Alport syndrome is the second most common inherited kidney disease, characterized by variable kidney manifestations ranging from persistent glomerular hematuria to early-onset kidney failure. Additionally, a considerable proportion of patients experience sensorineural hearing loss and ocular anomalies [1,2]. Before 2010, diagnosis primarily relied on traditional methods, including kidney biopsy and Sanger sequencing, with the prevalence of Alport syndrome estimated to be between 1 in 5,000 and 1 in 50,000 individuals [3,4]. However, with recent advances and widespread clinical applications of genetic testing, it has become evident that Alport syndrome is far more common than previously recognized [5]. Population-based genome sequencing data indicate that heterozygous variants in COL4A5 occur in approximately 1 in 2,500 individuals and that mutations in COL4A3 or COL4A4 may be found in about 1 in 200, suggesting that COL4A-related disorders collectively represent one of the most common causes of hereditary kidney disease [6–8].

Despite these findings, many patients with Alport syndrome remain undiagnosed until they progress to advanced kidney failure. Moreover, in some cases, kidney biopsy findings, such as focal segmental glomerulosclerosis, have led to a misdiagnosis of immune-mediated glomerulonephritis, resulting in potentially harmful immunosuppressive treatments [5,9]. Even following a confirmed diagnosis, some patients do not receive renin-angiotensin system (RAS) inhibitors, which have been reported to delay kidney failure by more than 10 years [10]. To increase the diagnosis rate and provide appropriate treatment to diagnosed patients, it is critical to first assess current diagnostic and treatment patterns.

Nevertheless, most epidemiological studies on Alport syndrome to date have been limited to regional hospital-based cohorts or collaborative nephrologist reports [4,11–14]. Although such studies are important for elucidating the natural course and genotype–phenotype correlations in Alport syndrome, they do not adequately determine whether the physician-based diagnosis rate aligns with the expected prevalence, nor do they address recent diagnostic and therapeutic trends on a nationwide level. To overcome these limitations, the present study leverages Korea’s mandatory health insurance system and its “rare disease subsidy program,” thereby enabling the inclusion of all physician-identified cases of Alport syndrome. Using this resource, we aim to (1) evaluate the prevalence of Alport syndrome in Korea and trends in its incidence, (2) investigate the kidney-related therapeutic journey before diagnosis was made, and (3) explore the extent to which patients receive appropriate treatments, particularly RAS inhibition, after diagnosis. Our hypothesis is that although improvements in genetic testing have led to increased detection of Alport syndrome across all age groups, the disease remains broadly underdiagnosed. Moreover, among the patients who are diagnosed, a significant subset may have initially received immunosuppressive therapy under the diagnosis of immune-mediated glomerulonephritis.

This study utilized data from the Korean National Health Information Database provided by the Korean National Health Insurance System (NHIS), a mandatory healthcare system covering the entire Korean population. Notably, a rare disease subsidy program has been in effect since 2006 for certain designated rare diseases. Under this program, once physicians issue the registration certificate, patients who receive medical services under the specific code for each rare disease can receive up to a 90% reduction in copayments. Because the NHIS can refuse registration if the diagnosis does not meet the specific criteria for each rare disease, the sensitivity and specificity of this rare disease coding are higher compared with general International Classification of Diseases (ICD) codes; previous population-based epidemiological studies on other rare diseases have employed these codes [15,16]. Among kidney diseases, autosomal dominant polycystic kidney disease, nephrogenic diabetes insipidus, and lupus nephritis are designated as rare diseases; Alport syndrome was added to this list on February 1, 2014. To qualify for Alport syndrome registration, patients need 1) documented laboratory examinations such as hematuria and/or proteinuria, and 2) either genetic or histopathological evidence compatible with Alport syndrome. In this study, individuals were defined as having Alport syndrome if they had at least one instance of rare disease registration with the specific Alport syndrome code (V267) and had received clinical care under that code.

This study followed the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines. The Institutional Review Board of Ajou University School of Medicine waived the ethical review for this research.

In this study, we found that the number of registered cases accounted for approximately 10% of the predicted burden based on population genetic estimates of male COL4A5 variants. While this comparison relies on assumptions regarding penetrance and genetic epidemiology that may differ in the Korean population, the observed discrepancy nonetheless suggests that a substantial proportion of potentially affected individuals are not captured by the registration dataset. This substantial diagnostic gap likely reflects multiple factors. First, limited awareness of Alport syndrome among healthcare providers, particularly in primary care and general nephrology settings, may result in missed opportunities for early recognition of characteristic clinical features such as persistent hematuria with a family history of kidney disease. Second, although genetic testing has become more accessible through programs such as the Korean Genetic Diagnosis Program for Rare Disease since 2017, the high cost of comprehensive genetic testing and limited insurance coverage for many genetic panels may create financial barriers to definitive diagnosis [13,17]. Third, inadequate family history taking in routine clinical practice may fail to identify the hereditary nature of kidney disease, leading to misclassification as idiopathic chronic kidney disease or glomerulonephritis. Additionally, the phenotypic variability of Alport syndrome, particularly in female carriers and patients with autosomal dominant forms, may contribute to diagnostic delays when classic extrarenal manifestations are absent.

A relevant comparison can be drawn from a Finnish study conducted in 1996, in which investigators contacted every nephrology center to identify patients with Alport syndrome; the prevalence was estimated to be 1 in 50,000 [4]. Despite the widespread adoption of genetic testing in the three decades since that study, including the partial reimbursement of next-generation sequencing for suspected hereditary diseases by the Korean national insurance system since 2017, the current prevalence rate, confirmed by physicians, has not markedly increased. The diagnostic challenges identified in our study align with recent findings from other healthcare systems. A survey of Asian pediatric nephrologists revealed that while genetic testing was available in 78% of institutions across 22 Asian countries, cost remained prohibitive in most settings [18]. This suggests that the diagnostic gap observed in Korea reflects broader regional challenges in accessing definitive genetic diagnosis for hereditary kidney disease. Moreover, although it is difficult to determine the genotypes of the patients enrolled in this study, considering that diagnoses were likely made primarily in severe cases, it can be inferred that most autosomal dominant Alport syndrome patients, estimated at about 1 in 200, remain undiagnosed [6]. According to the latest clinical guidelines, regular urinalysis and kidney function monitoring, as well as early RAS inhibition following the onset of microalbuminuria, are essential for these individuals. Studies have demonstrated that angiotensin-converting enzyme inhibitors can extend renal survival by an average of 10–15 years when initiated early in the disease course, with the greatest benefit observed when treatment begins before the development of proteinuria or significant kidney function decline [18–20].

An additional concern is the relatively frequent use of immunosuppressants, which did not show a clear declining trend even after diagnosis. Although our claims data cannot determine the indication and some prescriptions may reflect comorbid conditions managed by other specialties (e.g., rheumatology or hematology-oncology) or overlapping pathology, the persistent use of immunosuppression remains concerning because Alport syndrome is a hereditary nephritis that is not expected to respond to immunosuppressive therapy. Such treatments are not only ineffective but may expose patients to unnecessary side effects and complications, including increased infection risk, while delaying the implementation of evidence-based therapies such as RAS inhibition. Accurate diagnosis and effective dissemination of clinical guidelines could help reduce the unnecessary use of immunosuppressive therapy and its associated adverse effects. Encouragingly, RAS inhibitor prescriptions increased by approximately 25% following diagnosis, suggesting improved awareness of evidence-based treatment guidelines among clinicians. However, the overall prescription rate for RAS inhibitors remained around 50%, which may reflect several factors including physician unfamiliarity with Alport syndrome management guidelines, concerns about potential side effects in younger patients, or inadequate assessment of disease severity. Although the exact clinical status of these patients is unclear—whether they had only persistent hematuria or had progressed to microalbuminuria or proteinuria—the substantial diagnostic gap identified in our study suggests that many diagnosed cases likely represent more severe phenotypes that would clearly benefit from RAS inhibition. Given that approximately 90% of patients with Alport syndrome remain undiagnosed, those who do receive a diagnosis are presumably patients with more apparent clinical manifestations or advanced diseases. This selection bias toward more severe cases makes the suboptimal RAS inhibitor prescription rate even more concerning. Raising awareness of Alport syndrome among healthcare providers and emphasizing the importance of early RAS inhibition, regardless of clinical severity, is crucial for improving patient outcomes.

Over the years, cohort-based and collaborative studies have provided valuable insights into the natural history and genotype–phenotype correlations of Alport syndrome [14,21–24]. However, national-level reports were limited. This study plays an important role in bridging this knowledge gap by providing the first nationwide, population-based analysis of Alport syndrome diagnosis and treatment patterns. The use of mandatory health insurance data ensures comprehensive capture of all physician-diagnosed cases, eliminating selection bias inherent in hospital-based cohorts.

First, reliance on the V267 rare disease registration code, rather than the general ICD-10 code Q87.8, likely underestimated the true prevalence of clinically diagnosed Alport syndrome in Korea. We selected V267 because Q87.8 is not routinely available in the standard NHIS research database and because V267 requires confirmatory genetic or histopathologic testing, providing higher diagnostic certainty than Q87.8, which may be assigned presumptively. However, V267 registration also requires fulfillment of predefined clinical criteria (e.g., family history and extrarenal manifestations such as sensorineural hearing loss and/or ocular abnormalities). Consequently, milder phenotypes (e.g., isolated hematuria or early-stage disease) and patients who did not complete registration because of administrative burden may not have been captured. Further, comparisons with population genetic data require assumptions about penetrance and genetic epidemiology in the Korean population. Accordingly, our estimate (15.5 per million) reflects confirmed, registered cases rather than all individuals with Alport syndrome, and the true prevalence is likely higher. Additionally, we relied on physician-assessed Alport syndrome diagnoses, meaning all potential modes of inheritance may have been included. This broad inclusion criterion raises the possibility that some patients may also have coexisting immune-mediated glomerulonephritis, such as focal segmental glomerulosclerosis or immunoglobulin A nephropathy, especially in cases where individuals registered as having autosomal dominant Alport syndrome continued to receive immunosuppressants. Moreover, debate remains regarding the precise diagnostic boundaries of Alport syndrome, particularly in individuals with heterozygous COL4A3 or COL4A4 mutations who present only with persistent glomerular hematuria [8,25,26]. Nonetheless, there is a clear consensus that these conditions are not benign and warrant vigilant long-term follow-up. As genetic diagnostic methods continue to advance, physicians’ awareness of Alport syndrome has also increased, which bodes well for earlier detection and better patient management in the future.

Future research should focus on developing systematic screening protocols for at-risk individuals, implementing educational programs for healthcare providers, and establishing genetic counseling services to improve family cascade screening. The substantial diagnostic gap identified in this study suggests the need for expanded insurance coverage of genetic testing for hereditary kidney diseases and the implementation of systematic screening protocols to improve early detection of Alport syndrome. Encouragingly, diagnostic rates have increased over time, reflecting improved awareness. These findings highlight the need for expanded genetic testing access and clinician education to optimize early diagnosis and evidence-based treatment for Alport syndrome patients.