Hemolytic-uremic syndrome: 24 years' experience of a pediatric nephrology unit / Síndrome hemolítico-urêmica: 24 anos de experiência de uma unidade de nefrologia pediátrica

Abstract Introduction: A better understanding of hemolytic-uremic syndrome (HUS) pathophysiology significantly changed its treatment and prognosis. The aim of this study is to characterize the clinical features, severity, management, and outcomes of HUS patients. Materials and Methods: Retrospective study of HUS patients admitted to a Pediatric Nephrology Unit between 1996 and 2020. Demographic and clinical data regarding etiology, severity, treatment strategies, and patient outcome were collected. Results: Twenty-nine patients with HUS were admitted to our unit, but four were excluded. Median age at diagnosis was two years (2 months - 17 years). Clinical manifestations included diarrhea, vomiting, oliguria, hypertension, and fever. During the acute phase, 14 patients (56%) required renal replacement therapy. Infectious etiology was identified in seven patients (five Escherichia coli and two Streptococcus pneumoniae). Since 2015, 2/7 patients were diagnosed with complement pathway dysregulation HUS and there were no cases of infectious etiology detected. Six of these patients received eculizumab. The global median follow-up was 6.5 years [3 months-19.8 years]. One patient died, seven had chronic kidney disease, four of whom underwent kidney transplantation, one relapsed, and seven had no sequelae. Conclusion: These results reflect the lack of infectious outbreaks in Portugal and the improvement on etiological identification since genetic testing was introduced. The majority of patients developed sequels and mortality was similar to that of other countries. HUS patients should be managed in centers with intensive care and pediatric nephrology with capacity for diagnosis, etiological investigation, and adequate treatment. Long-term follow-up is essential.

Resumo Introdução: Um melhor entendimento da fisiopatologia da síndrome hemolítico-urêmica (SHU) mudou significativamente seu tratamento e prognóstico. Este estudo teve como objetivo caracterizar condições clínicas, gravidade, manejo e desfechos de pacientes com SHU. Materiais e Métodos: Estudo retrospectivo de pacientes com SHU admitidos numa Unidade de Nefrologia Pediátrica entre 1996-2020. Foram coletados dados demográficos e clínicos sobre etiologia, gravidade, estratégias de tratamento, desfechos de pacientes. Resultados: 29 pacientes com SHU foram admitidos em nossa unidade, mas quatro foram excluídos. A idade mediana ao diagnóstico foi dois anos (2 meses-17 anos). Manifestações clínicas incluíram diarreia, vômitos, oligúria, hipertensão e febre. Durante a fase aguda, 14 pacientes (56%) necessitaram de terapia renal substitutiva. Identificou-se a etiologia infecciosa em sete pacientes (cinco Escherichia coli; dois Streptococcus pneumoniae). Desde 2015, 2/7 pacientes foram diagnosticados com SHU por desregulação da via do complemento e não foram detectados casos de etiologia infecciosa. Seis desses pacientes receberam eculizumab. A mediana global de acompanhamento foi 6,5 anos [3 meses-19,8 anos]. Um paciente faleceu, sete apresentaram doença renal crônica, sendo quatro submetidos a transplante renal, uma recidiva e sete sem sequelas. Conclusão: Estes resultados refletem a ausência de surtos infecciosos em Portugal e a melhoria na identificação etiológica desde que os testes genéticos foram introduzidos. A maioria dos pacientes desenvolveu sequelas e a mortalidade foi semelhante à de outros países. Pacientes com SHU devem ser manejados em centros com cuidados intensivos e nefrologia pediátrica com capacidade para diagnóstico, investigação etiológica e tratamento adequado. O acompanhamento alongo prazo é essencial.

Hemolytic-uremic syndrome: 24 years' experience of a pediatric nephrology unit.

INTRODUCTION: A better understanding of hemolytic-uremic syndrome (HUS) pathophysiology significantly changed its treatment and prognosis. The aim of this study is to characterize the clinical features, severity, management, and outcomes of HUS patients. MATERIALS AND METHODS: Retrospective study of HUS patients admitted to a Pediatric Nephrology Unit between 1996 and 2020. Demographic and clinical data regarding etiology, severity, treatment strategies, and patient outcome were collected. RESULTS: Twenty-nine patients with HUS were admitted to our unit, but four were excluded. Median age at diagnosis was two years (2 months - 17 years). Clinical manifestations included diarrhea, vomiting, oliguria, hypertension, and fever. During the acute phase, 14 patients (56%) required renal replacement therapy. Infectious etiology was identified in seven patients (five Escherichia coli and two Streptococcus pneumoniae). Since 2015, 2/7 patients were diagnosed with complement pathway dysregulation HUS and there were no cases of infectious etiology detected. Six of these patients received eculizumab. The global median follow-up was 6.5 years [3 months-19.8 years]. One patient died, seven had chronic kidney disease, four of whom underwent kidney transplantation, one relapsed, and seven had no sequelae. CONCLUSION: These results reflect the lack of infectious outbreaks in Portugal and the improvement on etiological identification since genetic testing was introduced. The majority of patients developed sequels and mortality was similar to that of other countries. HUS patients should be managed in centers with intensive care and pediatric nephrology with capacity for diagnosis, etiological investigation, and adequate treatment. Long-term follow-up is essential.

Current Practices on Diagnosis, Prevention and Treatment of Post-Transplant Lymphoproliferative Disorder in Pediatric Patients after Solid Organ Transplantation: Results of ERN TransplantChild Healthcare Working Group Survey.

(1) Background: Post-transplant lymphoproliferative disease (PTLD) is a significant complication of solid organ transplantation (SOT). However, there is lack of consensus in PTLD management. Our aim was to establish a present benchmark for comparison between international centers and between various organ transplant systems and modalities; (2) Methods: A cross-sectional questionnaire of relevant PTLD practices in pediatric transplantation was sent to multidisciplinary teams from 17 European center members of ERN TransplantChild to evaluate the centers' approach strategies for diagnosis and treatment and how current practices impact a cross-sectional series of PTLD cases; (3) Results: A total of 34 SOT programs from 13 European centers participated. The decision to start preemptive treatment and its guidance was based on both EBV viremia monitoring plus additional laboratory methods and clinical assessment (61%). Among treatment modalities the most common initial practice at diagnosis was to reduce the immunosuppression (61%). A total of 126 PTLD cases were reported during the period 2012-2016. According to their histopathological classification, monomorphic lesions were the most frequent (46%). Graft rejection after PTLD remission was 33%. Of the total cases diagnosed with PTLD, 88% survived; (4) Conclusions: There is still no consensus on prevention and treatment of PTLD, which implies the need to generate evidence. This might successively allow the development of clinical guidelines.

[Informed Consent - Vision and Perspectives of Adolescents, Parents and Professionals: Multicentric Study in Six Hospitals].

INTRODUCTION: According to the Convention on the Rights of Children and the national standards of the Portuguese Directorate-General for Health, adolescents have the right to make decisions about their own health. The aim of this study was to identify the dynamics of the implementation of assent and informed consent in hospital settings. MATERIAL AND METHODS: Cross-sectional and multicentre study based on surveys, which included adolescents from 14 to 18 years and their parents. Heads of departments of Pediatrics and attending physicians were also interviewed. RESULTS: 194 responses from adolescents and parents were collected, and 46 interviews were conducted with physicians and heads of department. Adolescents and parents consider participation in decision making important, but parents value their own participation significantly higher (91.7% vs 47.8%, p < 0.001 in the 14 - 15 year group, 91.8% vs 53, (89.6% vs 69.6%, p = 0.016 in the 14 - 15 year group, 91.8% vs 69.4%, p = 0.005 in the 16 - 17 years group). Information leaflets are difficult to understand by teenagers. The eight heads of department felt that doctors have awareness towards communication with teenagers but have little time available. Of the 38 attending physicians, 36 said they had learned from their older colleagues and confirmed gaps in postgraduate training. DISCUSSION: This pioneering study in Portugal enabled the identification of areas that can be optimized, through health education programs for parents and adolescents, written information that is adequate to the different age groups, training in undergraduate education for medical students and also education in health institutions for professionals. CONCLUSION: Adolescents and parents, are unaware of legal and ethical standards for consent and assent. The implementation of the adolescents' right to informed assent / informed consent was not observed. Our proposal is to implement local programs for adolescents and parents.

Introdução: A Convenção sobre os Direitos das Crianças e normas nacionais da Direção Geral da Saúde conferem aos adolescentes o direito às decisões sobre a sua saúde. O objectivo deste estudo foi identificar as dinâmicas de implementação do assentimento e do consentimento informado, em ambiente hospitalar. Material e Métodos: Estudo transversal e multicêntrico realizado a partir de inquéritos. Incluídos adolescentes dos 14 aos 18 anos e pais respectivos. Foram ainda entrevistados os diretores de serviço e assistentes hospitalares. Resultados: Obtiveram-se 194 respostas de adolescentes e pais e efetuaram-se 46 entrevistas a médicos e diretores dos serviços. Adolescentes e pais consideram importante a participação no processo de decisão mas os pais valorizam de forma significativamente superior a sua participação (91,7% vs 47,8%, p < 0,001 no grupo 14 - 15 anos; 91,8% vs 53,1%, p = 0,001, no grupo 16 - 17 anos), bem como a do médico (89,6% vs 69,6%, p = 0,016 no grupo 14 - 15 anos; 91,8% vs 69,4%, p = 0,005 no grupo 16 - 17 anos). Os folhetos informativos são pouco perceptíveis pelos adolescentes. Os oito diretores consideraram que os médicos estão sensibilizados para comunicar com os adolescentes mas têm pouco tempo disponível. Dos 38 assistentes, 36 afirma ter aprendido com os colegas mais velhos e confirmam lacunas na formação pós graduada. Discussão: Este estudo pioneiro em Portugal permitiu a identificação de áreas passíveis de otimização, através de programas da educação para a saúde para pais e adolescentes, informação escrita adequada à idade e formação no ensino pré graduado para estudantes de Medicina e educação nas instituições de saúde para os profissionais. Conclusão: Os adolescentes e pais desconhecem as normas legais e éticas quanto ao consentimento e assentimento. Não fica demonstrada a implementação do direito dos adolescentes ao assentimento informado / consentimento informado. Propõem-se programas locais de sensibilização para adolescentes e pais.

Tubulointerstitial nephritis and uveitis syndrome in children: report of three cases / Nefrite tubulointersticial e uveíte em idade pediátrica: descrição de três doentes

ABSTRACT Tubulointerstitial nephritis and uveitis syndrome is a rare and probably underdiagnosed condition. Renal and ocular manifestations may not occur simultaneously, making the diagnosis more difficult. Nephritis may be asymptomatic; therefore, renal function evaluation is essential for diagnosis. Urinary β2-microglobulin levels may be particularly useful. Uveitis, mostly anterior, nongranulomatous and bilateral, occurs usually after the onset of nephritis. Treatment includes corticosteroids and, eventually, other immunosuppressant agents. Renal disease is usually benign and resolves spontaneously or after treatment with systemic corticosteroids. Uveitis, however, may be chronic or recurrent. The authors described the cases of three pediatric patients diagnosed with tubulointerstitial nephritis and uveitis syndrome. The goal of this paper was to warn the medical community over the need to screen patients with uveitis for renal disease.

RESUMO A síndrome nefrite tubulointersticial e uveíte é uma doença rara, provavelmente subdiagnosticada. As manifestações renais e oculares podem não ocorrer simultaneamente, tornando o diagnóstico mais difícil. A nefrite é geralmente assintomática, tornando fundamental a avaliação da função renal em doentes com uveíte. O doseamento da excreção urinária de β2-microglobulina é particularmente útil para o diagnóstico. A uveíte, tipicamente anterior, não granulomatosa e bilateral, manifesta-se após a nefrite na maioria dos casos. O tratamento inclui corticoides e, por vezes, outros imunossupressores. A doença renal tem evolução benigna, resolvendo-se espontaneamente ou com terapêutica com corticoides sistêmicos na maioria dos casos, no entanto, a uveíte pode ser crônica ou recorrente. Os autores descrevem três casos de síndrome nefrite tubulointersticial e uveíte, diagnosticados em idade pediátrica, e pretendem alertar para a necessidade de pesquisar sempre alterações renais nos doentes com uveíte.

Tubulointerstitial nephritis and uveitis syndrome in children: report of three cases.

Tubulointerstitial nephritis and uveitis syndrome is a rare and probably underdiagnosed condition. Renal and ocular manifestations may not occur simultaneously, making the diagnosis more difficult. Nephritis may be asymptomatic; therefore, renal function evaluation is essential for diagnosis. Urinary ß2-microglobulin levels may be particularly useful. Uveitis, mostly anterior, nongranulomatous and bilateral, occurs usually after the onset of nephritis. Treatment includes corticosteroids and, eventually, other immunosuppressant agents. Renal disease is usually benign and resolves spontaneously or after treatment with systemic corticosteroids. Uveitis, however, may be chronic or recurrent. The authors described the cases of three pediatric patients diagnosed with tubulointerstitial nephritis and uveitis syndrome. The goal of this paper was to warn the medical community over the need to screen patients with uveitis for renal disease.

A child with tubulointerstitial nephritis and uveitis (TINU) syndrome.

Tubulointerstitial nephritis and uveitis syndrome is an uncommon disease, probably underdiagnosed in clinical practice. Its aetiology and pathogenesis remain unknown. This syndrome is defined by an association of uveitis and tubulointerstitial nephritis, with no evidence of systemic disease or infection that might cause both ocular and renal inflammation. Renal and ocular manifestations may not occur simultaneously, making the diagnosis even more challenging. Treatment includes topical and oral corticosteroids. Renal involvement usually resolves spontaneously with full recovery of kidney function, however uveitis can persist or recur years after its initial presentation. We report a case of a 13-year-old girl with tubulointerstitial nephritis and uveitis syndrome.

Mortality risk disparities in children receiving chronic renal replacement therapy for the treatment of end-stage renal disease across Europe: an ESPN-ERA/EDTA registry analysis.

BACKGROUND: We explored the variation in country mortality rates in the paediatric population receiving renal replacement therapy across Europe, and estimated how much of this variation could be explained by patient-level and country-level factors. METHODS: In this registry analysis, we extracted patient data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry for 32 European countries. We included incident patients younger than 19 years receiving renal replacement therapy. Adjusted hazard ratios (aHR) and the explained variation were modelled for patient-level and country-level factors with multilevel Cox regression. The primary outcome studied was all-cause mortality while on renal replacement therapy. FINDINGS: Between Jan 1, 2000, and Dec 31, 2013, the overall 5 year renal replacement therapy mortality rate was 15·8 deaths per 1000 patient-years (IQR 6·4-16·4). France had a mortality rate (9·2) of more than 3 SDs better, and Russia (35·2), Poland (39·9), Romania (47·4), and Bulgaria (68·6) had mortality rates more than 3 SDs worse than the European average. Public health expenditure was inversely associated with mortality risk (per SD increase, aHR 0·69, 95% CI 0·52-0·91) and explained 67% of the variation in renal replacement therapy mortality rates between countries. Child mortality rates showed a significant association with renal replacement therapy mortality, albeit mediated by macroeconomics (eg, neonatal mortality reduced from 1·31 [95% CI 1·13-1·53], p=0·0005, to 1·21 [0·97-1·51], p=0·10). After accounting for country distributions of patient age, the variation in renal replacement therapy mortality rates between countries increased by 21%. INTERPRETATION: Substantial international variation exists in paediatric renal replacement therapy mortality rates across Europe, most of which was explained by disparities in public health expenditure, which seems to limit the availability and quality of paediatric renal care. Differences between countries in their ability to accept and treat the youngest patients, who are the most complex and costly to treat, form an important source of disparity within this population. Our findings can be used by policy makers and health-care providers to explore potential strategies to help reduce these health disparities. FUNDING: ERA-EDTA and ESPN.

[Peritoneal Dialysis in the First Two Years of Life: Experience of a Nephrology and Renal Transplantation Pediatric Unit]. / Diálise Peritoneal nos Dois Primeiros Anos de Vida: Experiência de uma Unidade de Nefrologia e Transplantação Renal Pediátrica.

INTRODUCTION: Peritoneal dialysis is the dialytic method of choice in chronic end-stage renal disease in children. This study main purpose was to characterize the long-term survival of a pediatric population who began peritoneal dialysis within the first two years of life. MATERIAL AND METHODS: A descriptive and retrospective study was performed in a portuguese nephrology and renal transplantation pediatric unit, between January 1991 and August 2014. End-stage renal disease etiology, mortality, comorbidities and complications of peritoneal dialysis and end-stage renal disease, growth and psychomotor development were evaluated. RESULTS: Twenty children started peritoneal dialysis within the first two years of life. There were six deaths, but no deaths of children with primary chronic kidney disease were registered over the past decade. The 14 living children were characterized; 13 were males. Congenital abnormalities of the kidney and urinary tract were the leading etiology of chronic kidney disease (45%). The average age start of peritoneal dialysis was 6.1 months; six children started before 30 days of life. Peritonitis was the most frequent cause of hospitalization. Ten children were transplanted at an average age of 5.3 years. All of the children who are still in peritoneal dialysis have short stature, but nine of the transplanted have final height within the expected for their mid-parental height target range. Nine (64%) had some type of neurodevelopmental delay. DISCUSSION: Peritoneal dialysis is a technique possible and feasible since birth, as evidenced in the study, as more than half of children successfully started it before 6 months of life. It allows long-term survival until the possibility of renal transplantation despite the associated morbidity, including peritonitis and complications of chronic renal disease. The ten transplanted children improved their growth, recovered from chronic anemia and improved dyslipidemia, compared with the period of dialysis. However, the average waiting time until the renal transplant was 5.3 years higher than other international centers. CONCLUSION: These data support the use of peritoneal dialysis from birth, but complications and the worst growth reflect the need to develop strategies to optimize care relating to nutrition, growth and development and to reduce pre-transplant time.

Introdução: A diálise peritoneal é o método dialítico de eleição perante doença renal crónica terminal em idade pediátrica. O objetivo deste estudo foi caracterizar a sobrevivência a longo prazo de uma população de crianças, que iniciou diálise peritoneal nos dois primeiros anos de vida. Material e Métodos: Estudo descritivo e retrospetivo, realizado numa unidade de nefrologia e transplantação renal pediátrica portuguesa, no período de janeiro de 1991 a agosto de 2014. Avaliou-se etiologia da doença renal crónica terminal, mortalidade, comorbilidades e complicações da diálise peritoneal e da doença renal crónica terminal, crescimento e desenvolvimento psicomotor.Resultados: Vinte crianças iniciaram diálise peritoneal antes dos dois anos. Ocorreram seis óbitos; não houve mortalidade em crianças com doença renal primária nos últimos 10 anos. Caracterizaram-se os 14 sobreviventes, 13 do sexo masculino. As anomalias congénitas do rim e do trato urinário constituíram a principal causa de doença renal crónica terminal (45%).O início de diálise peritoneal ocorreu em média aos 6,1 meses, em seis casos antes dos 30 dias de vida. A peritonite foi o motivo mais frequente de internamento. Dez crianças foram transplantadas, com idade média de 5,3 anos. Em relação ao crescimento, as quatro crianças que se mantêm em diálise peritoneal têm baixa estatura, mas nove dos transplantados têm uma estatura final dentro do esperado para a sua estatura-alvo familiar. Nove (64%) tiveram alterações no desenvolvimento psicomotor. Discussão: A diálise peritoneal é uma técnica possível e exequível desde o nascimento, tal como evidenciado nesta amostra, em que se iniciou com sucesso em mais de metade das crianças antes dos seis meses de vida. Permite uma sobrevivência a longo prazo até à possibilidade do transplante renal apesar da morbilidade associada, nomeadamente as peritonites e as complicações da doença renal crónica. As dez crianças transplantadas desta amostra melhoraram o seu crescimento, recuperaram da anemia crónica e melhoraram da dislipidémia, comparativamente com o período em diálise. No entanto, o tempo médio de espera até ao TR de 5,3 anos foi superior ao de outros centros internacionais.Conclusão: Estes dados apoiam a utilização da diálise peritoneal desde o nascimento, embora as complicações e o pior crescimento associados reflitam a necessidade de desenvolver estratégias para otimizar nutrição, crescimento e desenvolvimento e reduzir o tempo pré-transplante renal.

[Complications of pediatric renal transplantation]. / Complicações da transplantação renal em idade pediátrica.

BACKGROUND: Renal transplantation is the treatment of choice for children with end stage renal disease with positive impact on survival and quality of life. However, some complications affect morbidity and mortality. This study examines the renal transplantation complications profile in pediatric patients (<18 y). MATERIAL AND METHODS: Retrospective analysis of clinical files from renal transplantation patients followed in Pediatric Nephrology Unit from September 1995 to August 2010. Collection of data regarding: demography, end stage renal disease etiology, previous renal replacement therapy, graft loss and death, complications: surgical, infectious and non-infectious (acute and chronic rejection, primary disease recurrence, metabolic and cardiovascular risk factors). Descriptive statistical analysis was performed. RESULTS: 78 children (male: 48.7%), mean age at renal transplantation: 11.7 4.1 years. Previous peritoneal dialysis in 49 (62.6%). Five patients (6.4%) with preemptive renal transplantation. Median follow up: 37.5 months (1-169). Main end stage renal disease etiologies were urologic conditions in 41% and glomerular disease in 28.2%. Infectious complications occurred in 74%: viral: 56.4% (cytomegalovirus in 39.7%); bacterial in 53.8% (mainly urinary tract infections). Non-infectious complications were: 1) cardiovascular risk factors: hypertension in 85.9%, hyperlipidemia in 16.7% and new onset diabetes post transplantation in 7.7%; 2) acute graft dysfunction in 32.1%; graft chronic nephropathy 17.9%; 3) surgical complications 16.7%. In the first month after renal transplantation, surgical complications (11.5%) and bacterial infections were the most prevalent complications. Between the 1st and the 6th month there were more bacterial (34.6% patients) and viral (17.9% patients) infections. From 6th month on, cardiovascular risk factors (89.7% patients) became the more prevalent. There was one death. CONCLUSIONS: The most frequent infections were viral, mainly CMV. Acute graft dysfunction was frequent after the 6th month, probably associated with poor compliance. New morbidities, namely cardiovascular risk factors, are emerging with the evolution of new diagnostic, prophylactic and therapeutic strategies for renal transplantation.

Introdução: A transplantação renal é a terapêutica de eleição na criança com doença renal crónica terminal, evidenciando impacto positivo na sobrevida e qualidade de vida dos doentes. Não é, no entanto, isenta de complicações, algumas com importante morbilidade. Os autores pretendem caracterizar o perfil de complicações pós transplantação renal em doentes pediátricos (até 18 anos).Material e Métodos: Análise retrospectiva dos doentes submetidos a transplantação renal e seguidos na Unidade de Nefrologia Pediátrica entre Setembro de 1995 e Agosto de 2010. Dados obtidos dos processos clínicos: características demográficas, etiologia da doença renal crónica terminal, terapêutica de substituição renal, mortalidade e perda de enxertos, complicações cirúrgicas, infecciosas e não infecciosas (rejeição aguda e crónica, recidiva da doença de base, alterações metabólicas e factores de risco cardiovascular). Análise estatística descritiva simples.Resultados: Foram incluídas 78 crianças transplantadas (48,7% sexo masculino), com idade mediana à data da transplantaçãorenal de 12 anos (2 - 18). A maioria fez previamente diálise peritoneal: 49 (62,6%). Cinco doentes (6,4%) foram transplantados sem diálise prévia. A mediana do tempo de seguimento após transplante foi 37,5 meses (1 - 169). As principais etiologias de doença renal crónica terminal foram: uronefropatias (41%) e glomerulopatias (28,2%). As complicações infecciosas ocorreram em 74,4%; infecçõesvirais em 56,4%, sendo a mais prevalente a infecção citomegalovírus (39,7%); infecções bacterianas em 53,8% (na maioria infecções urinárias em doentes urológicos). Outras complicações: 1) factores de risco para doença cardiovascular: hipertensão arterial em 85,9%; dislipidémia em 16,7% e diabetes de novo em 7,7%; 2) episódios de rejeição aguda em 32,1% e nefropatia crónica do enxerto em 17,9%; 3) complicações relacionáveis com a cirurgia em 16,7%. No primeiro mês após transplantação renal as complicações maisfrequentes foram as infecções bacterianas que ocorreram em 15,4% dos doentes e as complicações associadas à cirurgia que ocorreram em 11,5%; entre 1º e 6º mês prevaleceram as infecções bacterianas (em 34,6%) e virais (em 17,9%) e a partir do sexto mês os factores de risco cardiovascular (hipertensão arterial em 85,9% e dislipidémia em 16,7%). Registou-se um óbito.Conclusões: As infecções mais frequentes foram as virais, nomeadamente a infecção citomegalovírus. A disfunção aguda do enxerto permanece uma complicação frequente. Com a evolução de novas estratégias diagnósticas, profilácticas e terapêuticas, assistiu-se a emergência de novas morbilidades, nomeadamente os factores de risco cardiovascular.

Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis.

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.

Impaired proteostasis contributes to renal tubular dysgenesis.

Protein conformational disorders are associated with the appearance, persistence, accumulation, and misprocessing of aberrant proteins in the cell. The etiology of renal tubular dysgenesis (RTD) is linked to mutations in the angiotensin-converting enzyme (ACE). Here, we report the identification of a novel ACE mutation (Q1069R) in an RTD patient. ACE Q1069R is found sequestered in the endoplasmic reticulum and is also subject to increased proteasomal degradation, preventing its transport to the cell surface and extracellular fluids. Modulation of cellular proteostasis by temperature shift causes an extension in the processing time and trafficking of ACE Q1069R resulting in partial rescue of the protein processing defect and an increase in plasma membrane levels. In addition, we found that temperature shifting causes the ACE Q1069R protein to be secreted in an active state, suggesting that the mutation does not affect the enzyme's catalytic properties.

Severe immune haemolytic anaemia due to ceftriaxone in a patient with congenital nephrotic syndrome.

AIM: To describe the first case of ceftriaxone-related haemolysis in a patient with congenital nephrotic syndrome (CNS). BACKGROUND: Severe haemolysis caused by an immune reaction to ceftriaxone has mostly been described in patients with underlying haematological or immune dysfunction. CASE REPORT: The authors present a 20-month-old boy with CNS of the Finnish type with several previous severe infections treated with ceftriaxone, admitted for suspected sepsis. Following ceftriaxone administration he developed shock secondary to an acute haemolytic reaction, with severe anaemia. Hypersensitivity to ceftriaxone was documented through positive agglutination tests. CONCLUSION: Onset of haemolysis following ceftriaxone administration, particularly in a patient previously exposed to the drug, must raise the suspicion of a possible immune reaction.

Rituximab use in pediatric autoimmune diseases: four case reports.

Rituximab (RTX) is currently used in many diseases, but its efficacy and safety in juvenile systemic lupus erythematosus (SLEj) is still unknown. In this chapter we present four case reports of children treated with RTX: three SLE and one immune thrombocytopenic purpura (ITP). Two of the three SLEj patients had class IV lupus nephritis (LN) and hematologic manifestations (pancytopenia), both reaching complete recovery of blood counts and improvement of LN with RTX treatment. Our third SLE patient had a severe onset with generalized microangiopathic manifestations in association with antiphospholipid antibodies and has been in remission for almost 1 year after RTX. However, our fourth case, a patient with ITP and renal failure, was treated with RTX without either hematologic or renal response.

IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria.

This European Community Biomedicine and Health Research-supported, multicenter, randomized, placebo-controlled, double-blind trial investigated the effect of an angiotensin-converting enzyme inhibitor (ACE-I) in children and young people with IgA nephropathy (IgAN), moderate proteinuria (>1 and <3.5 g/d per 1.73 m(2)) and creatinine clearance (CrCl) >50 ml/min per 1.73 m(2). Sixty-six patients who were 20.5 yr of age (range 9 to 35 yr), were randomly assigned to Benazepril 0.2 mg/kg per d (ACE-I) or placebo and were followed for a median of 38 mo. The primary outcome was the progression of kidney disease, defined as >30% decrease of CrCl; secondary outcomes were (1) a composite end point of >30% decrease of CrCl or worsening of proteinuria until > or =3.5 g/d per 1.73 m(2) and (2) proteinuria partial remission (<0.5 g/d per 1.73 m(2)) or total remission (<160 mg/d per 1.73 m(2)) for >6 mo. Analysis was by intention to treat. A single patient (3.1%) in the ACE-I group and five (14.7%) in the placebo group showed a worsening of CrCl >30%. The composite end point of >30% decrease of CrCl or worsening of proteinuria until nephrotic range was reached by one (3.1%) of 32 patients in the ACE-I group, and nine (26.5%) of 34 in the placebo group; the difference was significant (log-rank P = 0.035). A stable, partial remission of proteinuria was observed in 13 (40.6%) of 32 patients in the ACE-I group versus three (8.8%) of 34 in the placebo group (log-rank P = 0.033), with total remission in 12.5% of ACE-I-treated patients and in none in the placebo group (log-rank P = 0.029). The multivariate Cox analysis showed that treatment with ACE-I was the independent predictor of prognosis; no influence on the composite end point was found for gender, age, baseline CrCl, systolic or diastolic BP, mean arterial pressure, or proteinuria.

A new mutation (intron 9 +1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies.

BACKGROUND: Gitel syndrome is an inherited tubular disorder characterized by metabolic alkalosis, hypokalemia, and hypomagnesemia of renal origin and hypocalciuria. The majority of patients with Gitelman syndrome carry inactivating mutations in the SLC12A3 gene encoding the sodium-chloride cotransporter located in the distal convoluted tubule. The purpose of this study was to investigate the underlying mutation in Gitelman syndrome patients of Gypsy race from different geographic origin. METHODS: Twenty Gypsy patients with clinical and biochemical features of Gitelman syndrome were investigated by mutational analysis. The patients belonged to 12 unrelated Gypsy families living in four different European countries. The parents and unaffected siblings of each patient, as well as the DNA of a population of 200 healthy control patients, were also analyzed. RESULTS: All patients were homozygous for the same splice site mutation, guanine to thymine in the first position of intron 9 of SLC12A3 gene. This mutation was not found in the control population. Parents were heterozygous for the mutation. Despite sharing a common mutation, the clinical manifestations of the syndrome in the patients varied from lack of symptoms in six children to severe growth retardation in four. CONCLUSION: Demonstration of a novel point mutation within the SLC12A3 gene in our cohort of Gypsy families with Gitelman syndrome is highly suggestive of a founder effect. This finding will facilitate the identification of the genetic defect in further cases of Gitelman syndrome among the Gypsy population. Our study represents the largest series ever published of patients with Gitelman syndrome having the same underlying mutation, and supports the lack of correlation between genotype and clinical phenotype in this disease.

[Kidney failure associated with Plasmodium falciparum infection]. / Insuficiência renal associada a infecção por Plasmodium falciparum.

Plasmodium falciparum infection may be a cause of acute renal failure (ARF). Whereas renal failure appears to be a common complication of severe malaria in adults, it seldom occurs in children. The authors report a case of a previously healthy 9-year-old child, who was admitted with fever, vomits, diarrhoea, jaundice and obnubilation of consciencious. The results of laboratory tests performed confirmed the diagnosis of falciparum malaria. At the 2nd day of hospitalization she was in ARF and dialysis was necessary. We admitted that the probable underlying factors leading to this complication were: intravascular haemolysis, volume depletion, hypotension and hyperparasitaemia. Despite the presence of predictive factors of bad outcome the evolution was favourable with gradual recuperation of renal function.