RESUMO
The primary hyperoxalurias (PH 1, 2, and 3) are rare autosomal recessive disorders of glyoxylate metabolism resulting in hepatic overproduction of oxalate. Clinical presentations that should prompt consideration of PH include kidney stones, nephrocalcinosis, and kidney failure of unknown etiology, especially with echogenic kidneys on ultrasound. PH1 is the most common and severe of the primary hyperoxalurias with a high incidence of kidney failure as early as infancy. Until the recent availability of a novel RNA interference (RNAi) agent, PH care was largely supportive of eventual need for kidney/liver transplantation in PH1 and PH2. Together with the Oxalosis and Hyperoxaluria Foundation, the authors developed a diagnostic algorithm for PH1 and in this report outline best clinical practices related to its early diagnosis, supportive treatment, and long-term management, including the use of the novel RNAi. PH1-focused approaches to dialysis and kidney/liver transplantation for PH patients with progression to chronic kidney disease/kidney failure and systemic oxalosis are suggested. Therapeutic advances for this devastating disease heighten the importance of early diagnosis and informed treatment.
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BACKGROUND: The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. OBJECTIVES: To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. SEARCH METHODS: We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). AUTHORS' CONCLUSIONS: Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.
Assuntos
Antivirais , Infecções por Citomegalovirus , Ganciclovir , Transplante de Órgãos , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Aciclovir/uso terapêutico , Aciclovir/efeitos adversos , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Viés , Causas de Morte , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/uso terapêutico , Ganciclovir/efeitos adversos , Ganciclovir/análogos & derivados , Transplante de Órgãos/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Transplantados , Valaciclovir/efeitos adversos , Valaciclovir/uso terapêutico , Valganciclovir/efeitos adversos , Valganciclovir/uso terapêuticoRESUMO
Haemolytic uraemic syndrome (HUS) is a heterogeneous group of diseases that result in a common pathology, thrombotic microangiopathy, which is classically characterised by the triad of non-immune microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In this Seminar, different causes of HUS are discussed, the most common being Shiga toxin-producing Escherichia coli HUS. Identifying the underlying thrombotic microangiopathy trigger can be challenging but is imperative if patients are to receive personalised disease-specific treatment. The quintessential example is complement-mediated HUS, which once carried an extremely high mortality but is now treated with anti-complement therapies with excellent long-term outcomes. Unfortunately, the high cost of anti-complement therapies all but precludes their use in low-income countries. For many other forms of HUS, targeted therapies are yet to be identified.
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Injúria Renal Aguda , Síndrome Hemolítico-Urêmica , Microangiopatias Trombóticas , Humanos , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/terapia , Síndrome Hemolítico-Urêmica/etiologia , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/terapia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapiaRESUMO
RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. STUDY DESIGN: Phase 3, open-label, single-arm trial. SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 µmol/L at screening, including patients with or without systemic oxalosis. INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. OUTCOME: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. LIMITATIONS: Single-arm study without placebo control. CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. FUNDING: Alnylam Pharmaceuticals. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.
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Hiperoxalúria Primária , Hiperoxalúria , Nefropatias , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Hiperoxalúria Primária/complicações , Nefropatias/complicações , OxalatosRESUMO
BACKGROUND: Diagnosing genetic kidney disease has become more accessible with low-cost, rapid genetic testing. The study objectives were to determine genetic testing diagnostic yield and examine predictors of genetic diagnosis in children with nephrolithiasis/nephrocalcinosis (NL/NC). METHODS: This retrospective multicenter cross-sectional study was conducted on children ≤ 21 years old with NL/NC from pediatric nephrology/urology centers that underwent the Invitae Nephrolithiasis Panel 1/1/2019-9/30/2021. The diagnostic yield of the genetic panel was calculated. Bivariate and multiple logistic regression were performed to assess for predictors of positive genetic testing. RESULTS: One hundred and thirteen children (83 NL, 30 NC) from 7 centers were included. Genetic testing was positive in 32% overall (29% NL, 40% NC) with definite diagnoses (had pathogenic variants alone) made in 11.5%, probable diagnoses (carried a combination of pathogenic variants and variants of uncertain significance (VUS) in the same gene) made in 5.4%, and possible diagnoses (had VUS alone) made in 15.0%. Variants were found in 28 genes (most commonly HOGA1 in NL, SLC34A3 in NC) and 20 different conditions were identified. Compared to NL, those with NC were younger and had a higher proportion with developmental delay, hypercalcemia, low serum bicarbonate, hypophosphatemia, and chronic kidney disease. In multivariate analysis, low serum bicarbonate was associated with increased odds of genetic diagnosis (ß 2.2, OR 8.7, 95% CI 1.4-54.7, p = 0.02). CONCLUSIONS: Genetic testing was high-yield with definite, probable, or possible explanatory variants found in up to one-third of children with NL/NC and shows promise to improve clinical practice. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Cálculos Renais , Nefrocalcinose , Nefrolitíase , Criança , Humanos , Adulto Jovem , Adulto , Nefrocalcinose/diagnóstico , Nefrocalcinose/genética , Bicarbonatos , Estudos Transversais , Nefrolitíase/diagnóstico , Nefrolitíase/genética , Cálculos Renais/genética , Testes GenéticosRESUMO
BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018-004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here. METHODS: Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7-20.5) months). RESULTS: Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)). CONCLUSIONS: Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Hiperoxalúria Primária , Cálculos Renais , Criança , Pré-Escolar , Humanos , Lactente , Hiperoxalúria Primária/complicações , Hiperoxalúria Primária/tratamento farmacológico , Cálculos Renais/etiologia , Oxalatos/efeitos adversosRESUMO
BACKGROUND: Children with chronic kidney disease (CKD) generally have worse educational and psychosocial outcomes compared with their healthy peers. This can impair their ability to manage their treatment, which in turn can have long-term health consequences through to adulthood. We attempted to capture the experiences of children with CKD and to describe the perspectives of their parents and caregivers on access to educational and psychosocial support. METHODS: Children with CKD (n = 34) and their caregivers (n = 62) were sampled via focus groups from pediatric hospitals in Australia, Canada, and the USA. Sixteen focus groups were convened and the transcripts were analyzed thematically. RESULTS: We identified four themes: disruption to self-esteem and identity (emotional turmoil of adolescence, wrestling with the sick self, powerlessness to alleviate child's suffering, balancing normality and protection); disadvantaged by lack of empathy and acceptance (alienated by ignorance, bearing the burden alone); a hidden and inaccessible support system (excluded from formal psychological support, falling behind due to being denied special considerations); and building resilience (finding partners in the journey, moving towards acceptance of the illness, re-establishing childhood). CONCLUSIONS: Children with CKD and their caregivers encountered many barriers in accessing psychosocial and educational support and felt extremely disempowered and isolated as a consequence. Improved availability and access to psychosocial and educational interventions are needed to improve the wellbeing and educational advancement of children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Cuidadores , Insuficiência Renal Crônica , Adolescente , Criança , Humanos , Adulto , Grupos Focais , Pais/psicologia , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/psicologia , AnsiedadeRESUMO
PURPOSE: Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1. METHODS: This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate. RESULTS: All patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions. CONCLUSION: Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.
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Hiperoxalúria Primária , Terapêutica com RNAi , Pré-Escolar , Humanos , Hiperoxalúria Primária/complicações , Hiperoxalúria Primária/genética , Hiperoxalúria Primária/terapia , Lactente , Interferência de RNA , RNA Interferente PequenoRESUMO
RATIONALE & OBJECTIVE: The inconsistency in outcomes reported and lack of patient-reported outcomes across trials in children with chronic kidney disease (CKD) limits shared decision making. As part of the Standardized Outcomes in Nephrology (SONG)-Kids initiative, we aimed to generate a consensus-based prioritized list of critically important outcomes to be reported in all trials in children with CKD. STUDY DESIGN: An online 2-round Delphi survey in English, French, and Hindi languages. SETTINGS & PARTICIPANTS: Patients (aged 8-21 years), caregivers/family, and health care professionals (HCPs) rated the importance of outcomes using a 9-point Likert scale (7-9 indicating critical importance) and completed a Best-Worst Scale. ANALYTICAL APPROACH: We assessed the absolute and relative importance of outcomes. Comments were analyzed thematically. RESULTS: 557 participants (72 [13%] patients, 132 [24%] caregivers, and 353 [63%] HCPs) from 48 countries completed round 1 and 312 (56%) participants (28 [40%] patients, 64 [46%] caregivers, and 220 [56%] HCPs) completed round 2. Five outcomes were common in the top 10 for each group: mortality, kidney function, life participation, blood pressure, and infection. Caregivers and HCPs rated cardiovascular disease higher than patients. Patients gave lower ratings to all outcomes compared with caregivers/HCPs except they rated life participation (round 2 mean difference, 0.1), academic performance (0.1), mobility (0.4), and ability to travel (0.4) higher than caregivers and rated ability to travel (0.4) higher than HCPs. We identified 3 themes: alleviating disease and treatment burden, focusing on the whole child, and resolving fluctuating and conflicting goals. LIMITATIONS: Most participants completed the survey in English. CONCLUSIONS: Mortality, life participation, kidney function, and blood pressure were consistently highly prioritized by patients, caregivers, and HCPs. Patients gave higher priority to some lifestyle-related outcomes compared with caregivers/HCPs. Establishing critically important outcomes for all trials in children with CKD may improve consistent reporting of survival, kidney health, and clinical and life impact outcomes that are meaningful for decision making.
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Consenso , Técnica Delphi , Avaliação de Resultados da Assistência ao Paciente , Insuficiência Renal Crônica/terapia , Adolescente , Cuidadores , Criança , Feminino , Pessoal de Saúde , Humanos , Cooperação Internacional , Masculino , Resultado do Tratamento , Adulto JovemRESUMO
RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) has wide-ranging and long-term consequences for young people and their families. The omission of outcomes that are important to young people with CKD and their caregivers limits knowledge to guide shared decision making. We aimed to identify the outcomes that are important to young people with CKD and their caregivers. STUDY DESIGN: We used the nominal group technique whereby participants identified and ranked outcomes and explained their priorities. SETTINGS & PARTICIPANTS: Young people with CKD (stages 1-5, dialysis, or transplantation) and their caregivers were purposively sampled from 6 centers across Australia, the United States, and Canada. ANALYTICAL APPROACH: Importance scores were calculated (scale of 0-1), and qualitative data were analyzed thematically. RESULTS: 34 patients (aged 8-21 years) and 62 caregivers participated in 16 groups and identified 48 outcomes. The 5 highest ranked outcomes for patients were survival (importance score, 0.25), physical activity (0.24), fatigue (0.20), lifestyle restrictions (0.20), and growth (0.20); and for caregivers, kidney function (0.53), survival (0.28), infection (0.22), anemia (0.20), and growth (0.17). 12 themes were identified reflecting their immediate and current priorities (wanting to feel normal, strengthening resilience, minimizing intrusion into daily life, imminent threats to life, devastating family burdens, and seeking control over health) and considerations regarding future impacts (protecting health/development, remaining hopeful, concern for limited opportunities, prognostic uncertainty, dreading painful and invasive procedures, and managing expectations). LIMITATIONS: Only English-speaking participants were recruited. CONCLUSIONS: Kidney function, infection, survival, and growth were the highest priorities for patients with CKD and their caregivers. Young people with CKD also prioritized highly the outcomes that directly affected their lifestyle and sense of normality, while caregiver's highest priorities concerned the long-term health of their child, current health problems, and the financial and family burdens of caring for a child with CKD.
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Atitude Frente a Saúde , Cuidadores , Efeitos Psicossociais da Doença , Infecções , Insuficiência Renal Crônica , Adolescente , Austrália/epidemiologia , Canadá/epidemiologia , Cuidadores/psicologia , Cuidadores/estatística & dados numéricos , Criança , Autoavaliação Diagnóstica , Saúde da Família/economia , Feminino , Grupos Focais , Crescimento , Humanos , Infecções/epidemiologia , Infecções/psicologia , Masculino , Preferência do Paciente/estatística & dados numéricos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/psicologia , Insuficiência Renal Crônica/terapia , Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND & OBJECTIVES: Effective communication and shared decision making improve quality of care and patient outcomes but can be particularly challenging in pediatric chronic disease because children depend on their parents and clinicians to manage complex health care and developmental needs. We aimed to describe the perspectives of children with chronic kidney disease (CKD) and their parents with regard to communication and decision making. STUDY DESIGN: Qualitative study. SETTING & PARTICIPANTS: Children with CKD (n=34) and parents (n=62) from 6 centers across 6 cities in Australia, Canada, and the United States participated in 16 focus groups. ANALYTICAL APPROACH: Transcripts were analyzed thematically. RESULTS: We identified 4 themes: (1) disempowered by knowledge imbalance (unprepared and ill-informed, suspicion of censorship, and inadequacy as technicians), (2) recognizing own expertise (intuition and instinct unique to parental bond, emerging wisdom and confidence, identifying opportunities for control and inclusion, and empowering participation in children), (3) striving to assert own priorities (negotiating broader life impacts, choosing to defer decisional burden, overprotected and overruled, and struggling to voice own preferences), and (4) managing child's involvement (respecting child's expertise, attributing "risky" behaviors to rebellion, and protecting children from illness burden). LIMITATIONS: Only English-speaking participants were recruited, which may limit the transferability of the findings. We collected data from child and parent perspectives; however, clinician perspectives may provide further understanding of the difficulties of communication and decision making in pediatrics. CONCLUSIONS: Parents value partnership with clinicians and consider long-term and quality-of-life implications of their child's illness. Children with CKD want more involvement in treatment decision making but are limited by vulnerability, fear, and uncertainty. There is a need to support the child to better enable him or her to become a partner in decision making and prepare him or her for adulthood. Collaborative and informed decision making that addresses the priorities and concerns of both children and parents is needed.
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Comunicação , Tomada de Decisões , Pais/psicologia , Qualidade de Vida , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Austrália , Canadá , Criança , Estudos de Coortes , Efeitos Psicossociais da Doença , Gerenciamento Clínico , Feminino , Grupos Focais , Humanos , Internacionalidade , Masculino , Relações Pais-Filho , Pediatria , Prognóstico , Pesquisa Qualitativa , Insuficiência Renal Crônica/diagnóstico , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Idiopathic membranous nephropathy is an uncommon cause of nephrotic syndrome in children and can present treatment challenges. The current treatment options of steroids and cyclophosphamide, cyclosporine, or mycophenolate require prolonged treatment durations and the associated side effects may result in nonadherence in children, especially in adolescents. CASE-DIAGNOSIS: We report two adolescent patients with idiopathic membranous nephropathy with nephrotic range proteinuria and elevated anti-phospholipase A2 receptor levels who did not achieve remission with steroids and were later treated with rituximab. Both patients received two doses of rituximab and responded with remission. In addition, anti-PLA2R antibody levels normalized and/or significantly improved. CONCLUSIONS: Rituximab seems to be a safe and effective treatment option in children with idiopathic membranous nephropathy due to anti-PLA2R. Further studies are needed to evaluate this effectiveness.
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Glomerulonefrite Membranosa/tratamento farmacológico , Imunossupressores/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Rituximab/uso terapêutico , Adolescente , Feminino , Humanos , Rim/patologia , Masculino , Receptores da Fosfolipase A2/imunologiaRESUMO
PURPOSE: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT). METHODS: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs). RESULTS: In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development. CONCLUSION: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.
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Variações do Número de Cópias de DNA , Sequenciamento do Exoma/métodos , Predisposição Genética para Doença/genética , Anormalidades Urogenitais/diagnóstico , Refluxo Vesicoureteral/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/genética , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas Nucleares/genética , Fator de Transcrição PAX2/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases/genética , Proteínas Repressoras/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Adulto JovemRESUMO
BACKGROUND: Interventional catheterization procedures may be needed for patients with severe renal failure who are dependent on dialysis. To avoid the risk of fluid overload and electrolyte derangement during complex procedures in this oliguric/anuric patient population, we performed intra-procedural dialysis, either continuous renal replacement therapy (CRRT) or continous cycling peritoneal dialysis (CCPD). METHODS: We performed a retrospective review of a cohort of pediatric patients, ages 0-18 years, with dialysis-dependent renal failure who received CRRT or CCPD during catheterization procedures from January 2013 to March 2016. RESULTS: Eight patients underwent a total of nine interventional catheterization procedures while receiving intra-procedural dialysis. Median age was 4.5 years (range 8 months to 17 years) and weight, 11.6 kg (11.2-62.6 kg). Six patients had end-stage renal disease (ESRD) and two patients had acute kidney injury (AKI), one due to hepatorenal syndrome and one due to multifactorial causes associated with congenital heart disease. The most common reason for catheterization was occlusive venous thrombosis requiring recanalization. CRRT was used during five cases and CCPD during four cases. Median procedure time was 337 min (95-651 min) and median contrast dose 4.2 mL kg-1 (1.2-8.2 mL kg-1 ). Euvolemia was maintained based on pre- and post-catheterizations weights, and no significant electrolyte abnormalities occurred based on lab monitoring during and post-procedure. CONCLUSIONS: Intra-procedural dialysis using CRRT or CCPD enables even small pediatric patients with severe renal failure to undergo long and complex interventional catheterizations by reducing the risk of fluid overload and electrolyte abnormalities. Collaboration between nephrology, cardiology, and dialysis teams is necessary for successful management of this challenging patient population.
Assuntos
Cateterismo Periférico/métodos , Procedimentos Endovasculares/métodos , Hemodiafiltração , Falência Renal Crônica/terapia , Diálise Peritoneal Ambulatorial Contínua , Insuficiência Renal/terapia , Trombose Venosa/terapia , Adolescente , Fatores Etários , Cateterismo Periférico/efeitos adversos , Criança , Pré-Escolar , Meios de Contraste/administração & dosagem , Meios de Contraste/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Feminino , Hemodiafiltração/efeitos adversos , Humanos , Lactente , Iohexol/administração & dosagem , Iohexol/efeitos adversos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/fisiopatologia , Masculino , Diálise Peritoneal Ambulatorial Contínua/efeitos adversos , Insuficiência Renal/diagnóstico , Insuficiência Renal/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Centros de Atenção Terciária , Texas , Resultado do Tratamento , Ácidos Tri-Iodobenzoicos/administração & dosagem , Ácidos Tri-Iodobenzoicos/efeitos adversos , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/fisiopatologiaRESUMO
Minimizing IS to reduce side effects without compromising long-term renal transplant survival is the goal of all IS protocols. We conducted a retrospective study of pediatric renal transplants performed August 1988 to July 2008 and treated with two-drug maintenance therapy by one of three protocols: prednisone/cyclosporine without induction (SB) or with daclizumab induction (SBI), or tacrolimus/mycophenolate with daclizumab induction (SF). Kaplan-Meier survival curves were used to determine graft and patient survival at one, three, five, and 10 yr. Associations between graft survival and patient/transplant characteristics were determined using log-rank test and CPH model adjusting for treatment group. About 208 patients were included in the analysis (96 SB, 97 SBI, 15 SF; 148 DD, 60 LD, 37 pre-emptive). Overall graft and patient survival at one, three, five, and 10 yr were similar to the previously published results of pediatric renal transplants in similar years treated predominantly with three-drug maintenance therapy (https://web.emmes.com/study/ped/annlrept/2010). Only biopsy-proven TG was significantly associated with worse graft survival (HR 11.5, 95% CI: 3.4, 38.7). Malignancy rate was low (2.4%) with little PTLD (0.5%). Few opportunistic or other infections occurred (<5% patients). Minimizing IS to a two-drug maintenance regimen had no adverse effect on long-term transplant outcome and had low malignancy and infection rates.