RESUMEN
BACKGROUND: Because infections constitute a major cause of morbidity and mortality in paediatric renal allograft recipients, avoidance of preventable systemic infections by vaccination before transplantation is of utmost importance. However, data on the completeness of vaccinations and factors associated with incomplete vaccination coverage are scarce. METHODS: Within the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national, retrospective study investigating the vaccination coverage before transplantation of 254 European children with end-stage renal disease (mean age 10.0 ± 5.6 years). RESULTS: Only 22 out of 254 patients (8.7%) presented complete vaccination coverage. In particular, the respective vaccination coverage against human papillomavirus (27.3%), pneumococci (42.0%), and meningococci (47.9%) was low. Patients with complete pneumococcal vaccination coverage had numerically less lower respiratory tract infections during the first 3 years post-transplant than children without vaccination or with an incomplete status (16.4% vs 27.7%, p = 0.081). Vaccine-preventable diseases post-transplant were 4.0 times more frequently in unvaccinated than in vaccinated patients. Factors associated with an incomplete vaccination coverage were non-Caucasian ethnicity (OR 9.21, p = 0.004), chronic dialysis treatment before transplantation (OR 6.18, p = 0.001), and older age at transplantation (OR 1.33, p < 0.001). CONCLUSIONS: The vaccination coverage in paediatric kidney transplant candidates is incomplete. Paediatric nephrologists, together with primary-care staff and patients' families, should therefore make every effort to improve vaccination rates before kidney transplantation.
Asunto(s)
Fallo Renal Crónico , Trasplante de Riñón , Vacunación/estadística & datos numéricos , Adolescente , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND.: In 2011 Escherichia coli O104:H4 caused an outbreak with >800 cases of hemolytic uremic syndrome (HUS) in Germany, including 90 children. Data on the intermediate outcome in children after HUS due to E. coli O104:H4 have been lacking. METHODS.: Follow-up data were gathered retrospectively from the medical records of patients who had been included in the German Pediatric HUS Registry during the 2011 outbreak. RESULTS.: Seventy-two of the 89 (81%) patients were included after a median follow-up of 3.0 (0.9-4.7) years. Hypertension and proteinuria were present in 19% and 28% of these patients, respectively. Of 4 patients with chronic kidney disease (CKD) > stage 2 at short-term follow-up, 1 had a normalized estimated glomerular filtration rate, and 3 (4%) had persistent CKD > stage 2. In 1 of these patients, CKD improved from stage 4 to 3; 1 who had CKD stage 5 at presentation received kidney transplantation; and 1 patient required further hemodialysis during follow-up. One patient (1.4%) still had major neurological symptoms at the latest follow-up. Dialysis during the acute phase (P = .01), dialysis duration (P = .01), and the duration of oligo-/anuria (P = .005) were associated with the development of renal sequelae. Patients treated with eculizumab (n = 11) and/or plasmapheresis (n = 13) during the acute phase of HUS had comparable outcomes. CONCLUSIONS.: The overall outcome of pediatric patients after HUS due to E. coli O104:H4 was equivalent to previous reports on HUS due to other types of Shiga toxin-producing E. coli (STEC). Regular follow-up visits in patients are recommended after STEC-HUS.
Asunto(s)
Brotes de Enfermedades , Infecciones por Escherichia coli/complicaciones , Infecciones por Escherichia coli/microbiología , Escherichia coli O104/aislamiento & purificación , Síndrome Hemolítico-Urémico/complicaciones , Síndrome Hemolítico-Urémico/epidemiología , Adolescente , Anticuerpos Monoclonales Humanizados/uso terapéutico , Niño , Preescolar , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/epidemiología , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Tasa de Filtración Glomerular , Síndrome Hemolítico-Urémico/microbiología , Humanos , Hipertensión/epidemiología , Hipertensión/etiología , Trasplante de Riñón , Masculino , Registros Médicos , Pronóstico , Proteinuria/epidemiología , Proteinuria/etiología , Diálisis Renal , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/etiología , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: The epidemiology and morbidity of Epstein-Barr virus (EBV) infection in pediatric renal transplant recipients have been characterized insufficiently. METHODS: In a prospective, multicenter study among 106 pediatric kidney allograft recipients aged 11.4 ± 5.9 years, we investigated the epidemiology of EBV infection and the relationship between EBV load, EBV serology, and EBV-related morbidity (posttransplant lymphoproliferative disease [PTLD] or symptomatic EBV infection, defined as flu-like symptoms or infectious mononucleosis). RESULTS: EBV primary infection occurred in 27 of 43 (63%) seronegative patients and reactivation/reinfection in 28 of 63 (44%) seropositive patients. There was no association between the degree or duration of EBV load and EBV-related morbidity: The vast majority (17 of 18 [94%]) of patients with a high, persistent EBV load remained PTLD-free throughout a follow-up of 5.0 ± 1.3 years, while 2 of 3 (66%) patients with EBV-related PTLD exhibited only a low EBV load beforehand. Eight of 18 (44%) patients with a high, persistent EBV load remained asymptomatic during a follow-up of 5.3 ± 2.9 years. Multivariate analysis identified the EBV high-risk (D(+)/R(-)) serostatus (odds ratio [OR], 7.07; P < .05), the presence of human leukocyte antigen (HLA)-DR7 (OR, 5.65; P < .05), and the intensity of the immunosuppressive therapy (OR, 1.53; P < .01) as independent risk factors for the development of a symptomatic EBV infection. CONCLUSIONS: Presence of EBV high-risk seroconstellation, HLA-DR7, and intensity of immunosuppressive therapy are significant risk factors for a symptomatic EBV infection, whereas there is no close association between the degree or duration of EBV load and EBV-related morbidity. Clinical Trials Registration. NCT00963248.
Asunto(s)
Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4/aislamiento & purificación , Trasplante de Riñón/estadística & datos numéricos , Adolescente , Análisis de Varianza , Antivirales/uso terapéutico , Niño , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/terapia , Infecciones por Virus de Epstein-Barr/virología , Femenino , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/prevención & control , Herpesvirus Humano 4/inmunología , Humanos , Inmunosupresores/uso terapéutico , Trastornos Linfoproliferativos/epidemiología , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/virología , Masculino , Morbilidad , Estudios Prospectivos , Estadísticas no Paramétricas , Trasplantes/estadística & datos numéricos , Carga ViralRESUMEN
BACKGROUND: In May and June 2011 the largest known outbreak of hemolytic uremic syndrome (HUS) occurred in northern Germany. Because, quite unusually, a large number of adults was affected and the causative Escherichia coli strain, serotype O104:H4, showed an atypical virulence factor pattern, it was speculated that this outbreak was associated with an aggressive course and an unfavorable prognosis also in children. METHODS: Retrospective analysis of medical records of 90 children and comparison to previous outbreak and sporadic case series. RESULTS: Median age was unusually high (11.5 years) compared with that in historical series. Only 1 patient (1.1%) died in the acute phase. Most patients (67/90 [74%]) received supportive care only. Renal replacement therapy was required in 64 of 90 (71%) of the children. Neurological complications, mainly seizures and altered mental stage, were present in 23 of 90 (26%) patients. Ten patients received plasmapheresis, 6 eculizumab, and 7 a combination of both. After a median follow-up of 4 months, renal function normalized in 85 of 90 (94%) patients, whereas 3 patients had chronic kidney disease stage 3 or 4, and 1 patient (1.1%) still requires dialysis. Complete neurological recovery occurred in 18 of 23 patients. Mild to moderate and major residual neurological changes were present in 3 patients and 1 patient, respectively, although all patients were still improving. CONCLUSIONS: E. coli O104:H4 caused the largest HUS outbreak in children reported in detail to date and most patients received supportive treatment only. Initial morbidity, as well as short-term outcome, due to this pathogen, is comparable to previous pediatric series of Shiga toxin-producing E. coli HUS.
Asunto(s)
Brotes de Enfermedades , Síndrome Hemolítico-Urémico/epidemiología , Escherichia coli Shiga-Toxigénica/clasificación , Escherichia coli Shiga-Toxigénica/aislamiento & purificación , Adolescente , Niño , Preescolar , Femenino , Alemania/epidemiología , Humanos , Lactante , Masculino , Terapia de Reemplazo Renal/métodos , Estudios Retrospectivos , Escherichia coli Shiga-Toxigénica/genética , Resultado del TratamientoRESUMEN
Epstein-Barr virus (EBV) primary infection constitutes a serious risk for pediatric transplant recipients, particularly as regards the development of EBV-related post-transplant lymphoproliferative disease (PTLD). Currently, there is no established prophylactic regimen. We investigated the association between chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) and the incidence of EBV viremia in EBV-naïve pediatric renal transplant recipients (R-) who had received a graft from an EBV-positive donor (D+) and are therefore at high risk of EBV primary infection. In a prospective, multicenter trial (n = 114), we compared a cohort on chemoprophylaxis (n = 20) with a similar control cohort without chemoprophylaxis (n = 8). Over the 1-year study period, antiviral prophylaxis with VGCV/GCV was associated with a significantly decreased incidence of EBV primary infection: 9/20 patients (45%) in the prophylaxis group experienced an EBV primary infection compared to 8/8 controls (100%) (P < 0.0001). Chemoprophylaxis was associated with a significantly lower EBV viral load (P < 0.001). Type or intensity of immunosuppressive therapy did not influence the occurrence of EBV primary infection or the level/persistence of EBV viral load. Chemoprophylaxis with VGCV/GCV is associated with a reduced incidence of EBV viremia in high-risk pediatric kidney allograft recipients in the first year post-transplant. (ClinicalTrials.gov number: NCT00963248).
Asunto(s)
Infecciones por Virus de Epstein-Barr/prevención & control , Ganciclovir/análogos & derivados , Ganciclovir/uso terapéutico , Herpesvirus Humano 4/metabolismo , Trasplante de Riñón/métodos , Adulto , Antivirales/uso terapéutico , Quimioprevención/métodos , Niño , Estudios de Cohortes , Femenino , Humanos , Inmunosupresores/uso terapéutico , Trastornos Linfoproliferativos/etiología , Masculino , Pediatría/métodos , Estudios Prospectivos , ValganciclovirRESUMEN
BACKGROUND: Fetuin-A and vitamin D are significant correlates of cardiovascular morbidity in paediatric chronic kidney disease (CKD) patients. It is thus far unknown, whether or not serum fetuin-A is affected by the vitamin D status or treatment with vitamin D preparations in these patients. METHODS: In a cross-sectional study, serum concentrations of fetuin-A, 25-hydroxyvitamin D(3) (25OHD) and 1,25-dihydroxyvitamin D(3) (calcitriol) levels were determined in 112 paediatric patients with mild-to-severe CKD (Stages 1-5) and after renal transplantation. A25OHD supplementation and/or calcitriol treatment were given in 64% of the patients. RESULTS: Fetuin-A levels were clearly reduced in dialysis patients but were comparable to healthy controls in those with moderate CKD and after transplantation. Although 64 and 46% of all patients received 25OHD and/or calcitriol treatment, 48 and 20% of patients were 25OHD and/or calcitriol deficient, respectively. Within the whole patient cohort, fetuin-A correlated with serum calcium and yearly weight-related 25OHD dosage (each P < 0.01) but not with the vitamin D status per se. Multiple regression analysis revealed the need for dialysis treatment and cumulative 25OHD dosage as independent predictors of fetuin-A concentrations (model r(2) = 0.17). In dialysis patients, fetuin-A was inversely correlated with serum C-reactive protein but positively correlated with cumulative calcitriol dosage and serum parathormone (each P < 0.01). CONCLUSIONS: Fetuin-A levels are clearly reduced in children on dialysis but not in those with moderate CKD and after transplantation. Besides the degree of microinflammation, the cumulative intake of 25OHD and calcitriol are significantly correlated to fetuin-A in these patients. The impact of vitamin D treatment appears to be at least partly mediated by serum calcium.
Asunto(s)
Calcitriol/administración & dosificación , Fallo Renal Crónico/sangre , Vitamina D/análogos & derivados , Vitamina D/sangre , alfa-2-Glicoproteína-HS/metabolismo , Adolescente , Proteína C-Reactiva/metabolismo , Calcio/sangre , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Recién Nacido , Fallo Renal Crónico/tratamiento farmacológico , Trasplante de Riñón , Masculino , Hormona Paratiroidea/sangre , Diálisis Renal , Terapia de Reemplazo RenalRESUMEN
BACKGROUND: The extracellular protein fetuin-A is a potent soluble inhibitor of calcification, and its deficiency has been associated with vascular calcification in dialysis patients. In proteinuric patients, significant urinary losses of fetuin-A may cause low serum fetuin-A levels. METHODS: In a cross-sectional study, urinary/serum concentrations of fetuin-A were investigated in proteinuric children with glomerular diseases and preserved renal function (n = 58) in comparison to healthy controls (n = 246). RESULTS: Mean fetuin-A serum concentrations were clearly reduced in children with nephrotic syndrome (0.25 ± 0.14 g/l, p < 0.001), slightly reduced in children with large proteinuria (0.39 ± 0.15 g/l, p < 0.05), and comparable to controls in those with mild proteinuria (0.45 ± 0.14 vs. 0.46 ± 0.12 g/l). Fetuin-A was positively correlated with serum protein (r = 0.58), albumin (r = 0.57), and calcium (r = 0.64), but negatively correlated with proteinuria (r = -0.41), albuminuria (r = -0.46), and urinary fetuin-A excretion (r = -0.48; each p < 0.001). The fractional excretion of fetuin-A was significantly associated with the degree of proteinuria and serum fetuin-A levels. However, the urinary loss of fetuin-A and albumin in nephrotic children differed by three orders of magnitude and the mean fractional excretion of fetuin-A was only 1/10 of that of albumin (0.016 ± 0.029 vs. 0.162 ± 0.403%; p < 0.001). CONCLUSIONS: Fetuin-A is clearly reduced in children with nephrotic syndrome and associated with the degree of hypoalbuminemia. This is due to urinary fetuin-A loss and/or reduced hepatic synthesis. Persistent fetuin-A deficiency may have an impact on cardiovascular morbidity in nephrotic children.
Asunto(s)
Enfermedades Renales/sangre , Enfermedades Renales/orina , Proteinuria/sangre , alfa-2-Glicoproteína-HS/biosíntesis , alfa-2-Glicoproteína-HS/orina , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Hipoalbuminemia , Lactante , Recién Nacido , Glomérulos Renales/patología , Masculino , Nefrosis , Síndrome Nefrótico/sangre , Síndrome Nefrótico/orina , Proteinuria/orinaAsunto(s)
Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cromosomas Humanos Par 3/genética , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Fenotipo , Trastornos de la Pupila/genética , Trastornos de la Pupila/patología , Disomía Uniparental/genética , Secuencia de Bases , Biopsia , Resultado Fatal , Alemania , Haplotipos/genética , Humanos , Riñón/patología , Laminina/genética , Laminina/metabolismo , Masculino , Datos de Secuencia Molecular , Síndromes Miasténicos Congénitos , Síndrome Nefrótico , Análisis de Secuencia de ADNRESUMEN
DEAP-HUS [Deficiency of CFHR (complement factor H-related) plasma proteins and Autoantibody Positive form of Hemolytic Uremic Syndrome] represents a novel subtype of hemolytic uremic syndrome (HUS) with unique characteristics. It affects children and requires special clinical attention in terms of diagnosis and therapy. DEAP-HUS and other atypical forms of HUS share common features, such as microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia. However, DEAP-HUS has the unique combination of an acquired factor in the form of autoantibodies to the complement inhibitor Factor H and a genetic factor which, in most cases, is the chromosomal deletion of a 84-kbp fragment within human chromosome 1 that results in the absence of the CFHR1 and CFHR3 proteins in plasma. Special attention is required to diagnose and treat DEAP-HUS patients. Most patients show a favorable response to the reduction of autoantibody titers by either plasma therapy, steroid treatment, and/or immunosuppression. In addition, in those DEAP-HUS patients with end-stage renal disease, the reduction of autoantibody titers prior to transplantation is expected to prevent post-transplant disease recurrence by aiming for full complement control at the endothelial cell surface in order to minimize adverse complement and immune reactions.
Asunto(s)
Autoanticuerpos/inmunología , Factor H de Complemento/inmunología , Síndrome Hemolítico-Urémico , Autoanticuerpos/sangre , Autoantígenos/inmunología , Proteínas Sanguíneas/deficiencia , Niño , Proteínas Inactivadoras del Complemento C3b/deficiencia , HumanosRESUMEN
BACKGROUND: Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor. METHODS: After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion. RESULTS: A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease. CONCLUSIONS: Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Hipertensión/tratamiento farmacológico , Ramipril/administración & dosificación , Insuficiencia Renal Crónica/tratamiento farmacológico , Adolescente , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antihipertensivos/uso terapéutico , Presión Sanguínea , Monitoreo Ambulatorio de la Presión Arterial , Niño , Preescolar , Creatinina/orina , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/etiología , Estimación de Kaplan-Meier , Fallo Renal Crónico/prevención & control , Masculino , Proteinuria/etiología , Ramipril/efectos adversos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
BACKGROUND: Serum fetuin-A has been shown to be a strong risk marker for myocardial infarction/stroke in the general population, and has been associated with vascular calcifications in patients with chronic kidney disease. Although these issues are worthy of being addressed in children and adolescents as well, adequate age- and gender-related reference values are missing. METHOD: Within a healthy paediatric population (n = 246), fetuin-A serum concentrations were determined (ELISA kit; Epitope Diagnostics, San Diego, CA, USA) essentially as described by the manufacturer. At the same time, serum protein and serum albumin were measured with established procedures (Beckman Coulter Inc., Krefeld, Germany). Subjects were stratified according to age (<1 yr [n = 25], > or =1 and <6 yr [n = 65], > or =6 and <12 yr [n = 66], > or =12 yr and <16 [n = 45] and > or =16 yr [n = 45]), and both genders were equally distributed within each age cohort. RESULTS: Within each age cohort, fetuin-A serum concentrations were normally distributed, independent of age and gender and the respective reference range (mean +/- 1.96 SD) is 0.22-0.70 g/L (0.46 +/- 0.24 g/L). CONCLUSION: Fetuin-A serum concentrations are independent of age and gender in a healthy paediatric population and are well comparable with those determined in adults with the same assay.
Asunto(s)
Química Clínica/métodos , alfa-Fetoproteínas/biosíntesis , Adolescente , Niño , Preescolar , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Valores de Referencia , Factores de RiesgoRESUMEN
The aim of this study was to investigate the hepatic microsomal and cytosolic functions by using the 13CO2 breath test in healthy subjects either before or after consumption of red wine. Twelve adults received [13C2]aminopyrine and L-[1-13C]phenylalanine together with a standardised dinner. Expired air samples were taken over 6 h. After a wash-out period, the subjects consumed 0.4 ml ethanol per kg per day together with dinner over a 7.5-day period on average. Thereafter, 13C-tracer administration was repeated under identical conditions. The 13CO2 enrichments were measured by isotope ratio mass spectrometry. The mean cumulative percentage 13C-dose recovery after administration of [13C2]aminopyrine and L-[1-13C]phenylalanine either without or with red wine consumption amounted to 17.0+/-4.4 vs. 14.7+/-3.1% (p=0.170) and 14.0+/-2.8 vs. 11.5+/-3.9% (p=0.084), respectively. Moderate alcohol consumption does not induce significant short-term changes of the microsomal and the cytosolic function of the human liver in healthy subjects.
Asunto(s)
Aminopirina/análisis , Pruebas Respiratorias , Isótopos de Carbono , Etanol/farmacología , Hígado/efectos de los fármacos , Fenilalanina/análisis , Adulto , Aminopirina/metabolismo , Dióxido de Carbono/análisis , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hígado/metabolismo , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Fenilalanina/metabolismo , Vino , Adulto JovenRESUMEN
To investigate whether submicroscopic chromosomal deletions or duplications can be causative of unclear syndromic nephropathies, we analyzed ten patients with congenital abnormalities of the kidney and urinary tract or glomerulopathies combined with important extrarenal anomalies by whole-genome array-based comparative genomic hybridization. In a 14-year-old girl presenting with hematuria, proteinuria, mental retardation (MR), sensorineural hearing loss, dysmorphisms, and epilepsy, we detected a microdeletion in chromosome Xq22.3-q23. This deletion was verified and characterized by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification analyses, found to be de novo, uniallelic and 3.3 Mb in size. Electron microscopy of a kidney biopsy showed glomerular basement membrane thinning and segmental splitting of the lamina densa compatible with Alport syndrome. Cranial magnetic resonance and diffusion tensor imaging detected a severe neuronal migration disorder with double cortex formation and pronounced reduction of the fronto-occipital tract system. Thus, in one of ten patients with unclear syndromic nephropathies we identified a previously undescribed contiguous gene syndrome at Xq22.3-q23. The microdeletion contains the X-linked Alport syndrome gene COL4A5, the MR genes FACL4 and PAK3, and parts of the X-chromosomal lissencephaly gene DCX associated with double cortex formation in girls, MR, and epilepsy. The phenotype in our patient combines features of the Alport-MR contiguous gene syndrome with lissencephaly.
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos X , Eliminación de Gen , Enfermedades Renales/genética , Anomalías Urogenitales/genética , Adolescente , Encéfalo/patología , Hibridación Genómica Comparativa , ADN/análisis , Femenino , Humanos , Hibridación Fluorescente in Situ , Enfermedades Renales/patología , Imagen por Resonancia Magnética , Masculino , Nefritis Hereditaria/genética , Nefritis Hereditaria/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Síndrome , Anomalías Urogenitales/patologíaRESUMEN
Acute rejection episodes following pediatric renal transplantation have been progressively reduced by recent immunosuppressive regimens. Nevertheless, grafts continue to fail over time and surrogate parameters for long-term RGS are lacking. We investigated post-transplant renal function within the first yr as an independent predictor of long-term RGS in 104 pediatric first kidney transplant recipients (mean age 11.1 +/- 3.9 yr; mean follow-up 8.3 +/- 3.5 yr) transplanted between January 1989 and December 2000. GFR was assessed by use of the Schwartz formula at 30 days and six and 12 months after transplantation, respectively. Patients were further stratified at all times according to GFR: (i) GFR<45 mL/min/1.73 m(2), (ii) GFR 45-80 mL/min/1.73 m(2), and (iii) GFR>80 mL/min/1.73 m(2). Cox regression analysis including factors potentially influencing long-term RGS, e.g., age, gender, transplant yr, HLA-mismatch, underlying renal disease, clinical acute rejection, absolute GFR as well as the change in GFR within the first yr was performed. Graft failure occurred in 24 out of 104 patients (23%) 6.2 yr (mean) after transplantation corresponding to a cumulative five-yr graft survival of 87.5%. GFRs at 30 days and six and 12 months were significantly associated with long-term RGS in the univariate cox regression analysis (GFR at 30 days, p = 0.045; GFR at six months, p = 0.004; GFR at 12 months, p < 0.001). None of the other variables were significant parameters of correlation. Multivariate cox analysis revealed a GFR below 45 mL/min/1.73 m(2) at 12 months after transplantation as the only independent predictor of long-term RGS (hazard ratio 55.9, 95% CI 5.29-591, p = 0.001). GFR at 12 months post-transplant is an excellent surrogate parameter for long-term RGS in children. This parameter might be useful as a primary end-point in short-term pediatric clinical trials.
Asunto(s)
Tasa de Filtración Glomerular , Supervivencia de Injerto/fisiología , Enfermedades Renales/cirugía , Trasplante de Riñón/fisiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Enfermedades Renales/fisiopatología , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Factores de TiempoRESUMEN
Long-term survival of children and adolescents with chronic kidney disease (CKD) is mainly limited by cardiovascular disease. Pediatric CKD patients (n = 26) on conservative treatment, dialysis and after renal transplantation were compared with healthy controls (n = 24) with respect to cardiovascular status. Mean baseline diameter of the brachial artery was significantly higher, and mean flow-mediated vasodilation (FMD) was significantly reduced, in CKD patients. CKD patients showed significantly increased left ventricular mass index, blood pressure (BP) values and age-related values of mean carotid intima-media thickness [intima-media thickness-standard deviation score (IMT-SDS)] compared with those of controls. Approximately 60% of patients presented with impaired FMD (< or = 5.79%), which was significantly associated with intima-media thickening, although only three patients (12%) presented with both, impaired FMD and increased age-related IMT. The latter was significantly associated with higher values for day-time BP. In contrast, duration and degree of CKD, mode of renal replacement therapy, homocysteine levels and concomitant medication showed no association with cardiovascular status. The majority of our pediatric CKD patients showed reduced endothelial function, which may have preceded the development of carotid arteriopathy. Therefore, routine assessment of FMD may be a useful tool to identify CKD patients at risk of progressive cardiovascular morbidity.
Asunto(s)
Sistema Cardiovascular/patología , Sistema Cardiovascular/fisiopatología , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Adolescente , Presión Sanguínea/fisiología , Arteria Braquial/fisiopatología , Arterias Carótidas/patología , Estudios de Casos y Controles , Niño , Preescolar , Enfermedad Crónica , Progresión de la Enfermedad , Endotelio Vascular/fisiopatología , Femenino , Ventrículos Cardíacos/patología , Humanos , Masculino , Proyectos Piloto , Flujo Sanguíneo Regional/fisiología , Túnica Íntima/patología , Túnica Media/patología , Adulto JovenRESUMEN
The aim of this study was to investigate the hepatic microsomal and mitochondrial functions by using the 13CO2-breath test in healthy subjects either before or after the consumption of red wine. Fourteen adults received [13C]methacetin and [methyl-13C]methionine together with a standardised dinner. Expired air samples were taken over 6 h. After a wash-out period, the subjects consumed 0.4 ml ethanol/kg/day together with dinner over a 10-day period. Thereafter, 13C-tracer administration was repeated under identical conditions. The 13CO2-enrichments were measured by isotope ratio mass spectrometry. The mean cumulative percentage 13C-dose recovery (CPDR) after administration of [13C]methacetin and [methyl-13C]methionine either without or with red wine consumption amounted to 38.2+/-6.3 vs. 36.3+/-6.7% (p=0.363) and 9.5+/-3.3 vs. 8.8+/-2.5% (p=0.47), respectively. Moderate alcohol consumption does not induce significant short-term changes of the microsomal and the mitochondrial functions of the human liver in healthy subjects.
Asunto(s)
Consumo de Bebidas Alcohólicas/metabolismo , Pruebas Respiratorias/métodos , Isótopos de Carbono/análisis , Fase I de la Desintoxicación Metabólica/fisiología , Microsomas Hepáticos/metabolismo , Mitocondrias Hepáticas/metabolismo , Adulto , Estudios Cruzados , Etanol/metabolismo , Femenino , Humanos , Masculino , VinoRESUMEN
The efficacy and acceptability of cinacalcet for treatment of secondary hyperparathyroidism (SHPT) was assessed in seven pediatric patients suffering from end-stage renal disease (ESRD) presenting with inadequately controlled SHPT despite conventional management. Patients received daily treatment with cinacalcet (dosage 0.25 mg/kg body weight) for a total of 4 weeks. Within 4 h after application of the first dose, median levels of serum parathyroid hormone (PTH) had decreased from 932 pg/ml (range 511-1,938 pg/ml) to 584 pg/ml (88-937 pg/ml), and final pre-dose values after 4 weeks were 199 pg/ml (121-940 pg/ml; each P < 0.05 versus baseline). Median concentrations of serum calcium (Ca) decreased within 4 h of the first administration, from 2.56 mmol/l to 2.38 mmol/l, returning to 2.58 mmol/l at 24 h, and they remained slightly decreased compared to baseline values thereafter (each P < 0.05 versus baseline). Both the median levels of serum phosphorus (P) and the Ca x P ion product decreased significantly during the 4-week period. Cinacalcet was well tolerated and without drug-related adverse effects. Thus, even with approximately half of the dose usually given to adult dialysis patients, PTH and the Ca x P ion product were markedly reduced in pediatric ESRD patients presenting with inadequately controlled SHPT. Therefore, our results support the initiation of a randomized, controlled, long-term trial in children.
Asunto(s)
Hiperparatiroidismo Secundario/tratamiento farmacológico , Fallo Renal Crónico/complicaciones , Naftalenos/uso terapéutico , Adolescente , Adulto , Calcio/sangre , Niño , Preescolar , Cinacalcet , Femenino , Humanos , Hiperparatiroidismo Secundario/sangre , Lactante , Masculino , Naftalenos/efectos adversos , Hormona Paratiroidea/sangre , Fósforo/sangreRESUMEN
BACKGROUND: Severe growth failure is frequently observed in children suffering from end-stage renal disease (ESRD). METHODS: We analyzed the effect of renal transplantation (RTx) on longitudinal growth and final height in 37 children (19 girls) with ESRD with a mean follow-up of 8.5 years. The mean age at RTx was 11.3 years. RESULTS: In children transplanted before start of puberty, mean height velocity increased significantly from 4.9 to 8.0 cm/year (P < 0.01), resulting in an increase in standardized height of 0.6 SD within two years post RTx. Although peak height velocity during puberty was significantly increased compared with healthy children, total pubertal height gain was reduced by 20% because of its shortened duration. Mean standardized height significantly increased from the time of RTx until final height by 1.3 SD and 0.7 SD in children transplanted before and after start of puberty, respectively. Mean adult height (boys 170 cm; girls 151 cm) was normal (> -2 SD) in 68% of patients. Change in standardized height from RTx until adult height was associated with initial degree of stunting and glomerular filtration rate (GFR; cumulative r2 0.49). Total pubertal height gain was associated with the age at start of puberty, GFR, and age at RTx (cumulative r2 0.57). CONCLUSION: RTx in children with ESRD induces moderate catch-up growth during the prepubertal growth period. However, final height is reduced in about one third of patients due to the reduced pubertal height gain and preexisting height deficit at the time of RTx.
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Estatura , Trastornos del Crecimiento/prevención & control , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Adolescente , Niño , Femenino , Estudios de Seguimiento , Crecimiento , Trastornos del Crecimiento/diagnóstico , Humanos , Estudios Longitudinales , Masculino , Valor Predictivo de las Pruebas , PubertadRESUMEN
In contrast to the increased hepatic albumin synthesis in subjects with proteinuria, little is known about the corresponding whole-body protein turnover rates (WPTR). The WPTR and the reutilisation rates (R) were investigated in 20 patients divided in three groups of different degrees of proteinuria (groups I-III: < 1, 1-3, > 3 g/m2/day, respectively). [15N]glycine was administered as a single oral pulse. Urine samples were taken over 2 days. After removing urinary proteins by trichloracetic acid, 15N-enrichment in the supernatant was measured by isotope ratio mass spectrometry. A three-compartment model was used to calculate WPTR and R, which showed a statistically significant difference between groups I and III (2.64 vs. 4.63 g/kg/day, and 70.4% vs. 80.8%, respectively, P < 0.01), whereas the net protein gain remained unchanged (0.13 vs. 0.22 g/kg/day). The higher the protein loss the higher the WPTR and the corresponding R. The severe protein loss provokes increased WPTR and R as well.
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Síndrome Nefrótico/fisiopatología , Proteínas/metabolismo , Proteinuria/fisiopatología , Adolescente , Niño , Preescolar , Femenino , Glicina/administración & dosificación , Glicina/metabolismo , Humanos , Masculino , Isótopos de Nitrógeno , Distribución TisularRESUMEN
By screening patients with X-linked nephrogenic diabetes insipidus (NDI) for mutations within the V(2) vasopressin receptor (AVPR2) gene, we have identified six novel and two recurrent mutations. Additionally, one patient revealed a genomic deletion of 3.2 kb encompassing most of the AVPR2 gene and the last exon/3'-region of C1 gene, which is in close proximity to the AVPR2 locus. In-depth characterization of the mutant AVPR2s by a combination of functional and immunological techniques allowed to gain further insight into molecular mechanisms leading to the receptor dysfunction. Aiming at the functional reconstitution of mutant G protein-coupled receptors, several strategies of potential therapeutic usefulness have been tested. Because the functional rescue of truncated receptors is most challenging, we addressed this issue by applying an aminoglycoside approach. Here, we demonstrate that the misreading capacity of the aminoglycoside antibiotic geneticin was sufficient to restore function of mutant AVPR2s harboring premature stop codons in an in vitro expression system.