Doris Franke

Patterns of Growth after Kidney Transplantation among Children with ESRD

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.

Schimke-immuno-osseous dysplasia: new mutation with weak genotype-phenotype correlation in siblings.

Schimke‐immuno‐osseous dysplasia (SIOD) is a multisystem disorder with the following consistent clinical features: spondyloepiphyseal dysplasia with disproportional growth deficiency, nephrotic syndrome with focal and segmental glomerulosclerosis, and defective cellular immunity. Transitory ischemic attacks due to vaso‐occlusive processes are complications in some patients with severe SIOD. Recently, mutations of SMARCAL1, which encodes a putative chromatin remodelling protein, have been associated with SIOD. Patients with milder disease were observed to harbor a missense mutation on each allele, whereas patients with a severe form of the disease were predicted to have at least one allele with a nonsense, frameshift or splicing mutation. We report two brothers who are both compound heterozygous for the mutations 836 T > C and 2542 G > T detected in exons 4 and 17, respectively. We demonstrate the lack of genotype–phenotype correlation in these patients as one brother shows some features of the severe form while the other does not. Neither clinical nor molecular findings can fully predict the clinical course of SIOD.

Schimke Versus Non-Schimke Chronic Kidney Disease: An Anthropometric Approach

Schimke-immuno-osseous dysplasia is a rare autosomal-recessive multisystem disorder with the main clinical features of disproportionate growth deficiency, defective cellular immunity, and progressive renal disease. It is caused by mutations of SMARCAL1, a gene encoding a putative chromatin remodeling protein of unknown function. Because a detailed description of the clinical features is an essential first step in elucidating the function of SMARCAL1, we present the first detailed anthropometric data for Schimke-immuno-osseous dysplasia patients. By comprehensive anthropometric examination (28 parameters) of 8 patients (3 females) with the typical findings of Schimke-immuno-osseous dysplasia (mean age: 14.8 years; range: 4.9–30.5 years) and 304 patients (117 females) with congenital and hereditary chronic kidney disease (mean age: 10.7 ± 4.8 years; range: 3–21.8 years), we show that Schimke-immuno-osseous dysplasia patients differ significantly from those with other forms of chronic kidney disease. z scores were calculated with reference limits derived from 5155 healthy children (2591 females) aged 3 to 18 years. The key finding was that, in the latter group, median leg length was significantly more reduced than sitting height, whereas in Schimke-immuno-osseous dysplasia patients, the reduction of sitting height was significantly more pronounced than for leg length. Therefore, the ratio of sitting height/leg length might be a simple tool for the clinician to distinguish Schimke-immuno-osseous dysplasia from other chronic kidney disease patients. Schimke-immuno-osseous dysplasia is very likely if this ratio is <0.83. However, other forms of chronic kidney disease have to be discussed in case of a ratio >1.01.

Benign liver tumors in pediatric patients - Review with emphasis on imaging features

Benign hepatic tumors are commonly observed in adults, but rarely reported in children. The reasons for this remain speculative and the exact data concerning the incidence of these lesions are lacking. Benign hepatic tumors represent a diverse group of epithelial and mesenchymal tumors. In pediatric patients, most benign focal liver lesions are inborn and may grow like the rest of the body. Knowledge of pediatric liver diseases and their imaging appearances is essential in order to make an appropriate differential diagnosis. Selection of the appropriate imaging test is challenging, since it depends on a number of age-related factors. This paper will discuss the most frequently encountered benign liver tumors in children (infantile hepatic hemangioendothelioma, mesenchymal hamartoma, focal nodular hyperplasia, nodular regenerative hyperplasia, and hepatocellular adenoma), as well as a comparison to the current knowledge regarding such tumors in adult patients. The current emphasis is on imaging features, which are helpful not only for the initial diagnosis, but also for pre- and post-treatment evaluation and follow-up. In addition, future perspectives of contrast-enhanced ultrasound (CEUS) in pediatric patients are highlighted, with descriptions of enhancement patterns for each lesion being discussed. The role of advanced imaging tests such as CEUS and magnetic resonance imaging, which allow for non-invasive assessment of liver tumors, is of utmost importance in pediatric patients, especially when repeated imaging tests are needed and radiation exposure should be avoided.

Elevated asymmetric dimethylarginine (ADMA) and inverse correlation between circulating ADMA and glomerular filtration rate in children with sporadic focal segmental glomerulosclerosis (FSGS)

BACKGROUND Steroid-resistant nephrotic syndromes (NS) with focal and segmental glomerulosclerosis (FSGS) can be differentiated into sporadic and syndromic forms. In sporadic NS, a circulating FSGS-factor is discussed in the pathogenesis and is thought to inhibit the synthesis of nitric oxide (NO) from L-arginine by blocking the NO synthase (NOS). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of all types of NOS. In a previous study we did not find an elevation of ADMA in a syndromic form of FSGS, the Schimke-immuno-osseous dysplasia. Here we report for the first time data on the L-arginine/NO pathway in sporadic FSGS of childhood. METHODS Nine children (5 to 18 years of age) suffering from sporadic FSGS and age-matched healthy controls were investigated. ADMA in plasma and urine as well as L-arginine in plasma were determined by gas chromatography-tandem mass spectrometry. The NO metabolites nitrate and nitrite were measured in plasma and urine by gas chromatography-mass spectrometry (GC-MS). The ADMA metabolite dimethylamine (DMA) was measured in urine by GC-MS. RESULTS We found elevated plasma levels of ADMA in children suffering from sporadic FSGS compared to healthy controls (851 nmol/L versus 684 nmol/L, P = 0.008). An inverse correlation between ADMA and glomerular filtration rate (GFR) was found in sporadic FSGS (Pearsons correlation coefficient -0.784, P = 0.012). CONCLUSION Our study suggests that ADMA synthesis is elevated in sporadic FSGS. This finding argues for the involvement of ADMA in the pathogenesis of this disease in childhood.

Prematurity, small for gestational age and perinatal parameters in children with congenital, hereditary and acquired chronic kidney disease

BACKGROUND Low birth weight has been identified as a risk factor for chronic kidney disease (CKD). METHODS We analysed perinatal parameters taken from the National Birth Certificates of 435 children with CKD stages 3-5 of different aetiology and time of onset of CKD. Diseases were classified as congenital with onset of renal disease during fetal life (n = 260; 60%), hereditary as genetically determined with onset after 3 months of life (n = 93; 21%) and acquired CKD (n = 82; 19%). RESULTS The rates of prematurity and small for gestational age (SGA) were elevated in children with congenital (39.3% and 29.2%), hereditary (24.7% and 22.6%) and acquired CKD (15.5% and 29.3%); these compared to 8% (for both) in the normal population. Newborns with congenital CKD had a significantly lower gestational age [median 38 weeks, interquartile range (IQR) 36-40 weeks] than those with hereditary (39.9 weeks, IQR 37.5-40 weeks) or acquired CKD (40 weeks, IQR 38-40 weeks; P < 0.001). Median birth weight and length were lower in newborns with congenital than in hereditary and acquired diseases [2975 g (IQR 2460-3420 g) versus 3250 g (IQR 2740-3580 g) and 3260 g (IQR 2858-3685 g) (P < 0.01); 49 cm (IQR 47-52) versus 50 cm (IQR 48-52.8) and 51 cm (IQR 49-53) (P < 0.01)]. Head circumference was smaller (P < 0.05), and Apgar scores were lower (P < 0.005) in newborns with congenital diseases than in hereditary and acquired diseases. CONCLUSIONS Children with congenital CKD had the highest rate of prematurity, a significantly lower birth weight, length, head circumference and Apgar score than newborns with hereditary or acquired CKD. Irrespective of the aetiology of CKD, all of the children had a significantly higher rate of SGA and prematurity than the reference population. We conclude that both SGA and prematurity predispose for advanced renal disease in childhood and that fetal kidney disease impairs fetal growth.

SMARCAL1 Mutations: A Cause of Prepubertal Idiopathic Steroid-resistant Nephrotic Syndrome

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal-recessive multisystem disorder with disproportionate growth failure, impaired T cell function, and steroid-resistant nephrotic syndrome. Recently, we presented the typical anthropometric features of SIOD. We now present data on two siblings who were initially classified as suffering from familial steroid-resistant nephrotic syndrome of unknown genetic origin. Apart from growth failure, no syndrome-specific symptoms were found until the age of 10 y. However, serial anthropometric examinations showed the development of a SIOD-like pattern with a decreased ratio of trunk to leg length in early adolescence. The growth pattern was significantly different from that seen in children with chronic renal failure of other origins. In prepuberty the siblings had proportionate short stature but developed disproportion only during adolescence. Molecular genetic analysis revealed compound heterozygosity for a known and a new mutation in the SMARCAL1 gene.Conclusion: the disease spectrum associated with SMARCAL1 mutations includes previously undescribed milder phenotypes that may be clinically overlooked, particularly before puberty. Serial anthropometric assessment can eventually identify patients with a growth pattern similar to that of SIOD. These patients should be tested for SMARCAL1 mutations to avoid overtreatment with immunosuppressive agents.

The influence of low donor age, living related donation and pre-emptive transplantation on end-organ damage based on arterial hypertension after paediatric kidney transplantation

BACKGROUND To date, no study has described the pre-transplant and transplant risk factors for end-organ damage based on arterial hypertension in children after kidney transplantation (KTX). METHODS A retrospective chart review was performed of 206 children with KTX between 1991 and 2007. Patients<120 cm were excluded as no validated percentiles for 24-h ambulant blood pressure monitoring (ABPM) exist. Complete data sets were available for 116 patients. Data were recorded at 12, 24 and 36 months post- KTX. We analysed the influence of donor age, age at transplantation, pre-emptive transplantation, living or deceased transplantation and glomerular filtration rate (GFR) on the presence of end-organ damage, ABPM, ABPM standard deviation score and the numbers of anti-hypertensives used. RESULTS Lower donor age and the decade of transplantation were associated with less detection of end-organ damage (P=0.001). A lower need for anti-hypertensive medication (P=0.001) was detected in children who received organs from living donors and from deceased donors with a donor age<35 years and who were transplanted pre-emptively. Low recipient age was the only factor associated with lower ABPM (P=0.001). In our study, the type of immunosuppressive regimen and the GFR had no influence on the blood pressure. CONCLUSIONS It may be speculated that the risk of arterial hypertension and associated end-organ damage in children after KTX could be reduced by using organs from young donors with an advantage for living related and pre-emptive donation.

Authors’ Reply to Letter: Role of Contrast-Enhanced Ultrasound (CEUS) in Paediatric Practice: An EFSUMB Position Statement

We thank the author for the interest in recent statement on use of contrast-enhanced ultrasound (CEUS) in the paediatric population [1], and note the number of concerns raised. The author makes numerous valid points with regards to the use of CEUS in the paediatric patient and highlights, quite correctly, the large number of limitations of CEUS.We believe the point of the position statement has been “missed”; CEUS will not replace CT and MR imaging but should be seen as an additional, problem solving or alternative child friendly diagnostic tool that is safe and easily repeatable in a clinical setting. The authors do not claim to be able to considerably reduce CT and MR imaging in clinical practice but advocate that there is potential for reduction with the use of CEUS. There will always be the need for CT and MR imaging, but very often, and this is true both in the adult and paediatric population, physicians and radiologists are all too eager to “press-the-button” to invoke the use of more expensive and often harmful imaging prior to exhausting the potential of the least harmful imaging modality, i. e. ultrasound. Of course assessment for staging of malignant disease will need CT imaging, but is CT imaging really needed when an incidental focal lesion is present on a baseline ultrasound [2]? Is CT follow-up really necessary when there is an isolated spleen injury following blunt abdominal trauma [3]? The ability to characterise a liver lesion immediately and accurately reduces parent anxiety particularly when the likelihood of malignancy is low. No doubt the addition of CEUS to an ultrasound examination requires valuable physician or radiologist time, but reduces potential patient morbidity considerably; the patient, in this case the child, is paying for the idleness of the physician or radiologist. It is far too easy to “order” a CT or MR examination, and report remotely at physician or radiologist convenience. Our statement is designed to encourage the paediatric imaging community to move forward and embrace this technique for the benefit of their clients, and highlights areas to consider where CEUS usefulness may be further explored. It is important to appreciate that the statement follows the introduction of SonoVueTM/LumasonTM (Bracco, SpA, Milan) for liver application in the paediatric population in the United States of America, licenced for use by the Food and Drug Administration (FDA) following approval without any prior conducted dedicated clinical trial. The reason for this is undoubtedly the need to reduce the medical radiation burden carried by the American child, carried into adulthood increasing the risk of later life cancer, based on real data [4]. The actuality of a CEUS examination is that licencing was restricted to adults (until recent FDA approval) for intravenous use, and then only to the heart, liver, breast and peripheral vessels. This has not hampered the adult physician and radiologist from dutifully exploring many other areas, and generally establishing the potency of CEUS in the diagnosis and management of many disease processes with numerous publications in the literature, summarised in EFSUMB guidelines [5]. Without this pioneering work by numerous practitioners in Europe the current status of CEUS would not be acknowledged as significant. This is pertinent to the point raised by the author with regards to the statement that conclusions are from a radiological culture based on adults. The many authors of the EFSUMB statement are drawn from a variety of backgrounds, all with extensive experience of CEUS both in adults and children, and many are paediatric practitioners; all driven by their vision of improving imaging care for the child using CEUS.Without the skill and observations of this group and many other unheralded practitioners across Europe, this position statement would not have been possible. The lead needs to be taken by paediatric practitioners, who to date, are unfortunately few in number. We believe the problem lies elsewhere; there is no ideal imaging method for children and any addition that resolves a problem should be welcomed. However, the rigid implementation of CT and MR imaging in many clinical protocols precludes the introduction of CEUS as a problem solving tool. This is clearly highlighted by the author’s statement that the recent guidelines issued by ESGAR/ESPR [6], excludes the use of CEUS in inflammatory bowel disease in children; has this been extensively investigated? The probability is that it has not and without encouragement will never be, driven by vested interests in existing techniques to the detriment of the child. Extensive literature exists in the adult [7] and this should be extended to the child; surely a rapid, safe, cost-effective and child friendly examination is a mandatory requirement in this young population with a potential lifelong disease. We hope this reply as well as the position statement will overcome reactionary attitudes to the more widespread use of CEUS in children and allow for the safe care of all our children.

Schimke-immunoossäre Dysplasie

ZusammenfassungHintergrund:Die Schimke-immunoossäre Dysplasie (SIOD) ist eine seltene autosomal-rezessiv vererbte Multisystemerkrankung, der Mutationen im SMARCAL-1-Gen (“SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1”) zugrunde liegen.Klinik:Zu den klinischen Hauptsymptomen zählen ein Kleinwuchs bei spondyloepiphysärer Dysplasie, eine Immunopathie sowie eine fortschreitende Glomerulopathie. Bei der schwer verlaufenden SIOD erweisen sich zerebrovaskuläre Symptome auf der Basis einer frühen generalisierten Arteriopathie oft als lebenslimitierend. Nur wenige Patienten erreichten bislang das Erwachsenenalter.Fallbeispiele:Exemplarisch wird über die Krankheitsverläufe bei vier adulten SIOD-Patienten berichtet.Schlussfolgerung:Patienten mit klinisch schwer verlaufender SIOD können heutzutage das Erwachsenenalter erreichen. Das Krankheitsbild der SIOD sollte dem Internisten/Hausarzt daher bekannt sein.AbstractBackground:Schimke immunoosseous dysplasia (SIOD) is a rare autosomal recessive multisystemic disorder caused by mutations of the SMARCAL 1 gene (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1).Clinical Features:Main clinical features are: disproportional growth deficiency due to spondyloepiphyseal dysplasia, nephrotic syndrome with focal and segmental glomerulosclerosis, and defective cellular immunity. Patients with severe SIOD have life-limiting complications like cerebral ischemia due to vasoocclusive processes. Only a few patients reached adulthood.Case Reports:The clinical course of four adult SIOD patients is presented.Conclusion:Even patients with severe SIOD can reach adulthood. Therefore, doctors working in the field of internal medicine and family doctors should be familiar with the clinical picture of SIOD.