KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease
CLINICAL PRACTICE GUIDELINES
GUIDELINE 9. DIALYSATE CALCIUM CONCENTRATIONS
9.1 The dialysate calcium concentration in hemodialysis or peritoneal dialysis should be 2.5 meq/L (1.25 mmol/L). (OPINION)
9.2 Higher or lower dialysate calcium levels are indicated in selected patients. (See Clinical Applications.) (OPINION)
The proposed dialysate calcium concentration appears most compatible with current clinical knowledge, the clinical necessity of vitamin D use, and the use of calcium-based phosphate binders. Such a dialysate calcium concentration will permit use of these agents with much less risk of calcium loading and hypercalcemia. With this level of calcium in dialysate, little or no calcium transfer occurs into the patient. When there is a need to remove calcium from the patient, a lower dialysate level will be appropriate. In patients in whom calcium supply is needed, calcium transfer into the patient may be achieved safely with dialysate levels up to 3.5 mEq/L.
The constituents of the dialysate have evolved over time in a generally logical fashion. Concentrations of the major electrolytes and acid/base components have been determined by studies directed at specific outcome measures. The reasons for the values selected have been defined and understood. The dialysate calcium concentration, on the other hand, has not been amenable to delineation or study. The problem has been to balance the dialysate calcium with the needs for control of other aspects of calcium pathophysiology in dialysis patients. It has not been possible to designate an optimal dialysate calcium concentration and it will not be possible until other aspects of the abnormal calcium metabolism in these patients are defined and stabilized. When these other aspects are clarified, studies can then be conducted to define and recommend the optimal dialysate calcium concentration.
The current dialysate calcium level has been arrived at over time, in conjunction with the evolution of other aspects of calcium metabolism in this population. In the 1960s, when dialysis was introduced, the constituents of the dialysate were arbitrarily determined to best match normal serum levels. Thus, ionized calcium levels were initially chosen at around 1.25 mmol/L to match the normal serum level. Because of impaired calcium absorption with resultant hypocalcemia, it soon became apparent that higher levels of dialysate calcium could be used to support the serum calcium level. Early studies of parathyroid hormone in the late 1960s showed that these higher dialysate calcium levels of 3.5 mEq/L (1.75 mmol/L) were also associated with lower parathyroid hormone levels.316
Another important and relevant development in the 1960s was the universal acceptance of aluminum compounds as the predominant phosphate binders. Aluminum was selected because it was "not absorbed" (actually, absorption was not detectable by the technology of that era) and seemed preferable to magnesium and calcium for a variety of reasons.317
In the 1970s, calcitriol was identified and synthesized, and it became available as a therapeutic agent. With its direct effect on gut absorption of calcium, the problems of hypocalcemia were ameliorated and the need for calcium loading via the dialysate were lessened. However, the traditional high calcium dialysate continued in most practices, with the goal being to maintain a high normal serum calcium using both dialysate and calcitriol in order to maximize PTH suppression. Phosphate control was achievable in most patients with the aluminum compounds, which we now know also directly inhibited PTH production and secretion.318
In the early 1980s, it became apparent that not only was aluminum absorbed from the gastrointestinal tract, but that it was also quite toxic.319 Initially, aluminum toxicity was treated with deferoxamine, the iron-chelating agent. However, it quickly became apparent that deferoxamine caused infections with siderophilic organisms, particularly mucormycosis, which had an extraordinarily high mortality rate.320 In the later 1980s, aluminum-based phosphate binders were gradually replaced by calcium-based phosphate binders and it was soon demonstrated that hypercalcemia occurred at a high rate, as a result of the combination of calcium-based phosphate binders, high calcium dialysate, and calcitriol use. In response to this marked increase in gut calcium absorption from both the high oral calcium intake and the potent vitamin D metabolite, calcitriol, lower calcium dialysates began to be introduced. Other attempts to resolve this issue led to the use of intravenous, bolus dosing with calcitriol (which had much less effect on gut absorption than oral treatment) and lower calcium dialysates, generally 1.25 mmol/L, became the norm.321
With the concerns about aluminum and calcium, the pursuit of better phosphate binders has been a focus of research in the 1990s. Several are being studied and one, sevelamer HCl, has been released.322 While these newer phosphate binders vary considerably in chemical characteristics, they do not contain calcium, magnesium, or aluminum and are, therefore, likely not to impact dialysis calcium concentrations directly. While they all appear safe, patient acceptability and effectiveness remain to be demonstrated.
While these historical developments in calcium/phosphate/PTH management were occurring, the bone disease that resulted was also evolving. In the first 25 years (until about 1985) the overriding concern was the suppression and prevention of bone disorders due to hyperparathyroidism. In the last 15 years, the appearance of adynamic bone disease, associated with low PTH, has been increasingly apparent and this is now the predominant form of osteodystrophy.14 Speculation as to the cause of this lesion focuses on oversuppression of PTH due to calcium loading and/or the use of more potent vitamin D metabolites. In conjunction with this, the problem of metastatic calcification, especially vascular calcification, has assumed increasing importance and is clearly associated with both positive calcium and phosphate balance.87,92
Thus, the choice of dialysate calcium concentration has been determined largely by other aspects of calcium metabolism over the first 40 years of dialysis therapy. Since these other aspects of calcium metabolism remain problematic, the actual dialysate calcium concentration will continue to evolve and, of necessity, needs to remain flexible as this dynamic area of research continues to challenge us. Ideally, the dialysate calcium concentration should be individualized to meet specific patient needs, but this is not readily feasible economically at this time.
Studies of dialysate calcium concentration have been carried out for the entire time that dialysis therapy has been used. Such studies were initiated with the best of intentions and often with quite careful designs. Changes in other aspects of our knowledge of calcium metabolism generally made these studies obsolete or even unethical before they were completed. Those that were completed were often so compromised by other changes in patient care that their results could either not be interpreted or were of marginal relevance.
Several studies over the last 30 years have evaluated the PTH response to dialysate calcium and consistently found that PTH correlated inversely with dialysate calcium. In the early days of dialysis, these findings resulted in recommendations for higher dialysate calcium levels (usually 1.75 mmol/L) in order to suppress PTH. In more recent years some studies of adynamic bone disease have begun to recommend lower dialysate calcium levels (usually 1.00 to 1.25 mmol/L) in order to increase PTH and bone formation in such patients. Since other factors have also assumed importance in PTH regulation, it is not entirely clear what role dialysate calcium concentration will play in this regard in the future. Probably, at least as much attention should be paid to the potential adverse effects of calcium loading and metastatic calcification as to the potential benefits of PTH suppression by this means.
A variety of studies over the last 30 years have attempted to assess the effects of various dialysate calcium levels on morbidity, mortality, infections (in peritoneal dialysis patients), various bone markers, and bone mineral density. Since the studies were done at different periods in the history of dialysis and at times when different measures to control calcium and phosphate were practiced, it is essentially impossible to document or ascertain any clear conclusions from these studies. What is clear is that studies to assess dialysate calcium in the future may be conducted when other aspects of calcium, phosphate, PTH, and bone pathophysiology are well understood and characterized. If and when that occurs, it may be possible to design a trial that will be practical and meaningful.
Strength of the Evidence
While the reasons for the recommendation of a 2.5 mEq/L dialysate calcium concentration appear clear from the historical record, there is little, if any, evidence to support this particular choice. Clinical experience, rather than outcome data, have really determined how we have come to this juncture. The difficulties, up to now, of obtaining outcome data on various dialysis calcium levels have been frustrated by all the other changes in our understanding and management of renal osteodystrophy. As noted above, once we have settled on a consistent approach to these issues it may be possible to return to a logically designed assessment of dialysate calcium concentration. For now, we must fall back on what appears to be a "best guess."
While this is a "best guess" at what the dialysate calcium should be, there are many unanswered questions that remain to be settled before being completely comfortable with this recommendation. In conjunction with all the other maneuvers, we may decide that a somewhat lower calcium concentration allows better regulation of PTH and bone disease. We may also find that, even at a 2.5 mEq/L calcium level, excess calcium loading occurs and contributes to vascular disease and calciphylaxis.
On the other hand, it has been recognized that cardiac arrhythmia is more common in patients being treated with lower-calcium dialysates.323 The prolongation of the QT interval, which is commonly seen during dialysis, is worse with lower calcium324 and in other settings than dialysis, this electrocardiographic abnormality is often associated with fatal outcomes. Thus, there remain serious unresolved questions which are likely to influence the choice of dialysate calcium levels in the future and clinicians will need to keep abreast of these issues.
At this point in time, the most logical dialysate calcium concentration appears to be one of 2.5 mEq/L. With the use of calcium-containing phosphate binders and active vitamin D metabolites, this level of dialysate calcium is currently the most convenient in allowing flexible use of other therapies directed at treating the bone and parathyroid gland abnormalities of this patient population. Because of the rapid evolution of management of calcium disorders in these patients, no data exist to document that any particular calcium dialysate is safer, more effective, or associated with fewer complications. Some studies have shown an increase in cardiac arrhythmias with lower calcium dialysates, but no increase in mortality or morbidity has been shown to result.
There may be times when calcium dialysate concentration should be altered. A lower calcium dialysate concentration (eg, 1.5 to 2.0 mEq/L) might be considered when a low PTH level is associated with adynamic bone disease. In this setting, PTH will be stimulated and bone turnover increased. The intact PTH should be allowed to rise to at least 100 pg/mL (11.0 pmol/L) to avoid low-turnover bone disease. However, the physician will need to be wary of overstimulating PTH and producing high-turnover bone disease. Thus, if PTH values exceed 300 pg/mL (33.0 pmol/L), the dialysate calcium may need to be modified again. Dialysate calcium concentrations of 1.5 to 2.0 mEq/L, or even lower, may be used to treat hypercalcemia both in chronic dialysis patients and patients without kidney disease. Because such treatment will lead to marked bone demineralization, it should not be prolonged. It is the primary cause of hypercalcemia that should be sought and treated.
Similarly, higher calcium levels in dialysates may be useful to sustain calcium balance when it cannot be maintained with routine treatment. Treatment of "hungry bone syndrome" is perhaps the best example, but standard therapies for this problem are usually effective without having to adjust dialysate calcium. In the early days of dialysis, high calcium concentration dialysates (typically 3.5 mEq/L) were employed because the patients calcium balance and calcium levels could not be sustained without them. Advances in vitamin D therapy have eliminated this need.
Recommendations for Research
There is a basic conflict in calcium pathophysiology that needs to be resolved in CKD patients, ie, the conflict between adequate suppression and control of PTH, and excessive calcium loading resulting in tissue injury. The resolution of this conflict will involve carefully designed trials to assess basic issues currently being widely discussed.
(1) Prospective long term studies of calcium balance and the accelerated atherosclerosis of CKD patients need to be coordinated to find the proper calcium balance that does not worsen these problems in patients.
(2) The regulation of PTH remains a challenge. Studies need to be done to determine what level of PTH is best (in terms of osteodystrophy) in the dialysis population. Once that is determined, the best ways to achieve the desired result will need to assess the coordination of the various biochemical and other approaches to PTH control, including dialysate calcium level.
(3) An acceptable balance between adequate control of PTH/bone disease and avoidance of accelerated atherosclerosis needs to be determined. Studies to define this balance will be both difficult and tedious.
© 2003 National Kidney Foundation, Inc.