PANEL DE DISCUSION |
Abstract
Secondary hyperparathyroidism and renal osteodystrophy are the consequences of abnormal calcium, phosphate and calcitriol metabolism ensuing from renal failure. Evidence suggests that calcium balance tends to become negative as we grow older than 35 years of age; however, the current dialysis modalities provide patients regardless of the age with excessive calcium during dialysis. Administration of calcitriol in the management of hyperparathyroidism further increases the calcium and phosphate absorption.
Furthermore, the current thrice weekly renal replacement therapies fail to remove the daily absorbed phosphate, and we have to use calcium carbonate as a primary phosphate binding agent to reduce intestinal phosphate absorption. The large calcium mass transfer and phosphate retention could lead to soft tissue calcification especially in older ESRD patients. Consequently, only by maintaining a negative calcium balance during renal replacement therapy can we safely use calcitriol and calcium carbonate for the management of secondary hyperparathyroidism. Recent studies have indicated that phosphate restriction alone independent of plasma calcitriol or calcium can lower plasma PTH in renal failure and prevent hyperplasia of parathyroid glands. Therefore, phosphate control perhaps is the most important means to prevent secondary hyperparathyroidism. Recent studies have demonstrated that ferric compounds are potent phosphate binding agents; ferric citrate has been used in ESRD patients and proven to be effective agent to reduce serum phosphate concentration in ESRD patients.
Index words: Calcium, Phosphate, Renal Failure, Secondary hyperparathyroidism, Renal osteodystrophy
Introduction
In order to manage calcium and phosphate metabolism in renal failure, we have to understand optimal intakes of calcium and threshold balances of calcium in patients with renal failure. Threshold balance of calcium varies with age (1).
For example net calcium balance for normal subjects is estimated to be +396 mg/day between 9 to 17 years and +114 mg/day for 18 to 30 years. As we grow older than 35 years of age, calcium balance tends to become negative (2). In normal subjects, adaptation of intestinal absorption (3) as well as renal excretion of calcium to excessive calcium ingestion confers protection against calcium overload. However, renal protection against calcium overload disappears as renal function deteriorates. For the last thirty years we have managed secondary hyperparathyroidism and renal osteodystrophy by increasing patients' exogenous calcium intake and dialysate calcium concentrations. More recently, we have included oral and intravenous pulses of calcitriol in the treatment of secondary hyperparathyroidism and renal osteodystrophy. Therapeutic pulses of calcitriol would further increase intestinal uptake of calcium and phosphate. Without taking into consideration of the threshold calcium balance for each individual patient, the current approach results in calcium overload and metastatic calcification frequently observed in elderly patients on hemodialysis (4). In this article, I will review calcium and phosphate balance in renal failure. Further, I will discuss the metabolic complications resulting from managing secondary hyperparathyroidism and renal osteodystrophy in chronic renal failure.
I. Calcium metabolism in normal subjects
Regulation of calcium absorption
If one ingests 1,000 mg of dietary calcium per day, approximately 800 mg of calcium is recovered in the feces (5). The intestine absorbs approximately 330 mg of ingested calcium and reabsorbs 70 mg of calcium secreted by the intestine (intestinal secretion is approximately 200 mg and 130 mg of the secreted is lost in the feces) (6). Balance study has shown that a low calcium diet increases and a high calcium diet decreases fractional calcium absorption. This regulation of calcium absorption primarily occurs in the ileum (3). Jejunal absorption is also decreased, although the adaptation is less complete. Consequently, the ileum is the primary site in regulating dietary calcium absorption and plays an important role in protecting the body against calcium deficiency when dietary ingestion of calcium is low and against calcium excess when dietary calcium is high (3). This important calcium homeostasis is altered in chronic renal failure, as the metabolism of both calcitriol and PTH is deranged in this state.
Calcium balance of normal adults consuming self-selected diets is slightly negative in female subjects age 20 to 53 years and male subjects age over 35 years, whereas it is slightly positive in male subjects age less than 35 years (2,7). In young adults age 19 to 25, calcium balance also depends on dietary protein and phosphorus intake. High protein diet tends to result in negative calcium balance (8). Hence, calcium balance on a self-selected diet is either in slightly positive, equilibrium, or negative balance in normal adults depending on age and sex. It should be noted that balance studies are inherently imprecise.
Therefore, Matkovic and Heaney collected 519 calcium balance studies in individual subjects from 34 published reports and calculated calcium intake thresholds. The intake threshold is defined as the level of dietary calcium below which calcium accumulation increases as a function of intake. At calcium intake above the threshold calcium accumulation remains constant despite further increases in intake (1). The calcium intake threshold determines an optimal calcium intake for normal subjects. The intake threshold was estimated at 1480 mg/day for 9 to 17 year-old subjects and 957 mg/day for 18 to 30 year old subjects. Threshold balance of calcium is the maximal calcium balance achieved when intake reaches the calcium intake threshold. The threshold balance was estimated to be +396 +164 (SD) mg/day and +114 + 133 (SD) mg/day for 9-17 and 18-30 year-old subjects, respectively. Hence further increases in calcium intake would not be expected to retain in the body or deposit into the bones, as the growth of the bone and mineral deposit are probably genetically determined (9). Intake threshold and balance threshold are not available in subjects older than 30; however, they are likely to be lower and the calcium balance threshold eventually becomes zero and negative with aging (2).
Effect of calcitriol on intestinal calcium absorption
While calcitriol increases the active absorption of calcium and phosphate in all segments of the small intestine, it only changes absorptive fluxes, but not secretory fluxes, of calcium and phosphate (10). Calcitriol stimulates active calcium and phosphate absorption greatest in the duodenum and the jejunum, respectively. The ratios of phosphate absorptive fluxes to calcium absorptive fluxes remain constant in duodenum, jejunum and ileum despite several fold increases in absorption induced by calcitriol, suggesting coupled calcium-phosphate transport or coordinate stimulation of calcium and phosphate absorptive processes by calcitriol (10).
Calcitriol stimulates intestinal calcium absorption through genomic and non-genomic actions. The genomic action of calcitriol is a receptor-mediated process. Calcitriol stimulates the synthesis of calbindin proteins which enhance calcium transport at the basolateral sites by activating Ca-ATPase activity (11). Non-genomic stimulation of intestinal calcium absorption (transcaltachia) was proposed by Nemere et al. (12). Calcium is incorporated into endocytic vesicles at the luminal sites by endocytosis, and these vesicles are transferred through microtubules to be extruded at the basolateral membrane by exocytosis. This non-genomic stimulation of duodenal calcium transport occurs within few minutes (13) as compared with hours for genomic stimulation which is dependent on protein synthesis (14).
II. Calcium metabolism in chronic renal failure
Calcium absorption in renal failure
Intestinal calcium absorption appears to be decreased in renal failure (15). Fractional absorption of calcium is inversely related with plasma concentration of blood urea nitrogen (15) . In patients with advanced chronic renal failure (serum creatinine > 2.5 mg/dl) eating an average of 300 mg Ca/day, fractional absorption of calcium is 17% compared to 25% in normal subjects with an average dietary calcium intake of 795 mg/day (16). Patients with chronic renal failure tend to ingest less calcium in their diets than normal subjects.
Accordingly, net calcium absorption is reduced in chronic renal failure as a consequence of both decreased fractional absorption and intake of calcium. In fact, investigators from one institution found that when dietary calcium intake is less than 20 mg/kg, patients with chronic renal failure have negative net intestinal calcium absorptions. However, they are able to achieve positive net intestinal absorptions of calcium comparable to those of normal subjects when calcium intake is greater than 40 mg/kg (17,18). On the other hand, most studies report that patients with chronic renal failure have a positive net calcium absorption at lower dietary intakes of calcium (5,19-22). The fractional calcium absorption of dialysis patients was approximately 19% on an average 500 mg calcium diet (16).
Urinary calcium excretion in renal failure
The kidney is the primary site for calcium excretion, although intestinal secretion of calcium could also account for small loss of calcium in the feces (6). Urinary calcium excretion is decreased starting from the early stages of renal failure and falls in proportion to the decrease in glomerular filtration rate (23,24) (Figure 1). The potential reasons for decreased calcium excretion include decreased filter loads, increased PTH or decreased intestinal absorptions. However, balance studies indicate that despite ingesting high calcium diets in patients with chronic renal failure, urinary excretion of calcium remains very low even when intestinal absorption is increased (19,20). Thus, decreased calcium excretion is due to decreased GFR and not to decreased intestinal absorption.
Calcium balance studies in patients with renal failure
Despite decreased calcium intake and intestinal absorption, calcium balance studies indicate that patients with chronic renal failure have only slightly negative balances (19,20). This is presumably due to decreased renal excretion and the resultant whole-body calcium retention in patients with renal failure (22). Hence, patients with renal failure can maintain a positive calcium balance, if they are provided with a normal or high calcium diet (25,26). Most patients with end stage renal disease (ESRD) have positive calcium balances as they have no route of calcium excretion. For example (Table 1), excluding dietary calcium absorption in ESRD patients, one can expect positive calcium fluxes of average +896 mg/4 hours (+384 mg/day) and +150 mg/4 hours (+64 mg/day) thrice weekly hemodialysis, respectively, when using 3.5 mEq/l and 2.5 mEq/l calcium dialysate (27).
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Dietary intake of Ca ~ 800 mg/day** Fractional absorption ~ 152 mg/day (19%)*** Total Ca balance ~ +536 mg/day
Dietary intake of Ca ~ 800 mg/day** Fractional absorption ~ 152 mg/day (19%)*** Total Ca balance ~ +216 mg/day
Dietary intake of Ca ~ 800 mg/day** Fractional absorption ~ 152 mg/day (19%)*** Total Ca balance ~ +52 mg/day ** Estimated daily dietary intake *** Fractional Ca absorption estimated from ref. (16). |
Similarly, peritoneal dialysate with 3.5 mEq/l and 1.5% dextrose provides positive calcium fluxes of an average 14 mg/exchange or approximately 56 mg/day in normocalcemic patients (28,29) (Table 2).
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Dietary intake of Ca ~ 800 mg/day** Fractional absorption ~ 152 mg/day (19%)*** Total calcium balance ~ +208 mg/day
Dietary intake of Ca ~ 800 mg/day** Fractional absorption ~ 152 mg/day (19%)*** Total Ca balance ~ +80 mg/day
Dietary intake of Ca ~ 800 mg/day** Fractional absorption ~ 152 mg/day (19%)*** Total Ca balance ~ +32 mg/day ** Estimated daily dietary intake *** Fractional Ca absorption estimated from ref. (16). ****Assuming four exchange/day and Ca flux estimated from ref. (28) |
In a metabolic balance study of CAPD patients using 3.5 mEq/l Ca, and 4.25% and 1.5% dextrose dialysate, the average net calcium balance was +112 (1 gm/kg protein diet) to +198 g (1.4 g/kg protein diet) per day (30). Assuming the ESRD patients consume an 800 mg/day of dietary calcium and an estimated fractional calcium absorption of 19% (16), the calculated daily calcium balances for the adult ESRD patients would exceed the average normal calcium threshold balance of 114 mg/day for age 18 to 30 estimated by Matkovic and Heaney (1). Addition of calcium carbonate as a phosphate binding agent or calcitriol for the treatment of renal osteodystrophy would further increase calcium absorption and retention (31). Therefore, the current treatment regimens provide excessive calcium to the ESRD patients who have no route to dispose the surplus of this mineral.
III. Phosphate metabolism in chronic renal failure
In normal adults, age 20 to 53 years, the daily phosphate balance is slightly negative or in equilibrium (2). Similar to calcium excretion, the kidney is the primary route for phosphate excretion. Plasma concentration of phosphate usually remains within normal ranges until glomerular filtration rate is below approximately 20 ml/min. The normal plasma phosphate in the presence of renal failure is due to increased phosphate excretion ensuing from elevation of plasma PTH. However, the plasma phosphate levels may not accurately reflect total body phosphate contents (32).
Although net phosphorus absorption is not different between chronic dialysis patients and normal subjects, intestinal absorption of phosphorus is increased in dialysis patients if they receive calcitriol treatment (dietary phosphate absorption increased from 60% to 86%) (31). During hemodialysis, phosphate efflux is approximately 1057 mg/dialysis or 3171 mg/week (27). The removal of phosphate through hemodialysis is therefore inadequate to eliminate the daily dietary absorption of phosphate (4,200 mg/week, assuming dietary intake of 1000 mg/day and fractional absorption of phosphate is 60% (31)) (Table 3).
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Phosphate balance in hemodialysis Negative P flux ~ -1057 mg/4h dialysis or -3171 mg/wk (-453 mg/day)* Dietary intake ~ 1000 mg/day** Fractional P absorption ~ 60% or 600 mg/day *** Total P balance +147 mg/day
** Estimated daily dietary intake *** Fractional P absorption estimated from ref. (31). |
In a balance study conducted in CAPD patients receiving four exchanges per day, phosphate balance remained positive even though these patients were taking 7.8+1.0 g aluminum hydroxide (30). Average net balance was +227+77 mg/day on 1000 mg P diet and +708+152 mg/day on 1,900 mg P diet. Therefore, the present management of phosphate in ESRD will invariably lead to an excessive phosphate retention in patients receiving long-term renal replacement treatments. Because dietary restriction of phosphate is difficult to accomplish, phosphate binding agents, such as aluminum containing agents or calcium carbonate are used to control plasma phosphate levels. Concerns about aluminum toxicity in renal failure have prompted increased use of calcium carbonate. It should be noted that patients with chronic renal failure are capable of absorbing calcium carbonate (25). Therefore, addition of calcium carbonate to the treatment may further aggravate calcium overloads in dialysis patients using high calcium dialysate (greater than 3.2 mEq/l) (33).
Phosphate restriction plays an important role in slowing down deterioration of renal function as well as soft tissue calcification in renal failure (34). A high intake of dietary phosphorus in experimental renal failure worsens renal function (35,36) and a low phosphate intake arrests progression of chronic renal failure (37). Although the mechanism of renal toxicity of phosphorus is not entirely clear, increased calcium-phosphate deposits in the kidney probably contribute to the interstitial fibrosis and deterioration of renal function (35). 3-phosphocitric acid, a compound of an inhibitor of calcium-phosphate precipitation, can prevent phosphate-induced progression of renal failure and reduce renal calcium content in renal failure rats fed with a high phosphate diet (38).
Previous studies have indicated that restricting phosphate intake alone can prevent secondary hyperparathyroidism (39). Recent studies have further corroborated this finding. Thus, phosphate restriction either increases plasma calcitriol and suppresses secondary hyperparathyroidism (40) or directly inhibits parathyroid cell proliferation (41,42). In vitro studies indicate that high phosphorus media stimulate PTH secretions in human (43) and rat parathyroid cells (44,45). Taken together, maintaining a normal plasma concentration and tissue content of phosphate perhaps is the most important means to prevent secondary hyperparathyroidism, renal osteodystrophy and soft tissue calcification in renal failure.
IV. Soft tissue calcification in renal failure: consequence of calcium and phosphate overload
Soft tissue calcification in renal failure has been recognized since 1901 (46). The exact incidence of soft tissue calcification in patients with renal failure is unknown since the detection of visceral calcification is difficult during the patient's life. Soft tissue calcification was studied in an autopsy study of 56 patients who died while they were on chronic hemodialysis at least six months, using a dialysate calcium concentration of 3.0 to 3.8 mEq per liter, similar to the concentrations utilized in most dialysis centers. Soft tissue calcification involving more than one internal viscus was found in 79% of the patients. The distribution of visceral calcification was 59% heart, 75% lung, 60% stomach, and 92% kidneys (4). Soft tissue calcification involving more than one internal viscus was found in 44% of non-dialyzed chronic renal failure patients. The distribution was 44% heart, 44% lung, 29% stomach, and 14% kidneys (4). Recent studies have indicated that myocardial (47,48) and pulmonary calcium (47) contents were significantly higher in patients on dialysis treatment. In a study of 23 hemodialysis patients, Faubert et al. (49) found 61% to have increased uptake in the lungs using 99mTc-diphosphonate. Radionuclide scanning is more sensitive in the detection of metastatic calcification. Myocardial and valvular calcification (50-54) are frequently associated with myocardial dysfunction, heart failure (47), and heart block (55), while pulmonary calcification is associated with cough, dyspnea, restrictive defects, decreased diffusion and hypoxia (49,56,57). Thus, soft tissue calcification is common in patients with chronic renal failure and in patients on renal replacement therapy. Although, there are a myriad of factors that contribute to metastatic calcification, including high PTH, calcitriol treatment, local tissue pH, high calcium-phosphate product, and magnesium deficiency (58,59), calcium and phosphate overload are perhaps the major factors leading to soft tissue calcification in renal failure.
V. Proposed management of calcium and phosphorus metabolism in patients with ESRD
Management of calcium
Since threshold calcium balance varies with age (1), using one concentration of calcium dialysate is not an appropriate treatment modality for all ESRD patients. The present utilization of 2.5 and 3.5 mEq/l Ca of hemodialysis dialysate or 3.5 mEq/l Ca of CAPD dialysate provide adequate calcium for patients under 20 years of age. These concentrations, however, provide excessive calcium load to ESRD patients age over 35 (27,28) (tables 1 and 2).
As stated previously, normal subjects eventually achieve zero or even negative calcium balance when they are over 35 years of age (2). Consequently, the excessive calcium retention would not necessarily accumulate in the bones of old ESRD patients (1). Although using low calcium dialysate concentrations of 1.5 mEq/l for hemodialysis (27) and 2.5 mEq/l for CAPD patients (28,29) can remove calcium from the patients during dialysis, this treatment regimens still cannot achieve a negative or zero calcium balance in older (greater than 35 years) ESRD patients (tables 1 and 2). Further studies are needed to fine tune the level of dialysate calcium concentration that can safely achieve a negative or zero calcium balance. It should be cautioned that low ionized calcium dialysate (e.g., less than 2.08 mEq/l) might precipitate hypotension and decrease myocardial contractility (60-62) and recent studies also suggest that low calcium dialysate (2.5 mEq/l) may aggravate secondary hyperparathyroidism (63,64).
Alternatively, each ESRD patient should have a Ca balance study every two weeks. These results would provide an adequate information of Ca removal during the following weeks of renal replacement therapy. Adequate phosphate control may be necessary before one can reduce dialysate calcium concentration. Alternatively, we can achieve negative calcium fluxes by ultrafiltration during dialysis using dialysates with concentrations of calcium identical to that of plasma ionized calcium. Assuming diffusible plasma calcium concentration of 5 mg/dl, 4 liters of ultrafiltration per dialysis will remove approximately 200 mg of calcium. Furthermore, since citrate has been shown to prevent metastatic calcificatiion (), one can consider using citrate dialysate solution instead of lactate as bicarbonate replacement. Citrate could be converted to bicarbonate as well. However, blood cloting and bleeding tendency may occur if plasma citrate concentration is increased to a toxic level. Management of phosphate
Dietary restriction of phosphate is difficult to achieve and thrice weekly dialysis alone can not remove daily absorbed phosphate (27). Consequently, phosphate binding agents (e.g., calcium carbonate or other calcium preparations) have generally been employed to control phosphate metabolism in renal failure. However, using these agents is not only inadequate to remove all the ingested dietary phosphate but also provides excessive calcium to the ESRD patients (31). Hence, only by maintaining a negative calcium balance during renal replacement therapy can we safely use calcium carbonate as a phosphate binding agent. In 1943, Liu and Chu (19) successfully used ferric ammonium citrate for several months to lower the plasma phosphate in two patients with chronic renal failure. The side effect of the ferric compound was occasional diarrhea. Animal experiments demonstrated that both aluminum and ferric salts drastically reduced bone ash, plasma phosphate, urinary phosphate excretion and bone phosphorus in guinea pigs and rabbits (65). Growing rats fed with ferric salts had growth retardation, hypophosphatemia, considerable loss of bone ash, and total body content of calcium and phosphorus. The rats developed rickets within one month (66,67). Ferric salts also produced severe rickets and hypophosphatemia in chicks in three weeks (68). Apparently the ferric salts precipitate phosphate in the intestine and limit its absorption. It is estimated that 9.14 gm of Fe combine chemically as ferric phosphate with 5.06 gm of phosphorus (66). Ferric compounds, therefore, warrant further trial in the management of phosphate metabolism in renal failure. Recent studies have proved that ferric citrate is capable of reducing phosphate retention in animal (69) and human studies (70) . It should be noted, however, that 7 g of aluminum hydroxide was unable to achieve a zero or negative phosphate balance in CAPD patients ingesting approximately 1,000 mg of dietary phosphate (30). Thus, increasing the frequency of dialysis, not the duration of dialysis hours (71,72)) is the alternative solution to achieve a negative or zero phosphate balance in ESRD patients.
VI. Treatment of secondary hyperparathyroidism and hyperparathyroid bone disease by calcitriol.
The plasma concentration of calcitriol is tightly regulated within a narrow range in normal subjects (73). Several studies suggest that the plasma calcitriol concentration is perceptibly decreased in the early phases of renal failure (74,75). The reasons for decreased calcitriol synthesis in renal failure are primarily due to loss of renal tissue (76), phosphate retention (40,77) and suppression of 1a-hydroxylase by uremic toxins (78). Decreased calcitriol synthesis underlies various pathophysiological abnormalities; however, this is an important adaptation and crucial to the survival of patients with renal failure because otherwise, the decreased calcium excretion and the normal levels of calcitriol production and normal absorption of intestinal calcium could lead to excessive calcium retention and soft tissue calcification. Thus, chronic replacement of calcitriol in patients with chronic renal failure may culminate in calcium overload and phosphate retention, even though it effectively suppresses PTH and prevents hyperparathyroid bone disease (79). Furthermore, even using lower concentrations of dialysate calcium to achieve negative calcium fluxes, oral or intravenous calcitriol can be safely administered only if dietary calcium and phosphorus ingestion are strictly controlled. Otherwise long-term administration of calcitriol would invariably lead to calcium and phosphate overload.
In summary, calcium intake threshold and balance threshold are likely to decline, and calcium balance threshold perhaps becomes zero or negative in normal adults with aging (2). Hence, using one concentration of dialysate calcium for various age groups of patients is not appropriate. The current regimens of dialysis treatment result in excessive calcium fluxes to patients older than 35 years. Further, thrice weekly dialysis is inadequate to remove the dietary ingestion of phosphate. Thus, calcium and phosphate retention in ESRD patients could lead to soft tissues calcification and not necessarily deposit into the bones. In view of recent studies which have indicated that restricting phosphate intake alone can prevent secondary hyperparathyroidism (41,43,80), it can be safely concluded that maintaining a normal plasma phosphate and tissue content of phosphate is the most important treatment to prevent secondary hyperparathyroidism and hyperparathyroid bone disease in renal failure.
References
1. Matkovic V, Heaney RP. Calcium balance during human growth: evidence for threshold behavior. Am J Clin Nutr 55:992-6, 1992.
2. Lakshmanan FL, Rao RB, Church JP. Calcium and phosphorus intakes, balances, and blood levels of adults consuming self-selected diets. Am J Clin Nutr :1368-79, 1984.
3. Norman DA, Fordtran JS, Brinkley LJ, Zerwekh ZE, Nicar MJ, Strowig SM, Pak CYC. Jejunal and ileal adaptation to alterations in dietary calcium. J Clin Invest 67:1599-1603, 1981.
4. Kuzela DC, Huffer WE, Conger JD, Winter SD, Hammond WS. Soft tissue calcification in chronic dialysis patients. Am J Pathol 86:403-24, 1977.
5. Coburn JW, Hartenbower DL, Massry SG. Intestinal absorption of calcium and the effect of renal insufficiency. Kidney Int 4:96-104, 1973.
6. Heany RP, Skiliman TG. Secretion and excretion of calcium by the human gastrointestinal tract. J Lab Clin Med 64:29-35, 1964.
7. Heaney RP, Recker RR, Saville PD. Menopausal changes in calcium balance performance. J Lab Clin Med 92:953-63, 1978.
8. Hegsted M, Schuette SA, Zemel MB, Linkswiler HM. Urinary calcium and calcium balance in young men as affected by level of protein and phosphorus intake. J Nutr 111:553-62, 1981.
9. Forbes RM, Weingartner KE, Parker HM, Bell RR, Erdman JJ. Bioavailability to rats of zinc, magnesium and calcium in casein-, egg- and soy protein-containing diets. J Nutr 109:1652-60, 1979.
10. Walling MW. Intestinal Ca and phosphate transport: differential responses to vitamin D3 metabolites. Am J Physiol 233:E488-94, 1977.
11. Walters JR. Calbindin-D9k stimulates the calcium pump in rat enterocyte basolateral membranes. Am J Physiol 256:G124-8, 1989.
12. Nemere I, Norman AW. The rapid, hormonally stimulated transport of calcium (transcaltachia) [editorial]. J Bone Miner Res 2:167-9, 1987.
13. Yoshimoto Y, Nemere I, Norman AW. Hypercalcemia inhibits the rapid stimulatory effect on calcium transport in perfused duodena from normal chicks mediated in vitro by 1,25-dihydroxyvitamin D3. Endocrinology 118:2300-4, 1986.
14. Wasserman RH, Fullmer CS. On the molecular mechanism of intestinal calcium transport. Adv Exp Med Biol 249:45-65, 1989.
15. Recker RR, Saville PD. Calcium absorption in renal failure: its relationship to blood urea nitrogen, dietary calcium intake, time on dialysis, and other variables. J Lab Clin Med 78:380-8, 1971.
16. Coburn JW, Koppel MH, Brickman AS, Massry SG. Study of intestinal absorption of calcium in patients with renal failure. Kidney Int 3:264-72, 1973.
17. Clarkson EM, Eastwood JB, Koutsaimanis KG, De Wardener Hd. Net intestinal absorption of calcium in patients with chronic renal failure. Kidney Int 3:258-63, 1973.
18. McDonald SJ, Clarkson EM, De Wardener HE. The effect of a large intake of calcium citrate in normal subjects and patients with chronic renal failure. Clin Sci 26:27-39, 1964.
19. Liu SH, Chu HI. Studies of calcium and phosphorus metabolism with special reference to pathogenesis and effects of dihydrotachysterol (A.T. 10) and iron. Medicine, Baltimore 22:103161, 1943.
20. Stanbury SW, Lumb GA. Metabolic studies of renal osteodystrophy. I. Calcium, phosphorus and nitrogen metabolism in rickets, osteomalacia and hyperparathyroidism complicating chronic uremia and in the osteomalacia of the adult Fanconi syndrome. Medicine, Baltimore 41:1-28, 1962.
21. Mountokalakis TH, Singhellakis PN, Alevizaki CC, Virvidakis K, Ikkos DG. Relationship between degree of renal failure and impairment of intestinal calcium absorption. Nephron 16:20-30, 1976.
22. Malluche HH, Werner E, Ritz E. Intestinal absorption of calcium and whole-body calcium retention in incipient and advanced renal failure. Mineral Electrolyte Metab 1:263-270, 1978.
23. Friis T, Hahnemann S, Weeke E. Serum calcium and serum phsophorus in uraemia during administration of osdium phytate and aluminium hydroxide. Acta Med Scand 183:497-505, 1968.
24. Popovtzer MM, Massry SG, Coburn JW, Kleeman CR. The interrelationship between sodium, calcium, and magnesium excretion in advanced renal failure. J Lab Clin Med 73:763-71, 1969.
25. Clarkson EM, McDonald SJ, De Wardener HE. The effect of high intake of calcium carbonate in normal subjects and patients with chronic renal failure. Clin Sci 30:425-438, 1966.
26. Clarkson EM, Durrant C, Phillips ME, Gower PE, Jewkes RF, De Wardener HE. The effect of high intake of calcium and phosphate in normal and patients with chronic renal failure. Clin Sci 39:693-704, 1970.
27. Hou SH, Zhao J, Ellman CF, Hu J, Griffin Z, Spiegel DM, Bourdeau JE. Calcium and phosphorus fluxes during hemodialysis with low calcium dialysate. Am J Kidney Dis 18:217-24, 1991.
28. Martis L, Serkes KD, Nolph KD. Calcium carbonate as a phosphate binder: is there a need to adjust peritoneal dialysate calcium concentrations for patients using CaCO3? Perit Dial Int 9:325-8, 1989.
29. Piraino B, Bernardini J, Holley J, Johnston JR, Perlmutter JA, Martis L. Calcium mass transfer in peritoneal dialysis patients using 2.5 mEq/l calcium dialysate. Clin Nephrol 37:48-51, 1992.
30. Blumenkrantz MJ, Kopple JD, Moran JK, Coburn JW. Metabolic balance studies and dietary protein requirements in patients undergoing continuous ambulatory peritoneal dialysis. Kidney Int 21:849-61, 1982.
31. Ramirez JA, Emmett M, White MG, Fathi N, Santa AC, Morawski SG, Fordtran JS. The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int 30:753-9, 1986.
32. Lau K 1990 Phosphate disorder. In: J. P. Kokko, Tannen RL (eds.) Fluids and Electrolytes, vol. Second. Saunders, Philadelphia, pp 505-571.
33. Slatopolsky E, Weerts C, Lopez HS, Norwood K, Zink M, Windus D, Delmez J. Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis. N Engl J Med 315:157-61, 1986.
34. Lau K. Phosphate excess and progressive renal failure: the precipitation- calcification hypothesis [clinical conference]. Kidney Int 36:918-37, 1989.
35. Haut LL, Alfrey AC, Guggenheim S, Buddington B, Schrier N. Renal toxicity of phosphate in rats. Kidney Int 17:722-31, 1980.
36. Karlinsky ML, Haut L, Buddington B, Schrier NA, Alfrey AC. Preservation of renal function in experimental glomerulonephritis. Kidney Int 17:293-302, 1980.
37. Lumlertgul D, Burke TJ, Gillum DM, Alfrey AC, Harris DC, Hammond WS, Schrier RW. Phosphate depletion arrests progression of chronic renal failure independent of protein intake. Kidney Int 29:658-66, 1986.
38. Gimenez L, Walker WG, Tew WP, Hermann JA. Prevention of phosphate-induced progression of uremia in rats by 3- phosphocitric acid. Kidney Int 22:36-41, 1982.
39. Slatopolsky E, Caglar S, Pennell JP, Taggart DD, Canterbury JM, Reiss E, Bricker NS. On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 50:492-9, 1971.
40. Portale AA, Booth BE, Halloran BP, Morris RC. Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 73:1580-1589, 1989.
41. Lopez Hs, Dusso AS, Rapp NS, Martin KJ, Slatopolsky E. Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol 259:F432-7, 1990.
42. Kilav R, Silver J, Naveh MT. Parathyroid hormone gene expression in hypophosphatemic rats. J Clin Invest 96:327-33, 1995.
43. Almaden Y, Hemandez A, Torregrosa V, Campistol J, Torres A, S. RM. High phosphorus directly stimulates PTH secretion by human parathyroid tissue. Am Soc Nephrol 6:957, 1995.
44. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M, Dusso A, MacDonald PN. Phosphorus restriction prevents parathyroid gland growth. J Clin Invest 97:2534-2540, 1996.
45. Almaden Y, Canalejo A, Hernandez A, Ballesteros E, Garcia-Navarro S, Torres A, Rodriguez M. Direct effect of phosphorus on PTH secretion from whole rat parathyroid glands in vitro. J Bone Miner Res 11:970-976, 1996.
46. Mulligan RM. Metastatic calcification. Arch Path 43:177-230, 1947.
47. Rostand SG, Sanders C, Kirk KA, Rutsky EA, Fraser RG. Myocardial calcification and cardiac dysfunction in chronic renal failure. Am J Med 85:651-7, 1988.
48. Sanders C, Frank MS, Rostand SG, Rutsky EA, Barnes GT, Fraser RG. Metastatic calcification of the heart and lungs in end-stage renal disease: detection and quantification by dual-energy digital chest radiography. Ajr Am J Roentgenol 149:881-7, 1987.
49. Faubert PF, Shapiro WB, Porush JG, Chou SY, Gross JM, Bondi E, Gomez LG. Pulmonary calcification in hemodialyzed patients detected by technetium-99m diphosphonate scanning. Kidney Int 18:95-102, 1980.
50. Maher ER, Young G, Smyth WB, Pugh S, Curtis JR. Aortic and mitral valve calcification in patients with end-stage renal disease. Lancet 2:875-7, 1987.
51. Mako J, Lengyel M, Szucs J. Intracardiac calcification in patients under chronic haemodialysis. Int Urol Nephrol 19:441-6, 1987.
52. Wade MR, Chen YJ, Soliman M, Kaptein E, Massry SG, Rahimtoola SH, Chandraratna PA. Myocardial texture and cardiac calcification in uremia. Miner Electrolyte Metab 19:21-4, 1993.
53. Maher ER, Pazianas M, Curtis JR. Calcific aortic stenosis: a complication of chronic uraemia. Nephron 47:119-22, 1987.
54. Huting J. Mitral valve calcification as an index of left ventricular dysfunction in patients with end-stage renal disease on peritoneal dialysis. Chest 105:383-8, 1994.
55. Terman DS, Alfrey AC, Hammond WS, Donndelinger T, Ogden DA, Holmes JH. Cardiac calcification in uremia. A clinical, biochemical and pathologic study. Am J Med 50:744-55, 1971.
56. Conger JD, Hammond WS, Alfrey AC, Contiguglia SR, Stanford RE, Huffer WE. Pulmonary calcification in chronic dialysis patients. Clinical and pathologic studies. Ann Intern Med 83:330-6, 1975.
57. Brodeur FJ, Kazerooni EA. Metastatic pulmonary calcification mimicking air-space disease. Technetium-99m-MDP SPECT imaging. Chest 106:620-2, 1994.
58. Contiguglia SR, Alfrey AC, Miller NL, Runnells DE, Le GR. Nature of soft tissue calcification in uremia. Kidney Int 4:229-35, 1973.
59. Meema HE, Oreopoulos DG, Rapoport A. Serum magnesium level and arterial calcification in end-stage renal disease. Kidney Int 32:388-94, 1987.
60. Henrich WL, Hunt JM, Nixon JV. Increased ionized calcium and left ventricular contractility during
hemodialysis. N Engl J Med 310:19-23, 1984.
61. Henrich WL. Effects of dialysis on myocardial contractility. Contrib Nephrol 52:54-9, 1986.
62. Lang RM, Fellner SK, Neumann A, Bushinsky DA, Borow KM. Left ventricular contractility varies directly with blood ionized calcium. Ann Int Med 108:524-9, 1988.
63. Argiles A, Kerr PG, Canaud B, Flavier JL, Mion C. Calcium kinetics and the long-term effects of lowering dialysate calcium concentration. Kidney Int 43:630-40, 1993.
64. Fernandez E, Borras M, Pais B, Montoliu J. Low-calcium dialysate stimulates parathormone secretion and its long- term use worsens secondary hyperparathyroidism. J Am Soc Nephrol 6:132-5, 1995.
65. Cox G, Dodds M, Wigman H, Murphy F. The effects of high doses of aluminum and iron on phosphorus metabolism. J. Biol Chem 92:Xi-Xii, 1931.
66. Brock J, Diamond L. Rickets in rats by iron feeding. J. Pediat 4:442-453, 1934.
67. Rehm P, Winters J. The effect of ferric chloride on the utilization of calcium and phosphorus in the animal body. J. Nutrition 19:213-222, 1940.
68. Deobald H, Elvehjem C. The effect of feeding high amounts of soluble iron and aluminum salts. Am J Physiol 111:118-123, 1935.
69. Hsu CH, Patel S, Young E. New phosphate binding agents: Ferric compounds. J Am Soc Nephrolo. 10:1274-1280, 1999.
70. Messana JM, Hsu C, Young E, Swartz RD. Ferric citrate, an alternative phosphorus (phos)-binder in ESRD patients on hemodialysis (HD). J. Am Soc Nephrol (abstract): 612A, Nov. 1999.
71. DeSoi CA, Umans JG. Phosphate kinetics during high-flux hemodialysis. J Am Soc Nephrol 4:1214-8, 1993
72. Ritz E. Phosphate removal during dialysis--does the membrane matter? Clin Nephrol 42:S57-60, 1994. agent: Ferric compounds. J Am Soc Nephrol 10:1274-1280, 1999.
73. Chesney RW, Rosen JF, Hamstra AJ, Smith C, Mahffey K, DeLuca HF. Absence of seasonal variations in serum concentration of 1,25-dihydroxyvitamin D despite a rise in 25-hydroxyvitamin D in summer. J Endocrino Metab 53:138-142, 1981.
74. Pitts TO, Piraino BH, Mitro R, Chen TC, Segre GV, Greenberg A, Puschett JB. Hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure. J Clin Endocrinol Metab 67:876-881, 1988.
75. Hsu CH, Patel S, Buchsbaum BL. Calcitriol metabolism in patients with chronic renal failure. Am J Kidney Dis 17:185-190, 1991.
76. Hsu CH, Patel SR, Young EW, Simpson RU. Production and degradation of calcitriol in renal failure rats. Am J Physiol 253:F1015-9, 1987.
77. Portale AA, Halloran BP, Murphy MM, Morris RJ. Oral intake of phosphorus can determine the serum concentration of 1,25-dihydroxyvitamin D by determining its production rate in humans. J Clin Invest 77:7-12, 1986.
78. Hsu CH, Patel S. Uremic plasma contains factors inhibiting 1a-hydroxylase activity. J Am Soc Nephrol 3:947-952, 1992.
79. Cannella G, Bonucci E, Rolla D, Ballanti P, Moriero E, De Grandi R, Augeri C, Claudiani F, Di Maio G. Evidence of healing of secondary hyperparathyroidism in chronically hemodialized uremic patients treated with long-term intravenous calcitriol. Kid int 46:1124-1132, 1994.
80. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M, Dusso A, MacDonald P, Brown A. Phosphate (PO4) restriction prevents parathyroid cell growth in uremic rats and high phosphate directly stimulates PTH secretion in tissue. Am Soc Nephrol 6:971, 1995.
