Vascular calcification: A stiff challenge for the nephrologist

Abstract

There has been an explosion of interest in vascular calcification in the last 5 years. Four key "germinal" findings have fallen onto very fertile soil. First, on the background of an increasing cardiovascular disease burden it has been found that at least cross-sectionally, and in a limited fashion prospectively, achieved dialysis plasma phosphate levels are linked to all-cause and cardiovascular mortality. Second, there are increasing reports of calcific uremic arteriolopathy in Australia and the United States. Third, we know know that the mechanical properties of the carotid artery, and the aorta, have a profound influence on survival for dialysis patients. Vascular calcification itself (as assessed by x-ray films and ultrasound) has been linked to aortic stiffness. Fourth, increasing numbers of studies are showing extremely extensive coronary artery calcification (CAC) in dialysis patients, even at a young age. From these apparently unlinked observations the following assertion has been posited-that in the widespread (over) use of calcium-containing oral phosphate binders (OPB) to prevent uremic osteodystrophy in our dialysis population we have unwittingly accelerated widespread uremic vasculopathy and thereby contributed to premature cardiovascular mortality. It is the purpose of this article to discuss vascular calcification (and particularly CAC) in dialysis patients as we understand it today. We will review the published series, with special reference to the Sevelamer Treat to Goal trial and also discuss the new Kidney Disease Outcome Quality Initiative (K-DOQI) guidelines on the use of phosphate binders in chronic kidney disease.

Mineral Metabolism and Vascular Damage in Children on Dialysis

“…Children provide an ideal opportunity to study the uremic influences on the arterial wall because they rarely have risk factors such as diabetes, dyslipidemia, and hypertension that are prevalent in adults. 14,20 The patients in our study were carefully selected so that they were free of such confounders, and capitalizing on detailed serial biochemistry over Ն3.5 yr, we were able to demonstrate the impact of iPTH and its management on the vascular phenotype. Whereas PO 4 has been shown to be an independent risk factor for cardiovascular disease, 8 including increased IMT, 4 -6 vessel stiffness, 3,21 and left ventricular hypertrophy, 5 PTH per se may contribute to vascular injury via mechanisms other than its effect on Ca-PO 4 homeostasis.…”

“…4,11,12,14,29 This study was not designed to determine the vascular effects of different PO 4 binders; sevelamer was used only as a second-line agent in our patients with persistently high iPTH levels and hypercalcemia. Goodman et al, 29 Litwin et al, 4 and Briese et al 33 showed a positive correlation between the cumulative PO 4 binder dosage and coronary calcification or cIMT, and in our study, IMT showed a weak correlation with PO 4 binder dosage approaching statistical significance.…”

“…However, it has to be remembered that high iPTH levels are per se a risk factor for vascular disease and soft tissue calcification. 10,14,15 At Great Ormond Street Hospital, we aim to prevent the escape of the parathyroid glands from normal control mechanisms by dietary and therapeutic intervention. We have shown that keeping iPTH levels in the normal range in stages 1 through 4 CKD and Ͻ2 ULN in children who are on dialysis maintains normal growth velocity 16 and bone mineral density, 17 but the presence of renal osteodystrophy was ubiquitous in children with CKD irrespective of iPTH levels.…”

Contribution of Bone and Mineral Abnormalities to Cardiovascular Disease in Patients with Chronic Kidney Disease

“…CUA typically causes cutaneous ischemia and necrosis and may eventually lead to death as a result of severe complicating infections. The pathogenesis of CUA remains largely unknown, although excessive calcium supplementation, especially in patients with diabetes, has been associated with its occurrence (61,62). Some investigators reported symptom resolution after parathyroidectomy, which suggests a link between excessive PTH secretion and CUA (63,64).…”

Complications and Managements of Hyperphosphatemia in Dialysis

“…Hyperphosphatemia is a known factor contributing to the increased risk of cardiac death both in patients with end-stage renal disease and in those under renal replacement treatment with dialysis (Goodman et al, 2000). In patients with renal disease, in fact, the well-known relationship between hyperphosphataemia, secondary hyperparathyroidism, bone turnover and extra osseous calcifications has recently been followed by the recognition of a major role played by elevated serum phosphorus levels in the induction of vascular calcification, cardiac interstitial fibrosis and arterial thickening which highly increase the risk of cardiac death (Goodman et al, 2000;Block & Port, 2000;Amann et al, 2003;Goldsmith et al, 2004;Floege & Ketteler, 2004).…”