Comparative study on clinicopathological features and prognosis of IgA vasculitis nephritis and IgA nephropathy in children

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 [1]. On the other hand, IgA nephropathy (IgAN) is one of the most common primary glomerular diseases in children, often characterized by recurrent proteinuria and hematuria [2]. IgAVN and IgAN, both IgA-mediated autoimmune disorders with similar predisposing factors, display characteristic glomerular IgA deposits, predominantly composed of IgA1 [2].

The Oxford classification for IgAN, first introduced in 2009, identified four histopathologic features—mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy and interstitial fibrosis (T)—as determinants of kidney prognosis independent of clinical features [3, 4]. By 2016, the addition of crescents (C) to the classification was recommended by the IgAN working group [5]. The Oxford classification has been widely utilized and its prognostic value affirmed in numerous studies [6‐8]. However, it inadequately addresses the type and severity of tubulointerstitial inflammation, which is a potentially overlooked prognostic factor. Asrar et al. [9] found that, upon excluding patients with severe pathological changes (T2), tubulointerstitial inflammatory changes were present in 90.2% of the remaining 247 patients, with moderate inflammatory changes being the most prevalent (49.4%). Importantly, the type and severity of tubulointerstitial inflammation correlated strongly with M, E, T, and C. Considering the predictive value of the MEST-C system for kidney regression in IgAN, tubulointerstitial inflammation may hold significant application potential. Similarly, Rankin et al. [10] discovered an independent association between tubulointerstitial inflammation and the prognosis of IgAN, surpassing even the predictive value of the MEST-C system.

In 2017, Koskela et al. [11] proposed a modified semiquantitative scoring system (SQC) for IgAVN, which evaluated kidney tissue via four aspects—glomerular, tubular, interstitial, and capillary changes. It distinguished between active and chronic lesions and scored each pathological index based on lesion severity. The authors reported that the SQC's predictive power for kidney prognosis was comparable to the International Study of Kidney Disease in Children (ISKDC) system when applied to IgAVN. In light of the existing clinical, immunological, and histological parallels between the two disorders and shared etiological factors [12, 13], as well as the effective application of the Oxford classification in recent IgAVN studies [14‐18], we sought to assess kidney pathology in IgAVN and IgAN using the SQC scoring system. Our focus was to explore the impact of the SQC pathology index on prognosis and identify the clinicopathological and prognostic similarities and differences. This would provide a stronger foundation for their clinical differentiation.

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 [32‐35].

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.

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.