Renal Osteodystrophy in Children: The Role of Vitamin D, Phosphorus, and Parathyroid Hormone

Renal Osteodystrophy in Children: The Role of Vitamin D, Phosphorus, and Parathyroid Hormone Russell W. Chesney, MD, Otto Mehls, MD, Constantine S. Anast, MD, Edward Brown, MD, Marc R. Hammerman, MD, Anthony Portale, MD, Michael D. Fallon, MD, John Mahan, Jr, MD, and Allen C. Alfrey, MD

A

CLEARER understanding of both the pathogenesis and treatment of childhood renal osteodystrophy (ROD) has emerged since the role of the kidney in the synthesis of 1,25-dihydrox yvitamin D (l,25-(OH)zD 3 ) has been clarified. t? However, anticipation that treatment with 1,25(OH)zD3 and l o hydroxyvitam in D would correct the clinical and biochemical features of ROD has not been realized . 2 As the pathogenesis of secondary hyperparathyroidism and of disordered vitamin D metabolism in chronic renal insufficiency (CRI) and failure (CRF) are better understood, new approaches to therapy are emerging . PARATHYROID HORMONE: SECRETION AND RENAL TUBULAR FUNCTION

Parathyroid hormone (PTH) plays an important role in the pathogenesis of the uremic state and contributes significantly to the development of ROD in children with CRI. 3 Recent studies have shed new light on the mechanisms controlling (PTH) secretion , PTH regulation of phosphorus (Pi) excretion by the renal tubule, and Pi suppression of 1,25-(OH)zD 3 synthesis in moderate renal insufficiency. Before addressing these new findings, it is useful to review the regulation of calcium (Ca) and Pi homeostasis and the role of PTH in this regulation . 4 Ca uptake by active transport is regulated at the intestinal mucosa, by I,25-(OH)zD 3 • 5 Since PTH stimulates the activity of the renal enzyme 25(OH)D -I a-hydroxylase, PTH secretion induced by hypocalcemia results in enhanced intestinal absorption of calcium . Pi homeostasis, by contrast, is regulated largely by the kidney. When hypophosphatemia develops , urinary Pi excretion falls and Pi is conserved . When hyperphosphatemia develops acutely, hypocalcemia results and this, in turn , causes PTH secretion and phosphaturia . An increase in dietary Pi intake causes suppression of 1,25-(OH)zD 3 synthesis , which results in reduced intestinal absorption of Pi. 5 The regulation of PTH secretion has been studied using dispersed parathyroid gland cells." Extra-

cellular Ca is a primary regulator of PTH secretion. There is an inverse relationship between extracellular Ca and PTH secretion that is defined by a sigmoid curve . Studies using the fluorescent Ca probe, QUIN-2, to measure the cytosolic concentration of calcium have shown that increasing extracellular Ca increases the cytosolic Ca as PTH secretion is inhibited. PTH secretion by proliferating parathyroid cells in vitro is less easily suppressed by extracellular Ca, which appears to be related to a decrease in the rise in cytosolic Ca relative to extracellular Ca . 6 7 In severe secondary parathyroid hyperplasia due to CRF, the setpoint for Ca to inhibit PTH release is increased. This is defined as the extracellular Ca causing half maximal inhibition of PTH release without a change in the maximal secretory rate per cell. 7 Parathyroid cells prepared from human adenomas behave similarly, ie, there is a close relationship between the effects of extracellular Ca on cytosolic Ca and PTH release . 8 The mechanism by which calcium influences PTH secretion is not defined . Early studies suggested that cyclic AMP played an important role.? A decrease in cyclic AMP in parathyroid cells exposed to high extracellular Ca was postulated to result from inhibition of synthesis and/or stimulation of breakdown of cyclic AMP. The observation that Ca directly inhibits cyclic AMP-dependent protein kinase activity suggests a possible mechanism by which Ca might inhibit the secretory procFrom the Departments ofPediatrics at The University of California (Davis). University of Heidelberg. Harvard Uni versity: the Ohio State University. and the University of California (San Francisco); the Departments of Medicine at Harvard University, Washington University. and the University of Colorado; and the Department of Pathology and Laboratory Medicine at the University of Pennsylvania. Supported . in part . by Grants AM-31682 and 3- R13 AM34590-0ISI. Address reprint requests to Russell W Chesney. MD, Division of Pediatric Nephrology. University of California . Davis. School of Medicine. 4301 X St. Sacramento, CA 95817. © 1986 by the National Kidney Foundation. Inc. 0272-6386/86/0704-0004$03.00/0

American Journal of Kidney Diseases, Vol VII, No 4 (April). 1986: pp 275-284

275

276

ess at a locus distal to the form ation and/o r breakdown of cyclic AMP. The inhibitory effects of Ca on PTH secretion may be partially independent of cyclic AMP.6-8 Four stages of abnormalities have been delineated as CRI progresses to CRE 10 In stage I, serum PTH increases before GFR decreases below 40 mLlmin and befor e ther e are det ect abl e changes in serum Pi or Ca . In stage II, there are increases in serum PTH and phosphoru s that are progressive; these are associated with a decrease in serum Ca. In Stage III, serum Ca rises to normal, and in stage IV, to above normal. The hypercalcemia that occurs in CRI may be due to the increase in parath yroid tissue mass as well as to an abnormality in the regulation of PTH secretion by Ca , as demonstrated by the increased Ca setpoint for PTH release in the hyperp lastic glands of patients with CRE 1 Once secreted, this horm one has among its actions the maintenance of serum Pi concentration, which is accom plished, in part , by PTH-induced phosphatur ia. This PTH -induced phosphaturia is mediated by a renal proximal tubular brush-border membrane cAMP-dependent protein kinase. U' ? The phosphatur ic action of PTH is associa ted with activation of adenylate cyclase activity in the basolateral membrane of the renal prox imal tubular cell! I that cont ains cAMP-dependent protein kinase activity.' ? It has been proposed that PTHinduced phosphaturia is effected by activa tion of adenylate cyclase followed by cAMP-dependent phosphorylation of brush-border membr ane proteins.P Phosphorylation of protein bands is demonstrable in autoradiograms of SDS-polyacrylamid e gels originating from brush-border membranes isolated from canine kidney, which had been incubated with ('}'-32P)ATP. Addition of cAMP to incubations results in 32P-phosphorylation of two additional band s with molecul ar weights of 52 ,000 and 96,000 daltons (Fig 1).13 Dephosphoryl ation is specific for the 62,000 molecular weight band seen in autoradiog rams of gels originating from brush-border memb ranes incubated with cAMP and ('}'-32P)ATp'14 Thus, cAMP-dependent phosphorylation and dephosphor ylation of specific proteins takes place in bru sh-bord er membr anes reflect ive of the activities of cAMP-depe nde nt protein kinase , an enzyme responsible for phos-

CHESNEY ET AL

-96,000 66 .2K-

-62,000

45K-

STD CB

A

AC

Fig 1. SOS-polyacrylamide gel electrophoresis and autoradiography of canine renal brush-border membranes. Shown is an electrophoresis of standard proteins of known M, (STO) and an electrophoresis originating from a brush-border membrane suspension stained with coomassie blue for protein (CB). Also shown are autoradiograms of gels originating from membranes incubated with 1-y-32[PJATP alone (A) and in combination with cAMP (AC).

phorylation, and of phosphoprotein phosphatase , an enzyme requ ired for dephosphorylation .13_1 4 Th is cyclic AMP-dependent phosphorylation of bru sh-border vesicles is associated with a reduction in Na + -stimulated phosphate tran sport into the interior of the vesicles. This reduction in Na +stimulated phosphate transport is related to the state of phosphorylation of the 62,000 -dalton protein . 13-14 Changes in the levels of circulating PTH in dogs affect 32P-phosphorylation of this protein in brushborder membranes isolated from kidneys of these anim als. Th is pro vides a link between PTH , cAMP-dependent phosphorylation of brush-border membrane proteins in vivo, and 32P-phosphorylation of isolated brush-border vesicles .P' t" The 62,OOO-dalton prote in in the brush-border vesicles appears to be the regulatory subunit of type II cAMP-dependent protein kinase in the brush-border membran e. 16

VITAMIN D, PI, AND PTH IN CHILDHOOD ROD

These findings are consistent with the hypothesis that PTH-induced phosphaturia is mediated by the cAMP-dependent phosphorylation of specific bru sh-border membrane proteins through the activity of membrane-bound cAMP-dependent protein kinase .P'!" and this action is modulated by phosphorylation of the regulatory subunit of A enzyme . Despite these mechanisms for augmenting PTH secretion and , thereby, reducing the reabsorption of Pi, hyperphosphatemia occurs in patients with severe renal insufficiency as the homeostasis mechanisms are overcome. Pi also affects the renal synthesis of 1,25-(OHhD 3 • VITAMIN D METABOLISM IN CHILDREN WITH CRI

This discussion will focus on three questions relating to vitamin D metabolism: (1) at what point in the course of progressive loss of renal function do circulating levels of 1,25-(OHhD 3 become reduced ; (2) what are the poss ible mechanisms respon sible for the reduction in the circulating level of 1,25-(OHhD 3 ; and (3) is a reduction in the circulating level of 1,25-(OHhD 3 important in the pathogenesis of secondary hyperparathyroidism? The relationship between serum levels of 1,25(OHhD 3 and residual renal function can be developed from published data in four stud ies.! "?? Serum levels of 1,25-(OHhD 3 vary directly with value s of GFR (r = 0.55 , P < 0 .001) . Children in whom the GFR is between 25 and 50 mUmin/ 1.73 m>, have levels of 1,25-(OHhD 3 reduced by 1.3 standard deviations from the normal value; in those in whom the GFR is < 25 mUmin/l. 73 m-, serum 1,25-(OHhD 3 are 2.5 standard deviations below normal. It now seems clear that the serum level of 1,25-(OHhD 3 decreases early in the course of progressive CRI in children . The serum levels of 25-hydroxyvitamin D (25OHD) usually are not reduced in children with CRI receiving conventional supplements of vitamin D in food .r"!? The serum concentration of 24,25-dihydroxyvitamin D is reduced in children with CRF (GFR < 15 mUmin/I.73 m-) but it is not significantly lower than normal values in children with mild to moderate renal insuffi-

ciency.!? Changes in dietary Pi affect 1,25-(OHhD 3 levels-? and production rates . ZI In ch ildren with

277 DIETARY INTAKE OF PHOSPHORUS

80

60

NORMAL

I

RESTlICUD

NORMAL

$UPPLIMENTIC

I ·

PLASMA

1.2S-(OH)20 (pg/mll

40

~-

20 peO.OOS

o

T

400r 120 100 SERUM iPTH

l..... eq/ml)

80 60 40 20 0

peO.OI

- '-

0

~

--+--

pe 0_05

At

1

~ :--r--

p eO_OS

Fig 2. Effect of 5 days of restriction and supplementation of dietary phosphorus on the plasma concentration of 1,25-(OH)2D and the serum concentration of C-iPTH in children with moderate renal insufficiency. The dietary intake of phosphorus was normal for 3 days and then either restricted or supplemented for 5 days. The horizontal bars depict means . (Reprinted with permission. 20)

moderate renal insufficiency (GFR of 25 to 50 mUmin/I.73 m-), Pi restriction induced an increase in the serum level of 1,25-(OHhD 3 from low to normal values and a reduction in serum PTH . Conversely, Pi supplementation induced a decrease in the serum levels of 1,25-(OHhD 3 and an increase in serum PTH (Fig 2) . There was an inverse correlation between the changes in serum 1,25-(OHhD 3 and those in serum iPTH . The inverse relationship implie s that changes in serum level of 1,25-(OHhD 3 are primary and effect the changes in the serum level of PTH . The children with moderate CRI, when given an average level of dietary Pi, had normal to low levels of serum Pi throughout the day (Fig 3) . It is proposed that when dietary intake of Pi is average and serum levels of Pi are normal, renal 25(OH)D-Ia-hydroxylase activity is suppressed and the circulating level of 1,25-(OHhD 3 is low ; this contributes to the hyperparathyroidism of these patients . zo

278

CHESNEY ET AL

o NORMAL CONTROLS (5) • PATIENTS (7)

6

(5 5 SERUM PHOSPHORUS (mg/dl)

4

3

SERUM

iPTH (pleq/ml)

!

•

lOl

-

•

::t ~,--_t-! 0800

1200

1600 TIME OF DAY

Changes in the dietary intake of Pi of normal adults induces large , and reciprocal , changes in the serum concentration of 1,25-(OHhD 3 • The diet-induced changes in serum concentration of 1,25-(OHh D 3 are due to chan ges in its production rate .>' BONE FACTORS AFFECTING MINERALIZATION

ROD is the result of many factors . 1.2 The perturbations of Ca and Pi homeo stasis that occur with renal disease underlie the development of ROD. Th erapeutic agent s , eg , glucocorticoids , aluminum-containing pho sphate-binding products, and diuretics that promote hypercalciuria, influence developing bone. New techniques of histomorphometry of bone , obtained by biopsy, photon absorptiometry to assess skeletal mineral status , and atomic absorption analy sis of bone samples, provide method s that impro ve the abilit y to monitor change within bone in response to these variables. 2 2 . 2 3 BONE HISTOLOGY AND HISTOMORPHOMETRIC ANALYSIS

The use of bone biop sy for evaluating ROD in children has been limited because biopsy has required general anesthesia and large biopsy needles. Processing smaller biop sy specimens has been diffi cult until recentl y. A simple biopsy tech nique suitable for use in children of all ages that can be done as an outpatient procedure employs a 2 rnm-diameter Jamshidi biopsy needle (Kor-Med , Glendale , Calit) . Because the biopsy sample is

!

~ ,J

2000' 0800

Fig 3. Serum concentrations of phosphorus and ciPTH during the daytime in 7 children with moderate renal insufficiency and in 5 healthy children. Studies were performed after both groups of subjects had received constant diets providing 1000 mg of calcium and 1200 mg of phosphorus per day for 2 days. On the day of study, meals (closed bars) were offered at 0830 , 1215 and 1715. The bracketed points depict mean values ± SEM. (Reprinted with permission. 20 )

smaller, the sample is embedded in nondecalcified cyclomethacrylate and cut with a glass knife , producing a specimen suitable for diagnosis and histomorphometric quanti tation . The biopsy technique is as follows: on days - 16, - 15, - 4 , and - 3 from the biopsy date , dirneth ylchlortetracycline-t is given in two daily oral doses of IS mg/kg for most children ; 10 mg/ kg/d is given those on dial ysis therapy. The maximum dose given is 600 mg/d. To aid absorpti on , antacid s and milk products are withheld for four hours after ingestion of the tetracycline . Patient s on maintenance hemodi alysis have their biopsies on interdialysis day s, and postbiop sy dialy sis is performed on the usual schedule. The biopsy is obtained from the superior aspect of the posterior iliac cre st with the child prone and hav ing a cloth roll placed under the anterior iliac cre sts. A point halfway between the posterior superior iliac spine and the spinous pro cesses of the vertebral column is ident ified and anesthetized with I % lidocaine hydrochloride down to the per iosteum. A Jamshidi trephine needle with an intern al diam eter of 2 mm is placed on the iliac crest perp end icular to the bone surface and rotated without the trocar while gentle pre ssure is applied. The needle is passed I to 2 ern into the bone ; with adequ ate anesthesia , pain is felt only when the needle enters the marrow cavity. At that point , the needle is gently rocked to all four sides to free the base of the bone specimen, and the needle is withdrawn with gentle rotat ion . A seco nd biopsy is ob-

279

VITAMIN 0, PI, AND PTH IN CHILDHOOD ROD

tained through the same skin incision . A pressure dressing is then applied and the child is able to leave the clinic after 15 minutes of observation . The cores of bone obtained are fixed immediately in either 70% ethanol or a solution of phosphate-buffered 10 % formalin (pH 7.4) containing 0.5% sucrose . Nondecalcified sections are produced by the previously described technique . 23 Serial sections are stained with toluidine blue (for cellular detail) , a trichrome stain (for determination of osteoid and mineralized bone), a prussian blue stain (for iron localization), and the aurin tricarboxylic stain (that detects aluminum and other heavy metals) . Unstained sections are examined with a fluorescent microscope. Using this technique, 68 iliac crest biopsies were performed in 37 children with metabolic bone diseases over the last 3 years . The children ranged in age from 0.8 to 16.0 years . In nine instances, the biopsy was performed in the operating room while the child was under general anesthesia for another surgical procedure. The other biopsies were performed in the outpatient clinic or on the hospital ward , and were well tolerated by all children . Local bone pain persisted more than 24 hours on three occasions and gradually resolved over two to three days . Twenty biopsies have been performed on children on dialysis . Giving dimethylchlortetracycline on two occasions was associated with nausea and vomiting . Tooth staining did not develop in any of 37 patients followed for up to 3 Vz years, in our experience and that of others using doses less than 50 mg/kg.> The sections obtained have satisfactory cellular detail (Figs 1 and 2). Serial sections have been easily obtained with frequent changes of the dry glass Table 1. Normal Pure osteitis fibrosa

Pure osteomalacia

Mixed bone disease

Aplastic bone disease

cutting knife . The four stains previously listed have been used on each specimen . Cellular morphology and fibrous tissue distribution is readily seen . When local anesthesia is employed, sedation is unnecessary. Sufficient tissue for histomorphometric studies can be obtained with procurement of two cores . We have made an accurate diagnosis of the patterns of ROD in children by using this method and have evaluated the response to different analogues of vitamin D therapy (Table 1). The abnormalities in the dynamics of trabecular bone remodelling in these children are similar to those of adults with ROD . Our results are consistent with descriptions of the histomorphometric changes without tetracycline labeling in bone biopsy specimens from children with ROD . 25 However, using in vivo tetracyc ine labeling is valuable for interpreting measurements of bone mineralization . Although osteomalacia appears as an increase in the quantity of osteoid, osteoid excess also results from accelerated matrix synthesis, which contributes to the ostoidosis seen in osteitis fibrosa . Therefore, the diagnosis of osteomalacia cannot be made by the examination of bone biopsies without tetracycline labeling . 26 Since ROD is a heterogeneous disorder, radiographic and biochemical tests, in general , are insensitive in defining the pathologic changes in bone remodelling. The correlation between these markers and bone histology in ROD is poor. Bone biopsy permits the accurate diagnosis of the bone lesions in ROD earlier and makes evaluation of therapy more precise.

Pediatric ROD Classification

Normal osteoid, no resorption, and normal mineralization . Increased bone resorption (fibrotic surface [%) ~ 1 and/or osteoclast number [per mm 2 ] > 2 SO above the mean) and increased mineralization (mineralization front [%) > 2 SO above the mean). Increased osteoid (osteoid volume [%) > 2 SO above the mean and/or osteoid surface [%) > 2 SO above the mean), no resorption (osteoclast number and fibrotic surface normal) , and decreased mineralization (mineralization front [%) > 2 SO below the mean). Increased osteoid (osteoid volume [%) > 2 SO above the mean and/or osteoid surface [%) > 2 SO above the mean) and increased resorption (fibrotic surface [%) ~ 1 and/or osteoclast number [per mrns] > 2 SO below the mean). Normal to decreased osteoid (osteoid volume [%) at or below the mean and/or osteoid surface [%) at or below the mean) with decreased osteoblastic osteoid (osteoblastic osteoid surface [%) > 2 SO below the mean), no resorption , and decreased mineralization (mineralization front [%) > 2 SO below the mean).

280 RADIOLOGIC DIAGNOSIS OF BONE DISEASE

The diagnosis of ROD in childhood by x-rays focuses on two theoretical and practical questions : (1) How can one differentiate between hyperparathyroidism and a defect in mineralization? (2) How can one make the diagnosis of aluminum bone disease? The histologic characteristics of ROD include both osteomalacia and osteitis fibrosa .v-" Subperiosteal resorption zones at the phalangeal cortex is a pathognomonic sign of osteitis fibrosa . The radiologic defects are due to substitution of wellmineralized cortical bone by undermineralized woven bone and fibrous tissue ." The radiolucent zone from undercalcified macrosections of biopsies from the middle phalange is filled with atypical bone matrix . Because turnover rate of bone in childhood is rapid, subperiosteal resorption zones develop in most skeletal sites , eg, the proximal humerus, the distal ulna and radius.P or the proximal tibia . The subperiosteal resorption zones do not always appear with a spiculated outline . The diagnosis of hyperparathyroidism in very young children requires films of the long bone because x-ray of the hand does not show subperiosteal resorption zones in the phalanges; cortical striation , when present, is caused by undermineralized bone along the haversian canals ; it is not, however, pathognomonic for primary or secondary hyperparathyroidism . Cortical striation is found with high bone turnover, as occurs in association with thyrotoxicosis or during the adolescent growth spurt. Thinning of cortical bone, determined by measuring the outer and inner diameter of a phalangeal bone, is reported to be a regular consequence of hyperparathyroidism in adults .>? The cortical area of hand metacarpals in children measured by the Garn index does not correlate with the degree of hyperparathyroidism, judged from the severity of subperiosteal resorption zones and the cortical area .?" The discrepancy between these results and those obtained in adults is puzzling. It is possible that hyperparathyroidism in the growing skeleton leads not only to endosteal bone resorption but also to a high bone aposition rate at the outer side of the cortical bone . Loss of alveolar septi within the jaw is an early sign of hyperparathyroidism. X-rays of the lower incisors and Panorex views of the maxilla and

CHESNEY ET AL

mandibula have been reviewed in 49 children with CRF and in 100 age- and sex-matched normal children .s? Complete alveolar erosions are characteristic of secondary hyperparathyroidism . Six of 49 patients with CRF, but no control subjects , showed complete erosion. Complete disappearance of alveolar septi on x-rays did not occur earlier than other radiologic features of secondary hyperparathyroidism . Thus, disappearance of alveolar septi are not an early ' sign of hyperparathyroidism or ROD .20 Looser zones are regarded as the most specific sign for osteomalacia. Whereas this sign is relatively common in adult patients with CRF, it is rare in children . However, looser zones appear predominately in patients who have osteomalacia in association with severe hyperparathyroidism . Although looser zones may be a marker of osteomalacia , the histologic correlate of this radiologic sign is not a broad band of unmineralized osteoid , but rather fibrous tissue occurring secondary to minor trauma. Looser zones also are present in patients with primary hyperparathyroidism .30 While information is gained by examining the bone trabeculae, changes in the trabecular surface cannot differentiate between osteitis fibrosa and osteomalacia. In advanced ROD, patchy rarefactions are often seen in tubular bones, mainly at the distal end of the metacarpals. Cystic rarefactions or Brown tumors are characteristic of both primary and secondary hyperparathyroidism, but they occur more frequently in secondary hyperparathyroidism .F Brown tumors were found in the metacarpal, the radius, the distal femur, and the proximal tibia in six of 191 children with CRF who had a total skeletal x-ray survey." The x-ray signs discussed are more characteristic of hyperparathyroidism than of osteomalacia. Looser zones can be present in both . The radiolu cent zones underneath the growth plates commonly are thought to be rickets . The basis for the rachitic-like radiolucent zones of long bones in CRF is not expanded growth cartilage and unmineralized chondroosteoid, as is found in nutritional rickets, but fibrous tissue and undermineralized woven bone that represent osteitis fibrosa . Consequently, one cannot diagnose a mineralization defect or osteomalacia from the radiologic appearance of the hand.v!'

VITAMIN D, PI, AND PTH IN CHILDHOOD ROD

Radiolucent zones in growing bone may indicate defec tive mineralization; however, when they occur in association with other signs characteristic of seco ndary hyperparathyroidism , rickets or osteomalacia is not likely to be the cause. In summa ry, the x-ray signs of ROD may all be due to osteitis fibrosa. There is not a single sign specific for osteomalacia . Children with rachitic lesions and slipped epiphysis have more seve re osteitis fibrosa than those with mild or no rachitic lesions." Parathyroid gland size has been measured by ultrasound in children with CRE Using the real time ultrasound technique with a 7.5 or 10 MH z detector, the parathyroid glands in 24 out of 33 dialysis patients, aged I to 18 yea rs, were identifie d and ranged in diameter from I to 12 mm; the dia meter correlated with seru m PTH levels . Parathyro id gla nds decreased in size following successful renal transplantation. ALUMINUM TOXICITY

During the past decade , ev idence had acc umulated that both dialysis-related encephalopathy and vitamin D-refractory bone disease are related to an . increase in total body aluminum (AI).32-37 The kidney in normal individuals excretes -15 mg Al/d and this is thought to be the amount of Al norm ally absorbed . Patients trea ted with hemodialysis in centers that used wate r with a high Al co ntent or patients, particularly infants and young children, who are give n AI(OH h to bind phosphate retain substantial quant ities of Al in bone .38 40 The studies in young childre n who have not been on dialysis therapy have led to the assumption that uptake of Al fro m the intestin e is greate r in young children. If this is the case , then infants are more at risk to deve lop AI-related osteomalacia . Vitamin D analogues, which promote intestinal phosphate abso rption , may increase the requirement for phosphate bind ing agents and increase Al uptake.:" The cli nical features of Al intoxication other than encephalopathy (see page 318) are osteomalacia, a proximal myopa thy, hypercalcem ia, relatively low immunoreactive PTH concentrations, resistance to the action of vitamin D, and a positive bone aluminum stain.37 On biopsy of the iliac crest, osteo malacia , in the absence of osteitis fibrosa and indete rm inant tetracycline lab eling

281

(when that was attempted), are characte ristic.v Vitamin D therapy appears to worsen hypercalcemia and to offe r no benefit. It may increase Al uptake. The diagnosis of AI-associated osteo malacia is diffi cult unless a bone biopsy is perform ed . However, giving the chelating agent deferoxamin e (DFO) , which binds both aluminum and iron, can test for increased body AI.34.37 Adult patient s undergoing hemodialysis, who have a rise in plasma Al of more than 150 t-tg/L from base line followi ng a standardized DFO infusion , are likely to have AI-associated osteo malacia .>? Plasma Al levels correlate with the intake of AI(HO h, 43 The pathogenesis of this disord er is uncertain . The disorder is contro lled by treating dialysate water to remove AI, by reduc ing dietary Pi to reduce the need for phosphate binding, and by using CaC0 3 or newe r phosphate-bind ing age nts to lower Pi uptake. Al can be removed by the long term use of DFO .43The DFO dose of 40 mg/kg/24 h appea rs to rem ove Al fro m bound tissue sites; and the Al plus chelate is removed by dia lysis . LONG TERM MEASUREMENT OF BONE DENSITY IN CHILDHOOD RENAL DISEASE

Photon absorpt iometr y measures bone mineral cont ent (BMC) and bone density acc urately and precisely. The technique depends on the deflection of a photon beam delivered from a highly co llimated 125Iodine source. The BMC and bone density have been co mpared in childre n with renal disease. v in children undergoing long-term glucocort icoid therapy of chronic glomerular disease ;" and in children following renal transplantation .44 Ch ildren with tubul oint er stitial disease are at greatest risk for demin eralization . Children with glomerular disease develop demi nera lization more freq uently when trea ted with glucocorticoids . Daily therapy is assoc iated with more extensive dem ineralization than alternate-day therapy.4445 Renal transplantation does not correct dem ineralization and some children have progressive demineralization followi ng ren al transplant ation , presumably related to glucoco rtico id therapy used posttransplantation. w We have measured BMC and bone density in 48 childre n serially for 15 to 120 month s; each child had an average of six measurement s. These patients were divided into those give n glucocorti-

282

CHESNEY ET AL

Table 2.

Patient Characteristics

Steroid

Patients Measurements Months follow-up Average follow-up Age at onset (yrs) Progression to CRF or transplant (no. pts, %) Initial BMC SO from mean Range Final BMC SO from mean Range Height (Z score) Initial Final Height velocity (cm/yr) Serum creat inine (mg/dL) Highest

Nonsteroid

p

33 230

15 72

57.0 12.2 ± 0.7*

40 .1 12.5 ± 1.0

NS NS

14 (42.4%)

8 (53.0%)

NS

-2.05 ± 0.26 ( - 5.16 to + 2.84)

-1 .32 ± 0.38 ( - 4.85 to + 0.53)

NS

-2.33 ± 0 .25 ( - 4.61 to + 1.0)

-1.35 ± 0 .31 (-3.13 to +0.62)

< 0.05

± ± ± ±

NS NS

-1 .65 -1 .70 4.00 2.07

± 0.23

± 0 .32 ± 0.41 ± 0.43

-1.27 - 1.16 6.39 4.12

1.04 0 .61 0.55 1.27

< 0.02 < 0 .05

'Values are given as mean ± SE. Abbreviations: Z score, SO score; NS, not significant.

coids and those who were not (Tables 2 and 3). Patients receiv ing glucocorticoids had a lower serum creatinine (SCT) and a lower growth velocity (P < 0 .02) ; this group also had lower BMC than those who were not treated . BMC did not correlate with height velocity or SCTor creatinine clearance derived from SCT and height. However, BMC and standard dev iation (SD) score were correlated in both groups . Over the per iod of observation, extending from 15 month s to 10 years , many indexes tended to track, eg , SD score for height, and BMC SD score both in children with low and high SCTvalues. PaTable 3.

tients receiving steroids were shorter, had a lower height velocity, had a lower BMC SD score, and had a lower BMC for a given SCT' The probability that these findings were significant was greater than 95 %, however, oral 1,25-(OH)zD 3 therapy improved BMC in four children in the nonsteroid group , but did not in three children in the steroid group . These results illustrate uses of BMC and how B~C stature are correlated. Improved growth velocity does not correlate with change in BMC . The tendency for height and BMC to track over time is an unexpected finding requiring further study.

Relationship Between Stature, Renal Function, and Bone Mineral Status Steroid Correlation Coeffic ient

BMC v Z score Initial Final BMC v cm/yr BMC v Cc , BMC Cr < 1.2 mg/dL Initial Final BMC Cr > 1.2 mg/dL Initial Final 'Values are given as mean ± SE.

0 .510 < 0.001 0.176 < 0.1 > 0 .05 n = 33 0.129 NS n = 27 0.0514 NS n = 221

Nonsteroid Correlat ion Coeff icent

0.483 0.789 n = 15 0 .017 n = 11 0 .0755 n = 76

-1.77 ± 0 .34' -2.04 ± 0 .32

- 0.89 ± 0.45 -1.14 ± 0 .30

-2.53 ± 0 .37 -2.83 ± 0.38

-1.81 ± 0.61 -1 .59 ± 0.58

P

< 0 .01 < 0.001 NS NS

283

VITAMIN 0, PI, AND PTH IN CHILDHOOD ROD

CONCLUSION

The discovery of the renal site of production of 1,25-(OHhD 3 has led the new research in childhood ROD . The questions of the 1970s related to the efficacy and safety of the l o-hydroxylated metabolites and to the influence of therapy on improvement of skeletal deformities of ROD . The problems of Pi retention , its effect on increased bone resorption, and on suppression of 1,25-

(OHhD 3 synthesis currently are being examined . These findings and the risks of using AI-containing phosphate-binding gels has stimulated research on how to control the effects of too much dietary Pi. The concept that the setpoint for suppression of PTH secretion has been altered in ROD has been developed . How these relate to bone morphology and how Pi intake will be controlled as eRI progresses are subjects under current investigation .

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loading in children with chronic renal failure . Kidney Int 41. Chesney RW, Moorth y AV, Eisman JA . et al: Increa sed gro wth after long-term oral l- alph a.Zfi-vitarnin 0 3 in ch ildhood renal osteodystrophy. N Engl J Med 298:238-242 , 1978 42 . Hodsman AB, Sherrard OJ, Alfr ey AC, et al: Bone aluminum and histomorphometric features of renal osteodystrophy . J Clin Endocrinol Metab 54:539-596, 1982 43 . Milliner OS, Hercz G. Miller JH , et al : Clearance of aluminum by hemodialysis : Effect of deferoxamine . Kidney Int 29:100-103 , 1986 (suppl 18) 44 . Chesney RW, Mazess RE , Rose PG , et al : Bone mineral status measur ed by direct photon absorptiornetry in childhood renal disease . Pediatrics 60:864-872 , 1977 45. Chesney RW, Maze ss RB, Jax OK, et al: Effect of prednisone on growth and mineral content in childhood glomerular disease . Am J Dis Child 132:768-772, 1978 46 . Chesney RW. Rose PG. Mazess RB: Persistence of dimin ished bone mineral content following renal transplantati on in childhood. Pediatri cs 73:459-466, 1984