Sixty-nine publications were included for this review, among which 38 were from mainland China (2015–2021) [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48], 15 from Japan (2003–2021) [49,50,51,52,53,54,55,56,57,58,59,60,61,62,63], 10 from South Korea (2010–2020) [64,65,66,67,68,69,70,71,72,73], 3 from Taiwan (2014–2019) [74,75,76], and 3 from Australia (2001–2021) [77,78,79]; characteristics of the studies are shown in Supplementary Table S2. Approximately 83% the publications reported a retrospective study design (n = 57). For publications from mainland China, sample sizes ranged from 74 [37] to 4,367,829 [47], and male percentages ranged from 37.5% [17] to 97.3% [32]. For publications from Japan, sample sizes ranged from 52 [53] to 270,902 [63]; the male percentage ranged from 37.1% [58] to 56.96% [52]. For publications from South Korea, sample sizes ranged from 25 [64] to 5,114 [67]; the male percentage ranged from 36% [64] to 66.6% [73]. For publications from Taiwan, sample sizes ranged from 91 [75] to 7,073 [76]; the male percentage ranged from 45.9% [76] to 52.7% [75]. For publications from Australia, sample sizes ranged from 1,147 [78] to 2,457 [79]; the male percentage ranged from 60% [77] to 69.7% [79]. The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline [1] and 2 country-specific guidelines [80, 81] were also included for evidence on treatment patterns.
Sixty-eight journal articles were assessed for study quality (all details of the quality assessment are shown in Supplementary Table S3); one white paper was not included in the study quality assessment. Approximately 75% (51/68 articles) were deemed to be of good quality (i.e., without inherent flaws). Few studies reported the incidence/prevalence of IgAN directly and percentage of IgAN were extracted from included studies. The appropriateness of the statistical analysis conducted was not clear or not specified in 5 studies, as they did not define P values and the level of significance for all observations. Across studies, outcome measures were generally considered reliable. However, 33 articles stated that the results could be generalized to routine practice. In one case-control study, the similarity of both groups at the outset of the study was not clear.
Incidence
Six publications provided evidence on IgAN incidence [30, 61, 63, 74, 77, 78] in Australia (n = 2), Japan (n = 2), mainland China (n = 1), and Taiwan (n = 1). Most were cross-sectional observational studies (n = 4), and sample sizes ranged from 156 [74] to 270,902 [63].
In Australia, IgAN incidence was estimated to be 1.41–10.5 per 100,000 people per year [77, 78]. According to Briganti 2001 [78], IgAN incidence in Australia was lowest (0.0 per 100,000 per year) among male children and highest (10.7 per 100,000 per year) among male adults [78]. In Japan, only 2 studies reporting incidence data among children were identified. Utsunomiya 2003 [63] reported an incidence rate of 4.5 per 100,000 per year among 270,902 junior high and elementary school students; Kajiwara 2020 [61] reported a rate of 3.3 per 100,000 per year among 60,816 junior high and elementary school students. Both publications collected urine samples through a school urinary screening system in students 6 to 15 years old. In mainland China, the incidence rate of IgAN was estimated to be 6.3% among elderly patients who underwent renal biopsy and 24.7% among non-elderly patients who underwent renal biopsy [30]. In Taiwan, IgAN incidence was estimated to be 5.5 per million per year among the general population (around 23.5 million between 2014 and 2016), based on 1,445 renal biopsy records from a registry database [74]. In general, IgAN incidence was higher in males (5.7 per 100,000 per year) compared with females (2.9 per 100,000 per year) [78]. IgAN incidence was not reported in Korean populations.
Prevalence and diagnosis rate
IgAN prevalence among the general population was not reported in the included publications. But one cross-sectional study (n = 3,623) reported an IgAN prevalence rate of 0.03% among the general Chinese pediatric population [34]. Thirty-five publications were identified with diagnosis rates among 2 populations: patients who received renal biopsies and PGN patients [13, 14, 17,18,19, 21, 22, 24, 30, 31, 33,34,35,36, 39, 40, 43,44,45,46,47,48, 52, 59, 67,68,69,70,71,72, 74,75,76, 79]. Twenty-one publications were from mainland China [13, 14, 17,18,19, 21, 24, 30, 31, 33,34,35,36, 39, 40, 43,44,45,46,47,48], 6 from South Korea [67,68,69,70,71,72], 3 from Taiwan [74,75,76], 3 from Japan [52, 55, 59], and 1 from Australia [79]. The majority (88%) were cohort studies (n = 17) [13, 21, 31, 33, 35, 36, 39, 40, 43,44,45,46, 52, 68,69,70,71] and cross-sectional studies (n = 13) [14, 17,18,19, 21, 24, 34, 37, 47, 59, 67, 72, 74, 79], with the remainder being an annual report [76], a registry study [55] and a chart review [75]. Sample sizes ranged from 33 [70] to 43,67,829 [47].
In mainland China, the mean diagnosis rate of IgAN was estimated to be 24.1% among patients undergoing renal biopsies (median: 23.0%; range: 6.3-40.9%) [13, 19, 21, 22, 24, 30, 46] and 27.3% (median: 27.9%; range: 0-72.1%) [14, 19, 21, 33, 36, 40, 43,44,45, 48] among PGN patients (Fig. 1a); The mean IgAN diagnosis rate was estimated to be 21.7% (median: 17.5%; 17-30.4%) among children who underwent renal biopsy [17, 18, 35]. In Taiwan, the mean diagnosis rate of IgAN was 12.1% (median: 12.2%; range: 10.8-13.2%) among patients undergoing renal biopsies [74, 75] and was reported similar (26%) among PGN patients [74, 76] (Fig. 1b). In South Korea, the mean diagnosis rate was 41% (median: 38.1%; range: 25.8-61.9%) among patients undergoing renal biopsies [67, 69, 71, 72] and around 51.6% (average of 51.3% and 51.9%) among PGN patients [68, 70] (Fig. 1c). In Japan, Hattori 2016 reported a mean estimated IgAN diagnosis rate of 23% (median: 22.9%) among CKD patients [59]. In addition, the reported IgAN diagnosis rate among patients who underwent renal biopsy was 31%, with 6.9% in patients aged 65 to 80 years old and 10.5% in patients aged 80 years or older [52, 55]. In Australia, Lee 2020 reported an IgAN diagnosis rate of 13% among patients undergoing renal biopsy [79].
IgAN Prevalence in Mainland China, Taiwan and South Korea (Abbreviation: ANS, acute nephritic syndrome; CNS, chronic nephrotic syndrome; NHRI, National Health Research Institute & Taiwan Society of Nephrology; NS, nephritis syndrome(e; PGN, primary glomerulonephritis; RPG, rapidly progressive glomerulonephritis)
Disease progression and mortality
Among included studies, all-cause mortality was mainly reported as deaths due to ESRD. Seven publications from mainland China [23, 26,27,28,29, 41, 42], 7 from Korea [64,65,66, 68, 70, 71, 73], 4 from Japan [50, 51, 57, 62], and 1 from Taiwan [75] reported rate of progression to ESRD in IgAN. These studies varied in the definition of endpoint, patient characteristics, and follow-up duration. In China, the median rate of progression to ESRD was 4.1% [28] over 6 months, ranged from 1.3 to 15.8% (median: 1.3%) over 40–45 months [29, 41], ranged from 6.6 to 15% (median: 8.3%) over 4–10 years [23, 27, 42], and 33% over 15 years [42]. In Korea, the median rate of progression to ESRD ranged from 2.5 to 39.7% (median: 19%) from 60 to 100 months [64,65,66, 68, 70, 71, 73].
Regarding direct reports on mortality, in mainland China, 0.7% of adult IgAN patients progressed to death according to 1 study of 944 patients from 2003 to 2014 with a median follow-up of 4.2 years [23]. In South Korea, the median death rate was 5.3% (range: 4.4-5.9%) [65, 66, 68] for 1,364 IgAN patients with a median follow-up of 100 months. In addition, 2 publications reported a standard mortality ratio (expressed as the ratio between the observed and the expected number of deaths in the general population) of 1.43 (95% confidence interval:1.04–1.92) among 1,364 IgAN patients in relation to the general population [65, 68]. In Japan, IgAN mortality was estimated to be 0.3 per 100 person-years among non-smokers [51], 1.3 per 100 person-years among smokers [51] and 1.2 per 100 person-years among patients who received kidney replacement therapy [53] based on 2 retrospective studies [51, 53]. No mortality data was found among IgAN patients in Taiwan or Australia.
Treatment patterns
Twenty publications [1, 11, 15, 26, 27, 29, 42, 49, 50, 54, 56,57,58, 60, 62, 64, 68, 71, 73, 81] and 3 clinical guidelines reported treatment patterns. Nine from mainland China [11, 15, 26,27,28,29, 32, 41, 42], 8 from Japan [49, 50, 54, 56,57,58, 60, 62], and 4 from South Korea [64, 68, 71, 73]. 80% publications were retrospective studies (n = 16) [11, 15, 26, 27, 29, 42, 49, 56,57,58, 60, 62, 64, 68, 71, 73]. Sample sizes ranged from 25 [64] to 2,283 [50]. The KDIGO [1] and 2 country-specific treatment guidelines, 1 from mainland China [80] and 1 from Japan [81], were identified. No treatment guidelines were identified in Taiwan, South Korea, or Australia.
The KDIGO guidelines (2021 version) provide treatment recommendations for adults and children with IgAN [1]. The guidelines state that the management of IgAN should be multifaceted, optimized with supportive care, and include ACEIs/ARBs as tolerated or allowed, control blood pressure, minimize cardiovascular risk, and adherence to lifestyle changes including dietary counseling, smoking cessation, weight control, and exercise, as appropriate. The guidelines provide specific treatment recommendations according to the variant forms of IgAN, the level of proteinuria, and high-risk rate for progression after maximal supportive care. The main treatment regimens include ACEIs and ARBs, immunosuppressants, cyclophosphamide, tonsillectomy, and lifestyle modification [1]. Similar to the KDIGO guidelines, the primary treatment recommendations in the Chinese 2017 guidelines for children with IgAN were glucocorticoids, immunosuppressants, and ACEIs/ARBs [80]. Japanese 2020 guidelines covered children and adults, with different treatment recommendations based on symptoms and subtype of IgAN (the subgroup classification for adults was based on estimated glomerular filtration rate and proteinuria; symptoms among children were classified as mild or severe) [81].
In mainland China, 6 studies investigated adult populations [15, 26, 28, 29, 32, 42] (Table 1) and 3 investigated pediatric populations [11, 27, 41] (Table 2). For drug usage among adult patients, ACEIs/ARBs had the largest median percentage at 66.7% (range: 38-90%) [15, 26, 28, 29, 32, 42], followed by steroids, with median of 36% (corticosteroids/prednisone/intravenous methylprednisolone injection, range: 10-100%) [15, 26, 28, 29, 32, 42] and immunosuppressants (including in combination with steroids), with median of 25.9% (cyclophosphamide, tacrolimus and tripterygium wilfordii, range: 1.6-72%) [15, 26, 28, 29, 32, 42]. Among pediatric patients, immunosuppressants (cyclophosphamide/mycophenolate /Tripterygium wilfordii /leflunomide) were the common drugs recommended, with a median of 64% (range: 1.7–72.2%) [11, 27, 41], followed by ACEIs/ARBs, with a median of 49.5% (range: 2.5-70%) [11, 27, 41] and steroids with a median of 45% (range: 25.3-69.3% as sum of oral prednisone and intravenous methylprednisolone) [11, 27, 41].
In South Korea, 3 publications on adult IgAN patients [64, 68, 71] (Table 1) and 1 publication among pediatric patients [73] (Table 2) were identified. Among adults, ACEIs/ARBs were the most common treatments (27.7-83.4%) [68, 71, 73], followed by ACEIs/ARBs and corticosteroid combinations (33.9%) [64] and corticosteroids alone (12.4-28.8%) [68, 71, 73]. Among pediatric patients, the frequency of immunosuppressant use was 50.2% [73].
In Japan, 7 publications reported IgAN treatment patterns among adults [50, 54, 56,57,58, 60, 62] (Table 1) and 2 publications [49, 54] among pediatric patients (Table 2). Among adults, ACEIs/ARBs were the most common treatment (25-99.6%) [50, 54, 56,57,58, 60, 62], followed by antiplatelet agents (58.1-96.8%) [54] and corticosteroid-immunosuppressant combination therapy (1.5-74%) [62]. Notably, the rate of administering steroid-immunosuppressant combination was only 1.5% in a retrospective cohort study that sampled 1,012 IgAN patients with a mean age of 32.96 ± 12 years [56]. Among pediatric patients, ACEIs/ARBs were the most frequently administered treatments (0.9-95.7%) [49, 54], followed by antiplatelet agents (range: 1.2-82.6%) [49, 54] and immunosuppressants (range: 4.6-68.5%) [49]. The frequency of administering treatments varied greatly across different subgroups. For example, the frequency of administering ACEIs/ARBs ranged from 0.9% for the diffuse mesangial proliferation subgroup (n = 108) to 50.9% for the focal mesangial proliferation subgroup (n = 173) in 1 retrospective study in Japanese children with IgAN from 1990 to 2004 [49]. Tonsillectomy or tonsillectomy combined with steroid was mostly reported in Japanese studies, with frequencies ranging from 1 to 66.2% across publications (Table 1). This is in accordance with the KDIGO 2021 guidelines’ evidence that supports the routine use of tonsillectomy in Japanese high-risk patients with IgAN [1]. No publications reporting IgAN treatment patterns were identified for Taiwan or Australia.
Humanistic burden
Four publications in China reported QoL, measured by the 36-Item Short Form Health Survey (SF-36) [16, 25], Daily Living Ability Rating Scale (DLARS) [37], and QoL scale (QOLs) combined with Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) [38]. SF-36 scores reflect physical and mental health based on 8 health concepts, including physical and social functioning, role limitations due to physical and emotional problems, mental health, vitality, bodily pain, and general health (GH) perception [82]. Two publications evaluated the effects of individualized nursing intervention (INI, one improved nursing intervention which costs more time than routine nursing intervention [RNI]) on the psychological mood and QoL among IgAN patients [16, 25]. There were two subgroups, the patients in the control group received RNI and patients in the intervention group received INI [16, 25]. The mean GH score was 32.16 [16] among total IgAN patients (n = 98; mean age: 32.74 years; male percentage: 50%) in 2017 and 80.15 increasing from 69.93 at baseline [25] after intervention among total IgAN patients (n = 84; mean age: 33.57 years; male percentage: 60.7%) in 2019. In both publications, the intervention groups had higher mean GH scores than that in the control groups (39.47 vs. 24.84 [16] and 85.73 vs. 74.56 [25], respectively). Two other prospective studies assessed the effect of INI for IgAN patients [37, 38]. Results showed that both mean DLARS and QOLs scores were higher among the intervention group compared to the control group (88.5 vs. 75.7 and 39.5 vs. 24.8, respectively) [37, 38]. SAS and SDS scores were also evaluated by Qi 2021 [38], the mean SAS score decreased more in the intervention group (49.2 ± 6.3 decreased from 62.1 ± 5.8) than that in the control group (57 ± 4.9 decreased from 62.4 ± 6.1) from baseline. Similarly, the mean SDS score decreased more in the intervention group (43.3 ± 5.2 decreased from 56.2 ± 6) than in the control group (52.6 ± 6.4 decreased from 57 ± 6.2) from baseline [38].
Economic burden
No publications reported indirect costs, but 3 retrospective studies reported hospitalization costs for IgAN patients in China (see Supplementary Figure S1) [12, 20, 47]. Hospitalization cost per patient per year is ¥14,900 ($2,252.12; exchange rate of Chinese Yuan [CNY] and US dollar in 2018 was 6.616 [83]) as reported by Zheng 2018 [20], and between ¥9,618 ($1,532.26; exchange rate of CNY and US dollar in 2015 is 6.227 [83]) and ¥10,019 ($1,608.96) as reported by Peng 2015 [12]. One large database study covering 54.1% of tertiary hospitals in 31 Chinese provinces from 2010 to 2015 reported a hospitalization cost of ¥8,000/$1,284.73 (¥6,000-¥12,000) [47]. Drug costs accounted for 28.39% of total hospitalization costs, followed by diagnostic testing costs [12]. Length of stay per patient per year in China ranged from 10 to 14.3 days across 3 publications [12, 20, 47].
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