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BACKGROUND: The efficacy of continuous antibiotic prophylaxis in preventing urinary tract infection (UTI) in infants with grade III, IV, or V vesicoureteral reflux is controversial. METHODS: In this investigator-initiated, randomized, open-label trial performed in 39 European centers, we randomly assigned infants 1 to 5 months of age with grade III, IV, or V vesicoureteral reflux and no previous UTIs to receive continuous antibiotic prophylaxis (prophylaxis group) or no treatment (untreated group) for 24 months. The primary outcome was the occurrence of the first UTI during the trial period. Secondary outcomes included new kidney scarring and the estimated glomerular filtration rate (GFR) at 24 months. RESULTS: A total of 292 participants underwent randomization (146 per group). Approximately 75% of the participants were male; the median age was 3 months, and 235 participants (80.5%) had grade IV or V vesicoureteral reflux. In the intention-to-treat analysis, a first UTI occurred in 31 participants (21.2%) in the prophylaxis group and in 52 participants (35.6%) in the untreated group (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P = 0.008); the number needed to treat for 2 years to prevent one UTI was 7 children (95% CI, 4 to 29). Among untreated participants, 64.4% had no UTI during the trial. The incidence of new kidney scars and the estimated GFR at 24 months did not differ substantially between the two groups. Pseudomonas species, other non-Escherichia coli organisms, and antibiotic resistance were more common in UTI isolates obtained from participants in the prophylaxis group than in isolates obtained from those in the untreated group. Serious adverse events were similar in the two groups. CONCLUSIONS: In infants with grade III, IV, or V vesicoureteral reflux and no previous UTIs, continuous antibiotic prophylaxis provided a small but significant benefit in preventing a first UTI despite an increased occurrence of non-E. coli organisms and antibiotic resistance. (Funded by the Italian Ministry of Health and others; PREDICT ClinicalTrials.gov number, NCT02021006; EudraCT number, 2013-000309-21.).
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Antibacterianos , Antibioticoprofilaxia , Infecções Urinárias , Refluxo Vesicoureteral , Feminino , Humanos , Lactente , Masculino , Antibioticoprofilaxia/efeitos adversos , Antibioticoprofilaxia/métodos , Glomerulonefrite , Análise de Intenção de Tratamento , Refluxo Vesicoureteral/complicações , Refluxo Vesicoureteral/tratamento farmacológico , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Infecções Urinárias/etiologia , Infecções Urinárias/microbiologia , Infecções Urinárias/prevenção & controle , Farmacorresistência Bacteriana/efeitos dos fármacosRESUMO
Infantile hypercalcemia (IH) is a rare genetic disorder characterized by hypercalcemia, hypercalciuria, low parathyroid hormone, and nephrocalcinosis during the first months of life. Biallelic variants in the genes CYP24A1 and SCL34A1 cause IH1 and 2, respectively. We present the case of a newborn with an antenatal diagnosis of IH2 due to the identification of echogenic, yet normal-sized kidneys at 23 weeks gestation. Trio whole-exome sequencing initially identified only a heterozygous pathogenic variant in SLC34A1. Re-analysis of the exome data because of the clinical suspicion of IH2 revealed a 21-basepair deletion in trans that had initially been filtered out because of its high allele frequency. The diagnosis of IH2 enabled postnatal screening for hypercalcemia, present already at week 1, resulting in early treatment with phosphate supplementation and vitamin D avoidance. In the subsequent course, biochemical parameters were normalized, and the patient showed no obvious clinical complications of IH2, apart from the nephrocalcinosis.
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BACKGROUND: Extremely low birth weight (ELBW) neonates (birth weight ≤ 1000 g) are at high risk to develop drug-induced acute kidney injury (AKI). However, we lack a pragmatic detection tool to capture their time-dependent (patho)physiologic serum creatinine (Scr) patterns. Pottel et al. suggested rescaling Scr by dividing Scr with the mean Scr value of the age- and sex-specific reference population. We explored if this Pottel method can detect drug-related nephrotoxicity in ELBW neonates. METHODS: A previously reported dataset on Scr changes in ELBW neonates exposed to ibuprofen, amikacin, or vancomycin was updated to calculate Pottel scores for every available Scr value in the first 28 postnatal days. We hereby used previously published postnatal age-specific 50th centile values in an ELBW population. Linear mixed models were applied, analyzing Pottel scores as response variable and continuous time (day), drug exposure, and interaction thereof in the explanatory model. RESULTS: Serum creatinine (n = 3231) observations in 201 ELBW neonates were collected. A statistically significant rise of Pottel scores was observed with ibuprofen starting from postnatal day 4. In addition, a cumulative effect of treatment with mean Pottel scores on day 0 of 1.020 and on day 3 during treatment of 1.106 (95% CI 1.068-1.145, p < 0.001) was observed, corrected for effect of antibiotics. Antibiotic administrations showed a small but statistically significant difference up to postnatal day 5. CONCLUSIONS: As rescaled Scr biomarker, the Pottel method showed a clear association with ibuprofen-exposed ELBW neonates, suggesting its applicability as a pragmatic bedside alternative tool to assess nephrotoxicity.
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Injúria Renal Aguda , Amicacina , Creatinina , Ibuprofeno , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Farmacovigilância , Vancomicina , Humanos , Recém-Nascido , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/sangue , Creatinina/sangue , Feminino , Ibuprofeno/efeitos adversos , Masculino , Vancomicina/efeitos adversos , Amicacina/efeitos adversos , Antibacterianos/efeitos adversosRESUMO
BACKGROUND: Tolvaptan preserves kidney function in adults with autosomal dominant polycystic kidney disease (ADPKD) at elevated risk of rapid progression. A trial (NCT02964273) evaluated tolvaptan safety and pharmacodynamics in children (5-17 years). However, progression risk was not part of study eligibility criteria due to lack of validated criteria for risk assessment in children. As risk estimation is important to guide clinical management, baseline characteristics of the study participants were retrospectively evaluated to determine whether risk of rapid disease progression in pediatric ADPKD can be assessed and to identify parameters relevant for risk estimation. METHODS: Four academic pediatric nephrologists reviewed baseline data and rated participant risk from 1 (lowest) to 5 (highest) based on clinical judgement and the literature. Three primary reviewers independently scored all cases, with each case reviewed by two primary reviewers. For cases with discordant ratings (≥ 2-point difference), the fourth reviewer provided a secondary rating blinded to the primary evaluations. Study participants with discordant ratings and/or for whom data were lacking were later discussed to clarify parameters relevant to risk estimation. RESULTS: Of 90 evaluable subjects, primary reviews of 69 (77%) were concordant. The proportion considered at risk of rapid progression (final mean rating ≥ 3.5) by age group was: 15-17 years, 27/34 (79%); 12- < 15, 9/32 (28%); 4- < 12, 8/24 (33%). The panelists agreed on characteristics important for risk determination: age, kidney imaging, kidney function, blood pressure, urine protein, and genetics. CONCLUSIONS: High ratings concordance and agreement among reviewers on relevant clinical characteristics support the feasibility of pediatric risk assessment.
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Rim Policístico Autossômico Dominante , Tolvaptan , Adolescente , Criança , Humanos , Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversos , Progressão da Doença , Taxa de Filtração Glomerular , Rim , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/tratamento farmacológico , Estudos Retrospectivos , Tolvaptan/efeitos adversosRESUMO
OBJECTIVE: The objective of this study was to evaluate the available data on long-term kidney dysfunction, hypertension, and mortality after cardiac surgery-associated acute kidney injury (AKI) in the pediatric population. STUDY DESIGN: PubMed/MEDLINE, Embase, Scopus, and reference lists of relevant articles were searched for eligible studies published from inception through March 2022. Long-term outcomes after pediatric cardiac surgery complicated by AKI and those without were investigated. RESULTS: We identified 14 studies published between 2013 and 2022 that included a total of 6701 patients (AKI: 1376 patients; no AKI: 5325 patients). These studies used different well-established classifications to define AKI. All the studies suggested that AKI after heart surgery is common in the pediatric patient population and reported a potential link between cardiac surgery-associated AKI and important clinical outcomes. However, only 4 out of 11 studies found a strong association between (absence of recovery from) cardiac surgery-associated AKI and risk of developing chronic kidney disease, and 3 out of 5 studies found a significant increase in mortality rates for pediatric patients who developed AKI after cardiac surgery. Only 1 out of 4 studies found an association between AKI and hypertension at 12 months postoperatively, but found no association at later follow-up times. CONCLUSIONS: Although there is a trend, evidence on the long-term consequences of cardiac surgery-associated AKI in the pediatric population is mixed. Genetic syndromes, preexisting kidney disease, univentricular or cyanotic heart conditions, and/or high-complexity surgery may be more important for the development of kidney dysfunction by adolescence and early adulthood. Regardless, these children may benefit from a long-term kidney follow-up.
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Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Hipertensão , Insuficiência Renal Crônica , Adolescente , Criança , Humanos , Adulto , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Insuficiência Renal Crônica/complicações , Hipertensão/complicações , Fatores de Risco , Estudos RetrospectivosRESUMO
PURPOSE OF REVIEW: Acute kidney injury (AKI) affects up to 35% of all critically ill children and is associated with substantial short-term morbidity and mortality. However, the link between paediatric AKI and long-term adverse outcomes remains incompletely understood. This review highlights the most recent clinical data supporting the role of paediatric AKI as a risk factor for long-term kidney and cardiovascular consequences. In addition, it stresses the need for long-term surveillance of paediatric AKI survivors. RECENT FINDINGS: Recent large-scale studies have led to an increasing understanding that paediatric AKI is a significant risk factor for adverse outcomes such as hypertension, cardiovascular disease and chronic kidney disease (CKD) over time. These long-term sequelae of paediatric AKI are most often observed in vulnerable populations, such as critically ill children, paediatric cardiac surgery patients, children who suffer from severe infections and paediatric cancer patients. SUMMARY: A growing body of research has shown that paediatric AKI is associated with long-term adverse outcomes such as CKD, hypertension and cardiovascular disease. Although therapeutic pathways tailored to individual paediatric AKI patients are yet to be validated, we provide a framework to guide monitoring and prevention in children at the highest risk for developing long-term kidney dysfunction.
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Injúria Renal Aguda , Doenças Cardiovasculares , Hipertensão , Insuficiência Renal Crônica , Humanos , Criança , Doenças Cardiovasculares/complicações , Estado Terminal/terapia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Hipertensão/complicações , Hipertensão/terapia , Fatores de RiscoRESUMO
BACKGROUND: Young autosomal dominant polycystic kidney disease (ADPKD) patients are becoming the new target population for the development of new treatment options. Determination of a reliable equation for estimated glomerular filtration rate (eGFR) from early stages is needed with the promising potential interventional therapies. METHODS: Prospective and longitudinal study on a cohort of 68 genotyped ADPKD patients (age range 0-23 years) with long-term follow-up. Commonly used equations for eGFR were compared for their relative performance. RESULTS: The revised Schwartz formula (CKiD) showed a highly significant decline in eGFR with aging (- 3.31 mL/min/1.73 m2/year, P < 0.0001). The recently updated equation by the Schwartz group (CKiDU25) showed a smaller (- 0.90 mL/min/1.73 m2/year) but significant (P = 0.001) decline in eGFR with aging and also showed a significant sex difference (P < 0.0001), not observed by the other equations. In contrast, the full age spectrum (FAS) equations (FAS-SCr, FAS-CysC, and the combined) showed no age and sex dependency. The prevalence of hyperfiltration is highly dependent on the formula used, and the highest prevalence was observed with the CKiD Equation (35%). CONCLUSIONS: The most widely used methods to calculate eGFR in ADPKD children (CKiD and CKiDU25 equations) were associated with unexpected age or sex differences. The FAS equations were age- and sex-independent in our cohort. Hence, the switch from the CKiD to CKD-EPI equation at the transition from pediatric to adult care causes implausible jumps in eGFR, which could be misinterpreted. Having reliable methods to calculate eGFR is indispensable for clinical follow-up and clinical trials. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Rim Policístico Autossômico Dominante , Insuficiência Renal Crônica , Transição para Assistência do Adulto , Humanos , Criança , Feminino , Masculino , Adulto Jovem , Recém-Nascido , Lactente , Pré-Escolar , Adolescente , Adulto , Taxa de Filtração Glomerular , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/genética , Estudos Longitudinais , Estudos Prospectivos , CreatininaRESUMO
BACKGROUND: This cross-sectional study investigated quality of life (QoL) and illness-related parental stress in children with kidney diseases by (1) comparing mean levels of these two variables between several kidney disease categories; (2) exploring correlations between QoL and parental stress; and (3) describing which disease category reports lowest QoL and highest parental stress. METHODS: We included 295 patients with a kidney disease (0-18 years) and their parents, followed at 6 reference centers for pediatric nephrology. Children's QoL was assessed by the PedsQL™ 4.0 Generic Core Scales, and illness-related stress by the Pediatric Inventory for Parents. All patients were divided into 5 kidney disease categories according to the multidisciplinary care program criteria prescribed by the Belgian authorities: (1) structural kidney diseases, (2) tubulopathies and metabolic diseases, (3) nephrotic syndrome, (4) acquired diseases with proteinuria and hypertension, and (5) kidney transplantation. RESULTS: Child self-reports showed no differences in QoL between kidney disease categories, in contrast to parent proxy reports. Parents of transplant patients reported lower QoL in their child and more parental stress compared with the 4 non-transplant categories. QoL and parental stress were negatively correlated. Lowest QoL and highest parental stress scores were mainly found in transplant patients. CONCLUSIONS: This study showed lower QoL and higher parental stress in pediatric transplant patients compared with non-transplants, based on parent reports. Higher parental stress is associated with worse QoL in the child. These results highlight the importance of multidisciplinary care for children with kidney diseases, with special attention to transplant patients and their parents. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Nefropatias , Qualidade de Vida , Criança , Humanos , Estudos Transversais , Procurador , Nefropatias/terapia , Pais , Inquéritos e QuestionáriosRESUMO
PURPOSE: Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition characterized by massive kidney enlargement and developmental liver defects. Potential consequences during childhood include the need for kidney replacement therapy (KRT). We report the design of 2 ongoing clinical trials (Study 204, Study 307) to evaluate safety, tolerability, and efficacy of tolvaptan in children with ARPKD. METHODS: Both trials are of multinational, multicenter, open-label design. Age range at enrollment is 28 days to < 12 weeks in Study 204 and 28 days to < 18 years in Study 307. Subjects in both studies must have a clinical diagnosis of ARPKD, and those in Study 204 must additionally have signs indicative of risk of rapid progression to KRT, namely, all of: nephromegaly, multiple kidney cysts or increased kidney echogenicity suggesting microcysts, and oligohydramnios or anhydramnios. Target enrollment is 20 subjects for Study 204 and ≥ 10 subjects for Study 307. RESULTS: Follow-up is 24 months in Study 204 (with optional additional treatment up to 36 months) and 18 months in Study 307. Outcomes include safety, tolerability, change in kidney function, and percentage of subjects requiring KRT relative to historical data. Regular safety assessments monitor for possible adverse effects of treatment on parameters such as liver function, kidney function, fluid balance, electrolyte levels, and growth trajectory, with increased frequency of monitoring following tolvaptan initiation or dose escalation. CONCLUSIONS: These trials will provide data on tolvaptan safety and efficacy in a population without disease-specific treatment options. TRIAL REGISTRATION: Study 204: EudraCT 2020-005991-36; Study 307: EudraCT 2020-005992-10.
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Cistos , Rim Policístico Autossômico Dominante , Rim Policístico Autossômico Recessivo , Humanos , Criança , Recém-Nascido , Tolvaptan/uso terapêutico , Rim Policístico Autossômico Recessivo/diagnóstico por imagem , Rim Policístico Autossômico Recessivo/tratamento farmacológico , Rim , Estudos Longitudinais , Cistos/tratamento farmacológico , Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversosRESUMO
The development of a simple HILIC-LC-MS/MS method to quantify the plasma levels of allantoin, inosine, hypoxanthine, and adenosine, using stripped plasma for the bioanalytical method validation, was the purpose of this study. Chromatographic separation conducted using an XBridge BEH Amide column (2.1 × 150 mm, 3.5 µm) was achieved under gradient elution with two mobile phases: 0.1% formic acid-ACN (5:95) and 0.1% formic acid-ACN (50:50). Multiple reaction monitoring MS detection was performed using a triple quadrupole. The method validation experiments were performed according to the European Medicines Agency and the U.S. Food and Drug Administration guidelines. The lower LOQ was 50 nM, 5 nM, 20 nM, and 2 nM for allantoin, inosine, hypoxanthine, and adenosine, respectively. The recovery was repeatable and stable. The intraday precision ranged from 1.6% to 6.5%, while the interday precision ranged from 3.4% to 58.7%. Therefore, it is necessary to make a matrix-matched calibration curve each day to overcome this issue. Since the quality control samples' stability did not always comply with the guidelines, the samples need to be analyzed soon after collection.
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Alantoína , Espectrometria de Massas em Tandem , Adenosina , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Humanos , Hipoxantinas , Inosina , Purinas , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodosRESUMO
The apelinergic system (AS) is a novel pleiotropic system with an essential role in renal and cardiovascular physiology and disease, including water homeostasis and blood pressure regulation. It consists of two highly conserved peptide ligands, apelin and apela, and a G-protein-coupled apelin receptor. The two ligands have many isoforms and a short half-life and exert both similar and divergent effects. Vasopressin, apelin and their receptors colocalize in hypothalamic regions essential for body fluid homeostasis and interact at the central and renal levels to regulate water homeostasis and diuresis in inverse directions. In addition, the AS and renin-angiotensin system interact both systemically and in the kidney, with implications for the cardiovascular system. A role for the AS in diverse pathological states, including disorders of sodium and water balance, hypertension, heart failure, pre-eclampsia, acute kidney injury, sepsis and diabetic nephropathy, has recently been reported. Furthermore, several metabolically stable apelin analogues have been developed, with potential applications in diverse diseases. We review here what is currently known about the physiological functions of the AS, focusing on renal, cardiovascular and metabolic homeostasis, and the role of the AS in associated diseases. We also describe several hurdles and research opportunities worthy of the attention of the nephrology community.
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Peptídeos e Proteínas de Sinalização Intercelular , Nefropatias , Receptores Acoplados a Proteínas G , Humanos , Apelina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Rim/metabolismo , Ligantes , Receptores Acoplados a Proteínas G/metabolismo , Água/metabolismoRESUMO
Approval of the vasopressin V2 receptor antagonist tolvaptan-based on the landmark TEMPO 3:4 trial-marked a transformation in the management of autosomal dominant polycystic kidney disease (ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use.
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Rim Policístico Autossômico Dominante , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Feminino , Humanos , Rim , Masculino , Seleção de Pacientes , Rim Policístico Autossômico Dominante/tratamento farmacológico , Tolvaptan/uso terapêuticoRESUMO
Significant progress has been made in understanding the genetic basis of autosomal dominant polycystic kidney disease (ADPKD), quantifying disease manifestations in children, exploring very-early onset ADPKD as well as pharmacological delay of disease progression in adults. At least 20% of children with ADPKD have relevant, yet mainly asymptomatic disease manifestations such as hypertension or proteinuria (in line with findings in adults with ADPKD, where hypertension and cardiovascular damage precede decline in kidney function). We propose an algorithm for work-up and management based on current recommendations that integrates the need to screen regularly for hypertension and proteinuria in offspring of affected parents with different options regarding diagnostic testing, which need to be discussed with the family with regard to ethical and practical aspects. Indications and scope of genetic testing are discussed. Pharmacological management includes renin-angiotensin system blockade as first-line therapy for hypertension and proteinuria. The vasopressin receptor antagonist tolvaptan is licensed for delaying disease progression in adults with ADPKD who are likely to experience kidney failure. A clinical trial in children is currently ongoing; however, valid prediction models to identify children likely to suffer kidney failure are lacking. Non-pharmacological interventions in this population also deserve further study.
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Hipertensão , Rim Policístico Autossômico Dominante , Insuficiência Renal , Adulto , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Criança , Progressão da Doença , Feminino , Humanos , Hipertensão/tratamento farmacológico , Masculino , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/genética , Proteinúria/tratamento farmacológico , Insuficiência Renal/tratamento farmacológicoRESUMO
The clinical course of autosomal dominant polycystic kidney disease (ADPKD) starts in childhood. Evidence of the beneficial impact of early nephron-protective strategies and lifestyle modifications on ADPKD prognosis is accumulating. Recent studies have described the association of overweight and obesity with rapid disease progression in adults with ADPKD. Moreover, defective glucose metabolism and metabolic reprogramming have been reported in distinct ADPKD models highlighting these pathways as potential therapeutic targets in ADPKD. Several "metabolic" approaches are currently under evaluation in adults, including ketogenic diet, food restriction, and metformin therapy. No data are available on the impact of these approaches in childhood thus far. Yet, according to World Health Organization (WHO), we are currently facing a childhood obesity crisis with an increased prevalence of overweight/obesity in the pediatric population associated with a cardio-metabolic risk profile. The present review summarizes the knowledge about the role of glucose metabolism in the pathophysiology of ADPKD and underscores the possible harm of overweight and obesity in ADPKD especially in terms of long-term cardiovascular outcomes and renal prognosis.
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Obesidade Infantil , Rim Policístico Autossômico Dominante , Adulto , Criança , Progressão da Doença , Glucose/uso terapêutico , Humanos , Rim , Sobrepeso/complicações , Obesidade Infantil/complicações , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/terapiaRESUMO
BACKGROUND: Cardiac surgery-associated acute kidney injury (AKI) is associated with increased morbidity and mortality in both adults and children. OBJECTIVES: This study aimed to identify clinical risk factors for AKI following cardiac surgery in the pediatric population. DATA SOURCES: PubMed/MEDLINE, Embase, Scopus, and reference lists of relevant articles were searched for studies published by August 2020. STUDY ELIGIBILITY CRITERIA: Studies were included if (1) the population consisted of pediatric patients (< 18 years old), (2) patients underwent cardiac surgery, (3) risk factors were compared between patients who developed AKI and those who did not, and (4) studies were prospective or retrospective observational studies or randomized controlled trials. PARTICIPANTS AND INTERVENTIONS: Children undergoing pediatric cardiac surgery. STUDY APPRAISAL AND SYNTHESIS METHODS: Random-effects meta-analysis was performed, comparing potential risk factors between pediatric patients who developed CS-AKI and those who did not. RESULTS: Sixty-one publications including a total of 19,680 participants (AKI: 7257 participants; no AKI: 12,423 participants) were included from studies published between 2008 and 2020. The pooled estimated incidence of AKI was 34.3% (95% confidence interval 30.0-38.8%, I2 = 96.8%). Binary risk factors that were significantly and consistently associated with AKI were the presence of pulmonary hypertension, cyanotic heart disease, univentricular heart, risk adjustment for congenital heart surgery 1 (RACHS-1) score ≥ 3, vasopressor use, cardiopulmonary bypass use, reoperation, and sepsis. Significant continuous risk factors included younger age, lower body weight, lower preoperative creatinine, higher preoperative estimated glomerular filtration rate (eGFR), higher RACHS-1 score, longer surgery time, longer cardiopulmonary bypass time, longer aortic cross-clamp time, and higher red blood cell transfusion volume. LIMITATIONS: Results are limited by heterogeneity and potential residual confounding. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Our meta-analysis identified clinical risk factors that are associated with AKI in children undergoing cardiac surgery. This might help clinicians anticipate and manage more carefully this population and implement standardized preventive strategies. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42021262699. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Adolescente , Adulto , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Criança , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Acute kidney injury (AKI) occurs frequently after cardiac surgery in children. Although current diagnostic criteria rely on serum creatinine and urine output, changes occur only after considerable loss of kidney function. This meta-analysis aimed to synthesize the knowledge on novel biomarkers and compare their ability to predict AKI. PubMed/MEDLINE, Embase, Scopus, and reference lists were searched for relevant studies published by March 2021. Diagnostic accuracy parameters were extracted and analyzed using hierarchical summary receiver operating characteristic (HSROC) method. Pooled estimates of the area under the curve (AUC) were calculated using conventional random-effects meta-analysis. Fifty-six articles investigating 49 biomarkers in 8617 participants fulfilled our eligibility criteria. Data from 37 studies were available for meta-analysis. Of the 10 biomarkers suitable for HSROC analysis, urinary neutrophil gelatinase-associated lipocalin (uNGAL) to creatinine (Cr) ratio yielded the highest diagnostic odds ratio (91.0, 95% CI 90.1-91.9), with a sensitivity of 91.3% (95% CI 91.2-91.3%) and a specificity of 89.7% (95% CI 89.6-89.7%). These results were confirmed in pooled AUC analysis, as uNGAL-to-Cr ratio and uNGAL were the only elaborately studied biomarkers (> 5 observations) with pooled AUCs ≥ 0.800. Liver fatty acid-binding protein (L-FABP), serum cystatin C (sCysC), serum NGAL (sNGAL), and interleukin-18 (IL-18) all had AUCs ≥ 0.700. CONCLUSION: A variety of biomarkers have been proposed as predictors of cardiac surgery-associated AKI in children, of which uNGAL was the most prominent with excellent diagnostic qualities. However, more consolidatory evidence will be required before these novel biomarkers may eventually help realize precision medicine in AKI management. WHAT IS KNOWN: ⢠Acute kidney injury (AKI) occurs in about 30-60% of children undergoing cardiac surgery and is associated with increased in-hospital mortality and adverse short-term outcomes. However, in current clinical practice, AKI definitions and detection often rely on changes in serum creatinine and urine output, which are late and insensitive markers of kidney injury. ⢠Although various novel biomarkers have been studied for the diagnosis of AKI in children after cardiac surgery, it remains unclear how these compare to one another in terms of diagnostic accuracy. WHAT IS NEW: ⢠Pooled analyses suggest that for the diagnosis of AKI in children who underwent cardiac surgery, NGAL is the most accurate among the most frequently studied biomarkers. ⢠A number of other promising biomarkers have been reported, although they will require further research into their diagnostic accuracy and clinical applicability.
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Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Biomarcadores , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Criança , Creatinina , Testes Diagnósticos de Rotina , Feminino , Humanos , Lipocalina-2/urina , MasculinoRESUMO
Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.
Assuntos
Rim Policístico Autossômico Recessivo , Criança , Pré-Escolar , Estudos de Associação Genética , Humanos , Rim , Mutação , Fenótipo , Rim Policístico Autossômico Recessivo/diagnóstico , Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genéticaRESUMO
The presence of a dynamic and balanced equilibrium between the production of reactive oxygen (ROS) and nitrogen (RNS) species and the in-house antioxidant defense mechanisms is characteristic for a healthy body. During oxidative stress (OS), this balance is switched to increased production of ROS and RNS, exceeding the capacity of physiological antioxidant systems. This can cause damage to biological molecules, leading to loss of function and even cell death. Nowadays, there is increasing scientific and clinical interest in OS and the associated parameters to measure the degree of OS in biofluids. An increasing number of reports using LC-MS/MS methods for the analysis of OS biomarkers can be found. Since bioanalysis is usually complicated by matrix effects, various types of cleanup procedures are used to effectively separate the biomarkers from the matrix. This is an essential part of the analysis to prepare a reproducible and homogenous solution suitable for injection onto the column. The present review gives a summary of the chromatographic methods used for the determination of OS biomarkers in both urine and plasma, serum, and whole blood samples. The first part mainly describes the biological background of the different OS biomarkers, while the second part reports examples of chromatographic methods for the analysis of different metabolites connected with OS in biofluids, covering a period from 2015 till early 2020. The selected examples mainly include LC-MS/MS methods for isoprostanes, oxidized proteins, oxidized lipoproteins, and DNA/RNA biomarkers. The last part explains the clinical relevance of this review.
Assuntos
Biomarcadores , Cromatografia Líquida , Estresse Oxidativo/fisiologia , Espectrometria de Massas em Tandem , Biomarcadores/sangue , Biomarcadores/urina , Humanos , Peroxidação de Lipídeos/fisiologia , Lipoproteínas LDL/sangueRESUMO
Prof. Lesley Rees belongs to the women who changed science and has inspired so many young researchers, including myself. These inspiring women deserve more credit and recognition than they get because they serve as a role model for us. Indeed, despite advances towards women empowerment, progress has been slow, and discrepancy persists around the world. Unfortunately, science is not immune to such inequalities, and the voices of female leaders are important in cracking this gender filter. Women represent only a third of researchers globally and often face gender-based discrimination and lack equal opportunities. In this letter, I would like to highlight three astonishing researchers in an effort to underscore the importance of existing women mentorship, while transmitting the pride of the red lipstick rather than the victimization of the red cheeks.
Assuntos
Mentores , Sexismo , Feminino , HumanosRESUMO
Autosomal dominant polycystic kidney disease (ADPKD) is associated with distinct cytopenias in observational studies; the most consistent and strongest association is seen with alternations in the lymphocytic lineages. Although the underlying mechanism of these associations is unclear, it has been hypothesized to be secondary to sequestration of white blood cells in cystic organs, or related to the uremic environment in chronic kidney disease (CKD). However, since mutations in PKD1 or -2 affect several immunomodulating pathways, cytopenia may well be an unrecognized extrarenal manifestation of ADPKD. Furthermore, many important questions on the clinical implications of this finding and the effect on the disease course in these patients are unanswered. In this review article, we provide an overview of the current evidence on cytopenia in ADPKD and explore the underlying mechanisms of this association and its potential prognostic implications. Based on the current literature, we hypothesize that polycystin deficiency can disturb immune cell homeostasis and that cytopenia is thus an intrinsic feature of ADPKD, related to genetic factors. Taken together, these findings warrant further investigation to establish the exact etiology and role of cytopenia in patients with ADPKD.