Statural growth of children with renal disease

Kidney International, Vol. 14 (1978), pp. 334—339

Statural growth of children with renal disease DONALD E. POTTER and IRA GREIFER Children's Renal Center, University of California Medical Center, San Francisco, California, and Albert Einstein College of Medicine, Department of Pediatrics, Bronx, New York

It has been recognized for decades that children with kidney disease often do not grow normally. Growth failure has been identified in children with

attention. Broyer et al [2] reported that 4 of 17 children undergoing hemodialysis for longer than 1 yr

tubular disorders who have normal glomerular function and in those with renal insufficiency due to any etiology. In the last decade, growth failure also has been described in children undergoing chronic dial-

bone age. European Dialysis and Transplant Association figures for 1975 showed that 136 of 298 children (46%) undergoing hemodialysis and 49 of 103 (48%) after transplantation had growth rates greater than the 3rd percentile (> 2.5 SD) [3]. In the only report concerning children undergoing chronic pentoneal dialysis, 3 of 11 had growth rates maintaining stature within 2.5 SD of the normal [4]; the growth rates of children after transplantation are discussed elsewhere (see Travis et a!, this issue).

ysis and after renal transplantation. Thus, the potential for growth impairment exists in all stages, from the onset of renal disease to renal failure, and through phases of treatment with dialysis and transplantation. We will review the prevalence of growth

retardation during the stages of disease and treatment, the patterns of growth in renal disease, and the causes of growth failure.

grew at rates exceeding 80% of normal for their

Patterns of growth

Prevalence of growth retardation

The prevalence and severity of growth failure are

The prevalence of growth retardation in children during various stages of renal disease is shown in Table 1. Many of the children in the first two studies cited did not have renal insufficiency. A high percentage of children with renal disease have retarded

greater in children with congenital renal diseases

growth; this percentage does not change appre-

dren with chronic renal disease studied by

than they are in those with acquired diseases. Of the 21 children with growth retardation studied by West and Smith [51, 17 had congenital disease and 4 had nephritis with nephrotic syndrome. Of the 24 chil-

ciably during the progression of disease to renal fail-

Bergstrom, De Leon, and Van Gemund [61, 59% of

ure, through treatment with dialysis and trans-

those with congenital disease had growth failure, whereas the 2 children with acquired disease had normal height. In Stickler and Bergen's study of 64 children [7], 71% with congenital disease and 44%

plantation. There is little information concerning the growth rates of children with renal insufficiency. Betts and

Magrath [1] found that the growth velocity of 15

with acquired disease had retarded growth. In Betts and Magrath's report of 33 children [1], 50% with congenital disease and 10% with acquired disease had growth failure.

children with renal insufficiency from infancy maintained stature above the third percentile (within 2.5 SD

of the normal) until GFR fell below 25

mllmin/1.73 m2,

at which time growth rates de-

The higher prevalence of growth retardation in

creased. Growth rates of children undergoing dialysis and after transplantation have received more

children with congenital disease might be explained

by a higher incidence of tubular disorders in the former, by a longer duration of renal disease, or by an increased susceptibility of the rapidly growing infant to growth failure. The association of tubular disorders and growth impairment will be considered

0085-253817810014-0334$0I .20

© 1978 by the International Society of Nephrology. 334

Statural growth of children with renal disease

335

Table 1. Prevalence of growth retardation in children with chronic renal disease (CRD)

Category of patientsa CRD[51

CRD[6] CRD with BUN > 50 mg/dl [7]

CRDwithGFR < 7Oml/min/l.73m2[1]

Children at start of dialysis or transplantation [3] Children at transplantation' Children Ito 10 yr aftertransplantation'

No. of patients 41 24 64 33 360 50 50

No. with growth retardation

% With growth retardation

21

51 67

Not defined

16

36

56

< 3rd %

12

36

3rd%

147

41

28 34

56 68

< 3rd% < 3rd % < 3rd%

Definition of growth

retardation

3rd%

Numbers in brackets denote reference source from which data was derived. Potter, unpublished observations.

in the section "Causes of growth failure." Habib et al [8] demonstrated that children with congenital renal disease had a longer duration of disease before the development of terminal renal failure than those with acquired conditions had, but they did not examine the effects of renal disease on growth. Betts and Magrath [I] found that many children with congenital disease had severe growth retardation in infancy

associated with exacerbations of the disease, and

et al [2] noted that children with retarded growth and skeletal development who were undergoing chronic dialysis had rapid skeletal maturation and fusion of epiphyses without a corresponding increase in height, thus terminating growth. This pattern of rapid bone maturation with the loss of one or more years of potential growth at puberty has also

been noted by Pennisi et al [11] in children after

many years, until GFR fell below 25 mI/mm/I .73 m2,

transplantation and by Lewy and New [12] and limits the adult stature achieved by most children with growth retardation and renal disease. On the other hand, Lilly et al [13] reported that five growth re-

when growth decreased again. The consequences of

tarded children continued to grow after trans-

growth retardation in infancy are profound, since approximately one third of a child's total growth

plantation well past the usual age of puberty and ultimately achieved normal stature. The relation-

occurs in the first 2 yr of life. This pattern of growth, with the loss of 10 to 15 cm in the first 2 yr, may account for most of the loss of stature in children with congenital disease who are severely retarded when

ship of growth to the onset and duration of puberty and to bone maturation was not specified in their report.

that thereafter, renal function stabilized or improved

and growth proceeded at normal rates, often for

Causes of growth failure

they enter dialysis and transplant programs later in childhood.

A number of specific disorders commonly seen in

The ultimate stature achieved by a child with

kidney disease have been associated with growth

growth retardation will depend on the rate of growth relative to the rate of skeletal maturation. In a child with delayed skeletal maturation, the potential for further growth lies somewhere between that predicted from chronological age and that predicted from skeletal maturation [91. Betts and White [101

showed that in children who had retarded growth and skeletal development during infancy, chronologic age and skeletal maturation subsequently advanced in parallel. Under these circumstances, a child growing at a normal rate for chronologic age nevertheless has a progressive loss of growth potential. When growth temporarily ceases and skeletal maturation continues, as occurred in three children

failure. These include azotemia per se, acidosis, hyposthenuria, renal osteodystrophy, endocrine dysfunction, calorie deficiency, abnormalities of pro-

tein metabolism and glucocorlicoid therapy. The potential contribution of each mechanism varies with the type and stage of renal disease under consideration. There is good evidence that the profound acidosis which results from bicarbonate-

wasting in children with renal tubular acidosis (RTA) is a cause of growth failure. Nash et al [14] showed that eight of nine children with proximal RTA who had otherwise normal renal function and

four children with distal RTA who had con-

who developed osteodystrophy, there is an even

centrating defects were at or below the third percentile for stature. Correction of the acidosis with

greater loss of growth potential. At puberty, Broyer

bicarbonate resulted in normal growth in eight chil-

336

Potter and Greifer

dren who were evaluated. McSherry, Sebastian, and Morris, Jr., [15] reported catch-up growth and normal stature in 10 children whose acid-base stat-

us was maintained at normal with alkali therapy (see McSherry, this issue). The contribution of the less severe acidosis resulting from retention of hydrogen ions to growth

retardation in chronic renal insufficiency is less clear. Although West and Smith [51 found that 15 of

17 children with impaired growth and azotemia were acidotic, Stickler and Bergen [7] could find no relationship between growth and acidosis in 16 chil-

dren with renal insufficiency. Several authors [6, 12] have commented that treatment of the acidosis of renal insufficiency with bicarbonate does not improve growth. Chronic hemodialysis usually corrects acidosis, but the majority of children undergoing dialysis do not grow normally. West and Smith [5] found that impaired renal conservation of water was also a common factor associated with growth failure in children with renal disease although they noted several children with im-

paired concentrating ability who grew normally.

Stickler and Bergen [71 were unable to show an association between growth and concentrating ability. Some children with nephrogenic diabetes insipidus, who make large quantities of dilute urine, have im-

paired growth, apparently because their constant need for water interferes with adequate food intake [16]. Children with other tubular disorders and those with renal insufficiency often excrete moderately increased amounts of isotonic urine, but the need to replace these losses does not preclude normal food intake. Since failure to concentrate urine

is a common finding in children with renal insufficiency, its association with growth retardation in some children is not surprising and does not imply a cause and effect relationship. Osteodystrophy, especially rickets, is known to interfere with growth. In children with the Fanconi

syndrome and other tubular disorders, osteodystrophy has been considered to be a consequence of renal phosphate loss although some investigators have implicated impaired renal metabolism of vita-

min D [17, 18]. In renal failure, impaired metabolism of vitamin D and retention of phosphorus, leading to hyperphosphatemia, hypocalcemia, and secondary hyperparathyroidism, contribute to osteodystrophy. In children with rickets and growth

following parathyroidectomy. The suggestion by Stickler and Bergen [7], that subtle changes in calcium and phosphorus metabolism which are not accompanied by overt osteodystrophy cause growth

retardation in children, has not been adequately

tested (see also Avioli, this issue). The role of endocrine factors in the growth retardation of renal disease is unclear. Growth hormone levels are normal or elevated in children with renal faiure [20, 21]. Somatomedin, which mediates the effect of growth hormone on cartilage, has been reported to be low in growth retarded children with renal insufficiency [22, 23] and in children undergoing dialysis [24]. In the children studied by Saenger et a! [22], somatomedin activity increased into the normal range after transplantation and correlated with linear growth, although four patients with normal somatomedin levels continued to grow at subnormal rates. Somatomedin activity was measured by bioassay in these studies. Schwalbe et al [23] demonstrated a highly significant correlation between somatomedin activity and growth velocity in uremic children and a correlation between somatomedin activity and GFR. In six of seven patients, Pennisi et a! [24] showed that somatomedin levels increased after dialysis and that postdialysis levels correlated with growth. Using a radioreceptor assay, however, Arnold et a! [25] found that somatomedin levels were normal in children with mild renal insufficiency, elevated in those with more severe renal insufficiency, and highest in children on chronic dialysis. There was a correlation between somatomedin levels and growth in the children with severe renal insufficiency. It has been suggested [22] that there is an inhibitor of the bioassay in uremic serum which would account for some of the discrepancies in published results. Somatomedin levels have also been reported to be low in children

with protein calorie malnutrition [261 (see also Lewy and VanWyk, this issue). Most investigators have discounted the importance of azotemia itself in the etiology of growth failure. West and Smith [5] found that 16 of the 21

children with growth retardation had azotemia (blood urea nitrogen levels> 20 mg/dl or nonprotein nitrogen levels> 40 mg/dl) but 2 children with similar levels grew normally. Only 6 of 16 children with

growth retardation studied by Bergstrom et al [6]

retardation, treatment with vitamin D or its metabolites restores growth to normal [19], whereas in two

had azotemia. Stickler and Bergen [7], could find no association between growth and serum urea levels. Betts and Magrath [1] noted impaired growth in chil-

children with secondary hyperparathyroidism,

dren whose GFRs decreased to less than 25 mI/minim2.

Broyer et al [21 reported a dramatic growth spurt

There is some correlation, however, between high

Statural growth of children with renal disease

concentrations of blood urea nitrogen and toxic uremic symptoms; nitrogenous metabolites may inter-

fere with growth by causing anorexia or by interfering with protein metabolism, either directly or through action on hormonal systems (see also Holliday and Chantler, this issue). Malnutrition and abnormalities of protein metabolism

A large body of work has accumulated which sug-

gests that malnutrition, primarily calorie malnutrition, is a cause of growth failure in children with renal disease. West and Smith 115], using a weightfor-height index of less than 0.95 as an indicator of poor calorie intake, found that 8 of 16 nonedematous children with growth retardation had indices below this level and concluded that calorie malnutrition was an important factor in growth failure. Using the same criterion, however, Bergstrom et a! [6] and Stickler and Bergen [7] could find no evidence that calorie malnutrition caused growth failure. The most compelling evidence that poor calorie intake causes growth failure in uremic children was presented by Simmons et al [27], who showed that five dialysis patients with calorie intakes less than 67% of RDA (Recommended Daily Allowance) had growth rates 34% of normal, whereas seven children with calorie intakes greater than 67% of RDA had growth rates 117% of normal. When calorie supplements were given to four children with poor intakes, total calorie intake increased and growth rates became normal. Arnold et al [28] showed that growth in uremic children not on dialysis increased when calorie intakes were increased by the use of supplements. In a study by Betts and Magrath [1] of 27 children with renal insufficiency, 18 had calorie intakes below those recommended for children of the same height; in children with renal disease dating from infancy, there was a significant correlation between calorie intake and growth. In a more recent study, the same group [29], however, showed no increase in growth velocity in 11 children with renal insufficiency and calorie intakes less than 80% of RDA when their calorie intakes were increased with supplements; it was concluded that decreased calorie intake is a related but not casual factor in growth retardation. A relationship between calorie intake and growth also could not be established by Broyer et al [2] in 17 children undergoing dialysis, or by the London Children's Home Dialysis Group [30] in 24 children. The relationship of protein intake and protein metabolism to growth in uremic children is more com-

plex and less well defined. Children in developed

337

countries eat a surfeit of protein and, when total food consumption is reduced secondary to the ano-

rexia of renal failure, protein intake probably remains adequate in most children. The majority of children with decreased calorie intake and impaired growth studied by Simmons et al [27] had adequate

protein intake, as usually defined, as did the chil-

dren in the London Children's Home Dialysis Group [30], of whom 11 of 18 grew poorly. On the other hand, 69% of children studied by Betts and Magrath [1] had intakes below the average recommended for children of similar age, and 17% had intakes below minimal protein requirements.

Protein losses during chronic dialysis may increase the protein requirement of children undergoing these procedures. Amino acid and peptide losses during hemodialysis in adults are approximately 9 to 12 g [31, 32], whereas losses during pentoneal dialysis are somewhat less. Figures for children are not available. Protein losses, primarily albumin, during peritoneal dialysis were 9 to 15 g in

three children 10 to 14 yr of age (Potter, unpublished data). Most children undergoing chronic pentoneal dialysis in Seattle maintained normal serum albumin concentrations, however, and their growth

rates were comparable to those reported for children on hemodialysis [4]. Abnormalities of protein metabolism as well as

decreased intake may play a role in the malnutrition, muscle-wasting, and impaired linear growth in many uremic patients. Fürst et al [33] showed that

the incorporation of nitrogen-iS into muscle and plasma protein increased after a dialysis procedure, and they suggested that there is an inhibitor of protein synthesis in uremic serum. A number of inves-

tigators have found abnormal plasma amino acid patterns in uremic patients; although many of these abnormalities can be attributed to inadequate protein intake, when uremic and control patients were given an adequate diet, abnormalities persisted in the uremic patients [34] (see also Alvestrand et al,

this issue). Heidland and Kult [35] demonstrated that adult dialysis patients who were receiving an apparently adequate amount of calories and protein had decreased serum protein concentrations characteristic of protein malnutrition. These concentrations turned to normal when the patients were given i.v. infusions of essential amino acids for 16 weeks. In the only study of amino acids and growth, however, Counahan et al [36] could find no correlation between individual amino acid concentrations and growth rates in 16 children on chronic dialysis (see also Kopple; Holliday and Chantler, this issue).

Potter and Greifer

338

13. LILLY JR, GILES G, HURWITZ R, SCHROTER 0, TAKAGI H,

Summary

GRAY S, PENN I, HALGRIMSON CU, STARZL TE: Renal homotransplantation in pediatric patients. Pediatrics

Growth retardation occurs in 35 to 65% of children with kidney disease. It is especially common in

children with congenital diseases of the kidney, anomalies, and inherited disorders. Acquired disease, however, also may impair growth, particu-

larly where renal function (GFR) is below 25

47:548—557, 1971 14.

15.

mllminll.73 m2. Therapy used in renal disease, no-

tably prednisone, also impairs growth. Chronic dialysis therapy, both hemodialysis and peritoneal, are

associated with poor growth. Several specific

changes in renal disease are associated with growth failure. These include, in addition to azotemia, acid-

osis, hyposthenuria, renal osteodystrophy, endocrine disorders and resistance to hormone action, and nutritional disturbances.

References 1. BETTS PR, MAGRATH G: Growth pattern and dietary intake

of children with chronic renal insufficiency. Br Mcdi 2:189— 193, 1974 2.

BROYER M, KLEINKNECHT C, LOIRAT C, MARTI-ITIENNE-

C, Roy MP: Growth in children treated with long-term hemodialysis. J Pediatr 84:642-649, 1974 BERG

3. SCHARER K, CHANTLER C, BRUNNER FP, GURL AND HJ, JA-

COBS C, SELWOOD NH, Sivs G, WING AJ: Combined report on regular dialysis and transplantation of children in Europe, 1975. Proc Europ Dialysis Transplant Assoc 13:59— 4.

103, 1976 COUNTS Si, HICKMAN RO, TENCKHOFF H: Chronic perito-

neal dialysis: An alternative to hemodia!ysis, in Proc XIV mt Congr Pediatr, Buenos Aires, Cardiol Nephrol, 1974, pp. 260—270

5. WEST CD, SMITH WC: An attempt to elucidate the cause of growth retardation in renal disease. A,n J Dis Child 91:460— 476, 1956

6. BERGSTROM WH, DR LEON AS, VAN GEMUND ii: Growth

aberrations in renal disease. Pediatr Clin North Am 11:563— 575, 1964 STICKI.ER GB, BERGEN

Bi:

A review: Short

stature in renal

disease. Pediat Re.v 7:978—982, 1973 8. HABIB R, BROYERM, BENMAIZ H: Chronic

renal failure in

7.

Res 21:229,

Nephron 11:209—220, 1973 9. BAYLEY N, PINNEAU MA: Tables for predicting adult height from skeletal age: Revised for use with the Greulich-Pyle hand standards.. J Pediatr 40:423—441, 1952 10. BETTS PR, WHITE RHR: Growth potential and skeletal maturity in children with chronic renal insufficiency. Nephron 16:325—332, 1976 11. PENNISI AJ, C0sTIN 0, PHILLIPS LS, UITTENBOGAART C, ETTENGER RB, MALEKZADEHMH, FINE RN: Linear growth in long-term renal allograft recipients. Cl/n Nephrol children.

8:415—421, 1977

12. LEWY JE, NEW Ml: Growth in children with renal failure. A,n J Med 58:65—67, 1975

1973

16. HILLMAN DA, NEYZI 0, PORTER P, CUSHMAN A, TALBOT NB: Renal (vasopressin-resistant) diabetes insipidus. Pediatrics 21:430—435, 1958 17. BICKEL H, BAAR HS, ASTLEY R. DOUGLAS AA, FINCH E, HARRIS H, HARVEY CC. HICKMANS EM, PHILPOTT MG, SMALLW000 WC, SMELLIE iM, TEALL CG: Cystine storage disease with aminoaciduria and dwarfism (Lignac-Fanconi disease). Acta Paediat 18.

Reprint requests to Dr. D. E. Potter, University of California at San Francisco, Children's Renal Center, 400 Parnassus Avenue, A-276, San Francisco, California 94143, U.S.A.

NASH MA, TORRADO AD, GREIFER I, SElTZER A, EDELMANN CM iR: Renal tubular acidosis in infants and children. J Pediatr 80:738—748, 1972 MCSHERRY E, SEBASTIAN A, MORRIS RC iR: Correction of impaired growth in children with classic renal tubular acidosis (cRTA) by sustained correction of acidosis (abstr.). Clin

Scand (suppl.

90):1—237, 1952

BREWER ED, TSAI HC, MORRIS RC iR: Metabolism of 25hydroxyvitamin Di (25-OHD) in children with Fanconi's syndrome (FS) (abstr.). Kidney mt 8:397, 1975

19. DENT CE, HARPER C, PHILP0TT GR: The treatment of renalglomerular osteodystrophy. Q J Med 30:1—31, 1961 20. CZERNICI-IOW P, SELLEM C, BAILLY Du Bols M, RAPPAPORT R: Variation des taux plasmatiques de somathormone au cours du sommeil chez l'enfant normal et dans les retards

saturaux avec insuffisance renale chronique ou avec insuffisance somatotrophique. Arch Fr Pediatr 29:1033—1041. 1972

21. SAENGER P. SHUTZ 5, NEW M, RIGGI0 R, LEWY J, SCHWARTZ C, STENZEL K, WIEDEMANN E, SCHWARTZ E,

RUBIN A: Role of growth hormone and sulfation factor in growth of children before and after renal transplantation (abstr.). 5th mt Congr Nephrol, Mexico City, 1972, p. 152 22. SAENGER P, WIEDEMANN E, SCHWARTZ E, KORTH-SCHUTZ

S. LEWY iE, RIGGIO RR, ROBIN AL, STENZEL. KH, NEW MI: Somatomedin and growth after renal transplantation.

PediatrRes 8:163—169, 1974 23. SCHWALBE SL, BETTS PR, RAYNER PHW. Ruoo BT: Somatomedin in growth disorders and chronic renal insufficiency in children. Br MedJ 1:679—682. 1977 24. PENNISI Al, PHILLIPS LS, UITTENBOGAART C, ETTENGER R, MALEKZADEH MH, FINE RN: Somatomedin activity and linear growth in children undergoing hemodialysis (abstr.), in Western Dialysis and Transplant Society, 7th Annual Meeting, Seattle, 1976 25. ARNOLD WC, SPENCER EM, UTHNE KO, PIEI. CF. HOLLWAY MA: Radioreceptor assay for somatomedin-A in uremic children (abstr.). Pediatr Res 11:546, 1977 26. GRANT DB, HAMBLEY I, BECKER D, PIMSTONE BL: Reduced sulfation factor in undernourished children. Arch Dis Child 48:596—600, 1973 27. SIMMONS JM, WilsoN Ci, POTTER DE, HOI.LIDAY MA: Relation of calorie deficiency to growth failure in children on hernodialysis and the growth response to calorie supplementation. N Engl J Med 285:653—656, 1971 28. ARNOLD WC, ERHARD D, RAMIREZ i, HOLLIDAY MA: Effects of calorie supplementation in uremic children (abstr.). C/in Res 25:194, 1977 29. BETTS PR. MAGRATH Ci, WHITE RHR: Role of dietary energy supplementation in growth of children with chronic renal insufficiency. Br Mcdi 1:416—418, 1977

Statural growth of children with renal disease 30. WASS Vi, BARRAIT TM, HOWARTFI RV, MARSHALL WA, CHANTLER C, Quo CS, CAMERON iS, BA1LI.OD RA, MooRHEAD IF: Home hemodialysis in children. Report of the

London Children's Home Dialysis Group. Lancet

1:242—

246, 1977

31. GIORDANO C, DEPASCALE C, DECRISTOFARO D, CAP0DICASA G, BALESTRIERI C, BACZYK K: Protein malnutrition in

the treatment of chronic uremia, in Nutrition in Renal Disease, edited by BERI.YNE GM, Baltimore, Williams & Wilkins, 1968, p. 23 32. KOPPLE ID, SWENDSEID ME, SHINABERGER JH, UMEZAWA

CY: The free and bound amino acids removed by hemodialysis. Trans A in Soc Artif Intern Organs 19:309—313, 1973

33. FURST P, BERGSTROM

339

I, 1OSEPHSON B, NOREE 0: The effect

of dialysis and administration of essential amino acids on plasma and muscle protein synthesis, studied with 15N in uraemic patients. Proc Eur Dial Transpi Assoc 8:175—181, 1970

34. KOPPLE ID, SWENDSIED ME: Protein and amino acid metabolism in uremic patients undergoing maintenance hemodialysis. Kidney mt 7 (suppl. 2):S-64—S-72, 1975 35. HEIDLAND A, KULT I: Long-term effects of essential amino acids supplementation in patients on regular dialysis treatment. C/in Nephrol 3:235—239,1975 36. COUNAHAN R, EL-BISHTI M, Cox BD, Quo CS, Cl-IAN LER C: Plasma amino acids in children and adolescents on hemodialysis. Kidney mt 10:47 1—477, 1976