Rafael dos Santos Borges

The frequent association between renal and ocular anomalies suggests a common pathophysiological axis between the genetic and molecular mechanisms of the kidneys and multiple ocular structures during tissue formation, differentiation, and remodeling. The search was conducted in the PubMed, SciELO, Scopus, and Web of Science databases. This review article focuses on the common molecular and genetic bases of renal and ocular involvement in both systemic diseases and rare syndromes. The interdependence between renal and ocular morphogenesis is mediated by conserved molecular mechanisms, notably the Bone Morphogenetic Protein-7 (BMP-7) pathway, which regulates nephrogenesis and lens development, and the transcription factor Paired Box 2 (PAX2), which is essential for the formation of the genitourinary tract and the optic nerve. Shared expression of molecular components and dependency on their expression for the integrity of both the eye and the kidney lie in the stability of extracellular matrix components, specifically through laminin β2 (LAMB2) and type IV collagen, whose pathogenic variants underlie syndromic phenotypes such as Pierson and Alport syndromes. In addition, ciliopathies, developmental disorders, immune-mediated diseases, and inborn errors of metabolism, including Fabry disease, cystinosis, and primary hyperoxaluria, promote parallel injury to renal and ocular tissues through mechanisms involving abnormal cellular signaling, metabolite accumulation, complement activation and systemic inflammation. These mutual pathways affect diverse ocular structures, including the cornea, lens, retina, optic nerve, and basement membranes. Furthermore, the presence of the kidney–retina axis enables the use of the retina as a sentinel organ, allowing for non-invasive evaluation of glomerular microvasculature by means of high-resolution imaging technologies of retinal vessels. The kidneys and eyes share several genetic, developmental, structural, metabolic, and immunological mechanisms that explain the frequent association of congenital anomalies and acquired lesions in these organs and the associated diagnostic and prognostic implications. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Congenital human cytomegalovirus (cCMV) infection is a leading cause of sensorineural hearing loss and neurological sequelae in children. Although newborn screening strategies remain controversial, dried blood spots (DBS) collected for routine metabolic screening have been proposed as a low-cost method for large-scale detection. This systematic review assessed studies that evaluated the accuracy of DBS testing for screening newborns for cCMV infection. A systematic review was conducted following the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy and reported in accordance with PRISMA-DTA. The PIRT strategy included the following: Population (newborns undergoing screening for cCMV), Index test (detection of cCMV using DBS samples), Reference standard (confirmatory testing using saliva or urine PCR collected within 21 days of life), Target condition (cCMV infection). Searches were performed in PubMed/MEDLINE, Scopus, Bireme, Embase, LILACS, SciELO, and CENTRAL. The search identified 365 articles; after removing 210 duplicates, 155 were screened by title and abstract, and 9 studies were included. The included studies tested between 1174 and 551,034 DBS samples each. Confirmatory testing used PCR in urine (seven studies) or saliva (two studies). Three studies used paired samples for screening; sensitivity ranged from 28.3% to 79.3%, specificity from 99.9% to 100%. Positive predictive value (PPV) ranged from 39 to 100%, and negative predictive value (NPV) from 99.6% to 99.9%. Conclusion : Neonatal screening for congenital cytomegalovirus using DBS samples is promising, since it would allow early identification for timely interventions to reduce sequelae. What is Known: • Congenital CMV is a leading cause of sensorineural hearing loss and neurodevelopmental sequelae, with many cases asymptomatic at birth. Diagnosis relies on early viral detection, and while saliva/urine PCR is sensitive, newborn screening lacks consensus and feasibility is unknown in many settings. What is New: • DBS PCR emerges as a scalable, feasible low-cost screening alternative for cCMV screening. A few states in the USA and provinces in Canada have implemented newborn cCMV screening programs using DBS, but the sensitivity appears lower than in research studies. Improving DNA extraction and PCR methods are required as well as assessing feasibility of using other specimens (e.g., urine or saliva) for screening.

Pierson syndrome (PS) is a rare autosomal recessive disorder, primarily characterized by (1) congenital nephrotic syndrome, (2) ocular abnormalities, and (3) neurodevelopmental deficits. It is caused by mutations in the LAMB2 gene, which encodes the laminin β2 chain—a protein subunit that is part of a specific group of proteins known as laminins. These proteins are present in the glomerular basement membrane, neuromuscular junctions, and ocular structures. Although PS exhibits a wide spectrum of phenotypic presentations, the prognosis remains poor, with most patients not surviving beyond early childhood. Despite its rarity, PS is clinically significant due to its potential to cause end-stage kidney disease early in life. This review consolidates the latest insights into the etiopathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of PS.

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) are cytokines involved in B-cell activation and survival, contributing to the pathogenesis of IgAN. This meta-analysis aimed to evaluate the efficacy, safety, and biomarkers of BAFF- or APRIL-targeted therapies in patients with IgAN. We searched PubMed, Scopus, and the Cochrane Library for randomized controlled trials (RCTs) comparing BAFF- or APRIL-targeted drugs with placebo in adults with IgAN, published up to December 2024 and written in English. Efficacy outcomes were the mean percent change in the 24-hour urine protein-to-creatinine ratio (UPCR) and the mean change in the estimated glomerular filtration rate (eGFR) from baseline. Safety included the incidence of adverse events. The biomarkers we used were changes in serum Gd-IgA1, IgG, IgA, and IgM from baseline. The risk of bias and the certainty of evidence were assessed using RoB v2.0 and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). We used the R software version 4.2.1 for statistics. Four Phase II RCTs, including 331 patients, were included, with three studies having a low risk of bias, while there were some concerns regarding one study. Compared to placebo, BAFF- or APRIL-targeted drugs significantly reduced 24-hour UPCR (mean difference [MD] −38.94%; 95% confidence interval [CI] −58.98 to −18.90; P = 0.0001; I² = 0%) and significantly improved the eGFR (MD 7.05 mL/min/1.73 m²; 95% CI 3.83 to 10.27; P < 0.0001; I² = 0%). Adverse events did not significantly differ between the study groups. BAFF- or APRIL-targeted drugs significantly decreased serum Gd-IgA1, IgG, IgA, and IgM compared with placebo, indicating lower immune complex formation and response to treatment. BAFF- or APRIL-targeted therapies appear to be effective and safe in reducing proteinuria in patients with IgAN. CRD42024598157

Patients undergoing transcatheter aortic valve implantation (TAVI) often require long‐term oral anticoagulation (OAC), but it is unclear whether to continue or interrupt OAC during the procedure. This meta‐analysis compares clinical outcomes of continuing versus interrupting OAC during TAVI. PubMed, Embase, and Cochrane Central databases were searched from inception to September 2024 for studies comparing continuation versus interruption of OAC in patients undergoing TAVI with an indication for OAC, including vitamin K antagonists and direct oral anticoagulants. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a random‐effects model. Sensitivity analysis was performed using the Hartung‐Knapp‐Sidik‐Jonkman method. Three studies were included, one randomized controlled trial and two cohort studies, with 2773 patients, of whom 1314 (47.4%) continued OAC during TAVI. At a 30‐day follow‐up after TAVI, there were no significant differences between groups in all‐cause mortality (RR 0.74; 95% CI 0.45–1.20; p = 0.22), any bleeding (RR 1.08; 95% CI 0.81–1.43; p = 0.60), and major bleeding (RR 0.90; 95% CI 0.67–1.21; p = 0.48). However, the continued OAC group was associated with a lower stroke rate (RR 0.65; 95% CI 0.42–1.01; p = 0.053), also attested after a sensitivity analysis (RR 0.65; 95% CI 0.47–0.90; p < 0.03). In patients with an indication for OAC undergoing TAVI, uninterrupted anticoagulation is associated with similar thrombotic and hemorrhagic outcomes compared to interrupted OAC. Stroke risk was lower in the continued OAC group, with a significant reduction, as demonstrated in sensitivity analysis.

Background: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. BAFF (B-cell activating factor) and APRIL (A proliferation-inducing ligand) are cytokines involved in B-cell activation and survival, contributing to the pathogenesis of IgAN. This meta-analysis aimed to evaluate the efficacy, safety, and biomarkers of BAFF and APRIL-targeted therapies in patients with IgAN. Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered with PROSPERO (CRD42024598157). We searched PubMed, Scopus, and the Cochrane Library for randomized controlled trials (RCTs) comparing BAFF or APRIL-targeted drugs with placebo in adults with biopsy-confirmed IgAN. The efficacy outcomes were the mean percent change in the urine protein to creatinine ratio (UPCR) at 24 hours and the mean change in the estimated glomerular filtration rate (eGFR) from baseline. Safety included the incidence of adverse events. The biomarkers were changes in serum Gd-IgA1, IgG, IgA, and IgM from baseline. We used the R software version 4.2.1 for statistics. Results: Four phase II RCTs including 331 patients were included. Compared to placebo, treatment significantly reduced 24-hour UPCR (mean difference [MD] –38.94%; 95% confidence interval [CI] –58.98 to –18.90; p = 0.0001; I² = 0%) and significantly improved eGFR (MD 7.05 mL/min/1.73 m²; 95% CI 3.83 to 10.27; p<0.0001; I²=0%). The incidence of adverse events did not differ significantly in the treatment and placebo groups. The drug significantly decreased serum Gd-IgA1, IgG, IgA, and IgM compared to placebo. Conclusions BAFF and APRIL-targeted therapies effectively and safely reduce proteinuria in patients with IgAN.

Levetiracetam (LEV) and carbamazepine (CBZ) are effective monotherapies for focal epilepsy in children. However, the best drug remains controversial. Therefore, we performed a systematic review and meta-analysis comparing LEV and CBZ monotherapy in the management of pediatric focal epilepsy (PFE). We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCTs) published until February 2024 comparing LEV and CBZ monotherapy in PFE. Statistical analysis was performed using R version 4.2.2, heterogeneity was assessed using I² statistics, and the risk of bias was evaluated using the RoB-2 tool. Risk Ratios (RR) with p < 0.05 were considered significant. The outcomes of interest were seizure freedom, any adverse events, adverse events leading to treatment discontinuation, dermatologic adverse events, and the frequency of at least one seizure, defined as the proportion of patients experiencing one or more seizures during the treatment period. Four RCTs comprising 381 children with a mean age of 7.32 to 9.28 years were included, of whom 186 (48.8%) received LEV monotherapy. There was no significant difference between groups (RR: 1.15; 95% CI 0.88–1.50; p = 0.31; I² = 90%) regarding seizure freedom. The frequency of at least one seizure (RR: 0.71; 95% CI 0.52–0.97; p = 0.03; I² = 8%) and dermatologic adverse events (RR: 0.24; 95% CI 0.09–0.64; p < 0.01; I² = 0%) were both significantly lower in the LEV group. There were no significant differences in the presence of any adverse events (RR: 0.58; 95% CI 0.33–1.01; p = 0.05; I² = 36%) or adverse events leading to treatment discontinuation (RR: 0.67; 95% CI 0.13–3.42; p = 0.63; I² = 30%).Conclusion: In monotherapy, LEV was more advantageous than CBZ for PFE, with a lower frequency of seizures and fewer dermatological adverse events. However, both drugs are equally effective in achieving seizure freedom, adverse events without specification, and those that lead to treatment discontinuation. Our findings have important implications for clinical practice and decision-making in this condition. What is Known: • Both LEV and CBZ are effective monotherapies for pediatric focal epilepsy. • The use of LEV or CBZ monotherapy for the management of children with focal epilepsy remains controversial. What is New: • No significant differences were observed between the LEV and CBZ groups in terms of overall seizure freedom, safety, and tolerance. • However, LEV resulted in a lower frequency of at least one seizure and fewer dermatological adverse events than CBZ.

Introduction: In recent decades, an increase in the incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has been observed. Pediatric‐onset T2DM differs from the adult‐onset form, particularly regarding the durability of glycemic control and earlier appearance of complications. However, the scarcity of approved treatments and comprehensive studies on T2DM management in youth persists. Ongoing clinical trials seek to ascertain the efficacy and safety of sodium‐glucose cotransporter 2 inhibitors (SGLT2i) in patients aged between 10 and 24 years with T2DM. Therefore, we aimed to perform a meta‐analysis exploring the efficacy and safety of SGLT2i in pediatric patients and young adults with T2DM.Methods: We searched PubMed, Embase, Cochrane, and Web of Science for randomized controlled clinical trials on the efficacy and safety of SGLT2i in children, adolescents, and young adults with T2DM compared with placebo. Statistical analysis was performed using RevMan 5.4 and R statistical software 4.2.1. Heterogeneity was assessed with I² statistics.Results: We included three studies totaling 334 patients followed for 37.79 weeks. Reduction in HbA₁C (MD = −0.93; 95% CI = −1.36 to −0.49; p < 0.0001; I² = 0%) was significantly higher in SGLT2i group compared with placebo. The proportion of patients requiring rescue or discontinuation of study medication due to lack of efficacy was statistically lower in SGLT2i group compared with placebo (RR = 0.64; 95% CI = 0.43–0.94; p = 0.02; I² = 0%). SGLT2i and placebo were similar in terms of any adverse event (RR = 1.10; 95% CI = 0.96–1.27; p = 0.17; I² = 0%), serious side effects (RR = 1.06; 95% CI = 0.44–2.57; p = 0.90; I² = 0%), and individual adverse effects.Conclusion: In children, adolescents, and young adults with T2DM, SGLT2i appears to be effective and safe for glycemic control.