A pre-transplantation risk assessment tool for graft survival in Dutch pediatric kidney recipients.

Background: A prediction model for graft survival including donor and recipient characteristics could help clinical decision-making and optimize outcomes. The aim of this study was to develop a risk assessment tool for graft survival based on essential pre-transplantation parameters. Methods: The data originated from the national Dutch registry (NOTR; Nederlandse OrgaanTransplantatie Registratie). A multivariable binary logistic model was used to predict graft survival, corrected for the transplantation era and time after transplantation. Subsequently, a prediction score was calculated from the ß-coefficients. For internal validation, derivation (80%) and validation (20%) cohorts were defined. Model performance was assessed with the area under the curve (AUC) of the receiver operating characteristics curve, Hosmer-Lemeshow test and calibration plots. Results: In total, 1428 transplantations were performed. Ten-year graft survival was 42% for transplantations before 1990, which has improved to the current value of 92%. Over time, significantly more living and pre-emptive transplantations have been performed and overall donor age has increased (P < .05).The prediction model included 71 829 observations of 554 transplantations between 1990 and 2021. Other variables incorporated in the model were recipient age, re-transplantation, number of human leucocyte antigen (HLA) mismatches and cause of kidney failure. The predictive capacity of this model had AUCs of 0.89, 0.79, 0.76 and 0.74 after 1, 5, 10 and 20 years, respectively (P < .01). Calibration plots showed an excellent fit. Conclusions: This pediatric pre-transplantation risk assessment tool exhibits good performance for predicting graft survival within the Dutch pediatric population. This model might support decision-making regarding donor selection to optimize graft outcomes. Trial registration: ClinicalTrials.gov Identifier: NCT05388955.

Assessing causality by means of the Naranjo scale in a paediatric patient with life threatening respiratory failure after alemtuzumab administration: a case report.

BACKGROUND: Alemtuzumab is a T cell depleting antibody agent used as induction immunosuppressant therapy in solid organ transplant recipients. In addition, it is being increasingly used to treat severe or glucocorticoid-resistant graft rejection. Despite the effectiveness of the treatment, severe adverse events have been reported related to alemtuzumab administration. We present a similar event illustrating the severity of this adverse drug reaction (ADR) and we highlight the structure causality assessment provides in approaching such a case. CASE PRESENTATION: We report a case of life-threatening respiratory failure after alemtuzumab administration in a 17 year old paediatric kidney transplant recipient. He developed near fatal severe respiratory and circulatory failure based on acute respiratory distress syndrome (ARDS) with diffuse alveolar oedema and haemoptysis hours after his second alemtuzumab administration. As it was questionable whether alemtuzumab could be regarded as the origin of his reaction and in order to assess the causality of this reaction as well as to structure clinical reasoning, we applied a widely used ADR probability scale to systematically review our case. DISCUSSION AND CONCLUSIONS: Our case shows a severe ADR after alemtuzumab administration. It illustrates the importance of proper causality assessment, the structure it provides and the benefit of a clinical pharmacology consultation when a severe reaction is suspected to be an ADR. By taking our case as an example, we demonstrate the added value of structured causality assessment to clinical reasoning and in generating differential diagnoses.

Prognostic Factors on Graft Function in Pediatric Kidney Recipients.

BACKGROUND: Graft survival in pediatric kidney transplant recipients has increased in the last decades. Determining prognostic factors for graft function over time allows the identification of patients at risk for graft loss and could lead to improvement of current guidelines. METHODS: Data were collected among pediatric kidney transplant recipients in a single center during the first 5 years after transplantation. Mixed model analysis was used to indicate possible prognostic factors for the loss of graft function. RESULTS: A total of 100 pediatric kidney transplant recipients were analyzed. Negative prognostics of graft function are higher donor age and higher recipient age, presence of obstructive uropathology, re-transplant, and occurrence of BK viremia. The negative influence on graft function of both donor age and presence of obstructive uropathology increased over time. In this study, the factors that did not influence graft function over time were the number of HLA mismatches, pre-transplant dialysis, intra-abdominal graft placement, ischemia time, occurrence of acute rejection, presence of lower urinary tract dysfunction, occurrence of urinary tract infections, and infections with cytomegalovirus and Epstein-Barr virus. CONCLUSIONS: This study showed that a higher donor age and higher recipient age, presence of obstructive uropathology, a re-transplant, and the occurrence of BK viremia were negative prognostic factors of graft function over time, in the first 5 years after transplant. Graft function was comparable between steroid-sparing regimens (preferable in low-risk patients) and regimens including steroids (for special reasons).

Preparing for a kidney transplant: Medical nephrectomy in children with nephrotic syndrome.

Nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and general edema. These symptoms may persist in children who reach ESRD, which is unfavorable for the patient's allograft outcome. In addition, this may hamper early diagnosis of a relapse after transplantation. Surgical bilateral nephrectomy is often considered for that reason, but medical nephrectomy may be a less invasive alternative. In this retrospective single-center case series, we identified all children on dialysis with ESRD due to nephrotic syndrome in which a medical nephrectomy was attempted before kidney transplantation between 2013 and 2018. Outcome was measured by urine output and serum albumin levels. Eight patients with either congenital nephrotic syndrome or focal segmental glomerular sclerosis were included in the study. All patients received an ACE inhibitor as drug of first choice for medical nephrectomy, to which 5 patients responded with oligoanuria and a significant rise in serum albumin, and 3 patients responded insufficiently. In 1 of these 3 patients, diclofenac was added to the ACE inhibitor, with good result. In the other 2 patients, indomethacin was initiated without success, and surgical bilateral nephrectomy was performed. Overall, 6/8 patients had a successful medical nephrectomy and did not need surgical nephrectomy. No recurrence of nephrotic syndrome was found after kidney transplantation in all but one. Medical nephrectomy with ACE inhibitors and/or non-steroidal anti-inflammatory drugs is a safe and non-invasive therapy to minimize proteinuria in children with ESRD due to nephrotic syndrome before kidney transplantation. We suggest that this strategy should be considered as therapy before proceeding with surgical nephrectomy.

Oscillometric and intra-arterial blood pressure in children post-kidney transplantation: Is invasive blood pressure measurement always needed?

OBJECTIVE: Blood pressure (BP) monitoring in children immediately after kidney transplantation is ideally performed with an arterial line. Accurate measurement of BP is necessary for optimal management. However, during the first days postoperative, the arterial line is removed and BP measurement is switched to a non-invasive device. The aim of this study was to determine the accuracy and reliability of the automated oscillometric device compared to invasive arterial BP (IBP) monitoring in patients after renal transplantation in pediatric intensive care unit (PICU). METHOD: We analyzed all simultaneously measured BPs in children with a kidney transplant in the Amalia Children's Hospital Radboud University Medical Center between January 1, 2012, and January 1, 2016. BP measurements were performed according to the hospital protocol. Agreement between invasive and non-invasive methods was assessed using Bland-Altman plots. RESULTS: A total of 29 patients were included in this retrospective study. The majority of children were male (59%), and median age was 11 years (range 1-17 years). Totally, 80 BP measurements were recorded during the first days post-kidney transplantation. The correlation coefficients (R) of systolic, diastolic, and MAP of non-invasive (NIBP) and IBP measurements were 0.84, 0.76, and 0.77, respectively (P < 0.01). Overall, the average MAP (7.5 ± 1.2 mm Hg; P < 0.05) NIBP values were lower compared to IBP. In hypertensive patients, MAP (10.4 ± 10.0 mm Hg; P < 0.05) BP values were significantly lower using the NIBP device. Clinically relevant difference of >10 mm Hg was found in 51% (41/80) of measurements and mainly observed in hypertensive measurements. CONCLUSIONS: IBP measurement is considered the golden standard for monitoring BP in patients immediately after kidney transplantation. NIBP values showed a good agreement with invasive reading, but the variability of NIBP mainly in hypertensive patients is high as it is the number of clinically relevant differences to IBP. We conclude that IBP remains the golden standard to monitor BP in children directly postoperatively.

The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients.

BACKGROUND: Tacrolimus is an important immunosuppressive agent with high intra- and inter-individual pharmacokinetic variability and a narrow therapeutic index. As tacrolimus extensively accumulates in erythrocytes, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations. However, as hematocrit values in pediatric kidney transplant patients are highly variable after kidney transplantation, translating whole blood concentration targets without taking hematocrit into consideration is theoretically incorrect. The aim of this study is to evaluate the potential impact of hematocrit correction on tacrolimus target exposure in pediatric kidney transplant patients. METHODS: Data were obtained from 36 pediatric kidney transplant patients. Two hundred fifty-five tacrolimus whole blood samples were available, together responsible for 36 area under the concentration-time curves (AUCs) and trough concentrations. First, hematocrit corrected concentrations were derived using a formula describing the relationship between whole blood concentrations, hematocrit, and plasma concentrations. Subsequently, target exposure was evaluated using the converted plasma target concentrations. Ultimately, differences in interpretation of target exposure were identified and evaluated. RESULTS: In total, 92% of our patients had lower hematocrit (median 0.29) than the reference value of adult kidney transplant patients. A different evaluation of target exposure for either trough level, AUC, or both was defined in 42% of our patients, when applying hematocrit corrected concentrations. CONCLUSION: A critical role for hematocrit in therapeutic drug monitoring of tacrolimus in pediatric kidney transplant patients is suggested in this study. Therefore, we believe that hematocrit correction could be a step towards improvement of tacrolimus dose individualization.

Feasibility of exhaled nitric oxide measurements at various flow rates in children with asthma.

Measurement of bronchial and alveolar exhaled nitric oxide (NO) levels could be of clinical importance for the treatment of asthma. To discriminate between alveolar and bronchial NO, measurements need to be assessed at various flow rates. To study the feasibility, linearity, and long-term repeatability of NO measurements at four different exhalation flow rates in children with asthma. Twenty-one children with moderate persistent asthma, aged 6-12 yrs, were included in the study. NO was measured according to the ATS/ERS guidelines, using the NIOX analyzer with flow restrictors of 30, 50, 100, and 200 ml/s. Duration of the measurements ranged from 6-10 s, depending on the flow rate. The tests were repeated 3 and 6 months after the first NO measurement. Feasibility of NO measurements at these four flow rates increased from 67% to 91% and 95% at the first, second and third visit, respectively. A significant learning effect was present. Age and lung function indices did not influence success or failure of the tests. At the first measurements occasions, no problems occurred during the NO analysis at a 100 ml/s flow rate. There was a 75-90% success rate when performing the test using flow rates of 30, 50, and 200 ml/s. However, repeating the tests resulted in a 100% success rate. Measurements were not successful if: (i) children ran out of air; (ii) NO concentration exceeded 200 ppb; (iii) the measured NO flow was unstable; and (iv) the NO plateau was not formed. This study showed good feasibility and linearity of NO measurements in asthmatic children of 6 yrs and over at flow rates between 50-200 ml/s. A significant learning effect was present. The long-term reproducibility of alveolar and bronchial NO values during 6 months was moderate.

Structural lung changes, lung function, and non-invasive inflammatory markers in cystic fibrosis.

Cystic fibrosis (CF) lung disease is characterized by chronic airway inflammation and recurrent infections, resulting in (ir)reversible structural lung changes and a progressive decline in lung function. The objective of this study was to investigate the relationship between non-invasive inflammatory markers (IM) in exhaled breath condensate (EBC), lung function indices and structural lung changes, visualized by high resolution computed tomography (HRCT) scans in CF. In 34 CF patients, lung function indices (forced expiratory volume in 1 s, forced vital capacity [FVC], residual volume, and total lung capacity [TLC]) and non-invasive IM (exhaled nitric oxide, and condensate acidity, nitrate, nitrite, 8-isoprostane, hydrogen peroxide, interferon-gamma) were assessed. HRCT scans were scored in a standardized and validated way, a composite score and component scores were calculated. In general, the correlations between non-invasive IM and structural lung changes, and between IM and lung function were low (correlation coefficients <0.40). Patients with positive sputum Pseudomonas cultures had higher EBC nitrite levels and higher parenchymal HRCT subscores than patients with Pseudomonas-negative cultures (p < 0.05). Multiple linear regression models demonstrated that FVC was significantly predicted by hydrogen peroxide in EBC, and the scores of bronchiectasis and mosaic perfusion (Pearson correlation coefficient R = 0.78, p < 0.001). TLC was significantly predicted by 8-isoprostane, nitrate, hydrogen peroxide in EBC, and the mucous plugging subscore (R = 0.92, p < 0.01). Static and dynamic lung function indices in this CF group were predicted by the combination of non-invasive IM in EBC and structural lung changes on HRCT imaging. Future longitudinal studies should reveal whether non-invasive monitoring of airway inflammation in CF adds to better follow-up of patients.

Metabolomics of volatile organic compounds in cystic fibrosis patients and controls.

In cystic fibrosis (CF), airway inflammation causes an increased production of reactive oxygen species, responsible for degradation of cell membranes. During this process, volatile organic compounds (VOCs) are formed. Measurement of VOCs in exhaled breath of CF patients may be useful for the assessment of airway inflammation. This study investigates whether "metabolomics' of VOCs could discriminate between CF and controls, and between CF patients with and without Pseudomonas colonization. One hundred five children (48 with CF, 57 controls) were included in this study. After exhaled breath collection, samples were transferred onto tubes containing active carbon to adsorb and stabilize VOCs. Samples were analyzed by gas chromatography-time of flight-mass spectrometry to assess VOC profiles. Analysis showed that 1099 VOCs had a prevalence of at least 7%. By using 22 VOCs, a 100% correct identification of CF patients and controls was possible. With 10 VOCs, 92% of the subjects were correctly classified. The reproducibility of VOC measurements with a 1-h interval was very good (match factor 0.90 +/- 0.038). We conclude that metabolomics of VOCs in exhaled breath was possible in a reproducible way. This new technique was able to discriminate not only between CF patients and controls but also between CF patients with or without Pseudomonas colonization.

Comparison of the anti-inflammatory effects of extra-fine hydrofluoroalkane-beclomethasone vs fluticasone dry powder inhaler on exhaled inflammatory markers in childhood asthma.

BACKGROUND: Extra-fine hydrofluoroalkane-beclomethasone differs from other inhaled corticosteroids by its fine aerosol characteristics. Therefore, extra-fine hydrofluoroalkane-beclomethasone may be particularly useful for treating peripheral airway inflammation in asthma. OBJECTIVE: To analyze the anti-inflammatory effects of extra-fine hydrofluoroalkane-beclomethasone vs fluticasone dry powder inhaler (DPI) in asthmatic children by measuring bronchial and alveolar nitric oxide (NO) and inflammatory markers in exhaled breath condensate (EBC). METHODS: In a 6-month crossover study, 33 children aged 6 to 12 years with moderate persistent asthma were randomly treated with extra-fine hydrofluoroalkane-beclomethasone (200 microg daily via an Autohaler) and fluticasone DPI (200 microg daily via a Diskus). The primary outcome variables were alveolar NO concentration and bronchial NO flux. The secondary outcome variables were levels of inflammatory markers in EBC, lung function indices, symptoms, exacerbations, and adverse effects. All the variables were recorded at baseline and after each treatment period. RESULTS: Mean +/- SE alveolar NO concentration and bronchial NO flux were comparable after treatment with hydrofluoroalkane-beclomethasone vs fluticasone DPI (4.7 +/- 0.5 vs 4.3 +/- 0.5 ppb, P = .55, and 1,124.3 +/- 253.6 vs 1,029.1 +/- 195.5 pL/s, P = .70, respectively). In addition, levels of inflammatory markers in EBC, lung function indices, and symptoms did not differ between treatments. Patients used fewer beta2-agonists during the last 2 weeks of hydrofluoroalkane-beclomethasone treatment. CONCLUSION: The anti-inflammatory effects of hydrofluoroalkane-beclomethasone are similar to those of fluticasone DPI in children with moderate persistent asthma.

Biomarkers in exhaled breath condensate indicate presence and severity of cystic fibrosis in children.

Chronic airway inflammation is present in cystic fibrosis (CF). Non-invasive inflammometry may be useful in disease management. The aim of the present cross-sectional study was to investigate: (i) the ability of fractional exhaled nitric oxide and inflammatory markers (IM) [exhaled breath condensate (EBC) acidity, nitrite, nitrate, hydrogen peroxide (H(2)O(2)), 8-isoprostane, Th1/Th2 cytokines] to indicate (exacerbations of) CF; and (ii) the ability of these non-invasive IM to indicate CF disease severity. In 98 children (48 CF/50 controls), exhaled nitric oxide was measured using the NIOX, and condensate was collected using a glass condenser. In CF interferon (IFN-gamma) and nitrite concentrations were significantly higher, whereas exhaled nitric oxide levels were significantly lower compared with controls (3.3 +/- 0.3 pg/ml, 2.2 +/- 0.2 microM, 10.0 +/- 1.2 p.p.b. vs. 2.6 +/- 0.2 pg/ml, 1.4 +/- 0.1 microM, 15.4 +/- 1.4 p.p.b. respectively). Using multivariate logistic regression models, the presence of CF was best indicated by 8-isoprostane, nitrite and IFN-gamma [sensitivity 78%, specificity 83%; area under receiver operating characteristic curve (AUC) 0.906, p < 0.001]. An exacerbation of CF was best indicated by 8-isoprostane and nitrite (sensitivity 40%, specificity 97%, AUC curve 0.838, p = 0.009). Most indicative biomarkers of CF severity were exhaled nitric oxide, and condensate acidity (sensitivity 96%, specificity 67%; AUC curve 0.751, p = 0.008). In this cross-sectional study, the combination of different exhaled IM could indicate (exacerbations of) CF, and severity of the disease in children. Longitudinal data are necessary to further confirm the role of these markers for the management of CF in children.

Actual asthma control in a paediatric outpatient clinic population: do patients perceive their actual level of control?

Several epidemiological studies described poor asthma control in children. However, the diagnosis of childhood asthma in these studies is uncertain, and asthma control in children of an outpatient clinic population during treatment by a paediatrician is unknown. (1) to investigate the hypothesis that asthma control in a paediatric outpatient clinic population is better than epidemiological surveys suggest; (2) to find possible explanations for suboptimal asthma control. Asthmatic children aged 6-16 years, known for at least 6 months by a paediatrician at the outpatient clinic, were selected. During a normal visit, both the responsible physicians and parent/children completed a standardised questionnaire about asthma symptoms, limitation of daily activities, treatment, asthma attacks and emergency visits. Overall, excellent asthma control of 8.0% in this study was not significantly better than of 5.8% in the European AIR study (Chi-square, p = 0.24). Separate GINA goals like minimal chronic symptoms and no limitation of activities were better met in our study. Good to excellent controlled asthma was perceived by most children/parents (83%), but was less frequently indicated by the paediatrician (73%), or by objective criteria of control (45%) (chi-square, p = 0.0001). The agreement between patient-perceived and doctor assessed control was low, but improved in poorly controlled children. Patients were not able to perceive the difference between 'excellent asthma control' and 'good control' (p = 0.881).Too little children with uncontrolled disease got step-up of their asthma treatment. Although separate GINA goals like 'minimal chronic symptoms' and 'no limitation of activities' were significantly better in our study, overall, asthma control in this outpatient clinic population, treated by a paediatrician, was not significantly better than in the European AIR study. Poorly controlled disease was related to several aspects of asthma management, which are potentially accessible for improvements.

Free radicals in exhaled breath condensate in cystic fibrosis and healthy subjects.

Many markers of airway inflammation and oxidative stress can be measured non-invasively in exhaled breath condensate (EBC). However, no attempt has been made to directly detect free radicals using electron paramagnetic resonance (EPR) spectroscopy. Condensate was collected in 14 children with cystic fibrosis (CF) and seven healthy subjects. Free radicals were trapped by 5,5-dimethyl-1-pyrroline-N-oxide. EPR spectra were recorded using a Bruker EMX spectrometer. Secondly, to study the source of oxygen centered radical formation, catalase or hydrogen peroxide was added to the condensate. Radicals were detected in 18 out of 21 condensate samples. Analysis of spectra indicated that both oxygen and carbon centered radicals were trapped. Within-subject reproducibility was good in all but one subject. Quantitatively, there was a trend towards higher maximal peak heights of both oxygen and carbon centered radicals in the children with CF. Catalase completely suppressed the signals in condensate. Addition of hydrogen peroxide resulted in increased radical signal intensity. Detection of free radicals in EBC of children with CF and healthy subjects is feasible using EPR spectroscopy.

Cytokines in exhaled breath condensate of children with asthma and cystic fibrosis.

BACKGROUND: Inflammatory mediators in exhaled breath condensate (EBC) indicate ongoing inflammation in the lungs and might differentiate between asthma and cystic fibrosis (CF). OBJECTIVES: To evaluate the presence, concentration, and short-term variability of TH1- and TH2-mediated cytokines (interferon-gamma [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], interleukin 10 [IL-10], IL-5, IL-4, and IL-2) in EBC of children with asthma or CF and in controls and to analyze the discriminating ability of inflammatory markers in EBC between children with asthma or CF and controls. METHODS: Expired air was conducted through a double-jacketed glass tube cooled by circulating ice water. In 33 asthmatic children, 12 children with CF, and 35 control children, EBC was collected during tidal breathing. Cytokines were measured using flow cytometry. RESULTS: Interleukin 2, IL-4, IFN-gamma, and IL-10 were detected in 16%, 16%, 11%, and 9%, respectively, of all samples in asthma and CF. Interleukin 5 and TNF-alpha were not detected in children with CF. Cytokine concentrations did not differ significantly in children with asthma vs CF. In controls, IFN-gamma, TNF-alpha, and IL-10 were detected in 9%, 14%, and 3%, respectively; IL-2, IL-4, and IL-5 were not detected in controls. CONCLUSIONS: Cytokines such as IFN-gamma, TNF-alpha, IL-10, IL-5, IL-4, and IL-2 can be detected in EBC of children with asthma or CF. However, the concentrations found are close to the detection limits of the assay used. These findings emphasize the importance of developing more sensitive techniques for the analysis of EBC and of standardizing the EBC collection method.