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The role of abnormal phosphorus metabolism in the progression of chronic kidney disease and metastatic calcification
Kidney International, Vol. 66, Supplement 90 (2004), pp. S13–S17
The role of abnormal phosphorus metabolism in the progression of chronic kidney disease and metastatic calcification ALLEN C. ALFREY University of Colorado, Denver, Colorado
glomerular filtration rate (GFR) falls between 40% and 25% of normal, serum phosphorus begins to rise, with hyperphosphatemia being present in virtually all patients with end-stage renal failure (ESRF) [3]. In 1941, the clinical importance of hyperphosphatemia in the uremic state was first documented. Reduction in serum phosphorus levels by either dietary modifications or orally administered aluminum-containing phosphate-binding agents was found to increase plasma calcium in uremic children [4]. This was also associated with symptomatic improvement and healing of renal bone disease (renal rickets). However, it would appear that phosphate restriction, either by aluminum compounds or diet, was not widely, if at all, used for the management of hyperphosphotemia throughout most of the following three decades. It was not until after the advent of chronic hemodialysis that the clinical importance of hyperphosphatemia in ESRF was fully appreciated. In 1967, Berlyne [5, 6] suggested that Ca × P product in serum greater than 75 was responsible for conjunctival calcification noted in some uremic patients [5, 6]. At a similar time period Standbury [7] and Katz et al [8] also associated soft tissue metastatic calcification with an increased Ca × P product. As a result of these findings a number of investigators suggested that aluminum hydroxide might be useful in controlling serum phosphorus levels for the prevention and treatment of metastatic calcification in uremic patients [5–10]. Phosphate control in uremic patients was further emphasized by the studies of Bricker et al [11, 12], who documented the importance of hyperphosphatemia in the pathogenesis of secondary hyperparathyroidism. By the early 1970s, the majority of dialyzed uremic patients were routinely receiving aluminum-containing phosphate-binding gels as means of preventing both soft tissue calcification and secondary hyperparathyroidism. In 1976, aluminum neurotoxicity was first described in dialyzed uremic patients [13]. Subsequently, aluminuminduced osteomalacia and anemia were also reported in dialyzed uremic patients. Initially, aluminum toxicity was reported to be a consequence of aluminum transferred from aluminum-contaminated dialysate to the patient during the dialysis procedure [14]. However, it was
The role of abnormal phosphorus metabolism in the progression of chronic kidney disease and metastatic calcification. The role of abnormal phosphorus metabolism in the progression of renal disease and metastatic calcification. Hyperphosphatemia is a common biochemical abnormality in advanced renal failure. The resulting increase serum calcium × phosphorus product results in the deposition of hydroxyapatite crystals. The crystalline properties of these deposits incite an inflammatory response manifested by encapsulated tumoral deposits around joints, acute inflammatory arthritis, and irritative conjunctivitis. These deposits occur in association with marked elevation of serum phosphorus levels, and are prevented and eradicated by normalizing serum phosphorus levels. The calcium-phosphate deposits which occur in heart and lungs are nonapatitic. These deposits were never clearly related to hyperphosphatemia. They are mainly of historic interest because currently they are rarely seen. Their eradication appears to be more of a result of improved dialytic techniques than correction of serum phosphorus levels. The presence, persistence, and progression of vascular calcification are more closely related to patient age and duration of dialysis than hyperphposphatemia. This suggests that these deposits are a result of dystrophic calcification occurring de novo in a diseased or damaged vessel wall. Phosphorous restriction has also been shown to be protective of renal functional deterioration in experimental renal disease. It is unclear whether the protective effect is mediated through phosphate restriction or phosphate depletion. In conclusion, control of serum phosphorus levels in dialyzed uremic patients has clearly decreased morbidity associated with periarticular, articular, and conjunctiva hydorxyapatite deposits. In contrast, phosphorous control has had little effect on the presence or severity of vascular calcification.
Hyperphosphatemia is one of the more common biochemical abnormalities found in the uremic state. Early during renal failure serum phosphorus is maintained in the normal range by increased renal fractional excretion of phosphorus. This is mediated by a combination of increased secretion of parathyroid hormone (PTH) [1] and a non-PTH dependent mechanism that occurs as a result of a reduction in renal functional mass [2]. However, as
Key words: calcium × phosphorus product, hyperphosphatemia, aluminum, vascular calcification. C
2004 by the International Society of Nephrology S-13
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Table 1. Extraosseous calcification Metastatic calcification Tumoral Articular and periarticular Conjuctival Visceral Dystrophic calcification Arterial Renal parenchyma
I
II
subsequently demonstrated that aluminum was absorbed from orally administered aluminum compounds routinely given to uremic patients [15]. The toxicity of orally administered aluminum in uremic patients was documented by the finding in two large studies demonstrating that 25% to 30% of dialyzed uremic patients, whose only exposure to aluminum were these compounds, had aluminum-associated bone disease [16, 17]. As a result of these findings, alternate means of phosphate control were sought, and by the mid 1980s, aluminum phosphatebinding gels had largely been replaced with calcium compounds. Calcium-phosphate deposits can be divided into two major groups representing the factors responsible for their deposition. Metastatic calcification occurs when the calcium × phosphorus product or phosphorus compound exceeds its solubility in serum, resulting in their deposition in susceptible tissue. In contrast, dystrophic calcification results from the de novo deposition of calcium phosphorous in diseased or damage tissue. Examples of metastatic calcification include tumoral, articular, conjunctival, and visceral calcium phosphate deposits. Arterial and renal parenchyma calcifications are of the dystrophic variety (Table 1). It has been assumed at the body pH that all calcium phosphate deposits should be present as hydroxyapatite. However, in dialyzed uremic patients this has been shown not to be the case. Extraosseous metastatic calcium phosphate deposits can be divided into two groups, as determined by their crystallographic properties (Fig. 1) [18]. Type I has an x-ray diffraction pattern of hydroxyapatite identical to that found in bone. The Ca:PO 4 molar ratio is 1.64, also that of apatite. In contrast, type II deposits have an x-ray diffraction pattern of an amorphous compound, with thermochemical properties of whitlockite. Its Ca:PO 4 molar ratio is 1.48, which is dissimilar from apatite, and the deposits are rich in magnesium and aluminum. Because the solid product reflects the solution from which it is formed, this suggests that the pathogenic mechanism responsible for the development of these deposits is also different. As would be expected, dystrophic calcification, vascular, is hydroxyapatite. Tumoral calcification represents calcium phosphate deposits that are usually periarticular in location, but do not involve the joints or their capsules. These deposits are a
X-ray diffraction angle Fig. 1. X-ray diffraction pattern of tumoral deposit I (hydroxyapatite) and visceral deposit II (amorphous).
gritty liquid material that incites a pronounced fibrous response, which encapsulates the deposits. On examination, the crystals are needle- and boat-shaped with a length of 30 to 40 nm [9]. In general, tumoral deposits cause little discomfort or other symptoms. However, when they are quite large they may interfere with the range of motion of the joints [19] and rarely ulcerate through the skin with draining sinuses. When severe, the deposits can involve virtually all joints, as shown in Figure 2A and B. Clinically, conjunctival deposits are characterized by an unpleasant gritty sensation in the eyes that is associated with marked redness and inflammation of the conjunctiva. The calcium-phosphate deposits are also crystalline hydroxyapatite [6]. Calcific periarthritis, like pseudogout and gout, is characterized by recurrent attacks of acute monarticular arthritis. However, in contrast to gout there are no crystals in the joint fluid. Instead, there are hydroxyapatite crystals deposited in the periarticular area and articular cartilage [20, 21]. Tumoral, conjunctival, and periarticular calcification share not only identical deposits of hydroxyapatite, but also their occurrence is closely associated with overt hyperphosphatemia. In further support for the role of hyperphosphatemia in the pathogenesis of these deposits is the fact that they can be prevented by normalization of serum phosphorus levels. Normalization of serum phosphorous levels by any means, administration of phosphorous-binding agents, more aggressive dialysis [22], or renal transplantation [23] will also result in the mobilization of these deposits. The resolution of these deposits is dramatic following successful renal transplantation. Before transplantation, the patient in Figures 2A and B, and 3A and B had extensive tumoral deposits. Total body phosphorus was 969 g (normal 670 g) as determined by total body neutron activation analysis. Three months following renal transplantation, after the deposits had largely resolved (Fig. 3B), total body phosphorus decreased to a normal value of 670 g. These findings further support that the pathogenesis of these deposits is the combination of chronic hyperphosphatemia and
Alfrey: Role of abnormal phosphorus metabolism in CKD
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Fig. 2. X-ray of tumoral deposits around shoulder joint (A). X-ray of tumoral deposits around elbow joint (B).
Fig. 3. X-ray of calcium-phosphate deposits in hand prior to renal transplant (A). X-ray of calcium-phosphate deposits in hand after successful renal transplant (B).
severe total body phosphorus excess. In contrast, it would appear that the conjunctival and periarticular calcification result more from an acute hyperphosphotemic state. The role of hyperphosphatemia in the pathogenesis of visceral calcification is less clear. Visceral calcification occurs in a variety of tissues, but exerts its major clinical consequences in the heart and lung. As stated above, the calcium phosphate deposits of the visceral type are amorphous in nature, rather than crystalline, as found in the apatite deposits. In contrast to the crystalline deposits that incite an inflammatory and fibrotic response the amorphous deposits cause little tissue response and induce injury largely by replacing normal tissues. These deposits can have major clinical importance. Congestive cardiac failure can result from extensive calcification as a consequence of causing restrictive cardiac disease. In ad-
dition, the deposits have a predilection for deposition in the conduction system, resulting in death from complete heart block [24, 25]. In the lungs, the deposits are present in alveolar septa and wall of the small arteries [26]. This leads to a restrictive and diffusion abnormality that can be associated with hypoxemia. Cardiac calcification was a fairly common cause of death in some dialysis populations in the mid 1960s [24]. Similarly, pulmonary function disturbances and occasional death from respiratory insufficiency from pulmonary calcification were also seen with some frequency. During this time period, visceral calcium-phosphate deposits were found in up to 75% of dialyzed uremic patients seen at autopsy [27]. However, during the past 15 to 20 years there have been few well-documented reports of this condition in dialyzed patients [25]. The available
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Alfrey: Role of abnormal phosphorus metabolism in CKD
studies largely use indirect means of estimating visceral calcification, which may not always be reliable [28]. The reason for the virtual disappearance of visceral calciumphosphate deposits in dialyzed uremic patients is not totally clear. However, there is some evidence that suggests that these deposits represent a clinical corollary of what Selye described as calciphylaxis in animal models [29]. In this condition the animals undergo sensitization with a calcifying agent, such as PTH, vitamin D, or phosphate, followed by a challenger that was frequently an element that produced hydrosols. It is suggested that in the dialysis patients during the time period when visceral calcification was noted that the sensitizer was uremia with hyperphosphatemia, and the challenger represented the aluminum administered intravenously to the patient at time of dialysis. The aluminum, in association with phosphate and hydroxide, formed hydrosols (colloids), which adsorbed calcium and were deposited in the tissues. This is further supported by the fact that aluminum chloride given to rats not only causes soft tissue calcification but also induces acute and dramatic rises in serum calcium and phosphorus [30]. In further support of colloid formation is that the rise in serum calcium and phosphorous is in a nondiffusible form. This could also explain the unique crystalline features of the deposits, and the fact that this condition is rarely, if ever, seen following the combination of removal of aluminum from dialysate and correction of serum phosphorus levels in dialyzed uremic patients. In contrast to other types of extraosseous calcification, vascular calcification is extremely common in dialyzed uremic patients. Histologic evidence of vascular calcification occurs in very young individuals with end-stage renal disease (ESRD) [31], and by age 50, close to 100% of uremic patients have radiographic evidence of vascular calcification [32, 33]. The classic type of calcification found in media-size vessels in the extremities is the linear pipe stem-like arterial calcification [32, 33]. Although vascular calcification is common in peripheral arteries it is usually not associated with symptomatology. Occasionally, with extensive involvement peripheral gangrene can occur, resulting in loss of extremities [34, 35]. More recently, increasing attention has been directed at coronary artery calcification in uremic patients [36, 37]. Coronary artery calcification is common and widespread in uremic patients. It tends to be medial as well as intimal, and may not relate solely to atherosclerotic lesions [36, 37]. A variety of pathogenic mechanisms have been suggested for the development of arterial calcification in uremic patients, including the uremic state, hyperparathyroidism, hypercalcemia, hypertension, lipid abnormalities, and hyperphosphatemia. In contrast to other apatite calciumphosphate deposits, vascular calcification becomes more prevalent and severe with increasing duration of dialysis and age [32, 33, 37]. In addition, phosphate control in dialyzed uremic patients has had little effect on
the prevalence or progression of arterial calcification. Similarly, correction of serum phosphorus levels with a successful renal transplant also does not usually affect arterial calcium-phosphate deposits. These findings suggest that vascular calcification may be a dystrophic form of calcification occurring de novo as a result of damaged or diseased vessel wall, rather than metastatic calcification as a consequence of altered calcium-phosphate product. Another possible role for the beneficial effect of phosphorous restriction is the prevention of further renal damage and progressive functional deterioration in a diseased kidney. Dietary phosphorous restriction has been shown to be protective of renal functional deterioration in two models of renal failure in rats: remnant kidney [38] and nephrotoxic serum nephritis [39]. In addition, Brown et al [40] found that one-year mortality in dogs with remnant kidneys was 8.3% if maintained on a phosphorusrestricted diet, as opposed to 66.7% mortality in dogs maintained on a normal phosphorus intake. A number of studies concerning dietary phosphorus restriction in humans with chronic renal failure have also been carried out. However, most of these studies have involved manipulation of multiple dietary constituents, such as combined protein and phosphate restriction, addition of amino acids and ketoanalogs, and more aggressive control of hypertension, making it difficult to determine which of the factors were responsible for any beneficial effect noted [41–43]. It is suggested that phosphate restriction beneficial effect could be mediated by a number of different mechanisms, including prevention of renal parenchyma calcification and altered renal homodynamic events similar to those noted with protein restriction. It is also unknown whether the protective effect noted with dietary phosphorus restriction is a result of simple reduction of phosphate intake or a consequence of phosphate depletion. In view of this, at this time it would appear that other means of retarding progressive functional deterioration in a diseased kidney such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin (Ang) II receptor blockade should be utilized.
CONCLUSION Control of serum phosphorus in uremic patients with orally administered phosphate-binding compounds has been extremely successful in preventing and treating nonvascular extraosseous calcium-phosphate deposit diseases, and decreasing morbidity in uremic patients. It is less clear what role, if any, hyperphosphatemia plays in the pathogenesis of arterial calcification in the uremia state. Reprint requests to Allen C. Alfrey, Professor Emeritus, 3100 East Exposition Avenue, Denver, CO 80209. E-mail: [email protected]
Alfrey: Role of abnormal phosphorus metabolism in CKD
REFERENCES 1. SLATOPOLSKY E, GRADOWSKA L, KASHEMSANT C, et al: The control of phosphate excretion in uremia. J Clin Invest 45:672–677, 1966 2. SLATOPOLSKY E, ROBSON AM, ELKAN I, BRICKER NS: Control of phosphate excretion in uremic man. J Clin Invest 47:1865–1874, 1968 3. BRICKER NS, SLATOPOLSKY E, REISS E, AVIOLI LV: Calcium, phosphorus and bone in renal disease and transplantation. Arch Intern Med 123:543–553, 1969 4. FREEMAN S, FREEMAN WMC: Phosphorus retention in children with chronic renal insufficiency. The effect of diet and of the ingestion of aluminum hydroxide. Am J Dis Child 61:981–1002, 1941 5. BERLYNE GM, SHAW AG: Red eyes in renal failure. Lancet i: 4–7, 1967 6. BERLYNE GM: Microcrystalline conjunctival calcification in renal failure: A useful clinical sign. Lancet i:366–370, 1968 7. STANDBURY SW: Bone complication of renal disease, in Renal Disease, edited by Black DAK, Philadelphia, Davis, 1968, pp 665–713 8. KATZ AI, HAMPERS CH, MERRILL JB: Secondary hyperparathyroidism and renal osteodystrophy. Analysis of 195 patients with observations of the effects of chronic dialysis, kidney transplantation and total parathyroidectomy. Medicine 48: 337–374, 1968 9. PARFITT AM: Soft tissue calcification in uremia. Arch Intern Med 124:544–556, 1969 10. PENDRAS JP, ERICKSON RV: Hemodialysis, a successful therapy for chronic uremia. Ann Intern Med 64:293–302, 1966 11. SLATOPOLSKY E, CAGLAR S, PENNELL JP, et al: On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 50:492–499, 1971 12. BRICKER NS: On the pathogenesis of the uremic state. An exposition of the trade-off hypothesis. N Engl J Med 286:1093–1099, 1972 13. ALFREY AC, LEGENDRE GR, KAEHNY WD: The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 294:184–188, 1976 14. KAEHNY WD, ALFREY AC, HOLMAN RE, SHORR WJ: Aluminum transfer during hemodialysis. Kidney Int 12:361–365, 1977 15. KAEHNY WD, HEGG AP, ALFREY AC: Gastrointestinal absorption of aluminum from aluminum containing antacids. N Engl J Med 296:1389–1390, 1977 16. CHAN YL, FURLONG TJ, COMISH CJ, POSEN S: Dialysis osteodystrophy—A study involving 94 patients. Medicine 64:296– 309, 1985 17. LLACH F, FALSENFELD AJ, COLEMAN MD, et al: The natural course of dialysis osteomalacia. Kidney Int 29(Suppl 18):S74–79, 1986 18. LEGEROS RZ, CONTIGUGLIA SR, ALFREY AC: Pathological calcifications associated with uremia. Two types of calcium phosphate deposits. Calc Tiss Res 13:173–185, 1973 19. SCHENKIER SL, GERTNER E: Massive soft tissue calcification causing complete loss of extensor tendon function in renal failure. J Rheumatol 19:1640–1642, 1992 20. CANER JEZ, DECKER JL: Recurrent (gouty?) arthritis in chronic renal failure treated with periodic dialysis. Am J Med 36:571–574, 1964 21. MIRAHMADE KS, COBURN J, BLUESTONE R: Calcific periarthritis and hemodialysis. JAMA 223:548–549, 1973 22. KIM SJ, GOLDSTEIN M, SZABO T, PIERRATOS A: Resolution of massive uremic calcinosis with daily nocturnal home hemodialysis. Am J Kidney Dis 41(3):E12, 2000 23. ALFREY AC, JENKINS D, GROTH GC, et al: Resolution of hyperparathyroidism, renal osteodystrophy and metastatic calcification after renal transplantation. N Engl J Med 279:1349–1356, 1968
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24. TERMAN DS, ALFREY AC, HAMMOND WS, et al: Cardiac calcification uremia A clinical, biochemical and pathologic study. Am J Med 50:744–755, 1971 25. ISOTALO PA, MALIL A, GREEN M, et al: Metastatic calcification of the cardiac conduction system with heart bock: An under-reported entity in chronic renal failure patients. J Forensic Sci 45:1335–1338, 2000 26. CONGER JD, HAMMOND WS, ALFREY AC, et al: Pulmonary calcification in chronic dialysis patients. Ann Intern Med 83:330–336, 1997 27. KUZELA DC, HUFFER WE, CONGER JD, et al: Soft tissue calcification in chronic dialysis patients. Am J Pathol 86:403–424 1977 28. WADE MR, CHEN YJ, SOLIMAN M, et al: Myocardial texture and cardiac calcification in uremia. Miner Electrolyte Metab 19:21–24, 1993 29. SELYE H: Calciphylaxis, Chicago, University of Chicago Press, 1962 30. JOHANNSSON O, PERRAULT G, SAVOIE L, et al: Action of various metallic chlorides on calcaemia and phosphataemia. Br J Pharmac Chemother 33:91–97, 1968 31. IBELS LS, ALFREY AC, HUFFER WE, et al: Arterial calcification and pathology in uremic patients undergoing dialysis. Am J Med 66:790– 796, 1979 32. MEEMA HE, OREOPOULOS DG: Morphology, progression and regression of arterial and periarterial calcification in patients with end-stage renal disease. Radiology 158:671–677, 1986 33. MEEMA HE, OREOPOULOS DG, DEVEBER GA: Arterial calcification in severe chronic renal disease and their relationship to dialysis treatment renal transplant and parathyroidectomy. Radiology 121:315–321, 1976 34. RUBINGER D, FRIEDLAENDER MM, SILVER J, et al: Progressive vascular calcification with necrosis of extremities in hemodialysis patients. A possible role of iron overload. Am J Kidney Dis 7:125–129, 1986 35. WILKINSON SP, STEWART WK, PARHAM DM, GUTHRIE W: Symmetric gangrene of the extremities in late renal failure: A case report and review of the literature. Quart J Med 252:319–341, 1988 36. SHARPLES EJ, PEREIRA D, SUMMERS S, et al: Coronary artery calcification measured with electron-beam computerized tomography correlates poorly with coronary artery angiography in dialysis patients. Am J Kidney Dis 43: 313–319, 2004 37. GOODMAN WG, GOLDIN J, KUIZON BD, et al: Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478–1483, 2000 38. IBELS LS, ALFREY AC, HAUT L, et al: Preservation of function in experimental renal disease by dietary restriction of phosphate. N Engl J Med 298:121–126, 1978 39. KARLINSKY ML, HAUT L, BUDDINGTON B, et al: Preservation of renal function in experimental glomerulonephritis. Kidney Int 17:292– 302, 1980 40. BROWN S, FINCO D, CROWELL W, BARSANTI J: Beneficial effect of moderate phosphate in partially nephrectomized dogs on a low protein diet. J Am Soc Nephrology 19:223, 1986 41. ROSMAN JB, TER WEE PM, MEIJER S, et al: Prospective randomized trial of early dietary protein restriction in chronic renal failure. Lancet i:1291–1296, 1984 42. WALSER M: Keto-acid therapy and the progression of renal disease, in The Progressive Nature of Renal Disease, edited by Brenner BM, Stein JH, New York, NY, Churchill Livingstone, 1986, pp 231–244 43. BARSOTTI G, GIANNONI A, MORELLI E, et al: The decline of renal function slowed by very-low phosphorus intake in chronic renal patients following a low nitrogen diet. Clin Nephrol 21:54–59, 1984
The role of abnormal phosphorus metabolism in the progression of chronic kidney disease and metastatic calcification ALLEN C. ALFREY University of Colorado, Denver, Colorado
glomerular filtration rate (GFR) falls between 40% and 25% of normal, serum phosphorus begins to rise, with hyperphosphatemia being present in virtually all patients with end-stage renal failure (ESRF) [3]. In 1941, the clinical importance of hyperphosphatemia in the uremic state was first documented. Reduction in serum phosphorus levels by either dietary modifications or orally administered aluminum-containing phosphate-binding agents was found to increase plasma calcium in uremic children [4]. This was also associated with symptomatic improvement and healing of renal bone disease (renal rickets). However, it would appear that phosphate restriction, either by aluminum compounds or diet, was not widely, if at all, used for the management of hyperphosphotemia throughout most of the following three decades. It was not until after the advent of chronic hemodialysis that the clinical importance of hyperphosphatemia in ESRF was fully appreciated. In 1967, Berlyne [5, 6] suggested that Ca × P product in serum greater than 75 was responsible for conjunctival calcification noted in some uremic patients [5, 6]. At a similar time period Standbury [7] and Katz et al [8] also associated soft tissue metastatic calcification with an increased Ca × P product. As a result of these findings a number of investigators suggested that aluminum hydroxide might be useful in controlling serum phosphorus levels for the prevention and treatment of metastatic calcification in uremic patients [5–10]. Phosphate control in uremic patients was further emphasized by the studies of Bricker et al [11, 12], who documented the importance of hyperphosphatemia in the pathogenesis of secondary hyperparathyroidism. By the early 1970s, the majority of dialyzed uremic patients were routinely receiving aluminum-containing phosphate-binding gels as means of preventing both soft tissue calcification and secondary hyperparathyroidism. In 1976, aluminum neurotoxicity was first described in dialyzed uremic patients [13]. Subsequently, aluminuminduced osteomalacia and anemia were also reported in dialyzed uremic patients. Initially, aluminum toxicity was reported to be a consequence of aluminum transferred from aluminum-contaminated dialysate to the patient during the dialysis procedure [14]. However, it was
The role of abnormal phosphorus metabolism in the progression of chronic kidney disease and metastatic calcification. The role of abnormal phosphorus metabolism in the progression of renal disease and metastatic calcification. Hyperphosphatemia is a common biochemical abnormality in advanced renal failure. The resulting increase serum calcium × phosphorus product results in the deposition of hydroxyapatite crystals. The crystalline properties of these deposits incite an inflammatory response manifested by encapsulated tumoral deposits around joints, acute inflammatory arthritis, and irritative conjunctivitis. These deposits occur in association with marked elevation of serum phosphorus levels, and are prevented and eradicated by normalizing serum phosphorus levels. The calcium-phosphate deposits which occur in heart and lungs are nonapatitic. These deposits were never clearly related to hyperphosphatemia. They are mainly of historic interest because currently they are rarely seen. Their eradication appears to be more of a result of improved dialytic techniques than correction of serum phosphorus levels. The presence, persistence, and progression of vascular calcification are more closely related to patient age and duration of dialysis than hyperphposphatemia. This suggests that these deposits are a result of dystrophic calcification occurring de novo in a diseased or damaged vessel wall. Phosphorous restriction has also been shown to be protective of renal functional deterioration in experimental renal disease. It is unclear whether the protective effect is mediated through phosphate restriction or phosphate depletion. In conclusion, control of serum phosphorus levels in dialyzed uremic patients has clearly decreased morbidity associated with periarticular, articular, and conjunctiva hydorxyapatite deposits. In contrast, phosphorous control has had little effect on the presence or severity of vascular calcification.
Hyperphosphatemia is one of the more common biochemical abnormalities found in the uremic state. Early during renal failure serum phosphorus is maintained in the normal range by increased renal fractional excretion of phosphorus. This is mediated by a combination of increased secretion of parathyroid hormone (PTH) [1] and a non-PTH dependent mechanism that occurs as a result of a reduction in renal functional mass [2]. However, as
Key words: calcium × phosphorus product, hyperphosphatemia, aluminum, vascular calcification. C
2004 by the International Society of Nephrology S-13
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Alfrey: Role of abnormal phosphorus metabolism in CKD
Table 1. Extraosseous calcification Metastatic calcification Tumoral Articular and periarticular Conjuctival Visceral Dystrophic calcification Arterial Renal parenchyma
I
II
subsequently demonstrated that aluminum was absorbed from orally administered aluminum compounds routinely given to uremic patients [15]. The toxicity of orally administered aluminum in uremic patients was documented by the finding in two large studies demonstrating that 25% to 30% of dialyzed uremic patients, whose only exposure to aluminum were these compounds, had aluminum-associated bone disease [16, 17]. As a result of these findings, alternate means of phosphate control were sought, and by the mid 1980s, aluminum phosphatebinding gels had largely been replaced with calcium compounds. Calcium-phosphate deposits can be divided into two major groups representing the factors responsible for their deposition. Metastatic calcification occurs when the calcium × phosphorus product or phosphorus compound exceeds its solubility in serum, resulting in their deposition in susceptible tissue. In contrast, dystrophic calcification results from the de novo deposition of calcium phosphorous in diseased or damage tissue. Examples of metastatic calcification include tumoral, articular, conjunctival, and visceral calcium phosphate deposits. Arterial and renal parenchyma calcifications are of the dystrophic variety (Table 1). It has been assumed at the body pH that all calcium phosphate deposits should be present as hydroxyapatite. However, in dialyzed uremic patients this has been shown not to be the case. Extraosseous metastatic calcium phosphate deposits can be divided into two groups, as determined by their crystallographic properties (Fig. 1) [18]. Type I has an x-ray diffraction pattern of hydroxyapatite identical to that found in bone. The Ca:PO 4 molar ratio is 1.64, also that of apatite. In contrast, type II deposits have an x-ray diffraction pattern of an amorphous compound, with thermochemical properties of whitlockite. Its Ca:PO 4 molar ratio is 1.48, which is dissimilar from apatite, and the deposits are rich in magnesium and aluminum. Because the solid product reflects the solution from which it is formed, this suggests that the pathogenic mechanism responsible for the development of these deposits is also different. As would be expected, dystrophic calcification, vascular, is hydroxyapatite. Tumoral calcification represents calcium phosphate deposits that are usually periarticular in location, but do not involve the joints or their capsules. These deposits are a
X-ray diffraction angle Fig. 1. X-ray diffraction pattern of tumoral deposit I (hydroxyapatite) and visceral deposit II (amorphous).
gritty liquid material that incites a pronounced fibrous response, which encapsulates the deposits. On examination, the crystals are needle- and boat-shaped with a length of 30 to 40 nm [9]. In general, tumoral deposits cause little discomfort or other symptoms. However, when they are quite large they may interfere with the range of motion of the joints [19] and rarely ulcerate through the skin with draining sinuses. When severe, the deposits can involve virtually all joints, as shown in Figure 2A and B. Clinically, conjunctival deposits are characterized by an unpleasant gritty sensation in the eyes that is associated with marked redness and inflammation of the conjunctiva. The calcium-phosphate deposits are also crystalline hydroxyapatite [6]. Calcific periarthritis, like pseudogout and gout, is characterized by recurrent attacks of acute monarticular arthritis. However, in contrast to gout there are no crystals in the joint fluid. Instead, there are hydroxyapatite crystals deposited in the periarticular area and articular cartilage [20, 21]. Tumoral, conjunctival, and periarticular calcification share not only identical deposits of hydroxyapatite, but also their occurrence is closely associated with overt hyperphosphatemia. In further support for the role of hyperphosphatemia in the pathogenesis of these deposits is the fact that they can be prevented by normalization of serum phosphorus levels. Normalization of serum phosphorous levels by any means, administration of phosphorous-binding agents, more aggressive dialysis [22], or renal transplantation [23] will also result in the mobilization of these deposits. The resolution of these deposits is dramatic following successful renal transplantation. Before transplantation, the patient in Figures 2A and B, and 3A and B had extensive tumoral deposits. Total body phosphorus was 969 g (normal 670 g) as determined by total body neutron activation analysis. Three months following renal transplantation, after the deposits had largely resolved (Fig. 3B), total body phosphorus decreased to a normal value of 670 g. These findings further support that the pathogenesis of these deposits is the combination of chronic hyperphosphatemia and
Alfrey: Role of abnormal phosphorus metabolism in CKD
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B
B
Fig. 2. X-ray of tumoral deposits around shoulder joint (A). X-ray of tumoral deposits around elbow joint (B).
Fig. 3. X-ray of calcium-phosphate deposits in hand prior to renal transplant (A). X-ray of calcium-phosphate deposits in hand after successful renal transplant (B).
severe total body phosphorus excess. In contrast, it would appear that the conjunctival and periarticular calcification result more from an acute hyperphosphotemic state. The role of hyperphosphatemia in the pathogenesis of visceral calcification is less clear. Visceral calcification occurs in a variety of tissues, but exerts its major clinical consequences in the heart and lung. As stated above, the calcium phosphate deposits of the visceral type are amorphous in nature, rather than crystalline, as found in the apatite deposits. In contrast to the crystalline deposits that incite an inflammatory and fibrotic response the amorphous deposits cause little tissue response and induce injury largely by replacing normal tissues. These deposits can have major clinical importance. Congestive cardiac failure can result from extensive calcification as a consequence of causing restrictive cardiac disease. In ad-
dition, the deposits have a predilection for deposition in the conduction system, resulting in death from complete heart block [24, 25]. In the lungs, the deposits are present in alveolar septa and wall of the small arteries [26]. This leads to a restrictive and diffusion abnormality that can be associated with hypoxemia. Cardiac calcification was a fairly common cause of death in some dialysis populations in the mid 1960s [24]. Similarly, pulmonary function disturbances and occasional death from respiratory insufficiency from pulmonary calcification were also seen with some frequency. During this time period, visceral calcium-phosphate deposits were found in up to 75% of dialyzed uremic patients seen at autopsy [27]. However, during the past 15 to 20 years there have been few well-documented reports of this condition in dialyzed patients [25]. The available
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Alfrey: Role of abnormal phosphorus metabolism in CKD
studies largely use indirect means of estimating visceral calcification, which may not always be reliable [28]. The reason for the virtual disappearance of visceral calciumphosphate deposits in dialyzed uremic patients is not totally clear. However, there is some evidence that suggests that these deposits represent a clinical corollary of what Selye described as calciphylaxis in animal models [29]. In this condition the animals undergo sensitization with a calcifying agent, such as PTH, vitamin D, or phosphate, followed by a challenger that was frequently an element that produced hydrosols. It is suggested that in the dialysis patients during the time period when visceral calcification was noted that the sensitizer was uremia with hyperphosphatemia, and the challenger represented the aluminum administered intravenously to the patient at time of dialysis. The aluminum, in association with phosphate and hydroxide, formed hydrosols (colloids), which adsorbed calcium and were deposited in the tissues. This is further supported by the fact that aluminum chloride given to rats not only causes soft tissue calcification but also induces acute and dramatic rises in serum calcium and phosphorus [30]. In further support of colloid formation is that the rise in serum calcium and phosphorous is in a nondiffusible form. This could also explain the unique crystalline features of the deposits, and the fact that this condition is rarely, if ever, seen following the combination of removal of aluminum from dialysate and correction of serum phosphorus levels in dialyzed uremic patients. In contrast to other types of extraosseous calcification, vascular calcification is extremely common in dialyzed uremic patients. Histologic evidence of vascular calcification occurs in very young individuals with end-stage renal disease (ESRD) [31], and by age 50, close to 100% of uremic patients have radiographic evidence of vascular calcification [32, 33]. The classic type of calcification found in media-size vessels in the extremities is the linear pipe stem-like arterial calcification [32, 33]. Although vascular calcification is common in peripheral arteries it is usually not associated with symptomatology. Occasionally, with extensive involvement peripheral gangrene can occur, resulting in loss of extremities [34, 35]. More recently, increasing attention has been directed at coronary artery calcification in uremic patients [36, 37]. Coronary artery calcification is common and widespread in uremic patients. It tends to be medial as well as intimal, and may not relate solely to atherosclerotic lesions [36, 37]. A variety of pathogenic mechanisms have been suggested for the development of arterial calcification in uremic patients, including the uremic state, hyperparathyroidism, hypercalcemia, hypertension, lipid abnormalities, and hyperphosphatemia. In contrast to other apatite calciumphosphate deposits, vascular calcification becomes more prevalent and severe with increasing duration of dialysis and age [32, 33, 37]. In addition, phosphate control in dialyzed uremic patients has had little effect on
the prevalence or progression of arterial calcification. Similarly, correction of serum phosphorus levels with a successful renal transplant also does not usually affect arterial calcium-phosphate deposits. These findings suggest that vascular calcification may be a dystrophic form of calcification occurring de novo as a result of damaged or diseased vessel wall, rather than metastatic calcification as a consequence of altered calcium-phosphate product. Another possible role for the beneficial effect of phosphorous restriction is the prevention of further renal damage and progressive functional deterioration in a diseased kidney. Dietary phosphorous restriction has been shown to be protective of renal functional deterioration in two models of renal failure in rats: remnant kidney [38] and nephrotoxic serum nephritis [39]. In addition, Brown et al [40] found that one-year mortality in dogs with remnant kidneys was 8.3% if maintained on a phosphorusrestricted diet, as opposed to 66.7% mortality in dogs maintained on a normal phosphorus intake. A number of studies concerning dietary phosphorus restriction in humans with chronic renal failure have also been carried out. However, most of these studies have involved manipulation of multiple dietary constituents, such as combined protein and phosphate restriction, addition of amino acids and ketoanalogs, and more aggressive control of hypertension, making it difficult to determine which of the factors were responsible for any beneficial effect noted [41–43]. It is suggested that phosphate restriction beneficial effect could be mediated by a number of different mechanisms, including prevention of renal parenchyma calcification and altered renal homodynamic events similar to those noted with protein restriction. It is also unknown whether the protective effect noted with dietary phosphorus restriction is a result of simple reduction of phosphate intake or a consequence of phosphate depletion. In view of this, at this time it would appear that other means of retarding progressive functional deterioration in a diseased kidney such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin (Ang) II receptor blockade should be utilized.
CONCLUSION Control of serum phosphorus in uremic patients with orally administered phosphate-binding compounds has been extremely successful in preventing and treating nonvascular extraosseous calcium-phosphate deposit diseases, and decreasing morbidity in uremic patients. It is less clear what role, if any, hyperphosphatemia plays in the pathogenesis of arterial calcification in the uremia state. Reprint requests to Allen C. Alfrey, Professor Emeritus, 3100 East Exposition Avenue, Denver, CO 80209. E-mail: [email protected]
Alfrey: Role of abnormal phosphorus metabolism in CKD
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