Key words : Catch-up growth, Children, Renal transplantation

Introduction

Growth impairment is a common complication in children with chronic kidney disease (CKD).¹ Growth failure in patients with CKD is caused by multiple factors.¹ Electrolyte abnormalities, inadequate nutrition, metabolic acidosis, uremia, anemia, inflam-mation, and hormonal changes, namely vitamin D deficiency, hyperparathyroidism, hypogonadism, and disorders of the growth hormone/insulin-like growth factor axis,^2-5 are associated with height loss. Short stature is a marker of increased mortality in pediatric patients with CKD⁶ and is associated with negative psychosocial effects and deterioration of quality of life.⁷

Kidney transplant (KT) is considered the best treatment option to normalize the fluid volume, uremia, and endocrine and metabolic abnormalities of end-stage kidney disease. However, successful KT does not always result in sufficient growth improvement.⁸ The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) facilitated a multicenter assessment of growth following KT, and the authors reported that factors adversely affecting growth after KT were age at KT, steroid therapy, and degree of allograft function.⁹ Additionally, persistence of growth deficiency after KT was associated with preemptive transplant and pubertal growth spurt characteristics.⁸ Moreover, Franke and colleagues reported that growth before and after KT in children born small for gestational age (SGA; defined as birth weight or length below the 10th percentile for gestational age) is more impaired compared with patients who were not born SGA.¹⁰

The average incidence of end-stage kidney disease among Japanese children between 2006 and 2011 was 4.0 per million.¹¹ However, there have been relatively few pediatric studies in Japan and the greater Asian population¹² that describe growth and that characterize the prevalence of short stature before KT, as well as catch-up growth (CUG) and the associated factors in children with KT. Identifying strategies for achieving optimal growth improvement after KT and establishing accurate standards for pre- and posttransplant height changes and identifying factors contributing to treatment options to promote growth will contribute to improving knowledge of this problem in Japan.

Materials and Methods

Ethical approval
All procedures were in accordance with the ethical standards of the institution at which the studies were conducted (institutional review board no. 24-54/UMIN000008475) and of the national research committee and were performed in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent
Because data were obtained retrospectively from patient medical records, the institutional review board waived the requirement to obtain patient informed consent according to the ethical guidelines for medical and health research involving human subjects in Japan.

Patients
We reviewed data from 60 consecutive pediatric recipients ≤16 years old who underwent KT at our facility from November 2001 to March 2018. Patients were followed up until March 31, 2020, and the average follow-up time was 91.8 ± 54.5 months. We recorded the following variables from patient medical records: age, sex, duration of dialysis, ABO-incompatible KT, number of human leukocyte antigen mismatches, gestational age/birth weight, history of steroid therapy, and history of treatment with recombinant human growth hormone (rhGH). We also assessed donor factors, namely, deceased or living status, age, and sex. Because final height was generally defined as the final height measurement available after 18 years of age, we included only children with the potential for CUG (ie, those ≤16 years old in this study) to evaluate changes in height standard deviation score (HtSDS) over 2 years from the start of renal replacement therapy to the final height measurement.

Immunosuppression
All patients who underwent KT were administered basiliximab at the time of surgery and on postoperative day 4. Orally administered immunosuppressive agents were tacrolimus, mycophenolate mofetil, and methylprednisolone. All patients underwent steroid maintenance immunosuppression. Recipients of ABO-incompatible KT began oral immunosuppression on preoperative day 14 and low-dose rituximab on preoperative day 7.¹³ The patients also underwent 1 to 6 plasmapheresis treatments until anti-A/-B titers were reduced to ≤32, before transplant.¹³

Height standard deviation score
Height standard deviation score was calculated according to Japanese national reference data for children.¹⁴

Short stature
Short stature was defined as height over 2 HtSDS below the mean height for sex and chronological age.¹⁵

Catch-up growth
Changes in HtSDS from before transplant to 2 years after KT were calculated. Based on previous reports, CUG was defined as present if delta (Δ) HtSDS was ≥0.5 HtSDS per year during the first 2 years after KT.^12,16

Estimated glomerular filtration rate
According to values for the Japanese population, estimated glomerular filtration rate (eGFR) for children (age <18 years) was calculated using the equation shown in the published report.¹⁷

Allograft biopsy evaluation and pathological interpretation
Allograft diagnoses were performed using episode biopsies or 3- and 12-month protocol biopsies, in accordance with the Banff 2013 working classification.¹⁸ When a patient was diagnosed with acute rejection, treatment was conducted according to appropriate guidelines.¹⁹

Statistical analyses
Data are presented as mean ± standard deviation for normally distributed continuous variables, median (interquartile range) for nonnormally distributed continuous variables, and number (%) for categorical variables. Graft survival was calculated using Kaplan-Meier analysis. To evaluate the relationship between preoperative HtSDS and HtSDS 2 years after KT with the appropriate parameters, univariate linear regression analysis was performed to identify possible predictors for the dependent variables. Multivariate regression analysis was then performed, including all independent variables that were significant in the univariate analysis and variables known to be significant in previous studies. Univariate and multivariate logistic regression analyses were used to identify the factors associated with CUG, and receiver operating characteristic curve analysis was used to detect cutoff values. We used JMP software (version 14, SAS Institute) for all statistical analyses. P < .05 was considered statistically significant.

Results

Patient baseline characteristics are shown in Table 1. Among the 60 patients, median age was 11 years (5.3-14 y), and 24 (40.0%) were female. Mean follow-up duration was 91.8 ± 54.5 months, and mean preoperative HtSDS was -2.1 ± 1.5. Twenty-one children (35.0%) had preemptive KT. All of the living donors were first- or second-degree relatives, namely parents and grandparents. All children were alive during the observational period. The 2-, 5-, and 15-year graft survival rates were 96.7%, 94.4%, and 77.8%, respectively (Figure 1a). Two children lost their allografts within 2 years after KT. One allograft loss was because of chronic T-cell-mediated rejection (postoperative day 394), and the other was caused by chronic antibody-mediated rejection (postoperative day 458). Within 2 years after KT,¹⁸ 30.0% had rejection, and 32 (53.3%) had infections that required hospitalization; no children underwent rhGH therapy. Mean eGFR after KT was 51.8 ± 16.9 mL/min/1.73 m². Duration of dialysis (months) was associated with preoperative HtSDS (β = -0.020; standard error [SE]: 0.006; t = -3.23; P = .002; Table 2 and Figure 1b).

Table 3 shows patient characteristics classified according to with or without rhGH treatment before KT. The preoperative HtSDS of children treated with (n = 10) or without (n = 50) rhGH were -2.32 ± 1.43 and -2.11 ± 1.51, respectively (P = .682). There were no significant differences between children with and without rhGH treatment before KT regarding age at KT, sex, duration of dialysis, history of steroid therapy, deceased/living donor, or primary disease. Only SGA was significantly higher in children with rhGH treatment compared with those without rhGH treatment before KT (P = .016).

In total, 26 (43.3%) and 19 children (31.7%) had short stature preoperatively and 2 years after KT, respectively. Fourteen children (53.9%) remained with short stature even 2 years after KT. Preoperative short stature was significantly associated with short stature 2 years after KT (P = .002). We found that HtSDS in the first 2 years after KT was associated with age (β = -0.037, SE = 0.017, t = -2.20, P = .032), preoperative HtSDS (β = 0.812, SE = 0.047, t = 17.22, P < .001), and episodes of rejection (β = -0.217, SE = 0.075, t = -2.80, P = .005) (Table 4). Catch-up growth was observed in 23 patients (38.3%). Higher age and episodes of rejection were significant factors for loss of CUG (P < .001 and P = .023, respectively; Table 5). Receiver operating characteristic curve analysis showed that the cutoff value for age and CUG was 11 years (area under the curve, 0.821; Figure 1c).

Discussion

The present study showed the following: (1) duration of dialysis is associated with preoperative HtSDS; (2) episodes of rejection and higher age are significant risk factors for loss of CUG; and (3) although lower age can result in achieving CUG, lower preoperative HtSDS was still associated with lower HtSDS after 2 years. These findings suggest that shortening the period of dialysis before KT and intervention for short stature during dialysis may result in improved height for pediatric KT recipients.

In our study, there was an association between preoperative HtSDS and duration of dialysis before KT. This was consistent with previous studies.^2,3-5 Because patient management begins before the start of renal replacement therapy, it is essential that possible growth impairments are diagnosed and treated at this time.²⁰ However, in children with CKD, correction of growth retardation factors related to fluid and electrolyte abnormalities, anorexia with inadequate caloric intake, and renal osteodystrophy are not expected to result in sufficient growth.²¹ Resistance to growth hormone action may exist secondary to decreased growth hormone receptor density, impaired growth hormone-activated postreceptor JAK/STAT signaling, and reduced levels of free insulin-like growth factor-1 (IGF-1) because of increased inhibitory IGF-binding proteins in target organs.⁴

A multicenter randomized trial analyzing the use of rhGH in growth-retarded children with CKD demonstrated its efficacy.22 In 1993, rhGH was approved by the US Food and Drug Administration for treating growth failure in children with CKD before they undergo KT. The 2009 NAPRTCS cohort showed that greater effort in correcting these factors through optimizing nutrition, clinical care, and rhGH treatment have improved preoperative HtSDS from a mean of -2.43 in 1987 to -1.23. Furthermore, rhGH treatment was found to reduce the risk of serious complications associated with growth failure.5 The consensus statement5 for the use of rhGH proposed that rhGH should be considered in patients with GFR <75 mL/min/1.73 m2 and HtSDS < -1.88 (corresponding to the 3rd percentile) or ≤ -2. In this study, although we did not adequately assess the factors related to not using rhGH in those who were not treated with it, only 10 of 60 patients (16.7%) were treated with rhGH before KT. It is noteworthy that the preoperative HtSDS of children treated without rhGH was only -2.11 ± 1.51.

In a multicenter prospective study of children with CKD in Japan,20 only 25% of children with eGFR <15 mL/min/1.73 m² and HtSDS ≤ -2 were being treated with rhGH, and less than one-third of the total study population was treated with rhGH. The study implied that rhGH is underutilized in Japanese children with CKD, which may reflect a more stringent indication for rhGH in CKD in Japan (eGFR ≤50 mL/min/1.73 m² and HtSDS ≤ -2) as well as the additional cost of treatment, and pain, associated with injections.²⁰ Specifically, more patients born SGA were treated with rhGH before KT compared with the number of patients not born SGA.

Regarding the patients born SGA in the present study, rhGH utilization was not inferior to that of Franke and colleagues,¹⁰ which reported that rhGH was more frequently initiated in the pretransplant period in SGA patients compared with non-SGA patients (44.7% vs 32.5%, respectively; P < .05). This observation suggests that children born SGA may be more likely to receive interventions such as rhGH therapy than children not born SGA, as children born SGA often have shorter height from birth.

Improvements in immunosuppressive regimens leading to a reduced incidence of acute episodes of rejection have also had beneficial effects on growth by preventing graft dysfunction and reducing the doses of steroids required to treat rejection.⁹ Although episodes of rejection within the first month after transplantation were not reported to be statistically significant,²³ episodes of rejection within 2 years after KT affected loss of CUG in the present study. A possible explanation is that steroid pulse therapy for rejection may cause growth retardation. Poor allograft function was reported to negatively affect growth.²⁴ In our study, mean eGFR after KT was 51.8 ± 16.9 mL/min/1.73 m² and was relatively well maintained. In a prospective cohort study of Japanese children with CKD,²⁰ CKD stages 4 and 5 were risk factors for growth impairment compared with CKD stage 3. Moreover, there was no significant difference in eGFR between patients with or without episodes of rejection within 2 years after KT (P = .668). In addition, preemptive transplant (which is effective for preventing or avoiding the onset of dialysis) and born SGA were not significant factors for growth, likely because of the small number of patients.

We also showed that age at KT is important for CUG. Studies have reported that achieving greater CUG was restricted to younger age groups.^24-27 Our study also demonstrated an association between greater ΔHtSDS during the first 2 years after KT and younger age (P = .009; Figure 1d). Age <6 years in the ESPN/ERA-EDTA Registry study²⁴ and age <5 years in the NAPRTCS study restricted growth potential. In contrast, CUG was not observed in recipients >12 years old at the time of KT.²⁴ Our results were similar in that age at KT was negatively correlated with growth after KT.

In our study, HtSDS 2 years after KT correlated strongly with preoperative HtSDS. This was consistent with previous studies^12,28-30 and suggests the importance of early intervention to prevent height loss before KT. Born SGA tended to be associated with low HtSDS at 2 years (P = .079). Franke and colleagues¹⁰ also reported that, although rhGH was clearly beneficial and was used more frequently in SGA versus non-SGA patients in the pretransplant period, it apparently could not fully compensate for the preexisting growth deficit in children born SGA. However, 3 children were treated with rhGH 2 years after the observational period, whereas no children were treated with rhGH within 2 years after KT, in our study. The fact that recipients treated with rhGH have a slightly increased risk of graft rejection (risk ratio = 1.56; P = .074) must be considered, and patients who experience frequent episodes of rejection during rhGH treatment may suffer from more episodes.³¹ However, treatment with rhGH has been reported to be effective even in pubertal KT recipients,³² and a recent report revealed the efficacy and safety of rhGH for improving height in KT patients who began treatment during late puberty.³³ Therefore, even in puberty, growth improvement in KT recipients with rhGH treatment can be expected. Fine²¹ suggested that an additional approach to achieving normal final adult height is the use of rhGH at the onset of puberty until final adult height is achieved.

This study had several limitations. First, this was a single-center, retrospective, observational cohort study. Second, the sample size was small; therefore, the study may be underpowered. Third, we did not assess growth beyond 2 years after KT, including final adult height, or steroid withdrawal/cessation of immunosuppressive regimens or the effectiveness of growth hormone therapy after KT. Additionally, our conservative steroid regimen may have affected the low HtSDS 2 years after KT.

Conclusions

Our study suggests that, although successful KT could result in CUG in pediatric patients, short stature often persisted in recipients 2 years after KT and is affected by age, preoperative HtSDS, and episodes of graft rejection.

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