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
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.
While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against ...the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio 95% confidence interval 0.25, 0.10-0.62). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, 0.14-0.91). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio 95% confidence interval 1.16, 1.08-1.24). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.
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Gaucher disease (GD) diagnosis can be delayed due to non-specific symptoms and lack of awareness, leading to unnecessary procedures and irreversible complications. GAU-PED study aims to assess GD ...prevalence in a high-risk pediatric population and the presence, if any, of novel clinical or biochemical markers associated with GD.
DBS samples were collected and tested for β-glucocerebrosidase enzyme activity for 154 patients selected through the algorithm proposed by Di Rocco et al. Patients showing β-glucocerebrosidase activity below normal values were recalled to confirm the enzyme deficiency with the gold standard essay on cellular homogenate. Patients tested positive at the gold standard analysis were evaluated through GBA1 gene sequencing.
14 out of 154 patients were diagnosed with GD, with a prevalence of 9.09% (5.06-14.78%, CI 95%). Hepatomegaly, thrombocytopenia, anemia, growth delay/deceleration, elevated serum ferritin, elevated Lyso-Gb1 and chitotriosidase were significantly associated with GD.
GD prevalence in a pediatric population at high-risk appeared to be higher compared to high-risk adults. Lyso-Gb1 was associated with GD diagnosis. The algorithm proposed by Di Rocco et al. can potentially improve the diagnostic accuracy of pediatric GD, allowing the prompt start of therapy, aiming to reduce irreversible complications.
We evaluated the role of CYP3A5, ABCB1 and SXR gene polymorphisms in the occurrence of acute kidney rejection in a cohort of pediatric renal transplant recipients.
Forty-nine patients were genotyped ...for CYP3A5, ABCB1 and SXR polymorphisms and evaluated with tacrolimus through levels in a retrospective monocenter study.
Patients with the A allele of CYP3A5 treated with tacrolimus had a higher risk of acute rejection than those without the A allele, while patients carrying the homozygous GG variant for SXR A7635GG did not show any episode of acute rejection.
Genetic analysis of polymorphisms implicated in drug metabolism and tacrolimus trough levels may help to forecast the risk of acute rejection and individualize drug dosage in children undergoing renal transplantation.
Background and objectives Children with multi-drug resistant idiopathic nephrotic syndrome (MDR-INS) usually progress to end-stage kidney disease with a consistent risk of disease recurrence after ...transplantation. New therapeutic options are needed for these patients. Mesenchymal stromal cells (MSCs) are multipotential non-hematopoietic cells with several immunomodulatory properties and growing clinical applications. Cord blood-derived MSC have peculiar anti-inflammatory and immunosuppressive properties. We aimed at assessing safety and efficacy of cord-blood-derived MSCs (CB-MSCs) in children with MDR-INS. Design, setting, participants Prospective, open-label, single arm phase I-II pilot study. Pediatric patients with MDR-INS, resistant to at least two lines of therapy, were enrolled. Allogenic CB-MSCs were administered intravenously on days 0, 14, and 21 at a dose of 1.5 x 10.sup.6 cells/kg. Patients were followed for at least 12 months. The primary outcomes were safety and toxicity. The secondary outcome was remission at 12 months evaluated by urinary protein/urinary creatinine ratio (uPr/uCr). Circulating regulatory T cells (Tregs) were monitored. Results Eleven pediatric patients with MDR-INS (10 females, median age 13 years) resistant to a median of 3 previous lines of therapy were enrolled. All patients completed the CB-MSC infusion schedule. No patient experienced any infusion-related adverse event or toxicity. Nine patients were assessable for efficacy. At the 12 months follow-up after the treatment, the median uPr/uCr did not change significantly from baseline (8.13 vs. 9.07; p = 0.98), while 3 patients were in partial or complete remission. A lower baseline uPr/uCr was a predictor of remission (2.55 vs. 8.74; p = 0.0238). Tregs count was not associated with CB-MSCs therapy. Conclusions CB-MSCs are safe and may have a role in the immunosuppressive therapy of pediatric patients with MDR-INS. This preliminary experience paves the way toward further phase II studies addressing MSC efficacy in immune-mediated kidney diseases. Keywords: Idiopathic nephrotic syndrome, Mesenchymal stromal cells, Multi-drug resistant nephrotic syndrome, Children, Advanced therapy medical products, Cord-blood-derived mesenchymal stromal cells
Retinoids are lipophilic compounds derived from vitamin A, which have been extensively studied in cancer prevention and therapy. In pediatric oncology, they are successfully used for the treatment of ...acute promyelocytic leukemia (APL) and high-risk neuroblastoma (HR-NBL). APL is a subtype of acute myeloid leukemia (AML) clinically characterized by a severe bleeding tendency with a highrisk of fatal hemorrhage. The molecular hallmark of this disease is the presence of the promyelocytic leukemia (PML)-retinoic acid receptor-α (RAR α) gene fusion that plays a critical role in promyelocytic leukemogenesis and represents the target of retinoid therapy. The introduction in the late 1980s of all-trans retinoic acid (ATRA) into the therapy of APL radically changed the management and the outcome of this disease. Presently, the standard front-line therapeutic approach for pediatric APL includes anthracycline-based chemotherapy and ATRA, leading to a complete remission in almost 90% of the patients. Neuroblastoma (NBL) is an aggressive childhood tumor derived from the peripheral neural crest. More than half of patients have a high-risk disease, with a poor outcome despite intensive multimodal treatment. Although the exact mechanism of action remains unclear, the introduction of 13-cis-retinoic acid (13-cis-RA) in the therapy of NBL has improved the prognosis of this disease. Currently, the standard treatment for HR-NBL consists of myeloablative therapy followed by autologous hematopoietic stem cell transplantation (HSCT) and maintenance with 13-cis-RA for the treatment of minimal residual disease, leading to a 3-year disease-free survival rate (DFS) of about 50%. In this paper the authors provide a review of the peer-reviewed literature on the role of retinoids in the treatment of pediatric APL and HR-NBL, summarizing the most relevant clinical trial results of the last decades, analyzing the ongoing trials, and investigating future therapeutic perspectives of children affected by these diseases.
Idiopathic nephrotic syndrome (INS) is the most frequent primary glomerular disease in children, displaying high grade proteinuria and oedema. The mainstay of therapy are steroids, and patients are ...usually classified according to the treatment response (sensitive vs. resistant). The mechanisms involved in INS pathogenesis and treatment responsiveness have not yet been identified. In this context, the analysis of urinary extracellular vesicles (UEv) is interesting, since they represent a molecular snapshot of the parental cells, offering a "fingerprint" for monitoring their status. Therefore, the aim of this study is to verify the feasibility of using UEv of INS patients as indicators of therapy response and its prediction. UEv were isolated from the urine of pediatric patients in remission after therapy; they showed characteristic electrophoresis profiles that matched specific patient subgroups. We then built a statistical model to interpret objectively each patient UEv protein profile: in particular, steroid-resistant patients cluster together with a very distinct pattern from other INS patients and controls. In conclusion, the evaluation of the UEv protein profile looks promising in the investigation of INS, showing a disease signature that might predict clinical evolution.
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