Growth in children after renal transplantation: An update

Authors

  • Vinai M. Modini MD,

    1. Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas
    2. Division of Pediatric Critical Care, University of Texas Southwestern Medical Center, Dallas
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  • Mouin G. Seikaly MD

    1. Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas
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    • Member of D&T's editorial advisory board.


Abstract

Improving general health, sense of well-being, and quality of life are the primary objectives of renal transplanta-tion in children with chronic kidney disease (CKD). Final adult height achieved has a significant impact on medical, psychological, and social aspects of these patients. Growth is an important indicator of health in children with CKD. It seems intuitive then to expect improvement in growth after renal transplantation. Unfortunately, even with a functioning renal allograft, optimal growth remains elusive at times. Optimizing growth prior to transplant, early identification of growth delay, and timely intervention are essential in achieving optimal final adult height. Multiple factors lead to stunted growth in children after renal transplant.

In children, growth is a good predictor of the status of health and nutrition over time. This is especially true in children with chronic illnesses such as chronic kidney disease (CKD). The etiology of growth failure in children with CKD is multifactorial. Improving general health, sense of well-being, and quality of life are the primary management objectives for a child with CKD. Renal transplant is the best available renal replacement therapy for these children. Unfortunately, even with a functioning renal allograft, optimal growth remains elusive.

Assessment of Growth in Children With CKD

Growth in children can be assessed by change in stature, weight, body mass index (BMI), and head circumference over time.1 Change in stature is closely associated with skeletal growth and ceases by the end of the second decade of life. Height achieved at the end of the linear growth period is final. Hence, it is essential to identify linear growth delay early and to intervene swiftly when such a delay is identified. In contrast, weight gain is non-specific and does not have a cut-off period beyond which it ceases to change. BMI, which incorporates both weight and height, could be predictive of cardiovascular health. Head circumference is clinically relevant mainly in children younger than 3 years of age,2 and the typical child receiving a renal transplant is older.

When assessing height it is essential to use reliable and calibrated devices utilizing reproducible techniques.3 Standing height is typically measured using a stadiometer. Potential sources of error in measuring height are listed in TableI. Several growth parameters are available to assess growth (TableII). Since growth in children is dynamic, isolated measurements of height do not depict the complete picture of the growth status of a child. Profiles of the growth curves and growth velocity (GV) curves are better indicators of growth status over a period of time. Various age- and gender-based reference curves are available.4–8

Table I. Potential sources of error n measuring stature.
Source of ErrorError
Using an unreliable instrumentUnreliable measurement
Using a faulty techniqueOver- or underestimation
Using an inappropriate growth chartFaulty interpretation of growth
Inaccurate recording on the chartInaccurate growth curves
Table II. Recent references for growth curves.
Growth ParametersAge GroupSourceYear Published
Height, weight, BMI0–36 mo, 2–20 yCDC42000
Height, weight0–60 moWHO (Multicenter Growth Research Study Group)52006
Height, weight, BMI5–19 yWHO62007
Growth velocity2–19 yNational Center for Health Statistics Data71985
Sitting height12–17 yNational Health Survey (U.S. Dept. of Health, Education, and Welfare)1973

In normal children, linear growth can be divided into three phases.9, 10 The ini-tial phase (0–2 years) is characterized by a period of rapid growth and is primar-ily dependent on the nutritional status of the child. The second phase spans from 2 years of age to the beginning of the pubertal growth spurt. This is a growth hormone-sensitive phase. The third phase occurs during the pubertal growth spurt. This phase is predominantly driven by sex hormones. Linear growth in CKD has a predictable pattern.9, 10 CKD affects growth primarily during the two rapid growth phases. Hence children with CKD typically fall off the curve during infancy and then growth remains on the same percentile, albeit below the normal growth percen-tile and normal GV. This growth pattern persists until the pubertal growth spurt occurs. During puberty, the growth spurt is significantly delayed and shortened. When adult height is reached, it is often signifi-cantly lower than the general population.10 Height standard deviation score (SDS) is often a better parameter to assess growth. Furthermore, in a multiethnic population such as that of the United States, using a single growth curve could be misleading. Growth curves need to be assessed in the context of mid-parental height in order to assess genetic growth potential.

Management of children with CKD often focuses on maximizing caloric intake using various calorie-rich formulae. This often results in overweight children with height growth lagging behind.11 BMI is a good parameter to assess the relationship between weight and height.12 BMI could be either calculated or measured using various available devices.13, 14

Impact of Short Stature

Final adult height has both medical and psychosocial implications in patients post-transplantation. In their multivariate analy-sis of data from the U.S. Renal Data System, Wong et al. found a 14% increase in risk of death for every 1 SD decrease in height in children with CKD V.15 Similar findings were reported by Furth et al., who reviewed North American Pediatric Renal Trials and Cooperative Studies (NAPRTCS) data and found a relative hazard of death of 2.07 for children with height SDS of 2.5.16, 17 Broyer et al. reported an independent association of final height with educational level, paid activity during adulthood, marital life, and independent housing.18 They found a 10% increase in percentage with married life and 7% increase with independent housing for every 1-cm increase in final height. Recently a health-related quality of life assessment tool for children with CKD stage V and children with renal transplant was developed.19 This testing tool will enable us to evaluate the impact of height on the quality of life of children and young adults with CKD.

Growth Failure After Renal Transplantation

The NAPRTCS Experience

We have previously reviewed the NAPRTCS database and found that 36% of children with CKD stages 2–4 and 47% on dialysis have severe short stature (< − 1.88 SDS) at time of entry on the registry.20, 21 In children with CKD, glomerular filtration rate (GFR) <50 mL/min/1.73 m2, nonblack race, and congenital renal anomalies causing renal failure are associated with short stature at entry to the NAPRTCS database.22 The degree of growth retardation worsens as disease progresses through the various stages of CKD. Forty-two percent of children have severe short stature (< − 1.88 SDS) at the time of transplantation, with a mean height SDS of −2.15.23 Younger patients show greater deficits, with a mean height SDS of −3.04 at the time of transplantation.24

Renal transplantation often does not result in a sufficient catch-up growth to normalize the height deficit.23 Kohaut and Tejani23 reported that patients >6 years of age at transplantation did not show catchup growth (defined as a gain of +0.5 SD in height SDS). On the contrary, some children showed worsening of height deficit post-transplantation. Younger children showed only a modest catch-up growth in the first 2 years post-transplant, with a mean gain in height SDS of +0.75 SD in children <2 years of age and +0.64 SD in children between 2 years and 5 years of age. Tejani et al. reported that the youngest children with maximal deficit (mean SDS −3.04) at time of transplant had maximal height gain at 2, 3, and 5 years (mean gain height SDS +0.92).24Serum creatinine adversely affected the height gain, with a change in height SDS of −0.15 for every 1 mg/dL increase in serum creatinine. Caucasian children had better catch-up growth compared with African-American and Hispanic children. No significant difference was noted between living donor and deceased donor transplants.25 These authors also reported that about 75% of renal allograft recipients had no significant catch-up growth. Reduced allograft function was noted to have a negative impact on growth. Only modest improvements in height (gain of 0.75 cm) deficit and height SDS (gain of 0.32 SD) were noted during the first 2 years post-transplant, and no significant improvements were noted beyond 3 years post-transplant.

Fine et al. have recently summarized the 20-year NAPRTCS transplant and growth delay experience.26 In children transplanted before ages of 12 years, the mean baseline height SDS was −2.29, with younger children having lower height SDS, and the overall mean height SDS change from baseline to final height was 0.0.27 Younger children (6–8 years) showed more significant improvement in final height (mean change of +0.54 SD) in contrast to older children (mean change of −0.44 to −0.09). The mean final adult height SDS remained < − 2.0 SD. Lower baseline height SDS at time of transplantation and higher average dose of prednisone post-transplantation were associated with higher incidence of retarded final adult height (OR 2.56 and 2.37, respectively). GV curves in these children show a blunted and shortened pubertal growth spurt, which may contribute to the deficit in final adult height.

The European Experience

Most of the European experience is consistent with the NAPRTCS findings. The degree of height retardation at the time of transplantation depends on several factors. Such factors include: duration of CKD prior to transplantation, the primary renal disease, and the degree of delay in bone age.28 Younger children (<7 years) show the most height retardation at the time of transplantation.29 Girls were less heightretarded compared with boys at the time of transplantation (height SDS −1.3 vs. −2.7) as well as at 5 years post-transplantation (height SDS −0.6 vs. −1.5). There was a correlation between height and bone age (BA) delay.

Better catch-up growth has been reported in the European experience. Nissel et al. reported significant catch-up growth in children transplanted prior to the onset of puberty, with an increase in mean height velocity from 4.9 cm/y prior to transplant to 8 cm/y during the first 2 years, resulting in an increase in height SDS by 0.6.30 Children transplanted prior to or during the pubertal growth spurt exhibited a higher peak height velocity during puberty compared with normal children. However, the onset of the growth spurt was delayed and the total duration of the growth spurt was shorter, resulting in a 20% reduction in total pubertal height gain. Change in height SDS was proportional to height deficit and GFR at the time of transplantation. Improvement in height SDS from −2 to −1.5 at 2 years post-transplant was noted in children transplanted before 6 years of age.31, 32 In children transplanted before 2 years of age, height SDS improved from −1.74 to −0.34.33

Cyclosporine and a low-dose steroid regimen compared with azathioprine and a high-dose steroid regimen for post-transplant immunosuppression result in better growth.28 Children with pre-emptive transplantation had a height SDS that was close to the lower limits of normal. Qvist et al. reported catch-up growth in 81% of the children transplanted before the age of 5 years.34 Children younger than 2 years had less severe height retardation at transplantation and showed less impressive post-transplant growth. Children between 2 and 5 years of age showed improvement from a mean height SDS of −1.9 to a mean height SDS of −0.4. Growth beyond 5 years post-transplant correlated with GFR. Living-donor transplantation showed significantly higher catch-up growth and better height SDS compared with deceased-donor transplantation.25 This effect was independent of GFR in the living-donor group.

Andre et al. assessed growth in a cohort of French children with CKD diagnosed before the age of 16 years and reached final height without recombinant human (rh)GH therapy.35 In contrast, Englund et al. found that 75% of the children they studied attained a final height within the normal range, with a mean final height SDS of −1.1.29 A direct correlation was noted between measured GFR at 1 year post-transplantation and change in height SDS 5 years post-transplantation (r = 0.3, p = 0.03). Higher height SDS at the time of transplantation was associated with achievement of better final height SDS.

Etiology and Pathogenesis of Growth Retardation After Renal Transplantation

Many factors have been associated with growth retardation in children with a renal allograft.22, 24, 26, 30, 36, 37 The mean measured GFR at 4 years post-transplant is 40 mL/min/1.73 m2. Hence factors resulting in growth failure in CKD may also be operant post-transplant. Such factors include abnormalities in the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, a direct effect of uremia and acidosis on growth, malnutrition and anemia, and finally, renal osteodystrophy resulting from abnormalities in calcium-phosphorus metabolism (TableIII). Furthermore, the effect of immunosuppression on growth has been well described.38

Table III. Etiopathogenetic mechanisms affecting growth in CKD.
FactorMechanism of Growth Retardation
GH-IGF1 axis abnormalities80–86
  • GH insensitivity despite normal or elevated GH levels

  • Decreased GH secretion during pubertal growth spurt

  • Abnormalities in ghrelin secretion

  • Lower density of tissue GH receptors

  • Decreased IGF-1 production due to JAK2/STAT signaling pathways and overexpression of suppressors of cytokine signaling

  • Decreased bioactivity of IGF due to presence of IGF inhibitors and increased circulating levels of IGF binding proteins 1, 2, 4, and 6

Uremia84, 87
  • Deleterious effects of uremia on growth plate

  • GH receptor insensitivity caused by uremia

  • Decreased tissue density of GH receptors

  • Uremic toxins decrease IGF-1 bioactivity and act as IGF inhibitors

Malnutrition83
  • Aggravates GH insensitivity

Chronic inflammation83
  • Aggravates GH insensitivity

  • Causes overexpression of suppressors of cytokine signaling involved in IGF-1 production

Osteodystrophy87
  • Alterations in height of growth plate

  • Decreased volume of chondrocytes

  • Disorganization of columnar arrangement at growth plate

  • Dysregulation of dynamic equilibrium between chondrocyte proliferation and bone apposition

Abnormalities in the GH axis have also been well recognized in patients with CKD. GH levels in most children with CKD are typically either normal or elevated. This is a result of both increased secretion due to decreased feedback inhibition and decreased elimination due to decreased renal clearance. Despite the elevated levels, there is a general GH insensitivity in these children. Many studies have shown that children who are transplanted at a younger age tend to have more severe growth delay at the time of transplantation. With current prevalent practices and despite a better catch-up growth rate, young transplanted children are often shorter when they reach adulthood. Children with less severe growth retardation at transplantation attain a final height SDS closer to normal. Lower GFR post-transplantation has a negative impact on growth, with a direct correlation noted between estimated GFR at 30 days post-transplantation as well as estimated GFR at 1 year of age and the final height SDS. The type of immunosuppression also seems to have a significant impact on final height.38 Steroids have many effects lead-ing to impaired linear growth and skeletal maturation.39 Children with multiple trans-plants achieve much shorter adult height. This effect is mostly explained by the co-morbid conditions associated with CKD. Certain immunosuppressants such as siro-limus have been associated with growth retardation.40, 41 Similarly, although chil-dren with living donors tend to attain high-er final heights than those with deceased donors, most of the living-donor advantage results from less severe growth retardation at the time of transplantation. Gender does not seem to have any significant impact on post-transplantation growth.

Management of Growth Retardation in Renal Transplant Patients

It is intuitive that having a functioning renal allograft often has positive effects on growth. These beneficial effects include: improved renal function, improvement in osteodystrophy and increased 1,25(OH) vitamin D3 production, and the correction of uremia, anemia, and acidosis. All these in turn improve the growth delay associ-ated with CKD and may potentially lead to catch-up growth as well. Unfortunately, with current medical practices, renal trans-plant alone does not have a significant impact on final adult height. Thus manage-ment of growth retardation post-transplant should be modified to minimize growth-retarding factors as well as to provide growth-enhancing factors.

Steroid Avoidance and Steroid Minimization

Until recently, steroids have been a sig-nificant component of most post-transplant immunosuppression regimens. Long-term steroid usage is associated with various side effects including growth retardation. Chronic steroid usage can delay growth by inhibition of IGF-1 activity, suppression of the GH secretory response to GH-releasing hormone, downregulation of GH receptors, and impairment of type 1 collagen synthe-sis in the cartilage. Steroid minimization and avoidance regimens have had a posi-tive impact on final adult height. Currently there are three types of steroid minimi-zation protocols42, 43: 1) lower dose/alter-nate-day dosing; 2) steroid withdrawal; and 3) steroid avoidance. The two major concerns with these approaches are42, 43: 1) acute rejection with subsequent long-term decline in graft function and eventual graft failure; and 2) the need for higher dosage of other immunosuppressive agents, leading to more allograft fibrosis and dysfunction as well as other complications from excessive immunosuppression such as post-transplant lymphoproliferative disorder and increased risk of BK virus nephropathy44 and cyto-megalovirus infection.

Lower dose regimens have shown mod-est improvement in growth without sig-nificant improvement in final adult height.43 However, an increased risk of acute rejection and long-term graft dysfunction have been the major concerns with these regimens. Alternate-day regimens have been more successful in improving growth as well as minimizing the risk of rejection and graft dysfunction.45 Various investigators have attempted steroid withdrawal, both early as well as late.46–53 Early withdrawal has been associated with increased risk of acute rejec-tion. However, newer studies have shown no significant worsening in long-term graft function. Steroid withdrawal at 6 or 12 months has shown good results, especially in younger patients (6 years), with no sig-nificant increase in acute rejection or long-term graft dysfunction.51 Steroid-avoidance regimens are promising in terms of growth, especially in immunologically low-risk patients and younger patients.54–60 In adults, however, steroid avoidance has been associ-ated with increased use of other immuno-suppressants and resulting complications such as biopsy-proven acute rejection, graft loss, and death.61 The verdict on the benefits of steroid avoidance awaits further long-term studies.

The type of immunosuppresion used in these-steroid avoidance and steroid-minimizing regimens also has an impact on growth. NAPRTCS data have shown that improvement in height SDS is higher with tacrolimus compared with cyclosporine A.62 In these studies it is not clear whether some of this effect is a result of differences in the doses of steroid used. mTOR inhibitors such as sirolimus could have deleterious effects on the growth plate and longitudinal growth.40 Rangel et al. have reported a case in which they noted growth retardation after switching from calcineurin inhibitor to sirolimus.41 This retardation was probably partly attrib-utable to decreased GFR by the time the patient was switched to sirolimus. Studies by Iorember et al., in contrast, have shown good growth with sirolimus compared with steroid-based regimens.56

rhGH Treatment

The use of rhGH both before and after transplant has improved growth and final height in renal transplant patients.63–73 Steroid use has been the main component of most post-transplant immunosuppression regimens, as noted above. Steroids cause growth delay through the several mechanisms noted above. The use of rhGH attempts to reverse most of these negative effects.

Guest et al. have shown a significant increase in height velocity of children treat-ed with rhGH compared with controls at 1 year.74 A neta-analysis by Vimalachandra et al. has shown a trend toward higher increase in height SDS in patients treated with rhGH.38 We have previously reviewed the NAPRTCS database and shown that the rhGH group have a higher slope to the change in height SDS curve.21, 75 The catch-up growth seen is higher in the CKD group (both non-dialysis as well as dialy-sis patients) compared with the transplant group. This point emphasizes the impor-tance of pre-transplant rhGH since patients who start with a higher height SDS at the time of transplant end up with higher final height SDS.

The safety of rhGH in transplant patients has been well established.76–79 No significant adverse effects related to altered glucose metabolism, decline in GFR, and risks for acute rejection, aseptic necrosis of the hip, and cardiovascular events have been noted in multiple studies. The inci-dence of slipped capital femoral epiphysis is 2 in 1,000 in patients using GH com-pared with 1 in 1,000 in patients not on GH. Similarly, the incidence of aseptic necrosis of the hip was 8 in 1,000 vs. 6 in 1,000 in the two groups.79

Despite the proven benefits of rhGH, its utilization, even in the high-risk groups, is not adequate.21 We have previously shown that only 5% of eligible transplant patients are on rhGH 3 years after entry into the NAPRTCS registry. rhGH utiliza-tion is slightly better in Caucasians, older children, and males, but it is still below 10%. Major barriers to rhGH utilization include: 1) lack of urgency: short stature is perceived as a cosmetic issue only; 2) inad-equate evaluation; 3) patient compliance; 4) lack of physician guidelines; and 5) cost, insurance, and reimbursement issues: the cost-benefit value of rhGH usage is not well established.

Conclusions

Despite improved graft survival, growth retardation remains a major clinical issue facing children who receive a renal trans-plant. Young age at transplant, short stature prior to transplant, and the use of certain immunosuppressive drugs (especially ste-roids) are major risk factors for delayed final adult height. Management of growth retarda-tion should start early in the course of CKD. The use of rhGH before and after transplant and steroid minimization protocols offer the best chance at catch-up growth.

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