Serum Phosphorus and Association With Anemia Among a Large Diverse Population With and Without Chronic Kidney Disease

Lac Tran; Michael Batech; Connie M. Rhee; Elani Streja; Kamyar Kalantar-Zadeh; Steven J. Jacobsen; John J. Sim

Disclosures

Nephrol Dial Transplant. 2016;31(4):636-645. 

In This Article

Abstract and Introduction

Abstract

Background. We hypothesized that phosphorus has an effect on anemia in both normal kidney function and early chronic kidney disease (CKD). We sought to determine whether higher phosphorus levels are associated with anemia in a large diverse population without CKD and early CKD.

Methods. This study is a historical population-based study within the Kaiser Permanente Southern California health system (1 January 1998 to 31 December 2013) among individuals aged 18 years and older with estimated glomerular filtration rate >30 mL/min/1.73 m2 and measurements of serum phosphorus, creatinine and hemoglobin. Individuals were excluded if they had secondary causes of anemia. Odds ratio (OR) estimated for moderate anemia defined as hemoglobin <11 g/dL for both sexes. Mild anemia was defined as <12 g/dL (females) and <13 g/dL (males).

Results. Among 155 974 individuals, 4.1% had moderate anemia and 12.9% had mild anemia. Serum phosphorus levels ≥3.5 mg/dL were associated with both mild and moderate anemia. Moderate anemia OR (95% confidence interval) was 1.16 (1.04–1.29) for every 0.5 mg/dL phosphorus increase and 1.26 (1.07–1.48) in the highest versus middle phosphorus tertile. Additional independent anemia risk factors, including female sex, Asian race, diabetes, low albumin and low iron saturation, were observed, but did not alter the anemia–phosphorus association.

Conclusions. Higher phosphorus levels were associated with a greater likelihood for anemia in a population with early CKD and normal kidney function. Phosphorus may be a biomarker for anemia and may affect aspects of hematopoiesis.

Introduction

Phosphorus plays a major role in physiological functioning, including energy production, cellular replication and bone mineral metabolism. The level of phosphorus is tightly regulated by three main hormones [parathyroid hormone (PTH), vitamin D and fibroblast growth factor-23 (FGF-23)], which affect the intestinal absorption and renal excretion of phosphorus and bone mineral metabolism.[1] Dysregulation of these processes resulting in chronically low or high serum phosphorus has been associated with adverse outcomes.[2] Although chronic kidney disease (CKD) often leads to hyperphosphatemia, abnormalities in phosphorus levels have been observed in populations with and without kidney disease.

Hyperphosphatemia is associated with inflammation and may affect normal cellular physiology including erythropoiesis.[3,4] Phosphorus alone has been implicated in inhibiting red blood cell production in uremic patients.[5] In dialysis and kidney transplant patients, hyperphosphatemia is associated with anemia independent of other mineral bone disease components.[6,7] Along with anemia, hyperphosphatemia has been linked with lower bone mineral density in the peritoneal dialysis population.[5] It is also associated with high levels of PTH, which has been shown to inhibit erythropoiesis, induce hemolysis and cause bone marrow fibrosis in CKD states.[8–12] In addition, FGF-23 and its interplay with klotho, vitamin D and iron have been implicated with anemia.[13–15] In murine models that lack FGF-23 or klotho, the resultant hyperphosphatemia is associated with cell toxicity, premature aging and vascular calcifications.[16]

Determining a relationship between phosphorus levels and prevalence of anemia in the non-CKD population may have important clinical implications. A study evaluating the National Health and Nutrition Examination Survey population showed that serum phosphorus levels >4.4 mg/dL were associated with mild anemia among individuals with normal kidney function [estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2].[17] Another study of kidney transplant patients showed that a one standard deviation higher of serum phosphorous level (0.8 mg/dL) was associated with 77% greater odds for anemia.[7] These few studies that evaluated the relationship between serum phosphorus and anemia have been limited in various ways, including smaller population size, lack of heterogeneity and non-consideration of secondary causes of anemia.[7,17]

Given the biological importance of phosphorus, a better understanding of its levels in the body and association with pathophysiological processes such as anemia would provide invaluable insights. The objective of our study was to determine whether higher phosphorus levels were associated with anemia in a large diverse population with and without early CKD. We hypothesized that higher phosphorus levels increase the likelihood for anemia in people with both normal kidney function and mild CKD.

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