Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Renal osteodystrophy in end-stage renal failure Donald F. Nortman & Jack W. Coburn To cite this article: Donald F. Nortman & Jack W. Coburn (1978) Renal osteodystrophy in endstage renal failure, Postgraduate Medicine, 64:5, 123-130, DOI: 10.1080/00325481.1978.11714976 To link to this article: http://dx.doi.org/10.1080/00325481.1978.11714976

Published online: 07 Jul 2016.

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Fourth of eight symposium articles in this issue

Renal osteodystrophy in end-stage renal failure Consider What percent ofpatients with renal insufficiency have hyperparathyroidism? What is the role of 1,25-dihydroxycholecalciferol in renal osteodystrophy? How does initiation of maintenance hemodialysis affect calcium levels?

Donald F. Nortman, MD Jack W. Cobum, MD Decreased renal function is accompanied by many metabolic and endocrine changes that affect mineralization of bone. Hyperparathyroidism secondary to renal failure is an important cause of renal osteodystrophy; changes in parathyroid hormone metabolism are closely linked with changes in metabolism of calcium, phosphate, and vitamin D, agents that also affect bone. The term "renal osteodystrophy" in its broadest sense describes a number of skeletal syndromes and the alterations in homeostasis of divalent ions that result from renal insufficiency. The kidney plays a major role in the excretion of calcium (Ca) and inorganic phosphate (Pi), the hormonal activation of vitamin D, and the degradation of parathyroid hormone (PTH). With renal failure, alterations in Ca and Pi homeostasis and in vitamin D and PTH metabolism occur. The body's attempt to maintain homeostasis may result in loss of certain structural and metabolic functions and consequently in the skeletal syndromes that accompany renal failure. Interest in renal osteodystrophy has increased, largely because of widespread availability of hemodialysis and longer survival time of uremic patients. Biochemical and histologic features of renal osteodystrophy may appear in the early or moderate stage of renal insufficiency. However, overt or symptomatic bone disease generally becomes apparent only with end-stage renal failure, and usually not until hemodialysis has been instituted. Pathologic changes in the skeleton Renal osteodystrophy takes several forms (table l) and has a wide variety of skeletal pathologic features (table 2). Osteitis fibrosa, more correctly termed fibroosteoclasia, arises as a result of the secondary hyperparathyroidism that occurs in renal failure. Some feature of excess parathyroid continued

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Phosphate retention is thought to occur early in renal failure but to be compensated for until renal function declines below 25% of normal. Overt hyperphosphatemia and hypocalcemia then ensue.

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Table 1. Definition, features, and presumed pathogenesis of two major forms of renal osteodystrophy Form

Definition, features

Pathogenesis

Fibroosteoclasia (osteitis fibrosa)

Marrow fibrosis, increased osteoclastic resorption, augmented bone turnover, "woven" osteoid

Secondary hyperparathyroidism

Osteomalacia

Impaired mineralization of osteoid (features of secondary hyperparathyroidism often coexist)

Vitamin D deficiency, phosphate depletion, ?magnesium excess, ?fluoride accumulation, ?aluminum accumulation

activity is present in almost 90% of patients with renal insufficiency. PTH activates both osteoclasts and osteoblasts. As bone turnover increases due to increased plasma levels of PTH, strands of collagen laid down by increased osteoblastic activity are irregularly and haphazardly aligned. A "woven" pattern results, in contrast to the regular, lamellar pattern of normal osteoid. The disorganized collagen structure may result in bone with defective physical properties, so that an increased amount of inferior woven bone may be needed to maintain mechanical stability. The presence of increased quantities of woven bone also may contribute to the osteosclerosis of uremia. The pathogenesis of slipped epiphyses in children generally is that of fibroosteoclasia, despite the similarity of this lesion to that of rickets. Osteomalacia, osteoporosis, and growth retardation in children also are forms of renal osteodystrophy. Usually, some feature of secondary hyperparathyroidism coexists with osteomalacia, although defective mineralization may be an isolated finding.

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Pathogenesis Multiple factors contribute to altered metabolism of divalent ions and skeletal disease in uremia (table 3). A consideration of the mechanisms underlying some of these follows.

Phosphate retention and hypocalcemia-Normally the kidney regulates serum Pi level. Tubular resorption is regulated by body Pi stores and by PTH activity. Dietary phosphorus usually is well absorbed regardless of serum Pi level or the state of renal function. In renal disease, factors such as PTH secretion and skeletal response to this hormone, vitamin D deficiency and therapeutic supplementation with vitamin D, and dialysis can affect the serum Pi level. However, dietary intake of phosphorus and also of phosphate-binding antacids is still the most significant determinant of serum Pi level because phosphorus continues to be absorbed fairly well despite the deficiency of 1,25-dihydroxycholecalciferol (l ,25-dihydroxy-vitamin 0 3 ) that accompanies end-stage renal failure. It is thought that transient and undetectable elevations in serum Pi level may occur as renal function decreases in early renal failure. Consequently, because of the reciprocal relationship of Ca and Pi, the blood level of Ca declines; PTH secretion is then stimulated. The increased concentration of PTH reduces renal tubular resorption of Pi (TRP), and serum levels of Pi and Ca thus return toward normal. As renal failure progresses, this process continues. The serum Pi level remains normal until renal function decreases below 25% of normal. Then the capacity of the remaining nephrons to further reduce TRP is exceeded and overt hyperphosphatemia and hypocalcemia ensue. Observations that phosphorus ingestion stimulates PTH secretion in normal man, that reduction in phosphorus content of the diet proportional to the decrease in glomerular filtration rate can largely prevent secondary hyperparathyroidism in

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Lack of the active metabolite of vitamin D may be responsible for reduced intestinal absorption of calcium and phosphate, altered collagen synthesis, and impaired bone mineralization.

experimental renal failure, and that serum level of immunoreactive PTH correlates positively with that of Pi in advanced uremia support this concept. Observations that serum levels of both Pi and Ca are low in patients with mild renal failure are inconsistent with the concept that Pi retention causes hyperparathyroidism in mild renal failure. Abnormal vitamin D metabolism-Both exogenous and endogenous vitamin D undergo 25-hydroxylation in the liver and subsequent 1-hydroxylation in the kidney cortex to form the most potent form of vitamin D, 1,25-dihydroxycholecalciferol. This agent aids intestinal absorption of Ca and Pi, and under certain conditions, mobilizes them from bone. It may aid in bone mineralization in osteomalacia and rickets, may directly inhibit PTH secretion, and has some effect on renal tubular resorption of Ca and Pi. Renal production of 1,25-dihydroxy-vitamin D 3 is stimulated by PTH activity and by low dietary levels of Ca and Pi and is inhibited by high dietary concentrations of these two minerals and by the presence of the vitamin itself. Thus, the kidney is a major endocrine organ in metabolism of Ca, Pi, and vitamin D. In patients with end-stage renal failure, the failure of radiolabeled 25-hydroxy-vitamin D 3 to convert to the 1,25-dihydroxy form and low plasma levels of this form indicate impaired renal production of 1,25-dihydroxy-vitamin D 3• Treatment with the 1,25 form of vitamin D normalizes Ca absorption, lowers serum level of immunoreactive PTH, and often leads to improvement in renal osteodystrophy. Thus, lack of 1,25-dihydroxy-vitamin 0 3 in uremia may be responsible for reduced intestinal absorption of Ca and skeletal resistance to PTH (both of which may lead to or worsen secondary hyperparathyroidism) and for the apparent nonsuppressibility in blood of immunoreactive PTH following Ca infusion. Deficiency of 1,25-dihydroxy-vitamin D 3 also may alter collagen synthesis and impair mineralization and thereby directly contribute to development of os-

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Table 2. Radiologic abnormalities of bone in renal osteodystrophy Osteopenia (reduced density) Features associated with secondary hyperparathyroidism Subperiosteal resorption Cortical striations Cyst formation (brown turner) Slipped epiphysis Mottled ("salt and pepper") skull Periosteal new bone formation Rickets-like lesions (pseudorickets) Osteosclerosis Pseudofractures (Looser's zones) Genu valgum Protrusio acetabuli Vertebrae collapse (crush fracture) Spontaneous rib fracture Osteonecrosis (aseptic necrosis)

Table 3. Pathogenic factors in renal osteodystrophy Hypocalcemia and secondary hyperparathyroidism Phosphate retention Altered metabolism of vitamin D Reduced degradation of parathyroid hormone Skeletal resistance to parathyroid hormone activity Deficiency of calcitonin Defective skeletal mineralization Defective collagen synthesis (?vitamin D related) Abnormal crystal growth and maturation Skeletal accumulation of pyrophosphate and/or magnesium Reduced carbonate content of bone Other (role variable or uncertain) Heparin administration Acidosis Phosphate deficiency Skeletal accumulation of fluoride, aluminum Use of anticonvulsants Vitamin D supplementation Parathyroidectomy

teomalacia. Altered PTH metabolism-Normally, active PTH is secreted into the blood as an 84 amino acid chain, which is quickly degraded by the kidney and liver into smaller, biologically inactive fragments from the carboxyl, or C, end of the peptide chain. The C-terminal fragments are removed continued

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Parathyroid hormone is a major regulatory factor in calcium homeostasis in bone and blood; an excess induces many pathologic changes in the skeleton.

Donald F. Nortrnan (left) Dr Nortman is a fellow in nephrology, Veterans Administration Wadsworth Hospital Center, Los Angeles. He is a native of New Jersey and a graduate of Harvard Medical School. He has performed research on hepatitis at the National Institutes of Health, Bethesda. Jack W. Cobum (right) Dr Coburn, the guest editor of this symposium, is chief, nephrology section, Veterans Administration Wadsworth Hospital Center; professor, department of medicine, University of California School of Medicine, Los Angeles; and coordinator, divisions of nephrology, UCLA Hospitals. He is a native of California and a graduate of UCLA School of Medicine. He has had subspecialty training in metabolism at Wadsworth VA Hospital and has spent two years in the metabolism section of the Waiter Reed Army Medical Center, Washington, DC.

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from the circulation exclusively by the kidney. A major consequence of renal failure is persistence of these fragments in the circulation. This circumstance can result in detection of very high plasma levels of immunoreactive PTH when an antiserum directed toward the C-terminus of the PTH molecule is used for the test and also for the apparent nonsuppressibility of serum immunoreactive PTH mentioned previously. PTH is a major regulatory factor in Ca homeostasis in bone and blood, and excess of PTH induces many of the changes in the skeleton already noted. Although PTH aids resorption of Ca by the renal tubules and reduces resorption of Pi, these effects are insignificant in end-stage uremia. On the other hand, there is considerable evidence that very high serum levels of PTH may have toxic effects on the central and peripheral nervous system, blood vessels, and certain soft tissues. Thus, PTH itself could be considered a "liremic toxin." Skeletal resistance to PTH activity-The skeletal resistance to the ea-mobilizing action of PTH that is seen in renal failure could both create and perpetuate the hypocalcemia and secondary hyperparathyroidism associated with the condition. Infusion of exogenous parathyroid extract or secretion of endogenous PTH fails to elevate serum Ca levels in patients with mild or severe renal failure, an outcome unrelated to blood levels of Ca, Pi, or PTH. Postulated as being responsible is a deficiency of 1,25-dihydroxy-vitamin 0 3 or the presence of uremic metabolites, or both factors. Hypermagnesemia-Hypermagnesemia is common in end-stage renal failure and may contribute to renal osteodystrophy. Because intestinal absorption of magnesium is normal, loss of renal ability to excrete the mineral almost invariably leads to hypermagnesemia unless magnesium intake is curtailed. Ingestion of magnesiumcontaining laxatives and antacids may cause abrupt or marked hypermagnesemia. The level of

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Biochemical changes in blood seen with renal osteodystrophy include hypocalcemia and hyperphosphatemia and elevations in level of alkaline phosphatase and hydroxyproline.

magnesium in dialysate also significantly affects serum levels. Although an acute elevation of serum magnesium level causes suppression of PTH secretion in experimental animals, no data indicate that longstanding hypermagnesemia can mitigate secondary hyperparathyroidism in uremia. Indeed, the condition may be associated with abnormal bone mineralization, possibly owing to accumulation of magnesium pyrophosphate. Other-Loss of carbonate from bone, a consequence of buffering acidosis, and skeletal accumulation of fluoride or aluminum may inhibit normal bone crystal development. When phosphorus intake is reduced and phosphate-binding antacids are overused, hypophosphatemia may occur and lead to impaired bone mineralization. Diets low in protein and Ca, commonly prescribed for uremic patients, may worsen renal osteodystrophy. Biochemical features of renal osteodystrophy Biochemical changes in blood seen with renal osteodystrophy are shown in table 4. Hypocalcemia is common and may be mild to severe. Because complexing of Ca to various anions and proteins may increase in uremia, the blood level of ionized Ca actually may be lower than that calculated on the basis of total serum Ca concentration. Serum Pi levels, regulated by the factors already noted, commonly are elevated when the glomerular filtration rate falls below 20% to 25% of normal. An elevated serum level of alkaline phosphatase may be a consequence either of fibroosteoclasia or of osteomalacia and presumably is evidence of increased osteoblastic activity. An increased plasma hydroxyproline level may be an index of increased collagen turnover. (Assay for plasma hydroxyproline is not widely available in the United States.) The cyclic adenosine monophosphate (cAMP) level is elevated in plasma, although correlation is slight between level of eA MP and degree of secondary

Table 4. Biochemical changes in blood seen in renal osteodystrophy

Hyperphosphatemia Hypocalcemia Hypermagnesemia Elevated serum level of immunoreactive parathyroid hormone Reduced plasma level of 1,25-dihydroxycholecalciferol Elevated serum level of alkaline phosphatase Elevated plasma level of hydroxyproline Elevated plasma level of cyclic adenosine monophosphate Hypercalcemia (occasional) Hypophosphatemia (occasional) Elevated level of calcitonin

hyperparathyroidism. With initiation of regular hemodialysis, the reduced levels of both total and ionized Ca tend to increase toward normal. The reason is uncertain. Although an increase in Ca level may be related to a reduction in serum Pi level, it can occur despite persistent hyperphosphatemia. Signs and symptoms The signs and symptoms of uremic bone disease (table 5) vary widely in incidence and severity. Skeletal pain, fortunately uncommon, can become debilitating. It generally is vague, deepseated, inconstant, and variable. It may occur in the lower back, hips, legs, or knees and may be aggravated by weight bearing. The symptoms do not correlate well with radiologic or histologic evidence of severity of disease or with the type of pathologic skeletal change. Muscular weakness, primarily of the proximal muscles, may be a feature of renal osteodystrophy. Initially, the patient may note difficulty in climbing stairs or rising from a sitting position. As the problem progresses, walking becomes difficult and a waddling, penguin-like gait may appear. Manifestations may be identical to those of vitamin D deficiency from other causes. Pruritus sometimes is related to altered Ca metabolism. An elevated blood level of ionized Ca

continued

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An x-ray film of the hands made with fine-grain film is the best method to obtain radiologic evidence of renal osteodystrophy. Subperiosteal resorption will be found in a large number of patients on dialysis.

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Table 5. Some clinical manifestations of the metabolic alterations associated with uremia Acute periarthritis Altered mentation Bone pain Calciphylaxis Fractures Growth retardation Hypertension Impotence Muscle cramps

Myopathy Neuropathy Pancytopenia Pruritus Pseudogout Skeletal deformities Spontaneous tendon rupture

may contribute to pruritus in patients recelVlng too much vitamin D, those treated with dialysate containing a high Ca concentration, and those with overt secondary hyperparathyroidism. Resolution of pruritus in this last group commonly follows subtotal parathyroidectomy or treatment with an appropriate dosage and type of vitamin D. Bone deformities and growth retardation are frequent in uremic children; slipped epiphyses may aggravate the deformities. In adults, bone deformities may arise in association with fractures or because of marked derangement of the skeletal remodeling process. Occasionally, severe and totally debilitating bone pain and deformities develop over a period of months in previously stable active patients on hemodialysis. The deposition of Ca and Pi around joints and in the skin may cause painful lesions. Periarthritis with acute pain, redness, and swelling about one or more joints often is caused by the deposition of hydroxyapatite crystals. An unusual syndrome, calciphylaxis, is characterized by peripheral ischemic necrosis and vascular calcifications. Progressive lesions may develop in patients with advanced renal failure, whether or not on dialysis, or in recipients of a renal transplant. The lesions may begin as painful, violaceous mottling of the skin and progress to penetrating gangrenous ulcerations of fingers, toes, ankles, thighs, or buttocks. The lesions heal poorly and often lead to death from secondary infection. A history of marked

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hyperphosphatemia and elevated blood levels of immunoreactive PTH is common. Subtotal parathyroidectomy usually leads to regression. Radiologic features The types of radiologic abnormalities of bone that occur in renal osteodystrophy (table 2) and their incidence vary considerably in different dialysis centers. The variation may reflect true differences related to patient age, type of management, and duration of dialysis. However, the techniques employed, the type of film used, and the interest of the radiologist also account for differences. Physicians should insist that x-ray films of the hands be made with the use of fine-grain film, such as that employed for mammography. With such films and magnification techniques, abnormalities can be found in a large number of patients on dialysis. Subperiosteal resorption, or erosion, is the most common specific feature of secondary hyperparathyroidism. It occurs in the phalanges, pelvis, distal ends of the clavicles, interior surfaces of the ribs, femur, mandible, and skull. In the hand, the tuft of the terminal phalanx commonly shows such resorption. If hand x-ray films obtained using appropriate techniques are normal, bone resorption probably will not be found elsewhere in the skeleton. Cortical striations and cystic lesions sometimes accompany subperiosteal resorption, and periosteal new bone formation appears in a sizable number of dialysis patients as a consequence of secondary hyperparathyroidism. Abnormalities in the growth zone of bone occur in children with end-stage uremia and secondary hyperparathyroidism. Unlike true rickets, hyperparathyroidism produces no widening of the metaphyseal zone. Osteosclerosis, appearing as increased density of trabecular bone, is seen most commonly in the vertebral bodies, pelvis, ribs, skull, and leg bones; it is common in young patients, particularly those with other radiologic

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features of hyperparathyroidism. Several types of soft-tissue calcification complicate end-stage renal failure. They usually are first observed on x-ray film. The presence of an increase in the product of serum Ca and Pi, secondary hyperparathyroidism, alkalosis, and local tissue injury predispose to calcification. The lesions may involve the sclera, conjunctiva, skin, and periarticular areas. Soft-tissue calcification also may occur in the blood vessels, heart, and lungs and thus may contribute to calciphylaxis, disturbances of cardiac conduction, and restrictive lung disease. Prevention, management, and treatment The general objectives of therapy for renal osteodystrophy are (I) suppression of secondary hyperparathyroidism, (2) induction of normal mineralization of osteoid, (3) maintenance of near-normal blood concentrations of Ca and Pi, (4) correction of acidosis, and (5) prevention of extraosseous calcification. The cornerstones of prevention and management are the control of hyperphosphatemia and maintenance of normal blood Ca levels. In advanced uremia, modest restriction of dietary phosphorus to 800 to 1,000 mgjday, combined with the use of appropriate amounts of aluminum hydroxide or aluminum carbonate to bind Pi in the intestine, will lower the serum Pi level to normal. Modern efficient dialyzers also remove a significant amount of Pi. The reduction of serum Pi level to normal often is associated with a small increase in serum Ca level, a fall in serum immunoreactive PTH level, and a reduced incidence of overt signs of secondary hyperparathyroidism. However, secondary hyperparathyroidism may persist or progress in certain patients. One hypothesis is that dietary phosphorus restriction and administration of phosphate binders early in the course of renal insufficiency will prevent secondary hyperpara-

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thyroid ism. When hypercalcemia is appropriately controlled, serum Ca level can be increased to normal by the use of appropriate amounts of Ca in dialysate and in oral supplements. Use of dialysate containing 3.0 to 3.5 mEqjliter, which slightly exceeds the level of serum Ca not bound to protein, usually produces a small positive Ca balance during dialysis. Skeletal disease is less likely to progress with use of dialysate containing Ca in this range, while levels above 3.5 mEqjliter may increase the risk of extraskeletal Ca deposition. Dairy products, the foods highest in Ca content, also are rich in phosphorus and thus usually are restricted in renal failure. Oral Ca supplements, such as calcium carbonate or lactate, are needed to raise total Ca intake to 1.5 to 2.0 gm/day and prevent negative Ca balance. Since the skeletal deposition of magnesium and fluoride may aggravate uremic bone disease, the removal of fluoride from tap water and appropriate lowering of magnesium concentration in dialysate and diet also are important considerations. Control of uremic acidosis with use both of oral alkali, ie, sodium bicarbonate or citrate, and of appropriate levels of acetate in dialysate may reduce the loss of carbonate from bone. Despite adherence to these maneuvers, progressive and disabling bone disease continues to develop in significant numbers of dialysis patients. Those with evidence of secondary hyperparathyroidism may respond favorably to treatment with an active form of vitamin D, particularly I,25-dihydroxy-vitamin D 3; a fall in serum levels of immunoreactive PTH, improvement of symptoms, and amelioration of radiologic and histologic abnormalities may occur. Parathyroidectomy may be useful in patients with elevated levels of immunoreactive PTH and evidence of overt secondary hyperparathyroidism, particularly if hypercalcemia coexists. The healing of the bone lesions of osteomalacia may occur more slowly durcontinued

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Therapy alms at suppressing secondary hyperparathyroidism, Inducing normal mineralization of osteoid, maintaining normal blood concentrations of calcium and phosphate, and preventing extraosseous calcification.

ing treatment with vitamin D or 1,25-dihydroxyvitamin 0 3 than is the case for fibroosteoclasia, perhaps because of slower skeletal turnover in osteomalacia. A subgroup of patients may exhibit a mineralizing defect or osteomalacia in the absence of evidence of secondary hyperparathyroidism. The cause is unknown, but does not seem to relate to abnormal levels of Ca or Pi in plasma or to absence of I ,25-dihydroxy-vitamin 0 3• Summary

production of 1,25-dihydroxycholecalciferol (the most active form of vitamin D) are all interrelated and pathogenetic features of renal osteodystrophy. Types of abnormalities detected radiologically vary with patient age, type of management, and duration of hemodialysis, as well as with techniques and type of film used and interest of the radiologist. An x-ray film of the hands should always be made-it will show subperiosteal resorption in a large number of patients on dialysis. Prevention and management of renal osteodystrophy hinge on control of hyperphosphatemia and hypocalcemia.

Renal osteodystrophy has many skeletal pathologic features, eg, fibroosteoclasia (osteitis fibrosa), osteomalacia, osteopenia, pseudofracture, cyst formation, and osteosclerosis. Many of these are caused by the secondary hyperparathyroidism that usually accompanies renal failure. Derangements in parathyroid hormone secretion, calcium and phosphate metabolism, and renal

CME Credit Quiz begins on page 197.

Bibliography Avram MM, Feinfeld DA, Huatuco AH: Search for the uremic toxin. N Engl J Med 298:1000-1003, 1978 Bricker NS, Slatopolsky E, Reiss E, et al: Calcium, phosphorus and bone in renal disease and transplantation. Arch Intern Med 123:543-553, 1969 Brickman AS, Coburn JW, Norman AW: Action of 1,25-dihydroxycholecalciferol, a potent, kidney-produced metabolite of vitamin 0 3, in uremic man. N Engl J Med 287:891-895, 1972 Cobum JW, Hartenbower DL: Physiology of calcium, phosphorus and magnesium, and disorders affecting their metabolism. In Gonick HC (Editor): Current Nephrology. Los Angeles, Pinecliff Medical Publishing Co, 1977 Coburn JW, Hartenbower DL, Brickman AS: Advances in vitamin D metabolism as they pertain to chronic renal disease. Am J Clin Nutr 29:1283-1299, 1976 Cobum JW, Llach F: Renal osteodystrophy and maintenance dialysis. In Drucker W, Parsons FM, Maher JF (Editors): Replacement of Renal Function by Dialysis. The Hague, Holland, Martin us Nijhoff BV, Publishers, 1978, pp 571-600 DeLuca HF: The kidney as an endocrine organ involved in calcium homeostasis. Kidney lnt 4:80-88, 1973 - - : Metabolism of vitamin D: Current status. Am J Clin Nutr 29:1258-1270, 1976

Hill LF, Stanbury SW: Vitamin D and the kidney. Nephron I5:369-386, 1975 Hruska KA. Kopelman R, Rutherford WE, et al: Metabolism of immunoreactive parathyroid hormone in the dog: The role of the kidney and the effects of chronic renal disease. J Clin Invest 56:39-48, 1975 lbels LS, Alfrey AC, Haut L, et al: Preservation of function in experimental renal disease by dietary restriction of phosphate. N Engl J Med 298:122-126, 1978 Massry SG, Coburn JW, Lee DB, et al: Skeletal resistance to parathyroid hormone in renal failure. Ann Intern Med 78:357-364, 1973 Mawer EB, Backhouse J, Taylor CM: Failure of formation of 1,25-dihydroxycholecalciferol in chronic renal insufficiency. Lancet I:626-628, 1973 Parfitt AM: Clinical and radiographic manifestations of renal osteodystrophy. In David DS (Editor): Calcium Metabolism in Renal Failure and Nephrolithiasis. New York, John Wiley & Sons, 1976 Reiss E, Canterbury JM, Bercovitz MA, et al: The role of phosphate in the secretion of parathyroid hormone in man. J Clin Invest 49:2146-2149, 1970 Trohler U, Bonjour JP, Fleisch H: Renal tubular adaptation to dietary phosphorus. Nature 261:145-146, 1976

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Supponed in pan by US Public Health Service grant AM 14750.and by Veterans Administration research funds. Address reprint requests to Jack W. Coburn, MD, Nephrology Section, Veterans Administration Wadswonh Hospital Center, Wilshire and Sawtelle Blvds, Los Angeles, CA 90073.

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Renal osteodystrophy in end-stage renal failure.

Postgraduate Medicine ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20 Renal osteodystrophy in end...
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