JAMA: Trials need to prove biomarker link of CV events, chronic kidney disease
Data evaluating an association between serum levels of phosphorus, calcium or parathyroid hormone as risk factors for chronic kidney disease patients are lacking and larger randomized controlled trials (RCTs) should be conducted to better evaluate whether treating mineral disorders can improve these patients’ outcomes, according to a meta-analysis published in the March 16 issue of the Journal of the American Medical Association.

Suetonia C. Palmer, PhD, of the University of Otago in Christchurch, New Zealand, and colleagues evaluated the association between the levels of serum phosphorus, parathyroid hormone, calcium and risks of death, cardiovascular (CV) mortality and non fatal CV events in patients with chronic kidney disease by conducting a 47 study meta-analysis.

The studies included data for 327,644 patients with chronic kidney disease and all were published between 1995 and 2010—12 studies enrolled 5,000 or more patients.

The authors found that bias existed in the included studies due to incomplete or unclear data.

The researchers reported that the risk of death increased 18 percent for every 1 mg/dL increase in serum phosphorus; however, there was no significant association between all-cause mortality and serum level of parathyroid hormone or serum level of calcium.

“Overall, we were unable to demonstrate any strong or consistent association between death and serum levels of parathyroid hormone and calcium in individuals with chronic kidney disease,” the authors wrote.

While the authors reported that there could be an association between death and higher serum levels of phosphorus irrespective of the stage of kidney disease, data to prove this association are only available in single cohort studies and summary events of CV disease remain unavailable.

“Consequently, based on the available cohort data and the absence of randomized controlled trials, the evidentiary basis for current clinical guideline–recommended targets of serum phosphorus, parathyroid hormone, and calcium in chronic kidney disease is poor,” the authors wrote.

The studies that include “insufficient evidence” for the safety and efficacy for serum mineral levels in chronic kidney disease patients, could lead to unintended harm. “We now demonstrate that the evidence is similarly lacking for serum mineral target levels as risk factors for poor health outcomes in individuals with chronic kidney disease despite nearly universal adoption of such targets in the field of nephrology,” the authors wrote.

The current research does not support evidence that chronic kidney disease patients should be administered treatment to achieve targeted levels of serum parathyroid hormone or calcium to reduce mortality of CV morbidity, except in extreme cases where hypercalcemia and hypocalcemia result in adverse events including tetany and seizures.

In addition, Palmer et al noted that treatment for high phosphorus levels includes a large pill burden that is associated with a lower quality of life in these patients.

“While we do not conclude that normalizing serum levels of calcium or phosphorus or avoiding upper or lower extremes of serum level of parathyroid hormone is futile, high-quality evidence is required before specific treatment should be advocated strongly,” the authors noted.

Due to the association between phosphorus level and CV events found within the study, the authors recommended that large RCTs be conducted of vitamin D, calcimimetic agents or phosphorus binders in chronic kidney disease patients in order to better understand the benefits of interventions for the disease.

The limitations of the study stem from the fact that conclusions are supported “by low-quality data because cause summary effects are derived from uncontrolled cohort studies that are vulnerable to the unpredictable confounding effects of measured and unmeasured variables.”

Therefore, the authors concluded that evidence for the association between serum levels of phosphorus, calcium or parathyroid hormone as risk factors for outcomes in chronic kidney disease are insufficient and policy and practice guidelines cannot be based off them.

In an accompanying JAMA editorial, Bryan Kestenbaum, MD, of the University of Washington in Seattle, wrote, "Disturbances in phosphorus, calcium and vitamin D metabolic pathways develop early during chronic kidney disease and eventually affect most patients during the course of their disease."

He noted that inconsistent associations of "mineral metabolism markers with clinical outcomes may indicate no true relationship with disease, but also may reflect inherent deficiencies of these factors as biomarkers."

Kestenbaum also wrote that many drugs that are used to lower concentrations of phosphorus and parathyroid hormone "have not been approved for use in patients not receiving dialysis, resulting in substantial off-label drug use and associated costs." He also called for placebo-controlled RCTs to determine the true risks and benefits of these therapies.