Pediatric Imaging M. Ines Boechat, MD William D. Winters, MD Ronald J. Hogg, MD Richard N. Fine, MD Sandra L. Watkins, MD
Index terms: Femur, necrosis, 443.443, 443.54 Femur, radionuclide studies, 443.12172 Kidney, failure, 81.14, 81.54 Radiology 2001; 218:411– 413 Abbreviations: AVN ⫽ avascular necrosis IGF-1 ⫽ insulin–like growth factor 1 LCP ⫽ Legg-Calve´-Perthes 1
From the Department of Radiological Sciences, UCLA Medical Center, CHS-B2-252, 10833 Le Conte Ave, Los Angeles, CA 90095-1721 (M.I.B.); the Department of Radiology (W.D.W.) and Division of Nephrology (S.L.W.), Children’s Hospital and Medical Center, Seattle, Wash; the Division of Pediatric Nephrology, North Texas Children’s Hospital at Medical City Dallas (R.J.H.); and the Department of Pediatrics, SUNY at Stony Brook, New York (R.N.F.). Received November 11, 1998; revision requested December 29; final revision received July 5, 2000; accepted August 2. Supported in part by Genentech. Address correspondence to M.I.B. (e-mail:
[email protected]).
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RSNA, 2001
Author contributions: Guarantor of integrity of entire study, M.I.B.; study concepts, M.I.B., S.L.W.; study design, M.I.B.; definition of intellectual content, M.I.B.; literature research, M.I.B., S.L.W.; clinical studies, M.I.B., W.D.W.; data acquisition, S.L.W., R.J.H., R.N.F.; data analysis, M.I.B., S.L.W.; statistical analysis, M.I.B.; manuscript preparation, M.I.B.; manuscript editing, M.I.B., W.D.W., S.L.W.; manuscript review, all authors; manuscript final version approval, M.I.B.
Avascular Necrosis of the Femoral Head in Children with Chronic Renal Disease1 PURPOSE: To determine the incidence of avascular necrosis (AVN) of the femoral head in children with chronic renal failure. MATERIALS AND METHODS: Pelvic radiographs in 205 children (age range, 6 months to 16 years; mean age, 6 years ⫾ 3.5 [SD]) with chronic renal failure were reviewed. Serial radiographs were obtained every 6 months for 1–7 years (mean, 3 years ⫾ 2) to assess the presence of AVN of the femoral head; six children had metabolic renal disease, 21 had acquired renal disease, and 178 had structural renal lesions. RESULTS: Radiographic findings of AVN were seen in 14 of 205 patients (approximately one in every 15). The frequency of AVN was similar in boys and girls; AVN was observed in 11 (6.9%) of 159 boys and in three (6.5%) of 46 girls and was not related to the duration of renal disease, type of renal disease, or growth hormone therapy. Affected children were frequently asymptomatic, and, when present, the clinical complaints were mild. In two instances, AVN developed while the patients were receiving corticosteroids before entering this study. CONCLUSION: The results of this study indicate that AVN of the femoral head is a frequent complication in children with chronic renal failure, occurring in approximately 7% of this population. Unlike Legg-Calve´-Perthes disease, AVN in children with chronic renal failure is frequently asymptomatic and has no sex predilection.
Idiopathic avascular necrosis (AVN) or Legg-Calve´-Perthes (LCP) disease represents osteonecrosis of the proximal epiphysis of the femur of unknown cause. While there is sufficient evidence (1) to indicate that this condition is essentially AVN, until the cause is known, LCP disease will remain a separate syndrome from forms of femoral necrosis associated with known causes, such as trauma, synovitis, hypothyroidism, hemoglobinopathy, epiphysial dysplasia, and steroid therapy. AVN of the hip has also been associated with congenital anomalies of the genitourinary tract, and it has been suggested (2,3) that children with chronic renal failure may be at increased risk of developing AVN of the femoral head. In this population, AVN is frequently thought to be related to corticosteroid treatment, especially after renal transplantation (4,5). However, AVN can also occur in the absence of steroid therapy, which raises questions about the role played by underlying kidney disease, uremia, concomitant therapies, and environmental factors in the growth and development of the femoral neck. Presently, neither the exact incidence nor the reasons for the occurrence of AVN in children with chronic renal failure are known. In this study, we determined the incidence of AVN of the femoral head in a large cohort of children with chronic renal failure who underwent serial radiographic evaluation at 6-month intervals for a mean of 3 years and compared the findings with those reported for LCP disease in the healthy pediatric population. We also examined whether the risk of this complication was related to age, to the type of renal disease and the duration of the renal failure, or to corticosteroid or recombinant growth hormone therapy.
MATERIALS AND METHODS Between January 1990 and January 1996, 205 children (159 male, 46 female; age range, 6 months to 16 years; mean, 6 years ⫾ 3.5) with chronic renal failure but not end-stage renal 411
disease were enrolled in two multicenter, randomized, longitudinal studies (6,7) to evaluate the effects of subcutaneously administered recombinant growth hormone on skeletal growth in children with renal failure. The research protocol was approved by the institutional review board of the institutions involved, and informed consent from the parents or guardians was obtained for each patient enrolled. The height of all children was below the 5th percentile for chronologic age. Sixty-six children were randomly assigned to the control arm for a mean of 2 years ⫾ 1.8, and 139 received growth hormone treatment. The cause of renal failure was structural malformation in 178 children, acquired renal disease in 21, and metabolic disease (cystinosis and oxalosis) in six. Serial radiographic evaluations of the pelvis were performed at baseline and routinely thereafter at 6-month intervals during the study (range, 1–7 years; mean, 3 years ⫾ 2). If the children complained of bone or joint pain during the study, additional radiographs were obtained for diagnostic purposes. All pelvic radiographs were independently assessed for the presence of AVN of the femoral head independently by two experienced pediatric radiologists (M.I.B., W.D.W.). The radiologic diagnostic criteria used are described in the literature (1). In the initial phase of the disease, no abnormalities are found. In the early phase of AVN, there is increased bone density, a small ossific epiphysis, increased medial joint space, and a subchondral fissure. In the early intermediate phase, radiographs show intermixed lucencies, sequestra and immature bone, with a predominance of resorption. In the late intermediate phase, there is gradual reconstitution of the outline and integrity of the ossification center and of bone of mixed maturity. In the late phase, radiographs depict remodeling of amorphous bone into mature trabeculae. If there was any discordance of opinion, the radiographs were reassessed, and if the disagreement persisted regarding the diagnosis of AVN, a radionuclide bone study was performed. The diagnosis of AVN with a radionuclide scan was based on the presence of an uptake defect in the femoral head on a technetium 99m bone scan (1). Differences in age and duration of renal disease between children with and without AVN were determined by conducting unpaired t tests. Differences in sex and type of renal disease between children with and without AVN were tested 412
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with the two-sample z test of proportions. Potential differences in the incidence of AVN between groups receiving and not receiving growth hormone treatment were also determined by conducting unpaired t tests. All tests of significance were conducted at a P value of .05 and were two-tailed.
RESULTS Of the 205 children with chronic renal failure who were enrolled in this study, 14 (age range, 2–14 years) had a diagnosis of AVN of the femoral head, a mean of one in 15 children. The Table shows the number of patients, sex, age, cause of renal disease, duration of disease, and treatment in patients with and without AVN of the femoral head. The frequency of AVN in this cohort was similar in boys and girls; AVN was observed in 11 (6.9%) of 159 boys and in three (6.5%) of 46 girls. There were also no significant differences (P ⫽ .72) in the duration of the disease or in the type of renal disease in patients with and without this complication. Necrosis of the femoral head was manifested clinically in seven children who presented with a limp associated with minimal pain of limited duration. In the remaining children, the condition was asymptomatic. In three children, the diagnosis of AVN was made from the baseline radiographs, while in the remaining children, this condition developed during the course of the study. The right femoral head was affected in five children, the left was affected in six, and both were affected in three. The diagnosis was based solely on skeletal radiographs in 12 of 14 children, while in two children, AVN suggested on radiographs was confirmed with radionuclide studies. No significant differences (P ⫽ .72) were observed in the incidence of AVN between children with chronic renal failure who were treated or not treated with growth hormone. Necrosis of the femoral head developed in 10 (7.2%) of 139 children treated with recombinant growth hormone and in four (6.1%) of 66 untreated children. Among the 14 children in whom AVN of the femoral head developed, two had previously been treated with corticosteroid therapy; one was in the growth hormone–treated group, and the other was in the untreated group.
DISCUSSION Skeletal abnormalities are a major concern in the growing child with chronic
Clinical Characteristics of Children with Renal Failure with and without AVN of the Femoral Head Clinical Characteristics
AVN
Patients (M/F) 14 (11/3) Age (y) 5.6 ⫾ 2.8* Duration of disease (y) 3.9 ⫾ 1.7* Cause of disease Acquired 2 Metabolic 0 Structural 12 Therapy Corticosteroid 2 Growth hormone 10 None 4
No AVN 191 (148/43) 5.9 ⫾ 3.8* 3.7 ⫾ 2.1* 19 6 166 11 129 62
Note.—Data are number of patients unless otherwise specified. *Data are mean plus or minus the SD.
renal failure, and considerable information (8) is available regarding renal osteodystrophy in the population. The results of this study indicate that AVN of the femoral head is a frequent complication in children with chronic renal failure, occurring in approximately 7% of this population. While LCP disease, or idiopathic AVN of the femoral head, usually affects one in 1,000 –5,000 children, our results showed that approximately one in 15 children with renal failure had this condition, a frequency that was about 60 – 300 times higher than that of the healthy pediatric population (9,10). Because in this study we used conventional radiography, which is insensitive in the depiction of early changes of AVN in the hips (11), it is likely that our results caused underestimation of the true incidence of this complication in children with chronic renal failure. Although the radiographic depiction of AVN in children with renal failure is identical to that of LCP disease, several features of this complication in children with uremia should be stressed. LCP disease occurs more commonly in boys (male-to-female ratio, 5:1), and in about 10% of the cases, it is bilateral (1,9,10). In contrast, in children with renal failure, the incidence is similar in boys and girls, with a higher frequency of bilateral involvement than in those with idiopathic femoral necrosis. It should also be noted that the clinical manifestations of this complication were frequently vague; half of the children complained of leg pain (usually minimal) or presented with limping, while the other half had no Boechat et al
symptoms attributed to this complication. The pathogenesis of AVN in these patients remains unclear. AVN of the femoral head has long been known to be associated with congenital anomalies of the genitourinary tract. Catterall et al (2) found that 4.3% of patients with LCP disease had a congenital renal anomaly, including obstructive uropathy, nephrolithiasis, and duplicated collecting systems. This group had a higher incidence of bilateral disease than did patients with typical LCP disease, and they had a higher incidence of genitourinary abnormalities in first-degree relatives, which suggested an underlying genetic predisposition to the disease. More recently, Mehls et al (3) also reported findings in three children with renal hypoplasia, megacystis-megaloureter syndrome, and dysplasia with megaloureter who developed AVN of the femoral head among 102 children with end-stage renal disease who required dialysis. In the present study, however, no relationship was apparent between the type of kidney disease and the development of femoral necrosis. AVN was seen both in children with structural anomalies and in those with acquired renal disease. The results of this study also showed no relationship between duration of renal failure and the frequency of femoral necrosis. Growth hormone has been used for the alleviation of the severe growth failure associated with renal failure (6,7). Interestingly, findings of one report (12) have suggested that AVN of the femoral neck could be a complication of treatment with recombinant growth hormone in children with renal disease. However, in the present multicenter study that encompassed a relatively large number of children with renal failure treated or not treated with the hormone, we found no relationship between the development of AVN of the femoral head and growth hormone therapy. Necrosis of the femoral head was seen in 7.2% of the children with renal failure who were treated with recombinant growth hormone and in 6.1% of untreated patients. Similarly, although two of 14 children with AVN had been treated with corticosteroids, the condition was commonly seen in patients who did not receive steroid therapy. It should be noted that growth failure, manifested by short stature, retarded
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skeletal age, and constitutional delay, is both a particularly severe consequence of chronic renal insufficiency and a common finding in patients with LCP disease (13–15). Because growth is regulated, to a great degree, by growth hormone and its mediator, insulin–like growth factor 1 (IGF-1), investigators have hypothesized a causative relationship between this regulator and LCP disease. Rayner et al (16) found impaired growth hormone response to stimulation and elevated levels of IGF-1 activity in young male patients with LCP disease. Burwell (17) and Burwell et al (18) also found elevated levels of IGF-1 in a similar population; they postulated that in this condition disproportionate skeletal growth affects the hip joint, leading to vascular insufficiency to the femoral head. In contrast, however, Tanaka et al (19) found reduced levels of IGF-1 in children with LCP disease. Future studies are needed to determine the exact role, if any, that IGF-1 plays in the pathogenesis of AVN of the femoral head. In conclusion, AVN of the femoral head should be included in the list of skeletal complications associated with chronic renal disease and growth failure. Similarly, chronic renal failure should also be added to the differential diagnosis of the conditions that are manifested as AVN of the femoral head. Unlike LCP disease, AVN in children with chronic renal failure is frequently asymptomatic and has no sex predilection. Long-term studies are needed to determine the natural history of AVN in this population. Acknowledgments: We thank Joyce E. Kuntze, RN, for coordinating the clinical centers and Douglas F. Brown for performing the statistical analysis. We also acknowledge the participants in the Southwest Pediatric Nephrology Study Group and the Genentech Growth Hormone Study Group, as listed in the articles by Powell et al (6) and Fine et al (7). References 1. Ozonoff MB. The hip. In: Pediatric orthopedic radiology. 2nd ed. Philadelphia, Pa: Saunders, 1992; 240 –246. 2. Catterall A, Roberts GC, Wynne-Davies R. Association of Perthes’ disease with congenital anomalies of genitourinary tract and inguinal region. Lancet 1971; 1:996 – 997. 3. Mehls O, Ritz E, Kreusser W, Krempien B. Renal osteodystrophy in uraemic children. Clin Endocrinol Metab 1980; 9:151– 176. 4. Potter DE, Genant HH, Salvatierra O.
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Avascular necrosis of bone after renal transplantation. Am J Dis Child 1978; 132:1125–1129. Uittenbogaart CH, Isaacson AS, Stanley P, et al. Aseptic necrosis after renal transplantation in children. Am J Dis Child 1978; 132:765–767. Powell DR, Liu F, Baker BK, et al. Modulation of growth factors by growth hormone in children with chronic renal failure: The Southwest Pediatric Nephrology Study Group. Kidney Int 1997; 51:1970 – 1979. Fine RN, Kohaut EC, Brown D, Perlman AJ. Growth after recombinant human growth hormone treatment in children with chronic renal failure: report of a multicenter randomized double-blind placebo-controlled study—Genentech Cooperative Study Group. J Pediatr 1994; 124: 374 –382. Goodman WG, Coburn JW, Slatopolsky E, Salusky IB. Renal osteodystrophy in adults and children. In: Favus MJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 3rd ed. Philadelphia, Pa: Lippincott-Raven, 1996; 341–360. Fisher RL. An epidemiological study of Legg-Perthes disease. J Bone Joint Surg 1972; 54:769 –778. Molloy MK, MacMahon B. Incidence of Legg-Perthes disease (osteochondritis deformans). N Engl J Med 1966; 275:988 – 990. Kopecky KK, Braunstein EM, Brandt KD, et al. Apparent avascular necrosis of the hip: appearance and spontaneous resolution of MR findings in renal allograft recipients. Radiology 1991; 179:523–527. Watkins SL, Johanson A, Winters W, Avner ED. Legg-Perthes in children with chronic renal failure during growth (abstr). J Am Soc Nephrol 1990; 1:344. Staheli LT. Legg-Calve´-Perthes disease. In: Behrman RE, ed. Nelson textbook of pediatrics. 14th ed. Philadelphia, Pa: Saunders, 1992; 1708 –1709. Harrison MHM, Burwell RG. Perthes’ disease: a concept of pathogenesis. Clin Orthop 1981; 156:115–127. Kristmundsdottir F, Burwell RG, Harrison MHM. Delayed skeletal maturation in Perthes’ disease. Acta Orthop Scand 1987; 58:277–279. Rayner PHW, Schwalbe SL, Hall DJ. An assessment of endocrine function in boys with Perthes’ disease. Clin Orthop 1986; 209:124 –128. Burwell RG. Perthes’ disease: growth and aetiology. Arch Dis Child 1988; 63:1408 – 1412. Burwell RG, Vernon CL, Dangerfield PH, Hall DJ, Kristmundsdottir F. Raised somatomedin activity in the serum of young boys with Perthes’ disease revealed by bioassay: a disease of growth transition? Clin Orthop 1986; 209:129 –138. Tanaka H, Tamura K, Takano K, et al. Serum somatomedin A in Perthes’ disease. Acta Orthop Scand 1984; 55:135– 140.
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