SGLT2-Inhibition in Patients With Alport Syndrome.

Introduction: Large-scale trials showed positive outcomes of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in adults with chronic kidney disease (CKD). Whether the use of SGLT2i is safe and effective in patients with the common hereditary CKD Alport syndrome (AS) has not yet been investigated specifically in larger cohorts.

Methods: This observational, multicenter, international study (NCT02378805) assessed 112 patients with AS after start of SGLT2i.

Challenging the narrative of alport syndrome spectrum: no link with cystic phenotype.

Background: Alport Syndromes (AS) are the second leading genetic cause of Kidney Failure (KF). Whether multiple kidney cysts (MKC) phenotype belongs to the AS spectrum remains debated.

Methods: This multicenter retrospective study focused on patients genotyped with pathogenic COL4A3, COL4A4, or COL4A5 variants (classified as ACMG-AMP 4 or 5) between January 2011 and January 2023 across four French university hospitals.

Ezetimibe Enhances Lipid Droplet and Mitochondria Contact Formation, Improving Fatty Acid Transfer and Reducing Lipotoxicity in Alport Syndrome Podocytes.

Mitochondrial dysfunction is a critical factor in the pathogenesis of Alport syndrome (AS), contributing to podocyte injury and disease progression. Ezetimibe, a lipid-lowering drug, is known to inhibit cholesterol and fatty acid uptake and to reduce triglyceride content in the kidney cortex of mice with AS. However, its effects on lipid droplet (LD) utilization by mitochondria have not been explored.

Characterization of the Ocular Phenotype in a Col4a3 Knockout Mouse Model of Alport Syndrome.

Purpose: Alport syndrome (AS) is a genetic condition caused by a dysfunctional collagen (IV) α3α4α5 heterotrimer, leading to basement membrane instability and, ultimately, abnormalities in the kidney, inner ear, and eyes. This study aimed to characterize ocular pathology of AS by focusing on inflammatory and fibrotic markers.

Methods: Col4a3tm1Dec knockout (KO) mice eyes were evaluated for the localization of collagen (IV) α3 and collagen (IV) α4, then stained for transforming growth factor-β1 (TGF-β1), TGF-β2, connective tissue growth factor (CTGF), and β-catenin.

Diagnosis, management and treatment of the Alport syndrome - 2024 guideline on behalf of ERKNet, ERA and ESPN.

Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome (AS) is the second commonest hereditary kidney disease characterized by persistent haematuria progressing to the need of kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies. Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children. As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney) and European Society for Paediatric Nephrology (ESPN) Working Group Hereditary Kidney Disorders, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists and a kidney pathologist were selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions.

Mitophagy Regulates Kidney Diseases.

Background: Mitophagy is a crucial process involved in maintaining cellular homeostasis by selectively eliminating damaged or surplus mitochondria. As the kidney is an organ with a high dynamic metabolic rate and abundant mitochondria, it is particularly crucial to control mitochondrial quality through mitophagy. Dysregulation of mitophagy has been associated with various renal diseases, including acute and chronic kidney diseases, and therefore a better understanding of the links between mitophagy and these diseases may present new opportunities for therapeutic interventions.

A Case Report of a Patient with COQ8B Nephropathy Manifesting Atypical Renal Pathological Changes.

Background: COQ8B nephropathy is a hereditary mitochondrial kidney disease. Most cases present with steroidresistant nephrotic syndrome and focal segmental glomerulosclerosis, whereas this patient exhibited asymptomatic isolated proteinuria and mild renal histopathology.

Methods: Appropriate laboratory tests, abdominal ultrasonography, renal biopsy, and whole exome sequencing were performed to explore the cause of the disease.

Alport syndrome and eye.

Alport syndrome, characterized by renal failure, hearing loss, and ocular abnormalities due to collagen type IV gene mutations, exhibits distinctive ocular manifestations in the various ocular tissues including the cornea, lens, and retina. Ophthalmological examinations, providing noninvasive visibility of basement membrane anomalies caused by collagen type IV mutations, can have a role in Alport syndrome diagnostics. Lenticonus, macular fleck, and other abnormalities also can serve as indicators of inheritance patterns and predictors of severe mutations or early-onset renal failure.

Genotype-First Analysis in an Unselected Health System-Based Population and Phenotypic Severity of COL4A5 Variants.

Background: Our knowledge of X-linked Alport Syndrome comes mostly from selected cohorts with more severe disease.

Methods: We examined the phenotypic spectrum of X-linked Alport Syndrome in males and females with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health records. Patients with COL4A5 variants reported as pathogenic or likely pathogenic in ClinVar, or protein-truncating variants, were each matched with up to 5 controls without COL4A3/4/5 variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter.

Synergistic toxicity of compound heterozygous mutations in the COL4A3 gene causes end-stage renal disease in A large family of Alport syndrome.

Alport syndrome (AS) is a genetic disorder characterized by kidney disease and hearing/vision abnormalities, resulting from mutations in the COL4A3, COL4A4, or COL4A5 genes. While numerous mutations have been identified in AS cases, the precise molecular mechanisms, particularly for compound mutations, remain under investigation. This study investigated the molecular mechanisms of AS in a proband with end-stage kidney disease (ESKD) using whole exome sequencing, which identified two compound heterozygous COL4A3 missense mutations: NM_000091.

Ocular Coherence Tomography Unveils Alport Syndrome: A Critical Tool in Detecting Collagen IV Nephropathies.

Collagen IV pathogenic variants are present in Alport syndrome (AS) and some forms of familial focal segmental glomerulosclerosis (FSGS). These conditions pose diagnostic challenges due to overlapping clinical, histological, and genetic features. Ocular coherence tomography (OCT) has emerged as a pivotal diagnostic tool by revealing ocular manifestations characteristic of AS.

Renal transplantation in Alport syndrome.

Kidney transplantation is recognized as an effective treatment for end-stage renal disease in Alport syndrome, demonstrating outcomes comparable to or even superior to those in other causes of renal failure. When considering living related donor kidney transplantation for Alport syndrome patients, it is crucial to consider genetic factors during the donor selection process. In addition to a comprehensive health check, genetic testing is strongly recommended for potential donors at risk of carrying mutations in COL4A3-COL4A5 before undergoing kidney transplantation.

Hearing loss phenotypes in Alport syndrome: experience in a tertiary referral center.

Background: Despite previous reports of auditory phenotypes in Alport syndrome (AS), there have been no studies specifically addressing audiological phenotypes in South Korea. Herein, we elaborated on the audiological characteristics associated with AS based on their genotypes.

Methods: We reviewed data from in-house AS patients between March 2014 and February 2023, excluding those without audiological documentation or genetic diagnoses.

Alport syndrome: Expanding diagnosis and treatment.

Alport syndrome (AS) is the second common monogenic cause of end-stage kidney disease (ESKD) worldwide and is caused by defective type 4 collagen due to pathogenic variants of COL4A3, COL4A4, or COL4A5. Type 4 collagen also exists in the eyes and ears, and thus ocular defects and hearing loss occur in AS. The understanding of AS has expanded over the past two decades due to greater availability of genetic testing and research on genotype-phenotype correlation.

Dyspnea and nocturnal cough due to esophageal diffuse leiomyomatosis in a girl with hematuria.

A 7-year-old girl with hematuria and clinical suspicion of Alport syndrome (AS) presented with dyspnea and nocturnal cough, initially diagnosed and treated as asthma. Despite inhaled corticosteroid therapy, her symptoms persisted, and spirometry indicated obstructive lung function without bronchodilator response. Chest CT revealed diffuse thickening of the esophageal wall, tracheal compression, with involvement of the gastric cardia, suggestive of diffuse leiomyomatosis.

[Genetics in nephrology - any news?].

While genetic kidney diseases were long regarded as a rare cause of kidney failure, it has been shown in recent years that they account for a relevant proportion of cases. In cohorts of kidney transplant recipients, a monogenic cause is found in up to 30% of cases. Identifying the genetic cause of kidney disease has become much easier thanks to technological advances in DNA sequencing.

Clinical and Genetic Characteristics of Patients with Peripheral Retinal Flecks in Koreans.

Purpose: To describe the clinical and genetic features of Korean patients with peripheral retinal flecks unrelated to aging.

Methods: A retrospective analysis was conducted on the clinical characteristics of patients with symmetric peripheral retinal flecks. Age-related deposits such as reticular pseudodrusen were excluded, as well as secondary deposits related to intraocular inflammation, tumor, and drug toxicity.