In a single session study, we compared the changes of t-calcium, i-calcium, and int-PTH during HD with A(−)D or A(+)D. We found significant increase in i-calcium, t-calcium and decrease in int-PTH after HD with A(+)D. In contrast, there was no significant difference in i-calcium and int-PTH levels after HD with A(−)D. These differences could be affected by the post-dialysis iCa levels. Despite the calcium concentrations of A(−)D and A(+)D being the same level (3.0 mEq/L), A(−)D contains a small amount of citrate as a buffer source. Because citrate is an effective chelator of i-calcium, HD with A(−)D containing citrate might decrease serum i-calcium levels. Therefore, Ca chelating effect of citrate as well as alkalizing effect of A(−)D might decrease iCa which affects intPTH.
In the cross-over study, we conducted a stratified analysis, according to the target int-PTH levels of 60–180 pg/mL, as recommended by the 2006 guidelines for the management of secondary hyperparathyroidism in chronic dialysis patients by JSDT . In the patients with low int-PTH levels (< 60 pg/mL), we found significant increase in both int-PTH and BAP levels HD after A(−)D period, while it did not affect PTH levels in the patients with PTH levels >60 pg/ml. Thus, HD with A(−)D could contribute to the increase in PTH and BAP exclusively in the patients with low int-PTH levels.
Calcium concentrations in dialysate and bone metabolism
Past studies have reported the impact of calcium concentrations in dialysates on bone mineral metabolism and int-PTH levels [3–5]. In the presence of low PTH levels, the use of a low calcium dialysate has been shown to increase circulating PTH and BAP levels in MHD patients [9, 10]. However, with the excessive lowering of serum calcium during HD using a low calcium dialysate, calcium concentrations may be associated with hypotension and arrhythmias . Furthermore, in patients with hyperparathyroidism and high bone turnover disease, the excessive use of a low calcium concentration dialysate may further worsen their conditions .
There were no significant differences in pre-dialysis t-calcium and i-calcium levels during the cross-over study. On the other hand, in the single session study, we found significant increases in i-calcium and t-calcium and decreases in int-PTH levels after HD with A(+)D, while there were no significant differences in i-calcium or int-PTH between pre- and post-HD levels with A(−)D in the single session study. From these results, we presumed that citrate in the dialysate could chelate i-calcium during HD sessions with A(−)D. Also from the results of this study, we concluded that not only the decrease in the calcium concentration of dialysate but also the chelation of i-calcium by citrate in dialysate might affect int-PTH levels in patients undergoing MHD.
Metabolic acidosis and bone metabolism
The bone diseases that accompany CKD are due to alterations in PTH levels and vitamin D levels. However, a substantial quantity of data has been accrued to implicate chronic metabolic acidosis as an additional important factor . In our cross-over study, although there was no significant difference in int-PTH or BAP during the A(−)D and A(+)D periods in the patients with normal or high PTH levels, we found a significant increase in int-PTH and BAP levels during the A(−)D period exclusively in the patients with low PTH levels. This result is in agreement with the previous study , which was performed on 21 MHD patients with metabolic acidosis (serum HCO3
- levels: 15–16.8 mmol/L). The amelioration of metabolic acidosis by raising the dialysate base HCO3
- concentration was found to the rise in PTH, reduce bone resorption in the patients with low PTH levels, on the other hand, improve bone formation in the patients with high PTH levels. Furthermore, Krieger et al. reported, from an in vitro study, a direct, suppressive effect of metabolic acidosis on osteoblastic-induced collagen synthesis, which decreased by 15% after exposure to an acidic milieu . We did not know the exact mechanism why in crossover study PTH level as well as BAP increased exclusively in patients with low-PTH level. From these reports and our results, the optimal correction of metabolic acidosis might affect int-PTH and BAP levels in the patients with low PTH levels. On the other hand, there was no significant difference in int-PTH or BAP levels, in either the A(−)D period or A(+)D periods, in the patients with high PTH levels. Graham K. A. et al.  reported that, after the correction of metabolic acidosis in MHD patients with hyperparathyroidism, parathyroid hormone secretion was suppressed by increasing the sensitivity of the parathyroid glands to ionized calcium. Furthermore, sensitivity to vitamin D treatment in renal osteodystrophy is affected by metabolic acidosis, which induces resistance to vitamin D compounds and calcimimetics .
It had been reported that metabolic acidosis triggers an increase in bone resorption and a decrease in bone formation in parathyroidectomized rats . Furthermore, bone metabolism is affected by pH modulation of calcium-sensing receptor (CaR) activation. Quinn S. J et al. reported that CaR can sense changes in pH. They showed that changes in extracellular pH produced changes in intracellular calcium levels, a key intracellular signal which mediates the inhibition of PTH secretion by CaR activation . From these reports, we presumed that the optimal correction of metabolic acidosis might improve the response to vitamin D compounds and suppress the increase of int-PTH levels during the A(−)D period in the patients with high PTH levels.
Inflammatory condition and bone metabolism
Acetate induces the expression of pro-inflammatory cytokines in monocytes and polymorphonuclear neutrophil leukocytes, which may be responsible for chronic inflammation in HD patients . The removal of acetate from the dialysates and the purification of the dialysates would lead to a possible attenuation of chronic inflammatory conditions in MHD patients. Recently, Eleftheriadis T et al. demonstrated the negative correlation between serum IL-6 levels and bone turnover osteocalcin or the beta-isomerised C-terminal cross-linked peptide of collagen type I, which suggests a relationship between bone turnover and chronic inflammation in MHD patients . These reports indicate that the attenuation of a chronic inflammatory condition may improve low bone turnover in MHD patients. Although, this study did not compare the inflammatory conditions of A(−)D and A(+)D, the improvement in bone turnover found in this study could be caused by the attenuation of the chronic inflammatory condition by A(−)D.
The primary limitations of this study are the small patient population, the lack of values for pharmacological parameters such as the blood levels for citrate and acetate, and our inability to specify a single type of dialysis membrane, the glucose concentration or the pH in the dialysate.