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ABSTRACT: Dent’s disease is an X-linked proximal tubulopathy. It often manifests in childhood with symptoms of Fanconi syndrome and
low-molecular-weight proteinuria. We describe four boys from three unrelated families whose only presenting symptoms of Dent’s
disease were nephrotic-range proteinuria and histological findings of focal segmental and/or global glomerulosclerosis. In
all families, a causal mutation in the CLCN5 gene, encoding a voltage-gated chloride transporter and chloride-proton exchanger, was identified. All three mutations are
pathogenic: two are novel (p.Asp727fs and p.Trp122X), and one is a recurrent mutation, p.R648X. Given the atypical phenotype of these patients with Dent’s disease, it is possible that this clinical entity is markedly
underdiagnosed and that our report represents only the tip of the iceberg. The diagnosis of Dent’s disease should be considered
in all patients with nephrotic-range proteinuria without hypoalbuminemia or edema. Establishing the diagnosis of Dent’s disease
will prevent the administration of unnecessary immunosuppressive medications with their undesirable side effects.
Pediatric Nephrology 04/2012; 24(12):2369-2373. · 2.52 Impact Factor
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ABSTRACT: Myocardial damage and strain are common in children with chronic renal failure. The most prevalent pathologies, as defined by echocardiography, are left ventricular hypertrophy (LVH), diastolic and systolic dysfunction, and altered LV geometry. Troponin I and T, as well as B-type natriuretic peptide (BNP) and its cleavage fragment NT-proBNP, are known to be good markers of myocardial damage and stress, respectively, in the general adult population and among those with chronic kidney disease (CKD). In this study we measured the levels of troponins I and T, BNP, and NT-proBNP in a group of children and young adults with CKD stages 3-5 and determined their respective correlations with echocardiographic and laboratory abnormalities. BNP and NT-proBNP levels and their log values correlated well with the following parameters: diastolic blood pressure, estimated glomerular filtration rate, time-averaged hemoglobin levels, and LV mass. Both BNP and NT-proBNP levels, but not those of either troponin, were found to be reliable surrogate markers of strained hearts, defined as having LVH or diastolic or systolic dysfunction, in the pediatric CKD stages 3-4 group. The log NT-proBNP value was also found to be a good marker of cardiac strain in the CKD stage 5 group of patients. Serum BNP and NT-proBNP threshold concentrations of 43 and 529 pg/ml, respectively, were found to have the best sensitivity and specificity in predicting strained hearts. Based on these findings, we conclude that both BNP and NT-proBNP levels, but not those of troponins I and T, can serve as inexpensive, simple, and reliable markers of stressed hearts in the pediatric CKD patient population.
Pediatric Nephrology 04/2012; 27(4):617-25. · 2.52 Impact Factor
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ABSTRACT: Three patients with Dent's disease presented with complaints of impaired night vision or xerophthalmia and were found to have severely decreased serum retinol concentrations. Retinol, bound to its carrier retinol-binding protein (RBP), is filtered at the glomerulus and reabsorbed at the proximal tubule. We hypothesized that urinary loss of retinol-RBP complex is responsible for decreased serum retinol.
The study aim was to investigate vitamin A status and RBP in serum and urine of patients with genetically confirmed Dent's disease.
Eight patients were studied, three boys had clinical vitamin A deficiency, three had asymptomatic deficiency, and two young men with Dent's disease and impaired renal function had normal retinol values. Serum RBP concentrations were low in patients with vitamin A deficiency and were correlated with vitamin A levels. Urinary RBP concentrations were increased in all patients (2,000-fold), regardless of vitamin A status. This was in contrast to patients with glomerular proteinuria who had only mildly increased urinary RBP with normal serum RBP and vitamin A, and patients with cystinosis with impaired renal function who had massive urinary RBP losses but without a decrease in serum RBP or vitamin A levels. Treatment with vitamin A supplements in patients with retinol deficiency resulted in rapid resolution of ocular symptoms and an increase in serum retinol concentrations.
Vitamin A deficiency is common in patients with Dent's disease and preserved renal function. We therefore recommend screening these patients for retinol deficiency and treating them before visual symptoms develop.
Pediatric Nephrology 02/2012; 27(7):1097-102. · 2.52 Impact Factor
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ABSTRACT: An uncharacterized multisystemic mitochondrial cytopathy was diagnosed in two infants from consanguineous Palestinian kindred living in a single village. The most significant clinical findings were tubulopathy (hyperuricemia, metabolic alkalosis), pulmonary hypertension, and progressive renal failure in infancy (HUPRA syndrome). Analysis of the consanguineous pedigree suggested that the causative mutation is in the nuclear DNA. By using genome-wide SNP homozygosity analysis, we identified a homozygous identity-by-descent region on chromosome 19 and detected the pathogenic mutation c.1169A>G (p.Asp390Gly) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. The same homozygous mutation was later identified in a third infant with HUPRA syndrome. The carrier rate of this mutation among inhabitants of this Palestinian isolate was found to be 1:15. The mature enzyme catalyzes the ligation of serine to two mitochondrial tRNA isoacceptors: tRNA(Ser)(AGY) and tRNA(Ser)(UCN). Analysis of amino acylation of the two target tRNAs, extracted from immortalized peripheral lymphocytes derived from two patients, revealed that the p.Asp390Gly mutation significantly impacts on the acylation of tRNA(Ser)(AGY) but probably not that of tRNA(Ser)(UCN). Marked decrease in the expression of the nonacylated transcript and the complete absence of the acylated tRNA(Ser)(AGY) suggest that this mutation leads to significant loss of function and that the uncharged transcripts undergo degradation.
The American Journal of Human Genetics 02/2011; 88(2):193-200. · 10.60 Impact Factor
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Ruth Belostotsky,
Eric Seboun,
Gregory H Idelson,
Dawn S Milliner,
Rachel Becker-Cohen,
Choni Rinat,
Carla G Monico, Sofia Feinstein,
Efrat Ben-Shalom,
Daniella Magen,
Irith Weissman,
Celine Charon,
Yaacov Frishberg
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ABSTRACT: Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis. We determined that mutations in an uncharacterized gene, DHDPSL, on chromosome 10 cause a third type of PH (PH III). To overcome the difficulties in data analysis attributed to a state of compound heterozygosity, we developed a strategy of "heterozygosity mapping"-a search for long heterozygous patterns unique to all patients in a given family and overlapping between families, followed by reconstruction of haplotypes. This approach enabled us to determine an allelic fragment shared by all patients of Ashkenazi Jewish descent and bearing a 3 bp deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation. Our assumption is that DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline.
The American Journal of Human Genetics 09/2010; 87(3):392-9. · 10.60 Impact Factor
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ABSTRACT: Cardiovascular disease causes major morbidity and is an important determinant of premature death in the paediatric chronic kidney disease (CKD) population. It is composed of three separate, although interrelated, disease processes: atherosclerosis, arteriosclerosis (i.e. medial vascular calcifications) and myocardial disease. Myocardial consequences of atherosclerosis barely exist in children, thus providing a good opportunity to investigate the role that kidney disease plays in the development of cardiovascular disease.
We assessed 70 patients, aged 4 months to 18 years, with chronic kidney disease stages 3-5, for known risk factors of cardiovascular disease and for additional laboratory and clinical variables which may have an impact on this disease process. Carotid artery ultrasound was used to evaluate vascular structure and function, whereas myocardial disease was assessed by echocardiography.
Traditional risk factors, although present in this cohort, did not accumulate with progression of chronic kidney disease. Non-traditional risk factors increased in number and severity in correlation with the stage of CKD. The main myocardial abnormalities were left ventricular hypertrophy and diastolic dysfunction. Vascular function tests correlated with calcium-phosphate metabolism variables, homocysteine and time-averaged serum uric acid.
This study shows that children with CKD are exposed to risk factors and demonstrate signs of cardiovascular disease already at a young age. The possible role of uric acid and homocysteine in the evolution of cardiovascular disease is discussed. Further studies looking at possible interventions to prevent cardiovascular morbidity and mortality in this high risk population are needed.
Nephrology Dialysis Transplantation 11/2009; 25(3):785-93. · 3.40 Impact Factor
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ABSTRACT: Dent's disease is an X-linked proximal tubulopathy. It often manifests in childhood with symptoms of Fanconi syndrome and low-molecular-weight proteinuria. We describe four boys from three unrelated families whose only presenting symptoms of Dent's disease were nephrotic-range proteinuria and histological findings of focal segmental and/or global glomerulosclerosis. In all families, a causal mutation in the CLCN5 gene, encoding a voltage-gated chloride transporter and chloride-proton exchanger, was identified. All three mutations are pathogenic: two are novel (p.Asp727fs and p.Trp122X), and one is a recurrent mutation, p.R648X. Given the atypical phenotype of these patients with Dent's disease, it is possible that this clinical entity is markedly underdiagnosed and that our report represents only the tip of the iceberg. The diagnosis of Dent's disease should be considered in all patients with nephrotic-range proteinuria without hypoalbuminemia or edema. Establishing the diagnosis of Dent's disease will prevent the administration of unnecessary immunosuppressive medications with their undesirable side effects.
Pediatric Nephrology 10/2009; 24(12):2369-73. · 2.52 Impact Factor
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ABSTRACT: Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease, and it is prevalent in children with end-stage renal disease (ESRD) and after renal transplantation (RTx) on cross-sectional studies. Our aim was to compare prospectively left ventricular mass index (LVMI) in children with ESRD, before and after RTx. Thirteen patients aged 1.5-15 years underwent echocardiogram prior to and at least 3 months after RTx, and again in the second year after transplantation. A control group consisted of children with ESRD who remained on dialysis. Systolic and diastolic blood pressure index decreased significantly over the study period only in the children who had undergone RTx. Mean LVMI in children with ESRD decreased from 45.4 +/- 12.6 g/m(2.7) to 34.9 +/- 10.4 g/m(2.7) after RTx (P = 0.001), but it remained unchanged in patients who remained on dialysis. The prevalence of LVH decreased from 54% to 8% (P = 0.03) after RTx. Systolic and diastolic blood pressure index were correlated with LVMI. Mean body mass index increased during the study period from 17.3 +/- 2.5 to 20 +/- 4.6 (P = 0.05); however, no correlation was found with LVMI. LVH in children with ESRD is potentially reversible after RTx, especially with good control of hypertension.
Pediatric Nephrology 10/2008; 23(9):1545-50. · 2.52 Impact Factor
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ABSTRACT: Congenital analbuminemia is a rare autosomal recessive disease in which albumin is not synthesized. Patients with this disorder generally have minimal symptoms despite complete absence of the most abundant serum protein. We report a family in which the proband presented with acute glomerulonephritis and was found to have underlying congenital analbuminemia. Consequently, the patient's two older sisters were diagnosed with the same condition. Sequencing of the human serum albumin gene was performed, and a homozygous mutation in exon 3 was found in all three patients. Together with these three patients of Arab ethnicity, this mutation, known as Kayseri, is the most frequently described mutation in congenital analbuminemia. This article discusses clinical features and diagnostic challenges of this disorder, particularly in this case, where concomitant renal disease was present.
Pediatric Nephrology 10/2008; 24(2):403-6. · 2.52 Impact Factor
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Nephrology Dialysis Transplantation 07/2008; 23(6):2109. · 3.40 Impact Factor
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Yaacov Frishberg,
Nobuaki Ito,
Choni Rinat,
Yuji Yamazaki, Sofia Feinstein,
Itaru Urakawa,
Paulina Navon-Elkan,
Rachel Becker-Cohen,
Takeyoshi Yamashita,
Kaori Araya,
Takashi Igarashi,
Toshiro Fujita,
Seiji Fukumoto
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ABSTRACT: Two hyperphosphatemic patients with mutations in GALNT3 showed low intact FGF23 levels with marked increase of processed C-terminal fragments. FGF23 protein has three O-linked glycans and FGF23 with incomplete glycosylation is susceptible to processing. Silencing GALNT3 resulted in enhanced processing of FGF23. Decreased function of FGF23 by enhanced processing is the cause of hyperphosphatemia in patients with GALNT3 mutation.
Hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive entity manifesting as severe hyperphosphatemia associated with episodic bone pain and radiological findings of cortical hyperostosis and periosteal reaction. Persistent hyperphosphatemia is not counterbalanced by PTH or 1,25-dihydroxyvitamin D, posing a mirror image of hypophosphatemic states attributed to increased fibroblast growth factor (FGF)23 activity.
We describe two children with HHS who were found to be homozygous for a mutation in GALNT3 encoding a peptide involved in mucin-type O-glycosylation (ppGaNTase-T3). FGF23 levels were evaluated by two ELISAs and Western blotting. FGF23 protein was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Effect of silencing GALNT3 was evaluated using siRNA in cells transfected with expression vector for FGF23.
Both patients had low levels of the full-length FGF23 with markedly augmented amounts of the inactive fragments. Biologically active FGF23 has three O-linked glycans. FGF23 with only one or two O-linked glycans is processed into inactive fragments. Decreasing the expression of the GALNT3 gene by RNA interference resulted in enhanced processing of FGF23.
The primary defect in HHS is impairment of glycosylation of FGF23 resulting from mutations in GALNT3 and leading to augmented processing of FGF23. These changes in FGF23 abolish its phosphaturic effect and lead to severe persistent hyperphosphatemia. This study provides the pathogenetic mechanism of the first mucin-type O-glycosylation defect identified.
Journal of Bone and Mineral Research 03/2007; 22(2):235-42. · 6.37 Impact Factor
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ABSTRACT: Congenital nephrotic syndrome of the Finnish type (CNF, NPHS1) is a rare autosomal recessive disease caused by mutations in the NPHS1 gene encoding nephrin. We diagnosed congenital nephrotic syndrome in 12 children living in a village near Jerusalem. Most of the inhabitants are descendants of one Muslim family and have maintained their isolation by preference of consanguineous marriages. The aim of this study was to confirm that the NPHS1 gene is responsible for congenital nephrotic syndrome in our population, applying homozygosity mapping.
DNA samples were genotyped by four microsatellite markers that were in linkage disequilibrium with the NPHS1 gene on chromosome 19q13.1. Immunoperoxidase staining was used to study the expression of nephrin, and mutations were subsequently identified by direct sequencing of the entire coding region of the NPHS1 gene.
Haplotype analysis revealed several different haplotypes, leading us to assume erroneously that there was genetic heterogeneity of congenital nephrotic syndrome. Because nephrin was completely absent in kidney tissue of one patient, direct sequencing of all DNA samples was performed, yielding three novel mutations: c.1138C>T (p.Gln380X), c.2160_ 2161insC (p.Cys721fs), and c.1707C>G (p.Ser569Arg). Patients were either homozygous for one of these mutations or compound heterozygotes, and they differed in their phenotype.
We report the potential pitfalls of performing homozygosity mapping in a highly consanguineous population and discuss the phenomenon of multiple mutations in a given gene within an isolate.
Genetics in Medicine 03/2007; 9(3):180-4. · 4.76 Impact Factor
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ABSTRACT: Despite good outcomes in pediatric renal transplantation, life expectancy is reduced, mostly as a result of accelerated atherosclerosis. A comprehensive evaluation of cardiac status and risk factors for cardiovascular disease was performed in 60 patients after renal transplantation (age 3 to 29 yr; mean 15.8). Posttransplantation diabetes was diagnosed in 7%. Half of the patients did not engage in any physical activity, and this was associated with increased body mass index. Uncontrolled hypertension was found in 13% of patient, and 53% were on antihypertensive medications. BP index was associated with left ventricular mass index (LVMI). Dyslipidemia was relatively uncommon, with hypercholesterolemia found in 15% and elevated LDL cholesterol found in 10% of patients. Hyperhomocysteinemia was frequent (58%); in most patients, it was not due to folate or B(12) deficiency. Lipid and homocysteine abnormalities were associated with cyclosporine therapy. Echocardiography demonstrated normal LVMI in 93% of patients, although LVMI was higher than in healthy control subjects. Cardiac troponin I was normal in all patients, but N-terminal pro-brain natriuretic peptide was elevated in 35% and was associated with LVMI and renal function. Although present cardiac status is relatively normal in pediatric renal transplantation patients, cardiac risk factors are common, and strategies to prevent cardiovascular disease need to be developed.
Clinical Journal of the American Society of Nephrology 12/2006; 1(6):1284-92. · 5.23 Impact Factor
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ABSTRACT: The aim of the study was to analyze systematically our observation that children with severe nephrotic syndrome (NS) have hyperphosphatemia despite normal kidney function. Forty-seven children with NS and normal glomerular filtration rate (GFR) were studied [26 with steroid-sensitive nephrotic syndrome (SSNS) and 21 with persistent NS]. The plasma phosphate level was expressed as the number of standard deviations (SDs) from the mean levels in age- and gender-matched controls. In SSNS plasma phosphate concentration was elevated (+3.7+/-2.0 SDs) during relapse and normalized (-0.7+/-1.7 SDs) in remission. In persistent NS the phosphate level was +4.0+/-2.1 SDs. Patients with marked hyperphosphatemia (>4 SDs) were younger (p<0.001), had lower plasma albumin (p<0.001), and had higher urinary protein levels (p<0.05). Hyperphosphatemia did not correlate with GFR, plasma calcium, or urinary sodium levels. Children with persistent NS had decreased serum 25(OH)D(3) and insulin-like growth factor 1 (IGF-1) concentrations. Hyperphosphatemia is prevalent among children with persistent nephrotic syndrome and normal renal function, correlates with its severity, and may result from increased urinary IGF-1 wasting.
Pediatric Nephrology 10/2006; 21(10):1406-12. · 2.52 Impact Factor
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ABSTRACT: Lesch-Nyhan disease (LND) is a rare X-linked recessive disorder caused by virtually complete deficiency of activity of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT; EC 2.4.2.8). Human HPRT is encoded by a single structural gene located on the long arm of the X-chromosome (Xq26). The classical LND phenotype occurs almost exclusively in males, manifested in excessive purine production and characteristic neurological manifestations, including compulsive self-mutilation, choreoathetosis, spasticity, and occasionally developmental delay. Heterozygous females are usually phenotypically normal, due to the random inactivation of the X chromosome (Lyonization mechanism). However, six females were reported to be affected with the full biochemical and clinical manifestations of LND. All these cases were heterozygous for an HPRT mutation. Absence of transcription of the normal HPRT allele was attributed in all of them to non-random inactivation of the X chromosome carrying the normal allele. Here we describe an additional LND female, who presented with acute renal failure at the age of two months, in whom absence of transcription of the two HPRT alleles occurred due to as yet undescribed mechanism in LND females: the transcription of one HPRT allele was blocked due to a de novo X chromosome-autosome translocation 46,XX,t(X:2)(q26:p25), with a breaking point encompassing the HPRT gene locus, whereas the transcription of the normal allele was inhibited due to non-random inactivation of the second X-chromosome. Cultured fibroblasts from this patient exhibited the biochemical alterations in purine nucleotide metabolism characteristic of male LND fibroblasts.
Molecular Genetics and Metabolism 04/2006; 87(3):249-52. · 3.19 Impact Factor
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ABSTRACT: Mutations in the gene NPHS2 encoding podocin are responsible for a recessive form of steroid-resistant nephrotic syndrome (SRNS). The common phenotype is of massive proteinuria in early childhood that tends to progress to end-stage renal failure. Extrarenal manifestations have not been described. Twenty-two children with SRNS from six unrelated Arab families were found to be homozygous for the R138X mutation in NPHS2. Eighteen patients underwent cardiac evaluation at diagnosis of SRNS while they had normal BP and preserved renal function. Cardiac anomalies were detected in 16 (89%) children: Left ventricular hypertrophy in eight, pulmonary stenosis in six, discrete subaortic stenosis in two, and Ebstein anomaly and ventricular septal defect in one each. The remaining four affected individuals were assessed only once they had end-stage renal failure. They had severe left ventricular hypertrophy and experienced repeated episodes of heart failure. Two control groups were equally evaluated. The first consisted of 37 siblings without nephrotic syndrome, of whom only one carrier had a cardiac defect (P < 0.001). None of the second group, which included 22 children with persistent nephrotic syndrome as a result of other causes, had a cardiac anomaly (P < 0.001). Cardiac disorders in homozygotes for mutations in NPHS2 cannot be attributed to an association by chance or to a state of persistent nephrotic syndrome. Because human podocin mRNA is expressed in fetal heart, it is speculated that it may have a role in normal cardiac development. Cardiac evaluation is recommended at the time of diagnosis of SRNS due to mutations in podocin.
Journal of the American Society of Nephrology 01/2006; 17(1):227-31. · 9.66 Impact Factor
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ABSTRACT: To evaluate the prevalence of noncompliance and factors that influence poor adherence to immunosuppressive drug regimens among kidney transplant recipients.
We reviewed immunosuppressive drug compliance in 79 posttransplant patients. Patient self-report and low plasma calcineurin inhibitor levels served as indicators of noncompliance.
The prevalence of noncompliance was found to be highest in adolescents who were responsible for their own medications and who underwent cadaveric kidney transplantation (CTx; 45.5%) and lower after living related transplantation (28.6%). There were no documented cases of noncompliance among any recipient of living unrelated (commercial) transplantation. Among 13 noncompliant patients, the first indication of "drug holiday" was low plasma calcineurin inhibitor levels in 11 children. Two additional children presented with acute rejection. In 7 patients, repeated episodes of "drug holidays" led to acute rejection later: 21.4 +/- 13.2 months after the first decrease in plasma calcineurin inhibitor level had been recorded. All 9 patients who experienced acute rejection subsequently developed chronic rejection. In 4 patients, noncompliance did not influence graft function. Psychosocial factors that were associated with noncompliance included insufficient family support, low self-awareness caused by poor cognitive abilities, and denial.
The absence of cases of noncompliance in adolescents who underwent commercial living unrelated kidney transplantation suggests that although noncompliance is prevalent, it is not inevitable. Strategies to decrease noncompliance in young patients with chronic illnesses can be learned from the experience with transplant recipients. The general pediatrician has a central role in identifying and addressing the problem of noncompliance in adolescents with chronic disease.
PEDIATRICS 05/2005; 115(4):969-73. · 4.47 Impact Factor
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ABSTRACT: To evaluate the allocation and outcome of cadaver-donor renal transplantation (CDRTx) among Jewish and Arab children in Israel.
Data on CDRTxs in patients who had end-stage renal failure (ESRF), were younger than 18 years, and were on dialysis treatment were obtained for the 11-year period of January 1990 to December 2000 from the Israeli Dialysis and Transplant Registry, supplemented by 10 years of follow-up (January 1991-December 2000) from our own center.
The Israeli Dialysis and Transplant Registry data show that 64 of 130 available cadaver-donor kidneys (CDKs) were allocated to Jewish patients (49.2%) and 66 of 130 were allocated to Arab children (50.8%): Moslem, Druze, or Christian. The Jew/Arab patient ratio for a waiting time of <1 year was 0.97 and for 1 to 2 years was 1.45, whereas that ratio was 0.6 for 2 to 4 years and 2.0 for >4 years. The mean renal transplant score (RTx score), reflecting the urgency of the need for RTx of an ESRF patient, was identical for Jew and Arab: 4.93 and 4.96. Our own center data refer to 69 dialysis (47 Arabs and 22 Jews) and 4 predialysis patients younger than 18 years who underwent 78 RTxs. Eighteen Arab and 14 Jewish children from our center received 20 and 15 CDRTxs in Israel, with a mean waiting time of 29.6 and 25.4 months for Jew and Arab, respectively (ratio: 1.16). In our center, the outcome (after 7 years) of graft survival and function was not different between Jewish and Arab RTx recipients.
Allocation of CDRTxs between young Jewish and Arab ESRF patients on dialysis did not differ and was associated with comparable waiting times, identical RTx scores, and similar long-term outcome. This is a remarkable finding, certainly in the face of the unequal race allocation of RTxs in the United States as well as the long unstable local (Middle East) political situation.
PEDIATRICS 09/2003; 112(2):341-4. · 4.47 Impact Factor
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ABSTRACT: We report a girl with congenital nephrotic syndrome (CNS) associated with cytomegalovirus (CMV) infection and histological findings on renal biopsy that suggested a causal relationship between the two. She was subsequently found to be homozygous for a nonsense mutation in the NPHS2 gene encoding podocin (R138X), which is the true cause of her NS. Based on review of the literature and our findings in this patient, we propose that the clinical entity known as CMV causing CNS may not exist.
Pediatric Nephrology 04/2003; 18(3):273-5. · 2.52 Impact Factor
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ABSTRACT: We identified a novel point mutation (I137T) in the hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8) encoding gene, in a patient with partial deficiency of the enzyme (variant of Lesch-Nyhan syndrome). The mutation, ATT to ACT, resulting in substitution of isoleucine to threonine, occurred at codon 137 (exon 6), which is within the region encoding the binding site for 5-phosphoribosyl-1-pyrophosphate (PRPP). We suggest the mechanism by which the mutation-induced structural alteration of HPRT reduced the affinity of the enzyme for PRPP.
Molecular Genetics and Metabolism 03/2003; 78(2):158-61. · 3.19 Impact Factor
