Renal Osteodystrophy in Children with Chronic

Renal Failure: An Unexpectedly Common and

Incapacitating Complication

Anthony C. Hsu, MBBS, FRCP(C), Sang Whay Kooh, MD, PhD,

FRCP(C), Donald Fraser, MD, PhD,
William A. Cumming, MD, FRCP(C), and
Victor L. Fornasier, MD, FRCP(C)

From the Departments of Paediatrics, Radiology, and Pathology, University of Toronto

and Research Institute, The Hospital for Sick Children, Toronto

ABSTRACT. The incidence, age at onset, and progression etal manifestations of chronic kidney disease, (os-
of the biochemical, radiographic, and histologic charac- teomalacia, rickets, osteitis fibrosa, osteoporosis,
teristics of renal osteodystrophy were studied in 50 chil-
and sometimes osteosclerosis), the term “renal os-
dren in whom chronic renal failure had been recently
diagnosed. During a ten-year observation period, 19 pa-
teodystrophy” has superseded “renal rickets” as the
tients progressed to end-stage renal failure and radio- accepted designation of the bone lesion. Recent
graphic signs of renal osteodystrophy developed in 15 of estimates of the incidence of clinical or radiographic
these (79%). Renal osteodystrophy developed in all nine manifestations of bone disease in children with
patients whose chronic renal failure was diagnosed before
chronic renal failure (CRF) range from 41 to
3 years of age and in six of the ten children with later
onset of failure. The mean interval from diagnosis of renal
57%#{149}28 Most of these estimates refer to children
failure to development of osteodystrophy was 1.4 years. with advanced renal failure, the majority of whom
Radiographically, growth zone lesions predominated in were already undergoing hemodialysis. The status
the younger children, whereas cortical erosions were more of the skeleton in children with early renal insuffi-
prevalent in the older children. Histologic examination,
ciency has been examined in a few instances7tt but
performed in 38 patients, showed both defective mineral-
ization and excessive resorption and was a more sensitive the evolution of the bone lesions has not been
diagnostic index than radiography. Noticeable deformi- studied longitudinally as renal insufficiency prog-
ties developed in one third of the patients with osteodys- resses. Such knowledge is essential to evaluate reg-
trophy, despite medical treatment including vitamin D2 imens for preventing and treating renal osteodys-
therapy. Deformities were particularly frequent and Se-
trophy in children.
vere in patients whose renal failure developed in infancy.
In all 13 patients whose growth patterns were studied We studied 50 children in whom chronic renal
before and after osteodystrophy developed, the onset of failure had recently been diagnosed to ascertain the
bone lesions was associated with a deterioration of following: the incidence of renal osteodystrophy;
growth, indicating that osteodystrophy plays a major role the stage of renal failure at which it developed; the
in causing the growth retardation commonly observed in
early radiographic, biochemical, and histologic find-
children with chronic renal failure. Pediatrics 70:742-750,
1982; renal osteodystrophy, chronic renalfailure, rickets,
ings; the evolution of the skeletal lesions as renal
secondary hyperparathyroidism, osteomalacia. failure progressed, and their response to conven-
tional medical treatment.

MATERIALS AND METHODS

For nearly a century it has been recognized that
We studied all the patients in whom chronic renal
renal disease can lead to rickets and bone deform-
failure had been diagnosed at The Hospital for Sick
1 However, with modern knowledge of the skel-
Children, Toronto, between 1967 and 1977. The
criterion for diagnosis was elevation of serum cre-
Received for publication .July 31, 1981; accepted .Jan 6, 1982.
atinine concentration for more than three months.
Reprint requests to (J).F.) The Hospital for Sick Children, 555
Elevation was defined as a value of 1 .0 mg/100 ml
University Ave. Toronto, Ontario, Canada M5G 1X8.
PEDIATRICS (ISSN 0031 4005). Copyright © 1982 by the in children up to 3 years old and >1.3 mg/lOO ml in
American Academy of Pediatrics. those older than 3 years. These minimum values,

742 PEDIATRICS Vol. 70 No. 5 November 1982

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which are more than twice the normal levels in phosphate-binding agent as soon as the plasma
these age groups, are characteristic of relatively inorganic phosphate concentration was greater than
mild renal insufficiency. Patients who had meta- 7 mg/100 ml in children up to 5 years old or 5 mg/
bolic disorders known to cause skeletal abnormali- 100 ml in older children.
ties before onset of glomerular insufficiency (eg, Calcium Supplements. These were given only
Fanconi syndrome, primary renal tubular acidosis) when hypocalcemia was present (serum calcium
were excluded. Informed consent for the study was <7 mg/l00 ml for patients with nephrotic syndrome
given by the parents of all the patients. The study or <8.0 mg/100 ml for other patients).
protocol was approved by the Committee on Hu- Anticonvulsant Therapy. This treatment, which
man Experimentation, University of Toronto. affects calcium homeostasis and vitamin D metab-
We evaluated the development, progression, and olism, was not given to any patient.
treatment of renal osteodystrophy (ROD) for the Dialysis and Transplantation (D/T,). Patients
50 patients (aged 0 to 15 years at diagnosis) who were enrolled in the hospital’s renal dialysis and
complied with the assessment protocol. During the transplantation program when uremia could no
study, renal insufficiency progressed in all patients; longer be managed by conservative therapy (end-
15 required hemodialysis and/or transplantation stage renal failure). Some patients were considered
(D/T) and four patients died without undergoing unsuitable for transplantation and did not undergo
D/T. In the remaining 31 patients, renal failure was dialysis. At the time of the study, continuous am-
still being managed by medical therapy when the bulatory peritoneal dialysis had not yet been intro-
study was concluded in 1977. Because chronic di- duced as a therapeutic procedure.
alysis per se can adversely affect bone and mineral
Skeletal Assessment and Diagnosis of Renal
metabolism2’2 the start of hemodialysis was
Osteodystrophy
taken as the end point for assessment of growth and
skeletal development for this study. However, we Nephrologic and urologic examinations were car-
continued to record the patients’ growth and the ned out every three months beginning with the
response of their bone lesions to treatment after diagnosis of CRF. The skeletal status (ie, the pres-
dialysis was initiated. ence of deformities of the extremities, spine, and rib
cage) and mineral metabolism were usually assessed
Therapeutic Regimen every six months, occasionally every nine months.
The patient’s nephrologist or urologist managed Supine length or standing height was plotted on
the medical and surgical aspects of the renal dis- standard charts’4 and a measurement below the
ease. In general, the following measures were used. third percentile was the criterion of significant
General Medical Treatment. Patients had a nor- growth impairment. The growth velocity (height
ma! self-selected diet unless they had severe azo- increment per year) of each child was expressed as
temia, acidosis, hyperkalemia, or persistent hyper- a percentage of the mean velocity of normal chil-
tension. If these complications occurred, appropri- then of the same age and sex (growth-velocity in-
ate measures (dietary alterations, alkali therapy, dex).
antihypertensive medication) were instituted. Total calcium, inorganic phosphate, alkaline
Vitamin D2 Treatment. All children received a phosphatase activity, creatinine, and total protein
daily multivitamin supplement including 400 IU of were measured in serum by standard methods. Se-
vitamin D2. With the appearance of radiographic rum 25-hydroxyvitamin D (25-OHD) was measured
evidence of ROD, high doses of vitamin D were by a competitive protein-binding assay.” Serum
instituted, starting with lU/kg
200 of body weight 1,25-dihydroxyvitamin D (1,25[OH]2D) was not
per day and increasing by 25% every three months measured. Plasma immunoreactive parathyroid
until radiographic improvement or hypercalcemia hormone (iPTH) was measured at irregular inter-
(serum calcium 1 1.0 mg/100 ml) occurred. If there vals in most patients using an antibody with rec-
was improvement without hypercalcemia, the dose ognition sites for both N- and C-terminal fragments
was maintained. If hypercalcemia developed, vi- of the hormone molecule.’5
tamin D therapy was stopped until normocalcemia Serial radiography was carried out regularly be-
was restored (usually within a few weeks) and then ginning with diagnosis of CRF. At three- to six-
was resumed at a lower dose (approximately 759k of month intervals anteroposterior views were ob-
the previous level). The final dose of vitamin D tamed of the hands and wrists, knees, and ankles.
used for long-term treatment ranged from 5,000 to At each session, the radiograph of one hand was
135,000 lU/day (200 to 2,000 lU/kg of body weight taken on fine-grain film to show details of bone
per day). architecture. Radiographs of the shoulders, pelvis
Aluminum Hydroxide. Aluminum hydroxide, 100 and hips, lumbar spine, and skull were obtained at
mg/kg of body weight per day, was given as a six- to 12-month intervals. All films were assessed

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by one radiologist (W.A.C.) and calculation of the TABLE 1 . Underlying Renal Disease and Age Distri-

incidence of ROD was based only on his findings. bution at Diagnosis in 50 Pediatric Patients (Aged 0 to 15
Years) with Chronic Renal Failure
The radiographic criterion for diagnosis of ROD
was increased thickness and fraying of the radiolu- Diagnosis No. of Group I Group 2
Pa- (:s3 vr) (>3 yr)
cent zone in the region of the growth plates (growth tients
zone lesions) or subperiosteal erosion of the cortices
Congenital (29) (21) (8)
of the long bones and phalanges (cortical erosions). Renal dysplasia 9 7 2
Changes in bone density (osteoporosis or osteoscle- Obstructive uropathy 10 8 2
rosis) and coarsening of the trabecular pattern, Prune belly syndrome 5 4 1
Reflux nephropathy 5 2 3
often seen in the radiographs of patients with os-
Acquired (21) (4) (17)
teodystrophy, were not accepted per se as evidence
Focal glomerular sclerosis 10 1 9
of ROD in this study.6”1’ Chronic glomerulonephritis 4 1 3
Bone histology was evaluated at least once in 38 Juvenile nephrophthisis* 3 0 3
patients, usually when radiographic signs of ROD Renal vascular disease 2 1 1

were first noted. A core of cartilage and bone, 3 mm Chronic pyelonephritis 1 0 1

Renal tumor 1 1 0
in diameter, was taken from the anterior iliac crest
in the plane of the ileum, using a Vilaghy-Zellerman Total (50) (25) (25)

bone biopsy needle (Accurate Surgical Instruments, * An autosomal recessive condition. However, all three

Toronto).’7 In most cases, local anesthesia was ad- patients had clinical onset beyond 3 years of age.

equate for this procedure. All specimens were eval-

uated by one pathologist (V.L.F.). The specimen AGE
18
(YR)
A B
was examined by fine-detail microradiography to 17#{149} ECRF WITHOUT ROD
D

measure the thickness and number of mineralized 16. #{149}ROD ALSO

trabeculae. Also, longitudinal undecalcified and de- 15
calcified sections were examined histologically.
14
Findings were compared with those in specimens
from ten age-matched children who had died sud-
‘3.
D
4
D a
12-
denly in accidents. Unmineralized osteoid occupy-
ing more than 10% of the surface of trabeculae was
10.
taken as evidence of osteomalacia. Resorptive ac-
9.
tivity of endosteal bone, assessed by counting num-
8-
bers of osteoclasts and resorption cavities on tra-
7.
becular surfaces, was taken as a measure of para-
6
thyroid hormone (PTH) action on bone. Counts
5.
that obviously exceeded those of the age-matched
control subjects were considered to be indicative of
secondary hyperparathyroidism.

RESULTS
In the series of 50 patients reported in this study,
I_ ..*GROUP II -*- ‘4GROUPII
half had developed CRF by the age of 3 years. The
distribution of the patients according to age at Fig 1 Clinical
. outcome of 19 patients whose chronic

diagnosis of CRF is: 0 to 3 years, 25 patients; 3 to 6 renal failure (CRF) progressed to end-stage renal failure
during study: A, patients with renal osteodystrophy
years, ten patients; 6 to 9 years, six patients; 9 to 15
(ROD); B, patients without ROD; bottom of white col-
years, nine patients. The 25 patients (including 12 umn, age at diagnosis of CRF; bottom of black column,
neonates) who were s3.0 years of age when CRF age at diagnosis of ROD; top of black column, age at
was recognized, were designated as group 1 (Table dialysis (D), transplanation (T), or death (+).
1). Most patients in this group had congenital uro-
years (range, 0.9 to 9.9 years). This interval was
logic problems or congenital renal dysplasia. The
somewhat longer in the nine patients in group 1
remaining 25 patients, who were between 3. 1 and
than in the ten group 2 children (5.0 years vs 4.2
15 years of age at diagnosis, were designated as
years) but the difference was not statistically sig-
group 2. In two thirds of these the renal disease was
nificant.
classified as acquired. Of the 50 patients, 19 had
progressed to end-stage renal failure (dialysis, trans-
Incidence of Renal Osteodystrophy
plantation, and/or death) when the study was ter-
minated (Fig 1, Table 2). The interval from diag- ROD developed in 34 of the 50 patients, 19 in
nosis of CRF to end-stage renal failure averaged 4.6 group 1 and 15 in group 2. However, this gives a

744 RENAL OSTEODYSTROPHY

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TABLE 2. Intervals from Diagnosis of Chronic Renal the initial radiographic manifestations (Table 3). In
Failure to End-Stage Renal Failure (CRF-ESRF Inter- group 1 patients, there was a high incidence (12/19)
val) and from Diagnosis of CRF to Renal Osteodystrophy
of growth zone lesions (Fig 3, left), but in group 2
(CRF-ROD Interval) in Ten Patients Who Progressed to
ESRF During Study these lesions were uncommon (2/15) and cortical
erosions were the most conspicuous feature (Fig 4).
Group CRF-ESRF Patients CRF-ROD
Interval (yr) with Interval (yr) The erosions were most common at the distal ends
ROD of the ulna and radius, the neck of the humerus, the
middle phalanges of the second and third fingers,
Mean Range n % Mean Range
and the medial border of the proximal end of the
1 (n = 9) 5.0 1.8-9.9 9 100 1.2 0.3-2.8
tibia.
2 (n = 10) 4.2 0.9-5.9 6 60 2.8 1.0-4.7
Both (n = 19) 4.6 0.9-9.9 15 79 1.9 0.3-4.7 Correlation Between Early Renal
Osteodystrophy and Biochemical Indices
Number of
Patients The development of ROD correlated poorly with
15 the severity of CRF. In the 34 patients with bone
lesions, serum creatinine values ranged from 1.2 to
Group II
11.5 mg/100 ml when ROD was first apparent; the
16 patients without ROD at the completion of the
10#{149} study had similar serum creatinine values (1.0 to
12.6 mg/100 ml). More than three quarters of the
patients in group 1 (15/19) had levels s3 mg/100
ml when they first showed evidence of ROD (Fig
5
5), levels that would not usually be considered
indicative of severe renal failure. In comparison
with group 1, creatinine levels in group 2 tended to
be higher and their range much wider at the onset
0

CRF -.ROD Interval (years)

H of osteodystrophy.
In 24/34 patients no abnormalities of serum cal-
Fig 2. Interval between diagnosis of chronic renal fail- cium and inorganic phosphate levels were demon-
ure (CRF) and detection of bone lesions (CRF-ROD
interval) in 34 patients with renal osteodystrophy (ROD).
strable when ROD was diagnosed. Hypocalcemia
was present in two patients, hyperphosphatemia
spuriously low estimate of the true incidence, be- (inorganic phosphate >7.0 mg/100 ml) occurred in
cause more than half the patients had not reached four. Alkaline phosphatase >2 SD above the age-
end-stage renal failure when the study was termi- related normal value’5 was observed in seven pa-
nated. Of the 19 patients who had reached end- tients. All these patients had prominent growth
stage renal failure, 15 (79%) had radiographic evi- zone lesions.
dence of ROD (Table 2). Of the nine patients in Serum 25-OHD was measured in 26 patients at
group 1 who had reached end-stage renal failure, all diagnosis of ROD. In 23 patients values were from
had ROD, compared with only six of the ten pa- 12.8 to 39.4 ng/ml, within or slightly above the
tients in group 2. normal range in our region (8.1 to 33.1 ng/ml).’4 In
The mean period from diagnosis of CRF to ap- three patients with renal failure due to nephrotic
pearance of ROD (CRF-ROD interval) was 1.43 syndrome, the values were lower than normal as
years. In three quarters (25) of the 34 patients with has previously been reported. 19.21)

ROD, radiographic lesions appeared within 2.0

years of diagnosis of CRF; eight patients had ROD
Correlation of Skeletal Radiography, Bone
Histology, and Plasma Parathyroid Hormone
before their first birthday (Fig 2). In group 1 chil-
dren the mean CRF-ROD interval was 1.1 years Concentrations
(range 0.3 to 2.7 years), whereas in group 2 children Bone histology, skeletal radiography, and deter-
the mean CRF-ROD interval was somewhat longer
TABLE 3. Radiographic Findings in 34 Patients with
(2.0 years) and had a wide range (0 to 5.6 years).
Renal Osteodystrophy According to Age at Onset of
One child already had ROD when CRF was discov- Chronic Renal Failure
ered at 3.5 years of age.
Group Growth Cortical Both
Zone Erosion Lesions
Radiographic Characteristics of Early Lesions of Lesion Only
Renal Osteodystrophy Only

In the 34 patients in whom ROD developed, the 1 (n= 19) 6 7 6

2 (n= 15) 0 13 2
age at onset of CRF had an important bearing on

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 Fig 3. Radiographs of knee of 2.5-year-old boy with prune belly syndrome. Left, Severe
growth zone lesions before treatment. Right, Growth zone lesions healed after 1 1 months
of vitamin D2 treatment.

DOROUP I
us
GROUP II

0 4-
0
z 2-

‘, ‘P1.1-2
1_11n 2.1-3 3.1-4 4.1-5 5.1-6 6.1-7’8.1-9 9.1-10 11.1-12
SERUM CREA1ININE (mg/dI)

Fig 5. Serum creatinine concentration at diagnosis of

renal osteodystrophy in 34 patients.

evidence of ROD was present in every patient, and
in each biopsy both osteomalacia and excessive
resorptive activity were detected. Only 30 of the
patients had radiographic evidence of ROD: in
some, growth zone lesions and cortical erosions
were both evident, but others had only one of these
signs. Thus, histologic examination of iliac crest
bone was a more sensitive test than radiography for
presence of ROD.
Plasma iPTH levels were elevated (>0.3 ng/ml)
in 25 patients and normal in nine. All patients with
elevated iPTH values had radiographic evidence of
osteodystrophy but the magnitude of the iPTH
Fig 4. Radiographs ofwrist (left) and third finger (right)
elevation did not correlate with the severity of the
of 13-year-old child with chronic glomerulonephritis
showing marked cortical erosions but no growth zone
ROD ascertained radiographically or histologically.
lesions. Six of the nine patients with normal iPTH values
had normal radiographs; four of these six were also
mination of iPTH were carried out simultaneously examined histologically and no lesions were evident.
in 34 patients. In these patients CRF had been On the other hand, three patients with normal
present from 2.2 to 5.8 years and serum creatinine iPTH values had both radiographic and histologic
levels ranged from 1.1 to 8.1 mg/100 ml. Histologic evidence of ROD.

746 RENAL OSTEODYSTROPHY

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Effect of Vitamin D Treatment on Course of 3O -
Renal Osteodystrophy
20-
In the 34 patients treated with therapeutic doses
of vitamin D2, responses differed strikingly, depend-
110-
ing upon whether the lesions affected mainly the
growth zones or the cortices. The growth zone le-
100-
sions, present in 14 patients, disappeared within
weeks or months in nearly every instance (Fig 3, x
90-
right). On the other hand, cortical erosions, present 0
C
in 28 patients, invariably persisted without im-
80-
provement. In eight patients, the erosive lesions did V
0

not improve despite doses of vitamin D that caused > 70-

-C
mild hypercalcemia. In three patients in whom only
0.
growth zone lesions were visible initially, typical
0 60-
erosive lesions appeared in the course of vitamin D
treatment even though the changes in the growth
:
50-
zones had resolved satisfactorily.

40-
Growth Retardation and Skeletal Deformities
30i
Ofthe 16 patients without ROD, only three (19%) 0’-
were short (height < third percentile), and none 12 mos. before 12 mos. after
had deformities despite having CRF for one to ROD ROD
seven years. On the other hand, of the 34 patients Fig 6. Effect of renal osteodystrophy (ROD) on growth
who had radiographic evidence of ROD, 29 (85%) in 13 patients. Growth-velocity index (mean ± 2 SD) was
were stunted in height. Bone age was retarded by greater before development of renal osteodystrophy (86%
± 23%) than after detection of ROD (75% ± 24%), P <
more than one year in 22 patients (65%). Of the 13
0.01% (paired t test). Growth velocity index = (12-month
patients in whom data were available, growth ye- increment in patient’s height)/(12-month increment in
locity for the 12-month period immediately after mean height of normal children, same age and sex) x 100.
detection of ROD was significantly less than that patients and disappeared completely in four. Ab-
prior to development of ROD (Fig 6). In three
infants complete cessation of bone maturation was normal trabeculation remained.
noted.
DISCUSSION
Conspicuous skeletal deformities developed in
one third of the patients with ROD (12/34) despite Physicians treating children with chronic renal
vitamin D therapy (Table 4). Ten patients were in failure have become increasingly aware of its ad-
group 1 and most of these had congenital renal verse effects on the skeleton. Our investigation is
dysplasia or obstructive uropathy. Deformities had the first to study the evolution ofthe skeletal lesions
developed by 2.5 years of age, often by 1 year of systematically as chronic renal failure worsens. It
age. In group 2, deformities developed in two pa- indicates that renal osteodystrophy occurs more
tients, three and four years after diagnosis of CRF. frequently than has been suspected. Renal osteo-
Genu varum and genu valgum were equally corn- dystrophy occurred in 79% of the patients who
mon in group 1, whereas genu valgum was the only reached end-stage renal failure, compared with a
deformity observed in group 2. Four group 1 pa- figure of approximately 50% previously reported.27
tients had incapacitating deformities that necessi- We observed that bone lesions developed surpris-
tated orthopedic surgery. ingly soon after renal failure was recognized and
Renal transplantation was performed in six pa- were often deforming and seriously incapacitating.
tients in group 1; progressive ROD refractory to Renal osteodystrophy was an important factor con-
medical treatment was the reason for enrolling four tributing to the decreased growth rate frequently
patients in the dialysis/transplantation program, observed.
even though renal insufficiency was not yet very Skeletal lesions developed in all children less than
severe (serum creatinine level 6 mg/100 ml). The 3 years of age (group 1) by the time end-stage
skeletal lesions of the six patients in group 1 who failure had supervened. On average, bone lesions
received renal allografts were assessed following occurred 14 months after chronic renal failure was
transplantation. Within one year, the growth zone diagnosed. In group 2 patients, radiographic signs
lesions and the cortical erosions improved in all of osteodystrophy were apparent in 60% of patients

ARTICLES 747

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748 RENAL OSTEODYSTROPHY

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at end-stage failure and occurred within art average porosis, osteosclerosis, coarse trabeculation-were
of two years after diagnosis of chronic renal failure. not considered diagnostic. Iliac crest biopsies were
One child already had bone lesions when renal performed on two thirds of the patients, but this
failure was discovered. examination was not possible for all patients espe-
The types of primary renal and urologic condi- cially in the early stage of renal failure. Our evi-
tions in our series are similar to those reported for dence, like that of Norman et al7 indicates that
childhood chronic renal failure in general.21’22 How- histologic assessment is a more sensitive index of
ever, half the patients were younger than 3 years of renal osteodystrophy than is radiography. Micro-
age. It is possible that inclusion of several infants scopic evidence of osteodystrophy was present in
referred by the Urology Service accounts for the all patients examined, whereas three of these did
high overall incidence of renal osteodystrophy in not have osteodystrophy by radiographic criteria.
our series, because, as we have shown, such patients Although bone biopsy provides a more sensitive
are at high risk of developing skeletal lesions. sign of osteodystrophy, it should be emphasized
It is generally conceded that the cortical erosions that biopsy is not a practical means of screening for
seen in radiographs of the long bones are caused by early evidence of skeletal involvement. Plasma
secondary hyperparathyroidism. The growth zone iPTH was determined in two thirds of our patients
lesions of renal osteodystrophy are commonly but was not measured serially from the onset of
called “rickets.” However, the morphologic features renal disease. In most instances, the level was ele-
of these lesions differ significantly from those seen vated by the time assay was undertaken. Of those
in vitamin D deficiency, and have been shown his- with elevated iPTH levels 88% had renal osteodys-
tologically to possess several elements of hyper- trophy on radiographic examination, a figure similar
parathyroidism (fibrosis, excessive chondroclastic to that reported by Roof et al.25 Recent studies
and osteoclastic activity) #{149}23,24 These growth zone indicate that elevation of iPTH occurs early in renal
lesions are considered to be characteristic of child- insufficiency before signs are present radiographi-
hood renal osteodystrophy. In two thirds of the caily.7’25 However, in the studies of Norman et al7
patients in group 1, the predominant, sometimes renal osteodystrophy could be demonstrated histo-
the only, radiographic manifestations were growth logically in every child whose plasma iPTH level
zone lesions. By contrast, in children whose kidney was elevated. Clearly, serial estimations of plasma
disease was of later onset, fewer than 15% had iPTH concentration should be undertaken in as-
lesions in the growth zones, although all had cortical sessing children with chronic renal failure. The
erosions. This pattern has not been noted previ- timing of the onset of hyperparathyroidism in re-
ously. lation to the development of histologic and radio-
Skeletal deformities were observed in one third graphic lesions remains to be worked out. Our study
of patients who developed osteodystrophy. Deform- demonstrated, as did others, that measurements of
ities were much more common in group 1 patients. serum calcium, inorganic phosphate, and alkaline
They occurred early in the course of renal failure phosphata.se did not reliably identify the presence
and were sometimes so incapacitating that they of early renal osteodystrophy.
constituted the indication for transplantation. Serum 1,25[OHJ2D levels may be much reduced
Initially the growth zone lesions responded radio- in the advanced stages of renal failure.26’27 However,
graphically to treatment with pharmacologic doses because the technique is relatively recent it is not
of vitamin D2. On the other hand, there was little known whether serial determinations of this impor-
or no improvement in the cortical erosions even tant vitamin D metabolite would be helpful in di-
with doses of vitamin D sufficient to cause hyper- agnosing early osteodystrophy in childhood. Serum
calcemia, which would be expected to suppress 1,25[OH]2D levels were variously reported to be
parathyroid hormone secretion. Furthermore, de- low,2627 normal, or even elevated28 in patients with
formties tended to progress. The explanation for mild renal failure. We did not measure 1,25[OH]2D
the preponderance of the growth zone lesions we levels in our patients.
have observed in younger patients is not yet clear. Retardation of growth is a prominent and serious
Vitamin D deficiency was ruled out by the presence complication of chronic renal failure in childhood.
of normal serum concentrations of 25-OHD in these However, the extent to which this manifestation is
patients. Possibly the rapid growth in this age group attributable to uremia, nutritional deprivation, or
magnifies the disturbance in mineral metabolism at renal osteodystrophy is still unsettled.’2’32 In two
the growth plates. thirds of our patients with renal osteodystrophy,
In the present study, the diagnosis of osteodys- height was less than the third percentile of normal,
trophy was based upon radiographic evidence. Only whereas only a few of those without bone lesions
unequivocal signs-growth zone lesions, cortical were below the third percentile. Patients grew rel-
erosions-were accepted; less specific signs-osteo- atively well, albeit more slowly than normal, until

ARTICLES 749
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 radiographic evidence of skeletal disease appeared ofrenrl insufficiency and maintenance haemodialysis. Neph.
. but the growth rate decreased significantly after- ron 10:195, 1973
11. Stickler GB: Growth failure in renal disease. Pediatr Clin
wards. Furthermore, the observation that serum North Am 23:885, 1976
creatinine levels were similar in patients with and 12. West CD, Smith WC: An attempt to elucidate the cause of
growth retardation in renal disease. Am J Dis Child 91:460,
without renal osteodystrophy suggests that bone
1956
disease rather than uremia per se is the important 13. Tanner JM, Whitehouse RH, Takaishi M: Standards from
cause of the poor growth of children with renal birth to maturity for height, weight, height velocity and
weight velocity. I. British children, 1965. Arch Dis Child
failure. Studies in four children with renal osteo-
41:454, 1966
dystrophy suggest that treatment with active me- 14. Jones G: Assay of vitamins D2 and D., and 25-hydroxyvita-
tabolites of vitamin D resulted in improved growth mins D and D in human plasma by high-performance liquid
chromatography. Clin Chem 24:287, 1978
velocity.”” However, a more recent study of
15. Murray TM, Keutmann HT: The immunochemical specific-
1,25[OHJ2D3 treatment in 16 children who had Un- ity of antisera to bovine parathyroid hormone: an approach
dergone dialysis failed to improve growth velocity.t5 to region-specific radioimmunoassay. J Endocrinol 56:493,
1973
It is not known whether administration of
16. Mehls 0, Ritz E, Krempien B, et a!: Roentgenological signs
1,25[OHJ2D3 in the early stages of chronic renal in the skeleton of uremic children: an analysis of the anatom-
failure can prevent osteodystrophy and growth fail- ical principles underlying the roentgenological changes. Pe.
diatrRadiol 1:183, 1973
ure. 17. Vilaghy MI: A bone biopsy instrument of new design, in
Our study emphasizes that renal osteodystrophy Frame B, Parfitt AM, Duncan H (eds): Clinical Aspects of
is a frequent and early complication of chronic renal Metabolic Bone Disease. Amsterdam, Excerpta Medica,
1973, p 152
failure in children. The incidence and pattern of 18. Cherian AG, Hill JG. Percentile estimates ofreference values
evolution of childhood osteodystrophy must be for fourteen chemical constituents in sera of hildren and
borne in mind in establishing the relative merits of adolescents. Am J Cliii Pathol 69:24, 1 ::
19. Schmidt-Gayk H, Schmitt W, Grawunder C, et al: 25-Hy-
various treatment regimens and in evaluating pro- droxy-vitamin-I) in nephrotic syndrome. Lancet 2:105, 1977
posed prophylactic measures. 20. Goldstein DA, Oda Y, Kurokawa K, et a!: Blood levels of 25-
hydroxyvitamin D in nephrotic syndrome: Studies in 26
ACKNOWLEDGMENTS patients. Ann Intern Med 87:664, 1977
21. Habib R, Broyer M, Benmaiz H: Chronic renal failure in
This study was supported by grants from the Conn
children: Causes, rate of deterioration and survival data.
Smythe Research Foundation for Crippled Children, To- Nephron 11:209, 1973
ronto, the Bone Mineral Metabolism Unit, University of 22. Potter DE, Holliday MA, Piel CF. et al: Treatment of end-
Toronto, and the Ministry of Health, Province of Ontario. stage renal disease in children: A 15-year experience. Kidney
The authors thank Drs C. Phillips Rance, Gerald S. mt 18:103, 1980
Arbus, and J. Williamson Balfe, nephrologists, and Drs 23. Avioli LV, Teitelbaum SL: Renal osteodystrophy, in Edel-
Bernard Churchill, Brian Hardy, Robert Jeffs, and John man CM, Jr (ed): Pediatric Kidney Disease. Boston, Little,
Schfflinger, urologists, for close collaboration in our study Brown and Co. 1978, vol 1, p 366
24. Mehls 0, Ritz E, Kreusser W, et al: Renal osteodystrophy in
of their patients and for advice in preparing the manu-
uraemic children. Clin Endocrinol Metab 9:151, 1980
script.
25. Roof BS, Piel CF, Rames L, et al: Parathyroid function in
uremic children with and without osteodystrophy. Pediat.
REFERENCES
rics 53:404, 1974
1. Lucas RC: On a form of late rickets associated with albu- 26. Brumbaugh PF, Haussler DH, Bressler R, et al: Radiorecep-
minuria, rickets of adolescence. Lancet 1:993, 1883 tor assay for la,25-dihydroxyvitamin I) . Science 183:1089,
2. Potter DE, Wilson CJ, Ozonoff MB: Hyperparathyroid bone 1974
disease in children undergoing long-term hemodialysis: 27. Portale AA, Booth BE, Tsai HC, et al: Reduced plasma
Treatment with vitamin D. J Pediatr 85:60, 1974 concentration of l,25(OH)21) in children with moderate renal
3. Firor HV, Moore ES, Levitsky LL, et al: Parathyroidectomy insufficiency (MRI), abstracted. Kidney mt 16:922, 1979
in children with chronic renal failure. J Pediatr Surg 7:565, 28. Slatopolsky E, Gray R, Adams NI), et al: Low serum levels
1972 of 1,25(OH)D:i are not responsible for the development of
4. Mehls 0, Krempien B, Ritz E, et al: Renal osteodystrophy secondary hyperparathyroidism in early renal failure. ab-
in children on maintenance haemodialysis. Proc Eur Dial stracted. Kidney mt 14:733, 1978
Transplant As-soc 10:197, 1973 29. Holliday MA: Caloric intake and growth in uremia. Kidney
5. Balsan S, Royer P, Mathieu H: Les rachitismes et les fibroos- mt 7(suppl):S-73, 1975
t#{233}oclasies des insuff,sances r#{233}nales chroniques de l’enfant 30. Cooke RE, Boyden DG, Hailer E: The relationship of aci-
(#{233}tudebiologique et th#{233}rapeutique de 41 observations). Arch dosis and growth retardation. J Pediatr 57:326, 1960
Fr Pediatr 23:769, 1966 31. Stickler GB, Bergen
A review: BJ:Short stature in renal
6. Parfitt AM: Clinical and radiographic manifestations of renal disease. Pediatr 1973
Res 7:978,
osteodystrophy, in David DS (ed): Calcium Metabolism in 32. Betts PR, Magrath G: Growth pattern and dietary intake of
Renal Failure and Nephrolithiasis. New York, John Wiley children with chronic renal insufficiency. Br Med J 2:189,
& Sons, 1977, p 145 1974
7. Norman ME, Mazur AT, Borden S IV et a!: Early diagnosis 33. Chan JCM. DeLuca HF: Growth velocity in a child on
of juvenile renal osteodystrophy. J Pediatr 97:226, 1980 prolonged hemodialysis: Beneficial effect of in-hydroxyvi-
8. Fine RN, Isaacson AS, Payne V, et a!: Renal osteodystrophy tamin D.. JAMA 238:2053, 1977
in children: The effect of hemodialysis and renal homotrans- 34. Chesney RW. Moorthy AV, Eisman .JA, et al: Increased
plantation. J Pediatr 80:243, 1972 growth after long term oral ln.25-vitamin D. in childhood
9. Healy MI), Malluche HH, Goldstein DA, et al: Effects of renal osteodystrophy. N Engi J Med 298:238, 1978
long-term therapy with calcitriol in patients with moderate 35. Bulla M, Delling G. Benz-Bohm G. et a): Renale osteodys-
renal failure. Arch Intern Med 140:1030, 1980 trophie bei Kindern: Therapieversuch mit 1,25-Dihydroxy-
10. Ritz E, Krempien B, Mehls 0, et.al: Skeletal complications cholecalciferol. Kim Wochenschr 58:511, 1980.

750 RENAL OSTEODYSTROPHY

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 Renal Osteodystrophy in Children with Chronic Renal Failure: An Unexpectedly
Common and Incapacitating Complication
Anthony C. Hsu, Sang Whay Kooh, Donald Fraser, William A. Cumming and Victor L.
Fornasier
Pediatrics 1982;70;742

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been published continuously since . Pediatrics is owned, published, and trademarked by the American
Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright ©
1982 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

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 Renal Osteodystrophy in Children with Chronic Renal Failure: An Unexpectedly
Common and Incapacitating Complication
Anthony C. Hsu, Sang Whay Kooh, Donald Fraser, William A. Cumming and Victor L.
Fornasier
Pediatrics 1982;70;742

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://pediatrics.aappublications.org/content/70/5/742

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has
been published continuously since . Pediatrics is owned, published, and trademarked by the American
Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright ©
1982 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

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