Similar CV outcomes seen in patients with ESRD on calcium-free vs calcium-based phosphate binders

Keith Bellovich, DO

In this recent JAMA Internal Medicine article, Spoendlin and colleagues fail to find a significant difference in cardiovascular mortality among elderly dialysis patients (average age 75 years) who had been on dialysis for an average of 60 to 70 days and followed through crude and propensity scoring models for up to 5 years.

In July 2017, an update of the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the Diagnosis, Evaluation, Prevention and Treatment of Chronic Kidney Disease – Mineral and Bone Disorder suggested restricting use of calcium-based phosphate binders (CBPBs) in  patients with ESKD, irrespective of baseline serum calcium levels.

The debate has raged for more than a quarter of a century about the ideal targets of calcium, phosphorus and parathyroid hormone for not only bone health, but also the potential impact on cardiovascular mortality of our patients. Despite multiple attempts to answer this important question in controlled scientific studies, including the Renagel in New Dialysis, Reduce Cardiovascular Calcifications to Reduce QT Interval in Dialysis and the Dialysis Clinical Outcomes Revisited studies, conclusions drawn from those studies that have led to recommendations by the KDIGO workgroup are supported by no better than grade 2B evidence.

Limitations in these trials were several, including limited sample size leading to estimates with low precision; under representation of patients at greatest risk of cardiovascular events; inconsistent findings and high numbers of patients lost to follow-up, leading to incomplete outcome data and risks of bias. This all comes at a price: Generally, calcium-free binders are about seven times the cost of calcium-based binders.

Confounding these results is the inability to control for early CKD care and inherent cardiovascular risk factors, unknowns about the quantity of over-the-counter calcium intake by patients and accurately controlling for phosphate binder adherence by patients.

Hence “real-world” observational trials remain exceedingly vulnerable to a variety of errors.

After all this time, and with the latest data from Spoendlin and colleagues, why do we have such difficulty answering these seemingly simple questions? The answer lies in the tunica media of the vasculature and its inherent stiffness and not merely calcium-phosphorus precipitation in atherosclerotic plaques. We labor to maintain our patients within highly specific bone and mineral targets that vary widely and are infrequently or inaccurately measured. These changes begin at very early stages of CKD and lead to significant alterations in metabolism during many years. Interfering with these normal homeostatic mechanisms late at the time of onset of dialysis dependence can result in Monckeberg sclerosis when we either over or under treat to our recommended guideline targets. Many key regulators of bone formation and bone structural proteins are expressed in both calcified medial arterial layers and atherosclerotic plaques, suggesting that vascular calcification is an active process. There is also evidence that physiologic inhibitors of vascular calcification also exist.

So, it remains unclear if reasonable calcium intake (less than 2,000 mg per day of elemental calcium) truly leads to adverse cardiovascular outcomes. Likewise, it remains not yet carved in stone how to manage these patients most effectively. Our search for the real link between mineral metabolism and cardiovascular mortality continues.