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1.
Kidney Int Rep ; 9(6): 1684-1693, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38899185

RESUMEN

Introduction: We investigated the relationship between metabolic acidosis over time and allograft outcome in pediatric kidney transplantation (KTx). Methods: This registry study collected data up to 10 years posttransplant. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤ 30 ml/min per 1.73 m2 or ≥50% decline from eGFR at month 3 posttransplant was performed. The association of serum bicarbonate concentration (HCO3 -) < 22 mmol/l (metabolic acidosis) and HCO3 - < 18 mmol/l (severe metabolic acidosis) with allograft outcome was investigated using stratified Cox models and marginal structural models. Secondary analyses included the identification of risk factors for metabolic acidosis and the relationship between alkali supplementation and allograft outcome. Results: We report on 1911 patients, of whom 347 reached the composite end point. The prevalence of metabolic acidosis over time ranged from 20.4% to 38.9%. In the adjusted Cox models, metabolic acidosis (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.54-2.60) and severe metabolic acidosis (HR, 2.49; 95% CI, 1.56-3.99) were associated with allograft dysfunction. Marginal structural models showed similar results (HR, 1.75; 95% CI, 1.32-2.31 and HR, 2.09; 95% CI, 1.23-3.55, respectively). Older age was associated with a lower risk of metabolic acidosis (odds ratio [OR] 0.93/yr older; 95% CI, 0.91-0.96) and severe metabolic acidosis (OR, 0.89; 95% CI, 0.84-0.95). Patients with uncontrolled metabolic acidosis had the worst outcome compared to those without metabolic acidosis and without alkali (HR, 3.70; 95% CI, 2.54-5.40). Conclusion: The degree of metabolic acidosis is associated with allograft dysfunction.

2.
Kidney Int Rep ; 8(1): 81-90, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36644359

RESUMEN

Introduction: Little is known about the consequences of deranged chronic kidney disease-mineral and bone disorder (CKD-MBD) parameters on kidney allograft function in children. We examined a relationship between these parameters over time and allograft outcome. Methods: This registry study from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) collected data at baseline, months 1, 3, 6, 9, and 12 after transplant; and every 6 months thereafter up to 5 years. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤30 ml/min per 1.73 m2 or a ≥50% decline from eGFR at month 1 posttransplant was performed. Associations of parathyroid hormone (PTH), calcium, phosphate, and 25-hydroxyvitamin D (25(OH)D) with allograft outcome were investigated using conventional stratified Cox proportional hazards models and further verified with marginal structural models with time-varying covariates. Results: We report on 1210 patients (61% boys) from 16 European countries. The composite end point was reached in 250 grafts (21%), of which 11 (4%) were allograft losses. In the conventional Cox proportional hazards models adjusted for potential confounders, only hyperparathyroidism (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.82-4.74) and hyperphosphatemia (HR, 1.94; 95% CI, 1.28-2.92) were associated with the composite end point. Marginal structural models showed similar results for hyperparathyroidism (HR, 2.74; 95% CI, 1.71-4.38), whereas hyperphosphatemia was no longer significant (HR, 1.35; 95% CI, 0.87-2.09), suggesting that its association with graft dysfunction can be ascribed to a decline in eGFR. Conclusion: Hyperparathyroidism is a potential independent risk factor for allograft dysfunction in children.

3.
Pediatr Nephrol ; 34(12): 2571-2582, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31428929

RESUMEN

BACKGROUND: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients. METHODS: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6-17 years with initial eGFR of 10-60 ml/min per 1.73 m2. RESULTS: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 µmol/l (8.7) and 17.0 µmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors. CONCLUSIONS: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort.


Asunto(s)
Indicán/sangre , Insuficiencia Renal Crónica/sangre , Adolescente , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Niño , Cresoles/sangre , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Fenotipo , Insuficiencia Renal Crónica/complicaciones , Ésteres del Ácido Sulfúrico/sangre
4.
Transplantation ; 103(6): 1224-1233, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30130322

RESUMEN

BACKGROUND: BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking. METHODS: We analyzed the data of 313 patients in the Cooperative European Pediatric Renal Transplant Initiative Registry, with an observation period of 3.3 years (range, 1-5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score. RESULTS: Presumptive BKPyVAN (defined as sustained [>3 wk] high-level BK viremia >10 copies/mL) within 5 years posttransplant occurred in 49 (15.8%) of 311 patients, and biopsy-proven BKPyVAN in 14 (4.5%) of 313. BKPyV viremia was observed in 115 (36.7%) of 311 patients, of whom 11 (9.6%) of 115 developed viremia late, that is, after the second year posttransplant. In 6 (12.5%) of 48 patients with high-level viremia and in 3 (21.4%) of 14 with BKPyVAN, this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated not only with a higher net state of immunosuppression (odds ratio [OR], 1.3; P < 0.01) and with tacrolimus-based versus ciclosporin-based immunosuppression (OR, 3.6; P < 0.01) but also with younger recipient age (OR, 1.1 per y younger; P < 0.001) and obstructive uropathy (OR, 12.4; P < 0.01) as primary renal disease. CONCLUSIONS: Uncontrolled BKPyV replication affects a significant proportion of pediatric renal transplant recipients and is associated with unique features of epidemiology and risk factors, such as young recipient age, obstructive uropathy, and overall intensity of immunosuppressive therapy. BKPyV surveillance should be considered beyond 2 years posttransplant in pediatric patients at higher risk.


Asunto(s)
Virus BK/crecimiento & desarrollo , Inmunosupresores/efectos adversos , Enfermedades Renales/epidemiología , Trasplante de Riñón/efectos adversos , Infecciones Oportunistas/epidemiología , Infecciones por Polyomavirus/epidemiología , Infecciones Tumorales por Virus/epidemiología , Replicación Viral , Adolescente , Factores de Edad , Antivirales/uso terapéutico , Virus BK/efectos de los fármacos , Virus BK/inmunología , Niño , Preescolar , Europa (Continente)/epidemiología , Femenino , Humanos , Huésped Inmunocomprometido , Enfermedades Renales/inmunología , Enfermedades Renales/virología , Estudios Longitudinales , Masculino , Infecciones Oportunistas/tratamiento farmacológico , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/virología , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Infecciones Tumorales por Virus/tratamiento farmacológico , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Carga Viral
5.
Pediatr Nephrol ; 33(12): 2343-2352, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30058047

RESUMEN

BACKGROUND: JC polyomavirus (JCPyV)-associated nephropathy (JCPyVAN) is a severe, but rare complication in adult renal transplant (RTx) recipients. Related data in pediatric patients are scarce. METHODS: Based on the CERTAIN Registry, we therefore performed a multi-center, retrospective study on the JCPyV antibody status, prevalence of JCPyV replication, and its associated disease in 139 pediatric RTx recipients (mean age, 8.5 ± 5.3 years). JCPyV DNA in plasma and/or urine was measured by quantitative PCR at a median time of 3.2 (IQR, 0.3-8.1) years post-transplant. RESULTS: 53.2% of patients were JCPyV-seronegative prior to transplantation; younger age was associated with JCPyV seronegativity. 34/139 (24.5%) patients post-transplant showed active JCPyV replication in either urine (22.0%), plasma (13.4%), or both (7.6%). JCPyV viremia occurred significantly (p < 0.001) more often in patients with viruria (34.6%) than in those without (7.6%), but 7/118 (5.9%) had isolated viremia. High-level viruria (> 107 copies/mL) was found in 29.6% of viruric patients. A higher net state of immunosuppression constituted an independent risk factor for JCPyV replication both in urine and plasma (OR 1.2, p < 0.02). Male patients tended to have a higher risk of JCPyV viremia than females (OR 4.3, p = 0.057). There was one male patient (0.7%) with JCPyVAN 7 years post-transplant, which resolved after reduction of immunosuppressive therapy. No patient exhibited progressive multifocal leukoencephalopathy. CONCLUSIONS: This first multi-center study on JCPyV in pediatric renal transplant recipients shows that JCPyV replication is common (24.5%), with strong immunosuppression being a significant risk factor, but associated nephropathy is rare.


Asunto(s)
Virus JC/aislamiento & purificación , Enfermedades Renales/epidemiología , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/epidemiología , Viremia/epidemiología , Adolescente , Niño , Preescolar , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Terapia de Inmunosupresión/efectos adversos , Enfermedades Renales/inmunología , Enfermedades Renales/virología , Masculino , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Prevalencia , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos , Receptores de Trasplantes/estadística & datos numéricos , Viremia/inmunología , Viremia/virología
6.
Clin J Am Soc Nephrol ; 12(12): 1974-1983, 2017 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-29146700

RESUMEN

BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Ciliopatías/genética , Enfermedades Renales Quísticas/congénito , Fallo Renal Crónico/genética , Proteínas de la Membrana/genética , Fenotipo , Adolescente , Anemia/genética , Antígenos de Neoplasias/genética , Proteínas de Unión a Calmodulina/genética , Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Niño , Ciliopatías/complicaciones , Estudios Transversales , Proteínas del Citoesqueleto , Femenino , Tasa de Filtración Glomerular/genética , Homocigoto , Humanos , Riñón/diagnóstico por imagen , Enfermedades Renales Quísticas/complicaciones , Enfermedades Renales Quísticas/diagnóstico por imagen , Enfermedades Renales Quísticas/genética , Fallo Renal Crónico/fisiopatología , Cinesinas/genética , Estudios Longitudinales , Masculino , Proteínas de Neoplasias/genética , Enfermedades del Sistema Nervioso/genética , Poliuria/genética , Proteínas/genética , Ultrasonografía , Adulto Joven
7.
BMJ Open ; 7(6): e015593, 2017 06 12.
Artículo en Inglés | MEDLINE | ID: mdl-28606904

RESUMEN

OBJECTIVES: It is known that transition, as a shift of care, marks a vulnerable phase in the adolescents' lives with an increased risk for non-adherence and allograft failure. Still, the transition process of adolescents and young adults living with a kidney transplant in Germany is not well defined. The present research aims to assess transition-relevant structures for this group of young people. Special attention is paid to the timing of the process. SETTING: In an observational study, we visited 21 departments of paediatric nephrology in Germany. Participants were doctors (n=19), nurses (n=14) and psychosocial staff (n=16) who were responsible for transition in the relevant centres. Structural elements were surveyed using a short questionnaire. The experiential viewpoint was collected by interviews which were transcribedverbatim before thematic analysis was performed. RESULTS: This study highlights that professionals working within paediatric nephrology in Germany are well aware of the importance of successful transition. Key elements of transitional care are well understood and mutually agreed on. Nonetheless, implementation within daily routine seems challenging, and the absence of written, structured procedures may hamper successful transition. CONCLUSIONS: While professionals aim for an individual timing of transfer based on medical, social, emotional and structural aspects, rigid regulations on transfer age as given by the relevant health authorities add on to the challenge. TRIAL REGISTRATION NUMBER: ISRCTN Registry no 22988897; results (phase I) and pre-results (phase II).


Asunto(s)
Trasplante de Riñón/psicología , Transición a la Atención de Adultos/organización & administración , Transición a la Atención de Adultos/normas , Adolescente , Factores de Edad , Femenino , Alemania , Humanos , Entrevistas como Asunto , Masculino , Investigación Cualitativa , Encuestas y Cuestionarios , Factores de Tiempo , Adulto Joven
8.
Pediatr Transplant ; 21(3)2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28370750

RESUMEN

Dyslipidemia contributes to cardiovascular morbidity and mortality in pediatric transplant recipients. Data on prevalence and risk factors in pediatric cohorts are, however, scarce. We therefore determined the prevalence of dyslipidemia in 386 pediatric renal transplant recipients enrolled in the CERTAIN registry. Data were obtained before and during the first year after RTx to analyze possible non-modifiable and modifiable risk factors. The prevalence of dyslipidemia was 95% before engraftment and 88% at 1 year post-transplant. Low estimated glomerular filtration rate at 1 year post-transplant was associated with elevated serum triglyceride levels. The use of TAC and of MPA was associated with significantly lower concentrations of all lipid parameters compared to regimens containing CsA and mTORi. Immunosuppressive regimens consisting of CsA, MPA, and steroids as well as of CsA, mTORi, and steroids were associated with a three- and 25-fold (P<.001) increased risk of having more than one pathologic lipid parameter as compared to the use of TAC, MPA, and steroids. Thus, amelioration of the cardiovascular risk profile after pediatric RTx may be attained by adaption of the immunosuppressive regimen according to the individual risk profile.


Asunto(s)
Inmunosupresores/uso terapéutico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Adolescente , Adulto , Niño , Preescolar , Femenino , Tasa de Filtración Glomerular , Humanos , Terapia de Inmunosupresión/métodos , Lactante , Lípidos/sangre , Masculino , Prevalencia , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Esteroides/uso terapéutico , Resultado del Tratamiento , Triglicéridos/sangre , Adulto Joven
9.
Clin Infect Dis ; 64(12): 1637-1643, 2017 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-28329394

RESUMEN

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 Joven
10.
Transplantation ; 100(4): 862-70, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26736017

RESUMEN

BACKGROUND: Cytomegalovirus (CMV) replication and disease, with its associated morbidity and poor transplant outcome, represents a serious threat to transplant recipients. The pediatric kidney transplant population is at a particularly increased risk of CMV infection. METHODS: We therefore analyzed CMV epidemiology in a large cohort of pediatric renal transplant recipients (n = 242) and assessed the impact of antiviral chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) on CMV replication and morbidity. RESULTS: While antiviral chemoprophylaxis with VGCV or GCV in patients with a high (D+/R-) or intermediate (D+/R+) CMV risk (n = 82) compared to preemptive therapy (n = 47) had no significant effect on the incidence of CMV syndrome or tissue-invasive disease, chemoprophylaxis was associated with a better preservation of transplant function at 3 years posttransplant (loss of estimated glomerular filtration rate in the chemoprophylaxis cohort, 16.0 ± 3.4 vs. 30.1 ± 4.7 mL/min per 1.73 m(2) in the preemptive therapy cohort, P < 0.05).CMV replication was associated with a more pronounced decline of graft function (difference in estimated glomerular filtration rate of 9.6 mL/min per 1.73 m(2) at 3 years) compared to patients without CMV replication. However, patients undergoing VGCV or GCV chemoprophylaxis had more leukocytopenia. CONCLUSION: Antiviral chemoprophylaxis with VGCV or GCV in recipients with a high or moderate CMV risk is associated with a better preservation of transplant function. Hence, the prevention of CMV replication in this patient population has the potential to improve transplant outcome.


Asunto(s)
Antivirales/administración & dosificación , Infecciones por Citomegalovirus/prevención & control , Citomegalovirus/efectos de los fármacos , Ganciclovir/análogos & derivados , Trasplante de Riñón , Infecciones Oportunistas/prevención & control , Adolescente , Factores de Edad , Antivirales/efectos adversos , Niño , Preescolar , Citomegalovirus/patogenicidad , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Esquema de Medicación , Europa (Continente)/epidemiología , Femenino , Ganciclovir/administración & dosificación , Ganciclovir/efectos adversos , Supervivencia de Injerto/efectos de los fármacos , Humanos , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Incidencia , Trasplante de Riñón/efectos adversos , Masculino , Infecciones Oportunistas/epidemiología , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/virología , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Valganciclovir
11.
Clin J Am Soc Nephrol ; 11(2): 245-53, 2016 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-26668027

RESUMEN

BACKGROUND AND OBJECTIVES: Treatment of congenital nephrotic syndrome (CNS) and steroid-resistant nephrotic syndrome (SRNS) is demanding, and renal prognosis is poor. Numerous causative gene mutations have been identified in SRNS that affect the renal podocyte. In the era of high-throughput sequencing techniques, patients with nongenetic SRNS frequently escape the scientific interest. We here present the long-term data of the German CNS/SRNS Follow-Up Study, focusing on the response to cyclosporin A (CsA) in patients with nongenetic versus genetic disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cross-sectional and longitudinal clinical data were collected from 231 patients with CNS/SRNS treated at eight university pediatric nephrology units with a median observation time of 113 months (interquartile range, 50-178). Genotyping was performed systematically in all patients. RESULTS: The overall mutation detection rate was high at 57% (97% in CNS and 41% in SRNS); 85% of all mutations were identified by the analysis of three single genes only (NPHS1, NPHS2, and WT1), accounting for 92% of all mutations in patients with CNS and 79% of all mutations in patients with SRNS. Remission of the disease in nongenetic SRNS was observed in 78% of patients after a median treatment period of 2.5 months; 82% of nongenetic patients responded within 6 months of therapy, and 98% of patients with nongenetic SRNS and CsA-induced complete remission (normalbuminemia and no proteinuria) maintained a normal renal function. Genetic SRNS, on the contrary, is associated with a high rate of ESRD in 66% of patients. Only 3% of patients with genetic SRNS experienced a complete remission and 16% of patients with genetic SRNS experienced a partial remission after CsA therapy. CONCLUSIONS: The efficacy of CsA is high in nonhereditary SRNS, with an excellent prognosis of renal function in the large majority of patients. CsA should be given for a minimum period of 6 months in these patients with nongenetic SRNS. In genetic SRNS, response to CsA was low and restricted to exceptional patients.


Asunto(s)
Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Riñón/efectos de los fármacos , Síndrome Nefrótico/congénito , Adolescente , Austria , Biopsia , Niño , Preescolar , Estudios Transversales , Ciclosporina/efectos adversos , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Alemania , Humanos , Inmunosupresores/efectos adversos , Lactante , Péptidos y Proteínas de Señalización Intracelular/genética , Riñón/patología , Riñón/fisiopatología , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/genética , Estudios Longitudinales , Masculino , Proteínas de la Membrana/genética , Mutación , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/genética , Síndrome Nefrótico/fisiopatología , Fenotipo , Recuperación de la Función , Inducción de Remisión , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Proteínas WT1/genética
12.
J Am Soc Nephrol ; 27(2): 604-14, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26047794

RESUMEN

Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.


Asunto(s)
Hipercalcemia/genética , Enfermedades del Recién Nacido/genética , Errores Innatos del Metabolismo/genética , Mutación , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Proteínas Cotransportadoras de Sodio-Fosfato/genética , Animales , Genes Recesivos , Humanos , Lactante , Recién Nacido , Ratones , Ratones Noqueados
13.
Medicine (Baltimore) ; 94(48): e2196, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26632907

RESUMEN

Transition from child to adult-oriented care is widely regarded a challenging period for young people with kidney transplants and is associated with a high risk of graft failure. We analyzed the existing transition structures in Germany and Austria using a questionnaire and retrospective data of 119 patients transferred in 2011 to 2012. Most centers (73%) confirmed agreements on the transition procedure. Patients' age at transfer was subject to regulation in 73% (18 years). Median age at transition was 18.3 years (16.5-36.7). Median serum creatinine increased from 123 to 132 µmol/L over the 12 month observation period before transfer (P = 0.002). A total of 25/119 patients showed increased creatinine ≥ 20% just before transfer. Biopsy proven rejection was found in 10/119 patients. Three patients lost their graft due to chronic graft nephropathy.Mean coefficient of variation (CoV%) of immunosuppression levels was 0.20 ± 0.1. Increased creatinine levels ≥ 20% just before transfer were less frequently seen in patients with CoV < 0.20 (P = 0.007). The majority of pediatric nephrology centers have internal agreements on transitional care. More than half of the patients had CoV of immunosuppression trough levels consistent with good adherence. Although, 20% of the patients showed increase in serum creatinine close to transfer.


Asunto(s)
Trasplante de Riñón/estadística & datos numéricos , Transición a la Atención de Adultos/organización & administración , Transición a la Atención de Adultos/estadística & datos numéricos , Adolescente , Adulto , Austria , Femenino , Alemania , Rechazo de Injerto/epidemiología , Humanos , Inmunosupresores/uso terapéutico , Masculino , Cumplimiento de la Medicación/estadística & datos numéricos , Estudios Retrospectivos , Adulto Joven
14.
Clin J Am Soc Nephrol ; 10(5): 825-31, 2015 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-25818337

RESUMEN

BACKGROUND AND OBJECTIVES: The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012. RESULTS: Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P<0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR, 16.5-16.8]; P<0.001) and splice site mutations (12.3 [IQR, 7.9-18.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations. CONCLUSIONS: Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.


Asunto(s)
Genes del Tumor de Wilms , Enfermedades Renales/genética , Proteinuria/genética , Anomalías Urogenitales/genética , Adolescente , Adulto , Edad de Inicio , Austria , Niño , Preescolar , Exones/genética , Femenino , Alemania , Heterocigoto , Humanos , Lactante , Intrones/genética , Cariotipo , Enfermedades Renales/patología , Enfermedades Renales/terapia , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/cirugía , Trasplante de Riñón , Masculino , Mutación Missense , Nefrectomía , Fenotipo , Proteinuria/diagnóstico , Proteinuria/tratamiento farmacológico , Diálisis Renal , Estudios Retrospectivos , Suiza , Tumor de Wilms/diagnóstico , Tumor de Wilms/genética , Tumor de Wilms/cirugía , Adulto Joven
15.
Pediatr Nephrol ; 28(8): 1293-8, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23584849

RESUMEN

BACKGROUND: mTOR inhibitors (mTORI) have emerged as alternative and additive immunosuppressive agents in pediatric renal transplantation (pRTx). Their immunosuppressive, anti-proliferative, and anti-neoplastic mechanisms have been described to be effective, whereas some side effects are alarming. In particular, growth and pubertal development are of concern. The aim of this study was to look for long-term side effects of mTORI therapy in pRTx. PATIENTS AND METHODS: The retrospective analysis focused on side effects, growth, and pubertal development under mTORI therapy in 31 children. Eighteen children were routinely monitored for estradiol, testosterone, LH, and FSH levels. RESULTS: The occurrence of bacterial infections, lymphoceles, myelosuppression, and the course of overall linear growth was comparable with other pediatric renal transplant cohorts. According to the clinical puberty status, all but one patient showed normal age-related development in parallel to normal serum hormone levels. Only one patient experienced cytomegaly virus infection under mTORI, no post-transplant lymphoproliferative disorders (PTLD) occurred. CONCLUSIONS: Long-term mTORI therapy is safe in pRTx. No negative impact on growth and pubertal development was observed.


Asunto(s)
Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adolescente , Estatura/efectos de los fármacos , Niño , Desarrollo Infantil/efectos de los fármacos , Preescolar , Estradiol/sangre , Femenino , Hormona Folículo Estimulante Humana/sangre , Alemania , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Lactante , Hormona Luteinizante/sangre , Masculino , Pubertad/sangre , Pubertad/efectos de los fármacos , Estudios Retrospectivos , Factores de Riesgo , Serina-Treonina Quinasas TOR/metabolismo , Testosterona/sangre , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
16.
Pediatr Nephrol ; 26(7): 1149-56, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21461632

RESUMEN

Acute antibody-mediated rejections (aAMR) after renal transplantation are defined by rapidly deteriorating graft function, detection of donor-specific antibodies (DSA) and characteristic histological features. In adults, anti-rejection strategies comprise intravenous immunoglobulin (IVIG), steroid pulses, plasmapheresis and rituximab. Data of children with aAMR are scarce. We report four episodes of aAMR in three children (aged 10, 10 and 11 years respectively) occurring early after renal transplantation. Pre-transplant complement-dependent cytotoxicity crossmatches were negative; in the case of re-transplantation repeated antigens were excluded. Basic immunosuppression comprised cyclosporine A, MMF and steroids. All four rejection episodes were histologically proven and associated with acute renal failure. De novo DSAs were detected in two aAMRs; one patient was additionally tested positive for AT1-receptor antibodies. All aAMRs were treated with steroid pulses, tacrolimus, MMF, IVIG, plasmapheresis and one single dose of rituximab. Despite therapy one graft was lost; in the remaining three cases kidney function re-established within 1-8 weeks. At follow-up, 14, 15 and 22 months' post-rejection their GFRs were 65, 88 and 105 ml/min/1.73 m(2) respectively. A combined therapy of steroid pulses, IVIG, plasmapheresis and rituximab is potentially effective in the treatment of aAMR in children.


Asunto(s)
Lesión Renal Aguda/inmunología , Rechazo de Injerto/inmunología , Isoanticuerpos/sangre , Trasplante de Riñón/inmunología , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/terapia , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Biopsia , Niño , Quimioterapia Combinada , Femenino , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/terapia , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Donadores Vivos , Plasmaféresis , Diálisis Renal , Rituximab , Factores de Tiempo , Resultado del Tratamiento
17.
Pediatr Transplant ; 15(2): 214-20, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21309964

RESUMEN

Genetic polymorphisms of the RAS correlate with allograft function. We therefore analyzed common RAS polymorphisms in kidney donors and in children following RTx to determine the relationship between genotype and decline in GFR, blood pressure, and LVM. A total of 107 children who underwent RTx were included: 70 male, 37 female, mean age 8.8±4.9 yr, mean follow up 5.4 yr. The following RAS polymorphisms were studied in all 107 recipients, 48 donors, and 120 healthy controls: Renin (Renin Mbol 18G/A), ACE I/D; angiotensinogen (AGT M235T), and angiotensin II receptor type-1 (AT1R A1166C). Only patients homozygous for the ACE D allele had a significantly steeper decline in GFR compared with homozygous carriers of the ACE I allele (slope DD: -4.3±0.8 vs. II: -1.3±1.1 mL/min/1.73 m2 per yr; p=0.035). In four cases, a DD recipient received a kidney from a DD donor, and these patients showed a more pronounced decline in GFR (-5.2±0.5 mL/min/1.73 m2 per yr; p=0.002). MABP was not different before vs. after RTx and was independent of ACE I/D genotype. LVMI increased significantly in the majority of patients (36.6±13.9 g/m2.7 six months before RTx vs. 46.4±15.3 g/m2.7 12 months after RTx, p=0.015). However, this difference disappeared after stratification by ACE I/D genotype. The ACE DD genotype is a potential marker for identifying patients at high risk of poor allograft outcome.


Asunto(s)
Genes ras/genética , Trasplante de Riñón/efectos adversos , Polimorfismo Genético , Receptor de Angiotensina Tipo 1/metabolismo , Donantes de Tejidos , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Estudios de Seguimiento , Marcadores Genéticos/fisiología , Genotipo , Alemania , Rechazo de Injerto/genética , Humanos , Pruebas de Función Renal , Trasplante de Riñón/métodos , Modelos Lineales , Donadores Vivos , Masculino , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/genética , Receptor de Angiotensina Tipo 1/genética , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo , Trasplante Homólogo , Resultado del Tratamiento
18.
Clin J Am Soc Nephrol ; 5(11): 2075-84, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20798252

RESUMEN

BACKGROUND AND OBJECTIVES: Mutations in podocyte genes are associated with steroid-resistant nephrotic syndrome (SRNS), mostly affecting younger age groups. To date, it is unclear whether these patients benefit from intensified immunosuppression with cyclosporine A (CsA). The aim of this study was to evaluate the influence of podocyte gene defects in congenital nephrotic syndrome (CNS) and pediatric SRNS on the efficacy of CsA therapy and preservation of renal function. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Genotyping was performed in 91 CNS/SRNS patients, irrespective of age at manifestation or response to CsA. RESULTS: Mutations were identified in 52% of families (11 NPHS1, 17 NPHS2, 11 WT1, 1 LAMB2, 3 TRPC6). Sixty-eight percent of patients with nongenetic SRNS responded to CsA, most of them achieved complete remission. In contrast, none of the patients with genetic CNS/SRNS experienced a complete remission and only two (17%) achieved a partial response, both affected by a WT1 mutation. Preservation of renal function was significantly better in children with nongenetic disease after a mean follow-up time of 8.6 years (ESRD in 29% versus 71%). CONCLUSIONS: The mutation detection rate in our population was high (52%). Most patients with genetic CNS/SRNS did not benefit from CsA with significantly lower response rates compared with nongenetic patients and showed rapid progression to end-stage renal failure. These data strongly support the idea not to expose CNS/SRNS patients with inherited defects related to podocyte function to intensified immunosuppression with CsA.


Asunto(s)
Ciclosporina/uso terapéutico , Resistencia a Medicamentos , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/prevención & control , Riñón/efectos de los fármacos , Síndrome Nefrótico/tratamiento farmacológico , Esteroides/uso terapéutico , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Genes del Tumor de Wilms , Predisposición Genética a la Enfermedad , Alemania , Herencia , Hospitales Pediátricos , Hospitales Universitarios , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular/genética , Estimación de Kaplan-Meier , Riñón/fisiopatología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/genética , Fallo Renal Crónico/fisiopatología , Laminina/genética , Masculino , Proteínas de la Membrana/genética , Mutación , Síndrome Nefrótico/congénito , Síndrome Nefrótico/etiología , Síndrome Nefrótico/fisiopatología , Selección de Paciente , Fenotipo , Estudios Retrospectivos , Canales Catiónicos TRPC/genética , Canal Catiónico TRPC6 , Factores de Tiempo , Resultado del Tratamiento
19.
Pediatr Nephrol ; 25(2): 231-40, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18810502

RESUMEN

Renal cysts in childhood can be found in a variety of diseases, which can be congenital or acquired, or renal cysts may be part of a multiorgan disease or restricted to the kidneys only. Ultrasonography is the first-line diagnostic tool and is informative in many cases. However, there is a broad spectrum in the sonographic appearance of renal cysts, and family or genetic studies, a search for extrarenal organ involvement, or additional imaging modalities may be required to make a definitive diagnosis. The aim of this article is to summarize the diagnostic potential and limitations of ultrasonography and depict typical examples of the most important cystic entities.


Asunto(s)
Enfermedades Renales Quísticas/diagnóstico , Riñón/patología , Ultrasonografía/métodos , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Riñón/diagnóstico por imagen , Enfermedades Renales Quísticas/complicaciones , Enfermedades Renales Quísticas/congénito , Masculino , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados
20.
Nephrol Dial Transplant ; 25(4): 1257-65, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19934086

RESUMEN

BACKGROUND: Newborns with inborn errors of metabolism often present with hyperammonaemic coma, requiring prompt diagnosis and specific medical therapy, nutritional support and efficient toxin removal. Little information regarding the efficacy and safety of continuous venovenous haemodialysis (CVVHD) as an option for extracorporal ammonia detoxification in children is available. METHODS: Twenty-one patients with hyperammonaemia [19 neonates (mean age 4.1 +/- 2.4 days) and two children 1 and 7 years of age, respectively] were admitted to our hospital for dialysis between 1996 and 2008. Seventeen children (15 neonates), received CVVHD. Four neonates received continuous peritoneal dialysis (CPD). All started medical treatment with sodium benzoate, l-arginine hydrochloride and carnitine as well as protein-restricted parenteral diets with high caloric intake before dialysis. RESULTS: Plasma ammonia levels (range 464-7267 microg/dl before dialysis and 27-3317 microg/dl after dialysis) were significantly reduced by 50% within 4.7 +/- 2.5 h with CVVHD compared with 13.5 +/- 6.2 h with CPD (P < 0.0001). Plasma ammonia levels <200 microg/dl critical range were achieved within 22.4 +/- 18.1 h in CVVHD patients compared with 35.0 +/- 24.1 h with CPD. Depending on the weight and blood pressure stability of the patients, mean blood flow velocities of 9.8 +/- 3.4 ml/kg/min and mean dialysate flow rates of 3925 +/- 2398 ml/min/1.73 m(2) were employed. Blood and dialysate flows significantly correlated with ammonia clearance and decay of ammonia in vivo. Because of the severe underlying disease, 18% of CVVHD patients died compared with 50% undergoing CPD. In total, 82% of CVVHD patients survived the first 6 months after dialysis. Among these, 43% were without sequelae, 43% developed moderate mental retardation, and two (14%) developed severe mental retardation. CONCLUSION: CVVHD effectively and quickly eliminates plasma ammonia. To optimize long-term mental outcome, rapid identification and appropriate treatment of the underlying disease as well as starting dialysis early are of enormous therapeutic value.


Asunto(s)
Hiperamonemia/terapia , Errores Innatos del Metabolismo/terapia , Diálisis Peritoneal , Diálisis Renal , Amoníaco/sangre , Niño , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos
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