and cardiovascular disease-related death.
Patients with advanced chronic kidney disease are four times as likely to suffer bone fractures as people in the general population. As even early chronic kidney disease patients have been found to be at a high risk earlier than osteoporosis patients, it has been suggested that kidney dysfunction may be an overlooked contributing factor to bone loss in aging.
The impaired ability to regulate phosphate levels in chronic kidney disease is associated with both bone disease and vessel calcification. Moreover, high levels of phosphate in the blood are associated with increased risk of cardiovascular disease and cardiovascular death in chronic kidney disease and in the general population.
FGF23 and Klotho Proteins
Fibroblast growth factor 23 (FGF23), a protein primarily produced by bone cells, plays a crucial role in regulating levels of phosphate by preventing it from being reabsorbed into the blood or released from bone. For FGF23 to carry out these functions, it has to interact with klotho, a protein produced primarily in the kidneys. Reduced levels of klotho, as seen in chronic kidney disease patients, have been associated with cardiovascular conditions such as high blood pressure, abnormal heart muscle growth, and vessel calcification, but also bone loss, brain-wasting diseases, and kidney scarring. In mice, low levels have additionally been found to induce a progeria-like condition and in rhesus monkeys are associated with aging in certain areas of the brain. High levels of FGF23 have been strongly correlated with cardiovascular disease in the general population and reducing levels has been shown to reduce the risk of death or a serious cardiovascular event.
The Diagnosis and Treatment of Bone Diseases
Though invasive, studies have found bone biopsies (in which a small sample of bone tissue is extracted, and its makeup, density, and integrity are analyzed) are the most accurate way to diagnose and provide a prognosis for CKD-related bone disorders. FRAX, a way of predicting the ten-year risk of fracture based on a patient’s physical characteristics and medical history, has also been found to adequately predict fracture risk in the general population and in patients with mild-to-moderate chronic kidney disease. Though calcium supplementation is the most common treatment for bone loss, its effectiveness is contested. Additionally, cardiovascular complications, kidney stones, and irregular heartbeats have been reported with higher doses, more so in chronic kidney disease patients. The antibody therapy Denosumab has been shown to reduce bone loss in most patients but is associated with kidney problems in some cancer patients and elevated calcium levels in patients deficient in Vitamin D.
The findings of the review highlight links between age-related declines in kidney function, bone loss, and cardiovascular disease. Many of the same mechanisms may also be active in chronic kidney disease, and as such research involving chronic kidney disease patients may provide some insights into conditions affecting the population at large. Moreover, kidney function may play a more important role in bone and cardiovascular health than previously thought and may be a beneficial consideration in the diagnosis and treatment of bone disorders especially. FRAX was also highlighted as a possible non-invasive alternative to bone biopsies for predicting fracture risk in mild-to-moderate chronic kidney disease patients, though further study will be required to verify these results.
Written by Raishard Haynes, MBS
Covic, A. et al. (2017). Bone and mineral disorders in chronic kidney disease: implications for cardiovascular health and ageing in the general population. Lancet Diabetes Endocrinol. http://dx.doi.org/10.1016/S2213-8587(17)30310-8