8 Renal osteodystrophy in uraemic children

8 Renal Osteodystrophy in Uraemic Children OTTO MEHLS EBERHARD RITZ WILHELM KREUSSER BURKHARD KREMPIEN

The occurrence of metabolic bone disease and the associated retardation of growth in uraemic children have been known to clinicians for decades (FOrster, 1887; Barber, 1920; Albright, Drake and Sulkovitch, 1937). Since chronic haemodialysis and renal homotransplantation have become available for the treatment of end-stage renal failure, this problem has gained considerable importance, particularly since it has been found that chronic haemodialysis fails to correct the skeletal abnormality (Cameron, 1973). Several excellent reviews on this subject have appeared in recent years (Lewy and New, 1975; Avioli and Teitelbaum, 1976; Balsan, 1976; Beal et al, 1976; Chan, 1976; Stickler, 1976; Broyer et al, 1977; Holliday, 1978; Mehls et al 1978a). The present chapter will ,limit itself to a few points of current controversy or key interest. CLINICAL FINDINGS

Relation Between Osteodystrophic 'Rickets' and Underlying Disease The clinical presentation depends on whether or not renal disease is accompanied by tubular dysfunction, e.g. tubular phosphate loss, renal tubular acidosis or Fanconi's syndrome. These states will not be discussed further because they interfere with bone matrix mineralization and vitamin D metabolism (Brewer, Tsai and Morris, 1977; Striver et al, 1978; Meyer et al, 1980) by mechanisms different from those operating in renal disease with nephronal destruction. The clinical presentation of azotaemic 'rickets' may be modulated importantly by superimposition of other metabolic bone disorders, e.g. nephrotie syndrome, steroid therapy or diabetes mellitus. Severe osteopenia and growth retardation are common in nephrotic children treated with Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - - Vol. 9, No. 1, March 1980.

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steroids (Balsan, 1976). This may be due to protein malnutrition as well as vitamin D depletion resulting from renal loss of protein-bound vitamin D metabolites (Schmidt-Gayk et al, 1977). Steroid therapy may cause osteopenia by a combination of several effects: glucocorticoids inhibit bone cell function (Peck et al, 1969) and they interfere with calcium absorption (Favus, Walling and Kimberg, 1973) and vitamin D metabolism (Avioli and Hahn, 1978). Furthermore, some renal disorders are associated with specific defects of the skeleton and the growth apparatus, e.g. nephronopthisis may be associated with metaphyseal chondrodysplasia (Robins, French and Chakera, 1976) or the nail patella syndrome may be associated with skeletal abnormalities unrelated to renal insufficiency. Finally, some renal diseases cause specific histological changes in the skeleton, e.g. cystinosis, where cystine crystals are deposited in bone marrow macrophages, a finding which is without any clinical consequences. In contrast, in oxalosis, oxalate deposits (Matthews et al, 1979) provoke granulomatous reactions of the bone marrow and lead to resorptive defects or Paget-like bone lesions on x-ray (Poggi et al, 1979). Unusually severe hyperparathyroidism in this disorder might be due to a lowering effect of the permeant oxalate ion on cytoplasmic calcium in the parathyroids, since the Ca X oxalate solubility product is extremely low. Extraskeletal Lesions Azotaemic 'rickets' is commonly associated with a specific type of metabolic myopathy (Mehls et al, 1975a) which primarily affects proximal muscles of the pelvic and shoulder girdles. Clinically, patients may be profoundly asthenic and may encounter difficulties in raising their arms or in negotiating kerbstones. They almost uniformly exhibit 'waddling gait'. We observed consistently diminished force of the hand grip and this sign may provide a useful bedside method to monitor the progress of vitamin D therapy. Non-specific type II fibre atrophy, ultrastructural damage to the myofibrillar pattern and EMG changes are observed in such muscle (Ritz, Boland and Kreusser, 1980). Factors Influencing the Severity of Skeletal Lesions The age of onset of renal disease is an important determinant for the clinical presentation. It is of interest that anephric children do not exhibit abnormal skeletal development (Potter, 1972). On the other hand, children born to functionally anephric haemodialysed women, also have normal skeletons (Confortini et al, 1971). It is of note that placental transfer of vitamin D has been demonstrated in experimental animals (Haddad, Boisseau and Avioli, 1971) and to a certain extent the placenta is able to maintain normocalcaemia in the fetal circulation despite changes in maternal blood calcium concentration (Alexander et al, 1973). These considerations may explain why the development of the skeleton of fetuses of uraemie mother animals is not disturbed (Ritz et al, 1977a).

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In the postnatal period, congenital renal disease may lead to irreversible loss of growth potential secondary to episodes of dehydration and acidosis (Nash et al, 1972). Furthermore, children with congenital renal disease tend to have more advanced osteodystrophic 'rickets' and more severe growth retardation than children with acquired renal disease (Mehls et al, 1975a), presumably as a result of longer duration of renal insufficiency. Similarly, children suffering from congenital renal diseases with rapid progression into terminal renal failure tend to have less severe bone disease than children with diseases, for example oligomeganephronia, which tend to progress very slowly (unpublished observations). Finally, acquired vitamin D deficiency due to inadequate sun exposure, anticonvulsive therapy, reduced dietary intake of vitamin D or possibly melanosis of the skin, is by no means infrequent in uraemic children or adults (Offermann, Herrath and Schaefer, 1974). Such vitamin D deficiency may rapidly respond to vitamin D therapy, at least in incipient renal failure. This may have misled some authors to postulate that vitamin D consistently improves growth in azotaemic children. Furthermore, on self-selected diets dietary intake of calcium tends to be low in uraemic children. Because of the inability of intestine to adapt to low dietary calcium (Avioli and Teitelbaum, 1976), negative calcium balance may ensue and aggravate metabolic bone disease. This can also be demonstrated in experimental renal failure (Mehls et al, 1977b). Physical Findings Related to the Skeletal Disturbances Uraemic children are frequently stunted, i.e. below the third percentile of height expected for bone age. This finding is observed in one third of uraemic children put on haemodialysis (Chantler et al, 1977; Mehls et al, 1978a) and the percentage increases with progressive duration of dialysis (Broyer et al, 1979). In small children the skeletal findings resemble late rickets, i.e. rosary or Harrison's groove and enlargement of wrists and ankles. Deformities of the extremities are found in the metaphyseal zones, whereas typical bowing of the diaphysis of long bones is usually not seen. Craniotabes and bossing are less frequent since the onset of renal osteodystrophy is usually after the first year of life. In school age and prepubertal children, one notes commonly the following findings: s k e l e t a l d e f o r m i t i e s - - knock knees, ulnar deviation of the hand, waddling gait resulting from either myopathy or slipped epiphyses or a combination of both, enlargement of the wrist, ankles, medial end of clavicles and chondrocostal junctions resulting from metaphyseal deformities); b o n e f r a c t u r e s - - these are relatively rare, but may occur particularly after epileptic fits, e.g. vertebral collapse (TschOpe et al, 1973) and hip fracture (Parfitt, 1977); such fractures must be distinguished from Looser zones, which have been observed in children (Balsan, Royer and Mathieu, 1966) but are apparently much less frequent than in adults (own unpublished observations); b o n e erosion, which may lead to clubbing, i.e. collapse of the terminal phalanx with ensuing redundancy of soft tissue; d e n t a l d e v e l o p m e n t

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is impaired only if uraemia is present during infancy (Cadenat et al, 1977) and may then cause dental deformities and enamel defects. If uraemia is acquired later in life it may lead, however, to loosening of teeth resulting from resorption of alveolar bone (Prager et al, 1978). With the exception of serum P and alkaline serum phosphatase, serum chemistry in uraemic children is the same as in uraemic adults (Ritz et al, 1977c). As in adults, hyperparathyroidism and high calcium phosphate product may lead to pruritus, red eye syndrome, and corneal calcifications. Surprisingly, however, in contrast to adults, vascular and extraosseous tumoral calcifications are virtually never observed in uraemic children despite identical serum chemistry (Potter, Wilson and Ozonoff, 1974; Ritz et al, 1977c). The reasons for this discrepancy are unknown. As a rule, more signs are found on physical examination than one would anticipate from the patient's complaints, since uraemic children tend to restrict physical activity and avoid exercise of painful extremities. Consequently, such children tend to dissimulate and information on pain is usually not volunteered (Mehls et al, 1975a). Growth in Uraemie Children

At the beginning of haemodialysis treatment, height below the third percentile for age is found in one third of all uraemic patients (Gilli, 1975; Sch~irer, Chantler and Brunner, 1975). However, the actual growth velocity at the same time is abnormal (below the third percentile for bone age) in a much higher proportion of patients -- 50 per cent according to Mehls et al (1978a) and Broyer et al (1974). Growth velocity usually remains constantly abnormal during haemodialysis (Broyer et al, 1979) or may even deteriorate (Gilli, 1975). Uraemic children tend to be short for age. However, detailed analysis shows that the retardation in height age is usually more pronounced than retardation in bone age (Betts and White, 1976). In normal children, bone age, as judged from the maturation of ossification centres of standard bones (method of Tanner-Whitehouse) provides reliable information on growth potential. In uraemic children, such predicted growth can only be fully achieved if the metabolic abnormality is reversed, for instance in transplanted children without steroids. The more markedly advanced bone age, as compared to height age, thus indicates that growth potential is lost in uraemic children and such loss may be progressive with time according to most (Gilli et al, 1974), but not all (Broyer et al, 1979), authors. The onset of puberty is usually delayed in uraemic children, with or without dialysis, but the time course of puberty is considerably prolonged (Mehls et al, 1978a; Broyer et al, 1979) so that the gain in statural height is greater than anticipated on the basis of actual growth velocity spurt during the pubertal growth. HISTOLOGY OF THE GROWTH ZONE

For the purpose of this discussion, two different abnormalities are distinguished in the skeleton of uraemic children: the lesions in the growth

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apparatus and the lesions of cortical or spongy bone. In bone one encounters osteitis fibrosa, osteomalacia, or a combination of both; this pattern does not differ qualitatively from what one observes in the skeleton of adult uraemic patients (Ritz et al, 1973) and quantitative micromorphometric studies on cancellous bone fail to show differences between uraemic children and adults (Mehls et al, 1973b; Mehls et al, 1975b). The following discussion will be restricted to histological findings in the growth zone. A scheme is given in Figure 1, which shows an idealized version of the growth zone in a normally growing child, in rickets and in osteitis fibrosa.

CONTROL

RICKETS

OSTEITIS FIBROSA

Figure 1. Scheme of the growth zone in a normal child, a child with rickets and a child with osteitis fibrosa. For explanation, see text.

Normal Growth Zone

In a healthy growing child, growth cartilage comprises resting cartilage, which consists of undifferentiated chondrocytes, a subsequent zone of proliferating cartilage, in which cell proliferation and interstitial deposition of cartilage ground substance (chondroid) occurs causing progressive vertical displacement in the axial direction, the zone of degenerative cartilage, consisting of non-growing postmitotic cells which are vacuolated, and, finally, the zone of provisional calcification, in which the longitudinal septa, which are juxtaposed to apparently dead chondrocytes, mineralize. Subsequently, at the zone of transition between cartilage and bone, apparently necrotic chondrocytes and transverse chondroid septa are resorbed by vascular mesenchyme, which invades from the underlying metaphysis. In the zone of primary spongiosa new bone is added on pre-existing mineralized longitudinal chondroid septa by the action of osteoblasts. Primary spongiosa is transformed into secondary spongiosa by osteoclastic resorption of the majority of the densely packed primary trabecules, leaving only a restricted number of trajectorially oriented secondary trabecules.

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The hallmark of rickets is an increased width of the cartilaginous growth zone caused by the accumulation of persisting cartilage cells in the zone of degenerative cartilage; the longitudinal columnar arrangement of cartilage cells is lost; mineralization in the zone of provisional calcification is disturbed or absent; consequently, the process of vascular invasion is severely disturbed, presumably since a track for invading capillaries is lacking; cartilage gradually merges with metaphyseal spongiosa, which is covered by thick osteoid sheaths; chondroid and osteoid mingle, giving rise to a broad zone of chondro-osteoid (Pommer, 1885). Osteitis Fibrosa In advanced renal osteitis fibrosa the growth cartilage is narrow. Provisional calcification of cartilage ground substance is not defective. The transition between growth cartilage and metaphyseal bone is highly abnormal. Vascular invasion is virtually absent; growth cartilage is occluded by a bar of dense bone ('Abschlugplatte') and physically separated from metaphyseal bone (see Figure 4 in Krempien, Mehls and Ritz, 1974). In the metaphysis, trabecules arise de novo by metaptastic bone formation from primitive fibrous tissue. Such trabecules differ from normal ones in several ways: they are not in physical contact with cartilage, are devoid of a chondroid core, consist entirely of poorly mineralized woven bone and lack the usual trajectorial longitudinal orientation. Additional abnormalities are seen at the periosteal surface of the metaphysis, where intensive osteoclastic resorption occurs. A continuous layer of cortical bone is no longer recognizable since compact bone is subject to the process of cancellization. In the seminal paper of Pommer (1885) all transitions between these two patterns were described in children with vitamin D deficiency rickets. It seems logical to assume that the pattern of osteitis fibrosa supervenes when more advanced hyperparathyroidism is present which may lead to the disappearance of accumulated chondro-osteoid because chondroclastic and osteoclastic resorption is then more intense. In addition, mineralization of chondro-osteoid may be improved with progressive hyperphosphataemia. This concept is reminiscent of the observation of Stanbury (1967) that osteomalacia may apparently heal and be superseded by osteitis fibrosa in patients with advancing renal failure. In agreement with this notion, in animals with experimental renal failure, we were able to transform the ricketic pattern into a pattern which resembles osteitis fibrosa, as observed in children with advanced renal failure, by lowering dietary calcium and thus aggravating parathyroid overactivity (Mehls et al, 1977b). As far as one can judge from the scarce reports in the literature, primary hyperparathyroidism causes abnormalities in the growth zone that are indistinguishable, at least radiographically, and presumably also histologically, from the findings in advanced renal failure (Wood, George and Robinson, 1958; Rayasuriya et al, 1964; Lomnitz et al, 1966). Consequently, the presence of such lesions in the growth zone is not a direct reflection of impaired vitamin D metabolism, as tacitly assumed by many authors. Ricketic histology disappears in

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experimental animals under conditions of growth arrest or absolute starvation (Park, 1954). The effects of immobilization and severe disease on the one hand and the effects of renal osteodystrophy on the other hand, were analysed by micromorphometry in our laboratory (Krempien, Schnurr and Ritz, 1980). In previous reports, Hamperl and Wallis (1933) and Gilmour (1947) clearly observed ricketic histology in uraemic children. Although superimposed privational vitamin D deficiency is not excluded, the presence of ricketic histopathology in these children with renal failure corresponds to what is observed in experimental renal insufficiency in the rat (Mehls et al, 1977a). However, in children with terminal renal failure, we consistently found osteitis fibrosa (Krempien, Mehls and Ritz, 1974). These findings will be described in some detail because they provide a clearer understanding of the mechanism of epiphyseal slipping. As shown in Figure 2, resting cartilage showed no obvious abnormality, but the zone of proliferating cartilage was seriously disturbed. Chondrocytes no longer were aligned single file but were arranged in grape-like clusters; the longitudinal orientation of the columns was lost; the zone of hypertrophic cartilage was fairly irregular or entirely lacking, whereas the zone of provisional calcification, evaluated by the Van Kossa stain or by microradiography (Figure 3), was not disturbed. At the transition between growth cartilage and metaphysis, the normal sequence of vascular invasion, chondroclastic erosion of calcified chondroid and osteoblastic deposition of bone matrix on primary spongiosal trabecules was seriously disturbed. At some places, the transition between cartilage and metaphysis was represented by an osseous horizontal bar which occluded the growth plate. At other places, atypical sinusoidal vessels without perithelial cells were encountered underneath the cartilage plate without evidence of vascular invasion. Dense fibrous tissue was present underneath the growth cartilage and occasionally created cystic cavities between cartilage and metaphyseal bone (Figure 4). The overall width of the growth cartilage was reduced and this was also substantiated by micromorphometric measurements (Krempien, Schnurr and Ritz, 1980). In bones with epiphyseal slipping no evidence of traumatic separation was observed. Neither haemorrhage nor callus formation or rupture of the periosteal ring was noted. Epiphyseal slipping appeared as the result of coordinated lateral movement of the epiphyseal structure in the wake of intensive destructive and reparative processes at the epiphyseal--metaphyseal juncture. The histology in this zone resembled a Looser zone. The primary fault that alternately leads to the lateral movement of the epiphysis appears to be the failure of the trabecules of the primary spongiosa to form a tight stable interlocking complex with the growth cartilage, as evident from Figures 2 and 4. Consequently, under the influence of shearing forces the epiphysis moves laterally, sliding along the cleavage plane of fibrous tissue in the metaphysis (see Figures 2 and 4) and using it as a slipway. It is of note that in uraemia the plane of slippage is in the metaphysis, whereas in idiopathic epiphysiolysis, the plane of cleavage is provided for by the appearance of fibrous tissue within the damaged growth cartilage (Lacroix and Verbrugge, 1951).

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Figure 2. Growth zone (distal radius) in azotaemia (Masson-Goldner stain, X 125). Twelve-yearold boy with terminal renal failure resulting from obstructive uropathy. Growth cartilage on top, metaphysis on bottom. No vascular invasion of cartilage, which is devoid of orderly columns of chondrocytes; dense fibrous tissue replaces primary spongiosa; metaplastic formation of woven bone from fibrous tissue; no trajectorial orientation of trabecules. From Krempien, Mehls and Ritz (1974) with kind permission of the editor of Virchows Archly.

Figure 3. Zone of provisional calcification of the growth cartilage in the distal femoral epiphyseal plate. Undecalcified section, microradiography (70 ~ section X 60). Epiphyseal cartilage on top, metaphysis on bottom. Dense coarse well mineralized longitudinal septa and conspicuous transverse septa in the zone of provisional calcification. No defect of mineralization visible. Eight-year-old girl with terminal renal failure from ureteric ,malformation. From Ritz et al (1977b) with kind permission of the publisher.

Figure 4. Growth zone (distal radius) in azotaemia (van Kossa-stain, X 19). Ten-year-old girl with terminal renal failure resulting from oligonephronic hypoplasia. Numerous 'cystic' defects presumably resulting from excessive chondroclastic and osteoclastic activity replacing primary spongiosa; 'cysts' between growth cartilage and metaphysis filled with dense cellular fibrous tissue; narrow cartilage plate with irregular border towards the metaphysis. From Krempien, Mehls and Ritz (1974) with kind permission of the editor of Virchows Arehiv.

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X-RAY FINDINGS

In skeletal sites other than the growth zone, x-ray findings in uraemic children do not differ in principle from those found in adults. Such findings comprise the cortical lesion (subperiosteal resorption zones, Haversian striation and endosteal resorption), the cancellous bone lesion (focal accumulation of coarse trabecules with blurred outlines) associated or not with either osteosclerosis or osteopenia (Mehls et al, 1973a; Parfitt, 1977). Their intensity and rate of appearance may be greater, however, because of the intrinsically higher rate of bone turnover in the growing skeleton. Preferential localization of subperiosteal resorption zones may differ somewhat from adults, e.g. frequent occurrence in the metaphysis of the femoral neck ('rotten fence post' sign) or ulna (Figure S). Since these changes have been dealt with adequately elsewhere (Mehls et al, 1973a; Parfitt, 1977; Ritz et al, 1977b), the present discussion will focus on the x-ray changes in the growth zone. In the past, the interpretation of the roentgenological appearance of the epiphyseal growth plate of uraemic children has been confused considerably because histological documentation has generally been lacking. The relative contribution of osteitis fibrosa on the one hand and rickets on the other hand have not been defined clearly. In primary hyperparathyroidism of children (Wood, George and Robinson, 1958; Rayasuriya et al, 1964; Lomnitz et al, 1966; Kirkwood, Ozonoff and Steinbach, 1972) and in secondary hyperparathyroidism associated with target cell resistance to PTH (Frame et al, 1972) several authors reported the presence of rickets-like lesions. It appears likely that these cases represent an independent manifestation of hyperparathyroidism which induces a disturbance of enchondral ossification, which may resemble rickets radiographically despite a different histopathogenesis. As emphasized previously (Mehls et al, 1973a), not only the fastest growing metaphyses (i.e. lower femoral and upper tibial metaphyses) are affected in hyperparathyroidism but also slower-growing epiphyses (i.e. upper femoral and lower tibial metaphyses). This is in contrast to vitamin D deficiency rickets, which more commonly affects lower femoral and upper tibial metaphyses. An accurately aligned x-ray will usually show that the radiolucent zone is not due to widening of the growth plate but due to rarefaction in the metaphyseal spongiosa. The metaphysis is the site of subchondral and subperiosteal resorption and osteoclastic resorption of metaphyseal trabecules. This gives rise to the appearance of an irregular radiolucent zone underneath the epiphysis. It is obvious from the literature that some authors have genuinely, but mistakenly (Mehls et al, 1973a; Parfitt, 1977), believed that the x-ray changes that they described and illustrated were those of rickets rather than hyperparathyroidism. At least in advanced renal failure, the lesions at the end of long bones more commonly resulted from hyperparathyroidism than from rickets (Kirkwood, Ozonoff and Steinbach, 1972; Mehls et al, 1973a; Mehls et al, 197Sa). Although true rickets has been well documented by

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Figure 5(a) Ulnar deviation of right hand as clinical evidence of slipped epiphyses in severe renal osteodystrophy. No history of trauma, no pain, no impairment of function. Note pseudoclubbing of the fingers. Twelve-year-old boy with oligomeganephronic hypoplasia (serum ereatinine 9.2 mg/dl). From Mehls et al (1975) with kind permission of the publisher.

Figure 5(b). X-ray of the right hand skeleton. Same patient as 5(a) after initiation of vitamin D therapy. Slipping of radial epiphysis towards the ulnar side. Severe metaphyseal changes of ulna combined with subperiosteal resorption at the lateral cortex of the ulna. Note also severe subperiosteal resorption zones at the cortex of the metacarpals and acro-osteolysis of the terminal phalanges.

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appropriate histopathological studies in children with uraemia (Hamperl and Wallis, 1933; Gilmour, 1947), we have been unable to confirm its presence in histopathological studies of children with advanced renal failure (Krempien, Mehls and Ritz, 1974). It follows from the description of histology given above (see Figures 2 and 4) that the subepiphyseal radiolucent area in the xray does n o t represent cartilage or chondro-osteoid tissue in the growth plate, as in vitamin D deficiency rickets. To the contrary, it usually corresponds to undermineralized woven bone or fibrous tissue in the primary and secondary metaphyseal spongiosa, changes which reflect the action of PTH on the skeleton. If visible in properly aligned x-rays, the poorly delineated zone of provisional calcification, which is interposed between growth cartilage and primary spongiosa, permits assessment of the width of growth cartilage and this is usually narrow. Therefore, statements about the presence of rickets in the epiphyseal lesion of an uraemic child that are based on roentgenological evaluation alone must be regarded with considerable suspicion (Mehls et al, 1973a). Some typical roentgenological features of the growth zone in uraemia are shown in Figures 5, 6, and 7.

Figure 6. Hips in renal osteodystrophy. X-ray of pelvis. Four-year-old uraemic boy with oligomeganephronic hypoplasia (serum creatinine 4.1 mg/dl) after beginning of vitamin D therapy. Angles between femoral neck and temoral shaft reduced. Physeal plates in a more vertical position than normal (increased risk of epiphyseal slipping!). Looser zone in the right femoral neck.

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(a)

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~b~ Figure 7. Severe epiphyseal changes of femoral neck with epiphyseal slipping (left hip) in renal osteodystrophy. (a) Hip x-ray of seven-year-old girl with oligomeganephronic hypoplasia (serum creatinine 7.3 mg/dl). Grossly abnormal woolly metaphyseal texture underneath growth plate. Subperiosteal resorption zones around femoral neck ('rotten-fence-post' sign). Left femoral head epiphysis with incipient slipping to the medial side. The schematic drawing in (b) shows that the lateral femoral neck tangent does not touch femoral head.

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Epiphyseal slipping is the most severe manifestation of renal osteodystrophy in the growing skeleton. Although epiphyseal slipping was described decades ago (Broekman, 1927; Teall, 1928; Brailsford, 1933), it was presumed to be an infi'equent complication of renal failure (Shea and Mankin, 1966; Mankin, 1974; Floman et al, 1975). However, our own studies (Mehls et al, 1975a) clearly show that epiphyseal slipping is quite common in terminal renal failure; it was found in 10 of 33 untreated non-dialysed children and in one of 82 dialysed children. A rather high incidence was also reported by Goldman, Lane and Salvati (1977). Epiphyseal slipping tends to occur late in the terminal stage of renal failure (Mehls et al, 1975a; Mehls et al, 1975b) and may supervene with astonishing rapidity, i.e. within a few months. Epiphyseal slipping is more frequent in patients with congenital forms of renal disease with long duration of renal insufficiency. Children with epiphyseal slipping uniformly have more severe hyperparathyroidism than children without slipping. Mehls et al (1975a) found more profound hypocaleaemia, more elevated iPTH levels and more severe osteitis fibrosa in iliac crest bone (as evaluated by micromorphometry) in children with slipping. The rarity of epiphyseal slipping in dialysed children is puzzling in view of the persistence of hyperparathyroidism, as evident by iPTH and abnormal bone histology (Mehls et al, 1975a). Positive calcium balance and improved mineralization of woven bone in the metaphysis, or less severe hyperparathyroidism, or both, may be responsible for the decline in frequency of epiphyseal slipping. In contrast to previous explanations (Kirkwood, Ozonoff and Steinbach, 1972), histology gives no evidence of metaphyseal fractures in such children (Krempien, Mehls and Ritz, 1974). Epipbyseal slipping was found to represent a non-traumatic separation of epiphyseal cartilage from metaphyseal bone brought about by intense modelling processes in a Looser zone. A history of trauma is uniformly lacking in children with epiphyseal slipping. However, in children with slipped epiphysis sequential x-ray studies may show the occurrence of superimposed eccentric metaphyseal fractures as a late consequence of slipping (Mehls et al, 1975a) which may then promote further slipping. The pattern of epiphyseal involvement seems to be age-related. In preschool children slipping is observed in both upper and lower femoral epiphysis and in the distal tibial epiphysis, but not in the distal radial and ulnar epiphyses. In contrast, in older children only the upper femoral and/or radial and ulnar epiphyses are involved; in older pubertal patients the forearm epiphyses may be involved exclusively. However, in patients with extremely severe slipping of the femoral, radial or ulnar epiphyses, slipping can also be found, irrespective of age, in other epiphyses, such as the metatarsal, metacarpal, humeral, lower tibial and tubular epiphyses. Severe slipping leads to gross deformities of the skeleton, e.g. ulnar deviation of the hands (see Figure 5). In children with slipped upper femoral

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epiphyses, locomotion is uniformly impaired. Children are unable to walk or exhibit waddling gait, but they seldom complain about pain. Slipping of the upper femoral epiphyses must be diagnosed from hip x-rays (see Figure 7). Slippage occurs in a medial or dorsolateral direction. Medial slipping is present if a tangent parallel to the border of the lateral femoral neck no longer intersects with the femoral head, as evaluated in anteroposterior view hip x-rays (see Figure 7). Dorsolateral slipping can be evaluated best from the frog-leg position. PATHOGENESIS OF GROWTH FAILURE IN RENAL INSUFFICIENCY The pathogenesis of growth retardation in uraemic children has not been clarified so far (Lewy and New, 1975; Broyer et al, 1977; Mehls et al, 1978a). Nutritional factors, hormonal factors, disturbed chondrocyte metabolism, hyperparathyroidism and abnormal vitamin D metabolism may play a role. West and Smith (1956) postulated a role of energy and protein malnutrition in the genesis of growth retardation of renal failure, but this concept was soon criticized by Bergstr0m and de Leon (1964) because growth retardation was also observed in uraemic children without clinical evidence of malnutrition. More recent observations have again placed considerable emphasis on the role of energy malnutrition. Simmons et al (1971) found an increase in growth velocity after administration of an energy supplement. However, Betts, Magrath and White (1977) failed to observe increased growth velocity upon administration of an energy supplement, but this energy supplement may have been inadequate in quantity. In a retrospective study, Broyer et al (1974) failed to note a correlation between energy intake and growth velocity. Studies of Chantler, E1-Bishti and Counahan (1979) in addition to our own observations (Mehls et al, 1978a) suggest that high energy supplements may increase adipose tissue mass but fail to restore to normal growth velocity. Several hormones such as the STH-somatomedin system, insulin, thyroxine, adrenal hormones and sexual hormones play an important role in normal growth. There is considerable evidence for disturbances of these hormonal systems in uraemia, but their exact relation to the retardation of growth remains to be determined. Many of the abnormalities observed in uraemia are also encountered in malnutrition. Much interest has recently focused on a possible abnormality of somatomedin. Saenger et al (1974) found diminished levels of somatomedin with a bioassay technique. In contrast, using a radioreceptor assay, Takano et al (1976) and Spencer, Uthne and Arnold (1978) reported elevated somatomedin levels. Furthermore, inhibitors of somatomedin have been demonstrated in the serum of uraemic children (Takano et al, 1978). In view of the heterogeneity of the somatomedin system, the shortcomings of currently available methodology of measurement, and the inability to assess end-organ responsiveness, this problem elearly needs further investigation. Metabolism of ehondroeytes in growth cartilage may be disturbed in uraemia. Alterations of chondrocyte glycolysis and pentose cycle have been

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demonstrated in rats with experimental uraemia (Russel and Avioli, 1975). The cause of these metabolic abnormalities and their relation to growth failure remain to be established. Chondrocytes of the growth cartilage have an adenylate cyclase and guanylate cyclase system; the former is responsive to PTH (Figure 8), calcitonin (Nagata et al, 1976) and STH (Tell et al, 1973). Conditions which stimulate chondrocyte proliferation, e.g. hydraulic pressure, decreased cellular cAMP levels (Rodan et al, 1975). Altered responses of these systems in experimental uraemia have been observed (Kreusser and Ritz, in preparation) but the relation, if any, to disturbed growth still remains to be established. Finally, cellular growth has been shown to be regulated by sodium pump activity (Shank and Smith, 1976); in view of the disturbance of Na translocation across cell membranes observed in uraemia (Minkoff et al, 1972), this finding may be of relevance for impaired growth in uraemic children. If chondrocyte function is disturbed by some uraemic 'toxin', as speculated by some authors, such hypothetical toxin cannot be removed by dialysis, since several investigators noted that haemodialysis fails to abolish the growth defect of uraemic children (Mehls et al, 1978a; Broyer et al, 1979). The interaction between parathyroid hormone and the growth apparatus is complex. PTH induces mitosis in osteoprogenitor cells (Bingham, Barzel and Owen, 1969), thymocytes and growth cartilage (Shelling, 1936). A cAMP ( pM/m 9 protein ) 30

0

r-.//

Figure 8. Effect of PTH on chondroeyte cAMP content in control and uraemie rats ( n : 10 each group).

stimulatory effect of PTH on growth cartilage proliferation would also be supported by the clinical observation that patients with idiopathic hypoparathyroidism remain small despite restoration of normocalcaemia with

167

RENAL O S T E O D Y S T R O P H Y IN U R A E M I C CHILDREN

vitamin D therapy. Finally, a stimulatory effect of PTH has been postulated to explain the clinical observation that patients with pseudohypoparathyroidism and osteitis fibrosa are usually tall (Parfitt, 1977). However, children with advanced renal osteitis fibrosis are undoubtedly stunted (Broyer et al, 1979) and this clinical observation is not surprising in view of the disruption of the growth zone (as illustrated in Figure 4). A more subtle effect of hyperparathyroidism should also be noted. In uraemic children, maturation of epiphyseal bone, i.e. bone age, progresses in the absence of, or out of proportion to, the increase in statural height (Betts and White, 1976). Since the final height that can be achieved is related to bone age, growth potential is progressively lost. Cell kinetic studies may provide a rationale for this dissociation between proliferation of growth cartilage and bone cell turnover (Kimmel, Ritz and Krempien, 1979). Therapy with vitamin D analogues or transplantation was found to restore to normal bone maturation in children with chronic renal failure (Johannsen, Nielsen and Hansen, 1979). The relation between vitamin D and the growth abnormality of vitamin D deficiency or azotaemic rickets has recently been the subject of controversy.

cm/y 100

M B . 0~

OBSTRUCTIVE

/97.% HEIGHT VELOCITY

UROPATHY ~ 5 0 . %

cm/y t6

3.%

90 ¸

14

12

80 I0

VlT, D3

97

70 50

60

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50

.

.

.

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.

.

.

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.

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;

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AGE (YEARS) Figure 9. Effect of vitamin D on growth in a boy with chronic renal failure. Unusual catch-up growth (see height--velocity curve to the right) in a child with moderately advanced renal failure (Ccr 20 m l / m i n × 1.73m 2) and presumed superimposed vitamin D deficiency. From Gilli (1975) with kind permission of the author and the Editor of Monatsschriftfiir Kinderheilkunde.

O. MEHLS, E. RITZ, W. KREUSSER AND B. KREMPIEN

168

In pseudodeficiency rickets, presumably a genetically determined hypoactivity of, or a deficiency in, renal 1-alpha-hydroxylase, restoration of growth with catch-up growth can be observed with high dose vitamin D therapy (Prader, Illig and Heierli, 1961) and with slightly supraphysiological doses of 1,25(OH)2D (Balsan, 1979), at least in most patients. Vitamin D therapy may restore growth and even lead to catch-up growth in some patients with moderately advanced renal failure and nutritional vitamin D deficiency (Figure 9). However, such therapy consistently fails to restore normal growth or to produce catch-up growth in patients with advanced renal failure (Mehls et al, 1978a). Chesney et al (1978) recently described an increase in growth velocity upon administration of 1,25(OH)2D3 in uraemic children with osteitis fibrosa who had been refractory to previous administration of high doses of vitamin D. This was accompanied by disappearance of roentgenological signs of osteitis fibrosa. Other investigators (Bulla et al, 1979; Malekzadeh et al, 1979; own unpublished results) failed to note a consistent improvement or normalization of growth upon administration of 1,25(OH)2D3. In experimental studies, vitamin D increased, but failed to normalize, growth of severely uraemic rats (Mehls et al, 1978b), but food intake also increased and it remains undecided whether higher food intake is the cause or the consequence of improved growth. In particular, our laboratory failed to observe a difference of the effect on growth velocity between vitamin D and 1,25(OH)2D3 in rats with experimental uraemia (Figure 10). The situation is complicated further by

LONGITUDINAL GROWTH IN EXPERIMENTAL UREMIA EFFECT OF VITAMIN D AND 1,25 (OH)2 D

CUMULATIVEGAIN OF BODYLENGTH .,I cm

NX.D(n=I4) NX

~

(n=,,)

NX*!25(OH)2D(n=12)

~

NX

(n:12)

4

2

5

10

15

5

10

15

days

Figure 10.80 g male Sprague--Dawley rats were subjected to two-stage subtotal nephrectomy with irradiation (400 rad) of the remaining renal parenchyma: serum creatinine 2.0 -+ 0.266 mg/dl; pair-feedingof NX-untreated and NX-treated animals; groups: NX = solventinjection; NX + D = 1.4 ~g/d vitamin D3 i.p.; NX -k 1,25(OH)2D~ = 1.68 ng/d 1,25(OH)_~D3i.p. in two daily doses; measurement of snout--tail length during relaxation under anaesthesia; difference of increment in cumulativelength between -7 D and -7 1,25(OH)~Danimals not significant.

RENAL OSTEODYSTROPHY IN URAEMIC CHILDREN

169

the presence of 24-hydroxylase in growth cartilage (Garabedian et al, 1979) and the stimulatory effect of 24,25(OH)2D3 on proteoglycansynthesis in growth cartilage (Corvol et al, 1978). In addition, Ornoy et al (1979) claimed that presence of 24,25(OH)2D is necessary for enchondral ossification to occur and that this effect can be dissociated from that of 1,25(OH)2D. The results of other authors (Kraft and Offermann, 1979) are difficult to reconcile with this postulate. Further studies are necessary to delineate the requirements, if any, for vitamin D metabolites other than 1,25(OH)2D for growth cartilage function and their possible implication in azotaemic rickets.

THERAPY Diet There is considerable uncertainty about the required dietary intake of protein, calcium and phosphorus for optimal growth in uraemic children. Oral calcium supplements should be given because of the failure of the intestine to adapt to low dietary intake of calcium (Avioli and Teitelbaum, 1976). The growing organism is in positive phosphorus balance and serum phosphorus levels are commonly higher in children than in adults. Phosphorus deficiency would interfere rapidly with growth and homeostasis of skeletal mass (Cuisinier-Gleizes et al, 1976), but on the other hand, hyperphosphataemia undoubtedly aggravates hyperparathyroidism (Slatopolsky et al, 1971). In view of this dilemma, more information is necessary before more detailed recommendations with regard to phosphorus-restriction can be made. It would appear wise to maintain serum phosphorus levels in the upper range of the age-corrected norm. Based on animal experiments, it has been claimed that high dietary intake of protein, by aggravating uraemia, could interfere with growth; this would indicate that low protein diets are mandatory for optimal growth (Kleinknecht et al, 1979). However, protein intake in these experiments was considerably above the optimal level and the question has still to be answered whether dietary intake of protein may become rate limiting for growth when normal amounts of protein are given in the diet (Pennisi, Wang and Kopple, 1978). Vitamin D therapy Although rigorous prospective trials have not been performed to date, clinical experience indicates that prophylactic administration of vitamin D3 (5000 u/m2/day = 0.12 rag/day) or an equivalent dose of other metabolites, when administered at a glomerular filtration rate (GFR) approximately <60 ml/min × 1.73 m 2 will prevent severe azotaemic rickets in terminal renal failure (Mehls, 1975). Higher doses may cause hypercalcaemia and lower doses may be inefficacious. Our own clinical experience does not support the contention of other authors (Christiansen et al, 1978) that GFR may decrease despite no hypercalcaemia. In patients with symptomatic 'azotaemic rickets', vitamin D (Mehls et al, 1976) as well as 25OHD (Witmer et al, 1976; Garabedian and Balsan, 1978; Norman, Mazur and Gruskin, 1978),

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o. MEHLS, E. RITZ, W. KREUSSER AND B. KREMPIEN

1,25(OH)2D (Henderson et al, 1974; Malkzadeh et al, 1979) and 1-alphahydroxyvitamin D (Chan, Oldham and De Luca, 1977; Kanis et al, 1977; Johannsen, Nielsen and Hansen, 1979) have been found to be efficacious. The experience of the majority of authors may be summarized as follows: each of these compounds may raise serum calcium and lower iPTH; they improve markedly, but usually fail to abolish, osteitis fibrosa, but are less efficacious in reversing the mineralization defect; they promote maturation of ossification centres (Johannsen, Nielsen and Hansen, 1979), but fail to normalize the rate of longitudinal growth. In particular, despite prophylactic or therapeutic administration of vitamin D, bone histology is not normalized in children (unpublished observations) similar to the experience in adult uraemic patients (Malluche et al, 1978). Dialysis Although the incidence of symptomatic bone disease is lower in dialysed than in non-dialysed uraemic children (Mehls et al, 1975a), maintenance haemodialysis fails to reverse osteitis fibrosa or the mineralization defect in uraemic children (Mehls et al, 1973b). There is agreement amongst paediatric nephrologists that the dialysate calcium concentration should be maintained at approximately 3.5 mEq/1. Routine prophylactic administration of 0.12 mg vitamin D3/day (or equivalent metabolites) in asymptomatic children appears justified. A particular hazard of haemodialysis is development of phosphorus depletion, which frequently occurs in the anabolic refeeding phase upon institution of haemodialysis. Treatment of advanced osteitis fibrosa Parathyroidectomy to control hyperparathyroidism (Malekzadeh et al, 1979) is required only in a minority of dialysed children, less than 5 per cent according to our own experience. A particular therapeutic dilemma is presented by slipped femoral epiphysis. Several authors recommended early surgical intervention (Cattell et al, 1971; Mankin, 1974; Goldman, Lane and Salvati, 1978), which in our experience has proved uniformly disastrous, because mechanical devices (e.g. nails) will not stabilize dislocated epiphyses when the femoral neck consists of fibrous bone or even fibrous tissue (Mehls et al, 1976). It appears mandatory to first consolidate metabolic bone disease by appropriate therapy with vitamin D, with or without parathyroidectomy. Surgical correction of severely slipped epiphysis must be deferred until metabolic bone disease has been treated adequately. After healing of metabolic bone disease, corrective osteotomy to prevent late arthrosis should be performed in cases where spontaneous correction of an abnormal collodiaphyseal angle in the course of growth can no longer be expected. Skeletal growth is the most sensitive indicator of disturbed bone metabolism. Our inability to completely understand and therapeutically abolish osteodystrophy in the growing skeleton only reflects our limited insight into the pathogenesis of uraemic osteodystrophy in general. Osteodystrophy of the growing skeleton continues to be a fascinating challenge for the clinical investigator.

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ACKNOWLEDGEMENTS We thank Mss Stelz for secretarial help and Professor Dr Willieh (Department of Paediatries) for permission to reproduce skeletal x-rays.

REFERENCES

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