Secondary Logo

Share this article on:

To D or not to D: calcitriol and vascular calcification in end-stage renal disease

Joles, Jaap Aa; Lilien, Marc Rb

doi: 10.1097/01.hjh.0000166832.48065.dd
Editorial commentaries

Departments of aNephrology and Hypertension

bPediatric Nephrology, University Medical Utrecht, Utrecht, The Netherlands

Correspondence and requests for reprints to Dr J.A. Joles, Department of Nephrology and Hypertension, University Hospital Utrecth, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail:

Vascular calcification contributes importantly to cardiovascular morbidity and mortality in end-stage renal disease (ESRD) [1]. This is in addition to other factors, such as activation of the renin–angiotensin system, an imbalance of nitric oxide and reactive oxygen species, anemia, inflammation and sympathetic activation [2]. Alarmingly, vascular calcification can already be found in young patients with ESRD in their late teens or early twenties [3,4]. Predisposing factors are hyperphosphatemia, hypercalcemia due to secondary hyerparathyroidism, and an elevated Ca × P ion product [5]. Supplementation of 25-hydroxyvitamin D [25(OH)D3] reduces secondary hyperparathyroidism in vitamin D-deficient and vitamin D-insufficient patients with chronic kidney disease. In ESRD, renal conversion of 25(OH)D3 to the active compound calcitriol [1,25(OH)2D3] is insufficient and supplementation of active vitamin D compounds is then necessary ( However, these guidelines are not adapted to pediatric patients. Clearly, the situation in these growing patients is different [6]. At present, no published guidelines for management of bone metabolism in children with renal disease exist, but active vitamin D compounds are widely prescribed for this population. In patients with hyperphosphatemia, hypercalcemia or an elevated Ca × P ion product, vitamin D is not advised [7] because this may result in vascular calcification [8]. However, vascular calcification is also observed in ESRD patients with vitamin D supplementation and apparently adequate control of calcium and phosphate levels, suggesting that the Ca × P ion product is often on the verge of crystallization, and that renal disease in itself may be a permissive factor.

In this issue of the journal, Haffner et al. [9] convincingly show that treating uremic rats with non-hyercalcemic doses of calcitriol results in extensive diffuse vascular (aortic) calcification, formation of aneurysms, and left ventricular hypertrophy. In addition, 1,25(OH)2D3-treated, uremic rats showed severe growth retardation and increased mortality. None of these changes were present in either similarly uremic rats without 1,25(OH)2D3 treatment or control animals with identical 1,25(OH)2D3 treatment. Thus, the presence of the uremic state clearly acted as a permissive factor. These cardiovascular effects were so striking and obvious that precise quantification was not of practical importance. However, exactly what precipitated (literally!) these effects is much less clear and requires some comment.

The first issue to consider is calcium-phosphate metabolism. It was clearly the intent of the authors to avoid hypercalcemia. In this respect, they were very successful in that, despite 1,25(OH)2D3-treatment, the hypocalcemia present in the uremic rats was not affected. However, the dose of calcitriol relative to body weight was approximately 10-fold higher than usually prescribed to humans. Moreover, phosphate levels were very high in all groups irrespective of uremia or 1,25(OH)2D3 treatment (controls: 3.4 mmol; uremia + 1,25D3: 3.9 mmol, not significant). This was probably due to the high phosphorus content of the chow (1.2%) [10] and may well have contributed to suppressing serum calcium levels. It is well known that hyperphosphatemia leads to secondary hyperparathyroidism [11], which will certainly enhance the risk of vascular calcification. Following algorithm 4 in the K/DOQI Guidelines for Bone Metabolism and Disease in Chronic Kidney disease [7] would lead the practitioner to advise the renal patient to reduce phosphate intake and increase the phosphate binder dose. Unfortunately, for the uremic rats in this experiment, their only dietary option was to reduce food intake, which they did to such an extent (from 20 to 9 g/day) that normal growth came to a halt. Reduced food intake also explains the reduction in urinary phosphate excretion in the uremic rats with 1,25(OH)2D3 treatment, which was less than half that found in the control rats with 1,25(OH)2D3 treatment. However, the latter were able to mount a marked calciuric response that undoubtedly compensated for their more efficient intestinal Ca absorption. This effect has been described as a model of normocalcemic hypercalciuria [12]. Although urinary calcium excretion relative to body weight of the uremic rats treated with 1,25(OH)2D3 was approximately twice that of the uremic control rats, the calciuric response apparently was insufficient to prevent extensive vascular calcification. The fact that the plasma Ca × P product was very similar in both 1,25(OH)2D3-treated groups emphasizes the permissive role that renal disease plays in vascular calcification during 1,25D3 treatment.

A second remarkable finding is the extremely high parathyroid hormone (PTH) level in the uremic rats treated with 1,25(OH)2D3 (3173 pg/l; 349 pmol/l). This level was three-fold higher compared to uremic rats without 1,25(OH)2D3 treatment: 126 pmol/l in this study and 114 pmol/l in another study with similar phosphorus intake employing the same assay [10]. Due to the state of renal failure, these very high levels probably did not contribute to the renal conversion of 25-(OH)D3 to 1,25(OH)2D3 but may well have contributed to vascular calcification. Indeed, the authors concede that they did not control for this confounder by using parathyroidectomized rats. In the control rats treated with 1,25(OH)2D3, PTH levels were low (11 pmol/l), suggesting adequate negative feedback. Apparently, in the uremic rats, 1,25(OH)2D3 supplementation was being added to a state of tertiary hyperparathyroidism, otherwise PTH levels should have been suppressed (i.e. following algorithm 5 in the K/DOQI Guidelines for Bone Metabolism and Disease in Chronic Kidney disease) [7].

Unexpectedly, treatment with 1,25(OH)2D3 led to hypertension in both control and uremic rats. That the mechanism of this effect was not addressed is not a serious omission in a study directed at a side-effect. It is worth noting that absence of left ventricular hypertrophy and vascular calcification or aneurysms in the non-uremic group directly indicates that the whole spectrum of systemic cardiovascular disease observed in the uremic rats on 1,25(OH)2D3 treatment was blood pressure-independent. In ESRD, hypertension, in conjunction with loss of arterial compliance due to calcification, can result in severe left ventricular hypertrophy, as is well recognized [13]. However, the link with 1,25(OH)2D3 treatment deserves more attention [14], particularly in children with ESRD. Complete assessment of plasma Ca, P, PTH, 25(OH)D3 and 1,25(OH)2D3 levels, as well as urinary Ca and P excretion, are needed for adequate monitoring of vitamin D dose.

In summary, the study by Haffner et al. [9] emphasizes the importance of following K/DOQI Guidelines for Bone Metabolism and Disease in patients with chronic kidney disease [7]. The urgent need for an adequate assessment of guidelines regarding bone metabolism and disease and its treatment in pediatric patients with chronic kidney disease is emphasized by their study.

Back to Top | Article Outline


1 Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001; 38:938–942.
2 Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B. The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J 2005; 26:11–17.
3 Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, et al. Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 2002; 106:100–105.
4 Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342:1478–1483.
5 Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol 2004; 15:2959–2964.
6 Salusky IB, Kuizon BG, Juppner H. Special aspects of renal osteodystrophy in children. Semin Nephrol 2004; 24:69–77.
7 Eknoyan G, Levin A, Levin NW. Bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42(suppl 3):S84–S98.
8 Coburn JW, Maung HM. Use of active vitamin D sterols in patients with chronic kidney disease, stages 3 and 4. Kidney Int Suppl 2003:S49–S53.
9 Haffner D, Hocher B, Muller D, Simon K, Konig K, Richter C-M, et al. Systemic cardiovascular disease in uremic rats induced by 1,25(OH)2D3. J Hypertens 2005; 23:1067–1075.
10 Amann K, Tornig J, Buzello M, Kuhlmann A, Gross ML, Adamczak M, Ritz E. Effect of antioxidant therapy with dl-alpha-tocopherol on cardiovascular structure in experimental renal failure. Kidney Int 2002; 62:877–884.
11 Slatopolsky E, Brown A, Dusso A. Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 2001; 37:S54–S57.
12 Ordonez FA, Fernandez P, Rodriguez J, Martinez V, Munoz R, Coto T, Santos F. Rat models of normocalcemic hypercalciuria of different pathogenic mechanisms. Pediatr Nephrol 1998; 12:201–205.
13 London GM. Cardiovascular calcifications in uremic patients: clinical impact on cardiovascular function. J Am Soc Nephrol 2003; 14:S305–S309.
14 Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int 2001; 60:472–479.
© 2005 Lippincott Williams & Wilkins, Inc.