0021-972X/91/7204-0735$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 72, No. 4 Printed in U.S.A.
CLINICAL REVIEW 20 Recent Advances in the Pathogenesis and Therapy of Uremic Secondary Hyperparathyroidism JAMES A. DELMEZ AND EDUARDO SLATOPOLSKY Chromalloy American Kidney Center and the Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
T
HE association of renal failure with metabolic bone disease has been recognized since the time of Albright. The term "renal osteodystrophy" is not specific. It encompasses the lesions of osteitis fibrosa, osteomalacia, mixed lesions, osteoporosis, and growth retardation. The histological features of osteitis fibrosa include osteoclastosis, increased bone resorption, and marrow fibrosis. In addition, osteoblastic activity is increased with an abnormally large percent of bone surface involved in bone formation. This state of high bone turnover is also characterized by increased quantities of woven osteoid. It differs from normal lamellar osteoid in that there is a haphazard arrangement of collagen fibers. Although woven osteoid can be mineralized, the calcium is deposited as amorphous calcium-phosphate instead of hydroxyapatite. It is clear that osteitis fibrosa (and probably other uremic derangements) is the result of excessive secretion of PTH. With the advent of effective dialysis therapy, it is now common for patients to live for 10-20 yr without renal function, yet develop progressive uremic hyperparathyroidism. Hence, a thorough understanding of its pathogenesis and treatment is critical in directing a rational approach to therapy.
malization was at the cost of sustained PTH hypersecretion. Eventually, as GFR fell to less than 30% of normal, phosphaturia could not be further enhanced. This led to persistent hyperphosphatemia, hypocalcemia, and worsening hyperparathyroidism. The trade-off hypothesis was supported by a number of studies. When an oral load of phosphorus was given to normal subjects, an acute rise in phosphorus and fall in calcium levels were seen. This was accompanied by an increase in immunoreactive PTH (i-PTH) values. The long-term feeding of normal animals with a diet high in phosphorus was shown to produce parathyroid gland hyperplasia, increased levels of i-PTH, and a mild reduction in calcium values. Studies in chronically uremic dogs showed that the reduction of dietary phosphorus in proportion to the fall in GFR could prevent or greatly ameliorate the development of secondary hyperparathyroidism. Similar results have also been demonstrated in uremic human subjects. In patients on chronic hemodialysis the serum i-PTH levels have been correlated with the severity of the hyperphosphatemia. Thus hyperphosphatemia has a role in causing parathyroid gland hypersecretion, but as the result of mechanisms that have subsequently been found to be vastly more complicated (Fig. 1).
Pathogenesis of Uremic Hyperparathyroidism The Trade-off Hypothesis
Calcium Malabsorption
The trade-off hypothesis proposed that increased PTH secretion served to maintain phosphorus balance in uremia. As glomerular filtrate rate (GFR) fell, it was reasoned that there would be a rise in serum phosphorus levels with a transient reciprocal fall in calcium concentrations. The latter would stimulate PTH secretion leading to a phosphaturia and a normalization of calcium and phosphorus levels. The trade-off was that this nor-
In 1970, it was discovered that calcitriol [1,25(OH)2D] was produced by renal tissues. Subsequent studies showed that, under normal circumstances, the kidneys produced the vast majority of calcitriol measured in the serum. Furthermore, calcitriol was found to be the most potent metabolite of vitamin D in promoting calcium absorption. Thus, renal failure may cause calcitriol deficiency, calcium malabsorption, and secondary hyperparathyroidism. Studies evaluating the level of renal function at which calcitriol levels become low have yielded conflicting results. This may be due to differences in the amount of dietary phosphorus. Calcitriol produc-
Received August 20, 1990. Address requests for reprints to: James A. Delmez, M.D., Chromalloy American Kidney Center, One Barnes Hospital Plaza, St. Louis, Missouri 63110.
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DELMEZ AND SLATOPOLSKY
736
Chronic Renal Failure Phosphate Retention
Low Levels 1,2S(OH)2D3
J C E & M • 1991 Vol 72 • No 4
PTH infusion returned the calcemic response to normal. It is possible that high levels of PTH in uremia somehow desensitize the bone to its biological effects leading to a vicious cycle. Altered Calcium-Regulated PTH Secretion
\
Hypocalcemia
Secondary Hyperparathyroidism
Shift in Set Point for Calcium FIG. 1. Factors involved in the pathogenesis of secondary hyperparathyroidism in chronic renal failure (see text).
tion is decreased with a diet high in phosphorus and increased with phosphorus restriction. In patients with a moderate degree of renal failure, calcitriol levels are either normal or slightly low. If dietary phosphorus is restricted, however, calcitriol levels rise toward normal. In severe renal failure, calcitriol levels are minimally affected by dietary factors presumably because of the loss of functioning renal tissue. These findings correspond well with studies evaluating the intestinal absorption of calcium in patients with varying degrees of renal insufficiency. In general, patients with mild to moderate renal insufficiency have normal calcium absorption whereas it is clearly impaired in those with severe renal insufficiency. Thus calcium malabsorption probably plays a minor direct role in the generation of hyperparathyroidism until the development of advanced stages of renal failure. It is, nonetheless, possible that the normal intestinal absorption of calcium and normal calcitriol levels in early renal failure are at the expense of excess PTH secretion. Skeletal Resistance to the Calcemic Action of PTH The calcemic response to an infusion of PTH extract is less in hypocalcemic patients with renal insufficiency than in normal subjects or patients with hypoparathyroidism. This suggests that higher levels of PTH may be needed to maintain normal serum calcium levels in patients with renal failure. It may also partially explain the hypocalcemia seen with renal failure. The mechanisms of the skeletal resistance to PTH have not been extensively studied. Some investigators found that calcitriol administration partially improved the calcemic response to PTH in dogs with acute renal failure. However, in dogs with chronic renal failure, calcitriol did not affect the calcemic response to PTH. A surgical parathyroidectomy performed 1 day before the
An insensitivity to the suppressive effects of calcium on PTH secretion has been shown in vitro in glands obtained from patients with chronic renal failure (1). This observation suggests that one mechanism for increased PTH levels in chronic renal failure may be a shift in the "set point" (defined as the calcium concentration producing half of the maximal inhibition of PTH release) in addition to an increase in the mass of parathyroid tissue. Thus, normal concentrations of calcium may not be sufficient to suppress the parathyroid glands in uremia and calcium levels may have to be increased to the upper limits of normal to control PTH. In the past 15 yr a number of studies have demonstrated a substantial effect of calcitriol on PTH synthesis and secretion. It is known that parathyroid glands contain a calcium binding protein with a mol wt of 14,500 and properties similar to that of the calcium binding protein found in intestinal mucosa. A calcitriol receptor has also been demonstrated in the cytosol and nucleus of parathyroid glands in vitro. A number of investigators have shown that prolonged incubation of parathyroid cells with calcitriol in the media suppressed PTH secretion in a dose-dependent manner. Subsequent studies performed in vitro and in vivo in rats revealed that calcitriol reduced pre-pro PTH messenger RNA levels (2). The reduction in the messenger RNA correlated with the decreased rate of PTH secretion. The mechanism for the lowering of pre-pro PTH messenger RNA levels appears to be decreased rates of gene transcription. More recently, it has been shown that new protein synthesis is not needed for calcitriol to act on the 5'-flanking portion of the PTH gene to decrease gene transcription. The low levels of calcitriol observed in patients with advanced renal failure could play a role in the abnormal secretion of PTH. Delmez et al. (3) characterized the role of calcitriol in the abnormal set point for the suppression of PTH by calcium. They studied the effects of changing ionized calcium levels on PTH secretion in hemodialysis patients before and after 2 weeks of treatment with iv calcitriol. During hypercalcemic suppression, the set point for PTH suppression by calcium fell significantly after calcitriol therapy. These effects in a representative patient are shown in Fig. 2. During hypocalcemic stimulation, the parathyroid response was blunted by calcitriol. These results suggest that administration of calcitriol directly suppresses PTH independent of changes in ionized calcium levels. In part, the suppression of PTH
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CLINICAL REVIEW 350
• Control O • 1.25(OH)2 D3 X=Set Point
325 300
J 275 -§ 250 £ 225 Z
200 175 -
4.6
5.0
5.4 5.8 ICo(mq/dl)
6.2
FIG. 2. The effects of iv calcitriol in PTH secretion during a calcium infusion in a hemodialysis patient. During the control infusion (•) the set point (x) of ionized calcium (I Ca) was 5.04 mg/dL. After 2 weeks of iv calcitriol (O) the PTH levels fell despite a lower I Ca and the set point decreased to 4.64 mg/dL (from Delmez et al, J Clin Invest. 1989;83:1349-1355; reproduced with permission).
secretion is due to increased sensitivity of the gland to ambient calcium levels. Phosphorus Retention Revisited Phosphate restriction may suppress PTH by stimulating calcitriol production or by raising calcium levels. Recently Lopez-Hilker et al. (4) evaluated another possible mechanism. In dogs with advanced renal failure, the amount of phosphorus in the diet was progressively decreased every 2 weeks. Dietary calcium was also decreased to prevent the development of hypercalcemia. Over a 2-month period, the ionized calcium decreased from 5.4 ± 0.04 to 5.2 ± 0.08 mg/dL and serum phosphorus from 6.3 ± 0.7 to 4.7 ± 0.2 mg/dL. Serum calcitriol levels remained low. However, i-PTH gradually decreased from 321 ± 46 to 95 ± 22 pg/mL. These studies suggest that a reduction in dietary phosphorus may improve secondary hyperparathyroidism by a mechanism that is independent of the levels of calcitriol or ionized calcium. Parathyroid Hyperplasia Parathyroid gland hyperplasia is a prominent finding in uremic patients with severe secondary hyperparathyroidism. Remarkably little is known about the factors that lead to the cellular proliferation. Studies in vivo in uremic rats, however, suggest that calcitriol administration suppresses parathyroid hyperplasia independent of changes in serum calcium levels. Hyperplasia, once established, was not reversed by short-term calcitriol treatment.
737
Diagnosis of Uremic Hyperparathyroidism Hyperparathyroidism is present, in varying severity, in the majority of patients with renal failure. The diagnosis of severe hyperparathyroidism is made by the finding of high levels of i-PTH and radiographic changes of osteitis fibrosa. Typically, these features include subperiosteal erosions of the phalanges, and erosions at the proximal end of the tibia, the neck of the femur or humerus, and the inferior surface of the distal end of the clavicle. In the skull, there is a mottled and granular (salt and pepper) appearance with areas of resorption commonly associated with areas of osteosclerosis. Osteosclerosis is due to an increase in the thickness and number of trabeculae in spongy bone and accounts for the typical "rugger jersey" appearance of the spine. The correct interpretation of i-PTH levels in renal failure depends on an understanding of the metabolism of PTH and the binding specificity of the assay used to measure the hormone. PTH is secreted into the circulation as the intact hormone containing 84 amino acids. To a lesser extent the gland also secretes mid- and carboxy-terminal fragments. Once in the circulation, intact PTH undergoes metabolism by the liver and kidneys, yielding fragments of biologically active amino- and biologically inactive carboxy-terminal regions. The removal of the latter depends primarily, if not exclusively, on glomerular filtration and subsequent reabsorption and degradation by the renal tubules. Therefore, in renal failure these fragments accumulate. This results in multiple forms of circulating PTH in which the concentration of biologically inactive carboxy-terminal fragments is about 100-fold greater than that of the biologically active amino-terminal fragments. Since different radioimmunoreactive assays of PTH recognize different regions of the molecule, confusion may arise in assessing the results in renal failure. In order to interpret these assays, it is crucial to know if the antibody recognizes the intact, amino-terminal, midterminal, and/or the carboxy-terminal portions of the molecule. For example, if one uses an assay which measures the mid- and carboxy-terminal region, the values associated with severe osteitis fibrosa may be 100-fold greater than the upper limits of normal determined in those with normal renal function. On the other hand, results of an assay specific for the amino-terminal portion of PTH may suggest severe osteitis fibrosa when the results are 5 times the upper limits of normal. In the absence of liver disease, the serum alkaline phosphatase levels often correlate with i-PTH and may confirm the presence of uremic hyperparathyroidism.
Prevention and Treatment of Uremic Hyperparathyroidism Phosphorus control Crucial in the prevention and treatment of uremic hyperparathyroidism is control of phosphorus accumu-
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DELMEZ AND SLATOPOLSKY
lation. Meat and dairy products are the most important dietary sources of phosphorus. These should be restricted. However, lowering phosphorus intake in proportion to the reduced GFR in patients with advanced renal failure is difficult. Low phosphorus diets are generally unpalatable to the tastes of most people living in the United States. In addition, some patients may go into negative nitrogen balance and become protein malnourished. When hemodialysis is instituted, a dietary protein intake of 1 g/kg day is generally prescribed. Hence, dietary phosphorus restriction alone does not prevent phosphorus accumulation in severe renal failure and agents which bind phosphorus in the gut are usually necessary. Historically, the most popular phosphorus binders were those containing aluminum in the form of aluminum hydroxide or aluminum carbonate. It is now clear that the aluminum is absorbed systemically. Because the kidney is the major route of excretion, prolonged ingestion of phosphorus binders containing aluminum results in aluminum accumulation. Its consequences include dementia, proximal myopathy, microcytic anemia, and osteomalacia. It is sad and ironic that a decade ago our patients who were the most compliant in ingesting phosphorus binders containing aluminum had little histological evidence of osteitis fibrosa but often at the cost of severe osteomalacia. Therefore, alternative phosphorus binders have been sought. Calcium carbonate has been shown by many investigators to be an effective phosphorus binder and is now widely used in hemodialysis patients. The dose of calcium carbonate administered with each meal should be adjusted to match the phosphorus intake at that time. Since there is both patient to patient variability and variability from meal to meal in the same patient, a thorough dietary history is essential. Mismatching of the amount of calcium and phosphorus ingested may lead to inadequate phosphorus control and hypercalcemia. In the United States, most patients undergo hemodialysis with a dialysate calcium concentration of 3.25 to 3.5 mEq/L. This usually causes an influx of calcium to the patient during each treatment. In patients requiring a large amount of calcium carbonate to control the serum phosphorus levels, hypercalcemia may occur. We and others have found that reducing the dialysate calcium concentration significantly reduced the frequency of hypercalcemia. In a long-term study we found that the combination of 2.5 mEq/L calcium dialysate and oral calcium carbonate resulted in excellent control of calcium and phosphorus levels and an elimination of the need for phosphorus binders containing aluminum in 20 hemodialysis patients (5). PTH levels fell but the change was not significant. It should be emphasized that this strategy should only be attempted in those patients who
JCE & M • 1991 Vol 72 • No 4
are compliant with their ingestion of calcium carbonate. It is likely that the negative calcium balance rendered by a dialysate low in calcium would worsen hyperparathyroidism in the absence of enteral supplementation. Recently, much interest has been focused on the use of calcium acetate as a phosphorus binder. Acute studies has shown that this compound binds about twice as much phosphorus per calcium absorbed compared to calcium carbonate (6). Long term studies are underway in several centers to determine if calcium acetate is of value in the treatment of hyperphosphatemia in hemodialysis patients. Control of calcium Since patients with severe renal failure absorb calcium abnormally, supplements are usually necessary to raise the calcium levels to the upper limits of normal. In general, this may be achieved by using calcium carbonate as a phosphorus binder with meals. However, in those patients whose phosphorus is well controlled yet whose calcium levels are low, calcium supplements between meals or at night may be warranted. Alternatively, some form of vitamin D may be instituted to increase the intestinal absorption of calcium. Vitamin D also increases the intestinal absorption of phosphorus. Use of vitamin D sterols Despite dietary phosphorus restriction, the use of phosphorus binders, the choice of an appropriate concentration of calcium in the dialysate, and an intake of sufficient amounts of dietary calcium, a significant number of patients still develop uremic hyperparathyroidism and osteitis fibrosa. Treatment with oral vitamin D2, dihydrotachysterol, 25-hydroxyvitamin D3 (calcifediol), la-hydroxyvitamin D3 (alfacalcidiol), and 1,25-dihydroxyvitamin D3 (calcitriol) have been shown to lessen symptoms, improve bone histology, and lower i-PTH levels. All forms of vitamin D therapy carry the risk of hypercalcemia even in the absence of renal function. This may be particularly prolonged with the use of vitamin D3 and may require several weeks for resolution. The hypercalcemia develops as a consequence of high 25-hydroxyvitamin D levels but normal to low serum concentrations of 1,25-dihydroxyvitamin D. Vitamin D sterols should not be used when hyperphosphatemia is present because an increase in the calcium-phosphorus product may lead to the development of extra-skeletal calcifications. Slatopolsky et al. (7) demonstrated that the iv administration of calcitriol markedly reduced the serum levels of i-PTH in hemodialysis patients. The decline in i-PTH was greater than that observed by raising the calcium
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CLINICAL REVIEW levels to a comparable degree with oral calcium carbonate. This difference was probably due to the additive direct effect of calcitriol on PTH secretion as discussed previously. Intravenous calcitriol may be more efficacious than the oral form in suppressing PTH. This may be due to the high concentrations of calcitriol after its iv administration. Studies in vitro have clearly demonstrated that the suppression of PTH secretion by calcitriol is dose dependent. Concomitant treatment of uremic hyperparathyroidism with calcitriol and large doses of oral calcium renders patients at a significant risk for hypercalcemia. A new analog of calcitriol, 22-oxa-l,25-(OH)2D3 (22-oxacalcitriol, OCT) has been shown in experimental animals to have little calcemic action, yet a comparable effect on PTH synthesis and secretion as calcitriol. Potentially, this drug could be administered with large amounts of oral calcium without the attendant risk of hypercalcemia. This promising drug has not been tested in humans. Surgical parathyroidectomy Despite implementation of the above measures, certain patients with chronic renal failure may require parathyroid surgery. When this option is entertained there must be strong evidence for severe secondary hyperparathyroidism. There should be multiple determinations of high levels of i-PTH that are known to correlate with the severity of osteitis fibrosa, as well as radiographic evidence of hyperparathyroidism. If the diagnosis is unclear, a bone biopsy is warranted. The reason is that if the patient actually has osteomalacia due to aluminum accumulation, the bone disease will worsen after parathyroidectomy. At the time of parathyroidectomy four parathyroid glands should be identified. Part of one gland is removed leaving 60-80 mg viable tissue in place. After frozen
739
sections confirm that the tissue is of parathyroid origin, the other three glands are removed. The remnant parathyroid tissue may undergo further hyperplasia leading to the recurrence of hyperparathyroidism. A second surgical procedure is associated with greater technical difficulties and complications compared to the initial operation. For these reasons, total parathyroidectomy with auto-transplantation of some parathyroid tissue to the forearm has been recommended. Tissue transplanted in this manner may be more accessible if subsequent surgical removal is necessary. To avoid the possibility of persistent hypoparathyroidism, parathyroid tissue should be frozen and stored to be implanted later if necessary. A total parathyroidectomy has little place in the management of uremic hyperparathyroidism because it may lead to a defect in bone mineralization.
References 1. Brown EM, Wilson RE, Eastman RC, Pallotta J, Marynick SP. Abnormal regulation of parathyroid hormone release by calcium in secondary hyperparathyroidism due to chronic renal failure. J Clin Endocrinol Metab. 1982;54:172-179. 2. Silver J, Russell J, Sherwood LM. Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci USA. 1985'82"4270—4273 3. Delmez JA, Tindira C, Grooms P, Dusso A, Windus DW, Slatopolsky E. Parathyroid hormone suppression by intravenous 1,25dihydroxyvitamin D: a role for increased sensitivity to calcium. J Clin Invest. 1989;83:1349-1355. 4. Lopez-Hilker S, Dusso A, Rapp N, Martin KJ, Slatopolsky E. Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol. 1990;F432-F437. 5. Slatopolsky E, Weerts C, Norwood K, Giles K, Fryer P, Finch J, Windus D, Delmez J. Long-term effects of calcium carbonate and 2.5 mEq/liter calcium dialysate on mineral metabolism. Kidney Int. 1989;36:897-903. 6. Mai ML, Emmett M, Sheikh MS, Santa Ana CA, Schiller L, Fordtran JS. Calcium acetate, an effective phosphorus binder in patients with renal failure. Kidney Int. 1989;36:690-695. 7. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest. 1984;74:2136-2143.
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Vol. 72, No. 4 Printed in U.S.A.
CLINICAL REVIEW 20 Recent Advances in the Pathogenesis and Therapy of Uremic Secondary Hyperparathyroidism JAMES A. DELMEZ AND EDUARDO SLATOPOLSKY Chromalloy American Kidney Center and the Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
T
HE association of renal failure with metabolic bone disease has been recognized since the time of Albright. The term "renal osteodystrophy" is not specific. It encompasses the lesions of osteitis fibrosa, osteomalacia, mixed lesions, osteoporosis, and growth retardation. The histological features of osteitis fibrosa include osteoclastosis, increased bone resorption, and marrow fibrosis. In addition, osteoblastic activity is increased with an abnormally large percent of bone surface involved in bone formation. This state of high bone turnover is also characterized by increased quantities of woven osteoid. It differs from normal lamellar osteoid in that there is a haphazard arrangement of collagen fibers. Although woven osteoid can be mineralized, the calcium is deposited as amorphous calcium-phosphate instead of hydroxyapatite. It is clear that osteitis fibrosa (and probably other uremic derangements) is the result of excessive secretion of PTH. With the advent of effective dialysis therapy, it is now common for patients to live for 10-20 yr without renal function, yet develop progressive uremic hyperparathyroidism. Hence, a thorough understanding of its pathogenesis and treatment is critical in directing a rational approach to therapy.
malization was at the cost of sustained PTH hypersecretion. Eventually, as GFR fell to less than 30% of normal, phosphaturia could not be further enhanced. This led to persistent hyperphosphatemia, hypocalcemia, and worsening hyperparathyroidism. The trade-off hypothesis was supported by a number of studies. When an oral load of phosphorus was given to normal subjects, an acute rise in phosphorus and fall in calcium levels were seen. This was accompanied by an increase in immunoreactive PTH (i-PTH) values. The long-term feeding of normal animals with a diet high in phosphorus was shown to produce parathyroid gland hyperplasia, increased levels of i-PTH, and a mild reduction in calcium values. Studies in chronically uremic dogs showed that the reduction of dietary phosphorus in proportion to the fall in GFR could prevent or greatly ameliorate the development of secondary hyperparathyroidism. Similar results have also been demonstrated in uremic human subjects. In patients on chronic hemodialysis the serum i-PTH levels have been correlated with the severity of the hyperphosphatemia. Thus hyperphosphatemia has a role in causing parathyroid gland hypersecretion, but as the result of mechanisms that have subsequently been found to be vastly more complicated (Fig. 1).
Pathogenesis of Uremic Hyperparathyroidism The Trade-off Hypothesis
Calcium Malabsorption
The trade-off hypothesis proposed that increased PTH secretion served to maintain phosphorus balance in uremia. As glomerular filtrate rate (GFR) fell, it was reasoned that there would be a rise in serum phosphorus levels with a transient reciprocal fall in calcium concentrations. The latter would stimulate PTH secretion leading to a phosphaturia and a normalization of calcium and phosphorus levels. The trade-off was that this nor-
In 1970, it was discovered that calcitriol [1,25(OH)2D] was produced by renal tissues. Subsequent studies showed that, under normal circumstances, the kidneys produced the vast majority of calcitriol measured in the serum. Furthermore, calcitriol was found to be the most potent metabolite of vitamin D in promoting calcium absorption. Thus, renal failure may cause calcitriol deficiency, calcium malabsorption, and secondary hyperparathyroidism. Studies evaluating the level of renal function at which calcitriol levels become low have yielded conflicting results. This may be due to differences in the amount of dietary phosphorus. Calcitriol produc-
Received August 20, 1990. Address requests for reprints to: James A. Delmez, M.D., Chromalloy American Kidney Center, One Barnes Hospital Plaza, St. Louis, Missouri 63110.
735
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DELMEZ AND SLATOPOLSKY
736
Chronic Renal Failure Phosphate Retention
Low Levels 1,2S(OH)2D3
J C E & M • 1991 Vol 72 • No 4
PTH infusion returned the calcemic response to normal. It is possible that high levels of PTH in uremia somehow desensitize the bone to its biological effects leading to a vicious cycle. Altered Calcium-Regulated PTH Secretion
\
Hypocalcemia
Secondary Hyperparathyroidism
Shift in Set Point for Calcium FIG. 1. Factors involved in the pathogenesis of secondary hyperparathyroidism in chronic renal failure (see text).
tion is decreased with a diet high in phosphorus and increased with phosphorus restriction. In patients with a moderate degree of renal failure, calcitriol levels are either normal or slightly low. If dietary phosphorus is restricted, however, calcitriol levels rise toward normal. In severe renal failure, calcitriol levels are minimally affected by dietary factors presumably because of the loss of functioning renal tissue. These findings correspond well with studies evaluating the intestinal absorption of calcium in patients with varying degrees of renal insufficiency. In general, patients with mild to moderate renal insufficiency have normal calcium absorption whereas it is clearly impaired in those with severe renal insufficiency. Thus calcium malabsorption probably plays a minor direct role in the generation of hyperparathyroidism until the development of advanced stages of renal failure. It is, nonetheless, possible that the normal intestinal absorption of calcium and normal calcitriol levels in early renal failure are at the expense of excess PTH secretion. Skeletal Resistance to the Calcemic Action of PTH The calcemic response to an infusion of PTH extract is less in hypocalcemic patients with renal insufficiency than in normal subjects or patients with hypoparathyroidism. This suggests that higher levels of PTH may be needed to maintain normal serum calcium levels in patients with renal failure. It may also partially explain the hypocalcemia seen with renal failure. The mechanisms of the skeletal resistance to PTH have not been extensively studied. Some investigators found that calcitriol administration partially improved the calcemic response to PTH in dogs with acute renal failure. However, in dogs with chronic renal failure, calcitriol did not affect the calcemic response to PTH. A surgical parathyroidectomy performed 1 day before the
An insensitivity to the suppressive effects of calcium on PTH secretion has been shown in vitro in glands obtained from patients with chronic renal failure (1). This observation suggests that one mechanism for increased PTH levels in chronic renal failure may be a shift in the "set point" (defined as the calcium concentration producing half of the maximal inhibition of PTH release) in addition to an increase in the mass of parathyroid tissue. Thus, normal concentrations of calcium may not be sufficient to suppress the parathyroid glands in uremia and calcium levels may have to be increased to the upper limits of normal to control PTH. In the past 15 yr a number of studies have demonstrated a substantial effect of calcitriol on PTH synthesis and secretion. It is known that parathyroid glands contain a calcium binding protein with a mol wt of 14,500 and properties similar to that of the calcium binding protein found in intestinal mucosa. A calcitriol receptor has also been demonstrated in the cytosol and nucleus of parathyroid glands in vitro. A number of investigators have shown that prolonged incubation of parathyroid cells with calcitriol in the media suppressed PTH secretion in a dose-dependent manner. Subsequent studies performed in vitro and in vivo in rats revealed that calcitriol reduced pre-pro PTH messenger RNA levels (2). The reduction in the messenger RNA correlated with the decreased rate of PTH secretion. The mechanism for the lowering of pre-pro PTH messenger RNA levels appears to be decreased rates of gene transcription. More recently, it has been shown that new protein synthesis is not needed for calcitriol to act on the 5'-flanking portion of the PTH gene to decrease gene transcription. The low levels of calcitriol observed in patients with advanced renal failure could play a role in the abnormal secretion of PTH. Delmez et al. (3) characterized the role of calcitriol in the abnormal set point for the suppression of PTH by calcium. They studied the effects of changing ionized calcium levels on PTH secretion in hemodialysis patients before and after 2 weeks of treatment with iv calcitriol. During hypercalcemic suppression, the set point for PTH suppression by calcium fell significantly after calcitriol therapy. These effects in a representative patient are shown in Fig. 2. During hypocalcemic stimulation, the parathyroid response was blunted by calcitriol. These results suggest that administration of calcitriol directly suppresses PTH independent of changes in ionized calcium levels. In part, the suppression of PTH
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 August 2015. at 08:21 For personal use only. No other uses without permission. . All rights reserved.
CLINICAL REVIEW 350
• Control O • 1.25(OH)2 D3 X=Set Point
325 300
J 275 -§ 250 £ 225 Z
200 175 -
4.6
5.0
5.4 5.8 ICo(mq/dl)
6.2
FIG. 2. The effects of iv calcitriol in PTH secretion during a calcium infusion in a hemodialysis patient. During the control infusion (•) the set point (x) of ionized calcium (I Ca) was 5.04 mg/dL. After 2 weeks of iv calcitriol (O) the PTH levels fell despite a lower I Ca and the set point decreased to 4.64 mg/dL (from Delmez et al, J Clin Invest. 1989;83:1349-1355; reproduced with permission).
secretion is due to increased sensitivity of the gland to ambient calcium levels. Phosphorus Retention Revisited Phosphate restriction may suppress PTH by stimulating calcitriol production or by raising calcium levels. Recently Lopez-Hilker et al. (4) evaluated another possible mechanism. In dogs with advanced renal failure, the amount of phosphorus in the diet was progressively decreased every 2 weeks. Dietary calcium was also decreased to prevent the development of hypercalcemia. Over a 2-month period, the ionized calcium decreased from 5.4 ± 0.04 to 5.2 ± 0.08 mg/dL and serum phosphorus from 6.3 ± 0.7 to 4.7 ± 0.2 mg/dL. Serum calcitriol levels remained low. However, i-PTH gradually decreased from 321 ± 46 to 95 ± 22 pg/mL. These studies suggest that a reduction in dietary phosphorus may improve secondary hyperparathyroidism by a mechanism that is independent of the levels of calcitriol or ionized calcium. Parathyroid Hyperplasia Parathyroid gland hyperplasia is a prominent finding in uremic patients with severe secondary hyperparathyroidism. Remarkably little is known about the factors that lead to the cellular proliferation. Studies in vivo in uremic rats, however, suggest that calcitriol administration suppresses parathyroid hyperplasia independent of changes in serum calcium levels. Hyperplasia, once established, was not reversed by short-term calcitriol treatment.
737
Diagnosis of Uremic Hyperparathyroidism Hyperparathyroidism is present, in varying severity, in the majority of patients with renal failure. The diagnosis of severe hyperparathyroidism is made by the finding of high levels of i-PTH and radiographic changes of osteitis fibrosa. Typically, these features include subperiosteal erosions of the phalanges, and erosions at the proximal end of the tibia, the neck of the femur or humerus, and the inferior surface of the distal end of the clavicle. In the skull, there is a mottled and granular (salt and pepper) appearance with areas of resorption commonly associated with areas of osteosclerosis. Osteosclerosis is due to an increase in the thickness and number of trabeculae in spongy bone and accounts for the typical "rugger jersey" appearance of the spine. The correct interpretation of i-PTH levels in renal failure depends on an understanding of the metabolism of PTH and the binding specificity of the assay used to measure the hormone. PTH is secreted into the circulation as the intact hormone containing 84 amino acids. To a lesser extent the gland also secretes mid- and carboxy-terminal fragments. Once in the circulation, intact PTH undergoes metabolism by the liver and kidneys, yielding fragments of biologically active amino- and biologically inactive carboxy-terminal regions. The removal of the latter depends primarily, if not exclusively, on glomerular filtration and subsequent reabsorption and degradation by the renal tubules. Therefore, in renal failure these fragments accumulate. This results in multiple forms of circulating PTH in which the concentration of biologically inactive carboxy-terminal fragments is about 100-fold greater than that of the biologically active amino-terminal fragments. Since different radioimmunoreactive assays of PTH recognize different regions of the molecule, confusion may arise in assessing the results in renal failure. In order to interpret these assays, it is crucial to know if the antibody recognizes the intact, amino-terminal, midterminal, and/or the carboxy-terminal portions of the molecule. For example, if one uses an assay which measures the mid- and carboxy-terminal region, the values associated with severe osteitis fibrosa may be 100-fold greater than the upper limits of normal determined in those with normal renal function. On the other hand, results of an assay specific for the amino-terminal portion of PTH may suggest severe osteitis fibrosa when the results are 5 times the upper limits of normal. In the absence of liver disease, the serum alkaline phosphatase levels often correlate with i-PTH and may confirm the presence of uremic hyperparathyroidism.
Prevention and Treatment of Uremic Hyperparathyroidism Phosphorus control Crucial in the prevention and treatment of uremic hyperparathyroidism is control of phosphorus accumu-
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lation. Meat and dairy products are the most important dietary sources of phosphorus. These should be restricted. However, lowering phosphorus intake in proportion to the reduced GFR in patients with advanced renal failure is difficult. Low phosphorus diets are generally unpalatable to the tastes of most people living in the United States. In addition, some patients may go into negative nitrogen balance and become protein malnourished. When hemodialysis is instituted, a dietary protein intake of 1 g/kg day is generally prescribed. Hence, dietary phosphorus restriction alone does not prevent phosphorus accumulation in severe renal failure and agents which bind phosphorus in the gut are usually necessary. Historically, the most popular phosphorus binders were those containing aluminum in the form of aluminum hydroxide or aluminum carbonate. It is now clear that the aluminum is absorbed systemically. Because the kidney is the major route of excretion, prolonged ingestion of phosphorus binders containing aluminum results in aluminum accumulation. Its consequences include dementia, proximal myopathy, microcytic anemia, and osteomalacia. It is sad and ironic that a decade ago our patients who were the most compliant in ingesting phosphorus binders containing aluminum had little histological evidence of osteitis fibrosa but often at the cost of severe osteomalacia. Therefore, alternative phosphorus binders have been sought. Calcium carbonate has been shown by many investigators to be an effective phosphorus binder and is now widely used in hemodialysis patients. The dose of calcium carbonate administered with each meal should be adjusted to match the phosphorus intake at that time. Since there is both patient to patient variability and variability from meal to meal in the same patient, a thorough dietary history is essential. Mismatching of the amount of calcium and phosphorus ingested may lead to inadequate phosphorus control and hypercalcemia. In the United States, most patients undergo hemodialysis with a dialysate calcium concentration of 3.25 to 3.5 mEq/L. This usually causes an influx of calcium to the patient during each treatment. In patients requiring a large amount of calcium carbonate to control the serum phosphorus levels, hypercalcemia may occur. We and others have found that reducing the dialysate calcium concentration significantly reduced the frequency of hypercalcemia. In a long-term study we found that the combination of 2.5 mEq/L calcium dialysate and oral calcium carbonate resulted in excellent control of calcium and phosphorus levels and an elimination of the need for phosphorus binders containing aluminum in 20 hemodialysis patients (5). PTH levels fell but the change was not significant. It should be emphasized that this strategy should only be attempted in those patients who
JCE & M • 1991 Vol 72 • No 4
are compliant with their ingestion of calcium carbonate. It is likely that the negative calcium balance rendered by a dialysate low in calcium would worsen hyperparathyroidism in the absence of enteral supplementation. Recently, much interest has been focused on the use of calcium acetate as a phosphorus binder. Acute studies has shown that this compound binds about twice as much phosphorus per calcium absorbed compared to calcium carbonate (6). Long term studies are underway in several centers to determine if calcium acetate is of value in the treatment of hyperphosphatemia in hemodialysis patients. Control of calcium Since patients with severe renal failure absorb calcium abnormally, supplements are usually necessary to raise the calcium levels to the upper limits of normal. In general, this may be achieved by using calcium carbonate as a phosphorus binder with meals. However, in those patients whose phosphorus is well controlled yet whose calcium levels are low, calcium supplements between meals or at night may be warranted. Alternatively, some form of vitamin D may be instituted to increase the intestinal absorption of calcium. Vitamin D also increases the intestinal absorption of phosphorus. Use of vitamin D sterols Despite dietary phosphorus restriction, the use of phosphorus binders, the choice of an appropriate concentration of calcium in the dialysate, and an intake of sufficient amounts of dietary calcium, a significant number of patients still develop uremic hyperparathyroidism and osteitis fibrosa. Treatment with oral vitamin D2, dihydrotachysterol, 25-hydroxyvitamin D3 (calcifediol), la-hydroxyvitamin D3 (alfacalcidiol), and 1,25-dihydroxyvitamin D3 (calcitriol) have been shown to lessen symptoms, improve bone histology, and lower i-PTH levels. All forms of vitamin D therapy carry the risk of hypercalcemia even in the absence of renal function. This may be particularly prolonged with the use of vitamin D3 and may require several weeks for resolution. The hypercalcemia develops as a consequence of high 25-hydroxyvitamin D levels but normal to low serum concentrations of 1,25-dihydroxyvitamin D. Vitamin D sterols should not be used when hyperphosphatemia is present because an increase in the calcium-phosphorus product may lead to the development of extra-skeletal calcifications. Slatopolsky et al. (7) demonstrated that the iv administration of calcitriol markedly reduced the serum levels of i-PTH in hemodialysis patients. The decline in i-PTH was greater than that observed by raising the calcium
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CLINICAL REVIEW levels to a comparable degree with oral calcium carbonate. This difference was probably due to the additive direct effect of calcitriol on PTH secretion as discussed previously. Intravenous calcitriol may be more efficacious than the oral form in suppressing PTH. This may be due to the high concentrations of calcitriol after its iv administration. Studies in vitro have clearly demonstrated that the suppression of PTH secretion by calcitriol is dose dependent. Concomitant treatment of uremic hyperparathyroidism with calcitriol and large doses of oral calcium renders patients at a significant risk for hypercalcemia. A new analog of calcitriol, 22-oxa-l,25-(OH)2D3 (22-oxacalcitriol, OCT) has been shown in experimental animals to have little calcemic action, yet a comparable effect on PTH synthesis and secretion as calcitriol. Potentially, this drug could be administered with large amounts of oral calcium without the attendant risk of hypercalcemia. This promising drug has not been tested in humans. Surgical parathyroidectomy Despite implementation of the above measures, certain patients with chronic renal failure may require parathyroid surgery. When this option is entertained there must be strong evidence for severe secondary hyperparathyroidism. There should be multiple determinations of high levels of i-PTH that are known to correlate with the severity of osteitis fibrosa, as well as radiographic evidence of hyperparathyroidism. If the diagnosis is unclear, a bone biopsy is warranted. The reason is that if the patient actually has osteomalacia due to aluminum accumulation, the bone disease will worsen after parathyroidectomy. At the time of parathyroidectomy four parathyroid glands should be identified. Part of one gland is removed leaving 60-80 mg viable tissue in place. After frozen
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sections confirm that the tissue is of parathyroid origin, the other three glands are removed. The remnant parathyroid tissue may undergo further hyperplasia leading to the recurrence of hyperparathyroidism. A second surgical procedure is associated with greater technical difficulties and complications compared to the initial operation. For these reasons, total parathyroidectomy with auto-transplantation of some parathyroid tissue to the forearm has been recommended. Tissue transplanted in this manner may be more accessible if subsequent surgical removal is necessary. To avoid the possibility of persistent hypoparathyroidism, parathyroid tissue should be frozen and stored to be implanted later if necessary. A total parathyroidectomy has little place in the management of uremic hyperparathyroidism because it may lead to a defect in bone mineralization.
References 1. Brown EM, Wilson RE, Eastman RC, Pallotta J, Marynick SP. Abnormal regulation of parathyroid hormone release by calcium in secondary hyperparathyroidism due to chronic renal failure. J Clin Endocrinol Metab. 1982;54:172-179. 2. Silver J, Russell J, Sherwood LM. Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci USA. 1985'82"4270—4273 3. Delmez JA, Tindira C, Grooms P, Dusso A, Windus DW, Slatopolsky E. Parathyroid hormone suppression by intravenous 1,25dihydroxyvitamin D: a role for increased sensitivity to calcium. J Clin Invest. 1989;83:1349-1355. 4. Lopez-Hilker S, Dusso A, Rapp N, Martin KJ, Slatopolsky E. Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol. 1990;F432-F437. 5. Slatopolsky E, Weerts C, Norwood K, Giles K, Fryer P, Finch J, Windus D, Delmez J. Long-term effects of calcium carbonate and 2.5 mEq/liter calcium dialysate on mineral metabolism. Kidney Int. 1989;36:897-903. 6. Mai ML, Emmett M, Sheikh MS, Santa Ana CA, Schiller L, Fordtran JS. Calcium acetate, an effective phosphorus binder in patients with renal failure. Kidney Int. 1989;36:690-695. 7. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest. 1984;74:2136-2143.
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