Foreword: Extraskeletal calcifications in patients with chronic renal failure

Tilman B. Drüeke

INSERM U. 507 and Service de Néphrologie, Hôpital Necker, Paris, France

In recent years, increasing interest has been devoted to soft-tissue calcification in patients with chronic renal failure. Although it has been known for many years as a frequent complication of this condition, its high prevalence and prominent role in cardiovascular morbidity and mortality of uraemic patients have only been recognized recently.

There are several explanations for the greater prevalence of extraosseous calcifications in the last decade [1]. They include the steadily increasing age of the chronic dialysis population, the progressive improvement of survival for each age group with a prolonged exposition to factors predisposing to soft-tissue calcification, an uncontrolled serum calciumxphosphate (CaxP) product in a large portion of end-stage renal disease patients and, last but not least, an improvement in the objective, quantified assessment of calcium deposits.

The type, distribution, speed of progression and severity of extraskeletal calcifications vary widely from patient to patient, and also from centre to centre, depending on numerous factors in addition to the uraemic milieu [1]. Periarticular and vascular calcifications, also called non-visceral calcifications, are morphologically and pathogenetically distinct from visceral calcifications. Similarly, dystrophic calcium deposits differ from metastatic deposits. Such distinctions need to be made for the understanding of underlying mechanisms and the identification of appropriate therapeutic and prophylactic measures.

Another important consideration is that soft-tissue calcification in chronic renal failure has generally been considered to be a passive event, secondary to the elevation of the extracellular CaxP product. However, recent observations of spontaneous arterial calcifications in knockout mice [2] and in vitro experiments of vascular calcification in cell culture models [3,4] have provided evidence in favour of the participation of active inhibitory processes, involving specific cells and proteins.

In the past, it was generally believed that the main cause of soft-tissue calcification in uraemic patients was secondary hyperparathyroidism. It is noteworthy that the incidence of soft-tissue calcification has not decreased, despite a considerably improved control of parathyroid over-function in recent years. On the contrary, it has increased, although the predilection sites and the clinical expression of extraosseous calcium deposits may have changed in the majority of patients. Thus, for instance, diffuse media calcification of arterial vessels (‘mediacalcosis’) is a prominent feature in patients with excessive circulating parathyroid hormone (PTH) levels, whereas patchy intima calcification in conjunction with atherosclerosis is observed more frequently in patients with normal or low PTH levels.

The more efficacious management of parathyroid over-function in chronic renal failure patients in the last decade is certainly a major factor in the observed switch from a predominantly hyperparathyroid state with high bone turnover to a prevailing euparathyroid or hypoparathyroid state with low bone turnover. However, there has been a price to pay for this. The better control of secondary hyperparathyroidism was generally achieved by administering unphysiologic doses of either active vitamin D metabolites or calcium supplements, in the absence of a satisfactory control of the extracellular CaxP product, be it via an excessive calcium load or via persisting or worsened hyperphosphataemia. In fact, the obtention of a euparathyroid state has proved to be extremely difficult, and many patients actually developed adynamic bone disease, with an increased propensity towards soft-tissue calcification.

Consequently, new ways had to be found to circumvent this caveat. These new ways comprise a more efficient phosphate removal via improved renal replacement modalities, such as daily diurnal or nocturnal dialysis [5,6], very long dialysis sessions [7], and the use of novel oral phosphate binders which are free of calcium and aluminium, including sevelamer (Renagel®) [8,9] and ferric compounds [10].

It is our hope that a better awareness of the cardiovascular risk associated with an increased CaxP product and soft-tissue calcifications, the introduction of more precise methods to assess the extent and severity of vascular calcification and atherosclerosis, and the development of more efficient and less noxious therapeutic means to control hyperphosphataemia will lead to a better treatment and ultimately the prevention of cardiovascular morbidity and mortality in patients with chronic renal failure.

Notes

Correspondence and offprint requests to: Tilman B. Drüeke, MD FRCP, INSERM Unité 507, Hôpital Necker, 161 rue de Sèvres, F-75743 Paris Cedex 15, France. Email: drueke{at}necker.fr Back

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