KDOQI (Kidney Disease Outcomes Quality Initiative)


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KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Children With Chronic Kidney Disease


Guideline 10. Dialysate Calcium Concentrations

10.1 In patients receiving calcium-based phosphate binders, the dialysate calcium concentration should be targeted to 2.5 mEq/L (1.25 mM). (OPINION)

10.2 In patients not receiving calcium-containing phosphate binders, the dialysate calcium should be targeted to 2.5-3.0 mEq/L (1.25-3 mM) based on serum calcium levels and the need for therapy with active vitamin D sterols. (OPINION)

Background

In patients receiving dialysis, the normal homeostatic mechanisms for regulating calcium balance are impaired. Calcium absorption cannot be adjusted, due to the kidney's inability to produce 1,25(OH)2D. Further, the level of the peripheral tissue VDR may be reduced. Calcium excretion, usually regulated through urinary losses, is severely impaired or absent. Dialysate calcium, activated vitamin D sterols, and dietary calcium intake—itself highly influenced by the use of oral, calcium-containing phosphate binders—are the physician-prescribed determinants of calcium balance in patients receiving dialysis.

Because bone mass increases dramatically during childhood and adolescence, there is significant net body accretion of calcium, where, on balance, absorption must exceed losses. Inadequate calcium absorption is an important cause of 2° HPT and osteodystrophy in the setting of CKD. Historically, dialysate calcium levels were set at a physiological level of 2.5 mEq/L, approximately equivalent to the serum ionized calcium concentration. However, it became clear that many patients were in a negative calcium balance in the era when oral aluminum-containing salts were the principal phosphate binder. Consequently, in both hemodialysis and peritoneal dialysis, a supraphysiological dialysate calcium concentration (3.0-3.5 mEq/L) became standard, permitting transfer of calcium to the patient during dialysis. This was effective in reducing PTH levels.371 With the current widespread use of activated vitamin D sterols and oral, calcium-containing phosphate binders, calcium balance is shifted upward dramatically, so that a return to the use of 2.5 mEq/L calcium dialysate is safe. However, the use of calcium- and other metal-containing phosphate binders may require a higher dialysate calcium.

Rationale

There are three major clinical concerns related to excess calcium balance: bone, growth, and development of vascular calcifications. Patients may develop frank hypercalcemia, which most commonly occurs in patients receiving both oral calcium-containing phosphate binders, and activated vitamin D sterols. This may limit the use of calcium-containing phosphate binders to control hyperphosphatemia and 2° HPT. Excess calcium balance, resulting in hypercalcemia and thereby suppressing the parathyroid gland secretion of PTH, may contribute to the development of adynamic bone disease, which has become an increasing problem in both adults and children on maintenance dialysis.24,327,328,372 Patients with adynamic bone disease have an increased risk of hypercalcemia due to the limited capacity of their bone to incorporate calcium.207 There is concern that excessive calcium balance may contribute to systemic calcification, as reflected by EBCT evidence of enhanced coronary calcium scores, present in young adults who started dialysis as children.80,84 In addition, adynamic bone disease was associated with a greater degree of arterial calcification in patients on maintenance dialysis.373

The dialysate calcium concentration and the volume of ultrafiltrate determine calcium balance during dialysis. A higher dialysate calcium concentration increases diffusion of calcium into the patient. In contrast, the calcium present in the ultrafiltrate is a potentially important source of calcium loss from the patient. The calcium balance during peritoneal dialysis is usually negative with use of 2.5 mEq/L calcium dialysate and positive with 3.0-3.5 mEq/L calcium dialysate, although high volumes of dialysate ultrafiltrate can produce a negative calcium balance even with 3.5 mEq/L calcium dialysate.374-378 Calcium balance during hemodialysis may be neutral or negative with the use of a 2.5 mEq/L calcium dialysate.379,380 (See Guideline 14).

The use of dialysate with a calcium concentration of 2.5 mEq/L is an effective strategy for reducing calcium intake, and thereby reducing balance, if patients are treated with calcium-based phosphate binders. Studies in adults using this preparation have shown fewer episodes of hypercalcemia and patient tolerance of increased doses of calcium-containing phosphate binders without the development of hypercalcemia.381-384 Hyperparathyroidism may worsen after decreasing the dialysate calcium, but this often responds to increased use of calcium-containing phosphate binders and/or active vitamin D sterols.385,386 Patients with an elevated PTH prior to switching to a low-calcium dialysate are at greater risk for worsening hyperparathyroidism and may not tolerate the change.387 There are, however, biochemical data in patients suggesting that a 2.5 mEq/L calcium dialysate may have a positive effect on adynamic bone disease.388

Along with the reduction of dialysate calcium concentration, other strategies designed to decrease the intake of calcium have focused on active vitamin D sterols and calcium-containing phosphate binders. While reduction of the active vitamin D sterol dose is an alternative therapeutic option, the trade-off is decreased parathyroid gland suppression and possible worsening or production of 2° HPT. This has led to approaches such as intermittent active vitamin D sterol therapy, and the development of active vitamin D sterols that produce equivalent suppression of PTH but with less effective intestinal calcium absorption. Strategies to minimize calcium intake from calcium-containing phosphate binders include decreasing their use through improved control of dietary phosphorous intake, an increase in the dialysis prescription to improve phosphate clearance, and the use of calcium-containing phosphate binders that produce equivalent phosphate binding but less calcium absorption than calcium carbonate, such as calcium acetate.

Another approach to the excess dietary calcium intake is the substitution of a calcium-free phosphate binder.184,389-391 However, when only a resin is used, concern over appropriate calcium intake should be taken into consideration. Foodstuffs in younger children that provide calcium are often limited, since they represent sources of phosphorus too, and are therefore restricted. Such patients may benefit from a higher dialysate calcium concentration and/or calcium supplementation with a calcium-containing phosphate binder.204 No calcium and metal-free phosphate binder is currently approved by the FDA for use in children.

Finally, there is evidence in adult hemodialysis patients that a 2.5 mEq/L calcium dialysate may predispose patients to arrhythmias392,393 although a higher dialysate calcium during hemodialysis may impair cardiac relaxation and arterial compliance.394,395 Similar experiences have not been reported in children, but cardiovascular disease is the leading cause of death in children.

Strength of Evidence

There are no longitudinal studies evaluating different dialysate calcium concentrations in pediatric dialysis patients. There are few prospective adult studies addressing this issue. In these few adult-based studies, comparison of the data is difficult due to major differences in outcome measures, study design, and concurrent use of calcium-containing phosphate binders and active vitamin D sterols. In addition, the adult studies are characteristically in patients receiving either peritoneal dialysis or hemodialysis and these groups may not be comparable. Moreover, adult studies only include patients receiving CAPD or, less commonly, a mixture of patients receiving CAPD or CCPD, the latter being the most widely utilized form of dialysis in pediatric patients. The relevance of findings derived from CAPD patients to patients receiving CCPD is unknown.

A variety of outcome measures have been used in the adult studies. One study analyzed patient mortality, comparing a 3.5 mEq/L and 2.0 mEq/L calcium dialysate in patients receiving CAPD.396 There was no statistically significant difference, although both groups had a high attrition rate, making a meaningful analysis difficult. In the same study, the group that received 2.0 mEq/L calcium dialysate had fewer episodes of hypercalcemia and were able to receive more calcium carbonate.396 In contrast, another study of patients receiving either CCPD or CAPD found no statistically significant difference in the incidence of hypercalcemia when comparing 3.5 mEq/L and 2.0 mEq/L calcium dialysate, although the sample size was small.397

A number of studies have analyzed the risk of infection in patients receiving peritoneal dialysis with either a high or low dialysate calcium concentration, but none has shown an effect of the dialysate calcium concentration on the frequency of either peritonitis or exit-site infections.396,398,399

Three studies have compared BMD in adult patients randomized to high- or low-calcium dialysate. None of these studies demonstrated any effect of dialysate calcium on BMD, although all of these studies also had a small sample size.396,400,401

Four studies have analyzed the effect of dialysate calcium on biochemical bone markers. Among the three studies that evaluated serum alkaline phosphatase levels, one showed a greater increase in alkaline phosphatase among the patients on 2.0 mEq/L dialysate calcium versus those on 3.5 mEq/L dialysate calcium.396 The other two studies showed no significant difference, but both had small numbers of patients.400-402 Two studies evaluated the effect of dialysate calcium concentration on bone gla protein (BGP, or osteocalcin). Both studies reporting BGP data found significantly higher levels of BGP in patients on low-calcium dialysate after about 6 months of treatment; however, at 12 months, the effect was not statistically significant in the smaller study403 in contrast to the larger study396,400 in which the effect was statistically significant at 24 months.

Three studies reported PTH levels as an outcome measure after 6 months follow-up when comparing 3.5 mEq/L calcium dialysate to 2.5 mEq/L calcium dialysate. In a study of CAPD patients, significantly higher PTH levels were noted at 6 months in patients who received the 2.5 mEq/L calcium dialysate.403 The remaining two studies showed no statistically significant effect of dialysate calcium on PTH, but these studies had small sample sizes with a clear trend towards higher PTH values in the low-calcium groups.397,400Another study followed PTH levels in 10 dialysis patients with biopsy-proven adynamic bone disease after lowering the dialysate calcium from 3.25 mEq/L to 2.0 mEq/L.366 During the initial 9 months of follow-up, the mean PTH level increased from 37 to 106 pg/mL; there was no increase in the PTH level over the last 3 months of the study. In addition, hypercalcemia resolved.

Finally, there are studies that have evaluated the risk of hyperparathyroidism and the importance of calcium supplementation in patients treated with low-calcium dialysate but without use of calcium-containing phosphate binders. In adults receiving CAPD, it was shown that the use of 2.5 mEq/L calcium dialysate and aluminum hydroxide as a phosphate binder resulted in a significant increase in the PTH level (from 259 to 405 pg/mL; P = 0.0001). The limitation of this study was that no patient received an active vitamin D sterol.404

Clinical Applications

The use of 2.5 mEq/L calcium dialysate may help to prevent hypercalcemia, adynamic bone disease, and systemic calcification. This is recommended for children who are receiving calcium-containing phosphate binders. Alternate dialysate calcium concentrations may be required if calcium- and other metal-free phosphate binders are used. When the dialysate calcium concentration is decreased, careful monitoring of PTH is necessary to avoid the development of worsening 2° HPT and high-turnover bone disease. The risk is further increased if the PTH level is already elevated when the dialysate calcium is lowered. Patients on a 2.5 mEq/L calcium dialysate may require adjustment in activated vitamin D sterol dosing, or even a return to a higher dialysate calcium concentration. In the child with an inappropriately low PTH level (<150 pg/mL), even further reduction of the dialysate calcium concentration may be necessary in select circumstances. A reduction in the dialysate calcium concentration is also indicated in the child with symptomatic hypercalcemia, or hypercalcemia that does not respond to adjustments in the intake of oral calcium and/or active vitamin D sterol dosing.

Patients with hypocalcemia may require a 3.0 or 3.5 mEq/L calcium dialysate. This may also be necessary transiently in the setting of hungry bone syndrome following parathyroidectomy (see Guideline 15). A 3.0 mEq/L calcium dialysate may be necessary if persistent hypocalcemia (<8.5 mg/dL, corrected for serum albumin) persists despite adequate treatment with an active vitamin D sterol and there is refractory 2° HPT.

Children who are not receiving a calcium-containing phosphate binder probably do not have a positive calcium balance when they are on maintenance dialysis. They usually require a dialysate calcium concentration that allows for net absorption of calcium (≥3.0 mEq/L) and/or the use of a dietary calcium supplement, unless hypercalcemia is present. Such children must be monitored for adequate calcium intake and the development of 2° HPT. It may be that the use of non-calcium, non-metal containing phosphate binder, combined with a low dialysate calcium concentration, may allow the use of higher doses of active vitamin D sterols.

Limitations

There are no pediatric studies that have addressed the topic of dialysate calcium concentration with specific attention to the correlation between calcium balance and growth. Adult studies have focused on hypercalcemia, 2° HPT, and control of serum phosphorus as outcome measures. Another limitation is the fact that there is less information available for hemodialysis patients than peritoneal dialysis patients, and no studies address the dialysate calcium concentration in patients receiving CCPD. Finally, studies are difficult to compare because of wide variations in the use of active vitamin D sterols and calcium-containing phosphate binders, and there are limited data on the effect of the dialysate calcium concentration on long-term issues such as adynamic bone disease and systemic calcifications.

Recommendations for Research

Calcium balance studies are necessary in children receiving hemodialysis or peritoneal dialysis to determine the effect of different dialysate calcium concentrations. Research needs to determine the relative roles of dialysate calcium, active vitamin D sterols, and calcium-containing phosphate binders in the development of hypercalcemia, systemic calcifications, and adynamic bone disease. Calcium- and aluminum-free phosphate binders should be evaluated for use in children. Studies in patients not receiving calcium-containing phosphate binders should include an evaluation of higher dialysate calcium concentrations and/or oral calcium supplementation.