Phosphorus balance with daily dialysis

Hyperphosphatemia is an almost universal finding in patients with end-stage renal disease and is associated with increased all-cause mortality, cardiovascular mortality, and vascular calcification. These associations have raised the question of whether reducing phosphorus levels could result in improved survival. In light of the recent findings that increased per-session dialysis dose, as assessed by urea kinetics, did not result in improved survival, the definition of adequacy of dialysis should be re-evaluated and consideration given to alternative markers. Two alternatives to conventional thrice weekly dialysis (CHD) are nocturnal hemodialysis (NHD) and short daily hemodialysis (SDHD). The elimination kinetics of phosphorus as they relate to these alternative daily dialysis schedules and the clinical implications of overall phosphorus balance are discussed here. The total weekly phosphorus removal with NHD is more than twice that removed by CHD (4985 mg/week +/- 1827 mg vs. 2347 mg/week +/- 697 mg) and this is associated with a significantly lower average serum phosphorous (4.0 mg/dl vs. 6.5 mg/dl). In spite of the observed increase in protein and phosphorus intake seen in patients on SDHD, phosphate binder requirements and serum phosphorus levels are generally stable to decrease although this effect is strongly dependent on the frequency and overall treatment time.     

Removal of Phosphorus by Hemodialysis

The control of serum phosphorus by dialysis is made difficult by the fact that intradialytic blood levels tend to be low, and because phosphorus is removed almost exclusively from the plasma during its passage through the dialyzer. The most practical way to increase phosphorus removal is to extend dialysis time, although attention to dialysis efficiency (surface area, advanced membrane, and higher blood and dialysate flow rates) also plays a role. Benefits of hemodiafiltration in helping control serum phosphorus have been claimed, but not found in all studies. Because serum phosphorus levels tend to plateau during the later parts of a dialysis session, extending weekly dialysis time is of greater benefit for phosphorus removal than for urea removal. Increasing dialysis frequency also probably has a small benefit. It appears that 18–30 hours of dialysis per week are required to obviate the need for phosphorus binders. Several promising models of phosphorus kinetics are under development. These may help predict the change in treatment on serum phosphorus levels, but their ability to do so has not yet been critically assessed.     

Phosphorus management in end-stage renal disease

Chronic kidney disease is an important public health problem, with an increasing number of patients worldwide. One important outcome of renal failure is disordered mineral metabolism, most notably involving calcium and phosphorus balance. Of importance is that increased serum phosphorus levels are associated with increased mortality rates. Despite dietary restrictions, patients receiving dialysis invariably experience hyperphosphatemia and require treatment with phosphate binders. Existing phosphate binders are effective in reducing serum phosphorus levels, but are associated with a number of important disadvantages. Lanthanum carbonate, a new noncalcium, nonaluminum phosphate binder, represents a promising treatment for hyperphosphatemia.     

Dietary Phosphorus Acutely Impairs Endothelial Function

Excessive dietary phosphorus may increase cardiovascular risk in healthy individuals as well as in patients with chronic kidney disease, but the mechanisms underlying this risk are not completely understood. To determine whether postprandial hyperphosphatemia may promote endothelial dysfunction, we investigated the acute effect of phosphorus loading on endothelial function in vitro and in vivo. Exposing bovine aortic endothelial cells to a phosphorus load increased production of reactive oxygen species, which depended on phosphorus influx via sodium-dependent phosphate transporters, and decreased nitric oxide production via inhibitory phosphorylation of endothelial nitric oxide synthase. Phosphorus loading inhibited endothelium-dependent vasodilation of rat aortic rings. In 11 healthy men, we alternately served meals containing 400 mg or 1200 mg of phosphorus in a double-blind crossover study and measured flow-mediated dilation of the brachial artery before and 2 h after the meals. The high dietary phosphorus load increased serum phosphorus at 2 h and significantly decreased flow-mediated dilation. Flow-mediated dilation correlated inversely with serum phosphorus. Taken together, these findings suggest that endothelial dysfunction mediated by acute postprandial hyperphosphatemia may contribute to the relationship between serum phosphorus level and the risk for cardiovascular morbidity and mortality.Cardiovascular disease (CVD) is the most important factor contributing to life expectancy in chronic kidney disease (CKD).^1,2 Hyperphosphatemia has been recently recognized as an important factor in development of medial calcification by induction of differentiation of vascular smooth muscle cells to osteoblast-like cells.^3–6 On the other hand, endothelial dysfunction is the principal cause of atherosclerosis resulting in CVD.⁷ However, the effect of hyperphosphatemia on endothelial cell function, and its influence on the development of CVD is still unclear.Two recent papers reported that higher serum phosphorus (P) concentration, albeit within the normal range, was associated with development of atherosclerosis and mortality in the patients with normal kidney function⁸ and in the Framingham Offspring study participants.⁹ These studies suggested that long-term excessive P loading, even if it does not cause hyperphosphatemia, can be a risk factor for CVD. In addition, Onufrak et al. also demonstrated that serum phosphorus level was associated with carotid intima media thickness in the general population.¹⁰ Interestingly, continuous hyperphosphatemia in both klotho mutant mice and fibroblast growth factor 23 (FGF23)-deficient mice may also be a risk factor of a premature aging-like phenotype.^11–13 This may be inferred because P restriction diet partially ameliorated the phenotype in both klotho and FGF23 deficient mice.^14,15 In addition, hyperphosphatemia involved by chronic renal failure frequently causes hyperparathyroidism that affects the homeostasis of calcium and phosphate in plasma. Increased parathyroid hormone (PTH) has also been recognized as a risk factor of CVD.¹⁶ These factors complicate to understand the linking mechanism between serum P and CVD. Thus, a possible mechanism linking serum P and CVD risk should be clarified to gain insight into the potential impact of P on CVD and aging-related diseases. Here, we focused on the direct effect of P on endothelial function.In this study, we reported that dietary P loading in human caused postprandial elevation of serum P and impaired endothelium-dependent vasodilation and also demonstrated that the impairment of vasodilation was mainly due to decreased NO production in endothelial cells, suggesting that postprandial elevation of serum P level deteriorates endothelial function.     

Phosphorus control in peritoneal dialysis patients

Hyperphosphatemia is independently associated with an increased risk of death among dialysis patients. In this study, we have assessed the status of phosphate control and its clinical and laboratory associations in a large international group of patients on chronic peritoneal dialysis (PD) treatment. This cross-sectional multicenter study was carried out in 24 centers in three different countries (Canada, Greece, and Turkey) among 530 PD patients (235 women, 295 men) with a mean+/-s.d. age of 55+/-16 years and mean duration of PD of 33+/-25 months. Serum calcium (Ca(2+)), ionized Ca(2+), phosphate, intact parathyroid hormone (iPTH), 25-hydroxy vitamin D(3), 1,25-dihydroxy vitamin D(3), total alkaline phosphatase, and bone alkaline phosphatase concentrations were investigated, along with adequacy parameters such as Kt/V, weekly creatinine clearance, and daily urine output. Mean Kt/V was 2.3+/-0.65, weekly creatinine clearance 78.5+/-76.6 l, and daily urine output 550+/-603 ml day(-1). Fifty-five percent of patients had a urine volume of <400 ml day(-1). Mean serum phosphorus level was 4.9+/-1.3 mg per 100 ml, serum Ca(2+) 9.4+/-1.07 mg per 100 ml, iPTH 267+/-356 pg ml(-1), ionized Ca(2+) 1.08+/-0.32 mg per 100 ml, calcium phosphorus (Ca x P) product 39+/-19 mg(2)dl(-2), 25(OH)D(3) 8.3+/-9.3 ng ml(-1), 1,25(OH)(2)D(3) 9.7+/-6.7 pg ml(-1), total alkaline phosphatase 170+/-178 U l(-1), and bone alkaline phosphatase 71+/-108 U l(-1). While 14% of patients were hypophosphatemic, with a serum phosphorus level lower than 3.5 mg per 100 ml, most patients (307 patients, 58%) had a serum phosphate level between 3.5 and 5.5 mg per 100 ml. Serum phosphorus level was 5.5 mg per 100 ml or greater in 28% (149) of patients. Serum Ca(2+) level was > or =9.5 mg per 100 ml in 250 patients (49%), between 8.5 and 9.5 mg per 100 ml in 214 patients (40%), and lower than 8.5 mg per 100 ml in 66 patients (12%). Ca x P product was >55 mg(2)dl(-2) in 136 patients (26%) and lower than 55 mg(2)dl(-2) in 394 patients (74%). Serum phosphorus levels were positively correlated with serum albumin (P<0.027) and iPTH (P=0.001), and negatively correlated with age (P<0.033). Serum phosphorus was also statistically different (P = 0.013) in the older age group (>65 years) compared to younger patients; mean levels were 5.1+/-1.4 and 4.5+/-1.1 mg per 100 ml, respectively, in the two groups. In our study, among 530 PD patients, accepted uremic-normal limits of serum phosphorus control was achieved in 58%, Ca x P in 73%, serum Ca(2+) in 53%, and iPTH levels in 24% of subjects. Our results show that chronic PD, when combined with dietary measures and use of phosphate binders, is associated with satisfactory serum phosphorus control in the majority of patients.     

Phosphorus Binders and Survival on Hemodialysis

Although hyperphosphatemia is a risk factor for mortality, there are limited data on whether therapy with phosphorus binders affects survival. We analyzed a prospective cohort study of 10,044 incident hemodialysis patients using Cox proportional hazards analyses to compare 1-yr all-cause mortality among patients who were or were not treated with phosphorus binders. We performed intention-to-treat analyses to compare patients who began treatment with phosphorus binders during the first 90 d after initiating hemodialysis (n = 3555) with those who remained untreated during that period (n = 5055). We also performed as-treated analyses that modeled phosphorus binder treatment as a time-dependent exposure. We compared survival in a subcohort of treated (n = 3186) and untreated (n = 3186) patients matched by their baseline serum phosphate levels and propensity score of receiving phosphorus binders during the first 90 d. One-year mortality was 191 deaths/1000 patient-years at risk. Treatment with phosphorus binders was independently associated with decreased mortality compared with no treatment in the intention-to-treat, as-treated, and matched analyses. The results were independent of baseline and follow-up serum phosphate levels and persisted in analyses that excluded deaths during the first 90 d of hemodialysis. In summary, treatment with phosphorus binders is independently associated with improved survival among incident hemodialysis patients. Although confirmatory studies are needed in the dialysis setting, future placebo-controlled, randomized trials of phosphorus binders might focus on predialysis patients with chronic kidney disease and normal serum phosphate levels.Hyperphosphatemia is among the most common metabolic complications of ESRD.^1,2 Large observational studies have identified hyperphosphatemia as an independent risk factor for cardiovascular disease and mortality on dialysis,^1–5 and subsequent studies found that subtle increases in serum phosphate levels within the normal range are also associated with increased risk for death in predialysis and even non–kidney disease populations.^6–8 On the basis of these results, current national practice guidelines advocate more aggressive treatment of hyperphosphatemia to lower serum phosphate targets than in the past.⁹ Restricting dietary phosphorus intake is recommended, but because it is difficult to maintain and can exacerbate protein malnutrition, administration of dietary phosphorus binders to block intestinal phosphorus absorption is the cornerstone of therapy for hyperphosphatemia. Indeed, the majority of dialysis patients are eventually prescribed phosphorus binders with an estimated annual cost that is expected to exceed $1 billion worldwide.¹⁰The evidence linking hyperphosphatemia with adverse outcomes suggests that lowering serum phosphate levels in individual dialysis patients will improve their clinical outcomes, but no interventional or even observational studies have examined the impact of serum phosphate reduction on survival. Furthermore, all of the phosphorus binders used in clinical practice were approved by the Food and Drug Administration on the basis of their efficacy in lowering serum phosphate levels in short-term studies of dialysis patients.^11–14 No placebo-controlled studies have examined the impact of treatment with phosphorus binders on hard clinical end points, including survival. Indeed, although several studies aimed to determine which specific phosphorus binder is best for dialysis patients,^15,16 there are no data on whether any phosphorus binder treatment versus none alters clinical outcomes. We analyzed a prospective cohort study of incident hemodialysis patients to test the hypothesis that therapy with any phosphorus binder versus none is associated with a survival benefit.     

Phosphorus administration in patients with profound hypophosphatemia

The influence of severe hypophosphatemia (less than or equal to 1.0 mg/dl) on vitamin D metabolism was prospectively determined in 11 patients before and after intravenous phosphorus administration. Evidence of liver dysfunction was present in ten patients. The mean (+/- SE) plasma 25 hydroxycholecalciferol [25(OH)D] was significantly decreased before phosphorus therapy when compared to control subjects (9.4 +/- 1.3 vs. 17.8 +/- 1.3 ng/ml, P less than 0.001). With phosphorus administration, serum phosphorus increased from 0.59 +/- 0.07 to 2.58 +/- 0.09 mg/dl while 1,25 dihydroxycholecalciferol [1,25(OH)2D] decreased from 34.6 +/- 4.3 to 14.3 +/- 2.9 pg/ml (P less than 0.001). Plasma 25(OH)D, plasma immunoreactive PTH (both amino and carboxyterminal) and serum calcium did not change after phosphorus administration, suggesting that phosphorus alone was responsible for the change in plasma 1,25(OH)2D concentration. An inverse correlation was found between serum phosphorus and plasma 1,25(OH)2D (r = -0.62, P less than 0.005). In addition, a direct correlation was observed between plasma 25(OH)D and 1,25(OH)2D both before (r = 0.66, P less than 0.005) and after (r = 0.74, P less than 0.005) phosphorus administration. Thus, the decrease in 1,25(OH)2D levels with phosphorus therapy suggests a role of serum phosphate in the regulation of this sterol, and hypophosphatemia or phosphorus depletion may change the relationship of substrate [25(OH)D] to product [1,25(OH)2D].     

The Effect of Dietary Calcium and Phosphorus Supplementation in Zeolite A Treated Dry Cows on Periparturient Calcium and Phosphorus Homeostasis

Previous studies have proved the possibility of preventing parturient hypocalcaemia by zeolite A supplementation during the dry period, and a recent in vitro study has indicated a marked calcium (Ca) as well as phosphorus (P) binding effect of zeolite A in rumen fluid solutions. Because of the connection between the Ca and P homeostatic systems, the preventive effect against parturient hypocalcaemia may arise from zeolite induced decreased availability of dietary Ca as well as P. In the present study, the expected Ca and P binding capacity was challenged by feeding high and low levels of dietary Ca and/or P to zeolite A treated dry cows. Twenty‐one pregnant dry cows were assigned to four experimental groups receiving a dry cow ration unsupplemented or supplemented with extra Ca and/or P. During the last 2 weeks of the dry period all cows additionally received 600 g of zeolite A per day. A high level of dietary P prepartum significantly decreased the plasma Ca concentration before as well as immediately after calving (day 0–3). Conversely, the plasma inorganic phosphate concentration was higher among these cows than among cows receiving no supplemental P. The prepartum dietary Ca level significantly affected the serum 1,25‐dihydroxyvitamin D concentration during zeolite supplementation, whereas the periparturient plasma Ca concentration was apparently not affected by the dietary Ca level. During zeolite A supplementation plasma parathyroid hormone was significantly higher among cows receiving additional P. The urinary deoxypyridinoline/creatinine ratio was not affected by the prepartal dietary Ca or P level. Serum aluminium (Al) was significantly higher during zeolite A supplementation than during the preceding period, indicating partial destruction of the zeolite in the intestinal tract with subsequent release and absorption of Al. It is suggested that the effect of prepartum zeolite supplementation on the periparturient Ca homeostasis depends on the level of Ca as well as P in the dry cow ration.     

Phosphorus reduces renal receptivity for parathyroid hormone in rats

Changes in kidney calcium concentration and secreted parathyroid hormone were studied in weanling male rats (n = 12) fed diets containing either 0.5% (n = 6) or 1.5% (n = 6) total phosphorus. Calcium and phosphorus concentrations in the kidney of rats fed a high-phosphorus diet were markedly greater than those in rats fed a control diet. In addition, urinary excretion of phosphorus increased gradually after administration of a high-phosphorus diet, but there was no similar tendency of phosphorus/creatinine excretion, which decreased gradually from the starting day of feeding to the end of the feeding period. The high-phosphorus diet also produced greater serum parathyroid hormone (PTH) without urinary cyclic adenosine monophosphate (cAMP) excretion stimulated by PTH. The mean values of serum 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃) concentrations were significantly increased 1 h after injection of 2.77 g rat PTH(1–34) in all rats. However, in rats fed a high-phosphorus diet, the rise of serum 1,25(OH)₂D stimulated by exogenous PTH was lower than that in rats fed a control diet.     

Phosphorus balance and mineral metabolism with 3 h daily hemodialysis

Poor control of mineral metabolism is independently associated with mortality in patients receiving hemodialysis. We analyzed data from a 12-month, prospective, non-randomized, controlled study of daily hemodialysis (DHD) (six sessions/week 3 h each) (n=26) vs conventional hemodialysis (CHD) (three sessions/week 4 h each) (n=51) for achievement of mineral metabolism goals and we performed a substudy of weekly dialytic phosphorus removal in DHD vs CHD. Phosphorus control was superior in the DHD group (% change from baseline to end-of-study -27+/-30% vs +7%+/-35% in the CHD group, P=0.0001). Percentage of patients using phosphate binders decreased from 77 to 40% among subjects on DHD, whereas these parameters did not change (76 vs 77%) in the CHD group (P=0.03 by Breslow-Day test for homogeneity of the odds ratios). Weekly mean phosphorus removal was higher in the DHD group (2452+/-720 mg/week vs 1572+/-366 mg/week, P=0.04). Mean normalized protein catabolic rate increased (0.90+/-0.43-1.22+/-0.26 g/kg/day, P=0.0013). DHD was also associated with an increase in the percent of subjects achieving three or more mineral metabolism goals (for phosphorus, calcium x phosphorus and parathyroid hormone) (15 vs 46%, P=0.046). In conclusion, DHD improves phosphorus control by increasing dialytic phosphorus removal while maintaining nutritional status and reducing the use of phosphate binders. The net effect allows for improved achievement of mineral metabolism goals.