The Association Of Growth Retardation And Kidney Disease:
Chronic Kidney disease is often associated with extreme growth retardation, proving an association between the two. Even though this association may depend on many factors, but it is generally seen that those children who are diagnosed with a kidney disease early on stay well below the third percentile for height. The other factors that may interfere with growth include malnutrition, anemia, secondary hyperthyroidism due to deficiency of vitamin D, hyperphosphatemia, sex steroids, renal growth disturbances, and disorders of the HGH/IGF-1 system.
Growth Hormone For Kidney Function
Growth hormone is very important for the maintenance of Renal Plasma Flow and the Glomerular Filtration Rate, which are the two main processes assigned to the kidney to allow smooth functioning of the body. This effect of Growth Hormone on the kidney was further investigated in a study including healthy individuals who were given an intramuscular injection containing growth hormone. After getting the 0.15 mg/Kg HGH injection, these individuals were monitored for their serial PAH and insulin clearance rates for a total of 3 days. It was seen that the levels of Growth hormone in the plasma were at their greatest after 2.25 hours of being injected, and then started to decrease gradually. The next day, the plasma levels were only slightly elevated from their base reading, but by the third day, they had reached the baseline.
Since the function of HGH is closely related to plasma IGF-1, its levels were also recorded. While the levels of IGF-1 were not seen to increase on the first day of HGH injection, they started elevating by the second day and remained high throughout the third day.
The study concluded by proving:
Additional File : Figure S1
Side effects of growth hormone observed by the participating pediatric nephrologists within the last 5 years. Total number of participants n = 73. Figure S1 shows the number of reported side effects of recombinant human growth hormone therapy observed by the participating pediatric nephrologists within the past 5 years. The most commonly reported side effects were headache/benign intracranial hypertension and local reactions.
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Clinical Question: What Is The Significance Of Weight And Height Sd Scores When Assessing Growth
It is important to determine height, weight, and body mass index for age as percentiles or SD scores . A prime issue in assessing a child with CKD with poor growth is whether adequate nutrition is being achieved. Comparing height and weight SDS, and trends, can provide valuable insights. If the weight SDS is equal to or less than the height SDS, protein and calorie intake should be investigated. Similarly, if weight SDS decreases more rapidly than height SDS over time, or fails to improve as quickly as height SDS with interventions, this suggests insufficient nutrition.
Normalized protein catabolic rate is a measure of dietary protein intake and nutrition status in patients on maintenance hemodialysis, with goal 1.0. It is a better marker of protein intake than serum albumin, which can be affected by other factors, including acidosis, inflammation, infection, etc.
Gh And Igf Signaling In The Kidney
GH receptor
The GHR is expressed in most tissues, including the kidney. In 1989 GHR mRNA in the rat was already shown to be mainly expressed in the straight proximal tubules from embryonic day 20 onwards, increasing until postnatal day 40 and with constant levels thereafter . A much more widespread expression of GHR was revealed by immunostaining in human fetal kidneys, including all nephron segments. By contrast, only a very weak signal was detected in the glomeruli of fetal but not in adult kidneys . The latter suggests that GH may be involved in glomerular morphogenesis. Recent investigations in rodents and humans confirmed GHR expression in all tubular segments and this extended to the predominant glomerular cell types, i.e., mesangial cells and podocytes, when using quantitative real-time RT-PCR techniques . The concept of direct GH action on glomerular cells is supported by studies in transgenic mice overexpressing human or bovine GH showing progressive glomerulosclerosis, whereas IGF-1 overexpressing mice lack glomerular changes . Several studies confirmed the integrity of GH-signaling via GHR/JAK2/STAT5 pathway in the kidney by using renal cell lines .
Insulin-like growth factor-1 and 2
IGF-1 receptor
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Potential Effect Of Metabolic Acidosis
Metabolic acidosis is an early and frequent complication of pediatric CKD affecting approximately one-third of these children . It is a consequence of decreased ammonia excretion, which accompanies a decline in kidney function or impaired function of renal tubules commonly occurring in children with congenital anomalies of the kidney and urinary tract. There is a paucity of studies investigating the influence of metabolic acidosis on growth, even though nearly all children with renal tubular acidosis, the majority of whom have normal kidney function, exhibit growth restriction . However, from the few studies that do exist, perturbations in the GH/IGF axis as a result of metabolic acidosis appears to be one of the primary mechanisms. Using a nonuremic rat model, Challa et al. demonstrated that metabolic acidosis negatively alters GH secretory patterns. In follow-up studies, Challa and colleagues also posited that acidosis decreases both GHR mRNA and hepatic IGF-I mRNA . Brüngger examined the effects of metabolic acidosis further in 6 normal human participants and found reduced IGF-1 serum levels theorized to be related to dampened response to GH stimulation in states of acidemia . Given the prevalence of metabolic acidosis in pediatric CKD, especially as disease progresses, and widely available treatment for metabolic acidosis, more investigations of its potential adverse effects on growth are needed.
Clinical Question: How Should Children With Ckd Be Started And Subsequently Managed On Rhgh
The CKD GH resistance state can be overcome by achieving supraphysiologic GH levels through exogenous rhGH therapy . Modifiable factors should be successfully addressed for 34 months, and then, if minimal or no improvement in growth velocity or height SDS, rhGH should be started . Thyroid studies, hip and knee radiographs, bone age, and fundoscopic examination should be performed before rhGH initiation .
rhGH starting dose is 0.05 mg/kg per day by subcutaneous injection. For patients on dialysis, injections should be timed to minimize clearance: given 34 hours after hemodialysis completion, or during longest dwell for peritoneal dialysis patients .
Growth should be reassessed every 34 months . For children with CKD stages 24, the goal is for growth of 720 cm per year a lesser response is expected for children on dialysis. If the child grows < 2 cm more than the previous year then re-evaluation for other potential modifiable risk factors is important . Dose adjustment for weight gain is also necessary . Monitoring for potential rhGH side effects, including mild hyperglycemia, intracranial hypertension, and slipped capital femoral epiphysis, is important .
Good growth is the best outcome for the child with CKD, and must be the primary goal for the family and the health care team.
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Identification And Management Of Non
An adequate growth response can be assumed if height velocity during the first year of GH treatment is greater than 2cm per year over baseline. Such an increase would be approximately half of that reported in RCTs . For patients who do not adequately respond to GH therapy, we recommend assessment of patient adherence to GH therapy, including measurement of serum IGF1 levels, weight-adjusted GH dosage and assessment of nutritional and metabolic factors, as recommended before initiation of GH therapy. As outlined above, higher GH doses are not more efficient than lower doses therefore, higher GH doses cannot be recommended in non-responders.
How Do Health Care Professionals Diagnose Growth Failure In Children With Ckd
Health care professionals use growth charts to monitor how well children with CKD grow and to look for signs of growth failure. Your childs health care professional will regularly measure your childs heightor length, for children ages 2 years or youngerand will use the chart to track your childs growth over time.
Growth charts use percentiles, which appear as curved lines on the chart, to show how a childs height compares with other children who are the same age and sex. For example, if a childs height is on the 10th percentile curve, that means the child is taller than 10% of children the same age and sex and shorter than 90% of children the same age and sex.
Your childs health care professional will select and use the growth chart most appropriate for your child.
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How Do I Decide If A Clinical Trial Is Right For My Child
We understand you have many questions, want to weigh the pros and cons, and need to learn as much as possible. Deciding to enroll in a study can be life-changing for you and for your child. Depending on the outcome of the study, your child may find relief from their condition, see no benefit, or help to improve the health of future generations.
Talk with your child and consider what would be expected. What could be the potential benefit or harm? Would you need to travel? Is my child well enough to participate? While parents or guardians must give their permission, or consent, for their children to join a study, the children must also agree to participate, if they are capable . In the end, no choice is right or wrong. Your decision is about what is best for your child.
The National Institutes of Health is committed to ensuring you get all the information you need to feel comfortable and make informed decisions. The safety of children remains the utmost priority for all NIH research studies. For more resources to help decide if clinical trials are right for your child, visit Clinical Trials and You: For Parents and Children.
How Can Growth Failure In Children With Ckd Be Prevented
Growth failure in children with CKD often cannot be prevented. However, growth failure may be lessened by preventing or correcting the factors that contribute to growth failure. Starting treatment earlysoon after your child is diagnosed with kidney diseasemay give your child the best chance of growing at a normal rate.
If your child develops kidney failure, a kidney transplant offers your child the best chance of achieving a normal growth rate. Your childs health care team may adjust your childs immunosuppressive medicine to minimize its impact on your childs growth after the transplant.
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Availability Of Resources To Support Rhgh Treatment Program
Resources available for the support of rhGH treatment program were significantly different between small and large centers . Thus, while the majority of large centers had a renal dietitian , only half of small centers had a renal dietitian . Furthermore, in a third of small centers nutritional needs of children with growth failure and CKD were addressed solely by pediatric nephrologists. Conversely, 43.6% of small centers utilized endocrinology for most aspects of rhGH therapy, compared to 6.3% in large centers . Prior authorization for rhGH therapy was addressed primarily by the nurses , with slightly more availability of nursing support for prior authorization in large centers vs. small centers .
Table 2 Resources available to support growth hormone treatment program by the size of participating centers
Assessment Of Bone Changes In Ckd
1.3.1 In patients with CKD G2-5D, osteometabolic changes may be assessed by bone radiography .
1.3.2 In patients with CKD G2-5D, it is recommended to consider bone biopsy if clinical and biochemical findings are in disagreement with each other and/or in the presence of bone deformity or pain, fragility fracture, hypercalcemia and persistent hypophosphatemia .
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Limitations Of The Guideline Process
Most RCTs of GH use in children with CKD were performed in the 1990s when the conduct of trials was not as robust as that of current trials. For example, many of these RCTs did not include all enrolled participants in their analyses. In addition, the size of many RCTs was small owing to the low incidence of childhood CKD thus, the strength of most recommendations is weak to moderate. Owing to the limited budget of this ESPN initiative, the core group did not include physicians outside Europe or patient representatives. The lack of patient representatives in the core group was partly mitigated by including patient representatives from Germany, Italy, Belgium and the UK as external experts.
Which Children With Ckd Are More Likely To Experience Growth Failure
Many children with CKD are at risk for developing growth failure.
Children who are diagnosed with CKD at a younger age, particularly those 2 years old or younger, are more likely to develop growth failure. These children are also more likely to have growth failure that is more severe compared with children diagnosed with CKD later in childhood.1
Risk for poor growth in children with CKD increases when the loss of kidney function is more severe.1
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How Common Is Growth Failure In Children With Ckd
Growth failure in children with CKD is common. About one-third of all children with moderate to severe CKD have a height below the third percentile, which means they will be shorter than 97% of children the same age and sex.1
Among children with end-stage kidney diseasekidney failure that is treated with kidney transplant or dialysisup to 40% will have a final height below the third percentile.2
Assessment And Treatment Of Bone Disease In Kidney Transplantation
2.4.1 Monitoring of Ca, P, AP, PTH and 25vitamin D after KTx
2.4.1.1 In the early period :
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Assess serum Ca and P weekly until stabilization .
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Assess PTH and AP at the time of KTx .
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Assess vitamin D .
2.4.1.2 In the 3-12 month period, the frequency of assessment will depend on the magnitude of biochemical changes and the established therapeutics:
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Assess Ca and P monthly .
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Assess PTH and AP in the 6th and 12th month .
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Assess vitamin D every 6 months, or every 3 months in case of supplementation .
2.1.1.3 In the late period , the frequency of assessment will depend on the renal graft function and on the stabilization of previously detected biochemical changes .
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The same recommendations for CKD patients under conservative treatment should be followed in case of progressive loss of graft function .
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CKD 1-3T: Ca, P, AP and PTH annually.
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CKD 4T: Ca, P, AP, PTH .
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CKD 5T: Ca, P, AP and PTH every 3 months.
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Monitor vitamin D every 6 months, or every 3 months in case of supplementation .
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For patients with vascular and/or valve calcification, it is recommended undergoing annual echocardiograms .
2.4.2 Treatment of CKD-MBD
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Human Growth Hormone Guidelines In Ckd
Preamble
Growth retardation is a significant major concern in children with CKD. The etiology of growth retardation in children with CKD is likely multifactorial and factors such as acidosis, malnutrition, renal osteodystrophy and end organ resistance to rhGH despite normal or high levels are thought to play a major role. Growth hormone has been shown in multiple randomized clinical trials to not only improve growth in children with CKD but also ultimately to improve final height. The aim of these guidelines, based on the available literature and expert opinion, is to assist physicians caring for children with CKD when prescribing rhGH. The guidelines should not be seen as rigid and exclude the use of rhGH in certain specific patients e.g. it is inappropriate to exclude transplant patients with CKD from treatment.
Criteria for Eligibility
- CKD stages 2 to 5
- Bone age: epiphyses not fused
- Height and height velocity:
Height > 2 SD below the midparental height.
- Age 2 years Q 3 months or Q monthly when CKD Stage 4 or 5 and throughout period of therapy
- Age > 2 years Q 6 months or Q 3 months when CKD Stage 4 or 5 and throughout period of therapy.
- More frequent assessment should be done if there is evidence of malnutrition .
Nutrition: The dietary intake for children with Stage 2 to 5 CKD should be based on the Dietary Reference Intake and the Estimated Energy Requirement for chronological age.
Acidosis: Maintenance of bicarbonate 22 mmol/L
Exclusion criteria:Examination:GFR:
Treatment With Growth Hormone
2.3.1 For infants with CKD G2-5D, it is recommended performing a linear growth assessment every 3 months .
2.3.2 For children and adolescents with CKD G2-5D, it is recommended performing a linear growth assessment at least annually .
2.3.3 For children and adolescents with CKD G2-5D, who progress with height deficits, treatment with human growth hormone is recommended, after nutritional assessment and correction of acidosis and CKD-MBD biochemical abnormalities .
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How Do Health Care Professionals Treat Growth Failure In Children With Ckd
Health care professionals treat growth failure in children with CKD with
- adding calcium and vitamin D
Most children with CKD do not require all these dietary changes. Dont change your childs diet unless your childs health care professional recommends changes. Always talk with your childs health care professional before giving your child any dietary supplementssuch as vitamins and minerals, probiotics, complementary or alternative medicines, or any medicines that havent been prescribed for your child.
If your child isnt getting enough nutrients and calories from food and supplements taken by mouth, your childs health care professional may recommend using a feeding tubea thin, flexible tube that carries liquid food into the stomach. Feeding tubes are most often used for infants however, older children may benefit from them as well.
Encouraging children with CKD to develop healthy eating habits that help them grow properly and stay healthy is important. Your childs health care team will work with you and your child to create an eating plan with the right foods and nutrients in the right amounts for your child.
Encourage your child to develop healthy eating habits to help prevent poor nutrition and promote healthy growth.