Introduction
Alport syndrome (AS), the prototype of inherited progressive glomerulopathies, is often accompanied by sensorineural hearing loss (SNHL) and ocular abnormalities. Isolated microscopic hematuria (mHU) is the typical manifesting symptom of AS, which progresses with the development of microalbuminuria, followed by overt proteinuria and, ultimately, leads to declining kidney function. AS can either be inherited as X-linked (XLAS) by pathogenic variants in COL4A5, or as the autosomal recessive (ARAS) or dominant (ADAS) forms by pathogenic COL4A3 or COL4A4 variants. Males with XLAS and both genders with ARAS invariably end up with kidney failure, while females with XLAS and individuals with ADAS have better outcomes [1].
The prevalence of AS has been known to be approximately 1/50,000 and Korean prevalence is not known yet. However, recent population genetics have indicated a greater prevalence of predicted COL4A3–5 pathogenic variants: in a United Kingdom biobank analysis, 1 in 106 individuals had pathogenic heterozygous COL4A3 and COL4A4 variants, and 1 in 2,320 individuals had the pathogenic COL4A5 variants, making AS the most prevalent inherited kidney disease and probably more common than the autosomal dominant polycystic kidney disease [2]. Notably, thin basement membrane nephropathy (TBMN), traditionally labeled as “benign familial hematuria,” is often associated with pathologic variants causing ADAS, and some of the patients progress to kidney failure [3,4]. Moreover, the genetic tests for chronic kidney disease (CKD) of unknown cause and other kidney diseases including steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis (FSGS), immunoglobulin A nephropathy (IgAN), diabetes nephropathy, or hypertensive nephropathy often reveal the pathogenic variants of COL4A3–5 [5–8]. Currently, it is unclear if Korean nephrologists would consider AS in the above conditions.
Traditionally, kidney biopsy has been a gold standard to diagnose AS, with a typical “basket-weave” appearance in the glomerular basement membrane (GBM) and loss of collagen type IV α5 staining in GBM. However, early-stage or mild phenotypes might not exhibit the basket-weave pattern [9]. Furthermore, collagen type IV α5 staining can be normal in cases of non-truncating variants of collagen type IV novel chains [10–12]. On the other hand, genetic testing can overcome the limitations of kidney biopsy, enabling the early diagnosis of AS at any age and across all phenotypes, with a high sensitivity and specificity of over 95% [13] and offers prognostic insights [14,15]. Consequently, genetic testing for AS has emerged as the diagnostic gold standard over the last decade [6,13,16,17]. In Korea, genetic testing for AS is relatively affordable and available compared to other countries, but the practice pattern of using gene tests is highly variable between centers.
While there is no cure for AS, the renin-angiotensin system (RAS) blockade delays disease progression [18]. Early and aggressive intervention can enhance this effect significantly, especially in individuals with genotypes associated with poor kidney outcomes [19,20]. Thus, the Alport syndrome Research Collaborative strongly recommends prompt initiation of treatment following diagnosis for XLAS males and ARAS patients over 1 year of age and upon detection of microalbuminuria for XLAS females and ADAS patients. Maintenance of RAS blockade at the maximum tolerable dose is strongly advised, irrespective of proteinuria levels in all cases [21]. However, it is unknown whether the efficacy and necessity of early, aggressive treatment of AS is well understood by Korean doctors, as well as the requirement of regular screening of hearing impairment in this patient population.
Apparently, consensus on management for AS is lacking in Korea. Thus, the Genetic Kidney Disease Study Group under the Korean Society of Nephrology (KSN) is developing clinical practice recommendations (CPR). We conducted this survey because CPR should be tailored to the needs of Korean practice. The aim of this study is to assess the level of awareness among Korean nephrologists regarding AS and evaluate the understanding of patients and their caregivers regarding the condition and its treatment.
Methods
This study was approved by the Institutional Review Board of Bundang Seoul National University Hospital (No. B-2301-807-302). An online survey was conducted in South Korea from January 2023 to April 2023, by emailing registered members of the KSN and the Korean Society of Pediatric Nephrology (KSPN) to evaluate the current state of clinical practice in diagnosing and treating AS. A separate online survey was conducted on AS patients aged 18 years and older and caregivers of those under 18 years to assess their understanding of the disease and their unmet medical needs. The questions in the survey were generated by the corresponding author and reviewed by leading core members of the CPR production committee. The detailed survey form is provided in Supplementary Tables 1 and 2 (available online).
Statistical analysis was conducted using descriptive statistics to summarize the survey responses. The variables between different groups were compared using the chi-square and Fisher exact tests. The IBM SPSS Statistics version 20.0 (IBM Corp.) was used for all statistical analyses. A significance level of p < 0.05 was used to determine statistical significance.
Results
We received responses from 103 medical professionals (4.1%) among 2,528 email recipients. Seventy-five respondents were adult nephrologists, and 28 were pediatric nephrologists. Two-thirds of the respondents had worked at a tertiary medical center for more than 10 years. One-third had been treating five or more patients with AS and half had treated less than five. There was no significant difference in baseline characteristics between the adult and pediatric nephrologists.
Clinical suspicion of Alport syndrome
In a typical male AS case with an evident family history of CKD on the maternal side and suspected glomerular disease, 89 respondents (86.4%) suspected AS. However, only half of the responders considered the possibility of AS in each case of 1) asymptomatic mHU in school screening with a family history of hematuria, 2) a young female with suspected glomerulonephritis and family history of CKD, or 3) a young male with CKD of unknown cause accompanied by hematuria and proteinuria. In cases of recurrent gross hematuria with a febrile event at diapered age, only one-fifth of the respondents suspected AS.
Diagnosis of Alport syndrome
Over half of the respondents preferred the confirmation test immediately upon suspicion of AS, and the others responded that they would wait until overt proteinuria becomes evident (43.9%). Most adult nephrologists (70%) preferred kidney biopsy as confirmation testing, while more than half of the pediatric nephrologists chose genetic testing (p < 0.001) (Fig. 1). Genetic testing was considered essential for diagnosing AS by two-thirds of pediatric nephrologists and half regarded a kidney biopsy as unnecessary if AS is confirmed by genetic testing. In contrast, only one-fifth of adult nephrologists held this perspective (p < 0.001). About half of the centers had the facility for genetic testing. More than half of the respondents with access to genetic testing preferred a targeted exome sequencing panel that includes other kidney disease-related genes in addition to COL4A3–5. If genetic testing is unavailable, all pediatric nephrologists seek outsourcing, while one-fifth of adult nephrologists skip genetic testing (Table 1).
Eighty percent of the respondents diagnosed AS based on the pathologist’s judgment. While most respondents considered the basket-weave pattern or loss of staining for collagen type IV alpha 5 indicators of AS, only half or fewer recognized TBMN and FSGS might also imply AS. Twenty percent of the respondents considered IgAN, and 24% believed normal findings are possible in AS (Table 1).
Audiometry and ophthalmic examination in Alport syndrome
Seventy percent of respondents opined that audiometry and ophthalmic examinations should be conducted immediately after the diagnosis of AS. Fifteen percent of respondents believed that these exams are necessary when symptoms of hearing impairment or visual discomfort are present. Less than 10% of respondents thought that the decision must be made based on the inheritance type, proteinuria, or age.
Treatment of Alport syndrome
RAS inhibitors (RASi) were considered as the treatment choice for AS by all respondents, followed by sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists. More than 80% of respondents from both KSN and KSPN member groups did not use dual RAS blockade. With regards to the RASi options, angiotensin receptor blockers (ARB) were preferred over angiotensin-converting enzyme inhibitors (ACEi) by approximately 80% of the respondents. Almost all adult nephrologists prefer ARB, while about 70% of pediatric nephrologists prefer ACEi (p < 0.001). Most adult nephrologists have titrated RASi dosage based on the level of proteinuria. In contrast, half of the pediatric nephrologists would prescribe the dosage using body weight or body surface area, maintaining the maximum tolerable dose regardless of the amount of proteinuria (p < 0.001) (Table 2).
For male XLAS and ARAS patients, one-third of respondents preferred initiating treatment immediately upon diagnosis, whereas the other one-third preferred to wait until overt proteinuria becomes evident. For XLAS females and ADAS patients, half of the respondents preferred treatment at the microalbuminuria stage (Fig. 2). The timing of initiating treatment did not differ significantly between adult and pediatric nephrologists.
Genetic testing for family members and genetic counseling
Half of the respondents intended to perform genetic testing on first-degree family members of an AS patient if they have hematuria or proteinuria, and one-third performed genetic testing regardless of the urinalysis results. In case of a variant of unknown significance, over half of pediatric nephrologists would do family genetic testing even, while only one-fourth of adult nephrologists shared this perspective (p = 0.007) (Fig. 3). Most respondents supported genetic testing of family member candidates of transplantation; however, only 60% reported that they were currently testing in their practice. When a donor candidate was a heterozygote of the same variant as the patient, one-third of the respondents would decline the donor, while half responded that they would rely on the patient’s decision after a detailed discussion regarding the risks of kidney failure after donation.
Regarding genetic counseling, approximately 90% of the respondents stated that they would discuss the prognosis of AS patients, followed by management advice such as lifestyle modification and explanation of the inheritance risk to offspring.
Patients and caregivers’ perspectives
Approximately 350 patients or their caregivers were contacted, and 88 responses (25.1%) were collected. While 80% of the AS patients did understand the nature and prognosis of AS, only half of their family members did. Half of the participants were aware of the inheritance pattern of their disease. Forty percent of respondents were undergoing regular auditory exams, while 10% were not aware of the necessity of these exams. With regards to AS guidelines, three-quarters of the respondents opined that the guidelines should prioritize treatment, followed by genetic counseling and diagnosis. The primary regrets of the patients and their families included delayed diagnosis, insufficient explanation or lack of explanatory materials, lack of curative treatment options, and absence of patient support groups.
Discussion
In this study assessing the awareness of AS in Korean medical professionals, a significant gap was observed between reality and what is currently recommended in the literature. To begin with, most responders had treated fewer than 10 patients suffering from AS; considering the prevalence of AS is now known as high as approximately 1% of the general population [2], many AS patients may not have been recognized as AS, although the prevalence of pathogenic variants in Korea has not been investigated yet. This is probably because genetic testing is not readily available in the practice of nephrology. Given the high probability of AS in CKD of unknown origin and familial cases and the efficacy of early intervention, high suspicion of AS implementing genetic testing is highly warranted in Korea.
As treatment of AS, all surveyed nephrologists unanimously chose RAS blockade. However, only one-third of responders agreed with immediate prescription of RAS blockade following diagnosis of male XLAS and ARAS patients, while half would start treatment after detection of microalbuminuria in female XLAS and ADAS patients. Such reluctance has been previously documented in Asian countries [22]. Furthermore, while nearly half of the pediatric nephrologists have been maintaining the maximum tolerable dose of RAS blockade regardless of the amount of proteinuria, almost all the adult nephrologists have titrated its dose by proteinuria level. This suggests that when a patient transitions to internal medicine in adulthood, there may be changes in treatment, such as dose reduction, making continuity of care potentially challenging. Interestingly, among RAS blockade, ARB was strongly favored by adult nephrologists compared with their pediatric counterparts. Based on two large European clinical trials (ESCAPE [23] and EARLY PRO-TECT Alport [19] trials) on pediatric CKD and AS, indicating the efficacy and safety of ramipril in children, current guidelines recommend ramipril as a reference medication [21]. Although direct comparisons between ACEi and ARB in AS are scant, a systematic review has demonstrated comparable antiproteinuric effects in primary hypertension [24], thereby highlighting the need for more comprehensive research.
AS is a familial disease, and earlier intervention would lead to better outcomes for patients. Therefore, active screening of the other family members for the disease and genetic counseling are recommended. Genetic testing is particularly mandatory for potential living-related donors, considering the inheritance pattern of the family. If a potential donor possesses the same variant as an AS patient, the risk of CKD following kidney donation is not negligible, and therefore, such a person should refrain from donating even if being currently asymptomatic [17,25]. However, current Korean practice is not addressing this issue properly. Considering the difficulties encountered in finding a suitable kidney donor in Korea, the policy of donor selection from family members of AS patients needs to be discussed based on the best knowledge of current evidence.
The survey for the patients and caregivers revealed the unmet need for early diagnosis, sufficient explanation, and patient support groups. To facilitate better communication with patients and further enhance compliance, comprehensive explanatory materials, such as illustrative materials or videos, would be helpful. Moreover, establishing a registry and patient support groups similar to those in other countries, such as https://alportsyndrome.org/, would be advantageous. Importantly, regular auditory examinations are being conducted on less than half of the patients; SNHL is an important extra-renal symptom of AS, occurring in 60% of XLAS males by the age of 20 years and potentially being even more common in ARAS patients [26,27]. Even mild hearing loss in children can impact speech-language development, social behavior, cognitive development, and academic performance [28]; and early intervention with the installation of hearing aids could facilitate intelligence development [29]. Therefore, active surveillance and intervention are mandatory, and better awareness of this condition is needed.
This study had several limitations. First, limited numbers of voluntary responses to questionnaires could introduce both selection and recall biases. Second, only a few specialists are experienced in treating this disease. However, considering that the majority of active members of KSPN (approximately 30) responded and awareness of AS is higher among pediatric nephrologists than in adult counterparts, in addition to the rarity of diagnosed patients of AS in Korea, we believe the survey results can be considered representative. Nevertheless, this is the first survey to explore current clinical practices and perceptions of patients and caregivers regarding AS in South Korea. We hope that this survey will help raise awareness of AS, as well as serve as the cornerstone for future CPR for AS.
In conclusion, this study highlights that recent guidelines on AS have not been widely adopted in clinical practice in Korea. The concept of AS has drastically changed from a rare disease to a common condition, where early diagnosis and intervention can substantially improve patient outcomes. Considering the challenges faced in Korea, CPR tailored to local circumstances and a dedicated registry to ensure a better prognosis for Korean patients are warranted.
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