Introduction

IgA vasculitis (IgAV), a prominent type of vasculitis among pediatric populations, is marked by its capacity to impact small blood vessels in multiple organs, including the skin, and is distinguished by the presence of immunofluorescent IgA deposits. This condition is specifically termed IgA vasculitis nephritis (IgAVN) when it affects the kidneys [Treatment

Steroids combined with RARS were used in children with combined proteinuria at a starting steroid dose of 1.5–2 mg/kg/d, and steroids combined with immunosuppressants were used in children with proteinuria levels greater than 50 mg/kg/d; the commonly used immunosuppressant is cyclophosphamide. We recommend methylprednisolone pulse in cases of crescents with more than 25% of glomeruli.

Kidney prognosis

Grade A (complete remission): normal kidney function, without proteinuria or hematuria; Grade B (partial remission): persistent proteinuria (< 1.0 g/d), and/or hematuria (≥ 3 red blood cells/high power field) without kidney insufficiency; Grade C (no remission): persistent proteinuria (≥ 1.0 g/d), and/or hematuria with moderate kidney failure (< 30% decrease in the eGFR from the baseline); Grade D (kidney failure): ≥ 30% decline in the eGFR from the baseline, End-stage kidney disease (ESRD) or death. IgAVN and IgAN pediatric patients' kidney remission rates were compared using a plot of the Kaplan–Meier survival analysis of survival curves.

Statistical analysis

Data analysis was executed using SPSS for windows version 26 (IBM Corporation, Armonk, NY). Normally distributed data were expressed as the mean ± standard deviation (SD), and nonparametric data were expressed as the median and interquartile (IQR) range. The count data were expressed as percentages, and Chi-squared Test or Fisher's exact probability test was used for group comparison. Nonparametric variables were compared with the Kruskal–Wallis test. Kidney survival rates were analyzed by the Kaplan–Meier method and compared by log-rank test. The Cox proportional hazards regression model was conducted on univariable and multivariable analyses of SQC classification in the IgAVN and IgAN children. Univariable Cox regression analysis was performed for each pathological variable and deposition intensity of IgA and C3. Multivariable Cox regression analysis was performed to appraise the influence of SQC system and deposition intensity of IgA and C3 on the kidney outcome. Hazard ratio (HR) with 95% confidence interval (CI) for each variable was estimated. All probabilities were two-tailed, and P < 0.05 was considered statistically significant.

Results

Comparison of clinical data

Clinical baseline characteristics are provided in Table 1. IgAN and IgAVN showed higher prevalence during the spring and winter seasons, while IgAVN was more common in the autumn (P < 0.0001). As for clinical symptoms, IgAN presented a higher incidence of gross hematuria, whereas IgAVN was more likely to manifest as isolated microscopic hematuria (P < 0.0001). Conversely, IgAVN was associated with a higher incidence of hypertension (P = 0.005).

Table 1 Comparison of the clinical data of IgA vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN)
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Comparison of kidney pathological changes

IgAN was found to inflict more severe kidney tubulointerstitial injury compared to IgAVN (P < 0.0001). According to the SQC, cellular crescents were more prevalent in IgAVN glomerular lesions (P = 0.001). Additionally, statistically significant differences were observed between IgAVN and IgAN concerning the pathological scores for complete tubular atrophy (P < 0.0001), interstitial fibrosis (P = 0.002), interstitial or periglomerular inflammation (P = 0.002), capillary arteriosclerosis or arterial inflammation (P < 0.0001), and diffuse mesangial proliferation (P < 0.0001). IgAN demonstrated a higher chronicity index and total biopsy score compared to IgAVN (P < 0.0001). Further details can be found in Table 2.

Table 2 Comparison of pathological changes on kidney biopsy in IgA vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN)
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Comparison of immunopathology data

IgAVN frequently exhibits IgA +  +  + deposits, whereas IgA +  + deposition is more common in IgAN, and the difference is statistically significant (P = 0.003). While both IgAVN and IgAN demonstrate C3 + deposition dominance, the proportion of C3 + is considerably higher in IgAN (P < 0.0001). Moreover, IgA deposits are typically localized to the mesangium in IgAVN, whereas IgAN displays a higher propensity for IgA deposition within both the mesangium and the segmental loop (P < 0.0001). Further details can be found in Table 3.

Table 3 Comparison of immunopathological data between IgA vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN)
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Comparison of treatments and kidney prognosis of IgAVN and IgAN

The therapeutic measures and kidney prognosis are elaborated in Table 4. No significant distinction exists in treatment between IgAVN and IgAN. Both conditions receive more Renin-Angiotensin System Blocker (RASB) therapy, with a relatively low rate of immunosuppressant usage, implying a preponderance of patients with mild disease in our study cohort. The 1-, 3-, and 5-year kidney remission rates were markedly lower in the IgAN group compared to the IgAVN group (70.8% vs. 71.1%, 40.1% vs. 52.0%, and 25.1% vs. 40.0%; Log-rank test, P = 0.017) as depicted in Fig. 2. To investigate the impact of the Semiquantitative Scoring (SQC) system's pathological indicators and the intensity of immune complex IgA and C3 deposition on kidney remission rates of IgAVN and IgAN, Cox proportional hazard models were established, as shown in Table 5.

Table 4 Comparison of kidney prognosis in IgA vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN)
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Fig. 2
figure 2

Kaplan–Meier analysis of kidney remission rates in IgA vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN) (Log-rank test, P = 0.017)

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Table 5 Risk factors for kidney remission rates in IgA vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN)
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The Univariate Cox analysis model revealed associations between interstitial fibrosis, inflammation OR periglomerular inflammation, diffuse mesangial proliferation, intensity of immune complex IgA deposition, and adverse outcomes of IgAVN. Additionally, adverse outcomes of IgAN correlated with the presence of fibrous crescents, complete tubular atrophy, interstitial fibrosis, and inflammation OR periglomerular inflammation. In the multivariate Cox analysis, interstitial fibrosis and IgA +  + and IgA +  +  + appeared to be linked to poor kidney outcomes for IgAVN. For IgAN, only interstitial fibrosis was associated with poor kidney prognosis. Regarding IgAVN, when the intensity of IgA deposition varied, we compared kidney remission rates (Fig. 3). Expectedly, children with IgAVN exhibited significantly lower kidney remission rates when IgA deposition intensity reached +  +  + , indicating a pronounced impact of IgA +  +  + on prognosis.

Fig. 3
figure 3

Kaplan–Meier analysis of the effect of IgA deposition intensity on the kidney remission rates of IgA vasculitis nephritis (IgAVN) (Log-rank test, P < 0.0001)

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Discussion

Our study findings highlighted that both IgAVN and IgAN have a higher prevalence in males, with a relatively larger proportion in IgAN. The SQC chronicity index and total biopsy score were higher for IgAN than for IgAVN, which also exhibited more severe tubular interstitial injury. The deposition intensity of C3, and the rate of IgA pure deposition in the mesangium, were higher in IgAVN than in IgAN, with the intensity of IgA deposition also greater in IgAVN. Notably, IgAVN had a more favorable prognosis and a higher kidney remission rate. According to Cox regression, interstitial fibrosis in the SQC pathology system correlated with the prognosis of both IgAVN and IgAN. Further, IgA +  + and IgA +  +  + might impact the prognosis of IgAVN. Our study also demonstrated a significantly higher incidence of IgAVN during autumn compared to IgAN [21].

Additionally, we noted some significant distinctions; IgAN patients were more prone to gross hematuria than those with IgAVN. Fengmei Wang et al. [22] reported that patients with IgAVN and IgAN have a higher incidence of experiencing left kidney vein compression (nutcracker phenomenon) than those with other kidney diseases. Children with IgAN also reported higher rates of hematuria than those with IgAVN. This correlation warrants further investigation.

Koskela et al. [23] performed serial kidney biopsies on the cohort and assessed the prognostic value of the SQC system for IgAVN in children. They found higher activity scores at diagnostic biopsy, increasing activity and chronicity scores at follow-up biopsy, and that the activity scores declined while chronicity scores increased from the diagnostic biopsy to the follow-up biopsy in most patients, irrespective of proteinuria. The Cox regression results indicated that activity scores at the diagnostic biopsy independently predicted chronicity scores at the follow-up biopsy.

In another study, the authors applied the SQC system to score kidney biopsies in 80 patients with IgAVN and compared the prognostic implications of the International Study of Kidney Disease in Children (ISKDC) and SQC classifications. They found that patients with active kidney disease had higher SQC activity and chronicity scores. The area under the curve was not significantly different between the two at Receiver Operating Characteristic (ROC) curve analysis, demonstrating the effective applicability of the SQC system to patients with IgAVN [24]. A recent multicenter study also suggested that the SQC and Oxford classifications predicted poor kidney prognosis in IgAVN more accurately than the ISKDC classification [25].

In our study, we utilized the SQC system for the first time to assess the severity of kidney lesions in children with IgAVN and IgAN. Compared to the Oxford classification, the SQC system pays more attention to interstitial glomerular lesions. We discovered that pathological scores for complete tubular atrophy, interstitial fibrosis, interstitial inflammation or periglomerular inflammation, and capillary arteriosclerosis or arterial inflammation were higher in IgAN than in IgAVN. Moreover, the chronicity index and total biopsy scores were higher in IgAN, suggesting that kidney pathological changes in IgAN are more severe and demonstrate a chronic pathological course [26]. Our investigation revealed significantly more severe tubulointerstitial lesions in IgAN than in IgAVN, corroborating our findings.

In a retrospective study conducted in Japan, it was discerned that IgAN demonstrated a higher incidence of mesangial proliferation compared to IgAVN [27]. This observation found corroboration in a similar study executed in China [2]. Consistent with these previous findings, our research also showed a more pronounced degree of diffuse mesangial proliferation in IgAN than in IgAVN. The prognostic predictive value of M lesions under the Oxford classification was impacted by the use of immunosuppression, as discovered by Yu et al. [15]. In a similar vein, Shima et al. [28] found that lesion M lost its predictive power in patients undergoing immunosuppressive therapy. In the context of our study, we identified no significant disparity in the utilization rate of immunosuppressants between IgAVN and IgAN. The lack of correlation between mesangial proliferation and kidney prognosis in COX regression univariate and multivariate analyses might be attributed to the analogous mesangial proliferation scores in both groups.

This research found no divergence in the distribution of complex immune types deposited in IgAVN and IgAN. Furthermore, we observed no noticeable differences in the rates of IgG and IgM deposition in the kidneys of IgAVN and IgAN patients, which stood at 40.2% and 38.6%, 73.7% and 74.2% (data not shown), respectively. Mao et al.'s study investigating the clinicopathological relationship between IgAVN and IgAN in children unveiled a striking discrepancy in the blood biochemical parameters of IgAVN and IgAN when the types of immune complex deposition varied [29]. This may be connected to the pathogenesis variability of both conditions. An analysis of the relationship between immune complexes and clinical manifestations remains to be conducted in this paper, and future research is required for more comprehensive understanding.

Our findings indicate significant IgA deposition in the glomerular mesangial zone in both IgAVN and IgAN. Results derived from immunofluorescence deposition intensity revealed that IgA +  +  + predominated in IgAVN, whereas IgA +  + was more prevalent in IgAN. This suggests a higher intensity of IgA deposition in IgAVN, which could be relevant given the primarily acute alterations in the kidney pathophysiology of IgAVN. When a membrane attack complex (MAC) was deposited in the glomerular mesangial zone of IgAVN and IgAN patients' kidneys, alongside IgA and C3 deposits, patients exhibited more severe kidney impairment when MAC was highly expressed, as evidenced by a Canadian study [30]. Consequently, MAC may serve as an independent indicator of kidney injury severity in IgAVN and IgAN patients. However, the relationship between the degree of IgA and C3 deposition and MAC remains to be established. Future investigations are necessary to elucidate their connection to the severity of kidney injury and prognosis. IgAVN and IgAN both demonstrated a predilection for IgA deposition in the glomerular mesangium. In contrast, IgAN exhibited a higher incidence of IgA deposition in both the glomerular mesangium and the segment loop. The increased frequency of IgA deposition in the segment loop might be linked to the more conspicuous capillary alterations associated with IgAN. Furthermore, our study found no discernible disparities in the rates of C1q, C4, and FRA deposition between IgAVN and IgAN.

Our Kaplan–Meier survival analysis unveiled a notably superior prognosis for IgAVN, marked by significantly higher kidney remission rates at 1, 3, and 5 years in comparison to IgAN. As per a specific study, only 30–50% of patients diagnosed with IgAN reach the phase of clinical remission, contrasting sharply with nearly 98% of patients afflicted with IgAVN [31]. These findings align with our research. Through our Cox regression analysis, we ascertained that interstitial fibrosis of the semiquantitative score (SQC) and the strength of IgA deposition may be intertwined with the prognosis of IgAVN, while interstitial fibrosis of SQC was associated with the prognosis of IgAN. Given the comprehensive comparison, interstitial fibrosis emerged as a key determinant influencing kidney outcomes [32,33,34,35].

Furthermore, our research identified that cellular crescents were more prevalent in glomerular lesions of IgAVN, implying an acute trajectory of kidney lesions in IgAVN. Huang et al.'s study posited that the severity of kidney pathological presentations in IgAVN escalates with the proportion of crescents [36]. In contrast, our study did not establish a correlation between crescents and the prognosis of IgAVN. The connection between the percentage of crescents and kidney prognosis remains to be elucidated. Wu et al.'s study noted that 6.46% of children with IgAN progressed to kidney failure with cumulative kidney survival rates of 95.3%, 90.3%, and 84% at 5, 10, and 15 years, respectively [37]. Another study highlighted that 20% of children diagnosed with IgAN reached end-stage kidney disease (ESRD) 20 years post-diagnosis, underlining a gradual decline in prognosis in children with IgAN [38]. Given our study's relatively brief follow-up period, none of the children reached the stage of kidney insufficiency.

The strengths of our study include the large sample size, persuasive clinical comparisons, and the novel application of SQC for scoring and accurately assessing kidney pathology in IgAVN and IgAN. Despite these strengths, our study also has limitations: it is a single-center retrospective study, potentially carrying geographical differences and selection bias. Moreover, the data on clinical, laboratory, and treatment parameters are relatively undeveloped, the impact of treatment on pathological tissues remains unclear, the follow-up period is relatively brief, and our prognostic model only incorporates SQC pathological indicators. Future multicenter prospective studies are required to address these limitations.

Conclusions

Despite certain clinical and pathological similarities, IgAN exhibits more severe kidney impairment, conspicuous interstitial damage, and a poorer prognosis than IgAVN. Significant differences are observed in the intensity and location of immune complex deposition in the kidney. These differences do not support the notion of these two diseases being identical; rather, they suggest two distinct pathologies. The SQC pathological indicator associated with kidney prognosis in children with IgAVN and IgAN could be interstitial fibrosis. The intensity of IgA deposition may be linked to the prognosis of IgAVN.