High serum phosphorus levels in patients with normal renal function are associated with a greater risk of end-stage renal disease (ESRD) and death, according to researchers.

In a retrospective study of adults in a vertically integrated health plan, a team led by John J. Sim, MD, of Kaiser Permanente Los Angeles Medical Center in Los Angeles, identified 94,989 individuals without kidney disease (estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher). The study population had a mean age of 50 years and was 61% female, 38% white, 14% black, and 25% Hispanic. ESRD developed in 130 subjects (0.1%). Each 0.5 mg/dL increment in phosphorus level was associated with a 40% increased risk of ESRD and 9% increased risk of death in adjusted analyses, the investigators reported online ahead of print in the American Journal of Medicine.

Compared with patients who had baseline phosphorus levels in the first quartile (1.9-3.0 mg/dL), those with baseline levels in the fourth quartile (3.9-5.7 mg/dL) had a significant 48% increased risk of ESRD in adjusted analyses. Time-averaged serum phosphorus showed a similar relationship across quartiles and as a continuous variable, according to the investigators.

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In addition, ESRD was 2.4 times more likely to develop in men than women, 2.7 times more likely to develop in blacks than whites, and 2.2 times more likely to develop in Hispanics than whites.

“High serum phosphorus levels may represent a mechanism, intermediary step, or a surrogate marker for chronic kidney disease onset and advancement,” the authors wrote.

A potential mechanism underlying serum phosphorus levels and kidney disease onset or progression is increased nephrocalcinosis, Dr. Sim’s team noted. It has been postulated that higher serum phosphorus levels directly promote vascular injury and calcifications. Another possible mechanism may be related to serum fibroblast growth factor-23 (FGF-23), which is a key regulator of serum phosphorus in patients with chronic kidney disease (CKD), according to the investigators. FGF-23 levels have been found to increase early in the course of CKD, before development of overt hyperphosphatemia, the researchers pointed out. “Stimulation of the FGF receptor increases the production of angiotensin-converting enzyme and may activate the renin-angiotensin system, possibly facilitating the progression of kidney damage,” they observed.