Growth Acceleration Following Renal Transplantation in Children Less Than 7 Years of Age

(1)

Growth

Acceleration

Following

Renal

Transplantation

in Children

Less

Than

7

Years

of Age

Julie R. Ingelfinger, MD, Warren E. Grupe, MD, William E. Harmon,

MD,

Sandra K. Fernbach,

MD,

and Raphael H. Levey,

MD

From the Children ‘5 Hospital Medical Center, and Department of Pediatrics,

Harvard Medical School, Boston

ABSTRACT. Of 110 consecutive renal allografts

per-formed at Children’s Hospital Medical Center 12 were in 1 1 patients aged 3 to 7 years. Patient and graft survival and linear growth were evaluated in these ii children. All

1 1 are surviving, seven (64%) with functioning allografts 12 to 92 months after transplant. Six of these seven have normal renal function (on alternate day prednisone dose <0.7 mg/kg every two days plus daily azathioprine) and

all seven have shown catch-up growth, reaching and maintaining normal height for age. An eighth patient,

now returned to dialysis, grew from below the third percentile at age 3 years to the 25th percentile at age 8 years, after which renal function deteriorated. Three pa-tients rapidly rejected allografts and have had decreased growth velocity for age. In contrast, although many of the remaining 76 patients who received 98 transplants after age 7 years are growing, none showed accelerated linear growth sufficient to catch up if below the third percentile for age or to cross centile lines if above. Neither the

degree of pretransplant bone age retardation nor steroid

dose per kilogram accounted for lack of growth accelera-tion of those more than 7 years of age. Despite small sample size, the growth of renal transplant recipients less than 7 years of age suggests that they are good, and in

some ways, favored transplant candidates. Pediatrics 68:

255-259, 1981; renal transplant, adolescents, linear growth, renal osteodystrophy, renal function,

corticoste-roids.

Growth failure occurs among 36% to 56% of chil-dren affected with renal failure’ and occurs

in

68%

of

children observed from one to ten years post-transplant.2 Children and adolescents receiving

Received for publication Feb 19, 1980; accepted Dec 5, 1980. Presented before the American Society of Nephrology, New Orleans, November 1978.

Reprint requests to (JR.!.) Division of Nephrology, Children’s

American Academy of Pediatrics.

transplants appear to grow if bone age is less than 12 years at the time of renal transplantation, pro-viding renal function is good and corticosteroid dose

low (<1 mg/kg/day).3

Because we have observed growth acceleration

after transplant in young children on an alternate day corticosteroid regimen, the linear growth of

patients

receiving

allografts and observed for at least a year was assessed.

MATERIALS AND METHODS

As shown in Table 1, 12 of 110 renal allografts

performed between May 1971 and January 1979 at Children’s Hospital Medical Center were in 11 pa-tients aged 3 to 7 years at the time

of

transplanta-tion.

An additional 17 allografts were performed in 16 patients aged 7 to 12 years at the time of trans-plantation, the remaining 81 allografts being per-formed in patients 12 years of age or more at time

of engrafting.

Overall actual allograft survival

was

64% in pa-tients aged 7 and less, 64% in the 7

to

12 group, and

74% in those more than 12 years of age. Follow-up period ranged from one to seven years. No deaths occurred in the youngest age

group;

two

deaths occurred in the group aged 7 to 12 years; in the

group

more

than 12 years old at time of

transplan-tation,

12 children died. Two of 12 allografts were

from

cadavers in children less than age 7 years, three of 17 in those aged 7 to 12 years, and 29 of 81 in those more than 12 years of age.

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and transplant status of all the patients were re-viewed and compared.

In the transplant population at Children’s

Hos-pita.l Medical Center, alternate day steroid

admin-istration is used in patients with stable allografts.

Once the daily steroid dose is 1 mg/kg, the dose

every other day is gradually tapered so that the eventual alternate daily dose is <0.7 mg/kg every

two

days. Azathioprine is used in a daily dose of 1 to 2 mg/kg in all patients.

RESULTS

Change in linear height percentiles following renal transplantation is shown in Fig 1. Most

pa-tients aged 12 years or older either did not change

TABLE 1. Transplant Population: Survival Data*

percentiles after transplant, or grew less well than previously. Three fell from the 25th to below the

third percentile, and two from the tenth to below the third. Only one patient of 81 had any improve-ment in linear growth-from the third to the tenth

percentile.

Patients aged 7 through 11 years, either did not have any growth acceleration, or declined in their height percentiles. Only one, a boy aged 8 years,

grew

from

the third to the 25th percentile.

In contrast, eight of 11 patients who received

kidneys before age 7 years showed growth

acceler-ation,

striking in five cases. This is shown

graphi-cally in Figs 2 and 3. The height for age of six boys

I-z

-J

C/)

z

I.;-

I.-Cl)

0

3 4 5 6 7 8 9 10 11 12

AGE (YEARS) 50th

25th

10th

3rd

<3rd

A

DZEJ DO

Q 0

0000

00 00

00

tA 0 0

0 0

DOD

A ODD

A DOD 0

A DOD

AA4A 0

D0OD0 O

0OODD DO DO 0

ODDDO 0 DO 0

DDDDD 0

000001 I I

<3rd 3rd 10th 25th 50th

PRE-TRANSPLANT

cm

YEARS

Age (yr) Allografts/P Graft Survivalt

(%)

Deaths Cadaver! LRD

7 12/li 67 0 2/10

7-il 17/16 64 2 3/14

12 81/75 74 12 29/52

* Abbreviations used are: P, patients; LRD, living related

donor; similar courses of survival were noted for patients less than 7 years of age and those aged 7 to 11 years.

t

From date of transplant to date of study.

D.12 years, growing,

12 years, fused epiphyses

o7-11 years

A:c7 years

Fig 1. Pretransplant percentiles plotted on ordinate;

posttransplant percentiles shown on abscissa. Among

children less than or equal to age 7 years at transplant, majority experienced posttransplant growth acceleration.

Fig 2. Height for age of six boys receiving transplants

before age 7 years (top). Time of transplant is shown by arrow in three patients. Two patients, represented by dashed lines, had early, progressive rejection and did not grow. Growth increment curves of same six boys

(bot-tom). Two patients who failed to grow had early rejection. Patient represented by solid triangles had decreasing growth between ages 8 and 9 years, coincident with late

rejection. Dashed line represents normal growth velocity

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3 4 5 6 7 8 9 10 11 12

AGE (YEARS)

GROWTH INCREMENT CURVE : GIRLS

II

____,

\

...-0-0

I I _ I I I

10

8

cm

6

4.

2

4 6 8 10 12 14 16

YEARS

Fig 3. Height for age of five girLs receiving transplants before age 7 years (top). Patient represented by squares

had early, chronic rejection. Growth velocity curves for same five girls (bottom).

receiving transplants before age 7 years is shown in Fig 2 (top). Three youngsters grew to normal per-centiles from below the third percentile. The two not showing any growth acceleration had unremit-ting rejection and renal insufficiency, and, there-fore, would not have been expected to grow. The growth increment curve for these six boys is shown in Fig 2 (bottom), where a minimum of one year’s growth is plotted, to avoid month-to-month changes. Of the four patients experiencing catch-up growth, striking growth acceleration occurred within the first year after transplant, with rates 1.5 to 2 times that expected for their ages. The slopes of their growth curves at this time were at least as

steep as adolescent growth curves. Following growth acceleration the rate of growth was about mean for age. In one patient (represented by an X), growth decelerated severely between 8 and 9 years of age, concurrent with late rejection, followed by

allograft loss. Of the two boys who had chronic

rejection (represented by triangles) one had growth deceleration, and the other experienced no change

in a severely low growth curve.

Fig 3 (top) shows height for age in the five girls

receiving transplants before age 7 years. As can be seen, three girls have reached normal percentiles

for age

while

a

fourth is rapidly approaching the third percentile. All of these girls have normal renal

function.

The fifth girl, who had chronic rejection

necessitating

return

to

dialysis, has grown slowly.

The growth increment curves for these five girls are shown in Fig 3 (bottom). As can be seen, four girls have had striking growth acceleration, and all of

them have had normal growth sustained following “catch-up” growth. The one girl with poor growth (as was already shown) did not have any growth acceleration.

Original renal diseases are listed in Table 2 for

children less than age 7 years and

for

those aged 7 to 11 years at transplantation. Among the 11

chil-then

receiving

transplants before age 7 years, five had renal dysplasia, four had nephritis, one had

hemolytic uremic syndrome, and one had malignant hypertension. The largest category among the 16 children aged 7

to

11 years was also structural: eight

patients had dysplasia, five

of

these had obstructive uropathy; four children had nephritides; two pa-tients had malignant hypertension; one had renal vascular accident, and one had medullary cystic

disease. Thus, type of original diseases is not differ-ent in these two groups.

The degree of bone disease was not qualitatively

different in children less than 7 years

of age,

corn-pared to those aged 7 through 11 years, as shown in Table 3. All had elevated levels of parathyroid hormone. One boy, aged 6 years, had

parathyroid-ectomy before transplant, after medical manage-ment failed to improve severe renal osteodystrophy. He and a girl, aged 3 years at transplant, required femoral osteotomy after transplant to correct fern-oral deformity. Among those aged 7 through 11 years at transplantation, three had pretransplant parathyroidectomies, and one of these required posttransplant osteotomies. All of the patients re-quiring parathyroidectomy had had longstanding

TABLE 2. Original Renal

Children

Disease in Two Groups of

Agecz7yr Age7-llyr

Structural 5 8

Nephritis 4 4

Hemolytic urea syndrome 1 0

Malignant hypertension 1 2

Renal vascular accident 0 1

Medullary cystic 0 1

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renal failure, and the three children requiring oste-otomies had congenital structural lesions. Degree of

retardation of bone ages at time of transplantation

was no different in children less than 7 years of age

than in those between ages 7 and 12 years. When

patients less than and older than age 7 years were assessed before transplant, no significant difference

was found between bone ages as analyzed by test.

Of those less than age 7 years at transplant, 63%

had bone age more than 2 or 3 SD below mean for

age, and of those aged 7 to 1 1 years, this percentage

was not significant (55%). The renal osteodystrophy

appeared as rickets in children both less than and

more than 7 years of age. Posttransplant bone ages showed advancement in both groups, but not

strik-ing acceleration.

The length of advanced renal failure before trans-plant is shown in Table 3. Renal failure was defined

as creatinine level >2 mg/i#{174} ml or gbomerular

filtration rate <20 ml/min/sq m. As might be

antic-ipated the median length of renal failure in older patients was two to three years, whereas it was one to two years in the younger group. Only two of the

younger group had had renal insufficiency for more than three years, as compared to seven of those aged 7 through 11 years at transplantation. The contribution of mild renal failure preceding a

gb-merular filtration rate <20 ml/min/sq m was not assessed. The steroid dose after one year in patients less than age 7 years, and those aged 7 through 11 years is shown in Tables 3 and 4. Among those less than 7 years old, eight had achieved alternate day doses by one year after transplant, and 11 of those aged 7 through 1 1 years had also achieved this status in comparable doses per kilogram. Thus, there was no difference in steroid dose in these two

groups.

DISCUSSION

Our results clearly indicate that in young chil-dren, especially those less than age 7 years, a suc-cessful, normally functioning allograft appears to

permit striking growth acceleration with the achievement of normal height for age.

The relatively poor linear growth of the majority

of children receiving renal transplants remains problematic. Pennisi et al3 have suggested that chil-dren with bone ages greater than 12 at the time of

transplant grow poorly, and that growth potential

at transplant affects subsequent linear growth.4 It has been noted that alternate-day steroid dose,9

or low daily steroid dose2’3”#{176}’2 may encourage

growth in children receiving renal allografts. Thus,

if there is growth potential4 (ie, bone age less than

age 12 years) and adequate renal function, alternate day or low daily (0.2 to 0.03 mg/kg/day) steroid dosage would be expected to be associated with the best linear growth. Specific data concerning the subgroups mentioned in the present study, however, have not previously been published.

The growth inhibition seen with glucocorticoids may be related to direct effect on cell metabolism-by depression of energy metabolism in the cell, or by affecting receptors that modify protein or RNA synthesis.’’6 Glucocorticoids may inhibit growth hormone levels and somatomedin.’3’5 Furthermore, steroids suppress calcium absorption,17 decrease se-rum vitamin D levels,’7 increase parathormone,’8 and are associated with phosphaturia’9-all of

which cannot only affect growth, but which may exacerbate metabolic bone disease often seen in renal transplant recipients. The steroid dosages in

patients less than 7 years of age and in those

be-tween 8 and 11 years of age were not significantly

different. Thus, steroid dose alone does not explain

the growth acceleration seen in the young children.

Growth potential at transplantation seems to be

related to subsequent growth.3’4’#{176} However,

vir-TABLE 4. Prednisone Dose One Year After

Trans-plant in Two Groups of Children

Prednisone Dose Age <7 yr Age 7-11 yr (l2Grafts) (17 Grafts)

>1 mg/kg/day

:s1 mg/kg/day 2 2

>1 mg/kg/2 days 2

<1 mg/kg/2 days 1

<0.7 mg/kg/2 days

<0.5 mg/kg/2 days

4

3

(67%) 5

6

(%)

Steroids discontinued:graft 2 2

loss

TABLE 3 Clinical Data for Two Groups of Children Receiving Transplants*

Age (yr) Length of R enal Failure Alternate

Day Steroid Dose 1 yr

Me tabolic Bone Disease Bone Age Retarded

>3 SDt <1 yr 1-2 yr 2-3 yr >3 yr Elevated Parathyroid- Orthopaedic

after PTH (%) ectomy Procedures Transplant

(mg/kg)

<7 2 5 2 2 7 100 1/11 2/9 2/8

7-li 2 4 4 7 ii 100 3/17 1/14 4/11

* Abbreviation used is: PTH, parathyroid hormone.

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tually all of our patients through age 11 years were judged to have adequate growth potential.

Further-more, they were equally affected by metabolic bone disease. Similar proportions of children in the two groups had adequate renal function. The length of renal failure prior to transplantation appeared to be different, with the factors likely to cause growth failure present longer in older children.1 In the population herein reported, posttransplant growth

acceleration occurred in eight of 11 patients less than 7 years of age, but in only one of 16 patients

aged 7 through 11 years at the time of their trans-plant. Despite small sample size, the growth of renal transplant recipients less than 7 years of age sug-gests that such patients are good, and in some ways,

favored, transplant candidates.

REFERENCES

1. Potter DE, Greifer I: Statural growth of children with renal disease. Kidney

mt

14:334, 1978

2. Fine RN, Malekzadeh MH, Pennisi AJ, et al: Long-term results of renal transplantation in children. Pediatrics 61: 641, 1978

3. Pennisi AJ, Costin G, Phillips IS, et al: Linear growth in long-term renal allograft recipients, in Conference in Growth Retardation in Children with Kidney Dthease. Cannel, CA,

April 1977, pp 22-25

4. Grushkin CM, Fine RN: Growth in children following renal

transplantation. Am J Dis Child 125:514, 1973

5. Petrusick T, Cunningham RJ, Brouhard BH, et al: Enhanced growth following renal transplantation using alternate day steroid therapy. Proc Cliii Dial Transplant Forum 8:73,

1978

6. Hoda 0, Hasinoff DJ, Arbus GS: Growth following renal

transplantation in children and adolescents. Clin Nephrol 3: 6, 1975

7. McEnery PT, Gonzalez LL, Martin LW, et al: Growth and

development of children with renal transplants: Use of alter-nate day steroid therapy. Pediatrics 83:806, 1973

8. Reimold EW: Intermittent prednisone therapy in children

and adolescents after renal transplantation. Pediatrics 52: 235, 1973

9. Potter DE, Holiday MA, Wilson SJ, et al: Alternate day

steroids in children after renal transplantation. Transplant Proc 7:79, 1975

10. Potter DE, Belzer FO, Rames L, et a!: The treatment of chronic uremia in childhood. I.Transplantation. Pediatrics

45:432, 1970

11. Lilly JR, Giles G, HUrWitZ R, et al: Renal transplantation in pediatric patients. Pediatrics 47:548, 1971

12. DeShazo CV, Simmons RL, Berstein DM, et al: Results of

renal transplantation in 100 children. Surgery 76:461, 1974

13. Baxter JD: Mechanisms of glucocorticoid inhibition of

growth. Kidney

mt

14:330, 1978

14. Loeb JN: Corticosteroids and growth. N Engi J Med 295:

547, 1976

15. Pantelask SN, Sinaniotis CA, Sibiraski S, et al: Night and day growth hormone levels during treatment with cortico-steroids and corticotrophin. Arch Dis Child 47:605, 1972 16. Elders MJ, Wingfeld GS, McNutt ML, et al: Glucocorticoid

therapy in children. Am J Dis Child 129:1393, 1975 17. Klein RG, Arnaud SB, Gallagher JD, et al: Intestinal calcium

ab8orption in exogenous hypercortisonism: Role of

25-hy-droxy vitamin D and corticosteroid dose. J Clin Invest 60: 253, 1977

18. Fucik RF, Kukreja SC, Hargis GK, et al: Effect of

glucocor-ticoids on function of parathyroid glands in man. J Clin Endocrinol Metab 40:152, 1975

19. Pusi HC, Taiwalker YB, Musgrave JE, et al: Phosphaturia in pediatric renal transplant recipients. Clin Res 25:195A, 1977

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1981;68;255

Pediatrics

Raphael H. Levey

Julie R. Ingelfinger, Warren E. Grupe, William E. Harmon, Sandra K. Fernbach and

of Age