RARE DISEASE
Alport syndrome
Alport syndrome
Alport syndrome
Synonyms: Alport deafness-nephropathy, Alport hearing loss-nephropathy
Synonyms: Alport deafness-nephropathy, Alport hearing loss-nephropathy
Synonyms: Alport deafness-nephropathy, Alport hearing loss-nephropathy
Drug discovery
14
drugs
With orphan designations
Overview
Alport syndrome is a rare genetic disorder caused by mutations in COL4A3-5 genes, disrupting type IV collagen production. This leads to progressive glomerular basement membrane damage, resulting in hematuria, proteinuria, and eventual kidney failure. Extrarenal manifestations include sensorineural hearing loss (30–50%) and ocular abnormalities (e.g., anterior lenticonus). X-linked inheritance accounts for 80–85% of cases. Treatment focuses on RAAS blockade (ACE inhibitors/ARBs) to slow kidney disease progression, with dialysis or transplant required for end-stage renal disease [1][2][12].
Population
Prevalence: ~1 in 50,000 live births worldwide [4][16]; affects ~30,000–60,000 individuals in the U.S. [2][19].
Inheritance: X-linked (80–85%), autosomal recessive (15%), or dominant (rare) [12][16].
Severity: Males with X-linked form often develop ESRD by age 40; females typically have milder symptoms [12][16].
Burden
Clinical: ESRD in >90% of untreated X-linked males by mid-adulthood; hearing loss in 30–50%, ocular defects in ~30% [2][12][16].
Economic: Lifetime costs of dialysis/transplant; off-label drug use increases financial strain [3][5].
Psychosocial: Impacts quality of life due to multisystem involvement and hereditary transmission risks [5][18].
Therapies
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
594 drug discovery papers about Alport syndrome, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
594 drug discovery papers about Alport syndrome, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-04-09 | Umbilical cord-derived mesenchymal stem cells restore renal homeostasis in Alport Syndrome: Mechanistic insights and clinical translation.
X-linked Alport syndrome (AS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene, leading to end-stage renal disease in young adults. Current treatments are palliative with limited efficacy, highlighting a critical unmet medical need. This study aims to evaluate the therapeutic feasibility of mesenchymal stem cells (MSCs) for alleviating renal dysfunction in AS, and to investigate whether their therapeutic benefits are primarily mediated by extracellular vesicles (EVs). Our integrated translational research strategy encompassed preclinical and clinical investigations. In the Col4a5-deficient AS mouse model, animals received intravenous MSCs or EVs. Engrafted cells and EVs were tracked in vivo. Renal function was detected by albuminuria level, and lifespan was assessed by survival time. Therapeutic outcomes were rigorously assessed by measuring albuminuria, survival time, and comprehensive histological analyses, including tissue staining for pathology, transmission electron microscopy for ultrastructure, and specific markers for inflammation and fibrosis. Building on compelling preclinical efficacy and safety data, we initiated a first-in-human, open-label clinical trial (ISRCTN62094626) in pediatric AS patients. Patients received four infusions and were follow-up for over 12 months. Safety was evaluated by recording adverse events (AEs). Efficacy was assessed by renal function parameters. To determine the molecular mechanisms, multi-omics analysis of serial bio-samples was conducted, followed by in vitro validation to confirm the role of miR-146a-5p in mediating the therapeutic benefits of MSC-based strategy. In the AS mice, MSC treatment exhibited significant reno-protective potentials, markedly reducing albuminuria (p < 0.001), and extended lifespan (37.7 ± 2.8 weeks vs 28.8 ± 4.0 weeks, p < 0.001), along with alleviated renal inflammatory infiltration and fibrosis (p < 0.01), which were closely associated with macrophage modulation. Crucially, EVs recapitulated these therapeutic benefits, indicating EVs as primary mechanistic effectors. The subsequent clinical trial yielded promising preliminary results. The first pediatric patient exhibited a significant downward trend in albuminuria (Log-rank test p < 0.0001) with no treatment-related AEs throughout the 12-month follow-up. Multi-omics profiling revealed that MSCs likely attenuate pathology through a multi-level network targeting inflammation and fibrosis. Furthermore, in vitro studies confirmed the critical role of EV-enriched miR-146a-5p in modulating macrophage polarization, showing significant inhibition of IL-1β, TNF-α, and NF-κB (p < 0.05). This proof-of-concept study provides novel evidence bridging robust preclinical findings with initial human data, underscoring the therapeutic feasibility of MSC-based therapy for AS, with mechanistic studies revealing that MSC-EV-enriched miR-146a-5p plays a partial but critical role by modulating macrophage polarization toward an anti-inflammatory phenotype.
2025-07-31 | Successful management of a giant macular hole in Alport syndrome using autologous retinal translation as an initial procedure.
Alport Syndrome is a complex systemic disorder that interferes with collagen type IV synthesis and presents with a variety of ocular symptoms. Management of complications arising out of it is challenging. This article depicts a unique case of Alport Syndrome with rare ocular features and successful management of it. A 30-year female with known Alport syndrome presented with Bilateral anterior lenticonus and unilateral giant macular hole(1791µm) in OD. She underwent simultaneous cataract extraction along with macular hole surgery in right eye. Intraoperatively Internal Limiting membrane was not found with dye staining. The full-thickness macular hole was successfully closed with an autologous retinal graft. On follow-up, the graft was found in situ covering the defect until her last follow-up even after 6 months and her BCVA in OD improved to 20/40. This article discusses in detail the successful management of a giant macular hole in a patient with Alport Syndrome, using a primary Retinal graft as an initial procedure.
2024-11-19 | 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. Individuals carrying these mutations face an inherent risk of kidney disease and due to the possibility of further deterioration in renal function after nephrectomy for transplantation, they are not suitable as priority donors. Posttransplant anti-glomerular basement membrane nephritis is rare but can lead to graft loss, especially in males with X-linked Alport syndrome.
2024-04-01 | Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome
Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFβ1 and using allogenic bone marrow-derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.
2024-03-01 | Human umbilical cord mesenchymal stem cell therapy for renal dysfunction in Alport syndrome: protocol for an open-label, single-arm trial in China
Introduction Alport syndrome (AS) is one of the most common fatal hereditary renal diseases in human, with a high risk of progressing to end-stage renal disease without effective treatments. Mesenchymal stem cells (MSCs) have recently emerged as a promising therapeutic strategy for chronic kidney disease. However, the safety and therapeutic potential of MSC transfusion for patients with AS are still need to be confirmed. Therefore, we have designed a clinical trial to evaluate the hypothesis that intravenous infusion of human umbilical cord-derived MSC (hUC-MSC) is safe, feasible, and well-tolerated in children with AS. Methods and analysis We report the protocol of the first prospective, open-label, single-arm clinical trial to evaluate the safety and preliminary efficacy of hUC-MSC transfusion in children with early-stage AS. Paediatric patients diagnosed with AS who have persistent albuminuria will be candidates for screening. Twelve eligible patients are planned to recruit and will receive hUC-MSC infusions under close safety monitoring, and complete the efficacy assessments at scheduled follow-up visits. The primary endpoints include the occurrence of adverse events to assess safety and the albuminuria level for efficacy evaluation. Secondary endpoint assessments are based on haematuria and glomerular filtration measurements. Each patient’s efficacy endpoints will be evaluated against their baseline levels. Additionally, the underlying mechanism of hUC-MSC therapy will be explored through transcriptomic and proteomic analysis of blood and urine samples. Ethics and dissemination The protocol (V.1.0, date 17 January 2015) was approved by the institutional review board of the Affiliated Taihe Hospital of Hubei University of Medicine (ethical approval 03 March 2015). Written informed consent will be obtained from the patient and/or guardians before study specific process. In addition to publication in a peer-reviewed scientific journal, a lay summary of study will be available for participants and the public on the Chinese Organization for Rare Disorders website ( http://www.cord.org.cn/ ). Trial registration number ISRCTN62094626 .
small molecules
2026-09-03 | Finerenone Added to Renin-Angiotensin System- and Sodium-Glucose Cotransporter 2 Inhibition in Patients with Alport Syndrome: A Two-Center Case Series.
Alport syndrome is a common hereditary glomerular kidney disease characterized by a high risk of kidney failure. Despite renin-angiotensin system- (RASi) and SGLT2 inhibitors (SGLT2i), a subset of patients experience rapid decline in kidney function. Preclinical data in Alport mice suggest that the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone could provide additional nephroprotection. This case series evaluates the changes in albuminuria and the safety of finerenone as part of a triple-therapy regimen in individuals with Alport syndrome. In this retrospective, two-center observational case series, ten male individuals with Alport syndrome received finerenone (10 mg/day) in addition to baseline-therapy with RASi (100%) and SGLT2i (90%). Clinical parameters - including estimated glomerular filtration rate (eGFR), albuminuria, and serum potassium were analyzed over a mean follow-up period of 9 ± 5 months. Median albuminuria showed a non-significant decrease of 33% during follow-up, from 3506 [IQR 1645-4304] to 2346 [1858-2792] mg/g creatinine (p = 0.21). Median eGFR declined from 50 [47-112] to 43 [32-116] mL/min/1.73m2 (p = 0.03) and continued to decline in a subgroup of five individuals, who were followed for 12 months. Hyperkalemia occurred in half of the individuals, necessitating the use of potassium binders in two cases. Finerenone was discontinued in two individuals due to rapid decline of eGFR. No serious adverse events were observed. This real-world case series provides preliminary evidence that adding finerenone to baseline therapy with RASi and SGLT2i is feasible and may offer additional albuminuria reduction in Alport syndrome. However, the notable eGFR decline and the relevant incidence of hyperkalemia underscore the necessity for vigilant clinical monitoring. While multimodal nephroprotection remains a promising tool to delay disease progression, these real-world observations provide pilot data to inform the design of future large-scale prospective trials in patients with Alport syndrome.
2026-08-01 | Alport syndrome in children: bridging genetic insights to clinical management—a narrative review
Background and Objective: Alport syndrome is a hereditary disorder of type IV collagen that commonly presents in childhood with persistent hematuria and carries a lifelong risk of progressive kidney disease and extrarenal complications. Despite advances in genetic diagnostics, important gaps remain in early risk stratification, variant interpretation, and recognition of expanding phenotypes. This narrative review aims to synthesize current evidence on the genetic architecture, clinical spectrum, and management of pediatric Alport syndrome, with a focus on early diagnosis and disease-modifying interventions.Methods: A targeted literature search was conducted using PubMed/MEDLINE to identify English-language human studies published between January 2000 and September 2025. Search terms included “Alport syndrome”, “COL4A3”, “COL4A4”, “COL4A5”, “type IV collagen”, and related clinical and genetic keywords, combined using Boolean operators. Relevant cohort studies, clinical trials, systematic reviews, and consensus guidelines were prioritized, and reference lists of key articles were manually reviewed. Findings were synthesized using a narrative approach.Key Content and Findings: Alport syndrome demonstrates substantial genetic and phenotypic heterogeneity, with X-linked (XL), autosomal recessive (AR), autosomal dominant (AD), and digenic forms contributing to a broader disease spectrum than previously recognized. Genotype-phenotype correlations, particularly variant type and gene involvement, are critical determinants of disease severity and progression. Early initiation of renin-angiotensin-aldosterone system (RAAS) blockade, especially in genetically confirmed cases, has been shown to delay progression to kidney failure. Advances in next-generation sequencing have improved diagnostic yield but introduced challenges in variant interpretation, including variants of uncertain significance (VUS). Emerging phenotypes, such as cystic kidney disease, further expand the clinical spectrum and have implications for differential diagnosis and genetic counseling.Conclusions: A genetics-first approach is central to the management of pediatric Alport syndrome, enabling early diagnosis, risk stratification, and timely initiation of therapy. Integration of genetic findings with clinical features is essential for individualized care. Recognition of evolving phenotypes and ongoing advances in targeted therapies highlight the need for pediatric-specific research to optimize outcomes and refine precision medicine strategies.
2026-07-02 | Patient-derived human induced pluripotent stem cell podocytes uncover endoplasmic reticulum and oxidative stress-mediated dysfunction in X-linked Alport syndrome.
X-linked Alport syndrome (XLAS) is an inherited nephropathy caused by pathogenic COL4A5 variants that lead to podocyte dysfunction and progressive kidney failure. However, the involvement of endoplasmic reticulum (ER) stress and oxidative stress in the development of XLAS remains insufficiently understood. This study aims to elucidate the contribution of ER and oxidative stress to podocyte injury in XLAS employing a patient-derived human induced pluripotent stem cell (hiPSC)-based podocyte model. Induced pluripotent stem cells were derived from XLAS patient blood cells and differentiated into podocytes (XLAS podocyte). Expression of pluripotency, lineage-specific, and podocyte markers was confirmed. ER stress, oxidative stress, and mitochondrial morphology were assessed through molecular characterization, imaging, and functional assays, comparing XLAS podocytes to wild-type (WT) hiPSC-derived podocytes. XLAS patient-derived hiPSCs maintained typical pluripotency markers, exhibited normal karyotypes, and allowed for successful tri-lineage differentiation. Relative to WT podocytes, XLAS podocytes had diminished expression of NPHS1, WT1, and COL4A5, while COL4A1 was increased. ER stress marker expression was elevated, with lower levels of CANX and CALR, indicative of unfolded protein response (UPR) activation. Electron microscopy analysis demonstrated enhanced ER enlargement in XLAS podocyte, implicating ER stress in disease pathogenesis. Moreover, XLAS podocytes showed markedly raised oxidative stress markers and mitochondrial reactive oxygen species (ROS) levels, together with altered catalase protein expression. Viability assays further supported ER and oxidative stress as contributors to reduced podocyte survival in XLAS podocyte. Our findings indicate that ER stress and oxidative stress are critical drivers of podocyte dysfunction in XLAS. UPR activation, ROS accrual, and mitochondrial impairment point to important therapeutic opportunities.
2026-06-19 | Clinical practice recommendations for the management of Alport syndrome: a joint statement of the Korean Society of Nephrology and the Korean Society of Pediatric Nephrology.
Alport syndrome (AS) is a hereditary kidney disorder characterized by progressive hematuria, proteinuria, and kidney failure, frequently accompanied by hearing loss and ocular abnormalities. Although blockade of the renin-angiotensin system (RAS) is established as the first-line therapy, additional pharmacological interventions have been explored. To formulate evidence-based recommendations tailored to the Korean healthcare setting, the Genetic Kidney Disease Study Group of the Korean Society of Nephrology conducted a systematic review evaluating four therapeutic strategies: RAS blockade, cyclosporine, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i). The quality of evidence and strength of recommendations were assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. The review confirmed that early initiation of RAS blockade delays progression to kidney failure and improves long-term survival, with the greatest benefit when initiated at the stage of microscopic hematuria or microalbuminuria. In contrast, evidence supporting cyclosporine , MRAs, and SGLT2i remains limited, primarily derived from small observational studies with short follow-up and heterogeneous populations. Although cyclosporine and MRAs have demonstrated short-term reductions in proteinuria, neither has shown sustained renoprotective effects, and cyclosporine is associated with a substantial risk of nephrotoxicity. Evidence regarding SGLT2i is inconsistent, with insufficient data on long-term efficacy in AS. Accordingly, these guidelines strongly recommend early RAS blockade as the cornerstone of AS, while no recommendations are made for routine use of cyclosporine, MRAs, or SGLT2i. Well-designed clinical trials are needed to expand therapeutic options and improve long-term outcomes in AS.
2026-05-15 | Albuminuria drives hyperlipidemia in patients with Alport syndrome.
Hypercholesterolemia is a major driver of cardiovascular disease, a leading cause of premature mortality in patients with chronic kidney disease (CKD). Despite their typically young age, patients with Alport syndrome (AS), the second most prevalent genetic cause of CKD, may face a disproportionately high risk of hypercholesterolemia. This study investigates whether increased albuminuria precipitates hyperlipidemia in this population to a degree comparable with general CKD cohorts, while further delineating the risk factors underlying this development. This was a multicenter, observational, non-interventional, and retrospective study. Among 459 patients with AS, 59.3% had hypercholesterolemia and 58.5% had elevated low-density lipoprotein cholesterol (LDL-C). Despite lower eGFR and higher albuminuria, patients with lipid-lowering therapy (LLT) had significantly lower total cholesterol levels compared to the untreated patients (193.6 ± 55.2 mg/dL vs. 208.2 ± 51.0 mg/dL; p = 0.044). Similarly, LDL-C levels were significantly lower in the treatment group (111.6 ± 51 mg/dL, n = 59) compared to the untreated group (124.3 ± 40.2 mg/dL, n = 238; p = 0.041). Multivariable regression analysis adjusted for age, gender, BMI, eGFR, and LLT revealed that albuminuria was a significant independent determinant of total cholesterol (β=0.315; p < 0.001) and LDL-C levels (β=0.242; p < 0.001). Male gender was associated with significantly higher LDL-C and lower HDL-C levels. Conversely, eGFR and BMI were not significant predictors of cholesterol levels. This association was also observed in the pediatric cohort (n = 44), where albuminuria was the only independent predictor of cholesterol (β=0.728; p < 0.001). Hypercholesterolemia is highly prevalent in young patients with AS and is primarily driven by the severity of albuminuria, rather than other risk factors such as obesity or eGFR decline. These findings highlight a critical gap in current guidelines, support the implementation of early lipid screening and suggest that risk-adapted management may be necessary to prevent long-term cardiovascular complications.
gene therapies
2026-05-29 | Capsid Engineering of Adeno-Associated Viruses for Targeted Gene Therapy in Kidney Diseases.
The global burden of chronic and genetic kidney diseases poses a significant challenge to healthcare systems. Current therapies, including dialysis, transplantation, and supportive pharmacotherapies, cannot halt disease progression or address root causes, especially in monogenic disorders like Alport syndrome and Fabry disease. Adeno-associated virus (AAV)-based gene therapy is promising, enabling targeted correction of underlying genetic defects. However, renal delivery faces challenges, including cellular heterogeneity, anatomical barriers, and pre-existing immunity. This review evaluates advances in AAV capsid engineering to overcome these obstacles, focusing on strategies to enhance kidney-specific tropism, transduction efficiency, and immune evasion. We outline the evolution from conventional serotype selection to precision engineering via rational design, directed evolution, and in silico approaches. Artificial intelligence (AI) has emerged as a pivotal accelerator, with machine learning models and generative frameworks enabling data-efficient capsid optimization despite limited datasets. Multimodal AI, reinforcement learning, and agentic systems can refine renal targeting by balancing glomerular penetration, cell specificity, and safety. Future progress relies on scaling high-quality datasets through collaborative consortia, lab-in-the-loop validation, and explainable AI. By combining capsid engineering with renal pathophysiology insights, this roadmap paves the way for curative AAV therapies that move beyond current suboptimal treatments to correct underlying pathogenic mechanisms.
2026-05-28 | Alport syndrome: a genetically confirmed x-linked case with early family screening.
Alport syndrome (AS) is an inherited disorder of the glomerular basement membrane (GBM) resulting from pathogenic variants in the COL4A3, COL4A4, or COL4A5 genes, which encode the α3, α4, and α5 chains of type IV collagen, the main structural component of the GBM, cochlea, and lens capsule.Defects in this collagen network lead to progressive renal insufficiency, hearing impairment, and characteristic ocular lesions such as anterior lenticonus and retinal flecks.(1).AS affects approximately 1 in 50 000 live births.The disease is classically inherited in an X-linked pattern (85%), followed by autosomal recessive (15%) and autosomal dominant (< 1%) forms.The severity and age at onset vary depending on the mutation type and zygosity, with males with truncating COL4A5 variants typically progressing faster to end-stage kidney disease (ESKD).( 2 )
2026-04-25 | Disheveled associated activator of morphogenesis 2 variants may produce alport-like changes: a case report.
DAAM2 is an important formin, which plays an important role in the polymerization of monomeric actin into linear filaments. Previous studies have suggested that the DAAM2 variant mainly causes congenital Nephrotic Syndrome Type 24 (NPHS24), which is characterized by focal segmental glomerulosclerosis and steroid resistant nephrotic syndrome. We report a case of a young man diagnosed with IgA nephropathy by renal biopsy. Specifically, in addition to IgA nephropathy, this patient also had diffuse thinning of GBM, reduced segmental expression of type IV collagen α3 in the glomerulus, and binocular keratoconus which is consistent with features of Alport syndrome. However, whole exon sequencing eliminated the common variation in the type IV collagen-encoding gene and revealed a homozygous mutation in the formin homology 2 (FH2) domain of DAAM2, the core domain responsible for actin polymerization. In conclusion, our case suggests that the spectrum of DAAM2-associated nephropathies might be broader than previously recognized. We propose the novel hypothesis that mutations in the FH2 domain of DAAM2 could predispose to an Alport-like phenotype, potentially through cytoskeletal dysregulation affecting glomerular basement membrane (GBM) integrity. This expands the potential clinical heterogeneity linked to DAAM2 and warrants further investigation.
2026-04-20 | Phenotype of autosomal dominant Alport syndrome with a likely pathogenic heterozygous variant in the COL4A3 gene (Gly366Arg) and incidental teratozoospermia: A case report.
Autosomal dominant Alport syndrome (ADAS) is the least common form of Alport syndrome, the second most common monogenic cause of chronic kidney disease after autosomal dominant polycystic kidney disease. We report a 14-year follow-up of a patient with ADAS carrying a likely pathogenic heterozygous variant in COL4A3 (Gly366Arg substitution). The disease initially presented with microhematuria and no renal impairment on analysis or ultrasound. The patient progressively developed bilateral renal cysts and renal failure -a classic renal pattern of the syndrome- and bilateral hearing loss. Incidentally, infertility study (had not children) showed teratozoospermia and elevated levels of luteinizing hormone and progesterone, hormones associated with spermatogenesis. Long-term follow-up of rare variants of Alport syndrome helps refine genotype-phenotype correlations and disease progression. The incidental finding of teratozoospermia raises the possibility of an etiological association, that warrants further investigation as a3(IV) collagen chains involved in spermatogenesis are present in seminiferous tubules.
2026-03-19 | Update on Alport Syndrome: The Report of the 2024 International Workshop on Alport Syndrome.
The 2024 International Workshop on Alport syndrome brought together people living with Alport Syndrome, clinicians, laboratory scientists, and representatives of pharmaceutical companies to present recent data and discuss issues to advance understanding of this inherited condition. The workshop focused on diagnosis and management of Alport syndrome, with particular attention on genetic variant curation, and treatment strategies across the diverse spectrum of Alport syndrome phenotypes, from hematuria to early kidney failure, with or without hearing loss and eye abnormalities. Advances in genetic testing, especially for non-European populations, were discussed alongside challenges in variant interpretation and misclassification. Novel treatment approaches, including gene therapy, and ongoing trials of medications such as sodium-glucose cotransporter 2 inhibitors and endothelin receptor antagonists, offer hope for prolonging kidney function. Collaboration between high- and low-to-middle-income countries was highlighted, addressing disparities in diagnostic capabilities. In addition, the role of patient advocacy and the need for education in nephrology were emphasized. With ongoing research, Alport syndrome is moving closer to being not only actionable but highly treatable through the prevention of kidney failure.
proteins
2026-02-12 | Protective role of early Tnfsf15 upregulation in limiting glomerular injury and proteinuria in experimental Alport Syndrome.
Alport syndrome is a progressive kidney disease caused by pathogenic variants in genes encoding type IV collagen, a major structural component of the glomerular basement membrane (GBM). Abnormal GBM architecture impairs filtration and triggers inflammation, fibrosis, and eventual kidney failure. Because disease progression is irreversible, identifying early molecular changes is essential for understanding disease onset. We performed glomerular single-cell RNA sequencing (scRNA-seq) in a Col4a5 G5X Alport mouse model at 5 weeks of age, prior to detectable proteinuria or GBM/podocyte abnormalities (pre-onset), and at 8 weeks, when mild proteinuria and structural defects emerged. Despite the early stage, scRNA-seq revealed widespread transcriptional alterations, most prominently in podocytes. Among genes upregulated at both time points, we identified Tumor Necrosis Factor Superfamily Member 15 (Tnfsf15), previously associated with kidney disease susceptibility but with unclear function. To determine its role in Alport syndrome, we generated Tnfsf15-deficient Alport mice. Tnfsf15 homozygous knockout mice exhibited increased proteinuria and exacerbated glomerular injury compared with Tnfsf15(+/+) Alport mice during early disease. These findings support a protective role for Tnfsf15 in the early stages of Alport syndrome, mitigating proteinuria and limiting glomerular injury.
2025-10-01 | #2398 Exogenous a-Klotho supplementation significantly prolongs survival in a mouse model of alport syndrome, with comparable outcomes to RASi
Abstract Background and Aims Chronic kidney disease (CKD) affects over 10% of the global population and has become a leading cause of mortality in recent decades. Numerous studies have explored novel drugs aimed at slowing CKD progression. Among these, α-Klotho has emerged as a protein with many kidney-specific anti-aging properties. Produced by renal tubular cells, α-Klotho has been shown to prevent fibrosis and reduce tissue inflammation. However, its production diminishes in advanced CKD stages due to chronic and irreversible kidney damage, limiting attempts to stimulate endogenous synthesis. Despite its recognized benefits for kidney health, studies evaluating long-term exogenous α-Klotho supplementation are lacking. In this context, we hypothesized that prolonged α-Klotho administration would enhance mean survival in a mouse model of CKD. Method We conducted a preclinical study involving Col4a3-deficient mice, which spontaneously develop progressive CKD. Mice were equally divided into three groups: (a) control group (vehicle), (b) RASi treatment (ramipril mixed with food at 10 mg/kg), and (c) α-Klotho treatment (daily subcutaneous injections at 10 µg/kg/day). Both treatments started at six weeks of age and continued for eight weeks, unless termination criteria were met before. The primary endpoint was mean overall lifespan. Baseline histological analysis was performed, and additional analyses after 2.5 weeks of treatment will be conducted to further validate the drug's effects. Results Baseline characteristics were comparable across the three groups. Mean survival was as follows: 62.9 ± 7.3 days in the control group, 77.3 ± 5.3 days in the RASi group, and 73.6 ± 7.7 days in the α-Klotho group. Both treatments significantly extended lifespan (RASi: R = 0.71, P < 0.001; α-Klotho: R = 0.62, P < 0.001). Notably, α-Klotho was not inferior to RASi in slowing CKD progression (P = 0.426) (Fig. 1). Kaplan–Meier analyses stratified by sex revealed no significant differences (α-Klotho: R = 0.19, P = 0.53) (Fig. 2a). Both treatment groups experienced gradual body weight loss over time, with no significant differences between them (P = 0.769) (Fig. 2b). Tissue analysis at six weeks confirmed advanced disease at treatment initiation, as evidenced by significant chronic lesions. Despite this, CKD progression was effectively monitored through weekly urine sample visual analyses, which reflected a progressive decline in urine concentration capacity. This served as a surrogate for kidney function, given that GFR measurements were not feasible in our delicate CKD model (Fig. 2c). Conclusion Our findings demonstrate that exogenous α-Klotho supplementation, even when initiated during late-stage CKD, significantly extends renal lifespan and improves overall survival. Despite being tested on small-sized groups, the effect of α-Klotho was comparable to that of ramipril over an extended experimental period, without significant adverse effects. These results underscore the urgent need for randomized clinical trials in humans. Future research should explore the potential synergistic benefits of combining α-Klotho with existing approved therapies to enhance CKD management.
2025-10-01 | Early Variable Gene of Alport Syndrome, Tnfsf15, Is a Protective Factor and Effect Modifier Against Renal Pathology
Background: Alport syndrome (AS) is a genetic disease of progressive glomerulonephritis caused by a mutation in type IV collagen. The progression of AS is irreversible, and it is important to control the progression of the disease by early therapeutic intervention. To know the early molecular changes, we performed single-cell RNA-seq (scRNA-seq) analysis in 5-week-old pre-proteinuric Col4a5 G5X AS mice and 8-week-old AS mice at the early stage of the disease. Methods: Glomeruli from 5- and 8-week-old AS mice were collected using Dynabeads, processed for glomerular single cells, and sequenced. The scRNA-seq analysis revealed an early variable gene, Tnfsf15. To determine its function, we generated Tnfsf15 knockout (KO) AS mice and evaluated renal pathology. Results: Glomerular scRNA-seq analysis revealed a marked change in podocyte gene expression. In particular, we focused on Tnfsf15, a gene whose expression was markedly increased at 5 and 8 weeks. The function of Tnfsf15 in AS is unclear, although it has been reported to be clinically associated with susceptibility to renal disease. Tnfsf15 KO AS mice had increased proteinuria, BUN, plasma creatinine, and decreased renal function compared to AS control. Glomerulosclerosis was exacerbated in Tnfsf15 KO AS mice. Some inflammation-related genes were up-regulated, but renal damage markers and fibrosis-related genes were unaltered in Tnfsf15 KO AS mice. In Tnfsf15 heterozygous AS mice, proteinuria and glomerulosclerosis were unchanged. However, Tnfsf15 expression significantly correlated with the genes related to renal injury, inflammation, and fibrosis, and the positive correlation slope was higher than the AS control. This suggests that Tnfsf15 is a modifier that affects the gene expression of pathology-related genes in Tnfsf15 heterozygous AS mice. Conclusion: Tnfsf15, a podocyte-specific upregulated gene identified by scRNA-seq analysis, is suggested to be a protective factor and effect modifier of AS pathology.
2025-10-01 | ADAMTS13 Protects Kidney Function in Alport Syndrome
Background: Alport syndrome (AS) is a hereditary form of CKD caused by mutations in type IV collagen genes, leading to progressive renal failure. Despite advances in understanding its genetic basis, effective treatments to slow disease progression remain limited. Our research has shown that glomerular endothelial cells (GECs) are among the first to be damaged in AS and intravital imaging studies revealed that glomerular capillaries in AS mice are affected by microthrombi formations. We have previously shown that ADAMTS13, an enzyme responsible for cleaving von Willebrand factor (VWF) is consistently downregulated in human kidney biopsies affected by AS. This study investigates if disrupted fatty acid metabolism drives the downregulation of ADAMTS13, and whether ADAMTS13 administration in AS mice can protect glomerular microvasculature and slow down disease progression. Methods: In vitro, silencing experiments on primary human GEC were performed to study the role of fatty acid metabolism on ADAMTS13 expression. In vivo, Col4a5-KO Alport mice were treated with bi-weekly administration of recombinant ADAMTS13 protein and kidney function was assessed. Results: We established that glomerular ADAMTS13 expression is downregulated in Col4a5-KO Alport mice with moderate disease. Our analysis revealed that suppression of fatty acid synthesis downregulates ADAMTS13 expression in GECs. Knockdown of ADAMTS13 in GECs led to endothelial dysfunction, indicated by increased levels of the adhesion molecules VCAM-1 and ICAM-1. Notably, therapeutic administration of ADAMTS13 in Alport mice resulted in significant improvement in proteinuria. Conclusion: Our findings reveal that endothelial metabolic dysfunction and ADAMTS13 downregulation contribute to microvascular injury and endothelial dysfunction in AS. These results suggest that ADAMTS13 restoration may serve as a promising therapeutic strategy to preserve endothelial function and slow CKD progression in AS, and potentially other forms of CKD. Funding: NIDDK Support, Other U.S. Government Support, Private Foundation Support
2025-09-12 | Treatment Approaches for Alport Syndrome.
Alport syndrome is a progressive, hereditary disorder of basement membranes caused by variants in genes encoding the α 3, α 4, or α 5 chains of type IV collagen ( COL4A3, COL4A4 , and COL4A5 ) leading to glomerulopathy, kidney failure, hearing loss, and eye abnormalities. The absence or dysfunction of the α 3- α 4- α 5 (IV) heterotrimer triggers multiple compensatory and detrimental pathways within all layers of the glomerular filtration barrier. Developing a therapeutic strategy for patients with Alport syndrome depends on understanding these mechanisms of disease progression that are predominant at different times throughout the disease course. These strategies may include reconstitution of the α 3- α 4- α 5 (IV) network in the glomerular basement membrane, reducing biomechanical strain and glomerular hyperfiltration, chaperone therapy, blocking aberrant signaling between the glomerular basement membrane and podocytes, reducing endothelial cell injury, reducing inflammation, and blocking fibrosis pathways.
other
2026-09-11 | Alirocumab as add‑on to the therapy of an adolescent with heterozygous familial hypercholesterolemia, early‑onset carotid atherosclerosis, and Alport syndrome: A clinical observation
This article presents a clinical observation of a 17-year-old adolescent with genetically confirmed heterozygous familial hypercholesterolemia (HeFH), early-onset carotid atherosclerosis (ECAS), and concomitant Alport syndrome (AS). This patient with a strong family history of premature fatal myocardial infarction demonstrated significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) up to 6.73 mmol/L at baseline. Molecular genetic testing confirmed the presence of an HeFH-causing variant in the LDLR gene. In addition, it identified a hereditary nephritis/AS-associated variant in the COL4A3 gene. Brachiocephalic artery ultrasound revealed early atherosclerotic changes in the carotid arteries. Despite a combination therapy of rosuvastatin (10 mg/day) and ezetimibe (10 mg/day), LDL-C levels remained above goal and were 3.3 mmol/L. Given the genetically confirmed FH, early-onset vascular lesions, elevated lipoprotein(a) levels, burdened family history, and concomitant AS, we decided to intensify lipid-lowering treatment without further increase of rosuvastatin dosing. The treatment regimen was modified by adding alirocumab. The patient showed a reduction of LDL-C levels to 0.88–1.18 mmol/L with alirocumab 150 mg once every 2 weeks as part of combination therapy. No adverse events were reported; creatinine, transaminase, and creatine phosphokinase levels were within acceptable limits. This observation showed the potential for an individual choice of lipid-lowering treatment in an adolescent with high-risk FH and concomitant hereditary nephropathy.
2026-02-02 | Immune-Negative Focal Segmental Nephrotic Syndrome Disclosing a Novel Mutation of Autosomal Dominant Alport’s in a Female
Background: Alport syndrome (AS) is a rare genetic disease characterized by progressive renal failure due to glomerulopathy, variable high-frequency sensorineural deafness, and variable ocular anomalies. The case: A 33-year-old woman was referred for evaluation of progressive lower limb oedema for 2 weeks following 1 week after receiving the second dose of the Oxford–AstraZeneca COVID19 vaccine. She had hypertension, hematuria, and nephrotic syndrome with serum albumin at 19 g/L and 6 g/day proteinuria. Her parents did not have renal disease. She had no clinical, laboratory, radiological, or serological evidence of autoimmune disease or infections. Kidney biopsy showed focal and segmental glomerulosclerosis with negative immunostains, yet electron microscopy showed a basket-weave appearance of the glomerular basement membrane. Genetic testing disclosed an autosomal pattern with a novel pathogenic mutation in COL4A3 c.3829G>A p.(Gly1277Ser), and COL4A5 had a c.4436C>T sequence change, replacing alanine with valine at codon 1479 protein (p.Ala1479Val). She did not respond to 2 months of therapy with diet, Losartan, and diuretics (Furosemide and Spironolactone). Since acute nephrotic state was present, Mycophenolate mofetil and Tacrolimus were selected for treatment. By 1 month later, her proteinuria decreased to 1.9 g/day, and serum albumin increased to 34 g/L. By 5 months (3 months after Mycophenolate mofetil and Tacrolimus therapy), proteinuria reached 870 mg/day and serum albumin reached 39 g/L. Hence, these were replaced by yearly Rituximab infusions. Up to 2 years of follow-up, the patient remained clinically stable and with normal serum creatinine, albumin, and proteinuria at 530 mg/day. Conclusion: A new-onset and novel mutation of AS can present with nephrotic syndrome after a trigger that was amenable to immunosuppressive therapy. The genetic disorder may not be cured, yet autoimmunity may have a role in its acute flares in certain phenotypes.
2025-12-18 | Splice modulation of COL4A5 reinstates collagen IV assembly in an organoid model of Alport syndrome.
Kidney organoids are an emerging tool for disease modeling, especially genetic diseases. Among these diseases, X-linked Alport syndrome (XLAS) is a hematuric nephropathy affecting the glomerular basement membrane (GBM) secondary to pathogenic variations in the COL4A5 gene encoding the α5 subunit of type IV collagen [α5(IV)]. In patients carrying pathogenic variations affecting splicing, the use of antisense oligonucleotides (ASOs) offers immense therapeutic hope. In this study, we develop a framework combining the use of patient-derived cells and kidney organoids to provide evidence of the therapeutic efficacy of ASOs in XLAS patients. Using multiomics analysis, we describe the development of GBM in WT and mutated human kidney organoids. We show that GBM maturation is a dynamic process, which requires long organoid culture. Then, using semi-automated quantification of α5(IV) at basement membranes in organoids carrying the splicing variants identified in patients, we demonstrate the efficacy of ASO treatment for α5(IV) restoration. These data contribute to our understanding of the development of GBM in kidney organoids and pave the way for a therapeutic screening platform for patients.
2025-11-26 | Podocyte specific exon skipping after disease onset improves kidney pathology and function in a mouse model of Alport syndrome.
Alport syndrome (AS) is a hereditary kidney disorder caused by mutations in COL4A3, COL4A4, and COL4A5, which often lead to progressive renal failure. Although angiotensin II receptor blockers are available for symptomatic treatment, no radical or curative therapies currently exist. Given the genetic basis of AS, exon-skipping therapy has the potential to serve as a definitive treatment. In this study, we established a tamoxifen-inducible exon 21-skipping mouse model, enabling the evaluation of post-onset therapeutic intervention. We generated a novel AS mouse model harboring a patient-derived nonsense mutation (R471*) in exon 21 of Col4a5 on a C57BL/6 background. Using this strain, we further developed a tamoxifen-inducible, podocyte-specific exon 21-skipping model. Induction of exon skipping, either before or after disease onset, restored truncated collagen IV α5 expression, improved renal function, and ameliorated glomerular and tubular pathology. Notably, treatment initiated after the onset of proteinuria reversed glomerular injury, underscoring its therapeutic potential even in progressive stages. This model provides a robust platform for evaluating mutation-targeted therapies and supports the feasibility of exon-skipping approaches for AS and other monogenic kidney diseases.
2025-10-06 | Severe Clinical Phenotype in Alport Syndrome Due to 2 COL4A4 Exon-Skipping Events.
Alport syndrome (AS) is a genetically heterogeneous disorder caused by mutations in COL4A3, COL4A4, or COL4A5, leading to progressive kidney dysfunction. Although genetic screening has advanced, many cases remain undiagnosed due to deep intronic splice-site variants. We report a male patient diagnosed with autosomal recessive AS, characterized by hematuria, proteinuria, and chronic kidney disease progression. Initial kidney biopsy at age 10 revealed glomerular basement membrane thinning and focal segmental glomerulosclerosis, whereas targeted deoxyribonucleic acid sequencing failed to detect pathogenic variants. Over 15 years, kidney function declined, and a second biopsy showed severe glomerular basement membrane abnormalities with multilamellated structures. Whole-transcriptome sequencing revealed 2 events of exon skipping, specifically at exons 27 and 38 of the COL4A4 gene, which were verified by exon-specific PCR and Sanger sequencing. Intronic regions analysis revealed 2 heterozygous variants positioned 78 bp downstream of exon 27 and 8 bp upstream of exon 38, though their role in aberrant splicing remains uncertain. Immunofluorescence analysis confirmed disrupted α3α4α5(IV) heterotrimer assembly. This is the first documented case of dual exon-skipping events in COL4A4, highlighting their contribution to disease severity. Our findings emphasize the need for ribonucleic acid-based diagnostics and raise questions about potential benefit of exon-skipping therapy in autosomal recessive AS.
cell therapies
2026-04-09 | Umbilical cord-derived mesenchymal stem cells restore renal homeostasis in Alport Syndrome: Mechanistic insights and clinical translation.
X-linked Alport syndrome (AS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene, leading to end-stage renal disease in young adults. Current treatments are palliative with limited efficacy, highlighting a critical unmet medical need. This study aims to evaluate the therapeutic feasibility of mesenchymal stem cells (MSCs) for alleviating renal dysfunction in AS, and to investigate whether their therapeutic benefits are primarily mediated by extracellular vesicles (EVs). Our integrated translational research strategy encompassed preclinical and clinical investigations. In the Col4a5-deficient AS mouse model, animals received intravenous MSCs or EVs. Engrafted cells and EVs were tracked in vivo. Renal function was detected by albuminuria level, and lifespan was assessed by survival time. Therapeutic outcomes were rigorously assessed by measuring albuminuria, survival time, and comprehensive histological analyses, including tissue staining for pathology, transmission electron microscopy for ultrastructure, and specific markers for inflammation and fibrosis. Building on compelling preclinical efficacy and safety data, we initiated a first-in-human, open-label clinical trial (ISRCTN62094626) in pediatric AS patients. Patients received four infusions and were follow-up for over 12 months. Safety was evaluated by recording adverse events (AEs). Efficacy was assessed by renal function parameters. To determine the molecular mechanisms, multi-omics analysis of serial bio-samples was conducted, followed by in vitro validation to confirm the role of miR-146a-5p in mediating the therapeutic benefits of MSC-based strategy. In the AS mice, MSC treatment exhibited significant reno-protective potentials, markedly reducing albuminuria (p < 0.001), and extended lifespan (37.7 ± 2.8 weeks vs 28.8 ± 4.0 weeks, p < 0.001), along with alleviated renal inflammatory infiltration and fibrosis (p < 0.01), which were closely associated with macrophage modulation. Crucially, EVs recapitulated these therapeutic benefits, indicating EVs as primary mechanistic effectors. The subsequent clinical trial yielded promising preliminary results. The first pediatric patient exhibited a significant downward trend in albuminuria (Log-rank test p < 0.0001) with no treatment-related AEs throughout the 12-month follow-up. Multi-omics profiling revealed that MSCs likely attenuate pathology through a multi-level network targeting inflammation and fibrosis. Furthermore, in vitro studies confirmed the critical role of EV-enriched miR-146a-5p in modulating macrophage polarization, showing significant inhibition of IL-1β, TNF-α, and NF-κB (p < 0.05). This proof-of-concept study provides novel evidence bridging robust preclinical findings with initial human data, underscoring the therapeutic feasibility of MSC-based therapy for AS, with mechanistic studies revealing that MSC-EV-enriched miR-146a-5p plays a partial but critical role by modulating macrophage polarization toward an anti-inflammatory phenotype.
2025-07-31 | Successful management of a giant macular hole in Alport syndrome using autologous retinal translation as an initial procedure.
Alport Syndrome is a complex systemic disorder that interferes with collagen type IV synthesis and presents with a variety of ocular symptoms. Management of complications arising out of it is challenging. This article depicts a unique case of Alport Syndrome with rare ocular features and successful management of it. A 30-year female with known Alport syndrome presented with Bilateral anterior lenticonus and unilateral giant macular hole(1791µm) in OD. She underwent simultaneous cataract extraction along with macular hole surgery in right eye. Intraoperatively Internal Limiting membrane was not found with dye staining. The full-thickness macular hole was successfully closed with an autologous retinal graft. On follow-up, the graft was found in situ covering the defect until her last follow-up even after 6 months and her BCVA in OD improved to 20/40. This article discusses in detail the successful management of a giant macular hole in a patient with Alport Syndrome, using a primary Retinal graft as an initial procedure.
2024-11-19 | 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. Individuals carrying these mutations face an inherent risk of kidney disease and due to the possibility of further deterioration in renal function after nephrectomy for transplantation, they are not suitable as priority donors. Posttransplant anti-glomerular basement membrane nephritis is rare but can lead to graft loss, especially in males with X-linked Alport syndrome.
2024-04-01 | Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome
Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFβ1 and using allogenic bone marrow-derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.
2024-03-01 | Human umbilical cord mesenchymal stem cell therapy for renal dysfunction in Alport syndrome: protocol for an open-label, single-arm trial in China
Introduction Alport syndrome (AS) is one of the most common fatal hereditary renal diseases in human, with a high risk of progressing to end-stage renal disease without effective treatments. Mesenchymal stem cells (MSCs) have recently emerged as a promising therapeutic strategy for chronic kidney disease. However, the safety and therapeutic potential of MSC transfusion for patients with AS are still need to be confirmed. Therefore, we have designed a clinical trial to evaluate the hypothesis that intravenous infusion of human umbilical cord-derived MSC (hUC-MSC) is safe, feasible, and well-tolerated in children with AS. Methods and analysis We report the protocol of the first prospective, open-label, single-arm clinical trial to evaluate the safety and preliminary efficacy of hUC-MSC transfusion in children with early-stage AS. Paediatric patients diagnosed with AS who have persistent albuminuria will be candidates for screening. Twelve eligible patients are planned to recruit and will receive hUC-MSC infusions under close safety monitoring, and complete the efficacy assessments at scheduled follow-up visits. The primary endpoints include the occurrence of adverse events to assess safety and the albuminuria level for efficacy evaluation. Secondary endpoint assessments are based on haematuria and glomerular filtration measurements. Each patient’s efficacy endpoints will be evaluated against their baseline levels. Additionally, the underlying mechanism of hUC-MSC therapy will be explored through transcriptomic and proteomic analysis of blood and urine samples. Ethics and dissemination The protocol (V.1.0, date 17 January 2015) was approved by the institutional review board of the Affiliated Taihe Hospital of Hubei University of Medicine (ethical approval 03 March 2015). Written informed consent will be obtained from the patient and/or guardians before study specific process. In addition to publication in a peer-reviewed scientific journal, a lay summary of study will be available for participants and the public on the Chinese Organization for Rare Disorders website ( http://www.cord.org.cn/ ). Trial registration number ISRCTN62094626 .
small molecules
2026-09-03 | Finerenone Added to Renin-Angiotensin System- and Sodium-Glucose Cotransporter 2 Inhibition in Patients with Alport Syndrome: A Two-Center Case Series.
Alport syndrome is a common hereditary glomerular kidney disease characterized by a high risk of kidney failure. Despite renin-angiotensin system- (RASi) and SGLT2 inhibitors (SGLT2i), a subset of patients experience rapid decline in kidney function. Preclinical data in Alport mice suggest that the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone could provide additional nephroprotection. This case series evaluates the changes in albuminuria and the safety of finerenone as part of a triple-therapy regimen in individuals with Alport syndrome. In this retrospective, two-center observational case series, ten male individuals with Alport syndrome received finerenone (10 mg/day) in addition to baseline-therapy with RASi (100%) and SGLT2i (90%). Clinical parameters - including estimated glomerular filtration rate (eGFR), albuminuria, and serum potassium were analyzed over a mean follow-up period of 9 ± 5 months. Median albuminuria showed a non-significant decrease of 33% during follow-up, from 3506 [IQR 1645-4304] to 2346 [1858-2792] mg/g creatinine (p = 0.21). Median eGFR declined from 50 [47-112] to 43 [32-116] mL/min/1.73m2 (p = 0.03) and continued to decline in a subgroup of five individuals, who were followed for 12 months. Hyperkalemia occurred in half of the individuals, necessitating the use of potassium binders in two cases. Finerenone was discontinued in two individuals due to rapid decline of eGFR. No serious adverse events were observed. This real-world case series provides preliminary evidence that adding finerenone to baseline therapy with RASi and SGLT2i is feasible and may offer additional albuminuria reduction in Alport syndrome. However, the notable eGFR decline and the relevant incidence of hyperkalemia underscore the necessity for vigilant clinical monitoring. While multimodal nephroprotection remains a promising tool to delay disease progression, these real-world observations provide pilot data to inform the design of future large-scale prospective trials in patients with Alport syndrome.
2026-08-01 | Alport syndrome in children: bridging genetic insights to clinical management—a narrative review
Background and Objective: Alport syndrome is a hereditary disorder of type IV collagen that commonly presents in childhood with persistent hematuria and carries a lifelong risk of progressive kidney disease and extrarenal complications. Despite advances in genetic diagnostics, important gaps remain in early risk stratification, variant interpretation, and recognition of expanding phenotypes. This narrative review aims to synthesize current evidence on the genetic architecture, clinical spectrum, and management of pediatric Alport syndrome, with a focus on early diagnosis and disease-modifying interventions.Methods: A targeted literature search was conducted using PubMed/MEDLINE to identify English-language human studies published between January 2000 and September 2025. Search terms included “Alport syndrome”, “COL4A3”, “COL4A4”, “COL4A5”, “type IV collagen”, and related clinical and genetic keywords, combined using Boolean operators. Relevant cohort studies, clinical trials, systematic reviews, and consensus guidelines were prioritized, and reference lists of key articles were manually reviewed. Findings were synthesized using a narrative approach.Key Content and Findings: Alport syndrome demonstrates substantial genetic and phenotypic heterogeneity, with X-linked (XL), autosomal recessive (AR), autosomal dominant (AD), and digenic forms contributing to a broader disease spectrum than previously recognized. Genotype-phenotype correlations, particularly variant type and gene involvement, are critical determinants of disease severity and progression. Early initiation of renin-angiotensin-aldosterone system (RAAS) blockade, especially in genetically confirmed cases, has been shown to delay progression to kidney failure. Advances in next-generation sequencing have improved diagnostic yield but introduced challenges in variant interpretation, including variants of uncertain significance (VUS). Emerging phenotypes, such as cystic kidney disease, further expand the clinical spectrum and have implications for differential diagnosis and genetic counseling.Conclusions: A genetics-first approach is central to the management of pediatric Alport syndrome, enabling early diagnosis, risk stratification, and timely initiation of therapy. Integration of genetic findings with clinical features is essential for individualized care. Recognition of evolving phenotypes and ongoing advances in targeted therapies highlight the need for pediatric-specific research to optimize outcomes and refine precision medicine strategies.
2026-07-02 | Patient-derived human induced pluripotent stem cell podocytes uncover endoplasmic reticulum and oxidative stress-mediated dysfunction in X-linked Alport syndrome.
X-linked Alport syndrome (XLAS) is an inherited nephropathy caused by pathogenic COL4A5 variants that lead to podocyte dysfunction and progressive kidney failure. However, the involvement of endoplasmic reticulum (ER) stress and oxidative stress in the development of XLAS remains insufficiently understood. This study aims to elucidate the contribution of ER and oxidative stress to podocyte injury in XLAS employing a patient-derived human induced pluripotent stem cell (hiPSC)-based podocyte model. Induced pluripotent stem cells were derived from XLAS patient blood cells and differentiated into podocytes (XLAS podocyte). Expression of pluripotency, lineage-specific, and podocyte markers was confirmed. ER stress, oxidative stress, and mitochondrial morphology were assessed through molecular characterization, imaging, and functional assays, comparing XLAS podocytes to wild-type (WT) hiPSC-derived podocytes. XLAS patient-derived hiPSCs maintained typical pluripotency markers, exhibited normal karyotypes, and allowed for successful tri-lineage differentiation. Relative to WT podocytes, XLAS podocytes had diminished expression of NPHS1, WT1, and COL4A5, while COL4A1 was increased. ER stress marker expression was elevated, with lower levels of CANX and CALR, indicative of unfolded protein response (UPR) activation. Electron microscopy analysis demonstrated enhanced ER enlargement in XLAS podocyte, implicating ER stress in disease pathogenesis. Moreover, XLAS podocytes showed markedly raised oxidative stress markers and mitochondrial reactive oxygen species (ROS) levels, together with altered catalase protein expression. Viability assays further supported ER and oxidative stress as contributors to reduced podocyte survival in XLAS podocyte. Our findings indicate that ER stress and oxidative stress are critical drivers of podocyte dysfunction in XLAS. UPR activation, ROS accrual, and mitochondrial impairment point to important therapeutic opportunities.
2026-06-19 | Clinical practice recommendations for the management of Alport syndrome: a joint statement of the Korean Society of Nephrology and the Korean Society of Pediatric Nephrology.
Alport syndrome (AS) is a hereditary kidney disorder characterized by progressive hematuria, proteinuria, and kidney failure, frequently accompanied by hearing loss and ocular abnormalities. Although blockade of the renin-angiotensin system (RAS) is established as the first-line therapy, additional pharmacological interventions have been explored. To formulate evidence-based recommendations tailored to the Korean healthcare setting, the Genetic Kidney Disease Study Group of the Korean Society of Nephrology conducted a systematic review evaluating four therapeutic strategies: RAS blockade, cyclosporine, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i). The quality of evidence and strength of recommendations were assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. The review confirmed that early initiation of RAS blockade delays progression to kidney failure and improves long-term survival, with the greatest benefit when initiated at the stage of microscopic hematuria or microalbuminuria. In contrast, evidence supporting cyclosporine , MRAs, and SGLT2i remains limited, primarily derived from small observational studies with short follow-up and heterogeneous populations. Although cyclosporine and MRAs have demonstrated short-term reductions in proteinuria, neither has shown sustained renoprotective effects, and cyclosporine is associated with a substantial risk of nephrotoxicity. Evidence regarding SGLT2i is inconsistent, with insufficient data on long-term efficacy in AS. Accordingly, these guidelines strongly recommend early RAS blockade as the cornerstone of AS, while no recommendations are made for routine use of cyclosporine, MRAs, or SGLT2i. Well-designed clinical trials are needed to expand therapeutic options and improve long-term outcomes in AS.
2026-05-15 | Albuminuria drives hyperlipidemia in patients with Alport syndrome.
Hypercholesterolemia is a major driver of cardiovascular disease, a leading cause of premature mortality in patients with chronic kidney disease (CKD). Despite their typically young age, patients with Alport syndrome (AS), the second most prevalent genetic cause of CKD, may face a disproportionately high risk of hypercholesterolemia. This study investigates whether increased albuminuria precipitates hyperlipidemia in this population to a degree comparable with general CKD cohorts, while further delineating the risk factors underlying this development. This was a multicenter, observational, non-interventional, and retrospective study. Among 459 patients with AS, 59.3% had hypercholesterolemia and 58.5% had elevated low-density lipoprotein cholesterol (LDL-C). Despite lower eGFR and higher albuminuria, patients with lipid-lowering therapy (LLT) had significantly lower total cholesterol levels compared to the untreated patients (193.6 ± 55.2 mg/dL vs. 208.2 ± 51.0 mg/dL; p = 0.044). Similarly, LDL-C levels were significantly lower in the treatment group (111.6 ± 51 mg/dL, n = 59) compared to the untreated group (124.3 ± 40.2 mg/dL, n = 238; p = 0.041). Multivariable regression analysis adjusted for age, gender, BMI, eGFR, and LLT revealed that albuminuria was a significant independent determinant of total cholesterol (β=0.315; p < 0.001) and LDL-C levels (β=0.242; p < 0.001). Male gender was associated with significantly higher LDL-C and lower HDL-C levels. Conversely, eGFR and BMI were not significant predictors of cholesterol levels. This association was also observed in the pediatric cohort (n = 44), where albuminuria was the only independent predictor of cholesterol (β=0.728; p < 0.001). Hypercholesterolemia is highly prevalent in young patients with AS and is primarily driven by the severity of albuminuria, rather than other risk factors such as obesity or eGFR decline. These findings highlight a critical gap in current guidelines, support the implementation of early lipid screening and suggest that risk-adapted management may be necessary to prevent long-term cardiovascular complications.
gene therapies
2026-05-29 | Capsid Engineering of Adeno-Associated Viruses for Targeted Gene Therapy in Kidney Diseases.
The global burden of chronic and genetic kidney diseases poses a significant challenge to healthcare systems. Current therapies, including dialysis, transplantation, and supportive pharmacotherapies, cannot halt disease progression or address root causes, especially in monogenic disorders like Alport syndrome and Fabry disease. Adeno-associated virus (AAV)-based gene therapy is promising, enabling targeted correction of underlying genetic defects. However, renal delivery faces challenges, including cellular heterogeneity, anatomical barriers, and pre-existing immunity. This review evaluates advances in AAV capsid engineering to overcome these obstacles, focusing on strategies to enhance kidney-specific tropism, transduction efficiency, and immune evasion. We outline the evolution from conventional serotype selection to precision engineering via rational design, directed evolution, and in silico approaches. Artificial intelligence (AI) has emerged as a pivotal accelerator, with machine learning models and generative frameworks enabling data-efficient capsid optimization despite limited datasets. Multimodal AI, reinforcement learning, and agentic systems can refine renal targeting by balancing glomerular penetration, cell specificity, and safety. Future progress relies on scaling high-quality datasets through collaborative consortia, lab-in-the-loop validation, and explainable AI. By combining capsid engineering with renal pathophysiology insights, this roadmap paves the way for curative AAV therapies that move beyond current suboptimal treatments to correct underlying pathogenic mechanisms.
2026-05-28 | Alport syndrome: a genetically confirmed x-linked case with early family screening.
Alport syndrome (AS) is an inherited disorder of the glomerular basement membrane (GBM) resulting from pathogenic variants in the COL4A3, COL4A4, or COL4A5 genes, which encode the α3, α4, and α5 chains of type IV collagen, the main structural component of the GBM, cochlea, and lens capsule.Defects in this collagen network lead to progressive renal insufficiency, hearing impairment, and characteristic ocular lesions such as anterior lenticonus and retinal flecks.(1).AS affects approximately 1 in 50 000 live births.The disease is classically inherited in an X-linked pattern (85%), followed by autosomal recessive (15%) and autosomal dominant (< 1%) forms.The severity and age at onset vary depending on the mutation type and zygosity, with males with truncating COL4A5 variants typically progressing faster to end-stage kidney disease (ESKD).( 2 )
2026-04-25 | Disheveled associated activator of morphogenesis 2 variants may produce alport-like changes: a case report.
DAAM2 is an important formin, which plays an important role in the polymerization of monomeric actin into linear filaments. Previous studies have suggested that the DAAM2 variant mainly causes congenital Nephrotic Syndrome Type 24 (NPHS24), which is characterized by focal segmental glomerulosclerosis and steroid resistant nephrotic syndrome. We report a case of a young man diagnosed with IgA nephropathy by renal biopsy. Specifically, in addition to IgA nephropathy, this patient also had diffuse thinning of GBM, reduced segmental expression of type IV collagen α3 in the glomerulus, and binocular keratoconus which is consistent with features of Alport syndrome. However, whole exon sequencing eliminated the common variation in the type IV collagen-encoding gene and revealed a homozygous mutation in the formin homology 2 (FH2) domain of DAAM2, the core domain responsible for actin polymerization. In conclusion, our case suggests that the spectrum of DAAM2-associated nephropathies might be broader than previously recognized. We propose the novel hypothesis that mutations in the FH2 domain of DAAM2 could predispose to an Alport-like phenotype, potentially through cytoskeletal dysregulation affecting glomerular basement membrane (GBM) integrity. This expands the potential clinical heterogeneity linked to DAAM2 and warrants further investigation.
2026-04-20 | Phenotype of autosomal dominant Alport syndrome with a likely pathogenic heterozygous variant in the COL4A3 gene (Gly366Arg) and incidental teratozoospermia: A case report.
Autosomal dominant Alport syndrome (ADAS) is the least common form of Alport syndrome, the second most common monogenic cause of chronic kidney disease after autosomal dominant polycystic kidney disease. We report a 14-year follow-up of a patient with ADAS carrying a likely pathogenic heterozygous variant in COL4A3 (Gly366Arg substitution). The disease initially presented with microhematuria and no renal impairment on analysis or ultrasound. The patient progressively developed bilateral renal cysts and renal failure -a classic renal pattern of the syndrome- and bilateral hearing loss. Incidentally, infertility study (had not children) showed teratozoospermia and elevated levels of luteinizing hormone and progesterone, hormones associated with spermatogenesis. Long-term follow-up of rare variants of Alport syndrome helps refine genotype-phenotype correlations and disease progression. The incidental finding of teratozoospermia raises the possibility of an etiological association, that warrants further investigation as a3(IV) collagen chains involved in spermatogenesis are present in seminiferous tubules.
2026-03-19 | Update on Alport Syndrome: The Report of the 2024 International Workshop on Alport Syndrome.
The 2024 International Workshop on Alport syndrome brought together people living with Alport Syndrome, clinicians, laboratory scientists, and representatives of pharmaceutical companies to present recent data and discuss issues to advance understanding of this inherited condition. The workshop focused on diagnosis and management of Alport syndrome, with particular attention on genetic variant curation, and treatment strategies across the diverse spectrum of Alport syndrome phenotypes, from hematuria to early kidney failure, with or without hearing loss and eye abnormalities. Advances in genetic testing, especially for non-European populations, were discussed alongside challenges in variant interpretation and misclassification. Novel treatment approaches, including gene therapy, and ongoing trials of medications such as sodium-glucose cotransporter 2 inhibitors and endothelin receptor antagonists, offer hope for prolonging kidney function. Collaboration between high- and low-to-middle-income countries was highlighted, addressing disparities in diagnostic capabilities. In addition, the role of patient advocacy and the need for education in nephrology were emphasized. With ongoing research, Alport syndrome is moving closer to being not only actionable but highly treatable through the prevention of kidney failure.
proteins
2026-02-12 | Protective role of early Tnfsf15 upregulation in limiting glomerular injury and proteinuria in experimental Alport Syndrome.
Alport syndrome is a progressive kidney disease caused by pathogenic variants in genes encoding type IV collagen, a major structural component of the glomerular basement membrane (GBM). Abnormal GBM architecture impairs filtration and triggers inflammation, fibrosis, and eventual kidney failure. Because disease progression is irreversible, identifying early molecular changes is essential for understanding disease onset. We performed glomerular single-cell RNA sequencing (scRNA-seq) in a Col4a5 G5X Alport mouse model at 5 weeks of age, prior to detectable proteinuria or GBM/podocyte abnormalities (pre-onset), and at 8 weeks, when mild proteinuria and structural defects emerged. Despite the early stage, scRNA-seq revealed widespread transcriptional alterations, most prominently in podocytes. Among genes upregulated at both time points, we identified Tumor Necrosis Factor Superfamily Member 15 (Tnfsf15), previously associated with kidney disease susceptibility but with unclear function. To determine its role in Alport syndrome, we generated Tnfsf15-deficient Alport mice. Tnfsf15 homozygous knockout mice exhibited increased proteinuria and exacerbated glomerular injury compared with Tnfsf15(+/+) Alport mice during early disease. These findings support a protective role for Tnfsf15 in the early stages of Alport syndrome, mitigating proteinuria and limiting glomerular injury.
2025-10-01 | #2398 Exogenous a-Klotho supplementation significantly prolongs survival in a mouse model of alport syndrome, with comparable outcomes to RASi
Abstract Background and Aims Chronic kidney disease (CKD) affects over 10% of the global population and has become a leading cause of mortality in recent decades. Numerous studies have explored novel drugs aimed at slowing CKD progression. Among these, α-Klotho has emerged as a protein with many kidney-specific anti-aging properties. Produced by renal tubular cells, α-Klotho has been shown to prevent fibrosis and reduce tissue inflammation. However, its production diminishes in advanced CKD stages due to chronic and irreversible kidney damage, limiting attempts to stimulate endogenous synthesis. Despite its recognized benefits for kidney health, studies evaluating long-term exogenous α-Klotho supplementation are lacking. In this context, we hypothesized that prolonged α-Klotho administration would enhance mean survival in a mouse model of CKD. Method We conducted a preclinical study involving Col4a3-deficient mice, which spontaneously develop progressive CKD. Mice were equally divided into three groups: (a) control group (vehicle), (b) RASi treatment (ramipril mixed with food at 10 mg/kg), and (c) α-Klotho treatment (daily subcutaneous injections at 10 µg/kg/day). Both treatments started at six weeks of age and continued for eight weeks, unless termination criteria were met before. The primary endpoint was mean overall lifespan. Baseline histological analysis was performed, and additional analyses after 2.5 weeks of treatment will be conducted to further validate the drug's effects. Results Baseline characteristics were comparable across the three groups. Mean survival was as follows: 62.9 ± 7.3 days in the control group, 77.3 ± 5.3 days in the RASi group, and 73.6 ± 7.7 days in the α-Klotho group. Both treatments significantly extended lifespan (RASi: R = 0.71, P < 0.001; α-Klotho: R = 0.62, P < 0.001). Notably, α-Klotho was not inferior to RASi in slowing CKD progression (P = 0.426) (Fig. 1). Kaplan–Meier analyses stratified by sex revealed no significant differences (α-Klotho: R = 0.19, P = 0.53) (Fig. 2a). Both treatment groups experienced gradual body weight loss over time, with no significant differences between them (P = 0.769) (Fig. 2b). Tissue analysis at six weeks confirmed advanced disease at treatment initiation, as evidenced by significant chronic lesions. Despite this, CKD progression was effectively monitored through weekly urine sample visual analyses, which reflected a progressive decline in urine concentration capacity. This served as a surrogate for kidney function, given that GFR measurements were not feasible in our delicate CKD model (Fig. 2c). Conclusion Our findings demonstrate that exogenous α-Klotho supplementation, even when initiated during late-stage CKD, significantly extends renal lifespan and improves overall survival. Despite being tested on small-sized groups, the effect of α-Klotho was comparable to that of ramipril over an extended experimental period, without significant adverse effects. These results underscore the urgent need for randomized clinical trials in humans. Future research should explore the potential synergistic benefits of combining α-Klotho with existing approved therapies to enhance CKD management.
2025-10-01 | Early Variable Gene of Alport Syndrome, Tnfsf15, Is a Protective Factor and Effect Modifier Against Renal Pathology
Background: Alport syndrome (AS) is a genetic disease of progressive glomerulonephritis caused by a mutation in type IV collagen. The progression of AS is irreversible, and it is important to control the progression of the disease by early therapeutic intervention. To know the early molecular changes, we performed single-cell RNA-seq (scRNA-seq) analysis in 5-week-old pre-proteinuric Col4a5 G5X AS mice and 8-week-old AS mice at the early stage of the disease. Methods: Glomeruli from 5- and 8-week-old AS mice were collected using Dynabeads, processed for glomerular single cells, and sequenced. The scRNA-seq analysis revealed an early variable gene, Tnfsf15. To determine its function, we generated Tnfsf15 knockout (KO) AS mice and evaluated renal pathology. Results: Glomerular scRNA-seq analysis revealed a marked change in podocyte gene expression. In particular, we focused on Tnfsf15, a gene whose expression was markedly increased at 5 and 8 weeks. The function of Tnfsf15 in AS is unclear, although it has been reported to be clinically associated with susceptibility to renal disease. Tnfsf15 KO AS mice had increased proteinuria, BUN, plasma creatinine, and decreased renal function compared to AS control. Glomerulosclerosis was exacerbated in Tnfsf15 KO AS mice. Some inflammation-related genes were up-regulated, but renal damage markers and fibrosis-related genes were unaltered in Tnfsf15 KO AS mice. In Tnfsf15 heterozygous AS mice, proteinuria and glomerulosclerosis were unchanged. However, Tnfsf15 expression significantly correlated with the genes related to renal injury, inflammation, and fibrosis, and the positive correlation slope was higher than the AS control. This suggests that Tnfsf15 is a modifier that affects the gene expression of pathology-related genes in Tnfsf15 heterozygous AS mice. Conclusion: Tnfsf15, a podocyte-specific upregulated gene identified by scRNA-seq analysis, is suggested to be a protective factor and effect modifier of AS pathology.
2025-10-01 | ADAMTS13 Protects Kidney Function in Alport Syndrome
Background: Alport syndrome (AS) is a hereditary form of CKD caused by mutations in type IV collagen genes, leading to progressive renal failure. Despite advances in understanding its genetic basis, effective treatments to slow disease progression remain limited. Our research has shown that glomerular endothelial cells (GECs) are among the first to be damaged in AS and intravital imaging studies revealed that glomerular capillaries in AS mice are affected by microthrombi formations. We have previously shown that ADAMTS13, an enzyme responsible for cleaving von Willebrand factor (VWF) is consistently downregulated in human kidney biopsies affected by AS. This study investigates if disrupted fatty acid metabolism drives the downregulation of ADAMTS13, and whether ADAMTS13 administration in AS mice can protect glomerular microvasculature and slow down disease progression. Methods: In vitro, silencing experiments on primary human GEC were performed to study the role of fatty acid metabolism on ADAMTS13 expression. In vivo, Col4a5-KO Alport mice were treated with bi-weekly administration of recombinant ADAMTS13 protein and kidney function was assessed. Results: We established that glomerular ADAMTS13 expression is downregulated in Col4a5-KO Alport mice with moderate disease. Our analysis revealed that suppression of fatty acid synthesis downregulates ADAMTS13 expression in GECs. Knockdown of ADAMTS13 in GECs led to endothelial dysfunction, indicated by increased levels of the adhesion molecules VCAM-1 and ICAM-1. Notably, therapeutic administration of ADAMTS13 in Alport mice resulted in significant improvement in proteinuria. Conclusion: Our findings reveal that endothelial metabolic dysfunction and ADAMTS13 downregulation contribute to microvascular injury and endothelial dysfunction in AS. These results suggest that ADAMTS13 restoration may serve as a promising therapeutic strategy to preserve endothelial function and slow CKD progression in AS, and potentially other forms of CKD. Funding: NIDDK Support, Other U.S. Government Support, Private Foundation Support
2025-09-12 | Treatment Approaches for Alport Syndrome.
Alport syndrome is a progressive, hereditary disorder of basement membranes caused by variants in genes encoding the α 3, α 4, or α 5 chains of type IV collagen ( COL4A3, COL4A4 , and COL4A5 ) leading to glomerulopathy, kidney failure, hearing loss, and eye abnormalities. The absence or dysfunction of the α 3- α 4- α 5 (IV) heterotrimer triggers multiple compensatory and detrimental pathways within all layers of the glomerular filtration barrier. Developing a therapeutic strategy for patients with Alport syndrome depends on understanding these mechanisms of disease progression that are predominant at different times throughout the disease course. These strategies may include reconstitution of the α 3- α 4- α 5 (IV) network in the glomerular basement membrane, reducing biomechanical strain and glomerular hyperfiltration, chaperone therapy, blocking aberrant signaling between the glomerular basement membrane and podocytes, reducing endothelial cell injury, reducing inflammation, and blocking fibrosis pathways.
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2026-09-11 | Alirocumab as add‑on to the therapy of an adolescent with heterozygous familial hypercholesterolemia, early‑onset carotid atherosclerosis, and Alport syndrome: A clinical observation
This article presents a clinical observation of a 17-year-old adolescent with genetically confirmed heterozygous familial hypercholesterolemia (HeFH), early-onset carotid atherosclerosis (ECAS), and concomitant Alport syndrome (AS). This patient with a strong family history of premature fatal myocardial infarction demonstrated significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) up to 6.73 mmol/L at baseline. Molecular genetic testing confirmed the presence of an HeFH-causing variant in the LDLR gene. In addition, it identified a hereditary nephritis/AS-associated variant in the COL4A3 gene. Brachiocephalic artery ultrasound revealed early atherosclerotic changes in the carotid arteries. Despite a combination therapy of rosuvastatin (10 mg/day) and ezetimibe (10 mg/day), LDL-C levels remained above goal and were 3.3 mmol/L. Given the genetically confirmed FH, early-onset vascular lesions, elevated lipoprotein(a) levels, burdened family history, and concomitant AS, we decided to intensify lipid-lowering treatment without further increase of rosuvastatin dosing. The treatment regimen was modified by adding alirocumab. The patient showed a reduction of LDL-C levels to 0.88–1.18 mmol/L with alirocumab 150 mg once every 2 weeks as part of combination therapy. No adverse events were reported; creatinine, transaminase, and creatine phosphokinase levels were within acceptable limits. This observation showed the potential for an individual choice of lipid-lowering treatment in an adolescent with high-risk FH and concomitant hereditary nephropathy.
2026-02-02 | Immune-Negative Focal Segmental Nephrotic Syndrome Disclosing a Novel Mutation of Autosomal Dominant Alport’s in a Female
Background: Alport syndrome (AS) is a rare genetic disease characterized by progressive renal failure due to glomerulopathy, variable high-frequency sensorineural deafness, and variable ocular anomalies. The case: A 33-year-old woman was referred for evaluation of progressive lower limb oedema for 2 weeks following 1 week after receiving the second dose of the Oxford–AstraZeneca COVID19 vaccine. She had hypertension, hematuria, and nephrotic syndrome with serum albumin at 19 g/L and 6 g/day proteinuria. Her parents did not have renal disease. She had no clinical, laboratory, radiological, or serological evidence of autoimmune disease or infections. Kidney biopsy showed focal and segmental glomerulosclerosis with negative immunostains, yet electron microscopy showed a basket-weave appearance of the glomerular basement membrane. Genetic testing disclosed an autosomal pattern with a novel pathogenic mutation in COL4A3 c.3829G>A p.(Gly1277Ser), and COL4A5 had a c.4436C>T sequence change, replacing alanine with valine at codon 1479 protein (p.Ala1479Val). She did not respond to 2 months of therapy with diet, Losartan, and diuretics (Furosemide and Spironolactone). Since acute nephrotic state was present, Mycophenolate mofetil and Tacrolimus were selected for treatment. By 1 month later, her proteinuria decreased to 1.9 g/day, and serum albumin increased to 34 g/L. By 5 months (3 months after Mycophenolate mofetil and Tacrolimus therapy), proteinuria reached 870 mg/day and serum albumin reached 39 g/L. Hence, these were replaced by yearly Rituximab infusions. Up to 2 years of follow-up, the patient remained clinically stable and with normal serum creatinine, albumin, and proteinuria at 530 mg/day. Conclusion: A new-onset and novel mutation of AS can present with nephrotic syndrome after a trigger that was amenable to immunosuppressive therapy. The genetic disorder may not be cured, yet autoimmunity may have a role in its acute flares in certain phenotypes.
2025-12-18 | Splice modulation of COL4A5 reinstates collagen IV assembly in an organoid model of Alport syndrome.
Kidney organoids are an emerging tool for disease modeling, especially genetic diseases. Among these diseases, X-linked Alport syndrome (XLAS) is a hematuric nephropathy affecting the glomerular basement membrane (GBM) secondary to pathogenic variations in the COL4A5 gene encoding the α5 subunit of type IV collagen [α5(IV)]. In patients carrying pathogenic variations affecting splicing, the use of antisense oligonucleotides (ASOs) offers immense therapeutic hope. In this study, we develop a framework combining the use of patient-derived cells and kidney organoids to provide evidence of the therapeutic efficacy of ASOs in XLAS patients. Using multiomics analysis, we describe the development of GBM in WT and mutated human kidney organoids. We show that GBM maturation is a dynamic process, which requires long organoid culture. Then, using semi-automated quantification of α5(IV) at basement membranes in organoids carrying the splicing variants identified in patients, we demonstrate the efficacy of ASO treatment for α5(IV) restoration. These data contribute to our understanding of the development of GBM in kidney organoids and pave the way for a therapeutic screening platform for patients.
2025-11-26 | Podocyte specific exon skipping after disease onset improves kidney pathology and function in a mouse model of Alport syndrome.
Alport syndrome (AS) is a hereditary kidney disorder caused by mutations in COL4A3, COL4A4, and COL4A5, which often lead to progressive renal failure. Although angiotensin II receptor blockers are available for symptomatic treatment, no radical or curative therapies currently exist. Given the genetic basis of AS, exon-skipping therapy has the potential to serve as a definitive treatment. In this study, we established a tamoxifen-inducible exon 21-skipping mouse model, enabling the evaluation of post-onset therapeutic intervention. We generated a novel AS mouse model harboring a patient-derived nonsense mutation (R471*) in exon 21 of Col4a5 on a C57BL/6 background. Using this strain, we further developed a tamoxifen-inducible, podocyte-specific exon 21-skipping model. Induction of exon skipping, either before or after disease onset, restored truncated collagen IV α5 expression, improved renal function, and ameliorated glomerular and tubular pathology. Notably, treatment initiated after the onset of proteinuria reversed glomerular injury, underscoring its therapeutic potential even in progressive stages. This model provides a robust platform for evaluating mutation-targeted therapies and supports the feasibility of exon-skipping approaches for AS and other monogenic kidney diseases.
2025-10-06 | Severe Clinical Phenotype in Alport Syndrome Due to 2 COL4A4 Exon-Skipping Events.
Alport syndrome (AS) is a genetically heterogeneous disorder caused by mutations in COL4A3, COL4A4, or COL4A5, leading to progressive kidney dysfunction. Although genetic screening has advanced, many cases remain undiagnosed due to deep intronic splice-site variants. We report a male patient diagnosed with autosomal recessive AS, characterized by hematuria, proteinuria, and chronic kidney disease progression. Initial kidney biopsy at age 10 revealed glomerular basement membrane thinning and focal segmental glomerulosclerosis, whereas targeted deoxyribonucleic acid sequencing failed to detect pathogenic variants. Over 15 years, kidney function declined, and a second biopsy showed severe glomerular basement membrane abnormalities with multilamellated structures. Whole-transcriptome sequencing revealed 2 events of exon skipping, specifically at exons 27 and 38 of the COL4A4 gene, which were verified by exon-specific PCR and Sanger sequencing. Intronic regions analysis revealed 2 heterozygous variants positioned 78 bp downstream of exon 27 and 8 bp upstream of exon 38, though their role in aberrant splicing remains uncertain. Immunofluorescence analysis confirmed disrupted α3α4α5(IV) heterotrimer assembly. This is the first documented case of dual exon-skipping events in COL4A4, highlighting their contribution to disease severity. Our findings emphasize the need for ribonucleic acid-based diagnostics and raise questions about potential benefit of exon-skipping therapy in autosomal recessive AS.
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Drug Discovery Landscape
14 orphan drug designations for Alport syndrome.
14 orphan drug designations for Alport syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Exaluren sulfate | small molecules | EMA | FGK Representative Service GmbH | |
a human monoclonal antibody that blocks the function of semaphorin-3A | antibodies | FDA | Bayer HealthCare Pharmaceuticals Inc. | |
6'-(R)-Methyl-5-O-(5-amino-5,6-dideoxy-alpha-Ltalofuranosyl)-paromamine sulfate | small molecules | FDA | Eloxx Pharmaceuticals Inc. | |
Setanaxib | small molecules | EMA | Calliditas Therapeutics AB | |
setanaxib | small molecules | FDA | Calliditas Therapeutics AB | |
Vonafexor | small molecules | FDA | ENYO Pharma | |
Vonafexor | small molecules | EMA | ENYO Pharma | |
5-(3,4-Dichloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide | small molecules | EMA | — | Veristat Spain S.L. |
5-Arylnicotinamide ABCA1 inducer | small molecules | FDA | River 3 Renal Corp. | |
Ivaltinostat | small molecules | FDA | — | CG Invites Co., Ltd. |
Bardoxolone methyl | small molecules | EMA | Reata Ireland Limited | |
bardoxolone methyl | small molecules | FDA | Reata Pharmaceuticals, Inc. | |
Lademirsen [RG-012] | oligonucleotides | EMA | Sanofi B.V. | |
single stranded, chemically modified oligonucleotide that binds to and inhibits the function of micro RNA-21 | oligonucleotides | FDA | Genzyme Corporation |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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