Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by tubular defects, but ...glomerular, tubulointerstitial and cystic diseases have also been described. For example, defects in coenzyme Q10 (CoQ10) biosynthesis and the mitochondrial DNA 3243 A>G mutation are important causes of focal segmental glomerulosclerosis in children and in adults, respectively. Although they sometimes present with isolated renal findings, mitochondrial diseases are frequently associated with symptoms related to central nervous system and neuromuscular involvement. They can result from mutations in nuclear genes that are inherited according to classic Mendelian rules or from mutations in mitochondrial DNA, which are transmitted according to more complex rules of mitochondrial genetics. Diagnosis of mitochondrial disorders involves clinical characterization of patients in combination with biochemical and genetic analyses. In particular, prompt diagnosis of CoQ10 biosynthesis defects is imperative because of their potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes to the physiopathology of tissue injury, whereas mitochondrial biogenesis has an important role in the recovery of renal function. Potential therapies that target mitochondrial dysfunction or promote mitochondrial regeneration are being developed to limit renal damage during AKI and promote repair of injured tissue.
Developmental programming in the kidney has been recognised for more than two decades, but its contribution to the global burden of kidney diseases remains underappreciated by policy makers.3 In view ...of the many factors known to affect fetal kidney development, including maternal health and nutrition, exposure to stress, poverty, pollutants, drugs, and infections during gestation,3 a holistic strategy to prevent such programming effects is consistent with the life-course approach and aligns with the United Nations (UN) Sustainable Development Goals to foster health.2 Chronic kidney disease is an important contributor to the NCD burden that has been relatively neglected in WHO's Global Action Plan for the Prevention and Control of NCDs, despite chronic kidney disease being a major cause of hypertension and a major risk multiplier of cardiovascular disease.1,4 Although the prevalence of chronic kidney disease in many low-income countries remains unknown, the disease is most prevalent among disadvantaged populations within industrialised nations-eg, African-Americans and Aboriginal Australians.5 The number of people receiving dialysis or transplantation is projected to double, from 2·6 million in 2010 to 5·4 million in 2030.6 In 2010, 2·3-7·1 million adults died from lack of access to dialysis and transplantation in low-income countries.6 In view of the clinical outcomes and often prohibitively high costs of treatment, prevention and early detection are the only sustainable solutions to address this growing global burden. 16
Intercellular communication governs multicellular interactions in complex organisms. A variety of mechanisms exist through which cells can communicate, e.g., cell-cell contact, the release of ...paracrine/autocrine soluble molecules, or the transfer of extracellular vesicles (EVs). EVs are membrane-surrounded structures released by almost all cell types, acting both nearby and distant from their tissue/organ of origin. In the kidney, EVs are potent intercellular messengers released by all urinary system cells and are involved in cell crosstalk, contributing to physiology and pathogenesis. Moreover, urine is a reservoir of EVs coming from the circulation after crossing the glomerular filtration barrier—or originating in the kidney. Thus, urine represents an alternative source for biomarkers in kidney-related diseases, potentially replacing standard diagnostic techniques, including kidney biopsy. This review will present an overview of EV biogenesis and classification and the leading procedures for isolating EVs from body fluids. Furthermore, their role in intra-nephron communication and their use as a diagnostic tool for precision medicine in kidney-related disorders will be discussed.
Single mutations in COL4A3/COL4A4 genes have been described in patients with autosomal dominant Alport syndrome and thin basement membrane nephropathy, without a shared definition of these patients ...within the medical community. We aimed to better categorize this clinical entity by examining clinical manifestations, family history, pathological features and genetics.
We retrospectively analyzed patients with causative heterozygous COL4A3/COL4A4 mutations referred to us between 1990 and 2019. Index cases were defined as children who were the first to be diagnosed in their families.
The study included 24 index cases and 29 affected relatives, belonging to 25 families with a heterozygous mutation in the COL4A3/COL4A4 genes. During the follow-up, nine patients developed proteinuria median age 15.7 years (range 5.6-33), six at clinical diagnosis and four with progression toward chronic kidney disease (CKD) (three required kidney replacement therapy at 25, 45 and 53 years and one had CKD Stage 2 at 46 years). Extrarenal involvement was observed in 24.5% of patients. Hematuria was transmitted in consecutive generations, while CKD was reported in nonconsecutive generations of 11 families median age 53 years (range 16-80). Seventeen patients (32%) underwent kidney biopsy: findings were consistent with Alport syndrome in 12 cases and with thin basement membrane nephropathy in 5 cases.
Despite the benign course for these patients described in the literature, a significant percentage is at risk for disease progression. Consequently, we suggest that the assessment of these patients must take into account family history, genetic analysis and pathologic findings. After comparison with the literature, our data suggest that a different definition for Alport syndrome must be considered.
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most frequent form of malformation at birth and represent the cause of 40-50% of pediatric and 7% of adult end-stage renal disease ...worldwide. The pathogenesis of CAKUT is based on the disturbance of normal nephrogenesis, secondary to environmental and genetic causes. Often CAKUT is the first clinical manifestation of a complex systemic disease, so an early molecular diagnosis can help the physician identify other subtle clinical manifestations, significantly affecting the management and prognosis of patients. The number of sporadic CAKUT cases explained by highly penetrant mutations in a single gene may have been overestimated over the years and a genetic diagnosis is missed in most cases, hence the importance of identifying new genetic approaches which can help unraveling the vast majority of unexplained CAKUT cases. The aim of our review is to clarify the current state of play and the future perspectives of the genetic bases of CAKUT.
Background
Coronavirus Disease 2019 has spread from China as a global pandemic, Italy being one of the earliest affected countries. The infection displays a more complicated and often fatal course in ...adults with a history of kidney disease, while it does not seem to affect children in the same way. Pediatric patients with idiopathic nephrotic syndrome (INS), with or without chronic immunosuppressive therapy, are at greater risk of infections which may also trigger relapses.
Objectives
We performed a systematic review of the literature to identify all articles on SARS-CoV-2 infections in children with INS in order to describe the severity of all SARS-CoV-2 infections reported in children with INS, to evaluate the risk of new onset and relapses associated with SARS-CoV-2 infection, and to draw recommendations on their management and vaccination. The search was conducted on the following databases: MEDLINE (via Pubmed), Google Scholar, and Web of Science. The search methodology used with the selected free text terms or MesH was (“nephrotic syndrome” OR “idiopathic nephrotic syndrome”) and (“covid 19” OR "severe acute respiratory syndrome coronavirus 2" OR "2019-nCoV" OR "SARS-CoV-2").
Results
The literature search provided 36 records. After screening for their relevance to the topic, 11 studies were selected. Two additional publications were identified through the reference list of all included articles and 13 articles were included in the review. A total of 43 cases of children with INS and SARS-CoV-2 infection have been reported; the course of the disease was mild for most patients with low need of respiratory support and no death in high income countries. In 5 patients, the infection was complicated by relapse, which anyway showed a good response to steroids. Two children had a new onset of INS during a SARS-CoV-2 infection.
Conclusions
Children with INS, with or without immunosuppression, are not at higher risk of severe SARS-CoV-2 infection. Relapse is a possible complication, but steroid treatment is safe and effective. After summarizing the evidence, we have suggested recommendations for the management of children with INS during the pandemic and the vaccination campaign.
Graphical abstract
Ibuprofen is the most widely used non-steroidal anti-inflammatory drug (NSAID) for the treatment of inflammation, mild-to-moderate pain and fever in children, and is the only NSAID approved for use ...in children aged ≥3 months. Its efficacy and safety profile have led to its increasing use in paediatric care, even without medical prescription. However, an increase of suspected adverse reactions to ibuprofen has been noted in concomitance with the raised, often medically unsupervised, consumption of the drug. The purpose of this work was a critical review of the paediatric literature over the last 15 years on side effects and adverse events associated with ibuprofen, in order to highlight circumstances associated with higher risks and to promote safe and appropriate use of this drug. The literature from 2000 to date demonstrates that gastrointestinal events are rare, but (when they occur) include both upper and lower digestive tract lesions. Dehydration plays an important role in triggering renal damage, so ibuprofen should not be given to patients with diarrhoea and vomiting, with or without fever. Likewise, ibuprofen should never be administered to patients who are sensitive to it or to other NSAIDs. It is contraindicated in neonates and in children with wheezing and persistent asthma and/or during varicella. Most of the analysed studies reported adverse events when ibuprofen was being used for fever symptoms or flu-like syndrome. Ibuprofen should not be used as an antipyretic, except in rare cases. Ibuprofen remains the drug of first choice in the treatment of inflammatory pain in children.
Studies concerning the role of arachidonic acid (AA) and its metabolites in kidney disease are scarce, and this applies in particular to idiopathic nephrotic syndrome (INS). INS is one of the most ...frequent glomerular diseases in childhood; it is characterized by T-lymphocyte dysfunction, alterations of pro- and anti-coagulant factor levels, and increased platelet count and aggregation, leading to thrombophilia. AA and its metabolites are involved in several biological processes. Herein, we describe the main fields where they may play a significant role, particularly as it pertains to their effects on the kidney and the mechanisms underlying INS. AA and its metabolites influence cell membrane fluidity and permeability, modulate platelet activity and coagulation, regulate lymphocyte activity and inflammation, preserve the permeability of the glomerular barrier, influence podocyte physiology, and play a role in renal fibrosis. We also provide suggestions regarding dietary measures that are able to prevent an imbalance between arachidonic acid and its parental compound linoleic acid, in order to counteract the inflammatory state which characterizes numerous kidney diseases. On this basis, studies of AA in kidney disease appear as an important field to explore, with possible relevant results at the biological, dietary, and pharmacological level, in the final perspective for AA to modulate INS clinical manifestations.
The fatty acid profiles of patients with idiopathic nephrotic syndrome (INS) are different from that of healthy controls, even during remission, revealing an increase of the pro-inflammatory omega 6 ...series. It is still unknown whether the concomitance of nephrotic syndrome affects the potential positive effects of the Mediterranean diet on the levels of omega 3 and 6 fatty acids. We performed a cross-sectional study to evaluate the association between the adherence to the Mediterranean diet and fatty acid profile in 54 children with INS. The dietary habits were assessed through the validated Kidmed questionnaire. Patients with higher adherence had lower levels of linoleic acid and total omega-6. Moreover, a negative correlation between proteinuria and the anti-inflammatory omega-3 series was found. In conclusion, patients with INS with proteinuria and low adherence to the Mediterranean diet have an imbalance in the omega-6/omega-3 ratio that may benefit from following the Mediterranean diet.
We report the recommendations for the diagnosis, treatment, imaging evaluation and use of antibiotic prophylaxis in children with the first febrile urinary tract infection, aged 2 months to 3 years. ...They were prepared by a working group of the Italian Society of Pediatric Nephrology after careful review of the available literature and a consensus decision, when clear evidence was not available.
Conclusion: These recommendations are endorsed by the Italian Society of Pediatric Nephrology. They can also be a tool of comparison with other existing guidelines in issues in which much controversy still exists.
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