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Renal Osteodystrophy
Symposium on Pediatric Nephrology
Renal Osteodystrophy Mary G. Beale, M.D.,* Jose R. Salcedo, M.D.,t Demetrius Ellis, M.D.;+ and David D. Rao, M.S.§
Pediatricians involved in the care of children with chronic renal disease may have by necessity directed their attention toward controlling the complications of uremia, such as anemia, hypertension, growth failure, and renal osteodystrophy. Various treatment modalities introduced even during the early stage of the child's illness have been palliative at best. Recent discoveries in vitamin D metabolism have changed the traditional management of renal osteodystrophy by offering specific intervention through administration of active vitamin D metabolites and analogs. Current concepts on the pathogenesis and treatment of uremic bone disease form the basis of this review.
VITAMIN D The discovery that vitamin D is further metabolized to more active forms in man stands as a landmark in modern medical history. As early as 1943, Liu and Chu observed that patients with renal osteodystrophy were in negative calcium balance and that high doses of vitamin D did not increase intestinal calcium absorption. 63 Their work was confirmed and extended 20 years later by Dent et al. 28 and Stanbury and Lumb85 who demonstrated that calcium malabsorption in uremic patients could be overcome if very large doses of vitamin D were administered. The basis for the relative vitamin D resistance in renal failure can now be explained by the kidney'S role in endogenous vitamin D metabolism. The availability in the 1960's of a highly specific tritiated vitamin D and column chromatography made it possible to demonstrate more polar "Instructor in Child Health and Development, George Washington University School of Medicine and Fellow in Nephrology, Children's Hospital National Medical Center, Washington, D.C. tInstructor in Child Health and Development, George Washington University School of Medicine and Fellow in Nephrology, Children's Hospital National Medical Center, Washington, D.C. :;:Fellow in Nephrology, Children's Hospital National Medical Center, Washington, D.C. §Research Associate, Department of Nephrology, Children's Hospital National Medical Center, Washington, D.C. Supported in part by the Ruth and Arnold Orleans Kidney Research Fund, Washington Heart ASSOCiation, and NIH Grant RR-00284.
Pediatric Clinics of North America-Vol. 23, No.4, November 1976
873
874
MARY
2'~O~OH ~
~ CH,
CH, HO
HO
vitamin 0 3
CH, HO
25·0H·0 3
G.
BEALE ET AL.
Figure 1. The activating pathway of vitamin Da is depicted.
OH 1.25·{OH),·03
metabolites in circulating plasma. 67 When the labeled compound was given in physiologic amounts to animals, the radioactivity eventually concentrated in bone, intestine, and kidney. 67 Using the tritiated vitamin D in pigs, Blunt et al. 13 were able to isolate and identify the first polar metabolite, 25-hydroxyvitamin Da (25-0H-Da) (Fig. 1),13 The compound was successfully synthesized in 196912 and subsequently demonstrated to act directly on bone and intestine in vitro. 69 , 75 The site of conversion resides in the liver microsomes. l l , 70 The rate of reaction is regulated by substrate availability and the hepatic level of 25-hydroxyvitamin Da. Using competitive protein-binding techniques circulating levels of the hepatic metabolite have been measured in man. 9, 39 The values have been found to be low in a significant percentage of individuals receiving chronic anticonvulsants. 41 The mechanism is uncertain but an increase in the conversion of vitamin Da and 25hydroxy vitamin Da to polar, inactive metabolites has been postulated. 40 In view of the fact that antiepileptics are widely used in uremic children with seizure disorders, their potentially adverse effect on vitamin D metabolism should be recognized. In 1968 another polar vitamin D metabolite present in intestine was reported by Haussler et al. 47 and confirmed by Lawson et al. 62 In 1970 Fraser and Kodicek made the important discovery that the kidney was the sole site of formation of the newly recognized metabolite. 31 Even before it had been fully identified, studies showed that the compound acted more rapidly and more potently on intestinal calcium absorption and bone calcium mobilization than 25-hydroxyvitamin Da. 46 In 1971 the structure was simultaneously identified in two different laboratories, as 1,25-dihydroxyvitamin D3 (1,25-(OH)zD a) (Fig. 1).51,61 A year later it was successfully synthesized. 81 The most active vitamin D metabolite presently known is 1,25dihydroxyvitamin D 3. It is the major form of vitamin D present in both intestine and bone at the time of maximal intestinal calcium absorption. 32 , 33, 90 Its precursor, 25-0H-D3, is unable to stimulate bone calcium mobilization 49 or intestinal calcium absorption 15 and phosphate 23 absorption in nephrectomized animals. The conversion of 25-0H-Da to 1,25(OH)2D3 is therefore necessary for the antirachitic effects of vitamin D under physiologic conditions. In chronic renal failure, the hydroxylation of 25-0H-D3 to form 1,25(OH)zD a is impaired, resulting in changes in bone structure associated with pain, deformity, and fractures. In order to understand the pathogenesis of renal osteodystrophy, it is necessary to focus briefly on the factors controlling 1,25-(OH)zD3 production. For more detailed discussions of the subject the reader is referred to several recently published reviews.5, 25, 26, 60, 68
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Regulation of 1,25-(OHhD3 Synthesis The mitochondria of renal cells 37 are the site of conversion of 25-0H-D3 to 1,25-(OH)2D3' Hypocalcemia stimulates the production of 1,25-(OH)2D3' whereas normal or elevated calcium levels promote the formation of another metabolite,50 24, 25-dihydroxyvitamin D3 (24,25(OH)2D3' The 24-hydroxylase system is also located in the renal mitochondria and requires the presence of 1 ,25-(OH)2D3 for its induction. 59,88 In the absence of parathyroid hormone (PTH), production of 1,25-(OH)2D3 is curtailed even when dietary intake of calcium is low, demonstrating that the kidney's response to hypocalcemia is mediated through the parathyroid gland. 34 Normally, hypocalcemia stimulates PTH secretion. In the kidney, PTH stimulates 1,25-(OH)2D3 formation. In the intestine, 1,25-(OH)2D3 facilitates calcium absorption. In the bone, it increases calcium mobilization in the presence of PTH.35 It is possible that 1,25(OH)2D3 and PTH also enhance renal tubular reabsorption of calcium. 25, 86 The end result of this complex metabolic sequence is the restoration of a normal serum calcium concentration and removal of the stimulus to parathyroid hormone release (Fig. 2). In patients with renal failure, the normal trophic relationship between PTH and vitamin D is interrupted. 2 Decreased intestinal calcium absorption which is relatively resistant to vitamin D administration appears when the glomerular filtration rate falls below 25 to 30 ml/minute. 2 The reduction has been attributed to low 1,25-(OH)2D3 production rather than uremia per se. Moreover, 1,25-(0 H)2D3 cannot be detected in the sera of patients with chronic renal failure. 66 The serum phosphate concentration also plays a regulatory role in 1,25-(OH)2D3 synthesis. Animal studies 89 have shown that in the thyroparathyroidectomized state, hypophosphatemia stimulates formation of 1,25-(OH)2D3' When the phosphate concentration is normal or increased, 24,25-(OH)2D3 is the predominant metabolite. Changes in serum phosphate are reflected in the renal cortical phosphate content. Since PTH depresses renal cortical levels of phosphate by inhibiting tubular phosphate reabsorption, it has been postulated that the intracellular phosphate level ultimately determines the rate of 1,25-(OH)2D3 production. 26 Evidence that 1,25-(OH)2D3 augments phosphate transport independently of calcium in the intestine 23 and quite possibly the renal tubules 45 . 74 lends further support to a mechanism in which phosphate regulates 1,25-(OH)2D3 synthesis. The importance of phosphate in the development of renal osteodystrophy was recognized several years ago by Bricker, Slatopolsky et al., who suggested that phosphate retention was the primary event leading to renal osteodystrophy.17 According to their hypothesis, uremic patients
I Figure 2. Schematic representation shows feedback loop between serum calcium, parathyroid hormone and 1,25-(OH)2Da.
I . I ntestma. Ca absorptIOn
.P1asr .,.
(ca++'~
t
PTH secretion
L1'1,25.(OH'2 D 3
•
Bone resorption
I
-----..-J
876
MARY
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BEALE ET AL.
experienced transient elevations in serum phosphate concentration as the total number of functioning nephrons declined. The rise in phosphate, caused a reciprocal fall in calcium which acted as a stimulus for PTH secretion. A normal phosphate concentration was restored by the inhibitory action of PTH on renal tubular phosphate reabsorption. Stated another way, phosphate homeostasis was maintained at the expense of PTH overactivity.16 As a clinical application of the Bricker hypothesis 16 , 17 patients are given oral phosphate binding gels and low phosphate diets to control the progression of renal osteodystrophy. The possibility that hyperphosphatemia inhibits 1,25-(OH)2Da synthesis provides additional rationale for aggressive control of the serum phosphate concentration. Much remains to be learned about the relative importance and interaction of these two factors, i.e, increased parathyroid hormone secretion and reduced 1,25-(OH)2Da production, in the pathogenesis of uremic bone disease. New methods of measuring serum 1,25-(OH)2Dalevels on a broad scale should make it possible to quantitatively delineate the role of the active metabolite in renal osteodystrophy.
Parathyroid Hormone The current status of PTH assays warrants discussion. In 1968 Berson and Yalow proposed the idea that more than one molecular species of PTH was present in the circulation. 10 A number of investigators independently demonstrated in 1970 and 1971 that glandular PTH and secreted hormone were immunologically different and had different molecular weights. a, 4, 38, 73, 83. 84 Attempts to prepare a monovalent radioimmunoassay to human PTH have been hindered by the heterogeneity of hormonal fragments present in the circulation. Nonetheless, aminospecific and carboxyl-specific antisera have been developed for clinical use. Their application in uremic individuals has provided important insight into the functional changes in parathyroid gland activity associated with chronic renal disease. PTH levels using C-terminal antisera are uniformly elevated in patients on hemodialysis while values obtained from N-terminal antisera may fall within the normal range. 36 A prompt reduction in PTH secretion during calcium infusions can be demonstrated using N -terminal antisera at a time when little or no change is detected with C-terminal antisera. 36 Impaired degradation on N-terminal and particularly C-terminal fragments in uremia compounds the difficulty in interpreting results of PTH assays.53 Nevertheless, there is increasing evidence to suggest that the measurement of the N-terminal fragment is a sensitive indicator of acute changes in parathyroid gland activity, whereas the C-terminal fragment more closely reflects the chronic state of hormonal secretion. 36
Vitamin D Analogs Several vitamin D derivatives have been evaluated in patients with uremic bone disease. Recent studies have shown that dihydrotachysterol (DHT) undergoes 25-hydroxylation in the liver to form 25-0H-DHT (Fig. 3).43 A 180 rotation in the A ring of the molecule places the 3 betahydroxyl group in the 1 alpha position, eliminating the need for further processing by the kidney.42.44 Hence, 25-0H-DHT functions as the biologically active form of DHT. Two other compounds in which the 0
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RENAL OSTEODYSTROPHY
£f 1
'
Figure 3. Vitamin D analogs which are biologically active due to the hydroxy moiety in the carbon-lor pseudo carbon-l position are demonstrated.
I
OH
HO
DHT
I
I
H
1a-OH·D.
f"C" ~OH • • OH
5.6 trans D.
5.8 trans-25-0H-D.
3-hydroxyl moiety occupies the pseudo 1a position have been synthesized and studied in a limited number of patients: 5,6 trans Da and 5,6 trans25-0H-Da.87, 92 Their activity 48 is 100 to 1000 times less than the equivalent amount of 1,25-(OH)2Da. In 1973 an analog of 1,25-(OH)2Da, 1 alpha-hydroxyvitamin Da (laOH-Da), was synthesized from cholesterol (Fig. 3).6,52 In vivo studies have shown that the analog has approximately half the antirachitic potency of 1,25-(OH)2Da on a similar weight basis. 6,24,52 It is now known that 1a-OH-Da is converted to 1,25-(OH)2Da before acting on peripheral sites. 27 • 93
CLINICAL FEATURES Virtually all hemodialysis patients have histologic evidence of hyperparathyroidism on bone biopsy.29 The frequency of radiologic abnormalities ranges from 25 per cent56 to 50 per cent29 in adult studies and from 45 per cent30 to 58 per cent71 in pediatric series. In a survey of 84 children from nine European hemodialysis centers the incidence of bone pain was 10.5 per cent; skeletal deformities were reported in 18. 8 per cent.78 Potter et aI. have found a close correlation between the duration of uremia and the development of bone changes in children. 72 The importance ofprevention and treatment of renal osteodystrophy has been underscored by the serious problem of growth failure in chronic renal disease. Children with severe bone involvement do not grow well; moreover, their statural growth lags behind their rate of bone maturation, resulting in a permanent loss of height potential. 20 The need for judicious and aggressive 'medical control is readily apparent. Bone biopsies are being performed with increasing frequency in patients undergoing treatment for renal osteodystrophy. When the biopsy is taken from the iliac crest, the procedure can be carried out under local anesthesia on an outpatient basis. Direct examination of the tissue is the most definitive means of assessing the relative influence of increased PTH and decreased 1 ,25-(OH)2Dalevels on bone. In chronic renal disease, bone formation is generally reduced and the percent of osteoid bearing a calcification front is decreased. 76. 77 When bone resorption continues, the histology is consistent with hyperparathyroidism. If bone formation oc-
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curs under hypocalcemic or hypophosphatemic conditions, the volume of osteoid increases and the pathology is more typical of rickets. 55 Often, features of osteitis fibrosa cystic a and rickets can be seen in a single biopsy specimen. Although serial performance of bone biopsies is now considered the most reliable means of evaluating treatment efficacy, PTH levels can offer excellent monitoring of secondary hyperparathyroidism. Skeletal x-rays are a less sensitive but noninvasive means of detecting bone involvement. Hyperparathyroid changes are more frequently seen than rachitiform lesions in North America because of vitamin D supplements in the diet. The earliest radiologic abnormalities appear in the hands as subperiosteal erosions of the terminal phalanges. With more advanced disease, there may be resorption of the distal clavicles and erosion of the symphysis pubis and the sacroiliac joints. Flaring and irregularity along the epiphyseal plates oflong bones are typical signs of rickets. If not controlled, skeletal changes can progress to crippling deformities and pathologic fractures. Normally the skeleton serves as a reservoir of calcium and phosphate for the circulation. The release of ions is mediated through parathyroid hormone and 1,25-(OH)2D3.77 Calcitonin prevents release of calcium and phosphorus from the bone. In renal failure, bone becomes resistant to the calcemic action of PTH,64 but this resistance to PTH is more apparent than real in view of the fact that in chronic renal failure there is less calcium available from the bone for such release. Indirect evidence has suggested 65 that the blunted calcemic response is due to insufficient synthesis of 1,25-(OH)2D3. The net effect is a fall in serum calcium concentration which is further compounded by calcium malabsorption and reduced renal phosphate excretion. The parathyroid gland receives a continuous hypocalcemic stimulus, resulting in glandular hyperplasia and increased hormonal secretion. Hence, the typical serologic findings in patients with untreated renal osteodystrophy are hyperphosphatemia, elevated PTH, and increased alkaline phosphatase. Most patients with renal osteodystrophy in the United States have normal serum calcium levels and only those with osteomalacia or hypoalbuminemia show decreased serum calcium levels. There is a marked difference in the frequency of osteomalacia in England as compared to North America. The disparity may be related to previous vitamin D intake. Soft Tissue Calcification Metastatic soft tissue calcification is a rare complication of chronic renal failure in children. When it does occur, the most common site is the conjunctiva. 71 The condition is usually asymptomatic but occasionally leads to local inflammation. Vascular and periarticular calcifications have been described in a few pediatric patients. 71 Pruritus, a particularly disturbing symptom in uremia, is believed to result from calcium deposition in the skin. Treatment is directed toward controlling the serum calcium and phosphate concentrations. If serum phosphorus is lowered and adequate vitamin D is given, ectopic calcification is resorbed and there is rarely need for parathyroidectomy.
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THERAPY The medical management of renal osteodystrophy necessitates a combined therapeutic approach with the aims of simultaneously lowering serum phosphate, raising serum calcium, and restoring normal vitamin D activity. The serum phosphate level is controlled through the oral administration of phosphate binding gels, usually in the form of aluminum hydroxide at 1 to 2 gm daily. Overzealous treatment can result in phosphate depletion and further bone demineralization. 58 Hence the dosage should be reduced when the serum phosphate falls to physiological levels. Although aluminum-containing phosphate binding gels have been regarded as harmless, a recently published study reported increased levels of aluminum in muscle, bone, and brain of hemodialysis patients receiving aluminum antacids. 1 Moreover, the highest brain gray-matter aluminum values were found in a group of 10 patients who succumbed to an unexplained neurologic disorder.1 While the evidence is inconclusive, the data suggest that prolonged usage may have subtle and even toxic effects. The calcium intake of uremic patients averages only 300 to 500 mg per day due to anorexia and dietary protein restriction. In the absence of the active vitamin D metabolite, ingested calcium is poorly absorbed, resulting in either low or negative calcium balance. 63 Oral calcium supplementation with 1 to 2 gm of elemental calcium per day as calcium carbonate should be started when the glomerular filtration rate reaches 20 to 25 ml per minute. Patients already receiving hemodialysis can be dialyzed against dialysate calcium concentrations which will insure net positive calcium transfer to the patient. A minimum concentration of6.0 mg/dl is necessary to achieve such an end. 91 Improvement of hyperparathyroid bone changes has been reported in patients dialyzed at a calcium level of 7.0 to 8.0 mgldl. 54 However, the risk of causing metastatic calcification is significantly greater than with lower levels of calcium. The magnesium concentration influences PTH secretion in the same manner as calcium, i.e., low concentrations stimulate and high concentrations inhibit PTH synthesis and release. 82 For this reason, a high dialysate magnesium concentration of2.0 to 2.5 mgldl is used in some dialysis centers for patients with clinical hyperparathyroidism. 79 Conversely, demonstration of excessi ve magnesium levels in bone analyses from uremic patients has led other centers to use dialysate solutions containing no magnesium. Until more data are available concerning the role of magnesium in renal osteodystrophy, it is advisable to avoid states of either magnesium excess or depletion. Before 25-0H-D3 was synthesized in 1969, three forms of vitamin D were used in the treatment of renal osteodystrophy: vitamin D3 (cholecalciferol), vitamin D2 (calciferol), and dihydrotachysterol (DHT). These compounds are still being widely prescribed because of the limited availability of more active metabolites. Pharmacologic dosages of vitamin D ranging from 30,000 to 75,000 IU (1 IU = 0.025 fJ-g) per day have been reported to reverse hyperparathyroid bone disease in children receiving hemodialysis even in anephric patients. 71 • 72 Similarly, radiologic, histologic, and biochemical improvement have been achieved with DHT in dosages of 0.25 to 0.50 mg per day. 57. 71
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Despite its success, there is narrow separation between the toxic level and therapeutic range of vitamin D. Hypercalcemia and metastatic calcification are the most frequent complications encountered. Since vitamin D is a nondialyzable molecule and stays in body storage sites for months and even years after large amounts have been given, its actions, both beneficial and harmful, cannot be easily modified. Limited clinical studies have been conducted with the active vitamin D metabolites, 25-0H-D3 and 1,25-(OH)2D3' and with 1a-OH-D3 , a synthetic analog of 1,25-(OH)2D3' Orally administered 25-0H-D3 at a dosage of 100 J,Lg per day increased intestinal calcium absorption, reduced serum parathyroid concentration, and improved bone histology in patients with renal osteodystrophy.14 Since its potency is not significantly reduced in anephric individuals 80 and extrarenal sites of 1 hydroxylation have not been identified, it is assumed that the compound functions as an analog of 1,25-(OH)2D3 when used pharmacologically. In very small doses, 1,25-(OH)liD3 has been highly successful in the treatment of renal osteodystrophy. Brickman et al. observed a rise in serum calcium and phosphate concentration and an increase in intestinal calcium absorption in three adult uremic patients receiving 2. 7 J,Lg per day of 1,25-(OH)2D3 orally for 6 to 10 days.18 In a larger study involving 30 patients and extending over 3 to 7 months, administration of 0.14 to 2.0 J,Lg per day of 1,25-(OH)2D3 corrected biochemicallUld radiologic abnormalities, increased muscle strength and alleviated bone pain in a high percentage of symptomatic patients. 19 Zen graff et al. reported a fall in PTH secretion and an increase in bone cell activity in six patients receiving either 1,25-(OH)2D3 or 1a-OH-D3 , 5 J,Lg three times a week for a total of three weeks. 92 The analog 1 a-OH-D 3 appears to retain all the known biologic functions of 1,25-(OH)2D3' Chan et al. demonstrated improved calcium balance, a fall in PTH secretion and a rise in serum calcium in two uremic children given only 2 J,Lg per day for 6 to 9 days. 21.22 Long-term studies of 16 " to 19 months have shown that 1 a-OH-D 3 can effectively reverse hyperparathyroid bone disease although several months of treatment may elapse before metabolic and radiologic improvement are documented. 7 • 8. 22 The only recognized side effect of the new vitamin D derivatives is hypercalcemia. If detected early, the elevation can be easily controlled by reducing or discontinuing treatment. Until more extensive experience with this kidney hormone becomes available, the use ofthis compound in our institution is monitored by monthly determinations of serum calcium, phosphate, and alkaline phophatase to detect hypercalcemia and to evaluate therapeutic response. To quantitate reversal of the secondary hyperparathyroidism, PTH levels are also obtained serially every three months. The optimal dosage of 1a-OH-D3 or 1,25-(OH)2D3 will have to be titrated against the clinical, biochemical and radiologic status of the patient. Two important questions remain unanswered. One relates to the long-term efficacy of 1,25-(OH)2D3 and whether or not the drug is sufficient to control renal osteodystrophy over an extended period of several years. The second issue pertains to 1,25-(OH)2D3 prophylaxis and whether early administration of small amounts of the compound to uremic patients can prevent bone disease. Resolution of these questions will be a major focus for further clinical investigation.
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REFERENCES 1. Alfrey, A. C., LeGendre, G. R., and Kauhny, W. D.: The dialysis encephalopathy syndrome. New Engl. J. Med., 294:184, 1976. 2. Arnaud, C. D.: Hyperparathyroidism and renal failure. Kidney Int., 4:89, 1973. 3. Arnaud, C. D., Sizemore, G. W., Oldham, S. B., et al.: Human parathyroid hormone: Glandular and secreted molecular species. Am. J. Med., 50:630,1971. 4. Arnaud, C. D., Taso, H .. S., and Oldham, S. B.: Native human parathyroid hormone: An immunochemical investigation. Proc. Nat. Acad. Sci. U.S.A., 67:415, 1970. 5. Avioli, L. V.: Vitamin D metabolism in uremia. Kidney, 8:1,1975. 6. Barton, D. H. R., Hesse, R. H., Pechet, M. M., et al.: A convenient synthesis of 1 ahydroxy-vitamin Da. J. Am. Chem. Soc., 95:2748,1973. . 7. Beale, M. G., Chan, J. C. M., Oldham, S. B., et al.: Vitamin D: The discovery of its metabolites and their therapeutic applications. Pediatrics, 57:729, 1976. 8. Beale, M. G., Chan, J. C. M., Oldham, S. B., etal.: Management of renal osteodystrophy in two pediatric hemodialysis patients receiving I-alpha hydroxyvitamin Da. Abstracts. Am. Fed. Clin. Res., Boston, January 8-10, 1976. 9. Belsey, R., DeLuca, H. F., and Potts, J. T., Jr.: Competitive binding assay for vitamin D and 25-0H vitamin D. J. Clin. Endocrinol. Metab., 33:554,1971. 10. Berson, S. A., and Yalow, R. S. : Immunochemical heterogeneity of parathyroid hormone in plasma. J. Clin. Endocrinol., 28:1037,1968. 11. Bhattacharya, M. H., and DeLuca, H. F.: Subcellular location of rat liver calciferol-25hydroxylase. Arch. Biochem. Biophys., 160:58, 1974. 12. Blunt, J. W., and DeLuca, H. F.: The synthesis of 25-hydroxy-cholecalciferol: A biologically active metabolite of vitamin D,. Biochemistry, 8 :671, 1969. 13. Blunt, J. W., DeLuca, H. F., and Schnoes, H. K.: 25 Hydroxycholecalciferol: A biologically active metabolite of vitamin Da. Biochemistry, 7:3317, 1968. 14. Bone, M., Stein, P., et al.: The effects of25-hydroxycholecalciferolin renal osteodystrophy. Abstracts of Free Communications. Sixth International Congress of Nephrology, Florence, June 8-12, 1975. 15. Boyle, I. T., Miravet, L., Gray, R. W., et al.: The response ofintestinalcalcium transport to 25-hydroxy and l,25-dihydroxy vitamin D in nephrectomized rats. Endocrinology, 90:605,1972. 16. Bricker, N. S.: On the pathogenesis of the uremic state: an exposition of the "trade-off hypothesis." New Engl. J. Med., 286:1093, 1972. 17. Bricker, N. S., Slatopolsky, E., Reiss, E., et al.: Calcium, phosphorus and bone in renal disease and transplantation. Arch. Intern. Med., 124:417, 1969. 18. Brickman, A. S., Coburn, J. W., and Norman, A. W.: Action of l,25-dihydroxycholecalciferol, a potent, kidney-produced metabolite of vitamin D a, in uremic man. New Engl. J. Med., 287:891, 1972. 19. Brickman, A. S., Sherrard, D. J., Coburn, J. W., et al.: Management of renal osteodystrophy with l,25(OH)2 and 1 a(OH) hydroxy vitamin D: experience in 36 patients. Abstracts. American Society of Nephrology, Eighth Annual Meeting, Washington, D.C., November 25-26, 1975. 20. Broyer, M., Kleinknecht, C., Loirat, C., et al.: Growth in children treated with long-term hemodialysis. J. Pediat., 84:642, 1974. 21. Chan, J. C. M., Beale, M. G., and Albert, M. S.: Therapeutic implications of vitamin D metabolites. Clin. Proc. Child. Hosp. Nat. Med. Ctr., 30:59, 1974. 22. Chan, J. C. M., Oldham, S. B., Holick, M. F., et al.: The use of 1a-hydroxyvitamin Da, a potent analog of the kidney hormone, l,25-dihydroxyvitamin Da, in chronic renal failure. J.A.M.A., 234:47, 1975. 23. Chen, T. C., Castillo, L., Korycka-Dahl, M., et al.: Role of vitamin D metabolites in phosphate transport of rat intestine. J. Nutr., 104:1056, 1974. 24. Cork, D. J., Haussler, M. R., Pih, M. "J., et al.: 1a-hydroxyvitamin Da: A synthetic sterol which is highly active in preventing rickets in the chick. Endocrinology, 94: 1337, 1974. 25. DeLuca, H. F.: Recent advances in our understanding ofthe vitamin D endocrine system. J. Lab. Clin. Med., 87:7, 1976. 26. DeLuca, H. F.: Vitamin D-1973. Am. J. Med., 57:1, 1974. 27. DeLuca, H. F., Hollick, S. A., and Hollick, M. F.: Metabolism and function of 1 alpha hydroxyvitamin Da. In Pors Nielsen, S., (ed.): Proceedings of the Eleventh European Symposium on Calcified Tissues, F.A.D.L. Publishers, 1975. 28. Dent, C. E., Harper, C. M., and Philpot, G. R.: The treatment of renal glomerular osteodystrophy. Quart. J. Med., 30:1, 1961. 29. Eastwood, J. B., Bordier, Ph. J., and deWardener, H. E.: Some biochemical, histological, radiological and clinical features of renal osteodystrophy. Kidney Int., 4:128, 1973. 30. Fine, R. N., Isaacson, A. S., Payne, V., et al.: Renal osteodystrophy in children: The effect of hemodialysis and renal transplantation. J. Pediat., 80:243, 1972. 31. Fraser, D. R., and Kodicek, E.: Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature, 228:764,1970. 32. Frolik, C. A., and DeLuca, H. F.: Metabolism of l,25-dihydroxycholecalciferol in the rat. J. Clin. Invest., 51 :2900, 1971.
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33. Frolik, C. A., and DeLuca, H. F.: One,25-dihydroxycholecalciferol: The metabolite of vitamin D responsible for increased intestinal calcium transport. Arch. Biochem. Biophys., 147:143, 1971. 34. Garabedian, M., Holick, M. F., DeLuca, H. F., et al.: Controlof25-hydroxycholecalciferol metabolism by parathyroid glands. Proc. Nat. Acad. Sci. U.S.A., 69:1673, 1972. 35. Garabedian, M., Tanaka, Y., Holick, M. F., et al. : Response ofintestinal calcium transport and bone calcium mobilization to 1,25-dihydroxyvitamin Da in thyroparathyroidectomized rats. Endocrinology, 94:1022, 1974. 36. Goldsmith, R. S., Furszyfer, J., Johnson, W. J., et aI.: Etiology of hyperparathyroidism and bone disease during chronic hemodialysis. III. Evaluation of parathyroid suppressibility. J. Clin. Invest., 52:173,1973. 37. Gray, R. W., Omdahl, J. L., Ghazarian, J. G., et al.: 25-hydroxycholecalciferol-lhydroxylase: Subcellular location and properties. J. BioI. Chern., 247:7528, 1972. 38. Habener, J. F., Powell, D., Murray, T. M., et al.: Parathyroid hormone: Secretion and metabolism in vivo. Proc. Nat. Acad. Sci. U.S.A., 68:2986,1971. 39. Haddad, J. G., and Chyu, K. J.: Competitive protein-binding radioassay for 25hydroxychoiecalciferoi. J. Clin. Endocrinoi. Metab., 33:992, 1971. 40. Hahn, T. J., Berge, S. J., Scharp, C. R., et al.: Phenobarbital induced alterations in vitamin D metabolism. J. Clin. Invest., 51 :741, 1972. 41. Hahn, T. J., Henden, B. A., Scharp, C. R., et al.: Effects of chronic anticonvulsant therapy on serum 25-hydroxycholecalciferollevels in adults. New Engl. J. Med., 287 :900, 1972. 42. Hallick, R. B., and DeLuca, H. F.: Metabolites of dihydrotachysterol in target tissues. J. BioI. Chern., 247:91, 1972. 43. Hallick, R. B., and DeLuca, H. F.: 25-Hydroxydihydrotachysterol: Biosynthesis in vivo and in vitro. J. BioI. Chern., 246:5733, 1971. 44. Harrison, H. E., and Harrison, H. C.: Dihydrotachysterol: A calcium active steroid not dependent upon kidney metabolism. J. Clin. Invest., 51 :1919, 1972. 45. Harrison, H. E., and Harrison, H. C.: The renal excretion of inorganic phosphate in relation to the action of vitamin Da and parathyroid hormone. J. Clin. Invest., 20:47, 1941. 46. Haussler, M. R., Boyce, D. W., Littledike, E. T., et al.: A rapidly acting metabolite of vitamin Da. Proc. Nat. Acad. Sci. U.S.A., 68:177,1971. 47. Haussler, M. R., Myrtle, J. F., and Norman, A. W.: The association of a metabolite of vitamin Da with intestinal mucosa chromatin in vivo. J. BioI. Chern., 243:4055, 1968. 48. Holick, M. F., and DeLuca, H. F.: Vitamin D metabolism. Ann. Rev. Med.,25:349, 1974. 49. Holick, M. F., Garabedian, M., and DeLuca, H. F.: 1,25-Dihydroxycholecalciferol: metabolite of vitamin Da active on bone in anephric rats. Science, 176:1146, 1972. 50. Holick, M. F., Schnoes, H. K., DeLuca, H. F., et al.: Isolation and identification of 24,25dihydroxycholecalciferol: A metabolite of vitamin Da made in the kidney. Biochemistry, 11 :4251, 1972. 51. Holick, M. F., Schnoes, H. K., DeLuca, H. F., et al.: Isolation and identification of 1,25dihydroxycholecalciferol: A metabolite of vitamin D active in intestine. Biochemistry, 10:2799, 1971. 52. Holick, M. F., Semmler, E. J., Schnoes, H. K., et al.: 1 a-Hydroxy derivative of vitamin Da: A highly potent analog of la,25-dihydroxyvitamin Da. Science, 180:190, 1973. 53. Hruska, K. A., Kopelman, R., Rutherford, W. E., et al.: Metabolism of immunoreactive parathyroid hormone in the dog. J. Clin. Invest., 56:39, 1975. 54. Johnson, W. J., Goldsmith, R. S., Beabout, J. W., et al.: Prevention and reversal ofprogressive secondary hyperparathyrOidism in patients maintained by hemodialysis. Am. J. Med., 56:827, 1974. 55. Jowsey, J., Massry, S. G., Coburn, J. W., et aI.: Microradiographic studies of bone in renal osteodystrophy. Arch. Intern. Med., 124:539, 1969. 56. Kaye, M.: Concepts of therapy: Prevention and management of osteodystrophy in patients with long-term hemodialysis. Arch. Intern. Med., 124:656, 1969. 57. Kaye, M., Chatterjee, G., Cohen, G. F., et al.: Arrest of hyperparathyroid bone disease with dihydrotachysterol in patients undergoing chronic hemodialysis. Ann. Intern. Med., 73:225, 1970. 58. Kleeman, C. R., and Better, O. R.: Disordered divalent ion metabolism in kidney disease: comments on pathogenesis and treatment. Kidney Int., 4:73, 1973. 59. Knutson, J. C., and DeLuca, H. F.: 25-Hydroxyvitamin Da-24-hydroxylase: subcellular location and properties. Biochemistry, 13:1543, 1974. 60. Kodicek, E.: The story of vitamin D from vitamin to hormone. Lancet, 1 :325, 1974. 61. Lawson, D. E. M., Fraser, D. R., Kodicek, E., et al.: Identification of 1,25dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism. Nature, 230:228, 1971. 62. Lawson, D. E. M., Wilson, P. W., and Kodicek, E.: Metabolism of vitamin D: a new cholecalciferol metabolite involving loss of hydrogen at C-l, in chick intestinal nuclei. Biochem. J., 115:269,1969. 63. Liu, S. H., and Chu, H. I.: Studies of calcium and phosphorus metabolism with special
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reference to the pathogenesis and effect of dihydrotachysterol (AT 10) and iron. Medicine. 22:103, 1943. 64. Massry, S. G., Coburn, J. W., Lee, D. B. N., et al.: Skeletal resistance to parathyroid honnone in renal failure. Ann. Intern. Med., 78 :357, 1973. 65. Massry, S. G., Stein, R., Garty, J., et a!.: Studies on the mechanism of skeletal resistance to the calcemic action of parathyroid hormone: the role of 1,25-dihydroxycholecalciferol [1,25(OH)2D,J. Abstracts of Free Communications. Sixth International Congress ofNephrology, Florence, June 8-12, 1975. 66. Mawer, E. B., Backhouse, J., Taylor, C. M., et al.: Failure of fonnation of 1,25dihydroxycholecalciferol in chronic renal insufficiency. Lancet, 1 :626, 1973. 67. Neville, P. E., and DeLuca, H. F.: The synthesis of (1,2-'H) vitamin D, and the tissue localization of a 0.25 /Lg (10 IU) dose per rat. Biochemistry, 5:2201, 1966. 68. Nonnan, A. W., and Henry, H. L.: 1,25-Dihydroxyvitamin D" a honnonally active fonn of vitamin D,. Recent Progr. Honnone Res., 30:431, 1974. 69. Olson, E. B., and DeLuca, H. F.: 25-Hydroxycholecalciferol: Direct effect on calcium transport. Science, 165 :405, 1969. 70. Piel, C. F., Roof, B. S., and Avioli, L. V.: Metabolism of tritiated 25-hydroxycholecalciferol in children before and after successful renal homotransplantation. J. Clin. EndocrinoI. Metab., 37:944, 1973. 71. Potter, D. E.: Renal osteodystrophy in children. Dialysis and Transplantation, 5 :24, 1976. 72. Potter, D. E., Wilson, C. J., and Osonoff, M. B.: Hyperparathyroid bone disease in children undergoing long-term hemodialysis: Treatment with vitamin D. J. Pediat., 85 :60, 1974. 73. Potts, J. T., Jr., Tregeat, G. W., Keutmann, H. T., et al.: Synthesis of a biologically active N-terminal tetratriacontapeptide of parathyroid honnone. Proc. Nat. Acad. Sci. U.S.A., 68:63. 1971. 74. Pu schett, J. B., Moranz, J., and Kurnick, W.: Evidence for a direct action of chick calciferol and 25-hydroxycholecalciferol on the renal transport of phosphate, sodium and calcium. J. Clin. Invest., 51 :373, 1972. 75. Raisz, L. G., Trummel, C. L., and Simmons, H.: Induction of bone resorption in tissue culture: prolonged response after brief exposure to parathyroid honnone or 25hydroxycholecalciferoI. Endocrinology, 90:744, 1972. 76. Rasmussen, H., and Bordier, Ph.: The cellular basis of metabolic bone disease. N. EngI. J. Med., 289:25, 1973. 77. Rasmussen, H., and Bordier, Ph.: The Physiologic and Cellular Basis of Metabolic Bone Disease. Baltimore, Williams & Wilkins Co., 1974. 78. Ritz, E., Krempien, B., Mehls, 0., et al.: Skeletal abnonnalities in chronic renal insufficiency before and during maintenance hemodialysis. Kidney Int., 4:116, 1973. 79. Roof, B. S., Peil, C. F., Carpenter, B. J., et al.: National course of secondary hyperparathyroidism after successful renal transplantation. Proc. Dial. Transplant. Forum, 1 :11, 1971. 80. Rutherford, E., Blondin, J., Hruska, K., et aI.: The effect of 25-hydroxycholecalciferol [25(OH)D,J on calcium absorption in uremia. Abstracts. American Society of Nephrology, Seventh Annual Meeting, Washington, D.C., Nov. 25-26, 1974. 81. Semmler, E. J., Holick, M. F., Schnoes, H. K., et al.: The synthesis of 1<>,25dihydroxycholecalciferol-a metabolically active form of vitamin D,. Tetrah. Lett., 40:4147, 1972. 82. Sherwood, L. M., Abe, M., Rudman, J. S., et aI.: Parathyroid honnone: synthesiS, storage and secretion. In Talmage, R. V., and Munson, P. L. (eds.): Calcium, Parathyroid Honnone and the Calcitonins. Amsterdam, Excerpta Medica, 1972, pp. 183-196. 83. Sherwood, L. M., Lundberg, W. B., Jr., Targovnik, J. H., et al.: Synthesis and secretion of parathyroid honnone in vitro. Am. J. Med., 50:658, 1971. 84. Sherwood, L. M., Rodman, J. S., and Lundberg, W. B., Jr.: Evidence for a precursor to circulating parathyroid honnone. Proc. Nat. Acad. Sci. U.S.A., 67:1631, 1970. 85. Stanbury, S. W., and Lumb, G. A.: Metabolic studies of renal osteodystrophy 1. calcium, phosphorus and nitrogen metabolism in rickets, osteomalacia and hyperparathyrOidism complicating uremia and in the osteomalacia of the adult Fanconi syndrome. Medicine, 41 :1,1962. 86. Steele, T. H., Engle, J. E., Tanaka, Y., et a!.: Phosphatemic action of 1,25dihydroxyvitamin D,. Am. J. PhysioI., 229:489, 1975. 87. Steele, T. H., Manuel, M. A., Boner, G., et al.: Comparison of 1,25-dihydroxycholecalciferol and 5,6-trans cholecalciferol in uremic man (abstract). J. Clin. Invest., 52:81a, 1973. 88. Tanaka, Y., and DeLuca, H. F.: Stimulation of 24,25-dihydroxyvitamin D,. SCience, 183:1198, 1974. 89. Tanaka, Y., and DeLuca, H. F.: The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch. Biochem. Biophys., 154:566, 1973. 90. Tsai, H. C., Wong, R. G., and Nonnan, A. W.: Studies on calciferol metabolism. IV. Subcellular localization of 1,25-dihydroxyvitamin D, in intestinal mucosa and correlation with increased calcium transport. J. BioI. Chern., 247:5511, 1972.
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91. Wing, A. J.: Optimum calcium concentration of dialysis fluid for maintenance hemodialysis. Brit. Med. J., 4:145,1968. 92. Zen graff, J., Hordier, Ph., Gueris, J., et al.: Short term response of renal osteodystrophy to vitamin D3 metabolites or synthetic analogues. Abstracts of Free Communications. Sixth International Congress of Nephrology, Florence, June 8-12, 1975. 93. Zerwekh, J. E., Brumbaugh, P. F., Haussler, D. H., et aI.: 1a-Hydroxyvitamin D 3 • An analog of vitamin D which apparently acts by metabolism ofla,25-dihydroxyvitamin D3· Biochemistry, 13:4097,1974. Department of Child Health and Development George Washington University Medical School Children's Hospital National Medical Center 2125 Thirteenth Avenue, N.W. Washington, D.C. 20009
Renal Osteodystrophy Mary G. Beale, M.D.,* Jose R. Salcedo, M.D.,t Demetrius Ellis, M.D.;+ and David D. Rao, M.S.§
Pediatricians involved in the care of children with chronic renal disease may have by necessity directed their attention toward controlling the complications of uremia, such as anemia, hypertension, growth failure, and renal osteodystrophy. Various treatment modalities introduced even during the early stage of the child's illness have been palliative at best. Recent discoveries in vitamin D metabolism have changed the traditional management of renal osteodystrophy by offering specific intervention through administration of active vitamin D metabolites and analogs. Current concepts on the pathogenesis and treatment of uremic bone disease form the basis of this review.
VITAMIN D The discovery that vitamin D is further metabolized to more active forms in man stands as a landmark in modern medical history. As early as 1943, Liu and Chu observed that patients with renal osteodystrophy were in negative calcium balance and that high doses of vitamin D did not increase intestinal calcium absorption. 63 Their work was confirmed and extended 20 years later by Dent et al. 28 and Stanbury and Lumb85 who demonstrated that calcium malabsorption in uremic patients could be overcome if very large doses of vitamin D were administered. The basis for the relative vitamin D resistance in renal failure can now be explained by the kidney'S role in endogenous vitamin D metabolism. The availability in the 1960's of a highly specific tritiated vitamin D and column chromatography made it possible to demonstrate more polar "Instructor in Child Health and Development, George Washington University School of Medicine and Fellow in Nephrology, Children's Hospital National Medical Center, Washington, D.C. tInstructor in Child Health and Development, George Washington University School of Medicine and Fellow in Nephrology, Children's Hospital National Medical Center, Washington, D.C. :;:Fellow in Nephrology, Children's Hospital National Medical Center, Washington, D.C. §Research Associate, Department of Nephrology, Children's Hospital National Medical Center, Washington, D.C. Supported in part by the Ruth and Arnold Orleans Kidney Research Fund, Washington Heart ASSOCiation, and NIH Grant RR-00284.
Pediatric Clinics of North America-Vol. 23, No.4, November 1976
873
874
MARY
2'~O~OH ~
~ CH,
CH, HO
HO
vitamin 0 3
CH, HO
25·0H·0 3
G.
BEALE ET AL.
Figure 1. The activating pathway of vitamin Da is depicted.
OH 1.25·{OH),·03
metabolites in circulating plasma. 67 When the labeled compound was given in physiologic amounts to animals, the radioactivity eventually concentrated in bone, intestine, and kidney. 67 Using the tritiated vitamin D in pigs, Blunt et al. 13 were able to isolate and identify the first polar metabolite, 25-hydroxyvitamin Da (25-0H-Da) (Fig. 1),13 The compound was successfully synthesized in 196912 and subsequently demonstrated to act directly on bone and intestine in vitro. 69 , 75 The site of conversion resides in the liver microsomes. l l , 70 The rate of reaction is regulated by substrate availability and the hepatic level of 25-hydroxyvitamin Da. Using competitive protein-binding techniques circulating levels of the hepatic metabolite have been measured in man. 9, 39 The values have been found to be low in a significant percentage of individuals receiving chronic anticonvulsants. 41 The mechanism is uncertain but an increase in the conversion of vitamin Da and 25hydroxy vitamin Da to polar, inactive metabolites has been postulated. 40 In view of the fact that antiepileptics are widely used in uremic children with seizure disorders, their potentially adverse effect on vitamin D metabolism should be recognized. In 1968 another polar vitamin D metabolite present in intestine was reported by Haussler et al. 47 and confirmed by Lawson et al. 62 In 1970 Fraser and Kodicek made the important discovery that the kidney was the sole site of formation of the newly recognized metabolite. 31 Even before it had been fully identified, studies showed that the compound acted more rapidly and more potently on intestinal calcium absorption and bone calcium mobilization than 25-hydroxyvitamin Da. 46 In 1971 the structure was simultaneously identified in two different laboratories, as 1,25-dihydroxyvitamin D3 (1,25-(OH)zD a) (Fig. 1).51,61 A year later it was successfully synthesized. 81 The most active vitamin D metabolite presently known is 1,25dihydroxyvitamin D 3. It is the major form of vitamin D present in both intestine and bone at the time of maximal intestinal calcium absorption. 32 , 33, 90 Its precursor, 25-0H-D3, is unable to stimulate bone calcium mobilization 49 or intestinal calcium absorption 15 and phosphate 23 absorption in nephrectomized animals. The conversion of 25-0H-Da to 1,25(OH)2D3 is therefore necessary for the antirachitic effects of vitamin D under physiologic conditions. In chronic renal failure, the hydroxylation of 25-0H-D3 to form 1,25(OH)zD a is impaired, resulting in changes in bone structure associated with pain, deformity, and fractures. In order to understand the pathogenesis of renal osteodystrophy, it is necessary to focus briefly on the factors controlling 1,25-(OH)zD3 production. For more detailed discussions of the subject the reader is referred to several recently published reviews.5, 25, 26, 60, 68
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RENAL OSTEODYSTROPHY
Regulation of 1,25-(OHhD3 Synthesis The mitochondria of renal cells 37 are the site of conversion of 25-0H-D3 to 1,25-(OH)2D3' Hypocalcemia stimulates the production of 1,25-(OH)2D3' whereas normal or elevated calcium levels promote the formation of another metabolite,50 24, 25-dihydroxyvitamin D3 (24,25(OH)2D3' The 24-hydroxylase system is also located in the renal mitochondria and requires the presence of 1 ,25-(OH)2D3 for its induction. 59,88 In the absence of parathyroid hormone (PTH), production of 1,25-(OH)2D3 is curtailed even when dietary intake of calcium is low, demonstrating that the kidney's response to hypocalcemia is mediated through the parathyroid gland. 34 Normally, hypocalcemia stimulates PTH secretion. In the kidney, PTH stimulates 1,25-(OH)2D3 formation. In the intestine, 1,25-(OH)2D3 facilitates calcium absorption. In the bone, it increases calcium mobilization in the presence of PTH.35 It is possible that 1,25(OH)2D3 and PTH also enhance renal tubular reabsorption of calcium. 25, 86 The end result of this complex metabolic sequence is the restoration of a normal serum calcium concentration and removal of the stimulus to parathyroid hormone release (Fig. 2). In patients with renal failure, the normal trophic relationship between PTH and vitamin D is interrupted. 2 Decreased intestinal calcium absorption which is relatively resistant to vitamin D administration appears when the glomerular filtration rate falls below 25 to 30 ml/minute. 2 The reduction has been attributed to low 1,25-(OH)2D3 production rather than uremia per se. Moreover, 1,25-(0 H)2D3 cannot be detected in the sera of patients with chronic renal failure. 66 The serum phosphate concentration also plays a regulatory role in 1,25-(OH)2D3 synthesis. Animal studies 89 have shown that in the thyroparathyroidectomized state, hypophosphatemia stimulates formation of 1,25-(OH)2D3' When the phosphate concentration is normal or increased, 24,25-(OH)2D3 is the predominant metabolite. Changes in serum phosphate are reflected in the renal cortical phosphate content. Since PTH depresses renal cortical levels of phosphate by inhibiting tubular phosphate reabsorption, it has been postulated that the intracellular phosphate level ultimately determines the rate of 1,25-(OH)2D3 production. 26 Evidence that 1,25-(OH)2D3 augments phosphate transport independently of calcium in the intestine 23 and quite possibly the renal tubules 45 . 74 lends further support to a mechanism in which phosphate regulates 1,25-(OH)2D3 synthesis. The importance of phosphate in the development of renal osteodystrophy was recognized several years ago by Bricker, Slatopolsky et al., who suggested that phosphate retention was the primary event leading to renal osteodystrophy.17 According to their hypothesis, uremic patients
I Figure 2. Schematic representation shows feedback loop between serum calcium, parathyroid hormone and 1,25-(OH)2Da.
I . I ntestma. Ca absorptIOn
.P1asr .,.
(ca++'~
t
PTH secretion
L1'1,25.(OH'2 D 3
•
Bone resorption
I
-----..-J
876
MARY
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BEALE ET AL.
experienced transient elevations in serum phosphate concentration as the total number of functioning nephrons declined. The rise in phosphate, caused a reciprocal fall in calcium which acted as a stimulus for PTH secretion. A normal phosphate concentration was restored by the inhibitory action of PTH on renal tubular phosphate reabsorption. Stated another way, phosphate homeostasis was maintained at the expense of PTH overactivity.16 As a clinical application of the Bricker hypothesis 16 , 17 patients are given oral phosphate binding gels and low phosphate diets to control the progression of renal osteodystrophy. The possibility that hyperphosphatemia inhibits 1,25-(OH)2Da synthesis provides additional rationale for aggressive control of the serum phosphate concentration. Much remains to be learned about the relative importance and interaction of these two factors, i.e, increased parathyroid hormone secretion and reduced 1,25-(OH)2Da production, in the pathogenesis of uremic bone disease. New methods of measuring serum 1,25-(OH)2Dalevels on a broad scale should make it possible to quantitatively delineate the role of the active metabolite in renal osteodystrophy.
Parathyroid Hormone The current status of PTH assays warrants discussion. In 1968 Berson and Yalow proposed the idea that more than one molecular species of PTH was present in the circulation. 10 A number of investigators independently demonstrated in 1970 and 1971 that glandular PTH and secreted hormone were immunologically different and had different molecular weights. a, 4, 38, 73, 83. 84 Attempts to prepare a monovalent radioimmunoassay to human PTH have been hindered by the heterogeneity of hormonal fragments present in the circulation. Nonetheless, aminospecific and carboxyl-specific antisera have been developed for clinical use. Their application in uremic individuals has provided important insight into the functional changes in parathyroid gland activity associated with chronic renal disease. PTH levels using C-terminal antisera are uniformly elevated in patients on hemodialysis while values obtained from N-terminal antisera may fall within the normal range. 36 A prompt reduction in PTH secretion during calcium infusions can be demonstrated using N -terminal antisera at a time when little or no change is detected with C-terminal antisera. 36 Impaired degradation on N-terminal and particularly C-terminal fragments in uremia compounds the difficulty in interpreting results of PTH assays.53 Nevertheless, there is increasing evidence to suggest that the measurement of the N-terminal fragment is a sensitive indicator of acute changes in parathyroid gland activity, whereas the C-terminal fragment more closely reflects the chronic state of hormonal secretion. 36
Vitamin D Analogs Several vitamin D derivatives have been evaluated in patients with uremic bone disease. Recent studies have shown that dihydrotachysterol (DHT) undergoes 25-hydroxylation in the liver to form 25-0H-DHT (Fig. 3).43 A 180 rotation in the A ring of the molecule places the 3 betahydroxyl group in the 1 alpha position, eliminating the need for further processing by the kidney.42.44 Hence, 25-0H-DHT functions as the biologically active form of DHT. Two other compounds in which the 0
877
RENAL OSTEODYSTROPHY
£f 1
'
Figure 3. Vitamin D analogs which are biologically active due to the hydroxy moiety in the carbon-lor pseudo carbon-l position are demonstrated.
I
OH
HO
DHT
I
I
H
1a-OH·D.
f"C" ~OH • • OH
5.6 trans D.
5.8 trans-25-0H-D.
3-hydroxyl moiety occupies the pseudo 1a position have been synthesized and studied in a limited number of patients: 5,6 trans Da and 5,6 trans25-0H-Da.87, 92 Their activity 48 is 100 to 1000 times less than the equivalent amount of 1,25-(OH)2Da. In 1973 an analog of 1,25-(OH)2Da, 1 alpha-hydroxyvitamin Da (laOH-Da), was synthesized from cholesterol (Fig. 3).6,52 In vivo studies have shown that the analog has approximately half the antirachitic potency of 1,25-(OH)2Da on a similar weight basis. 6,24,52 It is now known that 1a-OH-Da is converted to 1,25-(OH)2Da before acting on peripheral sites. 27 • 93
CLINICAL FEATURES Virtually all hemodialysis patients have histologic evidence of hyperparathyroidism on bone biopsy.29 The frequency of radiologic abnormalities ranges from 25 per cent56 to 50 per cent29 in adult studies and from 45 per cent30 to 58 per cent71 in pediatric series. In a survey of 84 children from nine European hemodialysis centers the incidence of bone pain was 10.5 per cent; skeletal deformities were reported in 18. 8 per cent.78 Potter et aI. have found a close correlation between the duration of uremia and the development of bone changes in children. 72 The importance ofprevention and treatment of renal osteodystrophy has been underscored by the serious problem of growth failure in chronic renal disease. Children with severe bone involvement do not grow well; moreover, their statural growth lags behind their rate of bone maturation, resulting in a permanent loss of height potential. 20 The need for judicious and aggressive 'medical control is readily apparent. Bone biopsies are being performed with increasing frequency in patients undergoing treatment for renal osteodystrophy. When the biopsy is taken from the iliac crest, the procedure can be carried out under local anesthesia on an outpatient basis. Direct examination of the tissue is the most definitive means of assessing the relative influence of increased PTH and decreased 1 ,25-(OH)2Dalevels on bone. In chronic renal disease, bone formation is generally reduced and the percent of osteoid bearing a calcification front is decreased. 76. 77 When bone resorption continues, the histology is consistent with hyperparathyroidism. If bone formation oc-
878
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curs under hypocalcemic or hypophosphatemic conditions, the volume of osteoid increases and the pathology is more typical of rickets. 55 Often, features of osteitis fibrosa cystic a and rickets can be seen in a single biopsy specimen. Although serial performance of bone biopsies is now considered the most reliable means of evaluating treatment efficacy, PTH levels can offer excellent monitoring of secondary hyperparathyroidism. Skeletal x-rays are a less sensitive but noninvasive means of detecting bone involvement. Hyperparathyroid changes are more frequently seen than rachitiform lesions in North America because of vitamin D supplements in the diet. The earliest radiologic abnormalities appear in the hands as subperiosteal erosions of the terminal phalanges. With more advanced disease, there may be resorption of the distal clavicles and erosion of the symphysis pubis and the sacroiliac joints. Flaring and irregularity along the epiphyseal plates oflong bones are typical signs of rickets. If not controlled, skeletal changes can progress to crippling deformities and pathologic fractures. Normally the skeleton serves as a reservoir of calcium and phosphate for the circulation. The release of ions is mediated through parathyroid hormone and 1,25-(OH)2D3.77 Calcitonin prevents release of calcium and phosphorus from the bone. In renal failure, bone becomes resistant to the calcemic action of PTH,64 but this resistance to PTH is more apparent than real in view of the fact that in chronic renal failure there is less calcium available from the bone for such release. Indirect evidence has suggested 65 that the blunted calcemic response is due to insufficient synthesis of 1,25-(OH)2D3. The net effect is a fall in serum calcium concentration which is further compounded by calcium malabsorption and reduced renal phosphate excretion. The parathyroid gland receives a continuous hypocalcemic stimulus, resulting in glandular hyperplasia and increased hormonal secretion. Hence, the typical serologic findings in patients with untreated renal osteodystrophy are hyperphosphatemia, elevated PTH, and increased alkaline phosphatase. Most patients with renal osteodystrophy in the United States have normal serum calcium levels and only those with osteomalacia or hypoalbuminemia show decreased serum calcium levels. There is a marked difference in the frequency of osteomalacia in England as compared to North America. The disparity may be related to previous vitamin D intake. Soft Tissue Calcification Metastatic soft tissue calcification is a rare complication of chronic renal failure in children. When it does occur, the most common site is the conjunctiva. 71 The condition is usually asymptomatic but occasionally leads to local inflammation. Vascular and periarticular calcifications have been described in a few pediatric patients. 71 Pruritus, a particularly disturbing symptom in uremia, is believed to result from calcium deposition in the skin. Treatment is directed toward controlling the serum calcium and phosphate concentrations. If serum phosphorus is lowered and adequate vitamin D is given, ectopic calcification is resorbed and there is rarely need for parathyroidectomy.
879
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THERAPY The medical management of renal osteodystrophy necessitates a combined therapeutic approach with the aims of simultaneously lowering serum phosphate, raising serum calcium, and restoring normal vitamin D activity. The serum phosphate level is controlled through the oral administration of phosphate binding gels, usually in the form of aluminum hydroxide at 1 to 2 gm daily. Overzealous treatment can result in phosphate depletion and further bone demineralization. 58 Hence the dosage should be reduced when the serum phosphate falls to physiological levels. Although aluminum-containing phosphate binding gels have been regarded as harmless, a recently published study reported increased levels of aluminum in muscle, bone, and brain of hemodialysis patients receiving aluminum antacids. 1 Moreover, the highest brain gray-matter aluminum values were found in a group of 10 patients who succumbed to an unexplained neurologic disorder.1 While the evidence is inconclusive, the data suggest that prolonged usage may have subtle and even toxic effects. The calcium intake of uremic patients averages only 300 to 500 mg per day due to anorexia and dietary protein restriction. In the absence of the active vitamin D metabolite, ingested calcium is poorly absorbed, resulting in either low or negative calcium balance. 63 Oral calcium supplementation with 1 to 2 gm of elemental calcium per day as calcium carbonate should be started when the glomerular filtration rate reaches 20 to 25 ml per minute. Patients already receiving hemodialysis can be dialyzed against dialysate calcium concentrations which will insure net positive calcium transfer to the patient. A minimum concentration of6.0 mg/dl is necessary to achieve such an end. 91 Improvement of hyperparathyroid bone changes has been reported in patients dialyzed at a calcium level of 7.0 to 8.0 mgldl. 54 However, the risk of causing metastatic calcification is significantly greater than with lower levels of calcium. The magnesium concentration influences PTH secretion in the same manner as calcium, i.e., low concentrations stimulate and high concentrations inhibit PTH synthesis and release. 82 For this reason, a high dialysate magnesium concentration of2.0 to 2.5 mgldl is used in some dialysis centers for patients with clinical hyperparathyroidism. 79 Conversely, demonstration of excessi ve magnesium levels in bone analyses from uremic patients has led other centers to use dialysate solutions containing no magnesium. Until more data are available concerning the role of magnesium in renal osteodystrophy, it is advisable to avoid states of either magnesium excess or depletion. Before 25-0H-D3 was synthesized in 1969, three forms of vitamin D were used in the treatment of renal osteodystrophy: vitamin D3 (cholecalciferol), vitamin D2 (calciferol), and dihydrotachysterol (DHT). These compounds are still being widely prescribed because of the limited availability of more active metabolites. Pharmacologic dosages of vitamin D ranging from 30,000 to 75,000 IU (1 IU = 0.025 fJ-g) per day have been reported to reverse hyperparathyroid bone disease in children receiving hemodialysis even in anephric patients. 71 • 72 Similarly, radiologic, histologic, and biochemical improvement have been achieved with DHT in dosages of 0.25 to 0.50 mg per day. 57. 71
880
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Despite its success, there is narrow separation between the toxic level and therapeutic range of vitamin D. Hypercalcemia and metastatic calcification are the most frequent complications encountered. Since vitamin D is a nondialyzable molecule and stays in body storage sites for months and even years after large amounts have been given, its actions, both beneficial and harmful, cannot be easily modified. Limited clinical studies have been conducted with the active vitamin D metabolites, 25-0H-D3 and 1,25-(OH)2D3' and with 1a-OH-D3 , a synthetic analog of 1,25-(OH)2D3' Orally administered 25-0H-D3 at a dosage of 100 J,Lg per day increased intestinal calcium absorption, reduced serum parathyroid concentration, and improved bone histology in patients with renal osteodystrophy.14 Since its potency is not significantly reduced in anephric individuals 80 and extrarenal sites of 1 hydroxylation have not been identified, it is assumed that the compound functions as an analog of 1,25-(OH)2D3 when used pharmacologically. In very small doses, 1,25-(OH)liD3 has been highly successful in the treatment of renal osteodystrophy. Brickman et al. observed a rise in serum calcium and phosphate concentration and an increase in intestinal calcium absorption in three adult uremic patients receiving 2. 7 J,Lg per day of 1,25-(OH)2D3 orally for 6 to 10 days.18 In a larger study involving 30 patients and extending over 3 to 7 months, administration of 0.14 to 2.0 J,Lg per day of 1,25-(OH)2D3 corrected biochemicallUld radiologic abnormalities, increased muscle strength and alleviated bone pain in a high percentage of symptomatic patients. 19 Zen graff et al. reported a fall in PTH secretion and an increase in bone cell activity in six patients receiving either 1,25-(OH)2D3 or 1a-OH-D3 , 5 J,Lg three times a week for a total of three weeks. 92 The analog 1 a-OH-D 3 appears to retain all the known biologic functions of 1,25-(OH)2D3' Chan et al. demonstrated improved calcium balance, a fall in PTH secretion and a rise in serum calcium in two uremic children given only 2 J,Lg per day for 6 to 9 days. 21.22 Long-term studies of 16 " to 19 months have shown that 1 a-OH-D 3 can effectively reverse hyperparathyroid bone disease although several months of treatment may elapse before metabolic and radiologic improvement are documented. 7 • 8. 22 The only recognized side effect of the new vitamin D derivatives is hypercalcemia. If detected early, the elevation can be easily controlled by reducing or discontinuing treatment. Until more extensive experience with this kidney hormone becomes available, the use ofthis compound in our institution is monitored by monthly determinations of serum calcium, phosphate, and alkaline phophatase to detect hypercalcemia and to evaluate therapeutic response. To quantitate reversal of the secondary hyperparathyroidism, PTH levels are also obtained serially every three months. The optimal dosage of 1a-OH-D3 or 1,25-(OH)2D3 will have to be titrated against the clinical, biochemical and radiologic status of the patient. Two important questions remain unanswered. One relates to the long-term efficacy of 1,25-(OH)2D3 and whether or not the drug is sufficient to control renal osteodystrophy over an extended period of several years. The second issue pertains to 1,25-(OH)2D3 prophylaxis and whether early administration of small amounts of the compound to uremic patients can prevent bone disease. Resolution of these questions will be a major focus for further clinical investigation.
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