Abstract
One of the ultimate goals of successful solid organ transplantation in pediatric recipients is attaining an optimal final adult height. This manuscript will discuss growth following transplantation in pediatric recipients of kidney, liver, heart, lung or small bowel transplants. Remarkably similar factors impact growth in all of these recipients. Age is a primary factor, with younger recipients exhibiting the greatest immediate catch-up growth. Graft function is a significant contributing factor, with a reduced glomerular filtration rate correlating with poor growth in kidney recipients and the need for re-transplantation with impaired growth in liver recipients. The known adverse impact of steroids on growth has led to modification of the steroid dose and even steroid withdrawal and avoidance. In kidney and liver recipients, this strategy has been associated with the development of acute rejection. In infant heart transplantation, avoiding maintenance corticosteroid immunosuppression is associated with normal growth velocity in the majority of patients. With marked improvements in patient and graft survival rates in pediatric organ recipients, quality of life issues, such as normal adult height, should now receive paramount attention. In general, normal growth following solid organ transplantation should be an achievable goal that results in normal adult height.
Growth; Solid Organ Transplantation; Children; Growth Hormone; Steroid Avoidance
INTRODUCTION
Growth is frequently suboptimal in pediatric recipients of kidney, liver, heart, lung or small bowel transplants. Because the overwhelming majority of recipients are prepubertal at the time of transplantation, optimizing post-transplant growth to affect catch-up growth is imperative if the target adult height is to be achieved. The following will review the current data for growth after successful solid organ transplantation in children.
KIDNEY
What factors influence post-transplant growth in renal allograft recipients? The three major
factors are age at transplantation, allograft function and corticosteroid dose. Chronological age at
transplantation is predictive of the magnitude of post-transplant growth. The most recent data from
the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), which delineates
growth in children 0-1, 2-5, 6-12 and older than 12 years of age, shows that the two youngest age
groups of children, or children less than 6 years of age, all exhibit catch-up growth for the
initial 1-2 years following transplantation and then plateau after that time interval. However,
children who are greater than 6 years of age at the time of transplantation had no catch-up growth.
Therefore, older children do not exhibit any catch-up growth, and their final adult height will be
determined by height at the time of transplantation (11. North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). 2010
Annual Transplant Report. Rockville, MD. Available from:
https://web.emmes.com/study/ped/annlrept/2010_Report.pdf.
https://web.emmes.com/study/ped/annlrept...
).
Reduced renal allograft function has a significant effect on growth velocity. Studies by Tejani
et al. (22. Tejani A, Fine R, Alexander S, Harmon W, Stablein D. Factors predictive of
sustained growth in children after renal transplantation. The North American Pediatric Renal
Transplant Cooperative Study. J Pediatr. 1993;122(3):397-402,
http://dx.doi.org/10.1016/S0022-3476(05)83423-7.
http://dx.doi.org/10.1016/S0022-3476(05)...
) almost two decades ago showed that renal function
has a profound impact on growth, with a 0.17 decrease in the Z score (SDS) being associated with a
1.0 mg/dl increase in the serum creatinine level. These data indicate that as kidney function
deteriorates following renal transplantation, long-term growth velocity will decrease. Likewise, the
data emphasize the need for optimal graft function to achieve the optimal adult target height in
pediatric renal allograft recipients.
Steroid dose also has a significant impact on growth in pediatric allograft recipients. Switching
from daily to every-other-day steroids (33. Jabs K, Sullivan EK, Avner ED, Harmon WE. Alternate-day steroid dosing improves
growth without adversely affecting graft survival or long-term graft function. A report of the
North American Pediatric Renal Transplant Cooperative Study. Transplantation. 1996;61(1):31-6,
http://dx.doi.org/10.1097/00007890-199601150-00008.
http://dx.doi.org/10.1097/00007890-19960...
), steroid
withdrawal and steroid avoidance (44. Sarwal MM, Yorgin PD, Alexander S, Millan MT, Belson A, Belanger N, et al.
Promising early outcomes with a novel, complete steroid avoidance immunosuppression protocol in
pediatric renal transplantation. Transplantation. 2001;72(1):13-21,
http://dx.doi.org/10.1097/00007890-200107150-00006.
http://dx.doi.org/10.1097/00007890-20010...
) have all been associated
with improved growth velocity. A randomized controlled trial of early steroid withdrawal (TWIST
Study) randomized 98 patients to tacrolimus and mychophenolate mofetil with steroids being
discontinued on day 5 versus 98 patients randomized to receiving tacrolimus,
mychophenolate mofetil and steroids with the steroids being tapered but continued at a daily dose of
10 mg/m2. At 6 months, the standard deviation score improved by 0.13 in the steroid
withdrawal group compared to continued steroid group (55. Grenda R, Watson A, Trompeter R, Tönshoff B, Jaray J, Fitzpatrick M, et al.
A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal
transplantation: the TWIST study. Am J Transplant. 2010;10(4):828-36.). The
patients enrolled in this study were primarily prepubertal patients. All of the clinical parameters
were similar in the two groups except for increased infection and anemia rates in the steroid
withdrawal group. The long-term results of this study have continued to show improved growth
following early steroid withdrawal without any adverse impacts on allograft function. This regimen
will likely become the standard of care in the future. An alternative to steroid withdrawal is total
steroid avoidance. Preliminary studies from the Stanford Group (44. Sarwal MM, Yorgin PD, Alexander S, Millan MT, Belson A, Belanger N, et al.
Promising early outcomes with a novel, complete steroid avoidance immunosuppression protocol in
pediatric renal transplantation. Transplantation. 2001;72(1):13-21,
http://dx.doi.org/10.1097/00007890-200107150-00006.
http://dx.doi.org/10.1097/00007890-20010...
) seem to indicate that young children experienced significant improvements in growth
velocity following steroid withdrawal compared to a historical control group. Recently, Sarwal et
al. (66. Sarwal MM, Ettenger RB, Dharnidharka V, Benfield M, Mathias R, Portale A, et al.
Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter
randomized trial with three-year follow-up. Am J Transplant.
2012;12(10):2719-29.) reported the 3-year follow up from a multi-center,
NIAID-sponsored randomized controlled study of 130 children enrolled from 12 pediatric transplant
centers in the United States. The change in standard deviation score at 3 years for all of the
recipients was not different between the steroid-free and the steroid-based groups. However, when
the change in standard deviation score at 3 years in the 27 children less than 5 years of age was
analyzed, there was a significant difference in the growth velocity between the steroid-free and
steroid-based groups (p = 0.2). Biopsy-proven acute rejection at 3
years was similar in the steroid-free (16.7%) and steroid-based groups (17.1%). Patient survival was
100% in both groups, and graft survival was similar in both groups (steroid free 95% and steroid
based 90%). The systolic blood pressure and cholesterol levels were lower in the steroid-free group.
This randomized controlled study certainly indicates that steroid avoidance does not adversely
affect long-term graft function or increase the incidence of biopsy-proven acute rejection. However,
the impact on growth was less than anticipated because the steroid-free group only demonstrated an
effect on growth in the recipients less than 5 years of age. This study emphasizes that there are
factors other than steroids that affect growth velocity and catch-up growth, especially in older
pediatric transplant recipients. A strategy to address modifiable factors to enhance growth in older
recipients will need to be a significant focus in the future. The ultimate goal with respect to
growth in pediatric renal allograft recipients is attaining a normal final adult height. Recent data
from the NAPRTCS registry (11. North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). 2010
Annual Transplant Report. Rockville, MD. Available from:
https://web.emmes.com/study/ped/annlrept/2010_Report.pdf.
https://web.emmes.com/study/ped/annlrept...
) has shown that over the past
quarter century, there has been a significant increase in the average final adult height of
recipients entered into the registry. From 1987 to 1991, those patients who reached adult height had
a standard deviation score of -1.93, whereas for the patients who were entered into the registry
between 2002 and 2010 and reached final adult height, the standard deviation score was -0.94,
representing an almost 1 standard deviation improvement in final adult height over 15 to 20 years.
This improvement certainly is a remarkable achievement and indicates that pediatric renal allograft
recipients now have final adult heights that are approaching their target height.
One of the primary factors that have led to improved final adult height has been that the height deficit at the time of transplantation has improved markedly during the past decade. The most recent NAPRTCS registry data1 indicate that in 1987, the standard deviation score (Z score) for patients at the time of transplantation was approximately -2.5, whereas in patients who were transplanted in 2009, the Z score at transplantation was between -1 and -1.5. Again, over a quarter of a century, the standard deviation score for children at the time of transplantation has improved more than 1 standard deviation, which is similar to the improvement in adult height over the same period for the same patient population.
As indicated previously, the overwhelming majority of children over 6 years of age at the time of
transplantation do not exhibit any catch-up growth following transplantation. Therefore, if those
patients are to achieve normal adult height, some intervention to stimulate growth will be required.
This dilemma raises the question as to whether the use of recombinant human growth hormone (rhGH)
improves growth in growth-retarded renal allograft recipients. There have been four (77. Hokken-Koelega AC, Stijnen T, de Jong RC, Donckerwolcke RA, Groothoff JW, Wolff
ED, et al. A placebo-controlled, double-blind trial of growth hormone treatment in prepubertal
children after renal transplant. Kidney Int Suppl. 1996;53:S128-34.
8. Maxwell H, Rees L. Randomised controlled trial of recombinant human growth
hormone in prepubertal and pubertal renal transplant recipients. British Association for Pediatric
Nephrology. Arch Dis Child. 1998;79(6):481-7,
http://dx.doi.org/10.1136/adc.79.6.481.
http://dx.doi.org/10.1136/adc.79.6.481...
9. Fine RN, Stablein D, Cohen AH, Tejani A, Kohaut E. Recombinant human growth
hormone post-renal transplantation in children: a randomized controlled study of the NAPRTCS. Kidney
Int. 2002;62(2):688-96, http://dx.doi.org/10.1046/j.1523-1755.2002.00489.x
http://dx.doi.org/10.1046/j.1523-1755.20...
-1010. Guest G, Bérard E, Crosnier H, Chevallier T, Rappaport R, Broyer M. Effects
of growth hormone in short children after renal transplantation. French Society of Pediatric
Nephrology. Pediatr Nephrol. 1998;12(6):437-46,
http://dx.doi.org/10.1007/s004670050483.
http://dx.doi.org/10.1007/s004670050483...
) randomized controlled
studies that have studied rhGH treatment in growth-retarded renal transplant patients. In all four
studies, 1-year growth significantly improved in the group receiving rhGH compared to the control
group. The growth velocity in most of the studies doubled with rhGH treatment compared to the
control group. One concern regarding the use of rhGH following renal transplantation has been prior
anecdotal information that rhGH may stimulate the immune system and precipitate acute rejection. In
all four studies, there was no difference in the incidence of acute rejection in the rhGH group
compared to the control group.
A concern with one of the newer immunosuppressant drugs, sirolimus, was that this agent could
impair linear growth in pediatric solid organ transplant recipients. Two studies (1111. González D, García CD, Azócar M, Waller S, Alonso A, Ariceta G,
et al. Growth of kidney-transplanted pediatric patients treated with sirolimus. Pediatr Nephrol.
2011;26(6):961-6, http://dx.doi.org/10.1007/s00467-011-1811-3.
http://dx.doi.org/10.1007/s00467-011-181...
,1212. Hymes LC, Warshaw BL. Linear growth in pediatric renal transplant recipients
receiving sirolimus. Pediatr Transplant. 2011;15(6):570-2.) have addressed this
issue, which was raised primarily because animal models have shown decreased longitudinal growth due
to sirolimus-mediated inhibition of cell proliferation and vascular endothelial growth factor
expression in the long bone growth plate, which blocks insulin-like growth factor (IGF)
intracellular signaling in chondrocytes (1313. Alvarez-Garcia O, Carbajo-Pérez E, Garcia E, Gil H, Molinos I, Rodriguez J,
et al. Rapamycin retards growth and causes marked alterations in the growth plate of young rats.
Pediatr Nephrol. 2007;22(7):954-61, http://dx.doi.org/10.1007/s00467-007-0456-8
http://dx.doi.org/10.1007/s00467-007-045...
). A study by
Gonzalez et al. (1111. González D, García CD, Azócar M, Waller S, Alonso A, Ariceta G,
et al. Growth of kidney-transplanted pediatric patients treated with sirolimus. Pediatr Nephrol.
2011;26(6):961-6, http://dx.doi.org/10.1007/s00467-011-1811-3.
http://dx.doi.org/10.1007/s00467-011-181...
) evaluated 34 renal transplant recipients
who received sirolimus for 24 months and compared their height standard deviation scores to a
control group. There was no difference in the height standard deviation score between the sirolimus
and control groups at any time over the 24 months. However, the change in height was significantly
decreased in the sirolimus group at all of the follow-up times compared to the control group. The
authors concluded that the growth velocity was significantly decreased in the sirolimus group
compared to the control group. In contrast, Hymes and Warshaw (1212. Hymes LC, Warshaw BL. Linear growth in pediatric renal transplant recipients
receiving sirolimus. Pediatr Transplant. 2011;15(6):570-2.) studied 25 renal transplant recipients taking sirolimus who were followed for 24 months
and compared their height standard deviation scores to a control group receiving tacrolimus. The
height standard deviation scores were no different at baseline and 24 months between the sirolimus
and tacrolimus groups. The height standard deviation score increased by 52% in the sirolimus group,
and the authors concluded that sirolimus does not impair growth in renal allograft recipients.
LIVER
Al-Sinani and Dhawan (1414. Al-Sinani S, Dhawan A. Corticosteroids usage in pediatric liver transplantation: To be or not to be! Pediatr Transplant. 2009;13(2):160-70.) summarized the current data regarding growth following liver transplantation in 2009 by evaluating 20 reports between 1987 and 2008. The number of patients in each report varied from 21 to 236, and the follow-up period in each report varied from 1 to more than 8 years. The number of recipients who exhibited catch-up growth varied between 39 and 100%. The steroid regimen used in the various reports was variable, including daily to a tapered dose, every other day steroid therapy to steroid withdrawal and steroid-free regimens. Therefore, specifically analyzing each group was quite difficult. However, the authors attempted to identify the factors in these 20 reports that impacted growth. Their assessment was that the steroid dose impacted growth, with the cumulative dose, timing of tapering and withdrawal and the presence of daily steroid treatment having adverse impacts on growth. Height at the time of transplantation also had an impact on catch-up growth, with those who had decreased growth standard deviation scores at the time of transplantation having increased catch-up growth following transplantation. Age was also a factor that impacted growth in children less than 2 years of age at the time of transplantation: these children experienced increased catch-up growth. The primary diagnosis (cholestasis, fulminant liver failure, sclerosis or metabolic disease) had an impact on growth. Patients with cholestasis or hepatitis had better post-transplant growth. Graft dysfunction also impacted post-transplant growth, with those liver transplant recipients who required re-transplantation or developed post-transplant lymphoproliferative disease (PTLD) having a reduced growth velocity following transplantation. Alonso and colleagues (1515. Alonso EM, Shepherd R, Martz KL, Yin WAnand R; SPLIT Research Group. Linear growth patterns in prepubertal children following liver transplantation. Am J Transplant. 2009;9(6):1389-97.) reviewed the data for 1,143 recipients from the Studies of Pediatric Liver Transplantation (SPLIT) registry. The standard deviation score was -1.55 at transplant, and at 24 and 36 months, the scores were -0.87 and -0.68, respectively. These results demonstrate a significant improvement in the height standard deviation score following liver transplantation. However, subsequent follow-up showed limited catch-up growth after 36 months. The factors that negatively impacted growth were more than 18 months of steroid therapy following transplantation and the association of primary metabolic or non-biliary cholestatic disease with decreased catch-up growth.
Because the liver is thought to be less immunogenic than other organs, steroid withdrawal has
been used therapeutically in pediatric liver transplant recipients in the past to maximize linear
growth. Five uncontrolled studies using cyclosporine as the primary immunosuppressive agent have
withdrawn steroids between 3 and 58 months following transplantation, and acute rejection occurred
in 7 to 27% of the patients. Chronic rejection that occurred in less than 18 months was present
following steroid withdrawal in 4 to 13% of the patients and graft loss in 3 to 13%. More recently,
steroid withdrawal was attempted in three series of patients with tacrolimus as the primary
immunosuppressant (1616. Reding R. Steroid withdrawal in liver transplantation: benefits, risks, and
unanswered questions. Transplantation. 2000;70(3):405-10,
http://dx.doi.org/10.1097/00007890-200008150-00001.
http://dx.doi.org/10.1097/00007890-20000...
-1717. McDiarmid SV, Farmer DA, Goldstein LI, Martin P, Vargas J, Tipton JR, et al. A
randomized prospective trial of steroid withdrawal after liver transplantation. Transplantation.
1995;60(12):1443-50, http://dx.doi.org/10.1097/00007890-199560120-00013.
http://dx.doi.org/10.1097/00007890-19956...
). In a study from Johns Hopkins (1616. Reding R. Steroid withdrawal in liver transplantation: benefits, risks, and
unanswered questions. Transplantation. 2000;70(3):405-10,
http://dx.doi.org/10.1097/00007890-200008150-00001.
http://dx.doi.org/10.1097/00007890-20000...
), the steroid
was withdrawn at 6 months in 29 patients with a 29% acute rejection rate. In Kyoto (1717. McDiarmid SV, Farmer DA, Goldstein LI, Martin P, Vargas J, Tipton JR, et al. A
randomized prospective trial of steroid withdrawal after liver transplantation. Transplantation.
1995;60(12):1443-50, http://dx.doi.org/10.1097/00007890-199560120-00013.
http://dx.doi.org/10.1097/00007890-19956...
), the steroid was withdrawn at 8 months in 156 patients, all of
whom were recipients of livers from live related donors with a 14% acute rejection rate. In
Pittsburgh, the steroid was withdrawn within the first year in 166 patients, and in 21% of these
patients, reinstitution was required within 5 years due to rejection. The SPLIT data (1515. Alonso EM, Shepherd R, Martz KL, Yin WAnand R; SPLIT Research Group. Linear
growth patterns in prepubertal children following liver transplantation. Am J Transplant.
2009;9(6):1389-97.) indicate that at 24 months post-transplant, if steroids are
withdrawn less than 6 months, the increase in standard deviation score (1.7 increase) was greater
compared to steroids being withdrawn after 18 months (0.9 increase). These data indicate that
steroid withdrawal, especially if performed early, will result in an improved standard deviation
score and will potentially lead to improved adult height. However, there is a risk of rejection and
potential graft loss with steroid withdrawal.
What can one anticipate as the final adult height in pediatric liver transplant recipients? A
2008 study by Scheenstra et al. (1818. Scheenstra R, Gerver WJ, Odink RJ, van Soest H, Peeters PM, Verkade HJ, et al.
Growth and final height after liver transplantation during childhood. J Pediatr Gastroenterol
Nutr. 2008;47(2):165-71, http://dx.doi.org/10.1097/MPG.0b013e3181623279.
http://dx.doi.org/10.1097/MPG.0b013e3181...
) evaluated 23 recipients
with a median age of 13.3 years at transplantation. The standard deviation scores were -1 at
transplant and -1.4 at the final height, and the median target height was -1.3. Additionally, 12 of
the 23 had final adult heights below 1.3 standard deviations of their target heights. These data
indicate that a significant number of liver transplant recipients cannot reach their adult target
heights. Because a number of liver transplant recipients exhibit suboptimal post-transplant growth,
one could question whether or not there is any effective treatment for improving growth in this
population. Eight recipients with standard deviation scores greater than 2 were treated with rhGH
for more than 5 years. The standard deviation scores improved from -3.6 to -2.7 (1919. Puustinen L, Jalanko H, Holmberg C, Merenmies J. Recombinant human growth
hormone treatment after liver transplantation in childhood: the 5-year outcome. Transplantation.
2005;79(9):1241-6, http://dx.doi.org/10.1097/01.TP.0000161668.09170.F4.
http://dx.doi.org/10.1097/01.TP.00001616...
). There were no rejection episodes, and 1 patient who had
elevated liver enzyme levels prior to rhGH treatment was diagnosed with chronic rejection at 3
years. This single study on a limited number of patients would seem to indicate that severely growth
retarded liver transplant recipients could benefit from prolonged rhGH treatment post-transplant
without any adverse impact on graft function.
HEART
More than a decade ago, Chinnock and Baun (2020. Chinnock R, Baum M. Somatic growth in infant heart transplant recipients.
Pediatr Transplant. 1998 Feb;2(1):30-4.) evaluated
heart transplant recipients at their institution and delineated three factors that seemed to impact
post-transplant growth. These factors were the number of days in the hospital during the first
post-transplant year; the number of treated rejection episodes after the first post-transplant year;
and mid-parental height, the genetic growth potential for an individual, which is quite important
and had not been delineated by prior authors regarding growth following other organ transplants.
These authors evaluated 77 infants who were transplanted at less than 6 months of age and received
no maintenance steroid therapy. Catch-up growth was quite prevalent during the first post-transplant
year, and only 6 of 51 patients who were more than 5 years post-transplant had heights that were
less than the fifth percentile. This study demonstrated that the use of a steroid-free maintenance
protocol can lead to normal growth for very young infants transplanted at less than 6 months of age.
Peterson et al. (2121. Peterson RE, Perens GS, Alejos JC, Wetzel GT, Chang RK. Growth and weight gain
of prepubertal children after cardiac transplantation. Pediatr Transplant. 2008;12(4):436-41,
http://dx.doi.org/10.1111/j.1399-3046.2007.00826.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
) evaluated 46 heart transplant recipients
who were less than 11 years of age at the time of transplantation. Those recipients showed no
significant change in the height standard deviation score up to 24 months post-transplant. The
authors noted that a younger age at transplant had a positive impact on growth, and the length of
steroid treatment had a negative impact on the change in the standard deviation score
post-transplant. Their current practice is to wean low-risk patients with no rejection episodes off
steroids at 1 year. More recently, Bannister et al. (2222. Bannister L, Manlhiot C, Pollock-BarZiv S, Stone T, McCrindle BW, Dipchand AI.
Anthropometric growth and utilization of enteral feeding support in pediatric heart transplant
recipients. Pediatr Transplant. 2010;14(7):879-86,
http://dx.doi.org/10.1111/j.1399-3046.2010.01361.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
),
from Toronto Sick Kids, evaluated 130 heart recipients who were transplanted between 1990 and 2005
and had a mean follow-up of 4.4 years. Their mean height Z score was unchanged from transplant to
the last measurement, and the mean was -1.3. The authors felt that enteral feeding led to increased
height standard deviation scores in patients without sufficient caloric intake.
There are limited data on the use of rhGH in growth-retarded pediatric heart transplant
recipients. Mital et al. at Columbia (2323. Mital S, Andron A, Lamour JM, Hsu DT, Addonizio LJ, Softness B. Effects of
growth hormone therapy in children after cardiac transplantation. J Heart Lung Transplant.
2006;25(7):772-7, http://dx.doi.org/10.1016/j.healun.2004.11.317
http://dx.doi.org/10.1016/j.healun.2004....
) reported 10
recipients with a mean age of 7.8 years at transplant, a mean age at the initiation of rhGH
treatment of 13 years and a mean duration of rhGH treatment of 2.5 years. The growth velocity
increased from 2.5 cm per year at baseline to 8.6 cm per year during rhGH treatment. The authors
noted increases in left ventricular shortening fraction, left ventricular volume and cardiac output
in the patients who received rhGH treatment. The left ventricular volume remained increased
following the discontinuation of rhGH; therefore, this change was thought to be physiologic and not
pathologic.
LUNG
Recently, Elizur et al. (2424. Elizur A, Faro A, Huddleston CB, Gandhi SK, White D, Kuklinski CA, et al. Lung
transplantation in infants and toddlers from 1990 to 2004 at St. Louis Children's Hospital.
Am J Transplant. 2009;9(4):719-26.) from St. Louis
Children's Hospital reported on 36 infants <1 year of age and 26 toddlers 1-3 years of age
who underwent lung transplantations between 1990 and 2004. At transplant, the height standard
deviation scores were -1.76 for infants and -1.72 for toddlers. At 1, 3 and 5 years post-transplant,
the standard deviation scores became more negative (-1.89, -1.91 and -2.14, respectively).
Obviously, this report indicates that catch-up growth does not occur. Indeed, increased growth
retardation occurs following lung transplantation. Thus, rhGH has been used in a small series at St.
Louis Children's Hospital. Sweet and his colleagues (2525. Sweet SC, de la Morena MT, Schuler PM, Huddleston CB, Mendeloff EN. Association
of growth hormone therapy with the development of bronchiolitis obliterans syndrome in pediatric
lung transplant recipients. J Heart Lung Transplant. 2004;23(2 Suppl):S127,
http://dx.doi.org/10.1016/j.healun.2003.11.253.
http://dx.doi.org/10.1016/j.healun.2003....
)
reported that 8 of 9 lung transplant recipients who received rhGH developed bronchiolitis obliterans
syndrome, which was a higher incidence compared to the group who did not receive rhGH. Therefore,
Sweet and his colleagues caution the use of rhGH to enhance growth velocity in lung transplant
recipients.
SMALL BOWEL
The current data on growth in small bowel recipients was delineated by Nayyar and colleagues
(2626. Nayyar N, Mazariegos G, Ranganathan S, Soltys K, Bond G, Jaffe R, et al.
Pediatric small bowel transplantation. Semin Pediatr Surg. 2010;19(1):68-77,
http://dx.doi.org/10.1053/j.sempedsurg.2009.11.009.
http://dx.doi.org/10.1053/j.sempedsurg.2...
). Of 76 small bowel transplant recipients who received
transplants at a mean age of 2.6 years, 34 received standard immunosuppression with tacrolimus and
steroids, and 42 underwent a combination of anti-thymocyte globulin induction followed by tacrolimus
and only received steroids for acute rejection. Additionally, 48% of the patients who received
anti-thymocyte globulin remained steroid-free during the follow-up period, and the height standard
deviation score improved at 2 years in the steroid-free group. These data seem to indicate that
steroid-free immunosuppression has beneficial effects in the small bowel transplant population.
CONCLUSION
There are universal factors that impact growth velocity, catch-up growth and final adult height in all pediatric solid organ transplant recipients. The height at the time of transplant is certainly an important factor, with more severe growth retardation at transplant leading to a potential for greater catch-up growth following transplant. A normal target height at transplant has the potential to result in normal final adult height. The latter has certainly been shown in the renal transplant population.
The age at transplant also impacts growth, with younger recipients tending to be more growth-retarded at transplant; therefore, these patients may exhibit greater catch-up growth.
Likewise, graft dysfunction impacts growth, with the number of acute rejection episodes, number and length of hospitalizations, need for re-transplantation and need for surgical re-exploration all having adverse effects on growth.
Renal dysfunction, whether in renal allograft recipients or in recipients of other solid organ transplants, may have adverse impacts on growth. In renal allograft recipients, primary renal dysfunction certainly has been associated with an adverse effect on growth. In recipients of other solid organ transplants, renal dysfunction secondary to drug toxicity (i.e., calcineurin inhibitors, antibiotics and antivirals) can have adverse impacts on growth.
Bone dysfunction may impact growth, whether there is a persistent bone abnormality resulting from the primary disease or acquired bone dysfunction following solid organ transplantation.
Corticosteroids can certainly impact growth in all pediatric solid organ transplant recipients. Steroid-free regimens are optimal, with steroid withdrawal being a secondary option. In the studies where steroid withdrawal was effective, it was noted that earlier withdrawal was better. Receiving every-other-day steroid therapy had a positive impact on growth; however, adherence is a concern when every-other-day treatment is used. One of the major factors that may adversely affect the ultimate adult height is a suboptimal pubertal growth spurt. This spurt occurs to a significant degree in renal allograft recipients and may also occur in other solid organ transplant recipients. One potential therapeutic option to enhance pubertal growth is the use of rhGH to enhance the magnitude of the pubertal growth spurt; however, to my knowledge, there are no studies that have addressed this issue. Importantly, when one is determining the factors that affect growth following transplantation, genetic potential is a major factor that will determine target height. Thus, one should determine the mid-parental height when determining the anticipated target height for any recipient. In addition, one should also be cognizant that if the patient has significant growth retardation there may be a genetic abnormality causing primary short stature rather than the growth retardation being a consequence of the primary disease or other factors following organ transplantation.
REFERENCES
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1North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). 2010 Annual Transplant Report. Rockville, MD. Available from: https://web.emmes.com/study/ped/annlrept/2010_Report.pdf.
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23Mital S, Andron A, Lamour JM, Hsu DT, Addonizio LJ, Softness B. Effects of growth hormone therapy in children after cardiac transplantation. J Heart Lung Transplant. 2006;25(7):772-7, http://dx.doi.org/10.1016/j.healun.2004.11.317
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24Elizur A, Faro A, Huddleston CB, Gandhi SK, White D, Kuklinski CA, et al. Lung transplantation in infants and toddlers from 1990 to 2004 at St. Louis Children's Hospital. Am J Transplant. 2009;9(4):719-26.
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25Sweet SC, de la Morena MT, Schuler PM, Huddleston CB, Mendeloff EN. Association of growth hormone therapy with the development of bronchiolitis obliterans syndrome in pediatric lung transplant recipients. J Heart Lung Transplant. 2004;23(2 Suppl):S127, http://dx.doi.org/10.1016/j.healun.2003.11.253.
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26Nayyar N, Mazariegos G, Ranganathan S, Soltys K, Bond G, Jaffe R, et al. Pediatric small bowel transplantation. Semin Pediatr Surg. 2010;19(1):68-77, http://dx.doi.org/10.1053/j.sempedsurg.2009.11.009.
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No potential conflict of interest was reported.
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Publication in this collection
Jan 2014