CHAPTER 3

Abstract

Management of Serum Phosphate, Serum Calcium, and Parathyroid Hormone Recommendations Serum phosphate levels should be monitored and maintained within the normal range. (Grade C) To optimize control of serum phosphate, use restriction of dietary phosphate (Grade D), adjust the dialysis prescription (Grade D), and use oral phosphate binders. (Grade C) Background Elevated serum phosphate is common in individuals with stage 5 chronic kidney disease. Multiple studies have shown that elevated serum phosphate is associated with increased morbidity and mortality due to cardiovascular disease in the hemodialysis population (1–5). Increased serum phosphate is also involved in the pathogenesis of secondary hyperparathyroidism (6,7). The current Kidney Disease Outcomes Quality Initiative (K/DOQI) target level for serum phosphate levels (0.80 to 1.78 mmol/L) was partially based upon studies showing an association between cardiovascular disease morbidity and mortality and elevated serum phosphorus. In at least two of these studies, the association only reached significance at higher levels of serum phosphate (>2 mmol/L) (1,3). Decreasing phosphate levels toward the normal or target range might be associated with decreased mortality. However, to date, no randomized trials support this hypothesis. To achieve an optimal phosphate level, the following strategies can be used: Restriction of dietary phosphate. A phosphorus intake of 800 to 1000 mg per day is recommended to help achieve serum phosphorus levels of 0.80 to 1.78 mmol/L. On an intake of 1000 mg per day, about 60 to 70% is absorbed. Dietary counseling has been shown to improve phosphate control in hemodialysis patients (8,9). Further research is warranted to ascertain whether phosphorus levels differ on a diet high in plant protein versus animal protein. Removal of phosphate by hemodialysis. Phosphate is mainly intracellular; therefore, clearance of phosphate during hemodialysis follows a pattern of most efficient clearance within the first 1 to 2 h with a plateau, and then rebounds within the first 4 h after the end of the treatment (10). The amount of phosphate removed is dependent also on the predialysis level. On average, about 900 to 1000 mg of phosphate can be removed per dialysis treatment. High-flux (versus low-flux) efficiency membranes may have higher phosphate clearances but phosphate removal is not significantly altered. Dialysis phosphate clearance may be improved by the use of frequent and longer dialysis, especially nocturnal hemodialysis (10,11). Use of phosphate binders. Given that most hemodialysis patients are in positive phosphate balance, there is a need to use phosphate binders to decrease phosphate absorption in the gut. Because of the concern with aluminum toxicity, calcium-based binders continue to see extensive use. There has been increasing concern about the over-reliance of calcium-based phosphate binders due to the associated calcium load. Studies have found an association between daily calcium intake and coronary artery calcification (12–14) and calcification in other vascular beds (15). These data, plus extrapolation from studies of calcium balance and daily requirements, led the K/DOQI Mineral Metabolism Guideline Committee to recommend not exceeding the use of >1500 mg of elemental calcium in calcium-containing binders with a tolerable upper limit of 2500 mg for total calcium intake per day (16). Despite the availability of several classes of phosphate binders, the majority of hemodialysis patients continue to have elevated phosphate levels (17,18). This illustrates the lack of efficacy of the available binders. When deciding on the choice and dose of binder(s) to use, it is important to realize that many of the clinical studies are of short duration (19–24), nonrandomized (20–22,25–31), open-label (19–22,25–28,30–38), or use no direct comparator (20–22,26–28,30,31,35). In addition, average medication doses or changes in laboratory parameters are not always reported, and adherence to binders ranges from 69 to 91%. As a result, available evidence does not allow the recommendation of one (or several) phosphate binders as superior to any other. Recently, interest in the use of noncalcium-, nonaluminum-based binders has increased. Coronary artery calcification scores are lower in subjects treated with sevelamer compared with those treated with calcium binders (37). At the time of writing this guideline, only preliminary results were available from the Dialysis Clinical Outcomes Revisited (DCOR) trial. DCOR was a controlled clinical trial of approximately 2100 hemodialysis patients randomized to receive calcium-based phosphate binders or sevelamer. Three years after randomization, a 9% decrease in all-cause mortality (primary endpoint) was seen in those subjects assigned to sevelamer, although this did not reach statistical significance (P = 0.30) (39). Although subgroup analyses demonstrated that sevelamer use was associated with a reduction in mortality in subjects over 65 yr of age, interpretation of these data should await the final peer-reviewed publication. It should also be kept in mind that, compared with calcium-containing phosphate binders, use of sevelamer is no better at controlling serum phosphate and is associated with greater health care costs (23,40). Serum calcium levels should be monitored and maintained within the normal range. (Grade D) Background For the prevention of secondary hyperparathyroidism, individuals with kidney disease should have calcium levels maintained in the normal range defined by the testing laboratory. Although it is generally accepted that total serum calcium levels should be adjusted for serum albumin, Clase et al. found that total calcium had a higher correlation with the gold standard of ionized calcium measurement than many formulas (41). Calcium-based phosphate binders contribute to the total daily calcium load in hemodialysis patients. Higher daily calcium intake is associated with poor outcomes including coronary calcification (13,14) and rapid progression of calcification in other vascular beds (42). Although several studies have reported an association between hypercalcemia and decreased survival (2,18,43), this finding is not consistent across all reports (1,44). Serum calcium is also inversely associated with intact parathyroid hormone (PTH) (44). In the setting of low PTH, suggesting low turnover bone disease, an increased calcium load cannot be incorporated into bone, and thus can precipitate into blood vessels, heart valves, and other soft tissues (45). Given that the above results and hypotheses are based upon associative data, may be confounded by vitamin D use, and have not been tested in controlled clinical trials, firm recommendations limiting the daily oral calcium intake cannot be made by this committee. Dialysate calcium also impacts calcium balance. Fernandez et al. reported that the use of 1.25 mM dialysate calcium resulted in negative calcium balance, despite no change in serum ionized calcium values (46). However, compared with 1.75 mM dialysate calcium, 1.25 mM dialysate calcium led to higher parathyroid hormone levels and greater use of vitamin D. Measure PTH levels on a regular basis (at a minimum every 4 mo) (Grade D, opinion) and direct therapy to avoid both high and low PTH levels. (Grade C) Give priority to phosphate and calcium targets over the management of PTH. (Grade D, opinion) Avoid intach PTH (iPTH) levels below 100 pg/ml (10.6 pmol/L) (Grade C); iPTH levels >500 pg/ml (53 pmol/L) should be treated if accompanied by symptoms or clinical signs of hyperparathyroidism. (Grade D, opinion) Vitamin D sterols can be used in the treatment of secondary hyperparathyroidism, but should be discontinued when PTH levels decrease below target levels, or if calcium or phosphate levels increase above target levels. (Grade C) Parathyroidectomy should be considered for those patients who have failed standard treatments and have persistently elevated PTH levels with systemic complications. (Grade D, opinion) Background Given that PTH is a major regulator of bone turnover and skeletal cellular activity, PTH is widely used as a surrogate marker instead of bone histomorphometric analysis (the gold standard). Recently, many questions have been raised about the method of PTH measurement, the normal or optimal range of the PTH level, and the correlation of PTH levels with bone histology. The principal method of measurement of PTH over the last couple decades has been a two-site immunometric technique called the “intact” PTH (iPTH) assay. This form of measurement has been widely used and is the basis of current classification schemes for bone turnover. It is now known that assays measuring iPTH also measure a large PTH fragment (PTH 7 to 84). This has led to assays specific for PTH 1 to 84 (biointact or whole PTH assays). Although these new assays appear promising, much of the data with renal bone disease and the correlation with PTH levels exist for iPTH measurements. On this basis, the current guidelines use target levels based upon the iPTH assay. Users of these guidelines are instructed to determine the assay used locally and use sound clinical judgment if the biointact or whole PTH assay is used. Much of the research that correlates iPTH values to bone biopsy findings was done at least 10 yr ago, where iPTH levels <165 pg/ml (17.5 pmol/L) were associated with adynamic bone disease (low turnover disease) and iPTH levels >300 pg/ml (31.8 pmol/L) correlated with high turnover bone disease (47–49). However, it has also been shown that use of calcitriol modifies the relationship between iPTH and indices of bone formation and turnover (50). Coen et al. used receiver-operator characteristic (ROC) curves to determine that a cutoff value of 210 pg/ml (22.3 pmol/L) for iPTH had a positive predictive value of 100 and a negative predictive value of 45 in predicting adynamic bone disease versus mixed osteodystrophy or high turnover disease (51). In the K/DOQI bone metabolism guidelines, summary ROC curves from 5 individual studies revealed that a threshold iPTH level of 150 to 200 pg/ml (15.9 to 21.2 pmol/L) had a sensitivity of 93% and specificity of 77% for diagnosis of high turnover bone disease, while a PTH value of 60 pg/ml (6.4 pmol/L) or less had a sensitivity of 70% and specificity of 87% for low bone turnover (16). Controlling or preventing secondary hyperparathyroidism is important in patients with chronic kidney disease. Not only is there concern about renal bone disease, but also increasingly there is concern about other systemic toxicities. Several studies have shown that moderate to severe elevations of iPTH are associated with increased morbidity and mortality (1–3). In addition, decreased iPTH levels are also associated with increased morbidity and mortality (4,44,52). Therefore, iPTH values both above and below the current target range are undesirable. Specific treatment strategies include maintaining normal calcium and phosphate levels. Calcium supplementation may also be needed to maintain serum calcium with the normal range. Vitamin D analogs 1α(OH)D3 or 1,25(OH)2D3 are used to treat patients with elevated PTH levels as they act by suppressing prepro-PTH-mRNA in the parathyroid cell. Vitamin D analogs can be prescribed daily or intermittently, orally or intravenously. Clinical trials have been inconclusive in determining the best route of administration (53–55). Intravenous therapy after dialysis is an effective way to ensure compliance. All vitamin D analogues have the ability to increase serum levels of calcium and phosphate, and although this effect may be less with newer analogues, valid studies with relevant clinical outcomes are not available (5,56–63). Parathyroidectomy is used for secondary hyperparathyroidism that is not controlled by standard medical therapy, and is associated with other clinical indications, such as elevated serum calcium or phosphate, tendon rupture, resistant anemia, or bone pain. A recent analysis of US Renal Data System data shows that although mortality is higher for the first 3 mo after parathyroidectomy, a survival advantage is apparent 20 mo postoperatively (64). A calcimimetic agent, specifically cinacalcet, has recently been released for the treatment of secondary hyperparathyroidism in dialysis patients. Cinacalcet binds to the calcium-sensing receptor on the PTH gland cells and increases the sensitivity of the receptor to calcium. The largest study published confirmed that subjects treated with cinacalcet had a therapeutic response, with 43% achieving an iPTH level of <250 pg/ml (26.5 pmol/L) as compared with only 5% in the control group (65). The decrease in iPTH was seen at all levels of baseline iPTH. Additional benefits seen were significant decreases in serum phosphate, calcium and calcium × phosphorus product. Hypocalcemia can occur, but can be minimized by dose titration plus the addition of vitamin D analogues to maintain a normal serum calcium level. All the published studies with cinacalcet have been of relatively short duration, using the surrogate endpoints of iPTH, phosphate, and calcium. Longer-term use will be needed to determine the impact on use of phosphate binders, calcium supplements, and vitamin D analogues, and perhaps more importantly the impact of decreasing iPTH on morbidity and mortality. Recommendations for Research Although many studies have shown that elevated phosphate, calcium, and iPTH are associated with increased morbidity and mortality, prospective randomized studies are needed to determine whether achieving suggested targets for calcium and phosphate decreases mortality in hemodialysis patients. Studies are needed to determine the appropriate target range of PTH (intact or whole assays) for normal bone metabolism in stage 5 chronic kidney disease patients on dialysis. Evaluate the impact vitamin D sterols and calcimimetics on morbidity and mortality in hemodialysis patients.