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1.
Clin Genet ; 99(1): 143-156, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33040356

RESUMO

Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.


Assuntos
Colágeno Tipo IV/genética , Estudos de Associação Genética , Nefrite Hereditária/genética , Insuficiência Renal/genética , Adolescente , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Genes Ligados ao Cromossomo X/genética , Testes Genéticos , Humanos , Lactente , Rim/patologia , Masculino , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/patologia , Nefrite Hereditária/terapia , Insuficiência Renal/diagnóstico , Insuficiência Renal/patologia , Insuficiência Renal/terapia
2.
Pediatr Nephrol ; 36(12): 3923-3932, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34117528

RESUMO

OBJECTIVE: Pediatric patients spend significant time on maintenance hemodialysis (HD) and traveling. They are often not capable of participating in sports activities. To assess the effects of exercise training during HD on dialysis efficacy in children and adolescents, we set up a multi-center randomized controlled trial (RCT). METHODS: Patients on HD, age 6 to 18 years, were randomized either to 3× weekly bicycle ergometer training or to no training during HD for 12 weeks. Change in single-pool Kt/V (spKt/V) was the primary outcome parameter. RESULTS: We randomized 54 patients of whom 45 qualified (23 in the intervention and 22 in the waiting control group, 14.5 ± 3.01 years, 32 male and 13 female) for the intention-to-treat (ITT) population. Only 26 patients finished study per-protocol (PP). Training was performed for an average of 11.96 weeks (0.14-13.14) at 2.08 ± 0.76 times per week and for a weekly mean of 55.52 ± 27.26 min. Single-pool Kt/V was similar in the intervention compared to the control group (1.70 [0.33] vs. 1.79 [0.55]) at V0 and (1.70 [0.36] vs. 1.71 [0.51]) at V1; secondary endpoints also showed no difference in both ITT and PP analysis. No significant adverse events were reported. No bleeding or needle dislocation occurred in 1670 training sessions. CONCLUSIONS: Intradialytic bicycle training is safe, but does not improve dialysis efficacy and physical fitness. However, the study can be considered underpowered, particularly because of high dropout rates. Future studies need better strategies to increase motivation and compliance and other more effective/intensive exercise measures should be evaluated. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.Gov ( Clinicaltrials.gov identifier: NCT01561118) on March 22, 2012.


Assuntos
Treino Aeróbico , Diálise Renal , Adolescente , Criança , Terapia por Exercício , Feminino , Humanos , Masculino , Qualidade de Vida
3.
Kidney Int ; 97(6): 1275-1286, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32299679

RESUMO

Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.


Assuntos
Nefrite Hereditária , Ramipril , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Teorema de Bayes , Criança , Método Duplo-Cego , Taxa de Filtração Glomerular , Humanos , Nefrite Hereditária/genética , Estudos Prospectivos , Ramipril/efeitos adversos
4.
Ther Drug Monit ; 41(6): 696-702, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31425441

RESUMO

BACKGROUND: Mycophenolate mofetil (MMF) plays an increasingly important role in the treatment of children with nephrotic syndrome, especially in steroid sparing protocols. Recent publications show the relationship of exposure to its active moiety mycophenolic acid (MPA) and clinical efficacy. Performance of full-time pharmacokinetic (PK) profiles, however, is inconvenient and laborious. Established limited sampling strategies (LSS) to estimate the area under the concentration (AUC) versus time curve of MPA (MPA-AUC) in pediatric renal transplant recipients cannot be easily transferred to children suffering from nephrotic syndrome, mainly because of the lack of concomitant immunosuppressive therapy. We therefore aimed for the generation and validation of a LSS to estimate MPA exposure to facilitate therapeutic drug monitoring in children with nephrotic syndrome. METHODS: We performed 27 complete PK profiles in 23 children in remission [mean age (±SD):12.3 ± 4.26 years] to generate and validate an LSS. Sampling time points were before administration (C0) and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours after the administration of MMF. MPA was measured by enzyme multiplied immunoassay technique. There was no concomitant treatment with calcineurin inhibitors. RESULTS: Mean daily dose of MMF was 927 ± 209 mg/m of body surface area resulting in a mean MPA-AUC0-12 value of 59.2 ± 29.3 mg × h/L and a predose level of 3.03 ± 2.24 mg/L. Between-patient variability of dose-normalized MPA-AUC0-12 was high (coefficient of variation: 45.5%). Correlation of predose levels with the corresponding MPA-AUC0-12 was moderate (r = 0.59) in a subgroup of 18 patients (20 PK profiles, generation group). An algorithm based on 3 PK sampling time points during the first 2 hours after MMF dosing (estimated AUC0-12 = 8.7 + 4.63 × C0 + 1.90 × C1 + 1.52 × C2) was able to predict MPA-AUC with a low percentage prediction error (3.88%) and a good correlation of determination (r = 0.90). Validation of this algorithm in a randomized separate group of 6 patients (7 PK profiles, validation group) resulted in comparably good correlation (r = 0.95) and low percentage prediction error (5.57%). CONCLUSIONS: An abbreviated profile within the first 2 hours after MMF dosing gives a good estimate of MPA exposure in children with nephrotic syndrome and hence has the potential to optimize MMF therapy.


Assuntos
Monitoramento de Medicamentos/métodos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapêutico , Síndrome Nefrótica/sangue , Adolescente , Criança , Feminino , Humanos , Masculino , Ácido Micofenólico/sangue
5.
Pediatr Nephrol ; 34(2): 341-348, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30178240

RESUMO

BACKGROUND: Variable effects of steroid minimization strategies on blood pressure in pediatric renal transplant recipients have been reported, but data on the effect of steroid withdrawal on ambulatory blood pressure and circadian blood pressure rhythm have not been published so far. METHODS: In a prospective, randomized, multicenter study on steroid withdrawal in pediatric renal transplant recipients (n = 42) on cyclosporine, mycophenolate mofetil, and methylprednisolone, we performed a substudy in 28 patients, aged 11.2 ± 3.8 years, for whom ambulatory blood pressure monitoring (ABPM) data were available. RESULTS: In the steroid-withdrawal group, the percentage of patients with arterial hypertension, defined as systolic and/or diastolic blood pressure values recorded by ABPM > 1.64 SDS and/or antihypertensive medication, at month 15 was significantly lower (35.7%, p = 0.002) than in controls (92.9%). The need of antihypertensive medication dropped significantly by 61.2% (p < 0.000 vs. control), while in controls, it even rose by 69.3%. One year after steroid withdrawal, no patient exhibited hypertensive blood pressure values above the 95th percentile, compared to 35.7% at baseline (p = 0.014) and to 14.3% of control (p = 0.142). The beneficial impact of steroid withdrawal was especially pronounced for nocturnal blood pressure, leading to a recovered circadian rhythm in 71.4% of patients vs. 14.3% at baseline (p = 0.002), while the percentage of controls with an abnormal circadian rhythm (35.7%) did not change. CONCLUSIONS: Steroid withdrawal in pediatric renal transplant recipients with well-preserved allograft function is associated with less arterial hypertension recorded by ABPM and recovery of circadian blood pressure rhythm by restoration of nocturnal blood pressure dipping.


Assuntos
Glucocorticoides/efeitos adversos , Hipertensão/prevenção & controle , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Suspensão de Tratamento , Adolescente , Aloenxertos/imunologia , Aloenxertos/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Criança , Ritmo Circadiano/fisiologia , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Feminino , Taxa de Filtração Glomerular/fisiologia , Glucocorticoides/administração & dosagem , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/fisiopatologia , Rejeição de Enxerto/prevenção & controle , Humanos , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Imunossupressores/administração & dosagem , Rim/imunologia , Rim/fisiopatologia , Masculino , Metilprednisolona , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Estudos Prospectivos , Transplante Homólogo/efeitos adversos
6.
Pediatr Nephrol ; 33(2): 277-286, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28983704

RESUMO

BACKGROUND: This study correlates the clinical presentation of Henoch-Schönlein purpura nephritis (HSPN) with findings on initial renal biopsy. METHODS: Data from 202 pediatric patients enrolled in the HSPN registry of the German Society of Pediatric Nephrology reported by 26 centers between 2008 and 2014 were analyzed. All biopsy reports were re-evaluated for the presence of cellular crescents or chronic pathological lesions (fibrous crescents, glomerular sclerosis, tubular atrophy >5%, and interstitial fibrosis >5%). RESULTS: Patients with HSPN with cellular glomerular crescents were biopsied earlier after onset of nephritis (median 24 vs 36 days, p = 0.04) than those without, whereas patients with chronic lesions were biopsied later (57 vs 19 days, p < 0.001) and were older (10.3 vs 8.6 years, p = 0.01) than those without. Patients biopsied more than 30 days after the onset of HSPN had significantly more chronic lesions (52 vs 22%, p < 0.001), lower eGFR (88 vs 102 ml/min/1.73m2, p = 0.01), but lower proteinuria (2.3 vs 4.5 g/g, p < 0.0001) than patients biopsied earlier. Children above 10 years of age had lower proteinuria (1.98 vs 4.58 g/g, p < 0.001), lower eGFR (86 vs 101 ml/min/1.73m2, p = 0.002) and were biopsied significantly later after onset of nephritis (44 vs 22 days, p < 0.001) showing more chronic lesions (45 vs 30%, p = 0.03). Proteinuria and renal function at presentation decreased with age. CONCLUSIONS: In summary, we find an age-dependent presentation of HSPN with a more insidious onset of non-nephrotic proteinuria, impaired renal function, longer delay to biopsy, and more chronic histopathological lesions in children above the age of 10 years. Thus, HSPN presents more like Immunoglobulin A (IgA) nephritis in older than in younger children.


Assuntos
Vasculite por IgA/patologia , Rim/patologia , Nefrite/patologia , Fatores Etários , Biópsia , Criança , Feminino , Humanos , Masculino
7.
Pediatr Nephrol ; 31(6): 1021-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26754038

RESUMO

BACKGROUND: Febrile urinary tract infections (fUTIs) are common after kidney transplantation (KTx); however, prospective data in a multicenter pediatric cohort are lacking. We designed a prospective registry to record data on fUTI before and after pediatric KTx. METHODS: Ninety-eight children (58 boys and 40 girls) ≤ 18 years from 14 mid-European centers received a kidney transplant and completed a 2-year follow-up. RESULTS: Posttransplant, 38.7% of patients had at least one fUTI compared with 21.4% before KTx (p = 0.002). Before KTx, fUTI was more frequent in patients with congenital anomalies of kidneys and urinary tract (CAKUT) vs. patients without (38% vs. 12%; p = 0.005). After KTx, fUTI were equally frequent in both groups (48.7% vs. 32.2%; p = 0.14). First fUTI posttransplant occurred earlier in boys compared with girls: median range 4 vs. 13.5 years (p = 0.002). Graft function worsened (p < 0.001) during fUTI, but no difference was recorded after 2 years. At least one recurrence of fUTI was encountered in 58%. CONCLUSION: This prospective study confirms a high incidence of fUTI after pediatric KTx, which is not restricted to patients with CAKUT; fUTIs have a negative impact on graft function during the infectious episode but not on 2-year graft outcome.


Assuntos
Função Retardada do Enxerto/etiologia , Febre/epidemiologia , Nefropatias/cirurgia , Transplante de Rim/efeitos adversos , Infecções Urinárias/epidemiologia , Adolescente , Criança , Pré-Escolar , Função Retardada do Enxerto/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Febre/etiologia , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/etiologia , Humanos , Incidência , Masculino , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Resultado do Tratamento , Infecções Urinárias/complicações , Infecções Urinárias/etiologia
9.
J Peripher Nerv Syst ; 20(1): 52-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25676889

RESUMO

Mutations in the gene encoding inverted formin FH2 and WH2 domain-containing protein (INF2), a Cdc42 effector involved in the regulation of actin dynamics, cause focal segmental glomerulosclerosis (FSGS) and intermediate Charcot-Marie-Tooth neuropathy combined with FSGS (FSGS-CMT). Here, we report on six patients from four families with sensorimotor polyneuropathy and FSGS. Nerve conduction velocities were moderately slowed, and amplitudes of sensory and motor potentials were decreased. One patient had internal hydrocephalus and was intellectually disabled. Molecular genetic testing revealed two known and two novel missense mutations in the second and fourth exons of the INF2 gene. Investigations of one nerve biopsy confirmed the diagnosis of intermediate-type CMT and revealed occasional abnormal in- and outfoldings of myelin sheaths and expansions of the endoplasmic reticulum in axons and Schwann cells. While earlier reports suggested that mutations causing FSGS-CMT are restricted to exons 2 and 3 of the INF2 gene, we found one CMT-FSGS causing mutation (p.Glu184Lys) in exon 4 extending the critical region of INF2 for rapid CMT-FSGS molecular genetic diagnosis. Study of a nerve biopsy showed abnormalities that might be related to the known role of the INF2-binding partner CDC42 in myelination.


Assuntos
Axônios/patologia , Glomerulosclerose Segmentar e Focal/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Células de Schwann/patologia , Adolescente , Adulto , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/genética , Criança , Feminino , Forminas , Testes Genéticos , Glomerulosclerose Segmentar e Focal/complicações , Humanos , Músculo Esquelético/patologia , Nervos Periféricos/diagnóstico por imagem , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Ultrassonografia , Adulto Jovem
10.
N Engl J Med ; 365(5): 410-21, 2011 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-21675912

RESUMO

BACKGROUND: Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. METHODS: We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system. RESULTS: Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D(3) degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations. CONCLUSIONS: The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.


Assuntos
Hipercalcemia/genética , Mutação , Esteroide Hidroxilases/genética , Vitamina D/efeitos adversos , Animais , Células Cultivadas , Cricetinae , Cricetulus , Análise Mutacional de DNA , Feminino , Genes Recessivos , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hipercalcemia/induzido quimicamente , Lactente , Masculino , Linhagem , Fatores de Risco , Esteroide Hidroxilases/metabolismo , Vitamina D/metabolismo , Vitamina D/uso terapêutico , Vitamina D3 24-Hidroxilase
11.
Pediatr Nephrol ; 29(8): 1441-50, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24584665

RESUMO

BACKGROUND: Previous studies have found that pediatric solid organ transplant recipients suffer from adenotonsillar hyperplasia. However, as this condition is also common in normal children, it remains unclear whether the incidence is truly increased. The aim of this study was to compare the incidences of surgery on the adenoids and tonsils of normal children with those receiving renal transplants and to define risk factors in the transplant population. METHODS: Data on 49 consecutive children from a single renal transplant unit were compared to data from a large governmental survey of healthy German children (KiGGS). For analysis of 'survival without operation', controls were matched for gender, region and immigration status (n = 8,650), as well as for age to compare incidence rates (n = 637). RESULTS: The age-matched solid organ transplant recipients had a higher incidence of adenoidectomies [2.3-fold, [95 % confidence interval (CI) for relative risk 1.6-3.3) and a higher incidence of tonsillectomies/tonsillotomies (3.5-fold, 95 % CI 2.1-5.7). The normal peak of adenoidectomies was delayed by 2 years in the pre-school group, and transplanted teenagers showed an extra peak for both operations. Boys and those transplanted at a younger age were significantly more likely to need adenoidectomies. Ciclosporin levels, Epstein-Barr virus and cytomegalovirus infections did not influence the incidence of operations. CONCLUSION: Children receiving renal transplants are at markedly increased risk of adenotonsillar hyperplasia requiring surgery, especially males and young recipients.


Assuntos
Adenoidectomia/estatística & dados numéricos , Transplante de Rim/estatística & dados numéricos , Doenças Faríngeas/epidemiologia , Doenças Faríngeas/cirurgia , Tonsilectomia/estatística & dados numéricos , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Alemanha/epidemiologia , Inquéritos Epidemiológicos , Humanos , Hiperplasia/epidemiologia , Hiperplasia/cirurgia , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Incidência , Lactente , Masculino , Adulto Jovem
12.
Pediatr Nephrol ; 29(8): 1451-6, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24504730

RESUMO

BACKGROUND: An emerging number of clinically and genetically heterogeneous diseases now collectively termed ciliopathies have been connected to the dysfunction of primary cilia. We describe an 8-year-old girl with a complex phenotype that did not clearly match any familiar syndrome. CASE-DIAGNOSIS/TREATMENT: Hypotonia, facial dysmorphism and retardation were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Renal biopsy revealed tubular atrophy, interstitial fibrosis and segmental glomerulosclerosis. After exclusion of a chromosomal abnormality by array-comparative genomic hybridization (CGH), we performed next-generation sequencing (NGS) using a customized panel that targeted 131 genes known or hypothesized to cause ciliopathies. We identified the novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) that affects an evolutionarily highly conserved residue in the intraflagellar transport protein IFT144, is absent from databases and is predicted to be pathogenic by all bioinformatic sources used. CONCLUSION: Mutations in WDR19 encoding the intraflagellar transport component IFT144 have recently been described in single families with the clinically overlapping skeletal ciliopathies Jeune and Sensenbrenner syndromes, combined or isolated nephronophthisis (NPHP) and retinitis pigmentosa (RP) (Senior-Loken syndrome). Our patient emphasizes the usefulness and efficiency of a comprehensive NGS panel approach in patients with unclassified ciliopathies. It further suggests that WDR19 mutations can cause a broad spectrum of ciliopathies that extends to Jeune and Sensenbrenner syndromes, RP and renal NPHP-like phenotypes.


Assuntos
Cílios/patologia , Nefropatias/genética , Proteínas/genética , Criança , Proteínas do Citoesqueleto , Éxons/genética , Feminino , Crescimento/fisiologia , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Nefropatias/patologia , Mutação/genética , Análise de Sequência de DNA
13.
Clin Infect Dis ; 56(1): 84-92, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23042966

RESUMO

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.


Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4/isolamento & purificação , Transplante de Rim/estatística & dados numéricos , Adolescente , Análise de Variância , Antivirais/uso terapêutico , Criança , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Herpesvirus Humano 4/imunologia , Humanos , Imunossupressores/uso terapêutico , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/virologia , Masculino , Morbidade , Estudos Prospectivos , Estatísticas não Paramétricas , Transplantes/estatística & dados numéricos , Carga Viral
14.
Cells ; 12(9)2023 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-37174733

RESUMO

The urinary albumin- and protein-to-creatinine ratios (UACR and UPCR, respectively) are key endpoints in most clinical trials assessing risk of progression of chronic kidney disease (CKD). For the first time, the current study compares the UACR versus the UPCR head-to-head at early stages of CKD, taking use of the hereditary podocytopathy Alport syndrome (AS) as a model disease for any CKD. Urine samples originated from the prospective randomized, controlled EARLY PRO-TECT Alport trial (NCT01485978). Urine samples from 47 children with confirmed diagnoses of AS at very early stages of CKD were divided according to the current stage of AS: stage 0 (UACR < 30 mg/g), stage 1 (30-300 mg/g) or stage 2 (>300 mg/g). The range of estimated glomerular filtration rate was 75-187.6 mL/min. The mean age was 10.4 ± 4.5 years. In children at stage 0, proteinuria in spot urine, confirmed in 24 h urine, was almost ten times higher than albuminuria (106.4 ± 42.2 vs. 12.5 ± 9.7; p < 0.05); it was "only" about three times higher in stage 1 (328.5 ± 210.1 vs. 132.3 ± 80.5; p < 0.05) and almost equal in stage 2 (1481.9 ± 983.4 vs. 1109.7 ± 873.6; p = 0.36). In 17 children, UACRs and UPCRs were measured simultaneously in 24 h urine and spot urine in the same study visit. Interestingly, the UACR (and UPCR) in 24 h urine vs. in spot urine varied by less than 10% (266.8 ± 426.4 vs. 291.2 ± 530.2). In conclusion, our study provides the first evidence that in patients with normal glomerular filtration rate (GFR) and low amounts of albuminuria, especially in children with podocytopathies such as AS, measuring the UACR and UPCR in spot urine is a reliable and convenient alternative to 24 h urine collection. Our study advocates both the UACR and the UPCR as relevant diagnostic biomarkers in future clinical trials in children with glomerular diseases because the UPCR seems to be a very significant parameter at very early stages of podocytopathies. The German Federal Ministry of Education and Research funded this trial (01KG1104).


Assuntos
Nefrite Hereditária , Insuficiência Renal Crônica , Adolescente , Criança , Humanos , Albuminas/metabolismo , Albuminúria , Creatinina , Nefrite Hereditária/diagnóstico , Estudos Prospectivos
15.
Transpl Int ; 25(7): 723-31, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22533698

RESUMO

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).


Assuntos
Infecções por Vírus Epstein-Barr/prevenção & controle , Ganciclovir/análogos & derivados , Ganciclovir/uso terapêutico , Herpesvirus Humano 4/metabolismo , Transplante de Rim/métodos , Adulto , Antivirais/uso terapêutico , Quimioprevenção/métodos , Criança , Estudos de Coortes , Feminino , Humanos , Imunossupressores/uso terapêutico , Transtornos Linfoproliferativos/etiologia , Masculino , Pediatria/métodos , Estudos Prospectivos , Valganciclovir
16.
J Am Soc Nephrol ; 22(11): 2047-56, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22034641

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is typically a late-onset disease caused by mutations in PKD1 or PKD2, but about 2% of patients with ADPKD show an early and severe phenotype that can be clinically indistinguishable from autosomal recessive polycystic kidney disease (ARPKD). The high recurrence risk in pedigrees with early and severe PKD strongly suggests a common familial modifying background, but the mechanisms underlying the extensive phenotypic variability observed among affected family members remain unknown. Here, we describe severely affected patients with PKD who carry, in addition to their expected familial germ-line defect, additional mutations in PKD genes, including HNF-1ß, which likely aggravate the phenotype. Our findings are consistent with a common pathogenesis and dosage theory for PKD and may propose a general concept for the modification of disease expression in other so-called monogenic disorders.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Rim Policístico Autossômico Dominante/genética , Índice de Gravidade de Doença , Canais de Cátion TRPP/genética , Adulto , Idade de Início , Idoso , Sequência de Aminoácidos , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Rim Policístico Autossômico Dominante/epidemiologia , Rim Policístico Autossômico Dominante/patologia , Gravidez , Fatores de Risco
17.
Am J Kidney Dis ; 58(3): 453-5, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21705122

RESUMO

The spectrum of primary hyperoxaluria type I is extremely heterogeneous, ranging from singular to recurrent urolithiasis and early end-stage renal disease (ESRD). In infantile oxalosis, the most devastating form, ESRD occurs as early as within the first weeks of life. No kidney replacement therapy sufficiently removes endogenously overproduced oxalate. However, curative combined liver-kidney transplant often is impracticable in small infants. Oxalobacter formigenes (O formigenes), an anaerobic oxalate-degrading bacterium, is a colonizer of the healthy human colon. Oral administration of O formigenes has been shown to significantly decrease urine and plasma oxalate levels in patients with primary hyperoxaluria. We report compassionate use of O formigenes in two 11-month-old girls with infantile oxalosis and ESRD. They received O formigenes twice a day for 4 weeks (or until transplant). Dialysis regimens were unchanged. Plasma oxalate levels decreased from >110 µmol/L before to 71.53 µmol/L under treatment in patient 1 and from >90 to 68.56 µmol/L (first treatment period) and 50.05 µmol/L (second treatment period) in patient 2. O formigenes was well tolerated. No serious side effects were reported. Extremely increased plasma oxalate levels in patients with infantile oxalosis may enable intestinal elimination of endogenous oxalate in the presence of O formigenes. Therefore, O formigenes therapy may be helpful as a bridging procedure until transplant in such patients.


Assuntos
Hiperoxalúria/sangue , Hiperoxalúria/terapia , Oxalatos/sangue , Oxalobacter formigenes , Administração Oral , Fezes/microbiologia , Feminino , Humanos , Hiperoxalúria/complicações , Hiperoxalúria/genética , Hiperoxalúria Primária , Lactente , Transplante de Rim , Mutação de Sentido Incorreto , Nefrocalcinose/etiologia , Oxalobacter formigenes/isolamento & purificação , Insuficiência Renal , Transaminases/sangue , Transaminases/deficiência , Transaminases/genética
18.
Pediatr Nephrol ; 26(3): 401-10, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21181207

RESUMO

Current treatment regimens for childhood lupus nephritis (LN) are associated with significant side-effects and toxicity in vulnerable phases of growth and development. The paucity of biomarkers particularly in childhood impedes the appropriate clinical management and the development of new therapeutics. We analyzed markers of immune system (BAFF, RANTES), complement (Bb, C1q, C3d-CIC, C5a) and endothelial cell activation (sVCAM-1) in children with LN (n=22, mean age 14.8±4.7 years), nephrotic syndrome (n=13) and age-matched healthy controls (n=20) to define parameters that correlate with LN activity. Complement fragments of the alternative (Bb, p=0.0004) classical (C3d-CIC, p<0.0001) and common pathway (C5a, p<0.0001) and the levels of BAFF (p<0.0001), RANTES (p=0.0002) and sVCAM-1 (p=0.0004) were significantly higher in active compared to inactive LN. Activation of complement was associated with the occurrence of anti-C1q antibodies and reduced complement C1q. Complement-activation fragments highly correlated with the markers for immune system and endothelial cell activation. The ensemble of these parameters may be of great value in identifying early flares or remissions of childhood LN, and moreover may prove useful in the assessment of new treatments and in determining the optimization of their use.


Assuntos
Ativação do Complemento , Células Endoteliais/imunologia , Nefrite Lúpica/imunologia , Monitorização Imunológica/métodos , Adolescente , Áustria , Fator Ativador de Células B/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocina CCL5/sangue , Criança , Proteínas do Sistema Complemento/metabolismo , Feminino , Alemanha , Humanos , Imunossupressores/uso terapêutico , Modelos Lineares , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Masculino , Valor Preditivo dos Testes , Resultado do Tratamento , Molécula 1 de Adesão de Célula Vascular/sangue , Adulto Jovem
19.
Nephrol Dial Transplant ; 25(2): 617-24, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19793929

RESUMO

BACKGROUND: Long-term corticosteroid treatment impairs growth and increases cardiovascular risk factors. Hence, steroid withdrawal constitutes a major topic in paediatric renal transplantation and maintenance immunosuppression. METHODS: The lack of data from randomised controlled trials caused us to conduct the first prospective, randomised, multicentre study on late steroid withdrawal among paediatric kidney allograft recipients treated with standard-dose cyclosporine microemulsion (CsA) and mycophenolate mofetil (MMF) for 2 years. Forty-two low- or regular-immunologic risk patients were randomly assigned, >or=1 year post-transplant, to continue taking or to withdraw steroids over 3 months. RESULTS: Two years after steroid withdrawal, they showed a longitudinal growth superior to controls [mean height standard deviation score (SDS) gain, 0.6 +/- 0.1 SDS versus -0.2 +/- 0.1 SDS (P < 0.001)]. The prevalence of the metabolic syndrome declined significantly (P < 0.05), 2 years after steroid withdrawal, from 39% (9/23) to 6% (1/16). Steroid-free patients had less frequent arterial hypertension (50% versus 93% (P < 0.05)) and required fewer antihypertensive drugs [0.6 +/- 0.2 versus 1.5 +/- 0.3 (P < 0.05 versus control)]. Additionally, they had a significantly improved carbohydrate and lipid metabolism with fewer hypercholesterolaemia and hypertriglyceridaemia (P < 0.05 versus control). Patient and graft survival amounted to 100%. Allograft function remained stable 2 years after steroid withdrawal. The incidence of acute rejections was similar in the steroid-withdrawal group (1/23, 4%) and controls (2/19, 11%). CONCLUSION: Late steroid withdrawal in selected CsA- and MMF-treated paediatric kidney transplant recipients improves growth, mitigates cardiovascular risk factors and reduces the prevalence of the metabolic syndrome, at no increased risk of acute rejection or unstable graft function.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Glucocorticoides/administração & dosagem , Crescimento , Imunossupressores/uso terapêutico , Transplante de Rim , Complicações Pós-Operatórias/prevenção & controle , Adolescente , Criança , Ciclosporina/uso terapêutico , Feminino , Humanos , Masculino , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Complicações Pós-Operatórias/induzido quimicamente , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
20.
Nat Commun ; 9(1): 1960, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29773874

RESUMO

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.


Assuntos
Resistência a Medicamentos/genética , Glucocorticoides/farmacologia , Síndrome Nefrótica/tratamento farmacológico , Mapas de Interação de Proteínas/genética , Proteína rhoA de Ligação ao GTP/genética , Adulto , Animais , Criança , Pré-Escolar , Análise Mutacional de DNA , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Glucocorticoides/uso terapêutico , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Mutação , Síndrome Nefrótica/genética , Linhagem , Podócitos , RNA Interferente Pequeno/metabolismo , Resultado do Tratamento , Sequenciamento do Exoma , Proteína rhoA de Ligação ao GTP/metabolismo
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