Alport syndrome in children: bridging genetic insights to clinical management—a narrative review

Introduction

Alport syndrome was first identified in 1927 by a British physician, Arthur Cecil Alport. He noted a triad of hereditary nephritis, deafness, and ocular changes in a family. Anterior lenticonus had been reported as early as 1891, and in 1910 Jaworski described its association with nephropathies. Alport’s seminal contribution in 1927 was the identification of a link between progressive renal disease and sensorineural hearing loss, thereby establishing the hereditary nature of this clinical pattern (1). Alport syndrome was given its name in 1961 after the death of Arthur Cecil Alport in 1959. Subsequent research, conducted decades later, demonstrated that the syndrome is caused by pathogenic variants in the genes encoding type IV collagen chains, namely COL4A3, COL4A4, and COL4A5 (1,2). These correspond to X-linked (XL) Alport syndrome (OMIM #301050), autosomal recessive (AR) Alport syndrome (OMIM #203780), and autosomal dominant (AD) Alport syndrome (OMIM #104200).

Alport syndrome frequently presents during childhood with persistent hematuria and represents an important cause of inherited kidney disease in pediatric population (2,3). Early recognition in children is critical, as timely genetic diagnosis and initiation of therapy can significantly delay disease progression and improve long-term renal outcomes (4,5). Evidence from retrospective cohort studies, a systematic review and meta-analysis, and the EARLY PRO-TECT randomized controlled trial consistently demonstrates that early initiation of renin-angiotensin-aldosterone system (RAAS) blockade delays progression to kidney failure in Alport syndrome, with the greatest benefit observed when treatment is started before the onset of overt proteinuria (6-9). This review focuses on the pediatric presentation of Alport syndrome, emphasizing advances in genetic testing, genotype-phenotype correlations, and early management strategies relevant to childhood disease. The 2024 International Workshop on Alport Syndrome further underscored the importance of advancing genetic variant curation, expanding diagnostic access globally, and developing collaborative frameworks for clinical trials, including gene therapy approaches (10).

The objective of this narrative review is to synthesize current evidence on the epidemiology, genetic architecture, genotype-phenotype correlations, molecular pathophysiology, and clinical manifestations of Alport syndrome, with a specific focus on pediatric disease. This review aims to highlight the importance of early genetic diagnosis, delineate risk factors for disease progression in children, and summarize contemporary recommendations for surveillance and management. In addition, it seeks to identify emerging therapeutic strategies and key knowledge gaps to inform future research and improve outcomes for affected children.

While previous reviews have provided comprehensive overviews of Alport syndrome genetics and pathophysiology (11,12), this review differs by providing a dedicated pediatric focus that integrates the most recent 2024 European Rare Kidney Disease Reference Network (ERKNet)/European Renal Association (ERA)/European Society for Paediatric Nephrology (ESPN) guideline recommendations (4), incorporates emerging concepts such as digenic inheritance, cystic kidney phenotypes, and challenges in variant interpretation, and synthesizes the latest evidence on early RAAS blockade and novel therapeutic strategies in children. In doing so, this review addresses important knowledge gaps not covered by prior publications and provides an updated, clinically actionable synthesis for pediatric nephrologists. We present this article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-26-0027/rc).

Methods

This narrative review synthesizes current evidence on pediatric Alport syndrome, with a focus on genetic architecture, genotype-phenotype correlations, clinical manifestations, and management strategies.

A targeted literature search was conducted using PubMed/MEDLINE to identify relevant peer-reviewed articles published between January 2000 and September 2025. Search terms included combinations of Medical Subject Headings (MeSH) and free-text keywords such as “Alport syndrome”, “COL4A3”, “COL4A4”, “COL4A5”, “type IV collagen”, “glomerular basement membrane”, “pediatric”, “children”, “genotype-phenotype”, “hematuria”, “proteinuria”, “hearing loss”, “ocular abnormalities”, and “genetic testing”, combined using Boolean operators (“AND”, “OR”). Only English-language studies involving human subjects were included. Preclinical animal studies were included when directly relevant to understanding disease mechanisms or emerging therapies.

Articles were selected based on relevance to pediatric disease, genetic insights, and clinical management. Priority was given to cohort studies, clinical trials, systematic reviews, meta-analyses, consensus guidelines, and landmark genetic studies. Reference lists of selected articles and international guidelines were manually reviewed to identify additional relevant publications.

Study selection and interpretation were performed collaboratively by the authors through iterative discussion. Given the narrative nature of this review, formal systematic screening counts, PRISMA flow diagram reporting, and structured quality assessment tools were not applied. Instead, emphasis was placed on integrating high-quality and clinically relevant evidence to provide a comprehensive and balanced synthesis of current knowledge (Table 1).

Epidemiology

Using American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology criteria for predicted pathogenic variants in COL4A3, COL4A4 and COL4A5, population frequencies of Alport syndrome in individuals not known to have kidney disease showed predicted pathogenic COL4A5 variants (XL Alport syndrome) to occur in at least one in 2,320 individuals. Heterozygous COL4A3 or COL4A4 variants (AD Alport syndrome) were noted in one in 106 individuals (13). This shows the prevalence of COL4A3 and COL4A4 variants to be 20-fold higher than COL4A5 variants. Since this calculation excluded individuals with a known kidney disease, the overall prevalence is expected to be higher for all the variants. Of all the patients with Alport syndrome, 1.7% was comprised of digenic Alport syndrome (14). Pediatric-specific data remain limited, but a 15-year national-level retrospective study identified 85 children and adolescents with pathogenic or likely pathogenic COL4A3–COL4A5 variants, noting increasing incidence as genetic testing became more prevalent. In this cohort, autosomal forms accounted for 55.2% and XL forms for 43.6% of cases, with only 1.2% having digenic disease. One patient (1.2%) progressed to kidney failure during childhood, and six (7%) had extrarenal involvement (15). The true prevalence of Alport syndrome is now recognized to be substantially higher than earlier estimates, largely due to advances in genetic testing (13,16).

Genetic architecture and inheritance patterns

XL Alport syndrome results from a single pathogenic variant in the COL4A5 gene and demonstrates marked sex-related differences in clinical progression. Affected males have an almost universal risk of progression to end-stage kidney disease (ESKD), with approximately 70% reaching ESKD by 30 years of age and nearly 90% by 40 years. In contrast, disease progression in females is more variable; while most retain preserved kidney function into early adulthood, approximately 25% ultimately develop ESKD, with only about 12% affected by 40 years of age (17).

Historically, females with XL Alport syndrome were described as asymptomatic carriers. However, due to the noted risk of progression of kidney disease these individuals are considered to have Alport syndrome and not a carrier state; requiring continued monitoring for timely intervention, when needed (17,18). Variability in disease severity among affected females is partly attributed to X-chromosome inactivation patterns (19).

In males, microscopic hematuria is typically present from early childhood, often preceding the development of proteinuria by several years. Females frequently present with hematuria in childhood as well, although progression to proteinuria and kidney dysfunction is more variable and often delayed (3,17).

AR Alport syndrome is caused by biallelic pathogenic variants in COL4A3 or COL4A4, occurring in either a homozygous or compound heterozygous state. Both males and females are affected equally and have an almost 100% risk of progression to ESKD. Missense variants are generally associated with milder disease and later presentation. Alport syndrome patients without a missense mutation show earlier onset of disease with a higher prevalence of nephrotic range proteinuria, hearing loss, and ocular pathology (20).

In AR disease, renal manifestations are usually evident in early childhood, with rapid progression compared to other inheritance patterns, underscoring the importance of early diagnosis and close monitoring in pediatric patients (3,21,22).

AD Alport syndrome is caused by a single pathogenic variant in COL4A3 or COL4A4 and is characterized by variable clinical expression in both males and females. Approximately 24–29% of affected individuals progress to ESKD between 53 and 67 years of age. Extrarenal manifestations are less common, with sensorineural hearing loss reported in 8–16% of individuals and ocular abnormalities in 1–3% (23,24).

Children with AD Alport syndrome often present with isolated microscopic hematuria, and disease progression during childhood is uncommon, although long-term surveillance is required due to the risk of adult-onset kidney failure (3,23).

Digenic Alport syndrome is caused by pathogenic variants affecting two of the three type IV collagen genes; COL4A3, COL4A4, and COL4A5. When COL4A3 and COL4A4 variants occur in trans, the clinical course resembles AR inheritance, with a high risk of progression to ESKD. In contrast, variants occurring in cis produce a milder phenotype similar to AD disease (14,16).

As digenic inheritance can significantly modify disease severity, current guidelines recommend sequencing all three COL4A3–COL4A5 genes in children with suspected Alport syndrome (16). Pediatric patients with digenic disease often present earlier and with more severe renal involvement than those with single-gene heterozygous variants, underscoring the importance of comprehensive genetic testing in children with atypical or aggressive disease (2,16).

Challenges in variant interpretation

The expanding use of next-generation sequencing has significantly increased the detection of variants in COL4A3, COL4A4, and COL4A5, particularly in individuals with isolated hematuria or mild kidney disease (2,4,25). However, this has introduced substantial complexity in variant interpretation (10,16,26).

Variants are typically classified according to ACMG criteria as pathogenic, likely pathogenic, variants of uncertain significance (VUS), likely benign, or benign (3,27). A growing proportion of detected variants, particularly missense changes and noncanonical splice variants, fall into the VUS category, creating uncertainty in clinical decision-making (16,26). A systematic reassessment of previously reported variants in individuals with suspected Alport spectrum disorder found that 24% of index cases had ambiguous results at the variant, genotype, or both levels, and that 10 of 80 reassessed variants were downgraded from disease-causing to VUS, highlighting variant interpretation as a dynamic process (26). This is especially relevant in pediatric patients, where early diagnosis has important implications for monitoring and intervention (4,25).

Glycine substitutions within the collagenous domain of type IV collagen represent the most common pathogenic variant type and are strongly associated with disease severity, particularly when located in conserved regions (28-30). Pathogenic COL4A5 variants resulting in glycine substitutions with highly destabilizing residues (Arg, Val, Glu, Asp, Trp) reduced the median age at kidney failure by 7 years and age at hearing loss diagnosis by 21 years, while substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (29). In contrast, non-glycine missense variants and variants located outside the collagenous domain often demonstrate more variable or attenuated phenotypes, complicating prognostication (2,29,31).

Incomplete penetrance and variable expressivity further complicate interpretation, particularly in AD Alport syndrome associated with heterozygous COL4A3 or COL4A4 variants (2,4,23,32). Some individuals remain asymptomatic or exhibit only microscopic hematuria, while others develop progressive chronic kidney disease (CKD) (16,26). Notably, heterozygous non-truncating COL4A3/COL4A4 variants have been associated with a more severe phenotype compared to truncating variants in some cohorts, suggesting a potential dominant-negative effect (26). Mosaicism, although less commonly reported, may also contribute to intrafamilial variability (33,34). Somatic mosaicism in COL4A5 has been identified in apparently sporadic cases and can be confined to the kidney, escaping detection on standard peripheral blood testing (33,34). Hypomorphic COL4A5 variants, such as the common European founder variant p.(Gly624Asp), are associated with milder disease including hematuria only, late-onset kidney failure, or a thinned rather than lamellated glomerular basement membrane (GBM), yet remain actionable as they may eventually cause kidney failure and require monitoring (16,35).

Digenic inheritance adds an additional layer of complexity, as variants in more than one collagen IV gene can modify disease severity and blur traditional inheritance patterns (14,16,36). These challenges highlight the importance of integrating genetic findings with clinical phenotype, family history, and, when necessary, functional or segregation studies (4,16,27).

In pediatric practice, careful interpretation of genetic results is essential to avoid overdiagnosis, unnecessary anxiety, or inappropriate exclusion of potential kidney donors, while still enabling early identification of individuals at risk for progressive disease (4,16,37).

To better contextualize the spectrum of genetic variation in Alport syndrome, the major classes of COL4A3, COL4A4, and COL4A5 variants and their clinical correlations are summarized in Table 2. Missense variants, particularly glycine substitutions within the collagenous domain, represent the most common pathogenic variants, while truncating variants such as nonsense and frameshift mutations are generally associated with more severe disease (2,29-31). Increasing use of next-generation sequencing has also led to a higher detection of VUS, highlighting ongoing challenges in genetic interpretation (16,25,26).

Natural history and early clinical features in pediatric Alport syndrome

Alport syndrome in children typically presents with persistent microscopic hematuria, often detected incidentally during routine screening. Gross hematuria may occur transiently, particularly during intercurrent infections (3). Proteinuria develops later and signals disease progression. The rate of progression varies according to genotype, with earlier onset and more rapid kidney function decline in males with XL disease and in children with AR or digenic forms. Key early predictors of progressive disease include overt proteinuria, hypertension, and truncating or digenic variants (2,16). Recognition of these early features provides a critical opportunity for timely intervention to delay progression to ESKD (38).

Pathogenesis and molecular mechanisms

The GBM is an acellular extracellular matrix that forms the central layer of the glomerular filtration barrier, located between the fenestrated endothelium and the podocyte foot processes. Type IV collagen is the major collagenous component of the GBM that undergoes key transitions during glomerular development (39).

The embryonic GBM is composed almost exclusively of the α1α1α2(IV) heterotrimer network, which is produced by both endothelial cells and podocytes. As glomeruli mature and reach the capillary loop stage, podocytes begin to synthesize the α3α4α5(IV) heterotrimer network (encoded by COL4A3, COL4A4, and COL4A5), which gradually replaces the α1α1α2(IV) network in the subepithelial region of the GBM. Adult GBM is composed of two distinct type IV collagen networks: a subendothelial α1α1α2(IV) heterotrimer network and a subepithelial α3α4α5(IV) heterotrimer network. This adult network is a highly cross-linked, mesh-like structure with extensive interchain disulfide cross-links and confers greater resistance to mechanical and oxidative stresses, a property critical for the mechanical stability and integrity of the GBM. Mutations in COL4A3, COL4A4, or COL4A5 disrupt this transition, arresting the developmental switch and causing the GBM to retain the embryonic α1α1α2(IV) network and leading to the pathogenesis of Alport syndrome. Because all three chains are required for proper trimer formation, a defect in any one gene results in the absence of the entire α3α4α5(IV) heterotrimer network in the GBM (40,41).

In pediatric patients, these pathogenic mechanisms operate long before overt histologic abnormalities become apparent, explaining the discrepancy between early clinical findings such as hematuria and relatively preserved kidney function on routine testing. This underscores the importance of molecular diagnosis and early therapeutic intervention in childhood (42). These early molecular and biomechanical abnormalities initiate a cascade of compensatory and maladaptive pathways across the glomerular filtration barrier, including podocyte stress, endothelial injury, inflammation, and fibrosis. Recent work has demonstrated that the absence or dysfunction of the α3α4α5(IV) collagen network not only weakens the GBM structurally but also triggers aberrant signaling between the GBM, podocytes, and endothelial cells, ultimately driving progressive kidney injury (43) (Table 3).

Clinical manifestations

The classic triad of Alport syndrome includes hematuria, hearing loss, and ocular abnormalities (1,3). However, in individuals with a milder variant or AD inheritance, there may not be any extrarenal features (23,24). The specific genetic variant and inheritance pattern influence the variability in clinical features, age of onset and risk of progression (2,4).

Nearly all males with XL Alport syndrome have persistent microscopic hematuria from early childhood. Proteinuria typically develops in late childhood or adolescence and progression to ESKD occurs around 20–40 years of age. Sensorineural hearing loss and ocular abnormalities are common and often present close to the time of significant renal impairment (2,3,29). A very high incidence of hematuria is also seen in females with XL Alport syndrome, but proteinuria and ESKD are less frequent and tend to occur around 40–60 years of age along with hearing loss or ocular findings (3,18).

AR Alport syndrome affects both sexes equally, with hematuria seen from early childhood in nearly all of the individuals. Proteinuria starts in late childhood or adolescence and progression to ESKD is seen before age 40 years. Hearing loss is common and ocular abnormalities are seen in about half of these individuals (3,44).

The AD Alport syndrome usually presents with isolated hematuria. Proteinuria and decline in renal function may develop with advancing age, but progression to ESKD is less common. Hearing loss and ocular abnormalities are rare and are typically not seen until later age (3,16).

Digenic forms, involving pathogenic variants in two collagen IV genes, tend to have more severe renal and extrarenal manifestations and earlier onset than single-gene heterozygous inheritance (16,29).

The risk of ESKD and extrarenal manifestations varies among mode of inheritance and type of genetic variation. This genotype-phenotype correlation highlights the critical role of genetic testing in guiding prognosis and management of affected individuals and in facilitating informed reproductive counseling (2,4,45) (Table 4).

Emerging phenotype: cystic kidney disease in COL4A3–COL4A5 disorders

Recent studies have expanded the clinical spectrum of Alport syndrome and related collagen IV disorders to include cystic kidney phenotypes (46-48). Multiple bilateral renal cysts have been increasingly reported in individuals with pathogenic variants in COL4A5, as well as heterozygous COL4A3 and COL4A4 variants (16,49).

The prevalence of kidney cysts varies across cohorts but appears to be higher than previously recognized, particularly in adults with genetically confirmed disease. In a retrospective cohort study of 108 patients with Alport syndrome, cystic kidney phenotype was observed in 38%, significantly higher than in a comparison group with IgA nephropathy (46). Another multicenter study found that approximately 50% of individuals with heterozygous COL4A3 or COL4A4 variants had kidney cysts, a significantly higher proportion than in the general population (48). However, a separate multicenter analysis of 257 patients with Alport syndrome reported a lower prevalence of 14.8% and found no significant association between multiple kidney cysts and Alport syndrome after adjustment for age and sex, suggesting that the relationship remains debated (50). Although cysts are less commonly reported in pediatric populations, early cyst formation has been described and may become more apparent with improved imaging and longer follow-up (16,46).

The underlying mechanism is not fully understood but is thought to involve structural abnormalities of tubular basement membranes, leading to altered tubular integrity and cyst formation (47,51). Recent evidence has demonstrated that collagen α5(IV) is expressed within the tubular basement membrane of the distal renal tubule, and that ultrastructural irregularities of the tubular basement membrane occur in Alport syndrome, with tubulointerstitial fibrosis preferentially arising in the vicinity of affected distal tubules (51). This represents an extension of the basement membrane defect beyond the glomerulus to the tubular compartment. Renal cysts have been particularly associated with glycine missense variants in AD and XL forms (47). Clinically, this phenotype has important implications. Patients with collagen IV-related disease and kidney cysts may be misdiagnosed with AD polycystic kidney disease, particularly in the absence of a clear family history (46,49). A small number of patients may even present with cystic nephromegaly mimicking ADPKD (46,48). This distinction is critical, as disease progression, extrarenal manifestations, and genetic counseling differ significantly between these conditions. The presence of hematuria or a family history of hematuria or kidney disease should prompt consideration of COL4A3–COL4A5 testing even in the setting of cystic kidney disease (16,49).

Recognition of cystic features in pediatric patients is important for refining differential diagnosis, guiding genetic testing strategies, and informing family screening and kidney donor evaluation. As awareness increases, cystic kidney disease should be considered part of the broader phenotypic spectrum of collagen IV-related disorders, although further studies are needed to definitively establish the causal relationship and clarify the prevalence across different populations and age groups (47,50).

Kidney pathology

The type IV collagen abnormalities lead to a spectrum of glomerular pathology, ranging from thin basement membrane disease to focal segmental glomerulosclerosis (FSGS) (2). The severity of GBM disruption and subsequent renal damage varies by variant type. Truncating variants are associated with worse renal outcomes and younger age at onset of kidney failure compared to missense variants. This suggests that complete loss of functional collagen chains causes more severe GBM compromise than variants that produce structurally abnormal but partially functional collagen. Additionally, digenic inheritance may produce worse clinical outcomes than single-gene variants, likely reflecting structural abnormalities in two different type IV collagen genes and a more extensive disruption of the collagen network within the GBM (2). Structural weakness of the GBM results in increased biomechanical strain, which activates multiple pathogenic mechanisms. Persistence of the immature α1α1α2(IV) collagen network, which is less elastic and provides less biomechanical strength than the normal α3α4α5(IV) heterotrimer, leads to glomerular capillary distension and aneurysm formation (52).

The resulting mechanical stress interferes with integrin-mediated podocyte-GBM adhesion and increases podocyte strain via transcapillary filtration pressures. In addition, aberrant accumulation of laminin α2 within the GBM further aggravates podocyte injury. It causes defective podocyte-GBM adhesion contributing to podocyte depletion, and increases GBM susceptibility to proteolysis (52,53).

Podocyte depletion precedes overt histologic changes on light microscopy, with subtle abnormalities appearing after 30–50% depletion, FSGS developing above 50% depletion, and measurable decline in estimated glomerular filtration rate (eGFR) occurring only after more than 70% depletion. Low-grade proteinuria emerges at approximately 25% podocyte loss and increases progressively with further depletion (54). When urinary protein excretion exceeds tubular reabsorption capacity, protein uptake by proximal tubular epithelial cells activates intracellular signaling pathways and production of transcription factors and inflammatory mediators (53). Protein-truncating variants prevent α3α4α5(IV) collagen synthesis, whereas missense variants permit synthesis but cause retention of misfolded collagen within the endoplasmic reticulum, triggering cellular stress responses (2).

In children, kidney biopsy is increasingly reserved for cases in which genetic testing is unavailable, inconclusive, or discordant with the clinical presentation. When performed, electron microscopy is essential for identifying characteristic GBM abnormalities, particularly in younger children in whom light microscopy findings may be minimal or nonspecific (5,55).

Sensorineural hearing loss

Deficiency of type IV collagen disrupts the basement membrane of the organ of Corti in the inner ear, impairing auditory signal transduction and resulting in sensorineural hearing loss (56).

It was noted in the EARLY PRO-TECT Alport trial that hearing loss in children with Alport syndrome is relatively uncommon in early stages but increases in both prevalence and severity over time. In this trial the percentage of children with hearing impairment rose from 10% at baseline to 18% at the end of the trial, over a follow-up of up to six years, along with an increase in severity. Hearing loss was most pronounced at frequencies between 1–3 kHz (57).

Hearing loss in AR Alport syndrome and male XL Alport syndrome is progressive and typically shows a down-sloping audiogram configuration. Patients with truncated variants (e.g., nonsense or frameshift mutations) in AR Alport syndrome and male XL Alport syndrome have earlier onset and more severe hearing loss compared to those with non-truncated variants. In contrast, most female XL Alport syndrome and AD Alport syndrome patients maintain normal hearing, with no correlation between hearing loss and eGFR, regardless of genotype (58).

Ocular abnormalities

Collagen type IV is a critical component of basement membranes in the eye, including the lens capsule, Bruch’s membrane in the retina, and the corneal basement membrane. In Alport syndrome, mutation leads to defective or absent collagen α3α4α5(IV) networks, resulting in basement membrane thinning, fragility, and structural disorganization (59).

Common ocular abnormalities in Alport syndrome include recurrent corneal erosions, corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning. These features typically do not impair vision, except for lenticonus, which is correctable. However, rare complications such as posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy can cause visual loss (60).

The presence of lenticonus or central retinopathy in a young male with hematuria strongly points to XL Alport syndrome and a higher risk of renal failure before age 30 years. Ocular findings can also help infer inheritance patterns. Lenticonus is more common with a large deletion or a protein-truncating mutation compared with a non-truncating or abnormal slicing mutation (61,62). Peripheral retinopathy in a mother of an affected male suggests XL disease, while central retinopathy or lenticonus in a female suggests AR disease which is associated with early-onset renal failure (60). Ocular abnormalities are rare in AD Alport syndrome (23).

Ocular examination, slit lamp examination, retinal photography, and optical coherence tomography are recommended as they are accessible, safe, and useful for diagnosis, inferring the underlying genetic inheritance pattern and predicting the likelihood of early-onset renal failure—especially when genetic testing is unavailable or inconclusive. These ophthalmic assessments also help detect and prevent severe outcomes like blindness and retinal detachment (3,16,27,63).

Diagnostic approach in pediatric patients

A genetics-first diagnostic approach is now recommended for children with suspected Alport syndrome, particularly those with persistent hematuria, a family history of kidney disease, or extrarenal manifestations (4,16). Genetic testing allows for definitive diagnosis, avoids invasive procedures, and provides prognostic and reproductive counseling information at an early stage.

Multidisciplinary evaluation, including audiologic and ophthalmologic assessment, should be incorporated into the diagnostic pathway (3,4). Kidney biopsy should be considered selectively, primarily when genetic testing is not available or fails to identify a pathogenic variant despite strong clinical suspicion (3,5,16,55) (Figure 1).

Figure 1 Diagnostic algorithm for suspected Alport syndrome in children. This algorithm outlines a genetics-first approach to diagnosing Alport syndrome in children, emphasizing early genetic testing, selective kidney biopsy, and multidisciplinary evaluation to guide prognosis and management. AD, autosomal dominant; AR, autosomal recessive; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; OCT, optical coherence tomography; RAAS, renin-angiotensin-aldosterone system.

Indications for genetic testing and family screening

Genetic testing for COL4A3–COL4A5 genes is recommended for individuals with persistent unexplained hematuria, significant proteinuria, steroid-resistant nephrotic syndrome, biopsy-proven FSGS, unexplained kidney failure, or characteristic ocular or auditory findings, particularly when there is a family history of hematuria or kidney disease. It is also indicated when kidney biopsy shows GBM abnormalities or in familial IgA glomerulonephritis. Pathogenic variants are more frequently identified in familial cases, and detection rates are similar in children and adults (16).

All three COL4A3–COL4A5 genes should be evaluated for pathogenic variants, and pathogenic or likely pathogenic variants in any of these genes should be reported, even when a primary variant is identified, because of their potential role in modifying the phenotype (4,16).

Genetic testing helps confirm inheritance patterns, guides prognosis, and may eliminate the need for kidney biopsy. First-degree relatives of affected individuals should be tested to determine carrier or disease status, as hematuria alone is unreliable. Testing is also essential to confirm AR disease, assess disease severity based on variant configuration, evaluate reproductive risk in partners, and ensure suitability of potential kidney donors (16).

In pediatric patients, genetic testing should be accompanied by appropriate counseling to address ethical considerations, including psychosocial impact, disclosure within families, and implications for future insurability and reproductive decision-making (37).

Guideline-based management recommendations

Current management strategies for Alport syndrome are informed by international consensus guidelines, including the 2024 ERKNet/ERA/ESPN clinical practice guideline, which emphasizes early genetic diagnosis, proactive monitoring, and timely initiation of therapy (4) (Table 5). As genotype resolution improves, variant-specific risk stratification may increasingly inform clinical trial enrollment criteria in children, enabling more precise selection of patients most likely to benefit from early intervention and facilitating genotype-stratified trial designs (4,64).

Treatment strategies

Renal management

Early RAAS blockade significantly delays progression (6,7). Current therapeutic approaches are increasingly viewed as targeting overlapping, stage-specific disease mechanisms, including restoration of the α3α4α5(IV) collagen network, reduction of biomechanical strain and hyperfiltration, correction of misfolded collagen, modulation of abnormal GBM-podocyte signaling, protection against endothelial injury, and suppression of inflammation and fibrosis (43).

Because these pathways operate concurrently, combination therapy is likely required to achieve durable disease modification. In a retrospective study of 283 patients from Alport families, Gross et al. demonstrated that early angiotensin-converting enzyme (ACE) inhibition at the stage of hematuria or microalbuminuria prevented progression to renal failure, whereas treatment initiated at the proteinuria stage delayed median dialysis from age 22 to 40 years (6). A systematic review and meta-analysis of eight studies (1,182 patients) confirmed that RAAS blockers reduced the risk of ESKD [hazard ratio (HR) 0.33, 95% confidence interval (CI): 0.24–0.45], with the greatest benefit observed when treatment was initiated early in the disease course (7). In a retrospective study of 430 Japanese patients with male XL Alport syndrome, Yamamura et al. demonstrated that renin-angiotensin inhibitors delayed the median onset of ESKD from 28 years to over 50 years, with a strong genotype-phenotype correlation influencing treatment response (9). A randomized controlled trial evaluating lademirsen, an anti-miR-21 oligonucleotide, for its effect on kidney function decline in adults with Alport syndrome showed that lademirsen did not significantly slow the rate of eGFR decline compared to placebo (65).

In children, initiation of RAAS blockade at the earliest signs of disease, or even in the pre-proteinuric stage in high-risk genotypes, has been shown to significantly delay progression to kidney failure and is now considered standard of care (4,66).

Hearing management

In Alport syndrome, no disease-modifying treatments for hearing loss are currently approved. Hearing aids are commonly used for sensorineural hearing loss in Alport syndrome. Cochlear implantation is effective in severe cases and the results are comparable to other genetic conditions with sensorineural hearing loss (67).

Ophthalmologic management

Ocular abnormalities in Alport syndrome are primarily managed by supportive care or surgical interventions and the effectiveness of treatment modality varies by the specific abnormality. There is currently no disease-modifying therapy for the underlying collagen defect (63,68).

Visual loss in Alport syndrome is most commonly due to anterior lenticonus, the most distinctive ocular lesion, which can be effectively managed with cataract extraction and intraocular lens implantation. This approach is effective in restoring vision, though technical challenges exist due to lens capsule fragility (3,63,68).

Macular holes can be managed with vitrectomy. Retinal detachment, though rare, can be managed with standard retinal surgical techniques, but there is limited evidence on outcomes specifically in Alport patients (63). Fleck retinopathy and macular thinning are common but typically do not impair vision and do not require intervention (3,60,63,68).

Gene therapy and stem cell therapy are under investigation but remain experimental; current evidence does not support their clinical use for ocular manifestations. They do not address the developmental changes already present or prevent progression of ocular disease in Alport syndrome (11,63,68).

Emerging and future therapies

Emerging therapies for Alport syndrome are increasingly designed to target the earliest molecular drivers of disease rather than downstream scarring alone. Preclinical and early clinical studies now support a shift toward pathway-specific intervention, including gene repair or exon skipping to restore collagen IV networks, reduction of intraglomerular strain, modulation of podocyte-GBM signaling, endothelial protection, and antifibrotic strategies (43).

Sparsentan, a dual inhibition of the endothelin type-A and angiotensin II type 1 receptors, has shown a therapeutic advantage over standard RAAS blockade alone in preclinical models. Sparsentan significantly improved both renal and inner ear pathologies in AR Alport syndrome mouse models. It delayed the onset of glomerulosclerosis, interstitial fibrosis, proteinuria, and decline in glomerular filtration rate. It also improved lifespan compared to losartan. In the inner ear, sparsentan also prevented extracellular matrix accumulation in the strial capillary basement membranes and reduced susceptibility to hearing loss (69). Trichostatin A, a histone deacetylase inhibitor, reduced oxidative stress and inflammation in the cochlea in a COL4A3 knockout mouse model of Alport syndrome which significantly suppressed hearing loss (70).

Despite promising preclinical and early clinical data, pediatric participation in therapeutic trials remains limited, highlighting an urgent need for age-specific studies to establish safety, efficacy, and optimal timing of novel interventions in children with Alport syndrome (4,42).

Kidney transplantation and living donation

Kidney transplantation outcomes in children with Alport syndrome are generally excellent, with an exceedingly low risk of disease recurrence in the allograft. However, a small subset of patients may develop post-transplant anti-GBM disease, necessitating careful post-transplant monitoring (71,72). This rare complication occurs when the recipient’s immune system mounts an alloimmune response against normal type IV collagen α3/α4/α5 chains in the donor GBM—chains that are absent in the native kidneys of patients with severe mutations, particularly those with XL Alport syndrome. The incidence of clinically significant post-transplant anti-GBM nephritis is low (~2–5%), typically manifesting within the first year, although later onset has been reported (72,73). Clinically, it may present as rapidly progressive glomerulonephritis with linear IgG deposition along the GBM, which may not always be detected by standard serologic assays, often requiring biopsy for confirmation (73). When anti-GBM nephritis develops, it is frequently associated with graft dysfunction and an increased risk of graft loss, though milder, subclinical patterns of linear IgG deposition without overt nephritis have also been observed. Risk is higher in male recipients with severe COL4A5 mutations, and recurrence in subsequent transplants has been documented (74).

Individuals with pathogenic COL4A3–COL4A5 variants are generally unsuitable as kidney donors due to their inherent risk of progressive kidney disease. Females with COL4A5 variants and both genders with digenic COL4A3–COL4A5 variants should not donate kidneys. Emerging evidence indicates that heterozygous COL4A3 or COL4A4 variant carriers also experience greater post-donation decline in kidney function compared with other donors and should therefore be excluded. Genetic testing is recommended for potential donors with suspected COL4A3–COL4A5 variants to confirm diagnosis, define inheritance patterns, and inform donor eligibility, as results may preclude donation (16).

Psychosocial impact and transition of care

The presence of CKD, hearing impairment, and genetic diagnosis can have significant psychosocial effects on children and adolescents with Alport syndrome, influencing quality of life, educational attainment, and mental health (75,76). Structured transition from pediatric to adult nephrology care is essential to ensure continuity of monitoring, adherence to therapy, and informed reproductive counseling as patients reach adulthood (75,76).

Strengths and limitations

This review has several strengths. It provides a comprehensive synthesis of current evidence on Alport syndrome with a specific emphasis on pediatric disease, integrating advances in genetic diagnostics, genotype-phenotype correlations, and contemporary management strategies (2-4,16,29). The inclusion of emerging concepts, such as digenic inheritance and cystic kidney phenotypes, reflects the evolving understanding of collagen IV-related disorders and enhances the clinical relevance of the review (14,36,46,47).

However, several limitations should be acknowledged. As a narrative review, the methodology does not follow a formal systematic approach, and therefore may be subject to selection bias. Although a structured literature search was performed, formal study quality assessment and quantitative synthesis were not conducted. Additionally, variability in study design, population characteristics, and reporting across the included literature may limit direct comparison of findings.

Despite these limitations, the review aims to provide a balanced and clinically meaningful synthesis of current knowledge, with particular relevance to pediatric nephrology practice.

Future directions

Future research in Alport syndrome should prioritize pediatric-specific studies aimed at refining genotype-based risk stratification and optimizing the timing of therapeutic interventions (4,42,64). The 2024 ERKNet/ERA/ESPN guideline highlights the scarcity of clinical trials in children as a major knowledge gap (4). Expanding access to genetic testing and improving variant interpretation frameworks will be essential to address current diagnostic challenges, particularly for VUS (16,26,27).

There is a growing need for clinical trials that include pediatric populations to evaluate emerging therapies targeting early disease mechanisms, including gene-based approaches and pathway-specific interventions (43,66,77). Preclinical studies have demonstrated the feasibility of exon-skipping therapy for XL Alport syndrome, with restoration of collagen IV α5 chain expression and improvement in kidney pathology in mouse models (77). Gene editing using CRISPR/Cas9 has achieved variant-specific correction in patient-derived podocyte-lineage cells, and AAV9-mediated gene delivery to Alport podocytes has shown proof-of-concept in vivo. Multiple ameliorating therapies, including endothelin receptor antagonists, FXR agonists, and NOX1/4 inhibitors, are currently being evaluated in phase II clinical trials, though predominantly in adult populations (10,66). The 2024 International Workshop on Alport Syndrome emphasized the need for standardized variant interpretation across diverse populations, expanded access to genetic testing in low- and middle-income countries, and coordinated international efforts to accelerate clinical trial enrollment, including pediatric populations (10). In addition, further investigation into non-classical phenotypes, such as cystic kidney disease and digenic inheritance, will improve diagnostic accuracy and clinical management (14,36,46).

As precision medicine approaches continue to evolve, integrating genomic data with longitudinal clinical outcomes offers the greatest opportunity to improve long-term prognosis and quality of life for children with Alport syndrome (2,10,42,43).

Conclusions

Alport syndrome is a genetically heterogeneous disorder that frequently presents in childhood with persistent hematuria and carries a lifelong risk of progressive kidney disease and extrarenal complications (2,3). Advances in genetic testing have transformed diagnostic strategies, enabling earlier and more accurate identification of affected children, including those with AD and digenic disease (4,16,25,78).

In pediatric practice, a genetics-first approach is essential, as early diagnosis allows for risk stratification, targeted surveillance, and timely initiation of RAAS blockade, which has been shown to delay disease progression (6-8). The EARLY PRO-TECT trial demonstrated the safety and supportive evidence for efficacy of ramipril in children with early-stage Alport syndrome, reinforcing the value of preemptive therapy (8). Integration of genetic findings with clinical features is increasingly important for guiding management decisions and family counseling (12,16,29).

Recognition of expanding phenotypes, including cystic kidney disease, further underscores the need for precise molecular diagnosis (46-48). A multidisciplinary approach remains critical for optimal care, incorporating nephrologic, audiologic, ophthalmologic, and genetic expertise (3-5).

Acknowledgments

Artificial intelligence-assisted language tools were used to support manuscript editing for clarity and readability. All content was reviewed, verified, and approved by the authors, who take full responsibility for the accuracy, interpretation, and integrity of the work.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-26-0027/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-26-0027/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-26-0027/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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