The pathogenesis and treatment of pediatric Henoch–Schönlein purpura nephritis

Henoch–Schönlein purpura (HSP) is a systemic disorder characterized by leukocytoclastic vasculitis involving the capillaries and the deposition of IgA immune complexes. Renal involvement is the principal cause of morbidity and mortality in children with HSP. Thus, it is important to clarify the onset mechanism of Henoch–Schönlein purpura nephritis (HSPN) and to identify the most appropriate treatment. We herein review the pathogenesis and treatment of HSPN. As to the pathogenesis, several studies suggest that galactose-deficient IgA1 is recognized by anti-glycan antibodies, leading to the formation of circulating immune complexes and their mesangial deposition, thereby inducing renal injury. Aggressive therapies for the treatment of severe HSPN, including multiple drug combination therapy and plasmapheresis, have been shown to be effective in ameliorating proteinuria and histological severity. Nevertheless, detailed investigations of the pathogenesis of HSPN and double-blind randomized control studies on children with HSPN are still necessary.     

Analysis of a uteroglobin gene polymorphism in childhood Henoch–Schonlein purpura

Uteroglobin (UG) is a pleiotropic protein with anti-inflammatory properties. Mice rendered genetically incapable of expressing UG develop a form of renal disease that closely resembles human IgA nephropathy (IgAN). Furthermore, a single nucleotide polymorphism in the UG gene (A38G) has been associated with rapid progression of human IgAN. We examined whether the A38G polymorphism is associated with childhood Henoch–Schonlein purpura (HSP), a form of vasculitis associated with IgAN-like renal disease. We examined the prevalence of the A38G polymorphism in 34 children with HSP and in 38 ethnically matched controls. Only one patient had clinically evident renal involvement. As compared with controls, the prevalence of the 38G allele was slightly increased in children with HSP, but this increase was not statistically significant. Our results do not support a role for UG in susceptibility to childhood HSP in the population studied. Larger studies involving more patients with renal disease will be necessary to define whether UG is associated with increased risk for HSP nephritis.     

Aberrant glycosylation of IgA1 is inherited in both pediatric IgA nephropathy and Henoch-Schönlein purpura nephritis

Serum galactose-deficient immunoglobulin A1 (Gd-IgA1) is an inherited risk factor for adult IgA nephropathy (IgAN). In this paper, we determined the heritability of serum Gd-IgA1 levels in children with IgAN and Henoch-Sch?nlein purpura nephritis (HSPN), two disorders with clinical phenotypes sharing common pathogenic mechanisms. Serum Gd-IgA1 concentrations were quantified using a Helix aspersa-lectin-based enzyme-linked immunosorbent assay. As a group, 34 children with either disorder (20 with HSPN and 14 with IgAN) had significantly higher Gd-IgA1 levels compared with 51 age- and ethnicity-matched pediatric controls. Serum levels of Gd-IgA1 were also elevated in a large fraction of 54 first-degree relatives of pediatric IgAN and HSPN patients compared with 141 unrelated healthy adult controls. A unilineal transmission of the trait was found in 17, bilineal transmission in 1, and sporadic occurrence in 5 of 23 families when both parents and the patient were analyzed. There was a significant age-, gender-, and household-adjusted heritability of serum galactose-deficient IgA1 estimated at 76% in pediatric IgAN and at 64% in HSPN patients. Thus, serum galactose-deficient IgA1 levels are highly inherited in pediatric patients with IgAN and HSPN, providing support for another shared pathogenic link between these disorders.     

Clinical manifestations of Henoch–Schönlein purpura nephritis and IgA nephropathy: comparative analysis of data from the Japan Renal Biopsy Registry (J-RBR)

Background

The clinical presentation of Henoch–Schönlein purpura nephritis (HSPN) has not been thoroughly investigated among patients of different ages. We therefore compared the features of HSPN and IgA nephropathy (IgAN) based on data from the Japan Renal Biopsy Registry (J-RBR).

Methods

This cross-sectional study analyzed data from patients who were registered in the J-RBR between 2007 and 2012. Clinico-pathological findings at diagnosis were compared among children (aged ≤18 years), adult (aged 19–64 years) and elderly (aged ≥65 years) patients with HSPN (n = 513) and IgAN (n = 5679).

Results

The age at diagnosis considerably differed between HSPN and IgAN; HSPN peaked at 1–19 and at 60–69 years, whereas IgAN peaked at 30–39 years. The clinical features were significantly more severe for HSPN than IgAN, especially proteinuria (children, 1.28 vs. 0.57; adult, 1.95 vs. 1.05; elderly patients, 2.71 vs. 1.64 g/day), and low albumin levels (children, 3.72 vs. 4.13; adults, 3.62 vs. 3.99; elderly patients, 3.07 vs. 3.57 g/dL). The rate (%) of histologically classified endocapillary proliferative or crescentic glomerulonephritis was higher in patients with HSPN than with IgAN. Multiple regression analysis revealed that low albumin level and high BP were independent factors associated with decreased estimated glomerular filtration rates in adult and elderly patients with HSPN.

Conclusions

Age at HSPN diagnosis was bimodally distributed, and the clinical features of HSPN were more severe than those of IgAN across all age groups.

     

Toll-like receptors,immunoproteasome and regulatory T cells in children with Henoch–Schönlein purpura and primary IgA nephropathy

Background

Henoch–Schönlein purpura (HSP) nephritis and primary IgA nephropathy (pIgAN) present with glomerular IgA deposits, but differ with regard to clinical features. The suspected involvement of different immune system pathways is largely unknown.

Methods

This study was aimed at investigating some of the immunological features including Toll-like receptors (TLR), proteasome (PS)/immunoproteasome (iPS) switch, and the regulatory T cell system (Treg/Th17 cells) in 63 children with HSP with/without renal involvement and in 25 with pIgAN. Real-time PRC (Taqman) was used to quantify mRNA levels in peripheral blood mononuclear cells (PBMC).

Results

The expression of mRNAs encoding for TLR4 in both HSP and pIgAN was higher than in controls (HC) and in both diseases FoxP3mRNA and TGF-β1mRNA expression was significantly lower than in HC. A switch from PS to iPS (LMP2/β1) was detected only in PBMC of HSP and it correlated with the level of TLR2mRNA, which was selectively increased only in children with HSP.

Conclusion

Children with HSP and pIgAN present with similar signs of engagement of the innate immunity and regulatory T cell depression. The increased immunoproteasome switch, which correlated with TLR2 activation, may suggest an innate immunity pathway peculiar to HSP vasculitic presentation. This research area also deserves further investigation for possible therapeutic applications.     

Renal expression of alpha-smooth muscle actin and c-Met in children with Henoch–Schönlein purpura nephritis

Alpha-smooth muscle actin (α-SMA) is the actin isoform that predominates within vascular smooth-muscle cells and plays an important role in fibrogenesis. On the other hand, c-Met is the receptor for hepatocyte growth factor (HGF), which plays a role in protection from injury and has anti-fibrogenetic effects. To clarify whether α-SMA and HGF are associated with the progression of renal injury in Henoch–Schönlein purpura nephritis (HSPN), we evaluated the renal expression of α-SMA and c-Met in HSPN patients. Patients were divided into three groups. Group 1 consisted of eight patients (male:female 4:4) with stage II or less in the classification of the International Study of Kidney Disease in Children (ISKDC), Group 2 consisted of 20 patients (male:female 11:9) with ISKDC stage III or greater and a good prognosis, and group 3 consisted of seven patients (male:female 3:4) with ISKDC stage III or greater and poor prognosis. Renal biopsy findings, including c-Met and α-SMA staining, were investigated for each group. At first biopsy, the mean scores for renal α-SMA and glomerular c-Met in groups 2 and 3 were higher than those in group 1, while mean scores for neither renal α-SMA nor glomerular c-Met differed between groups 2 and 3. At second biopsy, the mean scores for renal α-SMA staining in group 3 were higher than those in group 2, and mean score for glomerular c-Met staining in group 3 was lower than that in group 2. In groups 2 and 3, the mean scores for glomerular and interstitial α-SMA staining at first biopsy were correlated with the chronicity index (CI) at second biopsy, but the mean score for glomerular c-Met staining at first biopsy correlated with neither the activity index (AI) nor CI in the first or second biopsies in all groups. Our findings suggest that the expression of renal α-SMA may be associated with progression of renal injury in HSPN.     

Serum levels of galactose-deficient IgA in children with IgA nephropathy and Henoch-Schönlein purpura

IgA nephropathy and Henoch-Schönlein purpura nephritis (HSPN) are related diseases characterized by deposits of IgA1-containing immune complexes in the renal mesangium. Adult patients with IgA nephropathy have aberrantly glycosylated IgA1 (galactose-deficient O-linked glycans) in the circulation and renal deposits. However, IgA1 glycosylation has not been studied in pediatric patients with IgA nephropathy. Using our quantitative lectin enzyme-linked immunosorbent assay (ELISA) test, we measured serum levels of galactose-deficient IgA1 of children with IgA nephropathy and HSPN and controls. Children with IgA nephropathy and HSPN had serum levels higher than those of healthy children or renal-disease controls with C1q nephropathy. Furthermore, lectin ELISA identified patients with HSPN whose clinical course mimicked that of IgA nephropathy. In summary, pediatric patients with IgA nephropathy and HSPN have an aberrancy in the glycosylation in IgA1 O-linked glycans that is similar to that in adults with IgA nephropathy.     

Urinary MCP-1/creatinine in Henoch–Schönlein purpura and its relationship with nephritis

Background

Monocyte chemotactic protein-1 (MCP-1) plays a direct role in the infiltration of macrophages and monocytes during the early stages of Henoch-Schönlein purpura (HSP) nephritis. The aim of this study was to compare the urinary MCP-1/creatinine levels in children with and without HSP nephritis and determine if they are associated with the severity of renal lesions.

Methods

We included 77 patients with HSP and 25 healthy control children. Levels of serum creatinine, urinalysis, and 12-h proteinuria assessments were performed. Urinary MCP-1 levels were determined by ELISA.

Results

Fifty-seven patients had nephritis (74 %). Urinary MCP-1/creatinine levels were significantly higher in patients with HSP nephritis (median, 653 pg/mg) compared to those with HSP without nephritis (median, 269 pg/mg) or healthy children (191 pg/mg). In addition, higher MCP-1/creatinine levels were observed in HSP patients who had renal biopsy (median, 1,412 pg/mg) in comparison to HSP patients without renal biopsy (median, 302 pg/mg). The urinary MCP-1 cut-off value of 530 pg/mg could be used to distinguish patients who undergo renal biopsy with a sensitivity of 81 % and specificity of 77 %.

Conclusions

Urinary MCP-1/creatinine levels are elevated in the early stages of severe HSP nephritis and can be used as a biomarker for HSP nephritis.     

Post-Staphylococcal infection Henoch–Schönlein purpura nephritis: a case report and review of the literature

Abstract

A 37-year-old man developed Henoch--Schönlein purpura nephritis (HSPN) with nephrotic syndrome and rapidly progressive glomerulonephritis after otitis media and externa due to methicillin-resistant Staphylococcus aureus infection. Despite resolution of the infection and prednisolone therapy, his kidney disease worsened. However, the addition of cyclosporine A finally resulted in complete remission of the nephrotic syndrome. A review of similar cases with post-Staphylococcal infection HSPN revealed strong similarities between this entity and immunoglobulin A-dominant postinfectious glomerulonephritis (IgA-PIGN), an increasingly recognized form of PIGN typically associated with Staphylococcal infection, in both clinical and morphological features. Post-Staphylococcal infection HSPN may constitute a subgroup of IgA-PIGN.     

The role of serum myeloid-related protein 8/14 complex in Henoch–Sch?nlein purpura nephritis

Myeloid-related protein (MRP) 8/14 complex is a marker of monocyte and neutrophil activation. We evaluated whether serum MRP8/14 complex is associated with clinical manifestations and pathological findings of Henoch–Sch?nlein purpura nephritis (HSPN). Patients were divided into two groups based on serum MRP8/14 complex levels at renal biopsy. Group 1 consisted of 18 HSPN patients with less than median (670 ng/ml) MRP8/14 complex levels, and Group 2 of 12 HSPN patients with greater than median levels. Clinical manifestations, laboratory findings and serum E-selectin levels, as a marker of vascular endothelial cell dysfunction, as well as histological and immunohistochemical findings were investigated for both groups. We also measured MRP8/14 complex levels in disease control and healthy control children. Urinary protein excretions, serum MRP8/14 complex levels, and serum E-selectin levels were all higher in Group 2 than in Group 1 patients. Serum MRP8/14 complex levels were higher in HSPN patients than in controls. Serum MRP8/14 complex levels were strongly associated with serum E-selectin levels. Pathological findings revealed that the proportions of patients with ISKDC grades III, IV and V in Group 2 were higher than in Group 1. Our findings suggest that serum MRP8/14 complex levels might be associated with the severity of renal injury and endothelial cell dysfunction in HSPN patients.     

The efficacy and safety of immunosuppressive agents plus steroids compared with steroids alone in the treatment of Henoch–Schönlein purpura nephritis: A meta-analysis

Background

Henoch–Schönlein purpura nephritis (HSPN) is the most severe symptom of Henoch–Schönlein purpura. The role of immunosuppressive agents combined with steroids is controversial in treating HSPN. Our meta-analysis was performed to assess the efficacy and safety of the combined therapy in the treatment of HSPN compared with steroids alone.

Methods

Cochrane Library, Pubmed, Embase, and Web of Science were searched and Newcastle–Ottawa Scale was used to assess the quality of the literatures. Odds ratios (OR) and standard mean difference (SMD) with a 95% confidence interval (CI) were used for dichotomous and continuous variables. A random-effect model or fixed-effect analysis was applied according to heterogeneity.

Results

A total of 9 articles were selected in our study. HSPN patients treated with combined therapy demonstrated a significant increase in complete remission rates (OR?=?1.95; 95% CI 1.17–3.23, P?=?0.010) and total remission rates (OR?=?2.30 95% CI 1.33–3.98, P?=?0.003) when compared with steroids alone. Children seemed to benefit more from combined treatment (OR?=?2.45; CI 1.20–5.02, P?=?0.014) than adults (OR?=?1.56; CI 0.76–3.20, P?=?0.225). Additionally, immunosuppressants plus steroids had an advantage on decreasing proteinuria (SMD?=?0.28; CI 0.05–0.52, P?=?0.019) and increasing the level of serum albumin (SMD?=?0.98; CI 0.35–1.60, P?=?0.002). However, significant differences were not found in the estimated glomerular filtration rate (eGFR) and rates of side-effects.

Conclusion

Administration of immunosuppressive agents combined with steroids may be a superior alternative for HSPN. Nevertheless, long-term, high-quality, large-sample, and multicenter RCTs are required to make the results more convincing.

     

Pretransplant and early posttransplant predictors of chronic allograft nephropathy in cadaveric kidney allograft—a single-center analysis of 1112 cases

This retrospective series reviews risk factors for chronic allograft nephropathy (CAN) based on the 10-year experience of a single institution. One thousand one hundred and twelve primary cadaveric renal transplant recipients whose graft survived for more than 6 months were followed for a mean of 4.6 years. The data were analyzed using the multivariate Cox proportional hazards model. CAN was defined as an irreversible rise of serum creatinine (SCr) by 30% in the absence of other causes and occurred in 42% of the patients. The risk of CAN was significantly increased in patients who experienced late rejections. Recipients of organs from donors that were older than 50 years and from such who died secondary to cerebrovascular accident were at increased risk of incurring CAN. Early markers of progression to CAN found at 6 months after transplantation included SCr levels of greater than 1.8 mg/ml, proteinuria, hypoalbuminemia, and hypertension. In conclusion, immune and non-immune factors affect progression to CAN in renal allograft recipients.