Calcium Metabolism in Renal Failure

DAVID S. DAVID, M.D. New York, New York

Osteodystrophy is almost universally present in chronic renal failure. Mild, but detectable, abnormalities-especially in parathyroid hormone (PTH) secretion- occur even when the glomerular filtration rate is greater than 30 cc/min. Osteomalacia is common in areas in which vitamin D intake and exposure to sunlight are minimal; when these factors are plentiful, osteitis fibrosa predominates. Osteoporosis is seen with increasing frequency in hemodialyzed patients. Nonosseous complications of secondary hyperparathyroidlsm include hypercalcemia, metastatic calcification and pruritus. The most important factor in the medical therapy of osteodystrophy is control of serum phosphate levels. Next, a positive calcium balance must be provided either by giving vitamin D as dihydrotachysterol, raising dialysate calcium or administering calcium orally. Parathyroldectomy is sometimes indicated, especially when the patients are transplant candidates and manifest hypercalcemia. Whether or not transplant is contemplated, patients with persistently high calcium-phosphate products, severe metastatic calcification or rapidly progressive osteodystrophy should be considered for parathyroidectomy. Newer, experimental vitamin D preparations, such as 1,25-dihydroxycholecaiciferol or 1-alpha-hydroxycholecalciferol, should improve the management of patients with renal osteodystrophy and decrease the need for parathyroidectomies. The study of calcium metabolism in renal failure is essentially the study of bone. In man, bone has two major functions. As an organ, it gives structural support, and, as a tissue containing 99 per cent of the total body calcium [ 11, it helps to maintain the intracellular and extracellular levels of this important cation. Study of such pathologic states as vitamin D deficiency and renal failure indicate that maintaining the level of ionized calcium is the more important function of bone, and this is accomplished even at the cost of d.+ stroying its ability to act as the structural support of the organism. ABNORMALITIES IN CALCIUM HOMEOSTASIS IN EARLY RENAL

FAILURE (GLOMERULAR FILTRATION RATE GREATER THAN 30 CC/ MN) The first detectable

From the Department of Medicine, St. Luke’s Hospital Center, Columbia University, College of Physicians & Surgeons, and the Rogosin Kidney Center, The New York Hospital-Cornell Medical Center, New York, New York. Requests for reprints should be addressed to Dr. David S. David, St. Luke’s Hospital Center, Amsterdam Avenue at 114th Street, New York, New York 10025.

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abnormality

in very early renal failure (glomeru-

lar filtration rate 70 to 80 cc/min) is a rise in serum parathyroid hormone (PTH) levels [2], with progressive increments as renal failure advances. The main cause for this early secondary hyperparathyroidism is inorganic phosphate retention [3]. The Bricker hypothesis [3] is as follows: as the glomerular filtration rate falls there is a temporary decrease in renal phosphate excretion, and phosphate retention occurs [4], leading to a small increase in plasma phosphate and a lower ionized plasma calcium [ 41. The drop in calcium ion increases PTH secretion, which in turn decreases tubular reab-

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sorption of phosphate and promotes a greater rate of phosphaturia per remaining nephron [ 141. Thus, total phosphate excretion by the kidney increases to equal the dietary phosphate intake, thus reducing plasma phosphate to normal [4]. A new state of phosphate balance ensues but at the cost of a higher rate of PTH secretion. The higher PTH secretion also acts on bone to raise the ionized calcium level to normal. With each decrease in glomerular filtration rate, the same cycle should recur, and, therefore, the levels of PTH should increase progressively as the degree of renal failure increases [ 2,4]. Factors other than phosphate retention that might exist in early renal failure and could contribute to parathyroid hyperplasia are the resistance of bone to the calcemic effect of PTH [5], depletion of body stores of magnesium [6] and abnormal metabolism of PTH [ 71. Massry et al. [5] noted a diminished calcemic response to exogenous PTH administration in patients with mild renal failure. This could be due to decreased production of 1,25dihydroxycholecaIciferol (1,25-DHCC) by the kidney [5] or to increased bony retention of calcium in renal failure [ 81. Hypomagnesemia, which can occur in some patients in renal failure [6], impairs parathyroid function (91 and leads to hypocalcemia, which in turn stimulates PTH secretion. The role of abnormal PTH metabolism is still under investigation [ 71. ABNORMALITIES IN CALCIUM HOMEOSTASIS IN LATE RENAL FAILURE (GLOMERULAR FILTRATION RATE LESS THAN 30 CCIMIN) As renal failure progresses to a glomerular filtration rate below 25 to 30 cc/min, renal phosphate clearance, despite administration of PTH, can no longer keep up with phosphate intake (on the Western diet [3,4]) and hyperphosphatemia develops. Vitamin D resistance also occurs at this point, manifested by impaired intestinal absorption of calcium [IO]. The development of hyperphosphatemia initiates a vicious cycle. Increased serum phosphate decreases ionized serum calcium and stimulates PTH production [lo]. PTH mobilizes both calcium and phosphate from bone, thus raising both serum calcium and serum phosphate levels [lo]. A paradox is seen in which the stimulus (hyperphosphatemia) for secondary hyperparathyroidism is aggravated by the body’s response (hyperparathyroidism) to the stimulus [lo]. Decreased synthesis of 1,25-DHCC by the kidney [ 1 I] leads, in some patients [ 12,131, to formation of unmineralized (osteomalacic) bone [ 141. This is more resistant than normal bone to the calcemic action of PTH [ 10,14,15] and further contributes to hypocalcemia and secondary hyperparathyroidism. Furthermore, since vitamin D may be necessary for nor-

January

mal bone resorption [ 161, there is an increase in resistance of even normally mineralized bone to the calcemic action of PTH. Another factor that contributes to decreased bone mineralization and bone resorption in this late stage of renal failure is the accumulation of pyrophosphates [ 17,181. Pyrophosphates prevent both bone calcification and bone resorption due to PTH [ 171. A rise in serum pyrophosphates occurs in renal failure primarily because of decreased renal clearance of pyrophosphates [ 17,181. Administration of effective doses of vitamin D, however, overcomes the effect of inhibitors to bone mineralization found in patients with renal failure [ 14,191. Vitamin D also increases the activity of local pyrophosphatases (compounds that hydrolyze pyrophosphates to phosphate) in the intestine [20], and possibly in bone [20]. One could speculate from these observations, that decreased formation of 1,25-DHCC in late renal failure also contributes to the increase in serum pyrophosphates and local pyrophosphates (in intestine and bone), and this contributes to the abnormalities in both mineralization and bone resorption [ 181. Decreased 1,25-DHCC synthesis also leads to decreased intestinal absorption of calcium [21]. However, experiments in animals [22] and recent studies in patients with renal failure [23] suggest that endorgan unresponsiveness also plays a role in the intestinal malabsorption of calcium. Abnormal calcium absorption is further aggravated by low dietary calcium in many of these patients, leading to a negative net calcium balance [21]. Their negative balance, in the presence of severe secondary hyperparathyroidism, could certainly contribute to osteoporosis [lo], and possibly osteomalacia, and thereby to hypocalcemia. This, in turn, would act as a further stimulus to compensatory secondary hyperparathyroidism. BONE CHANGES

IN RENAL FAILURE

The main difficulty in studying skeletal abnormalities in renal failure is in the technic available [24]. Since bone is not a homogeneous tissue [ 14,241, the response of bone to different hormonal and metabolic stimuli, although similar throughout most of the skeleton, may differ greatly in degree of response at different skeletal sites [ 14,24 1. Conclusions drawn from study of one skeletal site may, therefore, be misleading. In addition to this sampling error, it is difficult to determine with any accuracy the absolute rates of new bone formation and resorption. Unfortunately, one cannot extrapolate from the number of bone-resorbing and bone-forming surfaces seen on biopsy to the activity of these bone cells [24]. Bone in Early Renal Failure. Since clinically and roentgenographically detectable renal osteodystro-

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phy is uncommon in early chronic renal failure (glomerular filtration rate is greater than 30 cc/min), there have been no extensive systematic studies of bone in these patients [IO]. Ritz et al. [24] found changes suggestive of increased PTH activity and, in some patients, increased numbers of osteoid seams, suggestive of osteomalacia [ 241.

Osteomalacia.

Bone in later renal failure (glomerular filtration rate less than 30 cc/min) has been extensively studied [I, 10,13,14,19,24,25]. Some combination of osteitis fibrosa and osteomalacia, one or the other predominating [ 10,13,14,19,24,25], occurs in almost all patients. The definition of osteomalacia becomes important in evaluating the reported incidence of this disorder. If osteomalacia is defined not only as an excess of osteoid, but also as a diminution in the amount of calcification front in the lamella lying closest to calcified bone [ 131 with an increase in the mean thickness of osteoid seams [ 131, then the incidence of osteomalacia in the late renal failure varies from 10 to 60 per cent, depending on the geographic location [ 10,13,14]. It is more frequent earlier in the course of advanced renal failure [ 10,14,19] and is usually associated with a lesser degree of parathyroid hyperplasia than is osteitis fibrosa [ 13,141. The incidence of osteomalacia in patients with late renal failure is much higher in countries where vitamin D intake and exposure to sunlight are minimal [ 10,14,19]. Synthesis of 25hydroxycholecalciferol (25HCC) remains normal [26] in late renal failure, even though I,25DHCC is decreased, and is dependent on the state of vitamin D nutrition [26]. The geographic difference in the incidence of osteomalacia is then probably due to the effect of vitamin D nutrition on 25HCC synthesis. The serum level of 25HCC may also play an important role in the type of bone disease seen in uremia [27]. Patients undergoing chronic hemodialysis fell into two groups; those with low 25-HCC levels and osteomalacia, and those with normal or high levels of 25-HCC and osteitis fibrosa. Nevertheless, some patients with severe renal failure may still have sufficient, although undetectable [Ill, amounts of 1,25-DHCC, and manifest severe hypocalcemia and a further decrease in bone mineral content after bilateral nephrectomy [28,29]. Clinically symptomatic renal osteodystrophy develops more frequently in children than in adults [ 14,241. Growth [ 141, with its high bone turnover rate and increased requirement for vitamin D, is one factor. A less obvious cause is duration of renal failure [ 141. Stanbury [ 10,14,19] observed in both children and adults that the duration and rate of progression of renal failure were important determinants of the incidence and severity of renal osteodystrophy. The slower the progression, and the longer the dura-

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tion, the higher the incidence

of osteodystrophy,

in-

cluding osteomalacia [ 10,14] . Compensatory (secondary) hyperparathyroidism [30,31] contributes significantly to the osteomalacia of renal failure. It increases the rate of osteoid formation [32] and leads to a high incidence of hyperostosis and osteosclerosis [ 141. Hyperostosis, as well as relative resistance of osteoid to PTH, contributes to the large amounts of unmineralized osteoid seen in the bone of these patients [ 141 irrespective of the presence or absence of true osteomalacia. Phosphate balance also contributes to the development of osteomalacia. A strongly negative phosphate balance causes hypophosphatemic osteomalacia [ 10,14,19]. Increased serum phosphate, by its effect on PTH secretion, aggravates preexisting mineralization defects. Hypermagnesemia may interfere with bone mineralization [ 121 and also lead to osteomalacia. Since fluoride is cleared from the circulation by renal excretion and by uptake into bones, renal failure can lead to the development of skeletal fluorosis and osteomalacia in areas where water is highly fluoridated [ IO]. Clinical and roentgenographic manifestations of osteomalacia have been reviewed by Stanbury [ 141 and include growth retardation, skeletal deformities, fractures, bone tenderness, muscle weakness, slipping of the epiphyses and Looser’s zones [ 14,241. Osteomalacia is statistically associated with hypocalcemia and a near normal calcium X phosphate product [ 141, but normocalcemia and a high calcium X phosphate product does not rule out the possibility of osteomalacia [ 141. Serum alkaline phosphatase levels may be elevated or normal in osteomalacia. Serum alkaline phosphatase seems to correlate with the degree to which trabecular surfaces are covered by osteoid and osteoblasts, irrespective of whether osteitis fibrosa or osteomalacia is the predominant lesion [24]. Osteitis Fibrosa. Some degree of osteitis fibrosa is seen at all stages of renal failure [10,14,19,24]. It may be the predominant lesion in most patients at any stage of renal failure in locations in which vitamin D intake, or exposure to sunlight, is plentiful [lo], and in patients who live long enough to have massive parathyroid hyperplasia [ 141. Osteitis fibrosa is the predominant bony lesion in about 80 per cent of untreated uremic patients in the United States [ 331. That the incidence of osteitis fibrosa in the U.S.A. is higher than in Europe [ 141 is probably due not to a higher incidence or greater severity of secondary hyperparathyroidism but to a lower incidence of osteomalacia in this country. If any osteomalacia is present, the lesion is usually

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classified as osteomalacia no matter what the degree of osteitis fibrosa [ 1,14,24]. Conversely, since all patients with uremia have some evidence of osteitis fibrosa [ 13,241, the absence of osteomalacia automatically classifies the lesion as osteitis fibrosa [lo]. The higher incidence of osteitis fibrosa in the U.S.A. is therefore due to the higher dietary intake of vitamin D, and the resulting decreased incidence of osteomalacia. Osteitis fibrosa is usually associated with a near normal serum calcium, a high calcium X phosphate product and a massive degree of parathyroid hyperplasia [ 141. This hyperplasia is apparently sufficient to raise serum calcium levels to normal and to calcify unmineralized osteoid. In two reviews [14,33] of a large series of untreated uremic patients, the incidence of significant hypercalcemia was reported to be as high as 5 to 8 per cent. Roentgenographic manifestations of osteitis fibrosa have been reviewed extensively [ 13,14,24] and include subperiosteal resorption of the terminal phalanges, erosion of the outer ends of the clavicles, absence of the lamina dura, bone cysts, avascular necrosis and fractures [ 13,14,24]. Serum PTH levels are among the highest seen in any disease state in man including primary hyperparathyroidism [2]. Serum phosphate levels are elevated, and serum alkaline phosphatase levels may be normal or elevated [10,24]. Hyperostos/s. The true incidence of hyperostosis in untreated uremic patients is not known, but it is apparently quite high at all stages of renal failure [ 141. Hyperostosis is visible roentgenographically as osteosclerosis, when the increased osteoid becomes mineralized. This is especially common in patients treated with adequate doses of vitamin D, with a positive calcium balance or after subtotal parathyroidectomy [ 13,141. Osteosclerosis, when present, is usually patchy [ 141, and in the lumbar spine gives a classic “rugger jersey” appearance [ 13,141. Hyperostosis and osteosclerosis may be associated with either osteomalacia or osteitis fibrosa and may decrease in patients receiving chronic hemodialysis

[lOI. Osteoporosis.

Osteoporosis, an uncommon bony lesion in untreated uremic subjects [lo], has been seen with increased frequency among patients undergoing hemodialysis [ lo], associated with either osteitis fibrosa [33] or osteomalacia [lo]. The increased frequency with which clinical renal osteodystrophy is seen in hemodialysis patients [ 101 suggests that dialysis could either permit further evolution of renal bone disease by prolonging life or contribute new factors not found in undialyzed patients that influence the bone disease [lo].

Two important variables among dialysis centers that affect bone disease are the control of the hyperphosphatemia [ 10,341 and the calcium concentration in dialysate [ 10,341. Fournier et al. [30,31] and Parfitt et al. [34] both dialyzed American patients using a similar high calcium bath (equal to or greater than 6 mg/lOO ml of ionized calcium) with markedly different results. The former group noted a marked improvement in renal osteodystrophy [30,31], whereas the latter group found a rapid progression [34], including osteoporosis and severe soft-tissue calcification. The main difference between the two groups was the control of the serum phosphate. Fournier et al. [30,31], through diet and massive doses of phosphate-binding antacids, kept the serum phosphate level below 6 mg/lOO ml, whereas in the patients studied by Parfitt et al. (341, the serum phosphate level was greater than 6 mg/lOO ml. Thus, the higher serum phosphate level, by increasing the calcium X phosphate product and stimulating greater PTH secretion, accounts for the difference in soft-tissue calcification and the progression of osteodystrophy between these two groups [30,31,34]. Dialyzing against a low calcium bath (equal to or less than 5.5 mg/lOO ml) causes a net negative calcium balance during dialysis [lo] and aggravates secondary hyperparathyroidism. Dialyzing using a high dialysate calcium greater than 6.0 mg/lOO ml, on the other hand, decreases the incidence and severity of renal osteodystrophy as long as serum phosphate is maintained below 6 mg/lOO ml [30,31]. The net positive calcium balance during dialysis transiently increases ionized serum calcium and decreases serum PTH [lo]. The increase in serum calcium in the presence of a normal or high serum phosphate level, allows for deposition of calcium and phosphate into unmineralized osteoid, and calcification of the woven osteoid even in the absence of vitamin D [ 10,131. After enough osteoid becomes mineralized, serum calcium is easier to maintain and PTH secretion decreases significantly even between dialyses [ 10,30,31]. Decreased PTH and decreased bone resorption help to further decrease serum phosphate and its stimulus to PTH [lo]. The vicious cycle is thus broken, bone resorption is decreased, bone mineralization is increased, and renal osteodystrophy is diminished. Another important factor contributing to dialytic bone disease is the effect of hemodialysis on serum pyrophosphate, and possibly on other inhibitors of bone formation and resorption. David et al. [ 181 showed that serum pyrophosphate is markedly decreased during hemodialysis. Since pyrophosphate is a significant inhibitor of bone resorption [ 17,181, this decrease in serum pyrophosphate allows for a great-

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er effect of PTH on bone and enhances bone resorption [ 181. This helps to explain the higher incidence of osteoporosis in dialyzed patients with severe secondary hyperparathyroidism, and also the higher incidence of transient hypercalcemia in normocalcemic patients after they have been placed on dialysis [331. Roentgenographic manifestations of osteoporosis include decreased bone density, especially around joints and in the hands and feet, cortical thinning and coarsening of the tubecular pattern [25]. These signs may occur alone or in conjunction with roentgenographic evidence of osteomalacia or osteitis fibrosa. Clinically, bone pain and pathologic fractures are common. Serum PTH levels are elevated, serum calcium levels may be low, normal or high, serum phosphate levels are elevated, and serum alkaline phosphatase levels may be normal or elevated [25]. NONBONY COMPLICATIONS HYPERPARATHYROIDISM

OF SECONDARY

One of the most important nonHypercalcemia. bony complications of secondary hyperparathyroidism in uremia is hypercalcemia [35]. The mechanism for this hypercalcemia [ 14,33,35] is not known, but it usually is not due to adenoma, autonomy or overcompensation of the parathyroid glands [35]. Transient hypercalcemia occurring in normocalcemic patients after the start of dialysis therapy [33] is probably due to removal of uremic toxins and circulating inhibitors of bone resorption [35]. Hypercalcemia may also occur as a rare complication in the diuretic phase of acute renal failure [ 10). latrogenic hypercalcemia is common in chronic renal failure [lo]. Transient hypercalcemia sometimes occurs during dialysis using a high calcium bath (greater than 6.0 mg/lOO ml) [lo], but it can become persistent if a high calcium bath continues to be used after mineralization of the bones has occurred [lo]. Overdosage of vitamin D or calcium carbonate, especially after remineralization of the bone has occurred, is another common cause of iatrogenic hypercalcemia [ 10,14,19]. The use of calcium cation-exchange resins for the treatment of hyperkalemia has also caused hypercalcemia [36]. Hypercalcemia has also been induced by therapeutic doses of thiazide diuretics in patients with chronic renal failure [37]. Transient hypercalcemia occurs in about 30 per cent of patients after successful renal transplantation [38]. Although mobilization of soft-tissue calcification can contribute to hypercalcemia [39], the most common cause of post-transplant hypercalcemia is slow involution of the parathyroid glands with residual parathyroid hyperplasia, as demonstrated histologi-

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tally [38] and by a high serum PTH level [ 10,381. Post-transplant hypophosphatemia and the state of the patient’s bone may also be important contributing factors to hypercalcemia [ 10,381. If there is extensive unmineralized osteoid at the time of transplantation, bone will be poorly responsive to the calcemic effect of PTH [ 5, lo]. A net positive calcium balance will all go into mineralizing the excess osteoid, i.e., “bony sump” [lo]. It is not until bone is almost completely mineralized that residual parathyroid hyperplasia causes hypercalcemia. This mechanism not only helps to explain the delayed onset of hypercalcemia, but also explains the rapid onset and severity of hypercalcemia seen after successful renal transplantation in already hypercalcemic patients 140). These patients have both severe parathyroid hyperplasia and sufficiently mineralized bone to cause a severe hypercalcemic response when acquired vitamin D resistance is corrected and calcium balance becomes strongly positive after transplantation. Metastatic Calcification. Although tumoral calcinosis [ 131, calciphylaxis [ 131 and dystrophic calcification [24] may occur in chronic and acute renal failure, metastatic calcification [41] is still the most common type of calcification observed in uremia. The most important factor in the development of metastatic calcification is the supersaturation of extracellular fluid with calcium and phosphate ions, occuring usually with an ion product greater than 70 [ 13,191. Metastatic calcification can, however, occur in the absence of a high ion product, especially in the viscera [41]. Nonvisceral (soft-tissue, arterial, skin) deposits consist of hydroxyapatite crystals; whereas visceral (heart and lung) and skeletal muscle deposits consist of an amorphous or microcrystalline compound composed of magnesium, calcium and phosphate [41]. Nonvisceral calcification (hydroxyapatite) is preventable by reducing serum phosphate, and in turn the calcium and phosphate product [4 11, but visceral calcification may continue to occur [4 11. Visceral calcification is most lethal when it occurs in the heart and lungs [ 131. Metastatic calcification commonly occurs, and is easily detected, in the cornea and in the bulbar conjunctiva causing the “red eye” syndrome [24]. The calcification is most painful when it occurs in joints, usually as calcium pyrophosphate (pseudo-gout), or in muscle [ 13,241. Arterial calcification is quite common and is best seen roentgenographically in the arteries of the pelvis and the larger vessels of the legs [ 131. Metastatic calcifications in subcutaneous tissues can sometimes be palpated as nodules [ 131. The therapy of nonvisceral metastatic calcification is similar to its prevention, i.e., correction of hyperphosphatemia and lowering the calcium and phos-

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phate product [ 131. Some of the calcification will disappear with this therapy, especially in muscle and subcutaneous tissue [ 131, but arterial calcification diminishes very little if at all [ 131. This form of therapy guarantees neither the prevention nor the resolution of visceral calcification [41]. Subtotal parathyroidectomy [13] and successful renal transplantation [ 13,381 will usually help to resolve metastatic calcification. Pruritus. Pruritus is one of the most common symptoms of uremia and, at times, the most devastating aspect of the illness for the patient [42]. Although pruritus is usually associated with a high skin calcium content [42], it is not known whether the calcium is the cause of the pruritus [42]. The findings that PTH stimulates mast cell proliferation [42] and the favorable response of pruritus to subtotal parathyroidectemy [42] strongly suggest that pruritus is in some way related to secondary hyperparathyroidism. Furthermore, the poor response of pruritus to antihistamines suggests that factors other than PTH, such as the degree of azotemia, may be operative [42]. MEDICAL THERAPY Controlling Serum Phosphate. An elevated Serum phosphate level is the most important single factor that contributes to secondary hyperparathyroidism [ 1 O] Slatopolsky and Bricker [4] demonstrated in dogs that reducing dietary phosphorous by the same percentage as the decrease in glomerular filtration rate prevented secondary hyperparathyroidism even at the lowest levels of glomerular filfration rate. Preliminary studies in man [4] suggest that secondary hyperparathyroidism can be prevented by the “proportional reduction” of dietary phosphate down to a glomerular filtration rate of 30 cc/min [4]. At this level, the task of making the diet palatable becomes difficult [4], and phosphate-binding antacids can then be added [4,30,31]. Hypophosphatemia must be avoided, however, since this can cause osteomalacia [10,14,16]. Vitamin D Therapy. Indications for the use of vitamin D in chronic renal failure are based on the present commercially available preparations (vitamin D2 and dihydrotachysterol) and, therefore, are quite limited. The indications will be broadened once such preparations as 1,25-DHCC and l-alpha-hydroxycholecalciferol become available [ 23,431. The main indication for the use of vitamin D in both untreated and dialyzed patients is roentgenographic or clinical evidence of osteomalacia [44]. Hypocalcemia with a normal or low serum phosphate level should also probably be treated with vitamin D. Treatment of hypocalcemia associated with hyperphosphatemia

should first be directed toward control of serum phosphate [lo]. If, after such therapy, hypocalcemia persists, then vitamin D therapy may be considered in some patients. Hypocalcemia without roentgenographic or clinical evidence of renal osteodystrophy in nondialyzed patients can be treated with either vitamin D or oral calcium supplements [45] (the latter is contraindicated in patients with peptic disease due to increased gastric acid secretion secondary to oral calcium preparations [46]). Hypocalcemia with evidence of osteitis fibrosa or osteoporosis in nondialyzed patients may also be treated with either vitamin D or oral calcium. Vitamin D should be used to correct hypocalcemia after subtotal parathyroidectomy, irrespective of the type of bony lesion present [ 14,441. Contraindications to the use of vitamin D are a calcium X phosphate product greater than 70, metastatic calcifications and a serum calcium equal to or greater than 10.5 mg/lOO ml. If, however, I,25 DHCC [ 231 or 1-alpha-hydroxycholecalciferol [ 431 were available, these short-acting drugs in small doses might be used in such patients to correct secondary hyperparathyroidism and renal osteodystrophy without significant increase in serum calcium. Serum phosphate levels might actually fall with such therapy as bone resorption decreases with correction of secondary hyperparathyroidism [23]. There are few indications for the use of vitamin D2 or Ds in patients with renal failure because of the long half-life [44] of these preparations. Dihydrotachysterol, with a much shorter half-life, is presently the drug of choice for most patients with chronic renal failure. Preliminary studies with 1,25-DHCC and l-alphahydroxycholecalciferol [ 23,431 are very encouraging, and there is no doubt that these will be the drugs of choice in the vitamin D therapy of uremic osteodystrophy. The action of l-alpha-hydroxycholecalciferol may be direct on the end-organs, or it may be converted to 1,25-DHCC in the body [43]. High dialysate Dialysis Using a High Calcium Bath. calcium is probably the therapy of choice at present in treating hypocalcemic dialysis patients in the U.S.A., whether or not they have associated evidence of renal osteodystrophy. The only exceptions to this form of therapy are patients with evidence of osteomalacia or with active peptic ulcer disease. These patients should be treated with vitamin D. The former, because they require vitamin D, and the latter because a gradual increase in serum calcium with the use of vitamin D is probably less of a stimulant to gastric acid secretion than acute, intermittent increases in serum calcium. Patients with severe or progressive osteitis fibrosa and/or osteoporosis,

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even with normal serum calcium, should also be dialyzed against a high calcium. The contraindications to dialysis using high calcium are similar to those for vitamin D therapy, with the added relative contraindication in patients with active peptic ulcer disease. The concentration of the bath calcium must be adjusted for each patient, avoiding interdialysis or postdialysis calcium X phosphate equal to or greater than 80, or serum calcium equal to or greater than 11 mg/lOO ml. This therapy, although not as physiologic as the administration of vitamin D [45], is safer than presently available vitamin D preparations. Oral Calcium. Pharmacologic doses of oral calcium supplements in the form of carbonate, citrate and phosphate have been used successfully in the prevention and treatment of renal osteodystrophy [45]. The mechanism by which oral calcium improves renal osteodystrophy and the indications for the use of oral calcium are the same as those for high dialysate calcium. The use of oral calcium supplements should probably be restricted to patients not receiving chronic’hemodialysis, since in dialysis patients a high calcium bath is preferable. Control of Other Factors. Treatment of hypomagnesemia, when present, is an important part of the therapy of renal osteodystrophy. Systemic acidosis, although rarely a major factor in the development of renal osteodystrophy [ 14,191, can, by increasing bone resorption [47], contribute to renal osteodystrophy in some patients. Dialysis usually corrects acidosis, but in nondialyzed patients, with arterial pH less than 7.32, or venous carbon dioxide levels of less than 15 meq/liter, oral alkali therapy in the form of sodium bicarbonate, or rarely calcium carbonate, may be considered. Highly fluoridated water used for dialysis should be defluoridated as part of the prevention of renal osteodystrophy. SURGICAL

THERAPY

The best surgical therapy for renal osteodystrophy is successful renal transplantation [38]. Occasionally, subtotal parathyroidectomy may be necessary for severe secondary hyperparathyroidism. There are several indications for subtotal parathyroidectomy, but nonsuppressible PTH secretion alone is neither suggestive of parathyroid autonomy nor an indication for subtotal parathyroidectomy [48,49]. The calcium infusion test is, therefore, of little clinical value and may be hazardous to some patients [ 501. A calcium X phosphate product consistently greater than 80, associated with clinical evidence of severe metastatic calcification and/or rapidly progressive renal osteodystrophy, is an indication for

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subtotal parathyroidectomy. When the short-acting, more potent vitamin D preparations become available, they should be tried in all patients before parathyroidectomy is undertaken. Preliminary experience with these drugs suggests that they will eliminate the need for parathyroidectomy in most patients. Persistent, significant hypercalcemia (calcium greater than 11 mg/lOO ml) is another indication for parathyroidectomy. Potential renal transplant recipients with persistent hypercalcemia should probably undergo parathyroidectomy even if they are asymptomatic, since these are the patients in whom severe post-transplant hypercalcemia will develop and who will require emergency subtotal parathyroidectomy [40]. Dialysis using a normal or low calcium bath in patients who are asymptomatic, and not transplant candidates, can be performed in the hope of avoiding subtotal parathyroidectomy. Parathyroidectomy becomes necessary if the patient has a calcium X phosphate product greater than 80 associated with either progressive metastatic calcification and/or severe renal osteodystrophy. Severe pruritus has been suggested as an indication for subtotal parathyroidectomy [42], but the duration of the relief is questionable [42]. Since parathyroidectomy is associated with a certain amount of morbidity, it should not be undertaken for the therapy of pruritus until an optimal trial of good dermatologic skin care and topical and systemic therapy have all failed [42]. Indications for subtotal parathyroidectomy after a successful renal transplant are very few [38]. The main indication is hypercalcemic nephropathy, which is usually associated with serum calcium greater than or equal to 13 mg/lOO ml [38]. Renal osteodystrophy and soft-tissue calcification usually improve despite mild hypercalcemia (calcium less than or equal to 12 mg/lOO ml [38]. Peptic ulcer disease, pancreatitis, renal stones, polyuria and other side-effects directly attributable to hypercalcemia have not been reported, and the usually mild hypercalcemia responds well to oral phosphate supplements. Parathyroidectomy is thus rarely indicated [38]. There is significant morbidity associated with subtotal parathyroidectomy, other than the direct risk of anesthesia and surgery. The tendency to severe hypocalcemia is exaggerated in uremia because of the huge “bony sump” for extracellular calcium [ 141. Although the hyperphosphatemia is usually diminished postoperatively, it may still persist and contribute to the lowering of the serum calcium level. Dialysis against a low magnesium bath may add another factor to the development of hypocalcemia in uremia. All these factors combined with the rapid alkalinizing effect of hemodialysis may predispose to tetany. Tet-

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any in a uremic patient with severe osteodystrophy is catastrophic. Four days after parathyroidectomy a patient with severe osteodystrophy fractured both scapulas, clavicles and femurs during a single episode of tetany lasting only a few minutes while on the

dialysis machine.

It is important to treat postparathy-

roidectomy hypocalcemia vigorously with calcium and vitamin D. The new vitamin D preparations will make the management of all postparathyroidectomy patients much easier in the future.

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Calcium metabolism in renal failure.

Osteodystrophy is almost universally present in chronic renal failure. Mild, but detectable, abnormalities--especially in parathyroid hormone (PTH) se...
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