Impact of intrarenal arterial lesions on prognosis of IgA nephropathy: insights from a retrospective cohort study
IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide , yet its clinical and pathologic features show significant variability among affected individuals. Despite standard treatments, a significant proportion of IgAN patients (20–40%) progress to end-stage renal disease (ESRD) within two decades of diagnosis . This highlights the urgent need to identify risk factors associated with IgAN progression. Numerous studies have highlighted the association of various risk factors with prognosis in IgAN, including severe proteinuria, low estimated glomerular filtration rate (eGFR), hypertension and sex . Since IgAN is diagnosed based on kidney biopsy, kidney morphology has been shown to be closely related to outcome and may guide clinical management. The 2016 updated Oxford classification identified five morphology features (MESTC) for predicting the prognosis of IgAN: mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubulointerstitial fibrosis (T1-2), and crescent (C1-2) . Intrarenal arterial/arteriolar lesions (IALs) have received relatively little attention despite their high frequency in IgAN patients, being present in up to 72.2% of biopsy specimens . Current studies remain controversial on whether IALs is an independent predictor of renal prognosis . This controversy may stem from methodological limitations in existing studies, which often include only certain subcategories of IALs , or rely on binary classification (presence or absence) to analyze IALs and its subcategories . There is currently a lack of a reproducible and objective semiquantitative method for classifying and assessing the severity of IALs. Such an approach is needed to determine whether the subcategories and severity of IALs serve as better prognostic indicators. To address this issue, we conducted a single-center retrospective cohort study of 417 primary IgAN patients with more than 4 years of follow-up. Using a comprehensive assessment of IALs, including subclass and severity scores, we found that moderate-severe hyalinosis and intimal fibrosis are independent risk factors for clinical outcomes in IgAN. 

Patient cohort Between March 2010 and December 2020, a total of 2399 adult patients (aged ≥ 18 years) diagnosed with IgAN at the First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China) were enrolled in this retrospective study. The study adhered to the principles of the Declaration of Helsinki and was approved by the Medical Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang (approval number: KY2024-R118). The diagnosis of IgAN was based on kidney biopsy results showing IgA-dominant or co-dominant deposits in the mesangial region by immunofluorescence microscopy. Exclusion criteria included: (1) IgAN combined with other diseases, such as minimal change disease, membranous nephropathy, thin basement membrane nephropathy, post-infectious glomerulonephritis, diabetic nephropathy, and interstitial nephritis. (2) Secondary IgAN associated with systemic diseases such as Henoch–Schönlein purpura, other autoimmune diseases, hepatitis B-related nephritis, HIV infection, and kidney transplantation. (3) Renal biopsy specimens with fewer than eight evaluable glomeruli. (4) Patients with incomplete clinical and/or pathology data. (5) Individuals with a baseline eGFR < 15 mL/min/1.73 m 2 , loss to follow-up or time to the composite endpoint in less than one year. The composite endpoint was defined as a 40% decrease in eGFR or ESRD . Patients were followed up from the baseline examination date to the last follow-up date, and 417 patients who met the inclusion criteria were included in the analysis. These patients were divided into two groups based on whether or not they progressed to the composite endpoint. The workflow of this study is illustrated in . Clinical and laboratory data Baseline data collected within two weeks before the kidney biopsy included age, sex, blood pressure, body mass index (BMI), serum creatinine (sCr), eGFR calculated using the CKD-EPI (2021) formula , albumin, uric acid, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, serum C3, serum C4, blood urea nitrogen (BUN), hematuria, and 24-h urinary protein excretion. Hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg or the use of antihypertensive medication. Medications administered during follow-up, including renin-angiotensin-aldosterone system inhibitors (RASI), glucocorticoids, and other immunosuppressants (such as Tripterygium wilfordii , tacrolimus, cyclosporin-A, cyclophosphamide, leflunomide, and mycophenolate mofetil), were also documented. Pathology analysis Kidney biopsy specimens were examined by light microscopy, immunofluorescence microscopy, and electron microscopy. For light microscopy, multiple sequential sections of the biopsy were prepared and stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Masson’s trichrome, and Jones’ silver staining. Two experienced renal pathologists independently reviewed the slides and assessed parameters such as the Oxford classification criteria  and IALs. In cases of disagreement between the pathologists’ assessments, the biopsy specimen was reviewed again until consensus was reached. IALs included intimal fibrosis, hyalinosis, endothelial swelling ( ), and thrombotic microangiopathy (TMA, ). TMA is characterized by edematous intima with infiltration of fragmented erythrocytes and fibrinoid material, leading to lumen occlusion due to endothelial mucous degeneration, concentric intimal fibrosis, and intraluminal thrombosis. Frozen kidney biopsy sections were stained by direct immunofluorescence according to standard protocols with special emphasis on the detection of C3 deposition in the glomeruli and in the intima of intrarenal arteries/arterioles. IALs were scored semiquantitatively according to predefined criteria . The severity of hyalinosis was graded according to the extent of changes in arteries/arterioles as mild (small deposition in < 25% of arteries/arterioles; ), moderate (small deposition in 26–50% of arteries/arterioles or large depositions in < 25% of arteries/arterioles; ), and severe (extensive deposition in > 50% of arteries/arterioles; ). The severity of intimal fibrosis was assessed by the extent of luminal occlusion: mild (<25% luminal occlusion; ), moderate (26%−50% luminal occlusion; ), and severe (>50% luminal occlusion; ). This study excluded mild intimal fibrosis in large intrarenal arteries ( ), which is typically observed in middle-aged adults without hypertension. The highest severity of intrarenal arterial/arteriolar intimal fibrosis or hyalinosis observed in each specimen was recorded. Statistical analysis Continuous variables with a normal distribution were presented as mean ± standard deviation, while those with a non-normal distribution were presented as median with interquartile range (IQR). Categorical variables were expressed as percentages. Differences between variables were assessed using the independent samples t-test or Mann–Whitney U-test as appropriate. The chi-squared test was employed for comparing categorical data, with Bonferroni’s correction applied for multiple comparisons. Kaplan–Meier curves were used for survival analysis, and the log-rank test was used for univariate survival analysis. Univariate Cox regression analysis was conducted to identify factors significantly associated with the composite endpoint, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Statistical significance was defined as a P value of less than 0.05. All statistical analyses were performed with IBM SPSS Statistics software (version 26.0). 

Between March 2010 and December 2020, a total of 2399 adult patients (aged ≥ 18 years) diagnosed with IgAN at the First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China) were enrolled in this retrospective study. The study adhered to the principles of the Declaration of Helsinki and was approved by the Medical Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang (approval number: KY2024-R118). The diagnosis of IgAN was based on kidney biopsy results showing IgA-dominant or co-dominant deposits in the mesangial region by immunofluorescence microscopy. Exclusion criteria included: (1) IgAN combined with other diseases, such as minimal change disease, membranous nephropathy, thin basement membrane nephropathy, post-infectious glomerulonephritis, diabetic nephropathy, and interstitial nephritis. (2) Secondary IgAN associated with systemic diseases such as Henoch–Schönlein purpura, other autoimmune diseases, hepatitis B-related nephritis, HIV infection, and kidney transplantation. (3) Renal biopsy specimens with fewer than eight evaluable glomeruli. (4) Patients with incomplete clinical and/or pathology data. (5) Individuals with a baseline eGFR < 15 mL/min/1.73 m 2 , loss to follow-up or time to the composite endpoint in less than one year. The composite endpoint was defined as a 40% decrease in eGFR or ESRD . Patients were followed up from the baseline examination date to the last follow-up date, and 417 patients who met the inclusion criteria were included in the analysis. These patients were divided into two groups based on whether or not they progressed to the composite endpoint. The workflow of this study is illustrated in . 

Baseline data collected within two weeks before the kidney biopsy included age, sex, blood pressure, body mass index (BMI), serum creatinine (sCr), eGFR calculated using the CKD-EPI (2021) formula , albumin, uric acid, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, serum C3, serum C4, blood urea nitrogen (BUN), hematuria, and 24-h urinary protein excretion. Hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg or the use of antihypertensive medication. Medications administered during follow-up, including renin-angiotensin-aldosterone system inhibitors (RASI), glucocorticoids, and other immunosuppressants (such as Tripterygium wilfordii , tacrolimus, cyclosporin-A, cyclophosphamide, leflunomide, and mycophenolate mofetil), were also documented. 

Kidney biopsy specimens were examined by light microscopy, immunofluorescence microscopy, and electron microscopy. For light microscopy, multiple sequential sections of the biopsy were prepared and stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Masson’s trichrome, and Jones’ silver staining. Two experienced renal pathologists independently reviewed the slides and assessed parameters such as the Oxford classification criteria  and IALs. In cases of disagreement between the pathologists’ assessments, the biopsy specimen was reviewed again until consensus was reached. IALs included intimal fibrosis, hyalinosis, endothelial swelling ( ), and thrombotic microangiopathy (TMA, ). TMA is characterized by edematous intima with infiltration of fragmented erythrocytes and fibrinoid material, leading to lumen occlusion due to endothelial mucous degeneration, concentric intimal fibrosis, and intraluminal thrombosis. Frozen kidney biopsy sections were stained by direct immunofluorescence according to standard protocols with special emphasis on the detection of C3 deposition in the glomeruli and in the intima of intrarenal arteries/arterioles. IALs were scored semiquantitatively according to predefined criteria . The severity of hyalinosis was graded according to the extent of changes in arteries/arterioles as mild (small deposition in < 25% of arteries/arterioles; ), moderate (small deposition in 26–50% of arteries/arterioles or large depositions in < 25% of arteries/arterioles; ), and severe (extensive deposition in > 50% of arteries/arterioles; ). The severity of intimal fibrosis was assessed by the extent of luminal occlusion: mild (<25% luminal occlusion; ), moderate (26%−50% luminal occlusion; ), and severe (>50% luminal occlusion; ). This study excluded mild intimal fibrosis in large intrarenal arteries ( ), which is typically observed in middle-aged adults without hypertension. The highest severity of intrarenal arterial/arteriolar intimal fibrosis or hyalinosis observed in each specimen was recorded. 

Continuous variables with a normal distribution were presented as mean ± standard deviation, while those with a non-normal distribution were presented as median with interquartile range (IQR). Categorical variables were expressed as percentages. Differences between variables were assessed using the independent samples t-test or Mann–Whitney U-test as appropriate. The chi-squared test was employed for comparing categorical data, with Bonferroni’s correction applied for multiple comparisons. Kaplan–Meier curves were used for survival analysis, and the log-rank test was used for univariate survival analysis. Univariate Cox regression analysis was conducted to identify factors significantly associated with the composite endpoint, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Statistical significance was defined as a P value of less than 0.05. All statistical analyses were performed with IBM SPSS Statistics software (version 26.0). 

Clinical and pathology characteristics of the cohort As shown in , among the 417 patients enrolled in this study, the mean age was 37 years, with a predominance of females, accounting for 64.0% of the cohort. The median follow-up duration was 49 months. Within the cohort, 182 patients (43.6%) had hypertension. At baseline, the patients had a median proteinuria level of 1.2 g/24 h and a median sCr level of 81.0 μmol/L. Kidney biopsies revealed that 230 out of 417 patients (55.2%) exhibited IALs, while 187 (44.8%) did not. Among those with IALs, 125 (54.3%) showed intimal fibrosis, 207 (90.0%) had hyalinosis, 29 (12.6%) exhibited endothelial swelling, and 4 (1.7%) displayed TMA. Patients with IALs had higher age, hypertension prevalence, BMI, worse renal and lipid profiles, poorer histology, and increased risk of the composite endpoint (see Table S1 ). Incidence of IALs in progressive vs. non-progressive IgAN demonstrates a comparison of the clinical and laboratory features, pathological findings and medications between the progressive and nonprogressive groups. During the follow-up period, 18.7% of cases experienced progression to the composite endpoint, while 81.3% maintained relatively stable renal function. Sex and age did not differ significantly between the progressive and non-progressive groups. However, progressive patients had a higher incidence of hypertension and significantly elevated levels of BMI, sCr, uric acid, total cholesterol, triglycerides, LDL cholesterol, and BUN at baseline. These patients also exhibited severe proteinuria, reduced hematuria, lower eGFR and serum C3 levels. Kidney morphology characterized by more extensive global glomerulosclerosis, as well as M, S, and T1-2 lesions according to the Oxford classification, with less glomerular C3 deposition. In addition, the presence of IALs, particularly TMA, intimal fibrosis and hyalinosis, was more common in the progressive group, while endothelial swelling showed a numerical increase. Treatment with glucocorticoids, immunosuppressants, or RASI did not differ significantly between the two groups. Impact of IALs on long-term prognosis in IgAN Kaplan-Meier curve analysis demonstrated a significantly higher cumulative incidence of the composite endpoint in patients with IALs compared to those without over a 10-year follow-up period ( , p < 0.001). Subgroup analysis revealed significant differences among patients with endothelial swelling ( , p = 0.006), intimal fibrosis ( , p < 0.001), hyalinosis ( , p < 0.001), and the presence of TMA (not shown in the figure, p = 0.006). The severity of intimal fibrosis ( ) and hyalinosis ( ) significantly influenced the 10-year prognosis. Univariate and multivariate Cox regression analyses were performed to evaluate the impact of different types of IALs on the outcome of IgAN patients, as shown in . After adjustment for factors including age, hypertension, kidney function, and the Oxford classification, among others, the presence of IALs remained significantly associated with a higher risk of progression to the composite endpoint (Model 1, p < 0.001). This association persisted after further adjustments for glucocorticoids/immunosuppressants and RASI treatment (Model 3, p = 0.009). We further examined the contribution of each type of IAL to outcome. Moderate-severe but not mild hyalinosis and moderate-severe intimal fibrosis were identified as independent risk factors in Models 1 ( p = 0.001) and 3 ( p = 0.001). Notably, patients with mild intimal fibrosis did not show independent risk in Model 1 ( p = 0.144), but became significant in Models 2 ( p = 0.042) and 3 ( p = 0.045), suggesting a potential interaction effect of treatments. IALs and kidney progression in non-hypertensives shows that 102 out of the 230 cases were not diagnosed with hypertension, and most of these individuals presented with intimal hyalinosis. Notably, C3 deposits were observed in the arterial/arteriolar intima of 9 of these patients. As shown in Table S2 , IALs showed a weak association with the Oxford classification in these patients. Multivariate Cox regression analysis in non-hypertensive patients revealed that IALs, particularly the subtype of intimal fibrosis, remained independent risk factors for the composite endpoint (see Table S3 ). 

As shown in , among the 417 patients enrolled in this study, the mean age was 37 years, with a predominance of females, accounting for 64.0% of the cohort. The median follow-up duration was 49 months. Within the cohort, 182 patients (43.6%) had hypertension. At baseline, the patients had a median proteinuria level of 1.2 g/24 h and a median sCr level of 81.0 μmol/L. Kidney biopsies revealed that 230 out of 417 patients (55.2%) exhibited IALs, while 187 (44.8%) did not. Among those with IALs, 125 (54.3%) showed intimal fibrosis, 207 (90.0%) had hyalinosis, 29 (12.6%) exhibited endothelial swelling, and 4 (1.7%) displayed TMA. Patients with IALs had higher age, hypertension prevalence, BMI, worse renal and lipid profiles, poorer histology, and increased risk of the composite endpoint (see Table S1 ). 

demonstrates a comparison of the clinical and laboratory features, pathological findings and medications between the progressive and nonprogressive groups. During the follow-up period, 18.7% of cases experienced progression to the composite endpoint, while 81.3% maintained relatively stable renal function. Sex and age did not differ significantly between the progressive and non-progressive groups. However, progressive patients had a higher incidence of hypertension and significantly elevated levels of BMI, sCr, uric acid, total cholesterol, triglycerides, LDL cholesterol, and BUN at baseline. These patients also exhibited severe proteinuria, reduced hematuria, lower eGFR and serum C3 levels. Kidney morphology characterized by more extensive global glomerulosclerosis, as well as M, S, and T1-2 lesions according to the Oxford classification, with less glomerular C3 deposition. In addition, the presence of IALs, particularly TMA, intimal fibrosis and hyalinosis, was more common in the progressive group, while endothelial swelling showed a numerical increase. Treatment with glucocorticoids, immunosuppressants, or RASI did not differ significantly between the two groups. 

Kaplan-Meier curve analysis demonstrated a significantly higher cumulative incidence of the composite endpoint in patients with IALs compared to those without over a 10-year follow-up period ( , p < 0.001). Subgroup analysis revealed significant differences among patients with endothelial swelling ( , p = 0.006), intimal fibrosis ( , p < 0.001), hyalinosis ( , p < 0.001), and the presence of TMA (not shown in the figure, p = 0.006). The severity of intimal fibrosis ( ) and hyalinosis ( ) significantly influenced the 10-year prognosis. Univariate and multivariate Cox regression analyses were performed to evaluate the impact of different types of IALs on the outcome of IgAN patients, as shown in . After adjustment for factors including age, hypertension, kidney function, and the Oxford classification, among others, the presence of IALs remained significantly associated with a higher risk of progression to the composite endpoint (Model 1, p < 0.001). This association persisted after further adjustments for glucocorticoids/immunosuppressants and RASI treatment (Model 3, p = 0.009). We further examined the contribution of each type of IAL to outcome. Moderate-severe but not mild hyalinosis and moderate-severe intimal fibrosis were identified as independent risk factors in Models 1 ( p = 0.001) and 3 ( p = 0.001). Notably, patients with mild intimal fibrosis did not show independent risk in Model 1 ( p = 0.144), but became significant in Models 2 ( p = 0.042) and 3 ( p = 0.045), suggesting a potential interaction effect of treatments. 

shows that 102 out of the 230 cases were not diagnosed with hypertension, and most of these individuals presented with intimal hyalinosis. Notably, C3 deposits were observed in the arterial/arteriolar intima of 9 of these patients. As shown in Table S2 , IALs showed a weak association with the Oxford classification in these patients. Multivariate Cox regression analysis in non-hypertensive patients revealed that IALs, particularly the subtype of intimal fibrosis, remained independent risk factors for the composite endpoint (see Table S3 ). 

Our study found that IALs were present in 55.2% of IgAN patients, which is slightly lower than the 72.2% prevalence reported in a previous study , and similar to the 49.9% prevalence reported in another study . In our study, intimal fibrosis was detected in biopsy specimens from 30% of patients, which is lower than previous studies . Differences in definitions and variations in the proportions of IALs within studies may account for these discrepancies. In particular, our study excluded large arteries with mild intimal fibrosis, resulting in a more refined classification of IALs. In addition, our study found that endothelial swelling was observed in 7% of patients and TMA was observed in 0.9%, both of which are lower compared to previous studies [ , , ]. This may be due to our exclusion criteria, which excluded patients with secondary IgAN or primary IgAN combined with other glomerular diseases, many of which are known to be associated with endothelial injury or TMA . The exact etiology of IALs in IgAN remains incompletely understood. On the one hand, non-immune factors may contribute to the formation of IALs in IgAN. Our data showed that patients with IALs had higher levels of serum cholesterol, triglycerides, LDL cholesterol, uric acid, and more hypertension than those without IALs. It is well known that dyslipidemia can affect arterial morphology and function, while hyperuricemia can directly influence renal function and is independently associated with arteriolar damage and poor prognosis in patients with IgAN . Nocturnal hypertension has been implicated in the activation of the intrarenal renin-angiotensin system, which is associated with the development of intrarenal fibrosis in IgAN patients with normal daytime blood pressure . Interestingly, 24.5% of IgAN patients in this study did not have hypertension but exhibited pathologically characterized IALs, including hyalinosis, intimal fibrosis, endothelial cell swelling, and TMA. On the other hand, immunologic processes may play a role in the induction of IALs in IgAN. Although no IgA deposition was found in IALs in IgAN, we identified C3 deposits in the intimal layer of intrarenal arteries/arterioles in nine patients, consistent with findings from other studies . Patients with IALs showed higher intensity complement deposition, such as C3 and C4d, on intrarenal arteries and arterioles. This deposition was associated with global glomerulosclerosis, tubular atrophy, interstitial fibrosis, intimal fibrosis, and chronic microangiopathy . Circulating complexes containing galactose-deficient IgA1 have been implicated in local complement activation , with C3c and the endothelial cell marker CD31 co-deposited in the intrarenal arteriolar regions of patients with IALs . Additionally, elevated levels of anti-endothelial cell antibodies were observed in the serum of these patients . We hypothesize that complement overactivation by galactose-deficient IgA1 causes IALs via endothelial damage. A study showed similar vascular sclerosis scores in both glucocorticoids and control groups at baseline, but the steroid group had reduced proteinuria , which is often linked to vascular sclerosis . Therefore, glucocorticoids may benefit patients with IALs by inhibiting pro-inflammatory pathways and promoting protective molecules that sustain endothelial function . Glucocorticoids also reduce complement C3 secretion, suggesting a similar effect in IALs . Consistent with previous studies, we identified strong associations between poor kidney prognosis and traditional risk factors such as hypertension, uric acid, cholesterol, sCr, BUN, proteinuria, hematuria, global glomerulosclerosis, and Oxford classification scores including mesangial hypercellularity, segmental glomerulosclerosis, tubular atrophy and interstitial fibrosis . However, even after adjusting for these factors, IALs remained independently associated with decline in renal function. In contrast to a recent publication, we demonstrated that moderate to severe, but not mild, intimal fibrosis and hyalinosis were independently associated with prognosis . We propose that renal autoregulatory mechanisms may explain these discrepancies. The autoregulatory processes of the normal kidney maintain constant renal blood flow and optimal function within a blood pressure range of 80–180 mmHg, regulated primarily by myogenic responses and tubulo-glomerular feedback . Mild intimal fibrosis and hyalinosis may be mitigated by these autoregulatory mechanisms, whereas moderate to severe intimal fibrosis and hyalinosis may disrupt autoregulation, facilitating direct pressure transmission to the glomerulus and leading to glomerular injury . Hypertension is a major contributor to intimal fibrosis and hyalinosis. In the IgAN subgroup without hypertension, moderate to severe intimal fibrosis remains an independent risk factor for ESRD. Two other types of IALs, endothelial cell swelling and TMA, were risk factors in univariate analysis but became non-significant in a multifactorial Cox regression model. Interestingly, the Oxford classification showed no correlation between IALs and clinical prognosis in the majority of patients . We hypothesize that this variance may be due to differences in study populations, as the Oxford classification included predominantly non-Asian groups . Some studies in non-Asian patients have suggested that TMA is associated with poor prognosis in IgAN [ , , ]. In contrast, most studies in Asian populations have shown that IALs are associated with a poor prognosis, particularly intimal fibrosis [ , , , ]. In addition, the differences observed may have been influenced by our use of a composite endpoint that included ESRD and a 40% decline in eGFR, rather than considering ESRD alone. RASI and glucocorticoids have shown beneficial effects on endothelial and vascular smooth muscle cell function, and both improve kidney survival in IgAN patients . However, in our multifactorial Cox regression analysis, these two types of drug treatments did not alter the significant impact of IALs on clinical outcomes. This suggests the necessity of developing drugs that specifically target IALs in IgAN. Recent advances in treatment include the development of new drugs, such as atrasentan, an oral endothelin A receptor antagonist (ERA). Atrasentan has demonstrated significant reductions in glomerular injury, renal fibrosis, and proteinuria, particularly in diabetic nephropathy patients . Its protective mechanisms include improving mesangial matrix accumulation , protecting podocytes from injury , and reducing inflammation . Additionally, it offers vascular protection by lowering blood pressure and improving lipid profiles . Another ERA, sparsentan, has received accelerated approval from the FDA for the treatment of IgAN . In conclusion, our study demonstrated that moderate to severe intimal fibrosis and hyalinosis are independent risk factors for ESRD in IgAN among the Asian population. These findings are significant because they highlight that the impact of these lesions on kidney prognosis is independent of traditional risk factors such as hypertension as well as treatments with RASI and glucocorticoids. This underscores the urgent need to develop novel therapeutic strategies that specifically target these intrarenal arterial and arteriolar lesions in IgAN. Addressing these vascular lesions could potentially improve clinical outcomes and provide a more comprehensive approach to the management of this complex disease. 

Supporting_document1_revise2_clean copy.docx 

