Session Highlights Long-term Skeletal Effects of Kidney Diseases

October 22, 2020
Gianna Melillo
Gianna Melillo

Gianna is an assistant editor of The American Journal of Managed Care® (AJMC®). She has been working on AJMC® since 2019 and has a BA in philosophy and journalism & professional writing from The College of New Jersey.

Experts presenting the American Society of Nephrology’s Kidney Week session entitled “From Kids to Adults: Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Across the Life Course,” outlined the detrimental effects of childhood CKD and other kidney diseases on long-term health.

Experts presenting the American Society of Nephrology’s Kidney Week session entitled “From Kids to Adults: Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Across the Life Course,” outlined the detrimental effects of childhood CKD and other kidney diseases on long-term health.

Specifically, these diseases can result in exposure of the skeleton and vasculature to uremic toxins, which may contribute to an increased risk of bone fractures and lack of ascertainment of peak bone mass.

“Our goal as pediatricians is to optimize health development as our patients head into adulthood,” said Mary B. Leonard, MD, MS, a professor and chair of the Department of Pediatrics at Stanford University School of Medicine. According to Leonard, there are likely specific periods during a child’s growth and development where the skeleton and vasculature and uniquely vulnerable to the effects of CKD.

Peak bone mass is a lifelong determinant of skeletal health and can serve as a marker of certain conditions’ impacts on the skeleton. Meanwhile, when it comes to bone structure, sex hormones play a substantial role. For example, greater peak bone mass in boys isn't so much about higher density but really about larger bones, Leonard explained.

One study showed that during the periods of most rapid growth and bone accrual, healthy kids had significantly higher parathyroid hormone (PTH) levels and significantly higher 125 [vitamin] D levels, albeit in the normal range. This was independent of calcium intake and reflects the response to the increased needs for calcium during bone accrual, Leonard said.

In a separate study, researchers followed children who started renal replacement therapy prior to 14 years of age. Over 250 adults were included in the study and participants ultimately reported significant musculoskeletal morbidities. During adulthood, 37% reported clinical bone disease, 26% reported deformities, 13% reported aseptic bone necrosis, and 7% developed severe disabling bone disease. Overall, clinical bone disease was more apparent in those with a longer duration of renal replacement therapy, a start of renal replacement therapy earlier in history, and those with a history of severe hyperparathyroidism.

Yet another study demonstrated lower glomerular filtration rate and higher PTH were associated with fractures in children with CKD. This study also demonstrated a “very strong signal for phosphate binders with a 63% reduction in fracture rates,” unrelated to phosphorus levels or fibroblast growth factor 23 levels. Around 20% of children were on binders at any point in time during the study and the majority of these binders contained calcium.

“Our hypothesis is that, although these are observational data and we can't assume cause and effect, it is a suggestion that potentially speaks to the calcium demands of the growing skeleton,” Leonard said.

Abnormal mineral metabolism, decreased muscle mass, physical inactivity, inflammation and delayed maturation are all potential threats childhood CKD poses to long-term bone quality. Limited data also suggest that even after kidney transplantation, deficits in impaired expansion of periosteal circumference during growth are irreversible, despite recovery of muscle mass and improvements in metabolic parameters.

To identify strategies to promote gains in bone structure and optimize bone mineralization, prospective clinical trials ought to be carried out. “We need to know how to do this without exacerbating any vascular calcification, and this may vary according to growth and development stage,” Leonard concluded.

Apart from long-term implications of CKD on the skeleton, Michelle Denberg, MD, an attending physician in the division of nephrology and the cancer survivorship program at the Children’s Hospital of Philadelphia, reviewed the impacts of glomerular disease on the skeleton throughout an individual’s life course.

“With 90% of peak bone mass established by 18 years of age, threats to bone accrual in childhood and adolescence can have critical lifelong impact,” Denberg said, while “individuals with glomerular kidney disease are exposed to both disease-related and treatment-related factors that affect bone structure and metabolism.”

Altered vitamin D homeostasis, varying degrees of systemic inflammation and exposure to toxic medications may all contribute to compromised bone health in this population.

In particular, “glucocorticoid treatment is frequently used in patients with career their disease is the most common cause of secondary osteoporosis,” Denberg explained. Other medications such as calcineurin inhibitors like cyclosporine and tacrolimus “have been shown to induce a dose and duration dependent bone loss due to increased osteoclastogenesis.”

Even in remission, studies have shown that vitamin D deficient is highly prevalent among those with glomerular disease. However, supplementation can be protective in those with normal and impaired kidney function.

In the future, mechanistic studies leveraging advances in high-resolution bone imaging and bone biopsy techniques may help to better characterize mineral and bone disorders among those with glomerular disease. Studies should also investigate the impact of inflammation and immune dysregulation on bone health while also investigating the effect of combined medication exposures and interventions to mitigate skeletal morbidities in this population.