Causes and management of urinary system problems in children on long-term home invasive mechanical ventilation.

Many ventilator-dependent children have comorbid conditions including urinary tract disorders. We aimed to present a focused review of the literature describing the causes and management of urinary system problems in children with long-term home mechanical ventilation. We performed a literature search in PubMed/MEDLINE, Scopus, and Web of Science with keywords "children," "home mechanical ventilation," "urinary system," "urinary tract," "neurogenic bladder," "clean intermittent catheterization," "urinary tract infection," "urolithiasis," and "acute kidney injury." We included original articles, reviews, guidelines, and case reports published in English. Ventilator-dependent children may have neurogenic bladder/bowel dysfunction which renders them prone to urinary tract infection, high bladder pressure, vesicoureteral reflux, hydronephrosis, and renal dysfunction. These children require bladder catheterization, medications affecting parasympathetic/sympathetic nervous systems, or surgical procedures to prevent urinary infections, and to maintain continence and renal functions. However, bladder catheterization or surgical procedures like augmentation cystoplasty may also be complicated with urinary infections, urolithiasis, or urethral strictures. Urolithiasis frequency is also increased due to immobilization-related hypercalciuria, hypocitraturia caused by antiepileptic drugs, urinary stasis, and urinary infections. On the other hand, mechanical ventilation can impair renal function by reduction of cardiac output, redistribution of intrarenal blood flow and stimulation of sympathetic and hormonal pathways. Children requiring long-term invasive home mechanical ventilation may have other comorbid conditions, including urinary system diseases, which become manifest as these patients are being kept alive due to the advances in ventilation strategies. These children must be carefully observed for urological complications and managed accordingly to prevent kidney injury.

Urine soluble TLR4 levels may contribute to predict urinary tract infection in children: the UTILISE Study.

BACKGROUND: One of the most common bacterial infections in childhood is urinary tract infection (UTI). Toll-like receptors (TLRs) contribute to immune response against UTI recognizing specific pathogenic agents. Our aim was to determine whether soluble TLR4 (sTLR4), soluble TLR5 (sTLR5) and interleukin 8 (IL-8) can be used as biomarkers to diagnose UTI. We also aimed to reveal the relationship between urine Heat Shock Protein 70 (uHSP70) and those biomarkers investigated in this study. METHODS: A total of 802 children from 37 centers participated in the study. The participants (n = 282) who did not meet the inclusion criteria were excluded from the study. The remaining 520 children, including 191 patients with UTI, 178 patients with non-UTI infections, 50 children with contaminated urine samples, 26 participants with asymptomatic bacteriuria and 75 healthy controls were included in the study. Urine and serum levels of sTLR4, sTLR5 and IL-8 were measured at presentation in all patients and after antibiotic treatment in patients with UTI. RESULTS: Urine sTLR4 was higher in the UTI group than in the other groups. UTI may be predicted using 1.28 ng/mL as cut-off for urine sTLR4 with 68% sensitivity and 65% specificity (AUC = 0.682). In the UTI group, urine sTLR4 levels were significantly higher in pyelonephritis than in cystitis (p < 0.0001). Post-treatment urine sTLR4 levels in the UTI group were significantly lower than pre-treatment values (p < 0.0001). CONCLUSIONS: Urine sTLR4 may be used as a useful biomarker in predicting UTI and subsequent pyelonephritis in children with UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

The role of height and weight growth in spontaneous resolution of vesicoureteral reflux.

BACKGROUND: The aim of this study was to investigate the role of height and weight growth in the resolution of primary vesicoureteral reflux (VUR). METHODS: We retrospectively evaluated the data of 74 males and 135 females who were diagnosed with primary VUR. According to the vesicoureteral reflux resolution, patients were divided into two groups. Patients with complete or partial resolution of VUR were included in Group 1 and patients with no resolution of VUR were included in Group 2. Patients were evaluated for weight Z-score, height Z-score and body mass index at the diagnosis and in the follow-up. In addition, age, sex, grade of reflux and laterality were recorded. RESULTS: There were no significant differences between the two groups, according to height Z-score, weight Z-score and body mass index at the diagnosis, in the follow-up and also annual changes of these parameters. In addition, the same parameters did not significantly differ in Groups 1 and 2, between the initial and final evaluations. However, when we evaluate the patients older than 12 months old, weight Z-scores were significantly higher at the final evaluation than at the diagnosis, in Group 1. This significant difference was not detected in Group 2 at the same age. CONCLUSIONS: Although we could not detect the hectic pace of height growth as being important in the prediction of long-term outcomes of VUR, weight growth should be considered to predict the resolution of VUR.

Urinary HSP70 improves diagnostic accuracy for urinary tract infection in children: UTILISE study.

BACKGROUND: The accuracy of conventional urinalysis in diagnosing urinary tract infection (UTI) in children is limited, leading to unnecessary antibiotic exposure in a large fraction of patients. Urinary heat shock protein 70 (uHSP70) is a novel marker of acute urinary tract inflammation. We explored the added value of uHSP70 in discriminating UTI from other infections and conditions confused with UTI. METHODS: A total of 802 children from 37 pediatric centers in seven countries participated in the study. Patients diagnosed with UTI (n = 191), non-UTI infections (n = 178), contaminated urine samples (n = 50), asymptomatic bacteriuria (n = 26), and healthy controls (n = 75) were enrolled. Urine and serum levels of HSP70 were measured at presentation in all patients and after resolution of the infection in patients with confirmed UTI. RESULTS: Urinary (u)HSP70 was selectively elevated in children with UTI as compared to all other conditions (p < 0.0001). uHSP70 predicted UTI with 89% sensitivity and 82% specificity (AUC = 0.934). Among the 265 patients with suspected UTI, the uHSP70 > 48 ng/mL criterion identified the 172 children with subsequently confirmed UTI with 90% sensitivity and 82% specificity (AUC = 0.862), exceeding the individual diagnostic accuracy of leukocyturia, nitrite, and leukocyte esterase positivity. uHSP70 had completely normalized by the end of antibiotic therapy in the UTI patients. Serum HSP70 was not predictive. CONCLUSIONS: Urine HSP70 is a novel non-invasive marker of UTI that improves the diagnostic accuracy of conventional urinalysis. We estimate that rapid urine HSP70 screening could spare empiric antibiotic administration in up to 80% of children with suspected UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Late onset Bartter syndrome: Bartter syndrome type 2 presenting with isolated nephrocalcinosis and high parathyroid hormone levels mimicking primary hyperparathyroidism.

OBJECTIVES: Nephrocalcinosis is associated with conditions that cause hypercalcemia and the increased urinary excretion of calcium, phosphate, and/or oxalate. A monogenic etiology is found in almost 30% of childhood-onset nephrocalcinosis which is also a common manifestation of primary hyperparathyroidism. We discuss a child with nephrocalcinosis and features mimicking primary hyperparathyroidism. CASE PRESENTATION: A 7-year-old girl presented with nephrocalcinosis. Hypercalciuria, hyperphosphaturia, mild hypercalcemia, hypophosphatemia and elevated parathyroid hormone levels along with normal serum creatinine and absence of hypokalemic alkalosis suggested primary hyperparathyroidism. However, she was ultimately diagnosed with Bartter syndrome type 2 based on the presence of homozygous pathogenic variation in KCNJ1gene. CONCLUSIONS: This is the second reported case of late-onset Bartter syndrome type 2 without hypokalemic alkalosis. Patients with Bartter syndrome may present with high parathyroid hormone levels and hypercalcemia in addition to hypercalciuria. Thus, the present case suggests that the KCNJ1 gene should be included in genetic analysis even in older children with isolated nephrocalcinosis.

Comparison of clinical, pathological and long-term renal outcomes of children with Henoch-Schonlein purpura nephritis and IgA nephropathy.

PURPOSE: To compare clinical, pathological, and long-term renal outcomes of children with Henoch-Schonlein purpura nephritis (HSPN) and IgA nephropathy (IgAN). METHODS: The medical records of patients diagnosed as HSPN and IgAN during childhood were evaluated retrospectively. HSPN and IgAN groups were compared in terms of gender, age, upper respiratory infection history, blood pressure; presence of nephrotic and/or nephritic syndrome; hemoglobin level, leukocyte count, C-reactive protein (CRP), serum albumin (sAlb), creatinine, complement 3 (sC3), complement 4 (sC4) and immunoglobulin A (sIgA) levels; estimated glomerular filtration rate (eGFR) and proteinuria levels; and renal pathology findings at the onset of disease; total follow-up time; and blood pressure, eGFR and proteinuria levels at the last visit. RESULTS: Fifty-four patients were enrolled in the study [38 (70%) HSPN and 16 (30%) IgAN]. The median follow-up time was 60.5 and 72.0 months in HSPN and IgAN groups, respectively (p > 0.05). The HSPN and IgAN groups were also not different in terms of gender, age at the onset; leukocyte count, eGFR, sC3-sC4-sIgA levels; and the presence of endocapillary, extracapillary and mesangial proliferation, tubular atrophy, interstitial fibrosis and IgA, IgM, C3 accumulation in renal tissue. Upper respiratory tract infection history was more common in children with IgAN (8/16 vs 8/38, p = 0.045). sAlb (3.96 ± 0.58 vs 4.40 ± 0.46 g/dL, p = 0.005), hemoglobin (12.1 ± 1.3 vs 13.3 ± 1.2 g/dL, p = 0.004,) and the incidence of mesangial IgG deposition (15/38 vs 11/16, p = 0.049) were lower, while CRP (16.3 ± 7.2 vs 7.8 ± 4.4 mg/L, p = 0.002) and proteinuria (72.1 ± 92.4 vs 34.2 ± 37.9 mg/m2/24 h, p = 0.041) was higher in HSPN group at the onset of disease. Proteinuria and eGFR were similar between the two groups at last visit. CONCLUSION: Children with HSPN and IgAN have little clinical and histological differences in our population. The most prominent difference at presentation with nephritis was higher proteinuria in HSPN probably associated with inflammation due to systemic vasculitis. Long-term renal outcome was good in both HSPN and IgAN.

Assessments of left ventricular systolic and diastolic functions with tissue Doppler imaging and myocardial performance index in children with chronic kidney disease.

BACKGROUND: This study aimed to document early left ventricular (LV) dysfunction in chronic kidney disease (CKD) using methods such as tissue Doppler imaging and the myocardial performance index (MPI). METHODS: A total of 40 patients diagnosed with CKD (mean age, 10.1 ± 4.1 years) and 40 sex- and age-matched healthy controls (mean age, 9.6 ± 4.3 years) were examined. In the patient group, 20 patients had early stage (Stage 2-3) CKD and 20 patients had late-stage (stage 4-5) CKD, and 18 patients had hypertension. RESULTS: The pulmonary artery systolic pressure (PAPs) and LV mass index (LVMI) were significantly higher in the patient group (P < 0.05). The LV septal and lateral margins of the mitral annulus E'/A' ratio, E/E' ratio and MPI results were significantly different between the groups (P < 0.05). The MPI scores were higher in late-stage CKD than in early stage CKD (P < 0.05). The E'/A' ratio was lower and the MPI was higher in the hypertensive CKD group compared with the normotensive CKD group (P < 0.05). The E/E' ratio was correlated positively with the LVMI, and the PAPs, and negatively with glomerular filtration rate, S' value, E'/A' ratio. The MPI was correlated positively with blood pressure, LVMI, PAPs, and the S value, and negatively with the E'/A' ratio. CONCLUSIONS: The E'/A' ratio, the E/E' ratio, and the isovolumetric relaxation time measured by tissue Doppler imaging is highly accurate and easily applicable for detecting diastolic LV function, and the MPI is suitable for detecting both systolic and diastolic LV dysfunction. Their routine use may be useful in evaluating LV functions in children with CKD.

Clinical predictive value of the urine leukocyte esterase test positivity in childhood.

BACKGROUND: False negative or positive results may occur in the urine dipstick test for leukocyte esterase (LE), which is used to determine urinary tract infection (UTI). We aimed to investigate the clinical importance of the presence or absence of pyuria in urine sediment for diagnosing UTI in the presence of positive LE in dipstick analysis. METHODS: Patients admitted to the pediatric nephrology outpatient clinic with positive urine LE tests were divided into two groups: those without pyuria (Group 1) and those with pyuria (Group 2) in their urine sediment. Hospital files of the patients were evaluated retrospectively for demographic variables, lower or upper UTI symptoms, physical examination for phimosis and vulvovaginitis, urinalysis for LE and nitrite tests, urine sediment microscopy, urine culture, complete blood count and C-reactive protein. Both groups were compared for the significant growth of pathogenic bacteria in urine cultures along with clinical and laboratory parameters. RESULTS: Among 578 children giving samples for urinalysis, there were 287 cases with positive LE tests. Groups 1 and 2 included 123 and 164 cases, respectively. The proportion of girls was higher in Group 1 and vulvovaginitis rate was higher among the girls in Group 1. Girls with vulvovaginitis were mostly prepubertal. Upper UTI symptoms, significant pathogen growth rate, and elevated acute phase response were more common in Group 2. In addition, the phimosis rate was more common among the boys in Group 1 with false positive LE test. CONCLUSIONS: Children with positive LE tests without pyuria are mostly prepubertal girls and there is a high rate of vulvovaginitis in these girls. Unnecessary tests and treatments for UTI may be avoided with detailed history and physical examination in prepubertal girls who have a false positive LE test. We also found, for the first time, that a false positive LE test is significantly associated with phimosis in boys.

IL-1ß blockade in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: case-based review.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and familial Mediterranean fever (FMF) are considered as inflammasome disorders associated with uncontrolled interleukin (IL)-1ß production. Anti-IL1 agents are used in colchicine-resistant cases of FMF. Increase in pro-inflammatory mediators even between febrile attacks in PFAPA suggests that anti-IL1 treatment might be beneficial in these patients. We describe a child presenting with recurrent, self-limited febrile attacks at 1 year of age who was diagnosed as FMF being heterozygous for M694 V mutation. Her clinical findings were only controlled by the addition of canakinumab (2 mg/kg/8 week) to colchicine treatment. However, she developed typical PFAPA attacks during this treatment at 3 years of age. We conducted a literature search focusing on English articles with keywords including PFAPA, anakinra, canakinumab, and rilonacept. Five children and one adult patient with PFAPA were found and evaluated. Anakinra was reported to abort PFAPA attacks in children, while the adult patient first responded and then became resistant to anakinra. Canakinumab was effective in preventing febrile attacks in this patient. Failure of canakinumab to prevent PFAPA attacks in our case may arise from the differences in the pathophysiology of PFAPA and FMF. Thus, further experience with higher doses or shorter intervals of canakinumab is needed in children with PFAPA.

Evaluation of left ventricular systolic functions in two-dimensional speckle-tracking echocardiography in children with chronic renal failure.

BACKGROUND AND AIM: Chronic kidney disease may lead to left ventricular dysfunction. Early detection of cardiovascular disease in children with chronic kidney disease is essential to prevent cardiovascular morbidity and mortality in early adulthood. This study aimed to document the dysfunction using methods such as two-dimensional speckle-tracking echocardiography in the early stage. METHODS: A total of 34 patients diagnosed with chronic kidney disease (mean age ± standard deviation, 10.5 ± 4.1 years) and 37 sex- and age-matched (mean age 9.8 ± 4.2 years) healthy controls were studied. The results of the two groups were compared along with those of the published studies. RESULTS: The echocardiography measurements had no significant difference in the end-diastolic and end-systolic diameter values of left ventricular, ejection fraction, shortening fraction, mitral E value, mitral A value, and E/A ratio between the groups. Pulmonary artery systolic and diastolic pressure and left ventricular mass index were significantly higher in the patient group (p < 0.01). The longitudinal global strain values in the apical four-chamber, three-chamber, and two-chamber views and the total global strain values were significantly lower in the patients (p < 0.01). The circumferential global strain values in the apical, mid, basal, and total global strain were lower in the patient group, but this difference was statistically significant in the apical global and total global strain values (p < 0.05). CONCLUSIONS: Speckle-tracking echocardiography might help identify subclinical left ventricular dysfunction in patients with chronic kidney disease with unremarkable conventional echocardiography.

Rituximab-induced serum sickness and anaphylaxis in a child with nephrotic syndrome.

BACKGROUND: Rituximab is effective for treatment of children with refractory nephrotic syndrome (NS). However, the drug may cause serum sickness characterized by fever, rash, and arthralgia 10-14 days after primary antigen exposure or within a few days after secondary antigen exposure. Rituximab may also lead to anaphylaxis. It is important to recognize rituximab-induced serum sickness (RISS) clinically, as it may mimic various infectious or vasculitic diseases. CASE: A six-year-old male with NS treated with rituximab presented with diffuse arthralgia and myalgia eight days after the first dose. He developed an urticarial rash and arthralgia one week after the second dose, while he had swelling of lips and periorbital regions, choking sensation and erythematous rash in whole body within minutes after the third dose of rituximab. The first two reactions resemble typical serum sickness whereas the third reaction seem to be an anaphylaxis/anaphylactoid reaction. CONCLUSIONS: Although rituximab-induced serum sickness is typically self-limited, further infusions of rituximab should be avoided as it may provoke more severe symptoms. Most of the previous reported cases of RISS are patients with autoimmune or hematologic disorders. We present the first pediatric case with membranous nephropathy and RISS. The patient also developed anaphylactoid reaction during the third rituximab infusion.

Multimodal imaging features of a spontaneously resolved unilateral congenital macrovessel-related macular edema in a 13-year-old boy.

Purpose: Congenital retinal macrovessels (CRM) are large aberrant blood vessels that cross the horizontal raphe. Visual acuity may be negatively affected in cases afflicted with CRM due to macular serous detachment, hemorrhage, exudation, foveolar cyst formation and retinal artery occlusion. Even the presence of an anomalous vessel itself running through the foveal avascular zone may compromise the visual acuity. In this case report, we discuss the multimodal imaging characteristics of a case of symptomatic unilateral CRM-related cystoid macular edema and serous macular detachment in a 13-year-old boy. Observations: Optical coherence tomography angiography (OCTA) imaging of the superficial retina revealed the aberrant vessel and anomalous arteriovenous communication between the aberrant vessel and the retinal artery. The foveal avascular zone also appeared partly distorted. Conclusions: The present case reports the second-youngest patient afflicted with unilateral CRM and associated macular edema. There was spontaneous resolution of macular edema within six weeks. In light of the observations in this case and the literature review, the need to refrain from rapid therapeutic intervention in the eyes of patients affected with CRM and macular edema must be emphasized.

Unilateral Acute Macular Toxoplasmic Chorioretinitis Associated with White Dot-Like Choroidal Involvement Demonstrated on Indocyanine Green Angiography

A 9-year-old otherwise healthy boy was examined due to a 4-day history of visual decline in his right eye. Ophthalmological examination revealed an area of active retinochoroiditis in the right macula. Indocyanine green angiography (ICGA) demonstrated multiple hypocyanescent dots surrounding the active lesion extending 360 degrees towards the equator. Optical coherence tomography angiography (OCTA) exhibited dark dots on the choriocapillaris slab over areas corresponding to the hypocyanescent dots detected with ICGA. Full systemic examination and laboratory investigations were carried out. Toxoplasma gondii serology was positive. The diagnosis of toxoplasmic chorioretinitis with white dot-like choroidal involvement was made. Trimethoprim/sulfamethoxazole, azithromycin, and oral prednisolone were administered orally. On repeated ICGA 2 weeks later, the scattered hypocyanescent dots were significantly fewer in number. A month later, right visual acuity was improved, the macular chorioretinitis focus had become inactive, an epiretinal membrane had formed, and the dark dots on the choriocapillaris slab of OCTA were markedly diminished. ICGA may be helpful to observe possible, subtle choroidal involvement in patients with toxoplasmic chorioretinitis.

Obesity is associated with severe clinical course in children with Henoch-Schonlein purpura.

BACKGROUND: We aimed to evaluate the role of obesity on the clinical course and response to treatment in patients with Henoch-Schonlein purpura (HSP). METHODS: Data charts of children with HSP followed in a tertiary hospital between 2000 and 2018 were reviewed retrospectively. Persistent purpura was defined as skin involvement persisting for ≥ 30 days. Mild nephropathy was defined as the presence of microscopical hematuria and/or non-nephrotic proteinuria, while severe nephropathy as nephrotic proteinuria, nephritic syndrome, and/or kidney insufficiency. Obese and non-obese patients were compared for demographic, clinical, and laboratory parameters. RESULTS: There were 199 patients (M/F, 104/95; median (IQR) presenting age 7.1 (5.0-9.2) years; follow-up period 17.5 (6-50) months). Obese patients (n = 35 (17.6%)) had significantly higher rate of persistent purpura (46% vs 21%), severe renal involvement (58% vs 31%), high-grade renal histopathological lesions (83% vs 39%), hypertension (29% vs 9%), and increased erythrocyte sedimentation rate (79% vs 56%). Obese patients also showed delayed improvement of cutaneous (25 vs 14 days), articular (12.5 vs 10.0 days), and kidney (280 vs 57 days) symptoms. Obese children used steroids for significantly longer period of time (236 vs 40 days). Furthermore, need for immunosuppressive medications were higher in obese patients (40% vs 9%). CONCLUSIONS: Obese children with HSP had higher erythrocyte sedimentation rate, hypertension, and severe renal involvement; showed delayed improvement of skin, joint, and kidney findings; and need more immunosuppressive medications and a longer period of steroid treatment. These findings may be associated with the effect of adipose tissue on inflammation.

Characteristics of infant urolithiasis: A single center experience in western Turkey.

INTRODUCTION: Urolithiasis (UL) in infancy has different incidence, etiology, presentation and course compared to UL in childhood and in adults. We evaluated the clinical, radiological, metabolic factors and course of infant UL in western Turkey. METHODS: Medical records of the infants between 1 and 12 months of age with a diagnosis of UL were reviewed retrospectively for gender, gestational age, age at diagnosis, presenting symptoms, past medical history, parental consanguinity, family history of UL, urinary tract abnormalities, urinary tract infections, localization-size-number of stones, course of stones, treatment modality of UL (medical vs surgical) and follow up duration. Patients were grouped as those who did not require surgical intervention (Group 1) and those who underwent any kind of stone surgery (Group 2). Both groups were compared for the study parameters. RESULTS: There were 80 infants (48 males) with a mean age of 6.0 ± 2.9 months at diagnosis. Mean follow-up duration was 29.7 ± 23.1 months. Two thirds of the patients presented with symptoms/signs not directly related to urinary system. Predisposing factors included metabolic abnormalities in 24 (30%) patients and urinary tract malformations in 9 (11%) patients. Group 1 (n = 58) and Group 2 (n = 22) were not different with respect to the study parameters except for the larger stone size and higher rate of hyperuricosuria in Group 2. Stone size of 4.5 mm has a 72.7% sensitivity and 74.1% specificity for predicting surgical intervention. Infants treated medically and those followed by hydration only did not differ for regression rate of stones and for requirement for surgical intervention. However, metabolic abnormalities were significantly higher in medically treated infants. CONCLUSION: Every infant with urolithiasis should be evaluated for risk factors. Modification of such predisposing factors when possible may mitigate the notably high recurrence rate of UL in children. Increased awareness of infant UL may allow for earlier detection, improved evaluation and follow up, and may thereby decrease the morbidity of the disease.