Nephrology Dialysis Transplantation 2007 22(Supplement 7):vii176-vii180; doi:10.1093/ndt/gfm337
© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Growth in children with established renal failure—a Registry analysis (Chapter 14)
Malcolm Lewis1,
Joanne Shaw1,
Chris Reid2,
Jonathan Evans3,
Nicholas Webb1 and
Kate Verrier-Jones4
1Central Manchester & Manchester Childrens University Hospitals NHS Trust, 2Guys and St Thomas's; NHS Foundation Trust, 3Nottingham University Hospitals NHS Trust and 4University Hospital of South Wales NHS Trust
Correspondence and offprint requests to: Dr Malcolm A Lewis, Renal Office, Royal Manchester Children's; Hospital, Hospital Road, Pendlebury, Manchester M27 4HA, UK. Email: malcolm.lewis{at}cmmc.nhs.uk
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Abstract
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Short stature is a major problem in paediatric ERF patients
with 29% of transplant patients and 41% of dialysis patients
below the second percentile for height. Only 6.5% of transplant
patients and 15.5% of dialysis patients are receiving rhGH.
There is no significant difference in the height distribution
of patients commencing RRT and those who have had a functioning
allograft for at least 1 year. In patients with at least 2 years
between presentation and RRT, there is a significant fall in
height
Z score. This overall statistic is strongly influenced
by the very poor growth of patients with glomerular disease.
Keywords: chronic kidney disease; dialysis; end stage renal disease; epidemiology; ERF; established renal failure; growth; growth hormone; RhGH; transplantation
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Introduction
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Achieving reasonable growth in children with chronic kidney
disease and particularly those with ERF remains one of the greatest
challenges for the paediatric nephrologist. Even with control
of acidosis, electrolyte balance, renal osteodystrophy and supplemental
nutrition, many children grow poorly and this is a major problem
to the patients and their families. The recent Cochrane review
[
1] suggested that the use of recombinant human growth hormone
(rhGH) was effective for patients regardless of their pubertal
or treatment status. Since the initial studies of rhGH in patients
with CKD in the early 1990s it has been licensed for use in
the UK for over 10 years and certainly for the whole period
the paediatric registry has been collecting data. In a recent
review Mahan and Warady [
2] found that there was reluctance
amongst US paediatric nephrologists to use rhGH. They set out
an algorithm, developed by members of a consensus committee,
for the use of rhGH. In the light of this it seemed important
to examine the UK practice through the data available in the
paediatric registry.
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Analysis
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The Registry collects anthropometric data at presentation, ERF
commencement and annually thereafter. For the follow up records
a note is also made as to whether rhGH has been used over the
previous year. Data on rhGH usage over the past 5 years in patients
where a complete data set is available is shown in
Table 14.1.
These data are divided according to whether patients had a functioning
allograft or were on dialysis. In the dialysis population just
15.9% of patients on average, are receiving rhGH. These data
show that there is certainly no upward trend in rhGH usage and
if anything, the trend is downward. For transplant patients
the trend is towards increasing usage, but the proportion receiving
rhGH is much less, averaging just 4.3%.
These findings would be expected in a patient population that
was growing well with little consequent need for rhGH. However,
cross-sectional analysis shows this not to be the case. The
cumulative frequency distribution of height in 273 patients
with a functioning allograft for at least one year in 2005 and
between the ages of 2 and 16 years at the time is shown with
the data from 105 dialysis patients in that same age range in
Figure 14.1. Although the transplant patients are significantly
taller than those on dialysis (
Figure 14.2,
P = 0.004), both
groups are well below the normal range. For the transplant patients,
48% were below the tenth percentile with 39% being below the
fifth percentile and 27% below the second percentile. The corresponding
figures for dialysis patients were 61% below the tenth percentile,
54% below the fifth percentile and 44% below the second percentile.
Thus, based on this cross-sectional analysis, it appears that
rhGH is being under-used in the paediatric ERF population. This
analysis was based upon those between the ages of 2 and 16 years
of age as this is the group one would expect to potentially
most benefit from rhGH. Analysis of all patients from the age
of 2–20 years showed no difference and indeed, though
the usage of rhGH was low, overall the frequency of usage was
the same in those over the age of 16 as under the age of 16
years. The lower usage of rhGH in transplant patients compared
to dialysis patients could in part be secondary to the fear
of rhGH stimulating the growth of renal cell carcinomas as described
by Tyden
et al. [
3]. However, wider analysis of these data available
by Mehls
et al. [
4] and the Cochrane review have suggested that
this risk is low and should not prevent the usage of rhGH where
indicated by growth parameters.
These data on height in the paediatric ERF population are clearly
disappointing but not dissimilar to the findings of Mahan and
Warady analysing the NAPRTCS dataset. Clearly the two most influential
factors, after control of biochemical and nutritional status,
are growth after transplantation and before commencing RRT as
for the majority of paediatric patients, the longest periods
of treatment are either conservative before RRT or with a functioning
allograft. At present, the Registry does not collect data on
pre-ERF CKD patients but analyses of data at presentation to
nephrology services together with data at ERF commencement gives
some insight into the CKD phase.
For this analysis 236 patients with complete anthropometric data, presenting between 2 and 16 years of age between 1996 and 2005, who had a minimum of 2 years between presentation and commencement of ERF were selected. These selection criteria allowed study of a population who had a reasonable period of time in the paediatric CKD clinic and for whom all interventions, including the use of rhGH would have been available. The height distribution of this population at presentation to nephrology services and at ERF commencement is shown in Figure 14.3. The population is clearly significantly smaller than normal with 50% being below the tenth percentile, 42% below the fifth percentile and 33% below the second percentile at presentation. Overall, by the time these children entered ERF their height Z score had fallen rather than risen with 53% being below the tenth percentile, 45% below the fifth percentile and 34% below the second percentile (P = 0.0015, Figure 14.4).
There are numerous factors that could affect growth in children
with chronic kidney disease. One powerful factor is underlying
diagnosis. Some conditions are associated with biochemical disequilibrium
that is difficult to control or are likely to be treated with
steroid containing immunosuppressive regimes that will impair
growth. Others, like nephropathic cystinosis, have been shown
to respond well to rhGH in all phases of CKD management [
5].
The series of figures below, show the change in height
Z score
from presentation to ERF commencement and the distribution of
height
Z scores at these two points in the main diagnostic groups.
For patients with renal dysplasia, obstructive uropathy, reflux
nephropathy and tubulo-interstitial disease (
Figures 14.5–14.8
),
there is no significant difference in height
Z score from presentation
to ERF commencement. Tubulo-interstitial disease is in fact
the only one of these four diagnostic groups where the median
height
Z score at presentation is higher than at ERF commencement.
For the large number of patients with glomerular disorders however,
there is a significant fall in height
Z score from presentation
to ERF commencement (
P < 0.0001,
Figure 14.9).
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Fig. 14.5. (a) Change in height Z score from presentation to ERF commencement in patients with renal dysplasia. (b) Distribution of height Z score from presentation to ERF commencement in patients with renal dysplasia.
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Fig. 14.6. (a) Change in height Z score from presentation to ERF commencement in patients with obstructive uropathy. (b) Distribution of height Z score at presentation and ERF commencement in patients with obstructive uropathy.
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Fig. 14.7. (a) Change in height Z score from presentation to ERF commencement in patients with reflux nephropathy. (b) Distribution of height Z score at presentation and ERF commencement in patients with reflux nephropathy.
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Fig. 14.8. (a) Change in height Z score from presentation to ERF commencement in patients with tubulo-interstitial disease. (b) Distribution of height Z score at presentation and ERF commencement in patients with tubulo-interstitial disease.
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Fig. 14.9. (a) Change in height Z score from presentation to ERF commencement in patients with glomerular disease. (b) Distribution of height Z score at presentation and ERF commencement in patients with glomerular disease.
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The data for the 20 patients who had metabolic disease as a
cause of ERF are shown below in
Figure 14.10. All these patients
had cystinosis as the cause of their renal failure. Despite
the data from Wuhl
et al. [
5] suggesting that patients with
cystinosis grow well with rhGH, there is no significant difference
in the height
Z score of these patients from presentation to
ERF. To check that this was not just secondary to the small
numbers of patients studied, the selection criteria rules were
relaxed to allow inclusion of patients presenting below the
age of two years. This allowed the patient group to be almost
doubled to 37. The result however, was identical. It is clear
that whilst some patients are doing very well, others do badly.
Unfortunately, no data are available on the detailed management
of these patients so it is not possible to determine whether
this is simply because some patients are not being offered rhGH
or whether there were other factors leading to poor growth in
many of the patients.
Comparing the height distribution of the cohort of patients
studied above when they start ERF management with the height
distribution of the patients studied who were at least 1 year
post-transplant, there is no significant difference (
Figure 14.11).
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Conclusions
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Clearly, there are many factors that cannot be studied with
the data available from the Registry dataset. However, it seems
clear that growth in children with ERF is suboptimal. Growth
acceleration is not being achieved in either the pre-ERF stage
or after transplantation. Patients on dialysis are poorly grown.
One factor that may be contributing to this is the relatively
infrequent use of rhGH. Other factors that need to be considered
are the control of acidosis, renal osteodystrophy and nutrition.
Finally it is important to tease out the role of corticosteroids,
both in patients post transplant and pre ERF patients with glomerulonephritis.
Further studies using specific data collections from a Registry
cohort would be valuable in this regard.
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References
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- Vimalachandra D, Hodson EM, Willis NS, Craig JC, Cowell C, Knight JF. Growth hormone for children with chronic kidney disease. Cochrane Database Syst Rev (2006) 3:CD003264.[Medline]
- Mahan JD, Warady BA. Assessment and treatment of short stature in pediatric patients with chronic kidney disease; a consensus statement. Pediatr Nephrol (2006) 21:917–930.[CrossRef][Web of Science][Medline]
- Tyden G, Wernersson A, Sandberg J, Berg U. Development of renal cell carcinoma in living donor kidney grafts. Transplantation (2000) 70:1650–1656.[CrossRef][Web of Science][Medline]
- Mehls O, Wilton P, Berg U, et al. Does growth hormone treatment affect the risk of post-transplant renal cancer? Pediatr Nephrol (2002) 17:111–120.[CrossRef][Web of Science][Medline]
- Wuhl E, Haffner D, Offner G, Broyer M, van't Hoff W, Mehls O. Long-term treatment with growth hormone in short children with nephropathic cystinosis. J Pediatr (2001) 138:880–887.[CrossRef][Web of Science][Medline]
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Abstract
Introduction
