Nephrology Express Report

Publication date: 2007-05-10

Mortality from Cardiovascular Disease in ESRD: Beneficial Effects of Active Vitamin D Therapy

This report was reviewed for medical and scientific accuracy by Nicole Weinreb, MD, Consulting Physician, Lahey Clinic, Burlington, Massachusetts..

Expert Commentary

Keith A. Hruska, MD, Professor of Pediatrics, Division of Pediatric Nephrology; Professor of Medicine; Departments of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri

Chronic kidney disease (CKD) is a worldwide epidemic. Nearly 20 million adults in the United States are in various stages of CKD, ¹ with more than 400,000 individuals with end-stage renal disease (ESRD) and >300,000 individuals requiring maintenance hemodialysis. ² Major outcomes of CKD include progression to ESRD, complications of decreased kidney function, and cardiovascular disease which results in significant morbidity and mortality.

Since peaking in 1998, overall mortality rates in the prevalent dialysis population have fallen 11%.³ This varies significantly, however, in terms of patient vintage. Mortality rates for patients on dialysis <2 years have declined 24% (1985 to 2003), while patients on dialysis for ≥5 years have increased 12% during that same period. ³ It is significant to note that mortality rates in patients on dialysis for ≥5 years have recently stabilized and now appear to be declining, thus allowing the overall mortality rate to decrease as well. The US Renal Data System 2005 annual report states, “this phenomenon may be associated with many factors, such as improved dialysis therapy, changes in iron therapy, higher hemoglobin levels, and changes in overall medical practice. Vitamin D therapy, for example, underwent dramatic changes in 2000 and 2001 with the increased use of paricalcitol, which has now been associated with lower rates of mortality”. ³ The decrease in the overall rate of mortality in dialysis patients and the associated effects of changing medical practice clearly warrant further investigation.

Despite these therapeutic advances, however, annual mortality rates remain above 20% in patients receiving hemodialysis, ⁴ with more than 50% of patient deaths related to cardiovascular disease. ⁵ Indeed, cardiovascular mortality is 15 times greater in patients undergoing hemodialysis than in the general population. ⁶

Secondary hyperparathyroidism (SHPT) is an early and major complication of CKD, which progresses as glomerular filtration rate (GFR) decreases. ^7-9 Due to decreased 1a-hydroxylase activity, patients with advanced kidney disease have a limited ability to convert 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D (calcitriol), ⁹ the active form of vitamin D. Decreasing renal function results in diminishing production of calcitriol. The suboptimal levels of calcitriol decrease intestinal calcium absorption, leading to increased parathyroid hormone production and hyperproliferation of parathyroid cells¹⁰ which contributes to the development of SHPT. Ultimately, the prolonged stimulation of the parathyroid glands results in increased bone remodeling and loss of structural integrity. As a result of parathyroid-induced changes, excess bone resorption leads to loss of bone mineral, increased release of calcium and phosphorus from bone, and increased risk for vascular and soft-tissue calcification. Abnormalities in serum calcium, serum phosphorus, and elevated serum calcium-phosphorus product, have been associated with increased risk of cardiovascular complications and mortality in patients with CKD. ^11-13

In recent years, increased attention has been focused on the role of abnormal bone and mineral metabolism and its management as factors associated with cardiovascular disease in CKD. Recent data suggest a survival benefit from active vitamin D therapy in hemodialysis patients, ^14-19 but whether the survival benefit from active vitamin D therapy can be extrapolated to earlier stages of CKD remains to be explored.

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