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Commentary on Long-term Growth Following Renal Transplantation in Children

Fine, Richard N. MD1

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doi: 10.1097/TP.0000000000002727
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One of the onerous clinical aspects of long-term kidney disease (CKD) in infants, children, and adolescents is the failure to achieve statural height comparable to their peers. Before the availability of renal replacement therapy (RRT) and end-stage renal disease (ESRD), care-chronic dialysis and renal transplantation-minimal investigative efforts were involved in addressing this deficit because the ultimate clinical outcome of the primary disease was so dismal. With the availability of prolonging the lives of these patients with these new therapeutic modalities, it was anticipated that the growth retardation would improve, although a pediatrician with limited experience in the early 1960s questioned the use of renal transplantation in children when he proffered that the “kidney would be housed in a healthy dwarf.”

The pathogenesis of growth retardation in patients with CKD was considered multifactorial—acidosis, fluid and electrolyte abnormalities, anorexia with inadequate caloric intake, and renal osteodystrophy; however, despite correction of these abnormalities, suboptimal growth persisted.1 The seminal animal studies by Mehls et al in the early 1980s identified perturbations of the growth hormone/insulin-like growth factor axis (GH/IGF) as critical to growth failure in CKD.2 This led to a multicenter randomized, placebo-controlled trial of recombinant human growth hormone (rhGH) in growth-retarded children with CKD, which demonstrated the efficacy of treatment and led to US Food and Drug Administration approval of rhGH in the United States for the growth-retarded children with CKD and those undergoing dialysis.

Likewise, successful renal transplantation was not always associated with optimal acceleration in growth posttransplant resulting in abnormal adult height. The 3 factors that were indicated to have adverse impact on growth following transplantation were age at the time of transplantation, concomitant steroid therapy, and degree of allograft function.

The development of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) in 1987 facilitated the multicenter serial assessment of growth following renal transplantation. In 2010,3growth data from 20 years of the registry involving >10 000 recipients were analyzed to address 5 questions: (1) What is the impact of age, pubertal growth, gender, transplant history, donor source, and allograft function on growth after transplantation? (2) Has the height Z score at the time of transplantation changed during the past 2 decades, and has this influenced final adult height? (3) To what extent has rhGH been utilized in growth-retarded recipients after transplantation, and has it resulted in accelerated posttransplantation growth? (4) Has the use of steroids for maintenance of immunosuppression changed during the past 20 years, and how have the perturbations of steroid usage influenced posttransplant growth? and (5) Has changes in clinical care resulted in improved final adult height Z score during the past 2 decades?

The succinct conclusions of this report were that only children <6 years old at the time of transplantation exhibited accelerated growth; that the height Z score at the time of transplantation improved over the past 2 decades (Figure 1) as did final adult height with each succeeding era; that rhGH after transplantation resulted in a delta Z score of +0.5 SD; an increase or decrease in eGFR of 10 mL/min/1.73 m2 resulted in an increase or decrease in height Z score of 0.015 SD; and no steroids or alternate day steroids increased the height Z score compared to daily steroids.

FIGURE 1
FIGURE 1:
Standardized height at time of transplant. ESRD, end-stage renal disease. Reprinted with permission from the North American Pediatric Renal Transplant Cooperative Study.

Subsequently, a multicenter, randomized 3-year trial of steroid avoidance showed that only recipients aged <5 years demonstrated improved linear growth, although the absence of steroids had no adverse impact on graft outcome.4 The lack of improvement in height SD score despite absence of steroids in all but the youngest recipients indicates that there are other significant factors adversely impacting growth following transplantation. Reduced allograft function and the lack of an optimal pubertal growth spurt are likely putative factors.

In this issue of Transplantation, Bonthuis et al report on “Growth patterns after kidney transplantation in (3492) European children over the past 25 years: an ESPN/ERA-EDTA Registry study.”5 The time period covered in the NAPRTCS was 1987–2008 and in the current study, 1990–2012. The height SD score was in the normal range in only 55% of the recipients with 28% showing moderate and 17% showing severe growth deficit. Children aged <6 years were the shortest and showed the greatest increase in height posttransplant, whereas no catch-up growth was observed in recipients aged >12 years at transplant. Living kidney donation, pre-emptive kidney transplantation or dialysis for <1 year, steroid-free immunosuppression, and a higher estimated glomerular filtration rate (eGFR), not being hypertensive or anemic were associated with better posttransplant height. Catch-up growth occurred in both sexes, with height SD score +0.37 in boys and +0.33 in girls.

A major difference in the outcome data between the NAPRTCS report and the European Registry report is that there was no difference in height at the time of kidney transplantation or in posttransplant growth in different eras in the European Registry data. This suggests that the prevention of CKD-related growth retardation pretransplantation has remained inadequate in Europe compared with North America during the past 25 years and may contribute significantly to the fact that 45% of European children have height SD scores out of the normal range following transplantation.

Unfortunately, serial final adult height data were not available in the European registry report; however, it was observed that no catch-up growth occurred in children who were aged >12 years at the time of transplantation. The serial improvement in final adult height in the NAPRTCS may have its genesis in the serial improvement of the height Z score at the time of transplantation during the 2 decades of the registry.

Bonthuis et al5 suggest that improvement in posttransplant growth could be accomplished by promoting living donor and pre-emptive transplantation, steroid withdrawal/avoidance immunosuppressive regimens, and more regular use of rhGH. A recent report from the European Registry noted that only 22% of dialysis short patients and 6% of kidney transplant short patients received rhGH in Europe.6

I would suggest that one of the major therapeutic goals of RRT and ESRD care in infants, children and adolescents is the attainment of “normal” (50th percentile for mid-parental height) final adult height. If the adolescent patient has not achieved final adult height at the time of transplantation, it is likely that an optimal pubertal growth spurt will be required to achieve this goal. A multicenter study in the early 1990s indicated that the pubertal growth spurt in children with CKD was suboptimal.7 It is likely that a substantial number of kidney transplant recipients will have an eGFR consistent with stage 2 or stage 3 CKD at the time they initiate their pubertal growth spurt and that the lack of growth in recipients aged >12 years is attributable to a suboptimal pubertal growth spurt. I would suggest that an additional approach to achieving normal final adult height would be the use of rhGH at the initiation of puberty until final adult height is obtained. Certainly, a randomized controlled study would be required to validate the efficacy of this concept.

Treatment with rhGH has been shown to be effective in renal transplant recipients in randomized controlled trials with limited side effects.8 A previous report noted efficacy of rhGH treatment in pubertal renal transplant recipients9 and a recent report documented near-adult height in male recipients who initiated rhGH treatment in late puberty (testicular volume >8 mL).10 Therefore, it is possible to anticipate increments in growth velocity in renal transplant recipients with rhGH treatment even if they are pubertal.

In conclusion the recent European Registry report6 and the prior North American Registry report3 detailing long-term growth after successful renal transplantation indicated limited posttransplant catch-up growth except in very young (aged <5–6 y) recipients at transplantation. Since a significant number (±40%)6 of recipients are growth-retarded, it is necessary to achieve accelerated growth in such recipients if optimal final adult height is to be obtained. In addition to minimizing immunosuppression and optimizing allograft function, it is possible that judicious use of rhGH during puberty may result in optimal final adult height.

REFERENCES

1. Fine RN. Etiology and treatment of growth retardation in children with chronic kidney disease and end-stage renal disease: a historical perspective. Pediatr Nephrol. 2010; 25:725–732
2. Mehls O, Ritz E, Hunziker EB, et al. Improvement of growth and food utilization by human recombinant growth hormone in uremia. Kidney Int. 1988; 33:45–52
3. Fine RN, Martz K, Stablein D. What have 20 years of data from the north american pediatric renal transplant cooperative study taught us about growth following renal transplantation in infants, children, and adolescents with end-stage renal disease? Pediatr Nephrol. 2010; 25:739–746
4. Sarwal MM, Ettenger RB, Dharnidharka V, 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; 12:2719–2729
5. Bonthuis M, Groothoff JW, Ariceta G, et al. Growth patterns after kidney transplantation in European children over the past 25 years: an ESPS/ERA-EDTA Registry study. Transplantation. 2019
6. van Huis M, Bonthuis M, Sahpazova E, et al. Considerable variations in growth hormone policy and prescription in paediatric end-stage renal disease across european countries—a report from the ESPN/ERA-EDTA registry. Nephrol Dial Transplant. 2016; 31:609–619
7. Schaefer F, Seidel C, Binding A, et al. Pubertal growth in chronic renal failure. Pediatr Res. 1990; 28:5–10
8. Wu Y, Cheng W, Yang XD, et al. Growth hormone improves growth in pediatric renal transplant recipients—a systemic review and meta-analysis of randomized controlled trials. Pediatr Nephrol. 2013; 28:129–133
9. Hokken-Koelega AC, Stijnen T, de Ridder MA, et al. Growth hormone treatment in growth-retarded adolescents after renal transplant. Lancet. 1994; 343:1313–1317
10. Gil S, Aziz M, Adragna M, et al. Near-adult height in male kidney transplant recipients started on growth hormone treatment in late puberty. Pediatr Nephrol. 2018; 33:175–180
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