 Serum Levels of Phosphorus, Parathyroid Hormone, and Calcium and Risks of Death and Cardiovascular Disease in Individuals With Chronic Kidney Disease: A Systematic Review and Meta-analysis suetonia C. Palmer, MB ChB, PhD; Andrew Hayen, PhD; Petra Macaskill, PhD

Cardiovascular disease is the leading cause of morbidity and mortality in patients at every stage of CKD Recent epidemiologic evidence has shown a strong association between hyperphosphatemia and increased cardiovascular mortality rate in patients with stage 5 CKD and even in patients with earlier stages of CKD.hyperphosphatemia and hypercalcemia are associated with increased vascular calcification,but it is unclear HARRISON

Whether the excessive mortality rate is mediated by this mechanism

A 70 y/o man with CKD from 8 years ago He receiving hemodialysis PMH: DM In lab data(before any treatment ) Ca:8 mg/dl P:6 mg/dl PTH:300 pg/ml Do treatment strategies to achieve targeted levels of serum PTH;Ca or P reduce mortality or cardiovascular morbidity In this patient?

PICO P:Individual with CKD have treatment I:Treatment to achieve target level of Ca/PTH/P C:Individual with CKD do not have treatment O:cardiovascular mortality & morbidity

MEDLINE (1948 to December 2010) Data Sources: EMBASE ( 1947 to December 2010 )

Cardiovascular mortality and cardiovascular events were generally defined as: death or hospitalization due to myocardial infarction, atherosclerotic heart disease, cardiac arrest, or arrhythmia.

P :1 mg/dl (3.5 mg/dl ) PTH:100 pg/ml (200 pg/ml ) Ca:1 mg/dl (8.4 mg/dl )

Studies are stratified into adequate adjustment for confounding variables (all 5 covariates: age, race, time receiving dialysis [or estimatedGFR], cardiovascular disease, and diabetes mellitus) or partial adjustment (<5 covariates).

In 10 adequately adjusted studies, the relationship between serum phosphorus and all-cause mortality was more consistent and an increasing risk of death was apparent at higher levels of serum phosphorus (>5.5 mg/dL).

in the 3 studies reporting the outcome overall, the risk of cardiovascular mortality increased by 10% per 1- mg/dL increase in serum phosphorus (RR, 1.10; 95% CI, ). No data were available for the association between serum phosphorus and nonfatal cardiovascular events.

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

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

Broad adoption of health care practices that have insufficient evidence for safety or efficacy (in this case targeting serum mineral levels in individuals with chronic kidney disease) may lead to considerable unintended harm

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 evidence for an association between serum levels of phosphorus, calcium, or parathyroid hormone as risk factors for outcomes in individuals with chronic kidney disease (at any stage) is currently insufficient to inform clinical decision making, policy, or practice guidelines.

. Large placebo-controlled randomized trials of vitamin D compounds, phosphorus binders, and calcimimetic agents are now needed to evaluate whether treating mineral disorders improves health outcomes for individuals with chronic kidney disease

 Secondary hyperparathyroidism (SHPT) affects a significant number of hemodialysis patients, and metabolic disturbances associated with it may contribute to their high mortality rate. As patients with lower serum calcium, phosphorus, and parathyroid hormone are reported to have improved survival, we tested whether prescription of the calcimimetic cinacalcet to hemodialysis patients with SHPT improved their survival. We prospectively collected data on hemodialysis patients from a large provider beginning in 2004, a time coincident with the commercial availability of cinacalcet hydrochloride. This information was merged with data in the United States Renal Data System to determine all-cause and cardiovascular mortality. Patients included in the study received intravenous (i.v.) vitamin D therapy (a surrogate for the diagnosis of SHPT). Of 19,186 patients, 5976 received cinacalcet and all were followed from November 2004 for up to 26 months. Unadjusted and adjusted time-dependent Cox proportional hazards modeling found that all-cause and cardiovascular mortality rates were significantly lower for those treated with cinacalcet than for those without calcimimetic. Hence, this observational study found a significant survival benefit associated with cinacalcet prescription in patients receiving i.v. vitamin D. Definitive proof, however, of a survival advantage awaits the performance of randomized clinical trials.