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Fischbach M.,Service de Pediatrie 1 | Zaloszyc A.,Service de Pediatrie 1 | Schaefer B.,Center for Pediatrics and Adolescent Medicine | Schmitt C.P.,Center for Pediatrics and Adolescent Medicine
Pediatric Nephrology | Year: 2014

Not only adequate uremic toxin removal but also volume control is essential in peritoneal dialysis (PD) to improve patient outcome. Modification of dwell time impacts on both ultrafiltration (UF) and purification. A short dwell favors UF but preferentially removes small solutes such as urea. A long dwell favors uremic toxin removal but also peritoneal fluid reabsorption due to the time-dependent loss of the crystalloid osmotic gradient. In particular, the long daytime dwell in automated PD may result in significant water and sodium reabsorption, and in such cases icodextrin should be considered. Increasing dwell volume favors the removal of solutes such as sodium due to the increased volume of diffusion and the recruitment of peritoneal surface area. A very large fill volume with too high an intraperitoneal pressure (IPP) may, however, result in back-filtration and thus reduced UF and sodium clearance. Based on these principles and the individual transport and pressure kinetics obtained from peritoneal equilibration tests and IPP measurements, we suggest combining short dwells with a low fill volume to favor UF with long dwells and a large fill volume to favor solute removal. Results from a recent randomized cross-over trial and earlier observational data in children support this concept: the absolute UF and UF relative to the administered glucose increased and solute removal and blood pressure improved. © 2013 IPNA.


Mele C.,Mario Negri Institute for Pharmacological Research | Iatropoulos P.,Mario Negri Institute for Pharmacological Research | Donadelli R.,Mario Negri Institute for Pharmacological Research | Calabria A.,University of Milan | And 23 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Focal segmental glomerulosclerosis is a kidney disease that is manifested as the nephrotic syndrome. It is often resistant to glucocorticoid therapy and progresses to end-stage renal disease in 50 to 70% of patients. Genetic studies have shown that familial focal segmental glomerulosclerosis is a disease of the podocytes, which are major components of the glomerular filtration barrier. However, the molecular cause in over half the cases of primary focal segmental glomerulosclerosis is unknown, and effective treatments have been elusive. METHODS: We performed whole-genome linkage analysis followed by high-throughput sequencing of the positive-linkage area in a family with autosomal recessive focal segmental glomerulosclerosis (index family) and sequenced a newly discovered gene in 52 unrelated patients with focal segmental glomerulosclerosis. Immunohistochemical studies were performed on human kidney-biopsy specimens and cultured podocytes. Expression studies in vitro were performed to characterize the functional consequences of the mutations identified. RESULTS: We identified two mutations (A159P and Y695X) in MYO1E, which encodes a non-muscle class I myosin, myosin 1E (Myo1E). The mutations in MYO1E segregated with focal segmental glomerulosclerosis in two independent pedigrees (the index family and Family 2). Patients were homozygous for the mutations and did not have a response to glucocorticoid therapy. Electron microscopy showed thickening and dis-organization of the glomerular basement membrane. Normal expression of Myo1E was documented in control human kidney-biopsy specimens in vivo and in glomerular podocytes in vitro. Transfection studies revealed abnormal subcellular localization and function of the A159P-Myo1E mutant. The Y695X mutation causes loss of calmodulin binding and of the tail domains of Myo1E. CONCLUSIONS: MYO1E mutations are associated with childhood-onset, glucocorticoid-resistant focal segmental glomerulosclerosis. Our data provide evidence of a role of Myo1E in podocyte function and the consequent integrity of the glomerular filtration barrier. Copyright © 2011 Massachusetts Medical Society. All rights reserved.


Fischbach M.,University of Strasbourg | Schmitt C.P.,Center for Pediatrics and Adolescent Medicine | Shroff R.,Great Ormond Street Hospital for Children National Health Service Foundation Trust | Zaloszyc A.,University of Strasbourg | Warady B.A.,Childrens Mercy Hospital
Kidney International | Year: 2016

Optimal fluid removal on peritoneal dialysis (PD) requires removal of water coupled with sodium, which is predominantly achieved via the small pores in the peritoneal membrane. On the other hand, free-water transport takes place through aquaporin-1 channels, but leads to sodium retention and over hydration. PD prescription can be adapted to promote small pore transport to achieve improved sodium and fluid management. Both adequate dwell volume and dwell time are required for small pore transport. The dwell volume determines the amount of "wetted" peritoneal membrane being increased in the supine position and optimized at dwell volumes of approximately 1400 ml/m2. Diffusion across the recruited small pores is time-dependent, favored by a long dwell time, and driven by the transmembrane solute gradient. According to the 3-pore model of conventional PD, sodium removal primarily occurs via convection. The clinical application of these principles is essential for optimal performance of PD and has resulted in a new approach to the automated PD prescription: adapted automated PD. In adapted automated PD, sequential short- and longer-dwell exchanges, with small and large dwell volumes, respectively, are used. A crossover trial in adults and a pilot study in children suggests that sodium and fluid removal are increased by adapted automated PD, leading to improved blood pressure control when compared with conventional PD. These findings are not explained by the current 3-pore model of peritoneal permeability and require further prospective crossover studies in adults and children for validation. © 2016 International Society of Nephrology.


Malina M.,Center for Pediatrics and Adolescent Medicine | Malina M.,Charles University | Gulati A.,All India Institute of Medical Sciences | Bagga A.,All India Institute of Medical Sciences | And 3 more authors.
Pediatrics | Year: 2013

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy with severe clinical manifestation, frequent recurrence, and poor long-term prognosis. It is usually caused by abnormalities in complement regulation. We report 2 cases of children affected by a catastrophic extrarenal complication. A 4-year-old Indian girl developed gangrene of the finger tips 2 days after initial presentation of aHUS. Factor H autoantibodies were identified. Renal function continued to decline despite daily plasma exchanges, and she was started on peritoneal dialysis 5 days after admission. The distal tips of the left hand remained gangrenous with a line of demarcation. Three weeks later, she did not return for follow-up and died at home because of dialysis-related complications. An Arabic girl developed end-stage renal disease due to aHUS in the fourth month after birth. A de novo activating C3 mutation was found. At age 9 months, she suddenly developed ischemic changes in fingers of both hands and several toes. The lesions progressed, and several finger tips became gangrenous despite intense plasma exchange therapy. The decision was made to administer complement blocking therapy with the C5 antibody eculizumab. All nonnecrotic digits rapidly regained perfusion. The 3 already gangrenous fingers healed with loss of the end phalanges. During maintenance, eculizumab aHUS activity subsided completely and some late recovery of renal function was observed. aHUS may present by thrombotic macroangiopathy of small peripheral arteries. Eculizumab appears effective in preserving tissue viability if administered before gangrene occurs and should be considered as first-line rescue therapy in such cases. Pediatrics 2013;131:e331-e335. Copyright © 2013 by the American Academy of Pediatrics.


Taskiran E.Z.,Hacettepe University | Korkmaz E.,Hacettepe University | Gucer S.,Hacettepe University | Kosukcu C.,Hacettepe University | And 13 more authors.
Journal of the American Society of Nephrology | Year: 2014

Nephronophthisis (NPHP) is one of the most common genetic causes of CKD; however, the underlying genetic abnormalities have been established in ,50% of patients. We performed genome-wide analysis followed by targeted resequencing in a Turkish consanguineous multiplex family and identified a canonic splice site mutation inANKS6 associatedwith anNPHP-like phenotype. Furthermore,we identified four additional ANKS6 variants in a cohort of 56 unrelated patients diagnosed with CKD due to nephronophthisis, chronic GN, interstitial nephritis, or unknown etiology. Immunohistochemistry in human embryonic kidney tissue demonstrated that the expression patterns of ANKS6 change substantially during development. Furthermore, we detected increased levels of both total and active b-catenin in precystic tubuli in Han:SPRD Cy/+ rats. Overall, these data indicate the importance of ANKS6 in human kidney development and suggest a mechanism by which mutations in ANKS6 may contribute to an NPHP-like phenotype in humans. Copyright © 2014 by the American Society of Nephrology.


Doyon A.,Center for Pediatrics and Adolescent Medicine | Kracht D.,Hannover Medical School | Bayazit A.K.,Cukurova University | Deveci M.,Ege University | And 11 more authors.
Hypertension | Year: 2013

Carotid intima-media thickness (cIMT) and carotid artery distensibility are reliable screening methods for vascular alterations and the assessment of cardiovascular risk in adult and pediatric cohorts. We sought to establish an international reference data set for the childhood and adolescence period and explore the impact of developmental changes in body dimensions and blood pressure (BP) on carotid wall thickness and elasticity. cIMT, the distensibility coefficient, the incremental modulus of elasticity, and the stiffness index β were assessed in 1155 children aged 6 to 18 years and sex-specific reference charts normalized to age or height were constructed from 1051 nonobese and nonhypertensive children. The role of body dimensions, BP, and family history, as well as the association between cIMT and distensibility, was investigated. cIMT increased and distensibility decreased with age, height, body mass index, and BP. A significant sex difference was apparent from the age of 15 years. Age- and height-normalized cIMT and distensibility values differed in children who are short or tall for their age. By stepwise multivariate analysis, standardized systolic BP and body mass index were independently positively associated with cIMT SD scores (SDS). Systolic BP SDS independently predicted all distensibility measures. Distensibility coefficient SDS was negatively and β SDS positively associated with cIMT SDS, whereas incremental modulus of elasticity was independent of cIMT. Morphological and functional aspects of the common carotid artery are particularly influenced by age, body dimensions, and BP. The reference charts established in this study allow to accurately compare vascular phenotypes of children with chronic conditions with those of healthy children. © 2013 American Heart Association, Inc.


Schaefer F.,Center for Pediatrics and Adolescent Medicine | Warady B.A.,Childrens Mercy Hospitals and Clinics
Nature Reviews Nephrology | Year: 2011

Peritoneal dialysis is the preferred chronic dialysis modality for most children owing to its almost universal applicability and superior compatibility with lifestyle over other modalities. Although technological advances and increasing clinical experience have impacted favorably on patient and technique survival, clinical research in pediatric peritoneal dialysis has been hampered by the low incidence of end-stage renal disease (ESRD) in the pediatric population. To overcome this limitation, several international registries have emerged in the past few years to complement other long-standing registries, which together have provided useful information regarding technique-specific complications and comorbidities associated with ESRD in children undergoing chronic peritoneal dialysis. In this Review, we summarize the most relevant findings from these studies, highlighting the substantial variation in patient conditions, peritoneal dialysis practices and management of comorbidities encountered in different parts of the world. © 2011 Macmillan Publishers Limited. All rights reserved.


Warady B.A.,Childrens Mercy Hospital | Neu A.M.,Johns Hopkins University | Schaefer F.,Center for Pediatrics and Adolescent Medicine
American Journal of Kidney Diseases | Year: 2014

Providing optimal care to the infant, child, and adolescent patient who is treated with long-term dialysis therapy mandates that attention be directed to a variety of clinical issues in addition to those related to solute removal and fluid management. Therapeutic plans must be formulated by a multidisciplinary team of pediatric specialists to address the clinical parameters of growth, anemia and osteodystrophy management, cardiovascular health, nutritional adequacy, education, cognitive development, quality of life, preparation for transplantation, and transition to adult care. This review highlights key components of current management recommendations based on a combination of published guidelines, pediatric registry data, and the combined clinical experience of the authors. Whereas some components of this review reflect a modification of the content and recommendations contained in the original publication from more than a decade ago, the contrast emphasizes the advances in understanding and therapeutics of many aspects of pediatric dialysis care that have taken place in the interim. In turn, the content of this article should provide the reader with valuable guidance toward the goal of providing optimal care to patients receiving dialysis. © 2014 by the National Kidney Foundation, Inc.


Karmar R.T.,Karolinska Institutet | Holtback U.,Karolinska Institutet | Anita Bergh A.,Karolinska Institutet | Svensson E.,Karolinska Institutet | Wuhl E.,Center for Pediatrics and Adolescent Medicine
American Journal of Hypertension | Year: 2015

BACKGROUND: Casual blood pressure (CBP) is considered a reliable proxy for cardiovascular health. Although the auscultatory technique is the reference standard method for measuring CBP, oscillometric devices are increasingly being used in children. We sought to establish oscillometric CBP normative standards for Swedish children. METHODS: Cross-sectional oscillometric CBP readings were obtained by the Welch Allyn Spot Vital Signs 420 monitor and measured according to the International Guidelines' recommendations. Participants with elevated oscillometric CBP levels underwent verification by the auscultatory method. Ambulatory blood pressure monitoring (ABPM) was used to exclude casual hypertension. Data on 1,470 (772 males) apparently healthy Swedish schoolchildren aged 6-16 years were analyzed and sex-specific reference charts normalized to age or height were constructed. RESULTS: Systolic and diastolic CBP values were significantly higher with age, height, height standard deviation score (SDS), body mass index (BMI), and BMI SDS. Gender differences for systolic CBP were present starting from age of 15 years and revealed significantly higher values in boys than in girls, whereas for diastolic CBP, the differences were apparent at the age of 12 years, with higher values in girls. Increased BMI and BMI SDS were positively associated with CBP levels. Positive parental history of hypertension turned out to be a risk factor for higher systolic and diastolic CBP across all ages. CONCLUSIONS: Our normative standard for CBP can be used for blood pressure screening and control programs in Swedish children. The use of ABPM should be considered to confirm the diagnosis of casual hypertension. © 2014 © American Journal of Hypertension, Ltd 2014. All rights reserved.


Ozaltin F.,Hacettepe University | Ibsirlioglu T.,Hacettepe University | Taskiran E.Z.,Hacettepe University | Baydar D.E.,Hacettepe University | And 10 more authors.
American Journal of Human Genetics | Year: 2011

Idiopathic nephrotic syndrome (INS) is a genetically heterogeneous group of disorders characterized by proteinuria, hypoalbuminemia, and edema. Because it typically results in end-stage kidney disease, the steroid-resistant subtype (SRNS) of INS is especially important when it occurs in children. The present study included 29 affected and 22 normal individuals from 17 SRNS families; genome-wide analysis was performed with Affymetrix 250K SNP arrays followed by homozygosity mapping. A large homozygous stretch on chromosomal region 12p12 was identified in one consanguineous family with two affected siblings. Direct sequencing of protein tyrosine phosphatase receptor type O (PTPRO; also known as glomerular epithelial protein-1 [GLEPP1]) showed homozygous c.2627+1G>T donor splice-site mutation. This mutation causes skipping of the evolutionarily conserved exon 16 (p.Glu854-Trp876del) at the RNA level. Immunohistochemistry with GLEPP1 antibody showed a similar staining pattern in the podocytes of the diseased and control kidney tissues. We used a highly polymorphic intragenic DNA marker-D12S1303-to search for homozygosity in 120 Turkish and 13 non-Turkish individuals in the PodoNet registry. This analysis yielded 17 candidate families, and a distinct homozygous c.2745+1G>A donor splice-site mutation in PTPRO was further identified via DNA sequencing in a second Turkish family. This mutation causes skipping of exon 19, and this introduces a premature stop codon at the very beginning of exon 20 (p.Asn888Lysfs*3) and causes degradation of mRNA via nonsense-mediated decay. Immunohistochemical analysis showed complete absence of immunoreactive PTPRO. Ultrastructural alterations, such as diffuse foot process fusion and extensive microvillus transformation of podocytes, were observed via electron microscopy in both families. The present study introduces mutations in PTPRO as another cause of autosomal-recessive nephrotic syndrome. © 2011 by The American Society of Human Genetics. All rights reserved.

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