Childhood-onset IgA nephropathy: is long-term recovery possible?

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. While studies have primarily focused on identifying risk factors for disease progression, very few data exist on the likelihood of achieving complete recovery from the disease. METHODS: We conducted a single-center retrospective study on all consecutive patients with biopsy-proven IgAN diagnosed between 1986 and 2018 in our pediatric center. Biopsies were classified according to the MEST-C Oxford classification score. "Complete clinical remission" was defined as the absence of proteinuria, hematuria, and hypertension in patients with normal kidney function who had been off therapy for more than 2 years. RESULTS: Overall, 153 patients with age at onset of 10.6 ± 4 years were enrolled in the study. Of these, 41 achieved "complete clinical remission." The estimated probability of complete clinical remission at 10 years was 43% (95%CI 33-54). However, seven patients relapsed within 10 years. Multivariable analysis showed that higher age at onset (HR 0.89, 95%CI 0.80-0.98, p = 0.017) and segmental glomerulosclerosis lesions (HR 0.28, 95%CI 0.10-0.79, p = 0.017) decreased significantly the chances of achieving complete clinical remission. Immunosuppressive therapy was not significantly associated with clinical outcomes. CONCLUSIONS: Approximately one-third of patients with pediatric-onset IgAN achieve prolonged remission, in particular, very young children at disease onset without sclerotic glomerular lesions. Longer term follow-up is needed to assess if these patients have achieved permanent remission.

Complement inhibitors in pediatric kidney diseases: new therapeutic opportunities.

Historically, the complement system (classical, lectin, alternative, and terminal pathways) is known to play a crucial role in the etiopathogenesis of many kidney diseases. Direct or indirect activation in these settings is revealed by consumption of complement proteins at the serum level and kidney tissue deposition seen by immunofluorescence and electron microscopy. The advent of eculizumab has shown that complement inhibitors may improve the natural history of certain kidney diseases. Since then, the number of available therapeutic molecules and experimental studies on complement inhibition has increased exponentially. In our narrative review, we give a summary of the main complement inhibitors that have completed phase II and phase III studies or are currently used in adult and pediatric nephrology. The relevant full-text works, abstracts, and ongoing trials (clinicaltrials.gov site) are discussed. Data and key clinical features are reported for eculizumab, ravulizumab, crovalimab, avacopan, danicopan, iptacopan, pegcetacoplan, and narsoplimab. Many of these molecules have been shown to be effective in reducing proteinuria and stabilizing kidney function in different complement-mediated kidney diseases. Thanks to their efficacy and target specificity, these novel drugs may radically improve the outcome of complement-mediated kidney diseases, contributing to an improvement in our understanding of their underlying pathophysiology.

A simplified protocol of regional citrate anticoagulation with phosphate-containing solutions in infants and children treated with continuous kidney replacement therapy.

BACKGROUND: Regional citrate anticoagulation (RCA) is the preferred modality of anticoagulation used in continuous kidney replacement therapy (CKRT) in adults and less extensively in children. Potential metabolic complications limit widespread use in infants, neonates, and in children with liver failure. METHODS: We report our experience with a simplified protocol in 50 critically ill children, infants, and neonates, some of them with liver failure, with commercially available solutions containing phosphorous and higher concentration of potassium and magnesium. RESULTS: RCA allowed attainment of a mean filter lifetime of 54.5 ± 18.2 h, 42.5% of circuits lasted more than 70 h, and scheduled change was the most frequent cause of CKRT interruption. Patient Ca++ and circuit Ca++ were maintained in the target range with mean values of 1.15 ± 0.13 mmol/l and 0.38 ± 0.07 mmol/l, respectively. No session had to be stopped because of metabolic complications. The most frequent complications were hyponatremia, hypomagnesemia, and metabolic acidosis mostly related to primary disease and critical illness. No session had to be stopped because of citrate accumulation (CA). Transitory CA occurred in 6 patients and was managed without requiring RCA interruption. No patients with liver failure presented CA episodes. CONCLUSIONS: In our experience, RCA with commercially available solutions was easily applied and managed in critically ill children, even in patients with low weight or with liver failure. Solutions containing phosphate and higher concentrations of magnesium and potassium allowed reduction of metabolic derangement during CKRT. Prolonged filter life was ensured with no detrimental effects on patients and reduced staff workload. A higher resolution version of the Graphical abstract is available as Supplementary information.

A pediatric case of IgA nephropathy benefitting from targeted release formulation-budesonide.

BACKGROUND: The best treatment for IgAN is still debated. The trials NEFIGAN and NEFIGARD have demonstrated that TRF-budesonide (Nefecon) efficiently and safely reduced proteinuria in adults, leading to FDA approval of Nefecon for adult IgAN. In pediatric IgAN, an etiological treatment does not yet exist, and the main therapies remain RAAS inhibitors and oral steroids. To our knowledge, this is one of the few pediatric reports of TRF-budesonide therapy. CASE REPORT-DIAGNOSIS/TREATMENT: A 13-year-old boy underwent a kidney biopsy for recurrent macrohematuria and proteinuria, resulting in an IgAN diagnosis (MEST-C score M1-E1-S0-T0-C1). At admission, serum creatinine and UPCR were slightly increased. Three methylprednisolone pulses were performed, followed by prednisone and RAAS inhibitors therapy. However, after 10 months, macrohematuria became constant, and UPCR increased. A new kidney biopsy was performed, showing an increase in sclerotic lesions. Prednisone was discontinued, and a trial with IBD TRF-budesonide 9 mg/day started. One month later, macrohematuria episodes disappeared and UPCR decreased, with a stable kidney function. After 5 months, due to a reduction in morning cortisol levels and difficulty in drug provisioning, we started to wean TRF-budesonide by 3 mg every 3 months, with complete withdrawal after 1 year. During this period, episodes of macrohematuria dramatically decreased, and UPCR and kidney function were maintained stable. CONCLUSION: Our case demonstrates that TRF-budesonide could be considered an effective second-line treatment in pediatric IgAN, particularly when a long course of steroids is necessary to control active inflammation. However, pediatric clinical trials to identify the correct dosage and tolerability of TRF-budesonide are urgently needed.

Impact of the SARS-CoV-2 pandemic and associated restrictions on Pediatric Emergency Department utilization in Sardinia: a retrospective bicentric observational study.

BACKGROUND: The COVID-19 pandemic and associated public health measures have had a profound impact on health systems worldwide. The aim of this study was to assess quantitative and qualitative changes in Pediatric Emergency Department (PED) visits in Sardinia, Italy, during the early period of the COVID-19 pandemic. METHODS: We retrospectively investigated the number and characteristics of visits to two major Sardinian PEDs, in the periods January-June 2020 and January-June 2019. RESULTS: From January to June 2020, 8399 PED visits with 1160 hospital admissions (13.8% of PED visits) were registered, compared with 15,692 PED visits (Δ = -46.5%) and 1819 hospital admissions (11.6% of PED visits) occurring from January to June 2019. Comparing January-June 2020 with January-June 2019, we found differences in the percentage of visits for age groups, and significant changes in the proportion of triage codes, with a decrease in green codes (72.1% vs 74.2%, respectively) and an increase in white codes (19.0% vs 16.5%, respectively). Moreover, in the period January-June 2020, the frequency of skin disorders and acute respiratory disease significantly decreased, while the frequency of trauma, acute surgical disease, intoxication, and neuropsychiatric disease significantly increased. CONCLUSIONS: After the beginning of the Italian lockdown, we observed a marked drop in the number of PED visits, an increase in hospital admission rate, and radical changes in the reason for visit.

Reversible glomerular damage in disseminated intravascular coagulation.

BACKGROUND: Brain death secondary to traumatic brain injury is one of the main sources of organs for transplantation but it can be associated with disseminated intravascular coagulation, which has been considered a relative contraindication for kidney donation. METHODS: We describe two successful pediatric cases of kidney transplantation from a single donor with disseminated intravascular coagulation. RESULTS: A 17-year-old male donor died from head injury and both kidneys were offered to our center. Within 24 h, donor's Hb and platelets dropped to 8.3 g/dl and 32 000/mcl, respectively, serum creatinine reached 2.01 mg/dl, and urinalysis showed proteinuria (300 mg/dl). Pre-implant biopsy showed massive occlusion of glomerular capillaries by fibrin thrombi containing fragmented red blood cells and inflammatory cells, and acute tubular damage. Arterioles and small arteries were spared. A diagnosis of DIC was made. The kidneys were transplanted in a 16-year-old girl and a 13-year-old boy. Slow recovery of graft function was observed in both recipients. On post-operative day 3, platelets dropped to a minimum value of 66 000 and 86 000/mcl, respectively. Diuresis was always present. On day 4, platelets started to rise. Six months later, both recipients attained normal renal function. A six-month protocol biopsy showed no microthrombi or other signs of disseminated intravascular coagulation. CONCLUSIONS: Despite the limited data available in literature, the outcome of these two cases is positive. Thus, pre-implant kidney biopsy, even if it reveals massive thrombotic occlusion of glomerular capillaries compatible with diagnosis of disseminated intravascular coagulation, should not be considered an absolute contraindication to transplantation.

Infant botulism: an underestimated threat.

Infant botulism (IB) is defined as a potentially life-threatening neuroparalytic disorder affecting children younger than 12 months. It is caused by ingestion of food or dust contaminated by Clostridium botulinum spores, which germinate in the infant's large bowel and produce botulinum neurotoxin. Although the real impact of IB is likely underestimated worldwide, the USA has the highest number of cases. The limited reporting of IB in many countries is probably due to diagnostic difficulties and nonspecific presentation. The onset is usually heralded by constipation, followed by bulbar palsy, and then by a descending bilateral symmetric paralysis; ultimately, palsy can involve respiratory and diaphragmatic muscles, leading to respiratory failure. The treatment is based on supportive care and specific therapy with Human Botulism Immune Globulin Intravenous (BIG-IV), and should be started as early as possible. The search for new human-like antibody preparations that are both highly effective and well tolerated has led to the creation of a mixture of oligoclonal antibodies that are highly protective and can be produced in large quantities without the use of animals. Ongoing research for future treatment of IB involves the search for new molecular targets to produce a new generation of laboratory-produced antitoxins, and the development of new vaccines with safety and efficacy profiles that can be scaled up for clinical use. This narrative literature review aims to provide a readable synthesis of the best current literature on microbiological, epidemiological and clinical features of IB, and a practical guide for its treatment.

Ceftriaxone-associated biliary pseudolithiasis in children: do we know enough?

Ceftriaxone is an antibiotic agent frequently used in paediatric hospital practice for the treatment of severe bacterial infections. The use of this agent can result in cholelithiasis and/or biliary sludge, more commonly in children than in adults. This systematic review was aimed at analysing available literature concerning ceftriaxone-associated biliary pseudolithiasis in paediatric patients, with a special emphasis on the clinical aspects. A literature analysis was performed using Medline and Embase electronic databases (articles published in English up to December 2019), with the search terms and combinations as follows:'ceftriaxone', 'cholelithiasis', 'biliary sludge' 'gallstones' 'neonates' 'children' 'clinical aspects' 'management'. Several case reports, case series and prospective/retrospective studies have documented a relationship between ceftriaxone treatment and biliary pseudolithiasis in the paediatric population, even though literature data regarding neonates and infants are scarce. Ceftriaxone-associated biliary pseudolithiasis is dose-dependent and usually asymptomatic but, sometimes, it may present with abdominal pain, nausea and emesis. Abdominal ultrasonography should be performed when this complication is suspected. Generally, ceftriaxone-associated cholelithiasis resolves over a variable period of time (days to months) after cessation of therapy. Therefore, a conservative approach to this condition is advocated, but a prolonged follow-up may be necessary. A personalized assessment of factors predisposing to ceftriaxone-associated biliary pseudolithiasis before prescribing the drug can allow to minimize the risk of developing it, with significant advantages in terms of human and economic costs.

Current Challenges in Neonatal Resuscitation: What is the Role of Adrenaline?

Adrenaline, also known as epinephrine, is a hormone, neurotransmitter, and medication. It is the best established drug in neonatal resuscitation, but only weak evidence supports current recommendations for its use. Furthermore, the available evidence is partly based on extrapolations from adult studies, and this introduces further uncertainty, especially when considering the unique physiological characteristics of newly born infants. The timing, dose, and route of administration of adrenaline are still debated, even though this medication has been used in neonatal resuscitation for a long time. According to the most recent Neonatal Resuscitation Guidelines from the American Heart Association, adrenaline use is indicated when the heart rate remains < 60 beats per minute despite the establishment of adequate ventilation with 100% oxygen and chest compressions. The aforementioned guidelines recommend intravenous administration (via an umbilical venous catheter) of adrenaline at a dose of 0.01-0.03 mg/kg (1:10,000 concentration). Endotracheal administration of a higher dose (0.05-0.1 mg/kg) may be considered while venous access is being obtained, even if supportive data for endotracheal adrenaline are lacking. The safety and efficacy of intraosseous administration of adrenaline remain to be investigated. This article reviews the evidence on the circulatory effects and tolerability of adrenaline in the newborn, discusses literature data on adrenaline use in neonatal cardiopulmonary resuscitation, and describes international recommendations and outcome data regarding the use of this medication during neonatal resuscitation.

Vitamin D deficiency in childhood: old lessons and current challenges.

Hypovitaminosis D in childhood is a re-emerging public health problem in developed countries. New life style habits, current "epidemics" of obesity in children and adolescents worldwide, and other preventable risk factors may play a role in favoring the occurrence of vitamin D deficiency. In addition to skeletal consequences, hypovitaminosis D has been found to be involved in the development of serious health extra-skeletal problems in childhood, including atopy and autoimmunity. The increasing concerns about the global health impact of vitamin D deficiency make further research necessary to fill the gaps of knowledge in this field, and particularly to establish universally accepted "normal" serum 25(OH)D levels in the pediatric population, and to improve strategies for the screening, prevention and treatment of hypovitaminosis D. This review discusses the key points of hypovitaminosis D in childhood in the light of new knowledge, and highlights the limitations of current strategies to control this condition.

Supraventricular tachycardia during the first year of life: is subclinical inflammation the trigger?

BACKGROUND: Neutrophil/lymphocyte ratio (NLR) and red cell distribution width (RDW) may be associated with the onset of arrhythmias in adults, thus underlining a possible inflammatory etiology. Paroxysmal supraventricular tachycardia (SVT) is the most frequent pathological tachycardia in childhood. AIM: To verify NLR and RDW levels in a group of children (<1 year) affected by SVT with a structurally normal heart and without fever or inflammatory diseases; to compare NLR and RDW before and after SVT resolution, to verify whether the latter was related with the reduction in inflammatory state; to identify - in SVT subtypes caused by a reentry mechanism - an NLR and RDW cutoff point beyond which adenosine was ineffective in preventing SVT recurrence. METHODS: Eighteen SVT patients were recruited (mean age 18.9 ± 3.2 days; 50% males) and compared with 18 healthy peers. RESULTS: NLR was higher in SVT group than in controls (p < 0.03). A significant difference was revealed between NLR values obtained on admission and at discharge (p < 0.05). On the contrary, no significant differences were found for RDW. It was not possible to identify NLR or RDW cutoffs capable of predicting SVT recurrence. However, all patients featuring SVT recurrence following adenosine injection presented with a lymphocyte count >6000/mm3. CONCLUSIONS: Elevated NLR is associated with an increased risk of SVT during the first year of life, while its decline looks like to lead the SVT resolution. A subclinical inflammatory status, as assessed by lymphocytes count, influences SVT recurrence. These results provide further support for an inflammatory etiology of SVT in babies.