In patients with chronic kidney disease, high serum levels of phosphorus appear to be associated with increases in all-cause mortality, results of a large meta-analysis suggest.
There were no strong or consistent associations between increased levels of calcium and parathyroid hormone and all-cause mortality in this population of patients.
Such findings, coupled with the absence of randomized controlled trials, suggest that the evidentiary basis for "recommended targets of serum phosphorus, parathyroid hormone, and calcium in chronic kidney disease is poor," Dr. Suetonia C. Palmer of the department of medicine at the University of Otago, Christchurch, New Zealand, and colleagues reported in the March 16 issue of JAMA.
The researchers assessed the strength of the evidence linking each of the biomarkers with the risk of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease by searching MEDLINE and EMBASE databases for relevant cohort studies published from the late 1940s to December 2010. They also combed through reference lists from primary studies, review articles, and clinical guidelines (JAMA 2011;305:1119-27).
Of the 8,380 citations identified, 47 studies with a total of 327,644 patients were included in the final analysis. The population sizes of the studies ranged from 99 to 78,420 participants. Random effects meta-regression was used to summarize data across studies.
The investigators found that the risk of death increased 18% for every 1-mg/dL increase in serum phosphorus, for a relative risk (RR) of 1.18. No significant associations were seen between all-cause mortality and every 100-pg/mL increase in serum level of parathyroid hormone (RR 1.01), or for every 1-mg/dL increase in serum calcium level (RR 1.08).
The researchers were not able to estimate the association between each of the biomarkers and the risk of cardiovascular death in particular, because relevant data were available from only one adequately adjusted cohort study.
"The current data do not support the hypothesis that individuals with chronic kidney disease should have treatment to achieve targeted levels of serum parathyroid hormone or calcium to reduce mortality or cardiovascular morbidity, except at extreme levels in which hypocalcemia and hypercalcemia result in immediate, clinically apparent adverse events such as tetany and seizures," the researchers wrote.
"Furthermore, treating high phosphorus levels is linked to a substantial pill burden that is associated with lower quality of life in individuals with chronic kidney disease. 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 acknowledged certain limitations of their work, including the fact that the studies used in the meta-analysis "are vulnerable to the unpredictable confounding effects of measured and unmeasured variables," and that the study did not evaluate the association between mortality and serum levels of alkaline phosphatase or vitamin D, "which are both emerging as predictors of outcomes in populations with and without chronic kidney disease in cohort studies."
Dr. Palmer disclosed that she was the recipient of a Don and Lorraine Jacquot Fellowship from the Royal Australasian College of Physicians and received travel support from the Amgen Dompe fellowship to the Consorzio Mario Negri Sud. A coauthor of the study, Petra Macaskill, Ph.D., reported receiving grant support from the Australian National Health and Medical Research Council.