In this retrospective study, risk factors were determined between pediatric patients with HSPN who had or did not have renal crescent formation (ISKDC grade ≥ III versus ISKDC grade < III). Multivariate logistic analysis showed that urinary WBC count and urinary ACR were independent risk factors for crescent formation. To the best of our knowledge, these risk factors have not previously been identified in relation to pediatric HSPN.
Our study has focused on the risk factors in pediatric patients with HSPN, as crescent formation has shown to be a poor prognostic factor [7-10]. However, there have been reports that found that histopathological findings also have poor predictive value for the prognosis of HSPN [19, 20]. Koskela et al. [19] reported the value of follow up renal biopsies in prognosis assessment from 26 patients with HSPN, and they concluded that follow-up biopsies provide limited additional information beyond clinical symptoms in HSPN outcome prediction. At the same time, results based on the Oxford classification revealed that complement C1-2 showed differences in diagnostic biopsies between the two groups, supporting results that active treatment should be commenced before fibrosis of crescents; our results also supporting this finding. We found that clinical manifestations, such as abdominal pain and recurrence of skin rash more than three times, were different between HSPN patients with and without crescents; however, they were not independent risk factors for crescent formation. Our results are consistent with study of Soylemezoglu et al. [20], in that clinical findings do not seem to predict the outcome of HSP nephritis in children. They concluded that the presence of crescents in the first biopsy did not seem to predict the outcome of HSPN in children.
Proteinuria denotes severe renal injury, and proteinuria at the time of symptom onset was associated with poor prognosis [8, 21]. This is consistent with our study, where multiple proteinuria indicators of renal function were associated with crescent formation, based on our univariate analysis (Table 1 and 2). However, based on logistic regression analysis, only urinary ACR was found to be independent risk factor for predicting crescentic glomerulonephritis (ISKDC grades III–V). ACR is a sensitive indicator of glomerular damage with high specificity [22]. Significant elevation in 24-hour urinary protein levels and urinary protein/creatinine ratio were found in ISKDC grades IIb, IIIa, and IIIb HSPN patients compared to ISKDC grade I and IIa subjects (the area under the ROC curve was 0.767 and 0.731, respectively), suggesting that 24-hour urinary protein levels and urinary protein/creatinine ratio may predict the pathological classification of HSPN [23], supporting the view that the severity of clinical manifestations in HSPN is related to the formation of crescents [10]. Other studies employed log-term follow-up to assess renal outcome in children with HSPN. 24-hour proteinuria was associated with poor prognosis [21]. Additionally, multivariate analysis showed that patients with poor prognosis had a higher urinary albumin/creatinine ratio after 17 years of follow-up [8].
Increased urinary WBCs are an indicator of renal injury. Urinary WBCs with positivity defined as more than ten cells per high power microscopic field [24], positively correlated with complement C3 in HSPN subjects, suggesting that the complement system is involved in promoting renal injury [23]. Complement-leukocyte-dependent interactions cause glomerular damage. Indeed, data indicate that in HSP subjects, WBCs may incite renal vasculitis [25]. In children with HSP, increased peripheral blood leukocyte and neutrophil counts were risk factors for small vessel injury and kidney involvement [26]. Analysis of HSPN patient samples and renal biopsies from animals with experimental HSPN found that WBCs participated in crescent formation [7]. WBC count, CRP, and humoral immune complement C3 levels were identified risk factors for crescentic nephritis in this study. Additionally, cytokine-driven neutrophilia was associated with epithelial cell proliferation and fibrosis in Bowman’s space [7]. Nevertheless, in Jang’s study, the authors concluded that the activation of the complement system does not correlate with the clinical or pathological severity of HSPN [27]. They compared the differences in pathologic findings of 35 children and 12 adults with HSPN according to C4d positivity in groups, while our results revealed that the C3 complement of the complement system is involved in promoting renal injury. In addition, the differences between the two studies may be due to the application of different study groups, and different sample sizes.
Of further novelty, we found that abdominal pain and recurrence of skin rash more than three times were possible risk factors for the formation of HSPN crescents. Again, to the best of our knowledge, such associations have not been reported previously. Other studies noted that abdominal pain and persistent purpura (> 1 month) were risk factors for pediatric HSPN [28]; purpura relapses more than four times predicted a poor prognosis of HSPN [29]. Repeated rashes in the setting of HSPN may indicate increased inflammation/neutrophilia and vasculitis.
Hematuria is one of the initial renal manifestations of HSPN [15]. Urinary red blood cell count and level of urinary occult blood were possible risk factors in our study. The published data in this regard is mixed. For example, a meta-analysis showed that hematuria and mild proteinuria with hematuria were associated with better prognosis [11]. In contrast, patients with isolated hematuria or mild albuminuria at the onset of the disease had adverse consequences [30]. These conflicting reports may be due to different treatment schemes. For example, the current strategy for HSPN treatment is mostly based on the KDIGO guidelines [16], but some experts have pointed out that the current treatment schemes for HSPN are insufficient if only the KDIGO guidelines are followed, especially for mild types of HSPN [31].
Finally, few studies have shown that platelets are involved in the process of renal injury [32]. We found that platelet count, total cholesterol, and triglyceride levels were likely risk factors for crescent formation in pediatric HSPN. All these related indexes need to be further clarified in terms of their role in the pathogenesis and the prognosis of HSP and HSPN.
There are limitations to our study. First, the study was the from a single center and the sample size studied was small. Second, further detailed classification the pathological characteristics of the glomerular crescent (cellular, cellular-fibrous, and fibrous crescent) was not completed. This is important as it may affect the accuracy of the results. In addition, our study did not assess the risk of variables in relation to other pathologic classifications such as the Oxford classification (MEST-C) and the semi-quantitative classification (SQC), all of which are reported studies in HSPN [19]. Lastly, tissue assessment was not complemented with a control group of pediatric patients with renal disease. Thus, it is not clear if the pathologic lesions and risk factor associations are limited only to HSPN.