Elsevier

Cardiovascular Pathology

Volume 21, Issue 5, September–October 2012, Pages 372-381
Cardiovascular Pathology

Review Article
Phosphate: a stealthier killer than previously thought?

https://doi.org/10.1016/j.carpath.2012.02.008Get rights and content

Abstract

The kidneys excrete excess dietary phosphate, and patients with chronic kidney disease may suffer from phosphate overload and hyperphosphatemia. In chronic kidney disease, hyperphosphatemia has emerged as a risk factor for vascular calcification, cardiovascular mortality, left ventricular hypertrophy, and progression of chronic kidney disease. Serum phosphate at the upper limits of normal has also been associated with adverse outcomes in patients with relatively preserved kidney function. Of note, hyperphosphatemia is not a sensitive indicator of phosphate overload. In this regard, increased circulating fibroblast growth factor-23, a phosphatonin that is released in response to phosphate overload, is independently associated with adverse outcomes in patients with and without chronic kidney disease. Direct effects of extracellular phosphate on vascular calcification or cardiovascular cell biology; adverse consequences of adaptive mechanisms activated to limit phosphate overload, such as left ventricular hypertrophy induced by fibroblast growth factor-23; or epidemiological associations of additional cardiovascular risk factors with chronic kidney disease may underlie these observations. We now review the pathophysiology of phosphate, its relationship with cardiovascular outcomes, the potential consequences for patient care related to dietary phosphate and phosphate binders, and the clinical relevance for patients without overt chronic kidney disease.

Section snippets

Phosphate balance

Serum phosphate concentration (normal range 2.5–4.5 mg/dl) is the end result of a complex balance of phosphate fluxes from intestine, bone, the intracellular space, and kidneys (Fig. 1) [11]. Gastrointestinal phosphate excretion is around 150 mg/day, and urinary excretion is approximately 800 mg/day.

Phosphate balance in CKD

The prevalence of decreased eGFR and CKD is higher than thought a few years ago. The global prevalence of CKD stages 3–5 (eGFR <60 ml/min/1.73 m2) is 6.8% in Spain [32]. Patients with CKD gradually lose the capacity to excrete phosphate due to reduced nephron number, which results in a trend towards a positive phosphate balance [33]. Mild decrements in eGFR (<80 ml/min/1.73 m2) are already associated with decreased glomerular filtration of phosphate and compensatory responses to maintain

Serum phosphate as a cardiovascular risk factor

Most studies on phosphate and cardiovascular risk have been conducted in CKD patients. Serum phosphate is associated with mortality in CKD. A recent meta-analysis of 47 cohort studies (N=327,644 patients) confirmed that the risk of death increased 18% for every 1-mg/dl increase in serum phosphate (95% confidence interval 1.12–1.25), while there was no significant association between all-cause mortality and serum PTH or calcium [43]. In 25,588 patients on hemodialysis, serum phosphate level of

Cardiovascular risk and phosphate overload in the absence of hyperphosphatemia

The fact that serum phosphate levels within the normal reference range are associated with increased cardiovascular risk poses the question of whether there might be a better or earlier indicator of the adverse consequences of phosphate overload. In this regard, FGF-23 is considered an indicator of phosphate overload and is also a predictor of coronary calcification among CKD stage 2–3 patients (eGFR 30–90 ml/min/1.73 m2) even when serum phosphate levels are normal [55]. Circulating FGF-23

Potential pathophysiologic mechanisms relating phosphate and cardiovascular risk

There are several non-mutually exclusive hypotheses to explain the association between increased serum phosphate or phosphate overload and cardiovascular risk (Fig. 2).

The first hypothesis suggests that increased serum phosphate or phosphate overload directly promotes cardiovascular injury, including vascular calcification and arterial stiffness, endothelial dysfunction, and LVH. Transient postprandial hyperphosphatemia in the 2 h following a high dietary phosphate intake is associated with

Vascular calcification

Patients with CKD develop soft tissue calcification, including vascular wall calcification. Multiple factors favor vascular calcifications, including serum phosphate levels. Bone is the main reservoir of phosphate. Bone remodeling disorders, both high bone remodeling and adynamic bone disease, contribute to hyperphosphatemia. When bone is unable to maintain phosphate homeostasis, phosphate is deposited in new reservoirs, such as soft tissues and blood vessels. Hyperphosphatemic uremic animals

Clinical relevance: treating phosphate overload, not just hyperphosphatemia

Evidence is accumulating for a role of hyperphosphatemia and/or phosphate overload on cardiovascular injury in both CKD and non-CKD patients. Thus, mortality is increased in CKD and non-CKD patients with higher FGF-23, regardless of serum phosphate values [7], [8]. However, human data were obtained mainly from observational studies, and association does not imply causality. Results of studies addressing the survival impact of phosphate binders are needed. Phosphate binders decrease both serum

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  • Cited by (0)

    Grant support: ISCII and FEDER funds PS09/00447, PI10/00072, ISCIII-RETIC REDinREN/RD06/0016, RECAVA RD06/0014/0035, Comunidad de Madrid/CIFRA/S-BIO0283/2006, EUROSALUD (EUS2008/03565), Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to A.O.

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