J. Paediafr. Child Health (1992)28, 275-277
Annotation Recent advances in the management of chronic renal failure in childhood C.JONES, R. WALKER and H. POWELL Victorian Paediatric Renal Service, Royal Children’s Hospital and Royal Melbourne Hospital, Parkville, Victoria. Australia
The management of chronic renal failure has been revolutionized during the past few years by the introduction of potent medications stemming from developments in immunology and molecular biology. This paper will focus on two of these developments, recombinant human growth hormone (rHGH) and recombinant human erythropoeitin (rHuEPO), as they have a particular relevance to children with renal failure. The use of these agents has allowed the three major symptom complexes of chronic renal failure in childhood, renal osteodystrophy, growth failure and anaemia, to be treated effectively with replacement or supplementation of deficient hormones.
GROWTH AND RECOMBINANT HUMAN GROWTH HORMONE The onset and nature of growth failure in chronic renal failure follows a similar pattern.’ Growth failure usually occurs when the glomerular flitration rate is reduced to less than 25 mL/min per 1.73m2. However the presence of treatable factors such as chronic systemic acidosis, a caloric intake less than 85% of the patient‘s recommended dietary intake corrected for height age, salt losing nephropathies, uncontrolled hypertension or severe renal osteodystrophy also contribute to growth failure.’ Children who have renal failure from early infancy rapidly fall away from normal percentile values recorded at birth. At the end of infancy growth resumes below, but parallel to, the 3rd percentile. In general, ‘catch-up’ growth to recover these lost percentiles has not occurred using managements that have not included rHGH. The loss of height percentiles is directly correlated to the duration of chronic renal f a i l ~ r e . ~ T hother e period during which children with renal failure lose height percentiles is at puberty. Although puberty is delayed and often more prolonged than normal, the total growth achieved is less than normal. The physiological basis of the poor growth velocity is not clear. Children with chronic renal failure have high levels of growth hormone and adolescents have pulsatile hypersecretion of growth hormone. However serum concentrations of insulin like growth factors (IGF) I and I1 are not abnormal in uraemia. Correspondence: Dr C. L. Jones, Department of Nephrology, Royal Children’s Hospital, Parkville, Vic. 3052. Australia. C. Jones, MB, BS, FRACP, PhD, Nephrologist. R. Walker, MD, FRACP, Nephrologist. H. Powell. MB, BS, FRACP, Director. Accepted for publication 28 October 1991.
although serum IGF binding protein concentrations are increa~ed.~ Renal replacement does not improve the growth of children with renal failure. Haemodialysis allows approximately onethird of children to grow along a constant height percentile, while another third falls mildly behind, and the remaining third has severe growth failure. A mean annual height loss of 0.4 standard deviation (s.d.) units per year has been reported2 Growth in children treated with continuous ambulatory peritoneal dialysis is generally better than that on h a e m o d i a l y ~ i s but ,~~~ catch-up growth is rare. Growth following renal transplantation can be normal but, again, few patients show evidence of catch-up growth.3~~ Steroid dosages above 4-6 mg/m2 per 24 h,3*8poor graft f u n c t i ~ n , ~ , ~ age above 7 years7,’ or particularly bone age above 12 years,I0 and female sex3,9are associated with loss of height percentiles following transplantation. The use of cyclosporine A combined with low dose prednisolone immunosuppressive therapy has improved the growth of patients in our institution following transplantation over the last 5 years,” but few patients reach their target heights (as calculated from parental height^).^ Prednisolone, even in alternate day dosing, has been shown to reduce mean basal and stimulated growth hormone concentrations in prepubertal children with allografts, and to reduce overnight peak pulsatile concentrations of growth hormone in adolescents with allografts in a dose-dependent manner.4 The relationship between growth hormone concentrations and growth velocity in these patients is not clear. In addition to growth hormone hyposecretion these patients also have reduced somatomedin activity, and the reduced somatomedin activity has been significantly correlated to poor graft function and higher prednisolone dosage4 Thus the problem of growth in renal failure in childhood is a combination of loss of early infantile growth percentiles, failure during the mid-childhood growth period to ’catch-up’ and loss of pubertal growth. Renal replacement therapies have not made a significant difference, except in successful grafts performed at young ages. The initial trials using rHGH have demonstrated that acceleration of growth in mid-childhood and at puberty is possible in children with chronic renal failure. including those treated with peritoneal dialysis4 Acceleration in growth velocity has been reported for three consecutive years in nine patients with improvement in the mean s.d. scores from -3.19f1.2 at the initiation of treatment to - 1.29k1.3after 36 months of treatmentI2
C. Jones ef a/.
The patients had an increase in weight and mid-arm circumference indicating that an anabolic effect was achieved.* Numerous similar small studies, including a 1 year study of 12 children at our institution, have revealed similar results. Importantly, theoretical predictions of adverse effects on renal function and glucose tolerance have not been substantiated. Bone age has not been accelerated, so that the growth potential of these children has been preserved. Early data indicate that patients on peritoneal dialysis respond to rHGH in a similar manner to those not on dialysis.’’ Relatively few patients with renal allografts have been treated with rHGH. The magnitude of increased growth on rHGH was not found to be as great as that in patients with chronic renal failure! possibly because of the effects of prednisolone. In Australia, rHGH is available as a restricted pharmaceutical benefit on an individual patient basis for children with chronic renal insufficiency whose height is on or less than the 25th centile for bone age and whose growth velocity is on or less than the 25th centile for bone age. Twelve months of height readings prior to prescription are required and the glomerular filtration rate must be less than 30 mL/min per 1.73 m2. The medication is given by daily subcutaneous injection at a starting dose of 14 iu/m2 per week. The ultimate height outcome of patients treated with rHGH will not be known for some time. Importantly, under the guidelines governing the availability 01 rHGH for patient treatment, the infant with chronic renal insufficiency is excluded. There is some evidence that growth in this period is less growth hormone dependent than later, and fortunately catch-up growth in midchildhood occurs with rHGH. However aggressive management of other factors related to poor height and weight in infants with chronic renal failure is mandatory.
ANAEMIA AND RECOMBINANT HUMAN ERYTHROPOIETIN The anaemia of chronic renal failure is due to a combination of erythropoietin deficiency, shortened red cell survival, uraemic inhibition of erythropoiesis, hyperparathyroidism. aluminium excess and, in the dialysis patient, folate and iron deficiency and blood Of these, erythropoietin deficiency is the most important factor. The traditional management of the anaemia of chronic renal failure has been blood transfusion, usually when the haemoglobin concentration is less than 60 g/L. with haematinic supplements having had a minor role. Consequently most children with renal failure had chronic symptoms of anaemia including exertional intolerance, pallor, and a hyperdynamic circulation with flow murmurs. The long-term cardiovascular complications of cardiac failure and poor cardiac function that are frequently found in these patients were caused to a larger extent by chronic anaemia. In addition, these children faced the risks of multiple blood transfusions including fluid overload during the transfusion, viral infection transmitted with the blood, the development of anti-human leucocyte antigen (HLA) antibodies to white cells causing difficulty in cross-matching the child with potential renal donors, and iron overload. Erythropoietin is produced mainly by some outer medullary and cortical interstitial or peritubular capillary cells in the kidney and only 10% is produced outside the kidney.14 It is produced in response to hypoxia and major receptors are found on marrow erythroid progenitors. It has a serum half-life of 6-9 h. Recom-
binant human erythropoietin is immunologically and biologically identical to the native p r ~ t e i n . ’The ~ gene was found in 1983 and the glycoprotein was tested in animals in 1984, and then in humans in 1985.13The first step in its isolation and production was to sequence purified native human erythropoietin which was obtained from urine. Oligonucleotide probes were then constructed from the amino acid sequence and the gene was detected in a human foetal liver genomic library. The gene was spliced into a plasmid expression vector and this plasmid was used to transfect the nuclei of Chinese hamster ovary cells, so that the important post-translational protein glycosylation was performed in a mammalian cell. The rHuEPO is obtained from the supernatant of these cell culture^.'^ The introduction of rHuEPO has clearly improved the quality of life of children with chronic renal failure.16 and children treated with peritoneal” or haemodialysis.’e Haemoglobin concentrations can be kept in the range of 100-120 g / L with improved exercise tolerance, behaviour. attention span and school performance. The need for transfusions is eliminated except for situations of additional stress on the bone marrow such as infection or surgical blood loss. Iron store and anti-HLA antibody titres are decreased. Few serious complications of rHuEPO have been reported. A number of patients have developed hypertension due to increased red cell volume, and the introduction of anti-hypertensive agents or an increase in these medications has occasionally been required. Iron deficiency has been relatively common, and additional iron may be required and may need to be given parenterally in some cases. In patients treated with haemodialysis the number of arterio-venous fistula thromboses were increased and the heparin requirement for haemodialysis was increased. The medication may be given by subcutaneous injection and it is mildly painful, in contrast to the painless rHGH injections. The use of rHuEPO in our unit follows the guidelines for the Australasian Paediatric Nephrology Association multicentre open trial of rHuEPO, through which the initial supplies of rHuEPO (Epprex. Jansen Cilag, Australia) have been available in Australia. Initially 50 U/kg subcutaneously is given every 3-4 days until a target haemoglobin of 90-110 g / L is reached. The frequency of dosing is reduced to once a week as soon as this haemoglobin concentration is reached. The medication can be given intravenously or intramuscularly but cost-effectiveness is probably greatest using the subcutaneous route. The drug is supplied as 2000 U/mL in 1 mL ampoules and each costs approximately $40. Thus, 50 U/kg twice per week costs $104/kg per year. Future supply is expected to be funded initially by hospitals for 3 months and then by the Commonwealth Government.
REFERENCES 1 Betts P. R.. Magrath G. Growth pattern and dietary intake of children with chronic renal insufficiency. Br. Med. J. 1974; 2: 189-93. 2 Broyer M. Growth in children with renal insufficiency. Pediafr. Clin. North Am. 1982; 29: 991-1003. 3 Offner G.. AschendorH C.. Brodehl J. Growth after renal transplantation: An update. Pediatr. Nephrol. 1991; 5: 472-6. 4 Fine R. N. Growth hormone and the kidney: The use of recombinant human growth hormone (rHGH) in growth retarded children with chronic renal insufficiency.J. Am. SOC.Nephrol. 1991; 1: 1136-45.
Management of chronic renal failure
5 Stefandis C. J.. Hewitt I. K.. Balfe J. W. Growth in children receiving continuous ambulatory peritoneal dialysis. J. Pediatr. 1983; 102: 681-5. 6 Kohaut E. C. Growth in children treated with continuous ambulatory peritoneal dialysis. fnt. J. Pediatr. Nephrol. 1983; 4: 93-8. 7 lngelfinger J. R., Grupe W. E.. Harmon W. E.. Fernbach S. K.. Levey R. H. Growth acceleration following renal transplantation in children less than 7 years of age. Pediatrics1981; 66: 255-9. 8 Loeb J. N. Corticosteroids and growth. N. Engl. J. Med. 1976; 295: 547-52. 9 Fennel1 R. S., Moles M., lravani A. et a/. Growth in children following renal transplantation. Pediatr. Nephrol. 1990; 4: 335-9. 10 Fine R. N., Malekzadeh M. H., Pennisi A. J.. Ettinger R. B.,Vittenbogaart C. H., Negrete V. F., Korsch B. M. Long term results of renal transplantation in children. Pediatrics 1978; 61: 641 -50. 11 Walker R. G.. d’Apice A. J. F., Powell H. R.. Francis D. M. A,, McCredie D. A,. Kincaid-Smith P. Paediatric cadaveric renal transplantation -initial experience with a triple therapy immunosuppressiveregimen. Pediatr. Nephrol. 1987; 1: 61 1-14, 12 Tonshoff B., Mehls 0.. Heinrich U., Blum W., Ranke M. B., Schauer A. Growth-stimulating effects of recombinant human growth hormone in children with end-stage renal disease. J. Pediatr. 1990; 116: 561-6.
13 Eschbach J. W. The anaemia of chronic renal failure: Pathophysiology and the effects of recombinant erythropoietin. Kidney lnt. 1990; 35: 134-48. 14 Koury S.F.. Bondurant M. C.. Koury M. J. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood 1980; 71: 524-7. 15 Egrie J. C.. Strickland T. N.. Lane J. et a/. Characterization and biological effects of recombinant human erythropoietin. lmmunobiology 1986; 172: 213-24. 16 Baraldi E., Montini G., Zanconato S..Zachello G., Zachello F. Exercise tolerance after anaemia correction with recombinant human erythropoietin in end-stage renal disease. Pediatr. Nephrol. 1990; 4: 623-6. 17 Offner G.. Hoyer P. F., Latta K., Winkler L.. Brodehl J.. Scigalla P. One year’s experience with recombinant erythropoietinin children undergoing continuous ambulatory or cycling peritoneal dialysis. Pediatr. Nephrol. 1990; 4: 498-500. 18 Rigden S., Montini G., Morris M., Clark K. G. A,, Haycock G. 8. Chantler C., Hill R. C. Recombinant human erythropoietintherapy in children maintained by haemodialysis. Pediatr. Nephrol. 1990; 4: 618-22.