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Body growth, upper arm fat area and clinical parameters in children with nephropathic cystinosis compared with other pediatric CKD entities
Abstract
Children with infantile nephropathic cystinosis (INC), an inherited lysosomal storage disease resulting in cystine accumulation in all body cells, are prone to progressive chronic kidney disease (CKD), impaired growth and reduced weight gain; however, systematic anthropometric analyses are lacking. In this prospective multicenter study we investigated linear growth, body proportion, body mass index (BMI), upper arm fat area (UFA) and biochemical parameters in 43 pediatric INC patients with CKD stages 1-5 and 49 age-matched CKD controls, with 193 annual measurements. INC patients showed more impaired height than CKD controls (-1.8 versus -0.7 z-score; p<0.001), despite adequate cysteamine therapy, treatment for Fanconi syndrome and more frequent use of growth hormone. Only the youngest INC patients shared the same body pattern with CKD controls characterized by preferential impairment of leg length and rather preserved trunk length. In late-prepuberty, body pattern changed only in INC patients due to improved leg growth and more impaired trunk length. Mean UFA z-score in INC patients was slightly reduced in early childhood and progressively decreased thereafter reaching -0.8 z-score in adolescence, while CKD controls showed a steady increase in standardized BMI and UFA especially during adolescent age. Menarche in female INC patients was significantly delayed compared to CKD controls.
Our data indicate that with age and progression of disease, pediatric INC patients undergo unique changes of body growth and fat stores that are distinct from those with CKD stemming from other causes, suggesting other factors apart from CKD to contribute to this development.
This article is protected by copyright. All rights reserved.
... This was further enhanced in 1997 with the introduction of cystine-depleting therapy in Europe which prolonged the pre-terminal period, delayed the onset of complications, and increased life expectancy [13,14]. To date, INC patients present with characteristic impairments in body growth and composition, i.e., disproportionate short stature with short legs and increased chest depth and reduced body fat [15,16]. However, the dynamic changes in body morphology of INC children over the past decades remain largely unknown. ...
... Analysis of leukocyte cystine content levels was not feasible due to a lack of data from earlier time points. Annual anthropometric measurements included linear (height, sitting height, leg length) and transversal (chest depth and width) body dimensions and upper arm skin folds, while body mass index (BMI), sitting height index (ratio of sitting to total body height), upper arm fat area (UFA), and thoracic indices (chest depth to height ratio and chest depth to chest width ratio) were calculated as described in previous works [15,16]. UFA and BMI were used as indirect markers of body composition. ...
... This study expands upon a previously published study within this project which was initiated in 2016 [15,16]. Descriptive statistics are given in terms of mean and standard deviation or estimated marginal mean (Est. ...
Background
Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with no need for kidney replacement therapy. Still, detailed changes in INC patients’ clinical and morphological presentation over the past decades have not yet been thoroughly investigated.
Methods
Two groups with a respective total of 64 children with INC and 302 children with CKD, both treated conservatively and aged 2 to 18 years, were prospectively observed in the time span from 1998 to 2022 with 1186 combined annual clinical and morphological examinations clustered into two measurement periods (1998 to 2015 and ≥ 2016).
Results
In INC patients, thoracic proportion indices remained markedly increased, whereas body fat stores remained decreased over the past 25 years (+ 1 vs. below ± 0 z -score, respectively). Their CKD peers presented with overall improved growth, general harmonization of body proportions, and improved body fat stores, while INC patients only presented with an isolated significant increase in leg length over time (∆0.36 z -score). eGFR adjusted for age did not significantly change over the past 25 years in both groups. Alkaline phosphatase (ALP) showed a significant decrease in CKD patients over time, while remaining above normal levels in INC patients.
Conclusions
Disproportionate thoracic shape and impaired body fat stores remain the most characteristic morphological traits in INC patients over the past 25 years, while causal mechanisms remain unclear.
Graphical Abstract
... Extended author information available on the last page of the article are prone to progressive disproportionate short stature [10,11]. This is characterized by a shift from a trunk length preserving pattern shared with children with CKD of other causes to an INC-specific leg-focused growth pattern [10], prompting further examination of the morphology of the trunk of INC patients. ...
... Extended author information available on the last page of the article are prone to progressive disproportionate short stature [10,11]. This is characterized by a shift from a trunk length preserving pattern shared with children with CKD of other causes to an INC-specific leg-focused growth pattern [10], prompting further examination of the morphology of the trunk of INC patients. ...
... This analysis includes children with INC and hereditary or congenital CKD aged 2 to 17 years with CKD stages 1-5 only prior to kidney replacement therapy who are enrolled in the prospective multicenter observational cohort study "Growth and cognitive-motor abilities in children with nephropathic cystinosis and chronic kidney disease" [10,15]. Patients with complex or syndromic diseases were excluded. ...
Background:
Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk.
Methods:
Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1-5 and 97 age-matched patients with CKD of other etiology between the ages of 2-17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models.
Results:
Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2-6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2-6, 7-12, and 13-17 years).
Conclusion:
Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.
... These findings are consistent with previous results from the same center. However, these results are inconsistent with Kluck and his colleagues [13], who demonstrated the mean SD for height _1.80 (_2.05 to _1.55) and the mean SD for body mass index _0.28 (_0.55 to _0.02). ...
Background Nephropathic Cystinosis is a rare autosomal recessive lysosomal storage disorder. In addition to kidney
dysfunction, this disorder can also affect other organs, such as the eyes, thyroid, muscles, and central nervous system.
Methods The current cross-sectional study included 56 patients with nephropathic cystinosis to evaluate the clinical
outcome in nephropathic cystinosis patients cohort with regarding kidney function and the need for kidney replace-
ment therapy. Clinical and laboratory data were collected.
Results Among the 56 patients in our study, 32 (57.1%) were male. Furthermore, 52 (92%) of these patients were
offspring of consanguineous marriage. Patients’ mean age was 116.96 ± 54.1 months, and the mean onset of nephro-
pathic cystinosis suggestive symptoms was 7.63 ± 3.2 months. In addition, the mean age of confirmed diagnosis
was 45.38 ± 35.3 months, and the mean age of end-stage kidney disease (ESKD) was 104 ± 25.7 months. Eighteen
patients (32.1%)underwent hemodialysis, whereas 12 patients (21.4%) underwent kidney transplantation. When com-
paring siblings within the same family, we observed a significant difference in the age at diagnosis. The median age
for the first sibling was 60 months, while it was 24 months for the second sibling (p-value
=
0.031). Additionally, there
were significant differences in weight, chronic kidney disease (CKD) stage, and outcome.
Conclusion Improvement in the awareness and the accessibility to diagnosis over years, early sibling screen-
ing, and kidney transplantation have a significant impact on the survival of both patients and kidney in children
with nephropathic cystinosis.
Keywords Cystinosis, Children, Outcome, CKD, Kidney transplantation
... The transformations described above contribute to serious complications in children with CKD such as delayed growth and maturation [12], [13], metabolic acidosis [14], renal osteodystrophy [15], cardiovascular disease [16], [17] anemia [18], and depressive disorders [19]. To avoid these complications and slow the course of the disease, it is extremely important to diagnose and treat CKD, as well as to introduce a balanced diet containing age-appropriate amounts of macronutrients and micronutrients. ...
Introduction: Children with chronic kidney disease (CKD) require a specialized diet to manage their condition and support healthy growth and development. A proper diet for children with CKD aims to control the intake of certain nutrients, such as protein, lipid, calcium, phosphorus, potassium, sodium, and vitamin D, while ensuring they receive adequate nutrition for growth and development. Aim of the study: This article discusses the epidemiology, causes and pathomechanism of CKD in children. It also presents existing clinical trials and dietary recommendations from societies such as Kidney Disease: Improving Global Outcomes (KDIGO) 2024, Kidney Disease Outcomes Quality Initiative (KDOQI) and Pediatric Renal Nutrition Taskforce (PRNT) and identifies potential sources of selected macronutrients and micronutrients in children's diets. Materials and methods: Comprehensive literature searches were performed across the main electronic databases of PubMed, Google Scholar, KDIGO2024, KDQQI and PRNT recommendations for studies published in the English language about dietary recommendations for children with CKD. Results: The approach to nutrition for children with CKD is still evolving, and specific macronutrient and micronutrient ratios should be established based on the clinical condition, the child's age, and body weight. Care should be taken to ensure that the child's diet is varied, and a healthy eating style should be promoted.
Nephropathic cystinosis is a lysosomal storage disease due to biallelic pathogenic variants in the CTNS gene encoding the cystine transport protein cystinosin. Dysfunction of cystinosin results in the intralysosomal accumulation of the disulfide cystine, which crystallizes in some tissues and damages many parenchymal organs. Fanconi syndrome is the first presenting sign with all the features of generalized proximal tubular dysfunction. The natural history of cystinosis includes multisystem complications, the most prominent being glomerular failure at 9–10 years. If a kidney transplant prolongs life, other complications occur, with variable frequencies. Some of the most common are hypothyroidism, a distal vacuolar myopathy, pancreatic exocrine and endocrine insufficiency, male hypogonadism, and idiopathic intracranial hypertension. Cystinosis is diagnosed biochemically by measuring the cystine content of leucocyte and molecularly by identifying pathogenic variants in CTNS . Prenatal diagnosis is available. Treatment consists of replacement of kidney tubular losses, symptomatic management of systemic complications, and specific therapy directed at the basic defect, i.e., lysosomal cystine accumulation. This involves the free thiol cysteamine, which can deplete approximately 95% of the lysosomal cystine content. Oral cysteamine therapy has extended the time to kidney failure by approximately 7 years (to a mean of 16 years) and mitigates or prevents late complications of the disease. In addition, cysteamine eyedrops can dissolve corneal cystine crystals within months. Nevertheless, the mean age at death for individuals born between 1985 and 1999 has been 29 years, and earlier diagnosis by newborn screening, treatment with more palatable cystine-depleting agents, and trials with gene therapy are critical current pursuits.
Graphical abstract
Nephropathic cystinosis is an orphan autosomal recessive lysosomal storage disease characterized by a deficiency of cystinosin, a cystine transporter protein, leading to tissue damage, primarily in the kidney and cornea. With the introduction of cystine-depleting therapy with cysteamine and the possibility to survive to adulthood, new challenges of skeletal complications are a concern, with sparse data available regarding bone development. The aim of the current study was to gain more information on bone density and geometry in these patients. Fifty-one patients (29 males, 22 females) with genetically-proven nephropathic cystinosis were clinically evaluated with a medical history, physical examination, grip strength measurements, biochemical and imaging studies. Bone mineral density, bone geometry and muscle cross sectional area were measured, and muscle was evaluated. Results were compared with age- and gender-specific reference data. Z-scores for height (mean [M] = -1.75, standard deviation [SD] = 1.43), weight (M = -1.67, SD = 1.29), and BMI (M = -0.98, SD = 1.29) were lower than reference data. Medullary cross-sectional area (CSA) and cortical density z-scores were not compromised (M = 0.12, SD = 1.56 and M = -0.25, SD = 1.63, respectively), but cortical CSA z-scores and Strength-Strain Index (SSI) were reduced (M = -2.16, SD = 1.08, M = -2.07, SD = 1.08). Muscular deficits were reflected by reduced z-scores for muscle CSA (M = -2.43, SD = 1.27) and grip strength (M = -3.01, SD = 1.10), along with jump force (34% lower than reference value). Multiple regression analyses indicated an association of muscle mass with medullary CSA and SSI, but not with cortical CSA. While bone density parameters were normal, bone geometry was altered, resulting in a thinner cortex with possible impact on bone strength. Muscle weakness be partially responsible for altered bone geometry and could provide a potential treatment target.
The nutritional status and management of children with CKD are complex and require a combined pediatric nephrology team work approach with physicians, nutritionists, nurses, and physical/occupational therapists. Prospective observational studies such as Children with CKD (CKiD) in the US, the 4C study in Europe and the International Pediatric Peritoneal Dialysis Network (IPPN) have advanced the field. However, most recommendations and guidelines from international task forces such as Kidney Diseases Improving Global Outcomes (KDIGO) and Pediatric Renal Nutrition Taskforce (PRNT) are opinion- rather than evidence-based. There is exciting ongoing research to improve nutrition in children with CKD to help them thrive.
Background
Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder resulting in progressive chronic kidney disease (CKD) and a variety of extrarenal manifestations. This orphan disease remains a challenge for patients, their families and health care providers. There is currently no comprehensive study on patients' clinical course in Germany and Austria.
Methods
A retrospective cohort study including 74 patients at eleven centers of care was conducted. Data on time of diagnosis, CKD stage, leukocyte cystine levels (LCL), extrarenal manifestations, and treatment was collected from medical charts and subsequently analyzed using explorative statistics. Age at initiation of kidney replacement therapy (KRT) was evaluated by Kaplan–Meier analyses for different groups of patients.
Results
Patients were diagnosed at a median age of 15 months (IQR: 10–29, range: 0–110), more recent year of birth was not associated with earlier diagnosis. Oral cystine-depleting therapy (i.e., cysteamine) was prescribed at a median dose of 1.26 g/m ² per day (IQR: 1.03–1.48, range: 0.22–1.99). 69.2% of all 198 LCL measurements of 67 patients were within the desired target range (≤ 1 nmol cystine/mg protein). Median time-averaged LCLs per patient ( n = 65) amounted to 0.57 nmol cystine/mg protein (IQR: 0.33–0.98, range: 0.07–3.13) when considering only values at least 1 year after initiation of therapy. The overall median height of 242 measurements of 68 patients was at the 7 th percentile (IQR: 1–25, range: 1–99). 40.5% of the values were ≤ the 3 rd percentile. Patient sex and year of birth were not associated with age at initiation of KRT, but patients diagnosed before the age of 18 months required KRT significantly later than those patients diagnosed at the age of ≥ 18 months ( p = 0.033): median renal survival was 21 years (95% CI: 16, -) vs. 13 years (95% CI, 10, -), respectively.
Conclusion
Early diagnosis and initiation of cystine depleting therapy is important for renal survival in children with INC. Cysteamine doses and LCL showed that treatment in this cohort met international standards although there is great interindividual variety. Patient growth and other aspects of the disease should be managed more effectively in the future.
Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970’s to the 1990’s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.
Cystinosis is a rare lysosomal storage disorder caused by loss-of-function mutations of the CTNS gene, encoding cystinosin, a symporter that mediates cystine efflux from lysosomes. Approximately 95% of patients with cystinosis display renal Fanconi syndrome, short stature, osteopenia, and rickets. In this study, we investigated whether the absence of cystinosin primarily affects bone remodeling activity, apart from the influences of the Fanconi syndrome on bone mineral metabolism. Using microecomputed tomography and histomorphometric and bone serum biomarker analysis, we evaluated the bone phenotype of 1-montheold Ctns À/À knockout (KO) male mice without tubulopathy. An in vitro study was performed to characterize the effects of cystinosin deficiency on osteoblasts and osteoclasts. Microecomputed tomography analysis showed a reduction of trabecular bone volume, bone mineral density, and number and thickness in KO mice compared with wild-type animals; histomorphometric analysis revealed a reduction of osteoblast and oste-oclast parameters in tibiae of cystinotic mice. Decreased levels of serum procollagen type 1 amino-terminal propeptide and tartrate-resistant acid phosphatase in KO mice confirmed reduced bone remodeling activity. In vitro experiments showed an impairment of Ctns À/À osteoblasts and osteoclasts. In conclusion, cystinosin deficiency primarily affects bone cells, leading to a bone loss phenotype of KO mice, independent from renal failure. (Am J Pathol 2019, 189: 1053e1064; https://doi.
Dietary management in pediatric chronic kidney disease (CKD) is an area fraught with uncertainties and wide variations in practice. Even in tertiary pediatric nephrology centers, expert dietetic input is often lacking. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, was established to develop clinical practice recommendations (CPRs) to address these challenges and to serve as a resource for nutritional care. We present CPRs for energy and protein requirements for children with CKD stages 2–5 and those on dialysis (CKD2–5D). We address energy requirements in the context of poor growth, obesity, and different levels of physical activity, together with the additional protein needs to compensate for dialysate losses. We describe how to achieve the dietary prescription for energy and protein using breastmilk, formulas, food, and dietary supplements, which can be incorporated into everyday practice. Statements with a low grade of evidence, or based on opinion, must be considered and adapted for the individual patient by the treating physician and dietitian according to their clinical judgment. Research recommendations have been suggested. The CPRs will be regularly audited and updated by the PRNT.
Background:
In recent decades, the prevalence of obesity in children has increased dramatically. This worldwide epidemic has important consequences, including psychiatric, psychological and psychosocial disorders in childhood and increased risk of developing non-communicable diseases (NCDs) later in life. Treatment of obesity is difficult and children with excess weight are likely to become adults with obesity. These trends have led member states of the World Health Organization (WHO) to endorse a target of no increase in obesity in childhood by 2025.
Main body:
Estimates of overweight in children aged under 5 years are available jointly from the United Nations Children's Fund (UNICEF), WHO and the World Bank. The Institute for Health Metrics and Evaluation (IHME) has published country-level estimates of obesity in children aged 2-4 years. For children aged 5-19 years, obesity estimates are available from the NCD Risk Factor Collaboration. The global prevalence of overweight in children aged 5 years or under has increased modestly, but with heterogeneous trends in low and middle-income regions, while the prevalence of obesity in children aged 2-4 years has increased moderately. In 1975, obesity in children aged 5-19 years was relatively rare, but was much more common in 2016.
Conclusions:
It is recognised that the key drivers of this epidemic form an obesogenic environment, which includes changing food systems and reduced physical activity. Although cost-effective interventions such as WHO 'best buys' have been identified, political will and implementation have so far been limited. There is therefore a need to implement effective programmes and policies in multiple sectors to address overnutrition, undernutrition, mobility and physical activity. To be successful, the obesity epidemic must be a political priority, with these issues addressed both locally and globally. Work by governments, civil society, private corporations and other key stakeholders must be coordinated.
Failure of statural growth is one of the major long-term sequelae of chronic kidney disease (CKD) in children. In recent years effective therapeutic strategies have become available that lead to evidence based practice recommendations. To assess the current growth performance of European children and adolescents with CKD, we analyzed a cohort of 594 patients from 12 European countries who were followed prospectively for up to 6 years in the 4C Study. While all patients were on conservative treatment with a mean estimated glomerular filtration rate of 28 ml/min/1.73 m2 at study entry, 130 children commenced dialysis during the observation period. At time of enrolment the mean height standard deviation score (SDS) was −1.57; 36% of patients had a height below the third percentile. The prevalence of growth failure varied between countries from 7 to 44% Whereas patients on conservative treatment showed stable growth, height SDS gradually declined on those on dialysis. Parental height, pubertal status and treatment with recombinant growth hormone (GH) were positively, and the diagnosis of syndromic disease and CKD stage were negatively associated with height SDS during the observation period. Unexpectedly, higher body mass index (BMI) SDS was associated with lower height SDS both at enrolment and during follow up. Renal anemia, metabolic acidosis, and hyperparathyroidism were mostly mild and not predictive of growth rates by multivariable analysis. GH therapy was applied in only 15% of growth retarded patients with large variation between countries. When adjusting for all significant covariates listed above, the country of residence remained a highly significant predictor of overall growth performance. In conclusion, growth failure remains common in European children with CKD, despite improved general management of CKD complications. The widespread underutilization of GH, an approved efficacious therapy for CKD-associated growth failure, deserves further exploration.
Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multi‐disciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists’ geneticists and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from Cystinosis Metabolic Bone Disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for non‐renal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016. This article is protected by copyright. All rights reserved.
Biological covariates such as age and sex can markedly influence biochemical marker reference values, but no comprehensive study has examined such changes across pediatric, adult, and geriatric ages. The Canadian Health Measures Survey (CHMS) collected comprehensive nationwide health information and blood samples from children and adults in the household population and, in collaboration with the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER), examined biological changes in biochemical markers from pediatric to geriatric age, establishing a comprehensive reference interval database for routine disease biomarkers.
The CHMS collected health information, physical measurements, and biosamples (blood and urine) from approximately 12000 Canadians aged 3-79 years and measured 24 biochemical markers with the Ortho Vitros 5600 FS analyzer or a manual microplate. By use of CLSI C28-A3 guidelines, we determined age- and sex-specific reference intervals, including corresponding 90% CIs, on the basis of specific exclusion criteria.
Biochemical marker reference values exhibited dynamic changes from pediatric to geriatric age. Most biochemical markers required some combination of age and/or sex partitioning. Two or more age partitions were required for all analytes except bicarbonate, which remained constant throughout life. Additional sex partitioning was required for most biomarkers, except bicarbonate, total cholesterol, total protein, urine iodine, and potassium.
Understanding the fluctuations in biochemical markers over a wide age range provides important insight into biological processes and facilitates clinical application of biochemical markers to monitor manifestation of various disease states. The CHMS-CALIPER collaboration addresses this important evidence gap and allows the establishment of robust pediatric and adult reference intervals.
© 2015 American Association for Clinical Chemistry.
Background and objectives:
Poor linear growth is a frequent complication of CKD. This study evaluated the effect of kidney transplantation on age-related growth of linear body segments in pediatric renal transplant recipients who were enrolled from May 1998 until August 2013 in the CKD Growth and Development observational cohort study.
Design, setting, participants, & measurements:
Linear growth (height, sitting height, arm and leg lengths) was prospectively investigated during 1639 annual visits in a cohort of 389 pediatric renal transplant recipients ages 2-18 years with a median follow-up of 3.4 years (interquartile range, 1.9-5.9 years). Linear mixed-effects models were used to assess age-related changes and predictors of linear body segments.
Results:
During early childhood, patients showed lower mean SD scores (SDS) for height (-1.7) and a markedly elevated sitting height index (ratio of sitting height to total body height) compared with healthy children (1.6 SDS), indicating disproportionate stunting (each P<0.001). After early childhood a sustained increase in standardized leg length and a constant decrease in standardized sitting height were noted (each P<0.001), resulting in significant catch-up growth and almost complete normalization of sitting height index by adult age (0.4 SDS; P<0.01 versus age 2-4 years). Time after transplantation, congenital renal disease, bone maturation, steroid exposure, degree of metabolic acidosis and anemia, intrauterine growth restriction, and parental height were significant predictors of linear body dimensions and body proportions (each P<0.05).
Conclusions:
Children with ESRD present with disproportionate stunting. In pediatric renal transplant recipients, a sustained increase in standardized leg length and total body height is observed from preschool until adult age, resulting in restoration of body proportions in most patients. Reduction of steroid exposure and optimal metabolic control before and after transplantation are promising measures to further improve growth outcome.
Plasma-creatinine-based equations to estimate the glomerular filtration rate are recommended by several clinical guidelines. In 2009, Schwartz et al. adapted the traditional Schwartz equation to children and adolescents but did not find different k-coefficients between children and adolescents (k = 36.5 for all patients). We reevaluated the coefficient of the 2009-Schwartz formula according to sex and age in a pediatric population.
We used linear mixed-effects models to reestimate the 2009-Schwartz k-coefficient in 360 consecutive French subjects aged 1 to 18 years referred to a single centre between July 2003 and July 2010 (965 measurements). We assessed the agreement between the estimated glomerular filtration rate obtained with the new formula (called Schwartz-Lyon) and the rate measured by inulin clearance. We then compared this agreement to the one between the measured glomerular filtration rate and 2009-Schwartz formula, first in the French then in a Swedish cohort.
In Schwartz-Lyon formula, k was estimated at 32.5 in boys <13 years and all girls and at 36.5 in boys aged ≥13 years. The performance of this formula was higher than that of 2009-Schwartz formula in children <13 years. This was first supported by a statistically significant reduction of the overestimation of the measured glomerular filtration rate in both cohorts, by better 10% and 30% accuracies, and by a better concordance correlation coefficient.
The performance and simplicity of Schwartz formula are strong arguments for its routine use in children and adolescents. The specific coefficient for children aged <13 years further improves this performance.
Nephropathic cystinosis (NC) is an autosomal recessive disorder occurring in one to two per 100,000 newborns. Because of the rarity of NC, long-term outcome data are scarce.
245 NC patients from 18 countries provided data to the ESPN/ERA-EDTA registry. We matched NC patients on renal replacement therapy (RRT) to non-NC children on RRT.
Between 1979 and 2008, mean age at the start of RRT among NC children increased by 0.15 year per calendar year (95% confidence interval, 0.10 to 0.21) from 8.8 to 12.7 years, whereas we did not observe this in non-NC children. Five-year survival after the start of RRT improved in NC patients from 86.1% (before 1990) to 100% (since 2000) as compared with the control population (89.6% and 94.0%). NC patients received a renal allograft more often (relative risk, 1.09; 95% confidence interval, 1.00 to 1.17) as compared with matched RRT children, and 5-year graft survival was better (94.0% versus 84.0%). NC dialysis patients were less often hypertensive than non-NC children matched for age, country, and dialysis modality (42.7% versus 51.7%) and had lower parathyroid hormone levels (median, 56 versus 140 pg/ml). Although height at start of RRT slightly improved during the past decade, children with NC remained significantly shorter than non-NC children at the start of RRT.
We demonstrated improved survival of the renal function as well as better patient and graft survival after the start of RRT in a large European cohort of NC patients over the last two decades.
Nephropathic cystinosis, an autosomal recessive disorder resulting from defective lysosomal transport of cystine, is the most common inherited cause of renal Fanconi syndrome. The cystinosis gene has been mapped to chromosome 17p13. We found that the locus D17S829 was homozygously deleted in 23 out of 70 patients, and identified a novel gene, CTNS, which mapped to the deletion interval. CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. Eleven different mutations, all predicted to cause loss of function of the protein, were found to segregate with the disorder.
The effect of chronic kidney disease (CKD) on muscle mass in children, independent of poor growth and delayed maturation, is not well understood. We sought to characterize whole body and regional lean mass (LM) and fat mass (FM) in children and adolescents with CKD and to identify correlates of LM deficits in CKD. We estimated LM and FM from dual energy x-ray absorptiometry scans in 143 children with CKD and 958 controls at two pediatric centers. We expressed whole body, trunk, and leg values of LM and FM as Z-scores relative to height, sitting height, and leg length, respectively, using the controls as the reference. We used multivariable regression models to compare Z-scores in CKD and controls, adjusted for age and maturation, and to identify correlates of LM Z-scores in CKD. Greater CKD severity associated with greater leg LM deficits. Compared with controls, leg LM Z-scores were similar in CKD stages 2 to 3 (difference: 0.02 [95% CI: -0.20, 0.24]; P = 0.8), but were lower in CKD stages 4 to 5 (-0.41 [-0.66, -0.15]; P = 0.002) and dialysis (-1.03 [-1.33, -0.74]; P < 0.0001). Among CKD participants, growth hormone therapy associated with greater leg LM Z-score (0.58 [0.03, 1.13]; P = 0.04), adjusted for CKD severity. Serum albumin, bicarbonate, and markers of inflammation did not associate with LM Z-scores. CKD associated with greater trunk LM and FM, variable whole body LM, and normal leg FM, compared with controls. In conclusion, advanced CKD associates with significant deficits in leg lean mass, indicating skeletal muscle wasting. These data call for prospective studies of interventions to improve muscle mass among children with CKD.
Cystinosis is an autosomal recessive disorder which is characterized by both renal and extrarenal symptoms. Gastrointestinal dysfunction has been reported in adolescent with cystinosis, and it is rarely considered in the infants. The present case series reviewed gastrointestinal manifestations of these patients.
Gastrointestinal signs and symptoms of 23 children aged 5.99 +/- 0.50 years (range, 1.0 to 12.5 years) on average with cystinosis, admitted to our department of nephrology between 1996 and 2005, were retrospectively reviewed. The inclusion criteria were the presence of the crystals of cystine in bone marrow aspiration and corneal deposition detected by slit lamp examination.
Gastrointestinal signs and symptoms were as follows: vomiting in 16 patients (69.6%), hepatomegaly in 8 (34.8%), diarrhea in 6 (26.1%), splenomegaly in 5 (21.7%), constipation in 4 (17.4%), anorexia in 4 (17.4%), abdominal pain in 3 (13.0%), nausea in 2 (8.7%), and ascites in 2 (8.7%). Height below the 3rd percentile in was seen in 16 patients (69.6%) and weight below the 3rd percentile, in 17 (73.9%). Fifteen patients (65.2%) had both low weight and low height. Esophagogastroduodenoscopy had been performed in 6 cases and chronic inactive gastritis with H pylori infection was detected in 2 patients (8.7%).
Our study revealed a wide spectrum of gastrointestinal disturbances in young patients with cystinosis. Such findings should lead to greater awareness of the presence of gastrointestinal dysfunction in these children, encourage prompt gastrointestinal evaluation, and encourage treatment of more severely affected patients.
In a cross-sectional study of growth, 5,260 healthy children of both sexes from Zagreb (Croatia) aged 2 to 18 years were measured. Six transversal body dimensions were studied: biacromial, transverse chest, antero-posterior chest, biiliocristal, bicondylar humerus and bicondylar femur diamters. A significant increase in body diameters has been observed until the age of 14 to 15 in girls and until the age of 16 in boys, showing that girls have a 1 to 2 years shorter period of growth. Compared to boys of the same age, they achieved larger amounts of final transversal bone size throughout the whole growth period. The most pronounced example was the knee diameter that in girls attained 95% of adult size as early as the age of 10. In both genders, the adult size is achieved earlier in widths of the extremities than in those of the trunk. The studied transversal body segments showed different growth dynamics, which is gender-specific. While sexual dimorphism in pelvic and shoulder diameters emerged with pubertal spurt, gender differences in chest and extremities' diameters started early in life. In all ages, boys had larger chest, elbow and knee diameters. In pubertal age boys gained a significantly larger biacromial diameter (from the age of 13 onwards), while girls exceeded them in biiliocristal diameter (from 10 to 14 years). The findings of gender differences were compared to those reported for other European populations and their growth patters were discussed comparing viewpoints.
Maya families from Guatemala migrated to the United States in record numbers from the late 1970s to the early 1990s. Births to Maya immigrant women have created a sizable number of Maya American children. The height and sitting height of 5 to 12 years children (n = 431) were measured in 1999 and 2000. Leg length was estimated and the sitting height ratio was calculated. These data were compared with a sample of Maya children living in Guatemala measured in 1998 (n = 1,347). Maya American children are currently 11.54 cm taller and 6.83 cm longer-legged, on average, than Maya children living in Guatemala. Consequently, the Maya Americans have a significantly lower average sitting height ratio (i.e., relatively longer legs in proportion to length of the head and trunk) than do the Maya in Guatemala. These results add support to the hypothesis that both the height and body proportions of human populations are sensitive indicators of the quality of the environment for growth.
In a cross-sectional study of growth, 5,155 children (2,591 females, 2,564 males) from the town of Zagreb (Croatia) were measured. Four traits of linear dimensionality (stature, sitting height, arm and leg lengths) were studied in the age span of 3 to 18 years. A significant average annual increase of all four anthropometric parameters were observed up to 14 and 15 years of age in girls and 16 years of age in boys, showing that girls had a shorter growing period. In the prepubertal period until 9 years of age, gender differences were negligible. At the age of 10, boys were overgrown by girls in all parameters due to the earlier onset of puberty in girls. The growth gains for girls, when compared with those for boys, show a different pattern across variables. The female growth advantage remained in a two years period for the limbs length, but in a three year period for stature and the longest, for 4 years, for sitting height. The male predominance in size had an onset at the age of 13 for the limbs and in the age of 14 for stature and sitting height. The patterns of sexual dimorphism in stature and sitting height during growing years are similar to those observed in other populations of Europe. Growth of Croatian children and youth is very similar to that of the tallest European populations.
The impact of chronological age on longitudinal body growth from early childhood through adolescence using detailed anthropometric methods has not yet been studied in children with chronic kidney disease (CKD). We have evaluated growth failure by measuring four components of linear growth: body height (HT), sitting height (SHT), arm length (AL) and leg length (LL). Data were prospectively collected for up to 7 years on 190 boys (3-21 years old) with congenital or hereditary CKD (all had developed at least stage 2 CKD by the age of 10 years). Patients showed the most severe growth failure in early childhood, followed by an acceleration in growth in pre-puberty, a slowing-down of growth at puberty, as expected, and thereafter a late speeding-up of growth until early adulthood. This pattern was observed irrespective of the degree of CKD and different treatment modalities, such as conservative treatment, recombinant human growth hormone (rhGH) therapy or transplantation. LL showed the most dynamic growth changes of all the parameters evaluated and emerged as the best indicator of statural growth in children with CKD. A specific age-dependent pattern of physical growth was identified in pediatric male CKD patients. This growth pattern should be considered in the evaluation of individual growth and the assessment of treatment efficacy such as rhGH therapy.
Context:
Children with nephropathic cystinosis (NC) show persistent hypophosphatemia, due to Fanconi syndrome, as well as mineral and bone disorders related to chronic kidney disease (CKD), but systematic analyses are lacking.
Objective:
To compare biochemical parameters of bone and mineral metabolism between children with NC and controls across all stages of CKD.
Design:
Cross-sectional multicenter study.
Setting:
Hospital clinics.
Patients:
Forty nine children with NC, 80 CKD controls of the same age and CKD stage.
Main outcome measures:
Fibroblast growth factor 23 (FGF23), soluble Klotho, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin, osteoprotegerin (OPG), biochemical parameters related to mineral metabolism, and skeletal comorbidity.
Results:
Despite Fanconi syndrome medication, NC patients showed an 11-fold increased risk of short stature, bone deformities and/or requirement for skeletal surgery compared to CKD-controls. This was associated with a higher frequency of risk factors such as hypophosphatemia, hypocalcemia, low PTH, metabolic acidosis and a specific CKD stage-dependent pattern of bone marker alterations. Pre-transplant NC patients in mild to moderate CKD showed a delayed or lacking increase in FGF23 and sclerostin, and increased BAP, TRAP5b and OPG concentrations compared to CKD-controls. Post-transplant, BAP and OPG returned to normal, TRAP5b further increased, whereas FGF23 and PTH were less elevated compared to CKD-controls and associated with higher serum phosphate.
Conclusions:
NC patients show a more severe skeletal comorbidity associated with distinct CKD stage-dependent alterations of bone metabolism compared to CKD controls, suggesting impaired mineralization and increased bone resorption, which is only partially normalized after renal transplantation.
Background
Children with chronic kidney disease (CKD) have delays in normal growth and pubertal development. We describe factors associated with delayed menarche and the association of delayed menarche with short stature in girls with CKD.Methods
Two hundred eighty-seven girls with CKD onset prior to menarche within the Chronic Kidney Disease in Children (CKiD) cohort were studied. Delayed menarche was defined as menarche at age 15 years or older; short stature was defined as last available height 2 standard deviations below projected adult height. Kaplan-Meier cumulative incidence function was used to estimate median age at menarche. Chi-squared and Wilcoxon rank-sum tests were used to assess factors associated with delayed menarche. Chi-squared test was used to evaluate the association between delayed menarche and short stature.ResultsAmong 287 girls, 68 enrolled with prevalent menarche, 131 were observed to have incident menarche, and 88 were pre-menarchal at their last study visit. Median age at menarche was 12 years. Ten percent had delayed menarche. African American race, lower estimated glomerular filtration rate, ever corticosteroid use, and longer CKD duration were associated with delayed menarche (p < 0.05). Girls with delayed menarche had lower height and weight percentiles at the time of menarche (p < 0.05). Sixty-one percent of girls with delayed menarche had short stature compared with only 35% of girls without delayed menarche (p = 0.03).Conclusion
Median age at menarche is similar among girls with CKD and healthy girls. Ten percent of girls with CKD had delayed menarche and may be at risk for short stature.
Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. It is caused by a defect in the lysosomal cystine transporter, cystinosin, which results in an accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, a renal Fanconi syndrome is often the first manifestation of cystinosis, usually presenting within the first year of life and characterized by the early and severe dysfunction of proximal tubule cells, highlighting the unique vulnerability of this cell type. The current therapy for cystinosis, cysteamine, facilitates lysosomal cystine clearance and greatly delays progression to kidney failure but is unable to correct the Fanconi syndrome. This Review summarizes decades of studies that have fostered a better understanding of the pathogenesis of the renal Fanconi syndrome associated with cystinosis. These studies have unraveled some of the early molecular changes that occur before the onset of tubular atrophy and identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy and the regulation of energy balance. These studies have also led to the identification of new potential therapeutic targets and here, we outline the potential role of stem cell therapy for cystinosis and provide insights into the mechanism of haematopoietic stem cell-mediated kidney protection.
Background
Children with chronic kidney disease are frequently born small for gestational age (SGA) and prone to disproportionately short stature. It is unclear how SGA affects growth after kidney transplantation (KTx). Methods
Linear growth (height, sitting height, and leg length) was prospectively investigated in a cohort of 322 pediatric KTx recipients, with a mean follow-up of 4.9 years. Sitting height index (ratio of sitting height to total body height) was used to assess body proportions. Predictors of growth outcome in KTx patients with (n = 94) and without (n = 228) an SGA history were evaluated by the use of linear mixed-effects models. ResultsMean z-scores for all linear body dimensions were lower in SGA compared with non-SGA patients (p < 0.001). SGA patients presented with higher target height deficit and degree of body disproportion (p < 0.001). The latter was mainly due to reduced leg growth during childhood. Pubertal trunk growth was diminished in SGA patients, and the pubertal growth spurt of legs was delayed in both groups, resulting in further impairment of adult height, which was more frequently reduced in SGA than in non-SGA patients (50 % vs 18 %, p < 0.001). Use of growth hormone treatment in the pre-transplant period, preemptive KTx, transplant function, and control of metabolic acidosis were the only potentially modifiable correlates of post-transplant growth in SGA groups. By contrast, living related KTx, steroid exposure, and degree of anemia proved to be correlates in non-SGA only. Conclusions
In children born SGA, growth outcome after KTx is significantly more impaired and affected by different clinical parameters compared with non-SGA patients.
Growth channels phenomena in pubescence girls (aged 11.5 to 14.5 years) were used as a basis for a detailed analysis of the relation between the soft tissue growth component (related to growth channels) and menarcheal experience. The soft tissue component showed statistically significant differences between the growth channels (in all groups and at all time points). Generally it was shown that girls from the second growth channel (soft rounded physique) were the first to experience menarche (19% of them at the age of 11.5 years), and the first to complete it (100% at the age of 14.5 years). The first growth channel girls (elongated body shape) matured with some latency, compared to the second group during the first two years, however 97% of them got their first menstrual flow by the age of 14.5 years. In the third growth channel (short and thin body shape girls), menarche appeared with a marked latency, and only 5% had menarche at the age of 12.5, while 43% had it at the age of 13.5, and 95% at the age of 14.5 years. These data support the proposition that sexual maturation stages follow the specificity of the type of physique in pubescence girls.
Background:
Muscle wasting is a common complication in patients with infantile nephropathic cystinosis, but its mechanism and association with energy metabolism is not known. We define the metabolic phenotype in Ctns(-/-) mice, an established murine model of infantile nephropathic cystinosis, with focus on muscle wasting and energy homeostasis.
Methods:
Male Ctns(-/-) mice and wild-type (WT) controls were studied at 1, 4, 9, and 12 months of age. As Ctns(-/-) mice started to develop chronic kidney disease (CKD) at 9 months of age, 9- and 12-month-old Ctns(-/-) mice were also compared with age-matched WT mice with CKD. Serum and urine chemistry and energy homeostasis parameters were measured. Skeletal muscle histomorphometry and in vivo muscle function were measured. We studied expression of genes involved in muscle mass regulation, thermogenesis, energy metabolism, adipogenesis, and adipose tissue browning in Ctns(-/-) mice.
Results:
Ctns(-/-) mice showed loss of weight and lean mass and increased energy expenditure. Ctns(-/-) mice exhibited abnormal energy homeostasis before the onset of their CKD. Food intake in Ctns(-/-) mice was comparable with age-matched WT controls. However, significantly lower total body mass starting at 1 month of age and increased energy expenditure at 4 months of age preceded the onset of CKD at 9 months of age in Ctns(-/-) mice. Muscle accept content in 1- and 4-month-old Ctns(-/-) mice was significantly lower than that in age-matched WT controls. At 12 months of age, muscle fibre area and in vivo muscle strength was reduced in Ctns(-/-) mice than that in WT or CKD controls. Muscle wasting in Ctns(-/-) mice was associated with inhibition of myogenesis, activation of muscle proteolysis pathways, and overexpression of pro-inflammatory cytokines. Increased energy expenditure was associated with elevation of thermogenesis in skeletal muscle and adipose tissues. The development of beige adipocytes in Ctns(-/-) mice is a novel finding. Expression of beige adipose cell surface markers (CD137, Tmem26, and Tbx1) and uncoupling protein-1, which is a brown adipose tissue marker, was observed in inguinal white adipose tissue of Ctns(-/-) mice. Expression of key molecules implicated in the pathogenesis of adipose tissue browning (Cox2, cytochrome c oxidase subunit II; PGF2α, prostaglandin F2α; IL-1α, interleukin 1α; IL-6, interleukin 6; TNF-α, tumor necrosis factor α) was significantly increased in inguinal white adipose tissue of Ctns(-/-) mice than that in WT controls.
Conclusion:
This study describes a mouse model of nephropathic cystinosis presenting with profound muscle wasting. The mechanism for hypermetabolism in Ctns(-/-) mice may involve up-regulation of thermogenesis pathways in skeletal muscle and adipose tissues. This study demonstrates, for the first time, the development of beige adipocytes in Ctns(-/-) mice. Understanding the underlying mechanisms of adipose tissue browning in cystinosis may lead to novel therapy.
Background: The full burden of nephropathic cystinosis in adulthood and the effects of long-term oral cysteamine therapy on its nonrenal complications have not been elucidated.Objective: To assess the severity of cystinosis in adults receiving and not receiving oral cysteamine therapy.Design: Case series.Setting: National Institutes of Health Clinical Center.Patients: 100 persons (58 men and 42 women) age 18 to 45 years with nephropathic cystinosis examined between January 1985 and May 2006.Measurements: Historical data were collected on renal transplantation, administration of oral cysteamine, and time and cause of death. Patients were evaluated for height and weight; thyroid, pulmonary, and swallowing function; muscle atrophy; hypogonadism (in men); retinopathy; vascular and cerebral calcifications; diabetes mellitus; and homozygosity for the common 57-kb deletion in CTNS. Laboratory studies were also performed.Results: Of 100 adults with nephropathic cystinosis, 92 had received a renal allograft and 33 had died. At least half of the patients had hypothyroidism, hypergonadotropic hypogonadism (in men), pulmonary insufficiency, swallowing abnormalities, or myopathy. One third of the patients had retinopathy or vascular calcifications, and 24% had diabetes. Homozygosity for the 57-kb CTNS deletion was associated with an increased risk for death and morbidity. The 39 patients who received long-term ( >= 8 years) oral cysteamine therapy were taller and heavier, had a renal allograft later in life, had lower cholesterol levels, and experienced fewer complications and deaths than patients who received cysteamine for fewer than 8 years. The frequency of diabetes mellitus, myopathy, pulmonary dysfunction, hypothyroidism, and death increased as time off cysteamine treatment increased, and it decreased as time on cysteamine therapy increased.Limitations: The study was retrospective and not randomized. The criteria used to measure adequacy of treatment were arbitrary.Conclusions: Untreated nephropathic cystinosis causes extensive morbidity and death in adulthood. Long-term oral cysteamine therapy mitigates these effects.
Growth failure is common among children with chronic kidney disease (CKD). We examined the relationship of growth parameters with glomerular filtration rate (GFR), CKD diagnosis, sex and laboratory results in children with CKD.
Baseline data from 799 children (median age 11.0 years, median GFR 49.9 mL/min/1.73 m(2)) participating in the Chronic Kidney Disease in Children Study were examined. Growth was quantified by age-sex-specific height, weight, body mass index (BMI-age), and height-age-sex-specific BMI (BMI-height-age) standard deviation scores (SDS).
Median height and weight SDS were -0.55 [interquartile range (IQR) -1.35 to 0.19] and 0.03 (IQR -0.82 to 0.97), respectively. Girls with non-glomerular CKD were the shortest (median height SDS -0.83; IQR -1.62 to -0.02). Compared to those with a serum bicarbonate (CO2) level of ≥22 mEq/L, children with CO2 of <18 mEq/L had a height SDS that was on average 0.67 lower [95 % confidence interval (CI) -0.31 to -1.03]. Only 23 % of children with a height SDS of ≤-1.88 were prescribed growth hormone therapy. Forty-six percent of children with glomerular CKD were overweight or obese (BMI-height-age ≥85th percentile).
Growth outcomes in a contemporary cohort of children with CKD remain suboptimal. Interventions targeting metabolic acidosis and overcoming barriers to recombinant human growth hormone usage may improve growth in this population.
Nephropathic cystinosis (NC) is a severe disease that is complicated by early-onset chronic renal failure (CRF) and other complications related to cystine deposition in tissue. Since the 1980s, the prognosis of NC has dramatically improved after the introduction of cysteamine treatment. Limited data are available documenting improvement in prognosis. We reviewed our long-term data (follow-up 6.3-27.8 years) on 23 patients followed in the past 26 years. Overall, stage III CRF was reached at 10 years of age in >90% of patients, whereas >80% reached end-stage renal disease before the age of 14 years. Three patients died during the follow-up. Our analysis shows a clear improvement in renal outcome (p = 0.001) and linear growth (p = 0.04) in patients treated more recently. Improvement in the evolution of renal function was significantly associated with early initiation of cysteamine (p = 0.006), with the dose of cysteamine (p = 0.04), and with the use of angiotensin-converting enzyme inhibitors (p = 0.01). Nonrenal long-term complications are similar to previously reported data. Of note, 3/23 patients developed rare forms of primary tumors that were successfully treated. In conclusion, our experience shows a significant improvement in the renal and nonrenal complications of cystinosis over the past decades and highlights the importance of early diagnosis in order to initiate cysteamine as soon as possible.
Heterozygotes for the autosomal recessive disease cystinosis are currently detected by measuring the cystine content of mixed-leukocyte preparations. The present study was designed to reassess the accuracy of this method and to determine whether measuring the cystine content of purified polymorphonuclear leukocytes would improve heterozygote detection. Blood samples were obtained from 29 obligate heterozygotes for nephropathic cystinosis, one obligate heterozygote for benign cystinosis, and 18 individuals presumed to be normal. When the cystine content of mixed-leukocyte preparations was measured, three heterozygote values overlapped the normal range. When polymorphonuclear-leukocyte cystine content was measured, no heterozygote values were within the normal range. Measurement of the cystine content of purified preparations of polymorphonuclear leukocytes affords a simple method that improves the sensitivity of heterozygote detection for cystinosis.
Two hundred consecutive specimens received in this laboratory for "liver function tests" showed a wide range of abnormal protein concentrations. Calcium concentration correlated closely with albumin (r = 0.867) but less closely with total protein (r = 0.682). A simple formula for adjusting calcium concentration was derived from the regression equation of calcium on albumin. Adjusted calcium = calcium - albumin + 4.0, where calcium is in mg/100 ml and albumin in g/100 ml.Low calcium concentrations were found in 49 (24.5%) and raised concentrations in six (3%) of the 200 blood specimens taken for liver function tests. After adjustment, the 95% limits of the observed range were identical with the 95% limits of the normal range determined in this laboratory. Unlike adjustments based on total protein or specific gravity, the adjustment on albumin in 39 specimens which showed hypergammaglobulinaemia on electrophoresis gave normal calcium concentrations.
In patients with cystinosis, the concentration of free cystine in leukocytes was 80 times greater than normal, and six times
the normal content for their parents. This is the first demonstration of an abnormality in heterozygotes for this rare inherited
disease of childhood. Three-quarters of the cystine was recovered in the granular fraction of cystinotic leukocytes.
The secular trends in height, sitting height and leg length in Japanese children have been studied by fitting Preece-Baines Model I curves to the annual mean values from ages five to 17 of school data collected in 1957, 1967 and 1977. The method provides estimates of final adult value, and of age of maximum annual increment. Between 1957 and 1977 the maximal increments in height, sitting height and leg length all became earlier, by about a year in boys and a little less in girls. Japanese now mature about a year earlier than North Europeans. Adult height increased by 4.3 cm in boys and 2.7 cm in girls between 1957 and 1977, the increment being less in the second decade than in the first. Sitting height showed practically no increase whatever; almost the whole secular trend was due to change in leg length. Japanese now have trunk/leg proportions much more similar to those of North Europeans than was the case 20 years ago, but their adult height remains about one standard deviation lower.
Children with nephropathic cystinosis excrete large amounts of calcium and phosphate due to renal tubular Fanconi syndrome, and also receive substantial supplements of phosphate and alkalinizing agents. Since these constitute risk factors for nephrocalcinosis, we evaluated 41 children age 2 months to 15 years with nephropathic cystinosis and good renal function by performing retroperitoneal ultrasound examinations in a blinded fashion. We also retrospectively analyzed parameters of calcium and phosphate metabolism representing 216 person-years of data on these children. Fifteen children had no evidence of medullary nephrocalcinosis, while 18 had mild nephrocalcinosis, and 8 severe nephrocalcinosis; 5 had renal stones. Mean urine calcium and phosphate concentrations increased from 1.47 mM and 5.30 mM, respectively, in children without nephrocalcinosis to 1.60 mM and 5.69 mM in children with mild nephrocalcinosis to 1.66 mM and 6.19 mM in children with severe nephrocalcinosis. Mean urine pH ranged from 7.5 to 8.1. The mean (+/- SD) age of the 26 patients with nephrocalcinosis was 9.4 +/- 3.8 years compared with 5.1 +/- 3.8 years for those without nephrocalcinosis (P < 0.005). Serum calcium, phosphate, vitamin D, and parathyroid hormone did not correlate with frequency or degree of nephrocalcinosis. We conclude that nephrocalcinosis frequently accompanies nephropathic cystinosis, can be detected by ultrasound examination, and might be managed by reducing oral replacement of phosphate, calcium, vitamin D, and citrate. Consideration should be given to truncating phosphate replacement once bone growth ceases.
In a retrospective investigation growth and pubertal development were evaluated in 30 patients with nephropathic cystinosis. Growth was investigated during the stage of chronic renal insufficiency as well as after successful kidney transplantation and growth rates were related to kidney function. Pubertal development was evaluated in 17 patients between 12 and 25 years of age. Prepubertal growth rates were stable in a range between -2 and -3 height velocity SDS as long as glomerular filtration rate was above 20ml/min per 1.73m2. A decrease in glomerular filtration rate below this threshold was followed by further decrease in height velocity. After kidney transplantation a significant catch-up growth was seen if immunosuppression was performed with cyclosporine A and low dose prednisolone. This did not occur if conventional therapy with azathioprine and high-dose prednisolone was used. Onset of puberty was delayed in all patients. Gonadotropin and oestradiol levels in female patients showed normal fluctuations according to ovulatory cycles. In male patients after puberty there was an increase in gonadotropin levels above the normal range for adult men while testosterone levels remained in the low normal range. These results indicate that adult men with nephropathic cystinosis may develop hypergonadotropic hypogonadism.
The lysosomal storage disease cystinosis results in renal failure at approximately 10 years of age. Although oral cysteamine therapy is recognized to preserve kidney function, the extent of renal benefit has not been determined.
Between 1960 and 1992, we determined 24-hour creatinine clearances in 76 children with cystinosis during 1081 admissions to the National Institutes of Health. Seventeen children were considered to have received adequate treatment with cysteamine, since they had depletion of cystine from leukocytes and began therapy before the age of 2 years; treatment lasted a mean of 7.1 years. Thirty-two children were considered to have received partial treatment, since they had poor compliance with therapy or began treatment after the age of 2; treatment lasted a mean of 4.5 years. Twenty-seven children were followed in the era before cysteamine therapy and thus never received cysteamine.
Of the 27 children who never received cysteamine, 16 were followed at the National Institutes of Health until renal failure occurred; their mean (+/- SD) creatinine clearance was 8.0 +/- 4.8 ml per minute per 1.73 m2 of body-surface area at a mean age of 8.3 +/- 1.9 years. Of the 17 children who received adequate treatment, none had renal failure; their mean creatinine clearance was 57 +/- 20 ml per minute per 1.73 m2 at 8.3 +/- 3.8 years of age. The mean creatinine clearance of the children who received partial or adequate treatment with cysteamine increased with age up to the age of five years and then declined linearly with age at a normal rate. For the children who received adequate treatment, the mean creatinine clearance was predicted to reach 0 ml per minute per 1.73 m2 at the age of 74 years, as compared with 20 years of age for the children who received partial treatment. With no therapy, the mean creatinine clearance reaches 0 ml per minute per 1.73 m2 at 10 years of age.
Children with cystinosis who are treated early and adequately with cysteamine have renal function that increases during the first five years of life and then declines at a normal rate. Patients with poorer compliance and those who are treated at an older age do less well.
Nephropathic cystinosis, a rare autosomal recessive storage disease characterized by intracellular storage of free cystine due to a defect in lysosomal cystine transport, is the most common cause of Fanconi syndrome in childhood. Although manifestations of extrarenal organ involvement during the course of the disease are diverse, the spectrum of gastrointestinal (GI) problems has not yet been examined. In responses to a questionnaire from 70 (35%) of the 200 registered members of the Cystinosis Foundation, we found that GI symptoms are more common, more diverse, and occur at a younger age in patients with cystinosis than previously recognized. Ninety-three percent of interviewed subjects had GI symptoms at initial presentation, and the overall lifetime prevalence of GI problems in this group was 100%. Thirty percent have received gastric/jejunal tube feedings, and 7% required continuous or intermittent total parenteral nutrition. Fifty percent have been formally tested for GI abnormalities, and among these 77% have documented functional abnormalities (reflux/dysmotility, pseudo-obstruction, swallowing dysfunction). Early recognition and aggressive therapy of GI problems in cystinotic patients may ameliorate or prevent the development of disabling symptoms.
Increasing evidence suggests a close association between early sexual maturation (SM) and obesity in girls and female adults. Earlier maturing girls are more likely to be obese than nonearly maturers. However, limited research has been conducted in boys.
To examine the influence of early SM on fatness in boys and compare it with girls, and to test the hypothesis that the associations differ by gender because of the differences in growth and SM patterns in boys and girls.
Cross-sectional study.
One thousand five hundred one girls and 1520 boys (aged 8-14 years) who participated in the Third National Health and Nutrition Examination Survey survey (1988-1994) and had complete anthropometry (weight, height, skinfold thickness) and SM data.
Based on each individual's age and SM status (Tanner stages: genitalia stages for boys and breast stages for girls), the subjects were classified as: 1) early maturers (those who reached a certain Tanner stage earlier than the median age for that stage), and 2) the others (average and later maturers). Overweight was defined as a body mass index (BMI) > or =85th percentile, and obesity > or =95th percentile. Logistic regression analysis was to test how early maturation affected the risks for overweight and obese. Using multiple linear regression models, the associations between fatness (BMI and skinfold thickness) and SM were systematically examined. Covariates including age, ethnicity, residence, family income, energy intake, and physical activity were adjusted.
Early SM was positively associated with overweight and obesity in girls, but the associations were reverse for boys. The prevalence of overweight in early maturers versus the others was 22.6% versus 31.6% in boys and 34.4% versus 23.2% in girls; the figures for obesity were 6.7% versus 14.8% and 15.6% versus 8.1%, respectively. Odd ratios and 95% confidence intervals for obesity were 0.4 (0.2, 0.8) for boys and 2.0 (1.1, 3.5) for girls, and covariates were adjusted. Most significant differences in overweight and obesity among ethnic groups disappeared after controlling for SM. Fatness (BMI and skinfold thickness) was associated with SM stages and with early maturation in boys and girls, but the associations were in opposite directions. Compared with their counterparts, early maturing boys were thinner, whereas early maturing girls were fatter.
Obesity is associated with sexual maturation in both boys and girls, but the association differs. There is positive association in girls, but a negative one in boys. Maturation status should be taken into consideration when assessing child and adolescent obesity.
The full burden of nephropathic cystinosis in adulthood and the effects of long-term oral cysteamine therapy on its nonrenal complications have not been elucidated.
To assess the severity of cystinosis in adults receiving and not receiving oral cysteamine therapy.
Case series.
National Institutes of Health Clinical Center.
100 persons (58 men and 42 women) age 18 to 45 years with nephropathic cystinosis examined between January 1985 and May 2006.
Historical data were collected on renal transplantation, administration of oral cysteamine, and time and cause of death. Patients were evaluated for height and weight; thyroid, pulmonary, and swallowing function; muscle atrophy; hypogonadism (in men); retinopathy; vascular and cerebral calcifications; diabetes mellitus; and homozygosity for the common 57-kb deletion in CTNS. Laboratory studies were also performed.
Of 100 adults with nephropathic cystinosis, 92 had received a renal allograft and 33 had died. At least half of the patients had hypothyroidism, hypergonadotropic hypogonadism (in men), pulmonary insufficiency, swallowing abnormalities, or myopathy. One third of the patients had retinopathy or vascular calcifications, and 24% had diabetes. Homozygosity for the 57-kb CTNS deletion was associated with an increased risk for death and morbidity. The 39 patients who received long-term (> or =8 years) oral cysteamine therapy were taller and heavier, had a renal allograft later in life, had lower cholesterol levels, and experienced fewer complications and deaths than patients who received cysteamine for fewer than 8 years. The frequency of diabetes mellitus, myopathy, pulmonary dysfunction, hypothyroidism, and death increased as time off cysteamine treatment increased, and it decreased as time on cysteamine therapy increased.
The study was retrospective and not randomized. The criteria used to measure adequacy of treatment were arbitrary.
Untreated nephropathic cystinosis causes extensive morbidity and death in adulthood. Long-term oral cysteamine therapy mitigates these effects.
- W A Gahl
- J G Thoene
- J A Schneider
- Cystinosis
Gahl WA, Thoene JG, Schneider JA. Cystinosis. New England Journal of Medicine (2002);
Improved renal function in children with cystinosis treated with cysteamine
- T C Markello
- I M Bernardini
- W A Gahl
Markello TC, Bernardini IM, Gahl WA. Improved renal function
in children with cystinosis treated with cysteamine. N Engl J Med.
1993;328:1157-1162. doi:10.1056/NEJM199304223281604
Intrinsic bone defects in cystinotic mice
- G Battafarano
- M Rossi
- L R Rega
Battafarano G, Rossi M, Rega LR, et al. Intrinsic bone defects
in cystinotic mice. Am J Pathol. 2019;189:1053-1064. doi:
10.1016/j.ajpath.2019.01.015
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