Sevelamer, CaxP product and vitamin D

A. Fournier, J. Barsoum, R. Fickl, R. Oprisiu, N. El Esper and Ph. Moriniere

Service de Néphrologie, CHU Amiens, France

Sir,

We read with interest the article by Chertow et al. [1] reporting the long-term (46 weeks) efficiency of sevelamer hydrochloride in lowering plasma phosphates in dialysis patients (-0.7 mmol/l) and in improving their lipid profile (30% reduction of the LDL cholesterol and 18% increase of their HDL cholesterol).

However we have been puzzled by the fact that in contrast to previous short-term reports (8 weeks) [2] in which serum parathyroid hormone (PTH) decreased significantly (-70 pg/ml) with a parallel serum phosphate decrease (-0.83 mmol/l), no long-term significant decrease of PTH was observed (-18 pg/ml) despite concomitant higher doses of 1{alpha} hydroxylated vitamin D in 34% of the patients and higher serum concentrations of calcium (+0.08 mmol/l), magnesium (+0.04 mmol/l), and bicarbonate (+1.30 mmol/l). Furthermore, this lack of decrease of serum PTH is associated with a significant increase of alkaline phosphatase and the changes in PTH are directly correlated with dosage of sevelamer hydrochloride (-55, -16.5 and +10 pg/ml in patients with low, medium, and high doses respectively), suggesting a causal relationship.

The increase of alkaline phosphatase is related to the observations made with other bile-salt complexes like cholestyramine or colestipol, but no explanation or details of other hepatic enzymes markers of cholestasis are given. No mention is made of the well-known possible explanation already given for this observation with cholestyramine and colestipol, namely that these agents may deplete vitamin D by disrupting the enterohepatic cycle of vitamin D. Vitamin D is a lipid-soluble vitamin and therefore less well absorbed when bile salts are sequestrated, since this impairs fatty acid absorption [3]. Chertow et al. mention (without documenting actual data) that the levels of vitamins A and E remained unchanged; changes in serum levels of 25 OH vitamin D are not evoked.

Since this study was performed over the course of almost 1 year, the seasonal variations of 25 OH vitamin D would not significantly influence the comparison between initial and final serum 25 OH vitamin D. A difference between these levels could adequately document or dismiss (even without data of a control group) the potential vitamin-D-depleting effect of sevelamer hydrochloride, provided the intake of over-the-counter multivitamins containing vitamin D is taken into account.

A decrease of serum 25 OH vitamin D or calcitriol levels in these patients could actually be the only explanation of why serum PTH did not decrease in the long-term. The increase of serum concentrations of calcium, magnesium, bicarbonate, together with higher doses of vitamin D metabolites and the significant decrease of serum phosphate should have led to a decrease of serum PTH. It is well known that parathyroid hyperplasia and PTH synthesis and/or secretion are decreased by higher serum concentrations of calcium, magnesium, and calcitriol [4], by the correction of acidosis [5] and by lower levels of phosphate [4], these latter rendering parathyroid glands more sensitive to the suppressive effect of calcium and calcitriol [4]. Low serum 25 OH vitamin D levels are now recognized as a calcitriol-independent risk factor for Looser zones occurrence and of increased serum PTH levels [6] even though in renal patients with non-optimal vitamin D repletion the levels of calcitriol are dependent upon those of 25 OH vitamin D [7].

Therefore, we would greatly appreciate knowing the serum levels of 25 OH vitamin D and calcitriol as well as the multivitamin pill count for the patients who received Renagel for 46 weeks and the months during which they started and discontinued Renagel.

References

  1. Chertow GM, Burke S, Dillon M, Slatopolsky E for the Rena Gel Study group. Long-term effects of sevelamer hydrochloride on the calciumxphosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant1999; 14: 2907–2914[Abstract/Free Full Text]
  2. Slatopolsky EA, Burke SK, Dillon MA and the RenaGel Study group. RenaGel, a nonabsorbed calcium and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int1999; 55: 299–307[ISI][Medline]
  3. Fraser DR. Vitamin D. Lancet1995; 345: 104–107[ISI][Medline]
  4. Slatopolsky E, Finch J, Dende M, Ritter C, Dusso A, Brown AJ. Phosphorus restriction prevents parathyroid gland growth: high phosphorus directly stimulates PTH secretion in vitro. J Clin Invest1996; 97: 2534–2540[Abstract/Free Full Text]
  5. Fournier A, Achard JM, Morinière P. Chronic metabolic acidosis correction in haemodialysis patients actually has a direct suppressive effect on PTH secretion. An other view on published data (letter). Nephrol Dial Transplant1997; 12: 627
  6. Ghazali A, Fardellone P, Pruna A, Atik A, Garbedian M, Fournier A. Is low plasma 25 OH vitamin D a major risk factor for hyperparathyroidism and Looser's zone independent of calcitriol? Kidney Int1999; 55: 3169–3177
  7. Fournier A, Fardellone P, Achard JM, Ghazali A. Importance of vitamin D repletion in uraemia. Nephrol Dial Transplant1999; 14: 819–823[Free Full Text]

 

Reply

Glenn M. Chertow

Division of Nephrology, University of California, San Francisco, USA

Sir,

Fournier et al. enquire whether a reduction in 25-hydroxy vitamin D levels might explain the absence of a parathyroid hormone (PTH)-lowering effect in this study of haemodialysis patients treated with sevelamer hydrochloride (Renagel®) [1].

Analysis of patient subgroups showed that patients treated jointly with sevelamer and vitamin D metabolites did in fact experience a decrease in PTH [2]. The median change was -21.0 pg/ml among patients treated with sevelamer and vitamin D (P=0.19) and -77.5 pg/ml in patients treated with sevelamer, vitamin D, and a nocturnal calcium supplement (P=0.007). In 35 patients treated with sevelamer alone, there was an upward trend in PTH (+47.5 pg/ml, P=0.08).

There was significant seasonal variation in 25-hydroxy vitamin D levels, similar to what has previously been observed in non-uraemic individuals [3]. Mean 25-hydroxy vitamin D ranged from a low of 21.0±1.3 ng/ml in January to a high of 37.4±2.9 ng/ml in August. 1.25-dihydroxy vitamin D levels showed no seasonal variation.

We respectfully disagree with Professor Fournier and colleagues that a decrease in 25-hydroxy vitamin D or calcitriol levels ‘could be the only explanation of why serum PTH did not decrease in the long term.’ There is a direct correlation between PTH and dialysis vintage [4] that persists after adjustment for age, sex, race, dialysis dose, and the serum concentrations of phosphorus, calcium, magnesium, and bicarbonate [5]. A year accrued on dialysis appears to be associated with a 5–10% increase in PTH, on average.

In summary, there is no evidence that treatment with sevelamer in haemodialysis patients affects endogenous vitamin D levels via changes in absorption, enterohepatic circulation, or otherwise. Consideration of the effects of sevelamer on PTH must take into account the natural history of secondary hyperparathyroidism and the confounding effects of vitamin D and calcium therapy

References

  1. Chertow GM, Burke SK, Dillon MA, Slatopolsky E. Long-term effects of sevelamer hydrochloride on the calciumxphosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant1999; 14: 2907–2914 (published erratum in Nephrol Dial Transplant 2000; 15: 559)[Abstract/Free Full Text]
  2. Chertow GM, Dillon MA, Asim N, Burke SK. Sevelamer with and without calcium and vitamin D: observations from a long-term open label clinical trial. J Ren Nutr2000; 10: 125–132[Medline]
  3. Krall EA, Sahyoun N, Tannenbaum S, Dallal GE, Dawson-Hughes B. Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women. N Engl J Med1989; 321: 1777–1783[Abstract]
  4. Chertow GM, Plone M, Dillon MA, Burke SK, Slatopolsky E. Hyperparathyroidism and dialysis vintage. Clin Nephrol2000; 54: 295–300[ISI][Medline]
  5. Chertow GM, Lazarus JM, Lew NL, Lowrie EG. Determinants of intact parathyroid hormone in hemodialysis patients. J Am Soc Nephrol2000; 11: 573A