Risk Factors for Renal Involvement in Patients with Immunoglobulin A Vasculitis/Henoch–Sch?nlein Purpura: An Updated Review

Chi-Peng Guo and Chun Lu?

Department of Dermatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China.

Introduction

HSP with renal involvement, also known as Henoch–Sch?nlein purpura nephritis (HSPN), is one of the most common secondary glomerular diseases. Its clinical manifestations include microscopic or macroscopic hematuria, proteinuria, nephrotic syndrome, and renal dysfunction. The pathogenic mechanism of HSP remains unknown,but the onset of HSP as well as that of HSPN is thought to be associated with aberrantly glycosylated IgA1.4-5Among children aged 0–12 years, this was the major pathologic pattern(23%),6and it was characterized by glomerular mesangial proliferation and dominant IgA immune complex deposition in mesangial regions and capillary loops.7Patients with HSP were reported to have an estimated 20%–80% risk of progressing to renal involvement4;additionally,adults have a higher risk of this progression compared with children(70%–80%vs.30%–50%).8-9Here, we summarize the risk factors for renal involvement in patients with HSP based on a thorough literature review on PubMed, and to provide useful information for promoting early intervention for HSP treatment.

Genetic factors

Although the molecular mechanisms of HSP have not been completely elucidated, genetics is commonly thought to play a crucial role in the pathogenesis of this disease.Genetic variants within certain loci were genotyped to identify the genetic background of HSP, and the results suggest that some may be related to the disease, such as the human leukocyte antigen genes as well as gene markers associated with immune and inflammatory pathways.10

Regarding renal involvement in HSP, a few potentially related genes have also been reported. He et al.11found that the 1365G/A polymorphism of the C1GALT1 gene may contribute to the development of HSPN.

Jiang et al.12carried out a study in a Chinese population to investigate the potential association of inducible nitric oxide synthase (iNOS) polymorphisms with the risk of HSP as well as with the tendency for children with HSP to develop HSPN.Their results showed that the patients with nephritis exhibited a significantly higher frequency of the 12 CCTTT repeats and the rs2297518 allele compared with those without nephritis. In another study, the endothelial nitric oxide synthase (eNOS) T786C TT genotype was found to be associated with HSPN susceptibility.13Pang et al.14carried out a comparative study to explore the expression of long non-coding (lnc)RNAs and messenger(m)RNAs in the peripheral blood of children with HSPN and healthy children. The results revealed that the expression levels of lncRNAs, including ENST00000378432, ENST00000571370, uc001kfc.1,and uc010qna.2, were decreased in HSPN patients compared with those in healthy controls.These lncRNAs are associated with the p53 signaling pathway and apoptosis-associated genes.14

The genes described above cover only a small subset of those that have been linked to HSP. In a recent review,Raquel et al.10summarized several markers of renal damage and/or renal sequelae, including interleukin (IL)-1b,IL1ra,transforming growth factor beta 1(TGFb1),IL-8, chemokine (C-C motif) ligand 5 (CCL5), selectin E(SELP),angiotensin(Agt),angiotensin-converting enzyme,paired box 2 (PAX2), cytotoxic T lymphocyte-associated protein 4 (CTLA4), methylenetetrahydrofolate reductase(MTHFR), C1GALT1, nitric oxide synthase 2 (NOS2A),eNOS, vascular endothelial growth factor, and Mediterranean fever (MEFV). However, the various studies investigating these genes failed to come to a widely recognized conclusion.Consequently,further exploration with larger samples remains necessary.Additionally,genegene interactions should also be considered if the specific role of a single gene is small.

Epidemiological factors

Age of onset

The clinical spectrum and outcome of adults with HSP depends on the age of onset. HSP has a self-limiting course in children, whereas it presents a more severe form in adults,with more extensive renal involvement.15Wang et al.4found that older age at onset (over 6 years old) is one of the prognostic indicators for renal involvement and severe kidney disease in children with HSP.An age of>10 years old at onset was also reported to relate to renal involvement in pediatric patients in another study.16

Recent reports supported that renal involvement during HSP is more common in adults than in children. After a mean follow-up period of 2 years,Kang et al.17found that adults more commonly developed chronic renal failure compared with children (10.4% vs. 1.8%).8Adults also have a worse prognosis compared with children, mainly because of the presence of nephritis. Batu et al.15retrospectively evaluated the medical records of 35 adult and 159 pediatric (<18 years old)patients with a clinical diagnosis of HSP, and found that the levels of creatinine and C-reactive protein were higher among adults,and that skin biopsy, hypertension, renal involvement, hematuria,proteinuria,and renal insufficiency at diagnosis were more frequent in adults than in children.

從哈爾濱市政府日前印發(fā)的《關(guān)于制定和實施老年人照顧服務(wù)項目的實施意見》（以下簡稱《意見》）中了解到，哈市開始啟動制訂和實施老年人照顧服務(wù)項目工作，其中首次將居家和社區(qū)養(yǎng)老服務(wù)納入照顧服務(wù)項目。

Clinical findings identified old age as one of the risk factors for chronic kidney disease. Komatsu et al.18conducted a multicenter cohort study that compared the clinicopathological parameters between 106 adult (aged 19–64 years)and 46 elderly(aged ≥65 years)patients with HSPN. They found that the rates of hypertension,impaired renal function,hypoalbuminemia,and crescentic glomerulonephritis were all significantly higher among the elderly patients compared with the adult patients. Their findings support that the careful monitoring of renal function is necessary in patients aged over 65 years and in those with hypoalbuminemia.

Race/ethnicit y

HSPN is more common in Asia19and Europe than in the United States and Latin America.20O'Shaughnessy et al.20determined that glomerular disease frequencies differed by continent,even among patients of similar race/ethnicity.In addition, regional environmental and lifestyle factors, as well as local biopsy policies, might influence glomerular disease epidemiology independent of race/ethnicity.

To investigate the differences in ethnic distribution of children with HSP in the United States, a retrospective study was conducted by Okubo et al.21They concluded that race/ethnicity (eg, Hispanic, Asian, and Pacific Islander)was one of the factors associated with the length of hospital stay. Epidemiological surveillance helps to identify populations at risk and to guide subsequent investigations of cause.22

Season and infections

Yang et al.23found that HSP cases occur more commonly in the autumn and winter among a total of 2,759 children with HSP, who were <17 years old. A study by Wang et al.4found that cold season is a risk factor for renal involvement in HSP.These associations may be related to concurrent infections,given that infectious factors play an important role in the occurrence of HSP.

Hwang et al.24found that spring had the largest number of patients (5,252, 31.0%) and summer had the smallest number of patients(3,224,19.0%).The largest number of cases occurred in March(1,949,11.5%)and the smallest in August (959, 5.7%). However, among adolescent patients(12–18 years),more cases occurred in the summer(985, 24.8%) than in the fall (760, 19.1%). The positive detection rates for most viruses showed distinct seasonal variations.In the early childhood group(aged 2–5 years),the onset of HSP was found to be associated with epidemics of respiratory syncytial virus, influenza virus,and norovirus.In the middle childhood group(aged 6–11 years), influenza virus and norovirus epidemics were associated with the seasonality of HSP. The epidemic periods of bocavirus and rotavirus that of HSP among the adolescent patients.Their data also show that the epidemic patterns of influenza and rotavirus were temporally and statistically similar to that of HSP, which suggests that above respiratory or enteric viruses may play an important role in the pathophysiology of HSP.

Some infectious factors have also been reported to be related with the renal involvement in patients with HSP,such as odontogenic focal infection,25methicillin-resistant Staphylococcus aureus infection,26and human parvovirus B19 infection.27However, most of the publications reporting these links are case studies;no large-scale studies have been conducted yet.

Medical level

Wang et al.4retrospectively analyzed the demographic data among 2731 children with HSP diagnosed between 2012 and 2015, and they found that a longer interval between symptom onset and diagnosis is one of the prognostic indicators for renal involvement and severe kidney disease in children with HSP. Additionally, rural residence was also associated with an increased risk of renal involvement.

Clinical features

Relapse

The rate of HSP relapse has been reported to range from 2.7% to 51.7%; thus, there is broad variability among different studies. A multivariate analysis showed that the appearances of joint and gastrointestinal manifestations at thetimeofHSPdiagnosiswerethebestpredictorsofrelapse.

Chan et al.16revealed 20 possible and 13 significant risk factors associated with renal involvement in HSP in a meta-analysis of 13 studies including 2,398 children,among which relapse was one of the risk factors associated with renal involvement in pediatric HSP. Furthermore,Wang et al.4confirmed that recurrence is one of the independent risk factors of renal involvement and severe kidney disease in HSP.

Persistent purpura

Persistent purpura was found to be one of the significant risk factors for renal involvement in HSP in a multivariate analysis conducted in 1998.28Additionally, Chan et al.15reported that persistent purpura is associated with renal involvement during pediatric HSP, based on a metaanalysis.

Distribution of skin lesions

St. John et al.29indicated that skin lesion distribution on the extremities might be predictive of significant long-term renal involvement and be critical for risk stratification and the development of personalized diagnostics and therapeutics. In another study conducted on a total of 535 Chinese with HSP, purpura on sites other than the lower limbs was found to be one of the risk factors for nephritis development.30

Multiple systems involvement

In their meta-analyses,Chan et al.16found that abdominal pain (1.94, 1.24–3.04), gastrointestinal bleeding (1.86,1.30–2.65), severe bowel angina (3.38, 1.17–9.80), and arthritis/arthralgia(1.41,1.01–1.96)were associated with renal involvement in pediatric HSP. Relevant clinical interventions for these risk factors may exert positive effects on the prevention of kidney disease during the early stages of HSP. Mao et al.30found that the presence of occult blood in the stool is a risk factor for the development of nephritis.Central nervous system involvement in HSP has also been reported to be highly associated with severe kidney disease and to pose an increased risk for severe kidney disease.4

Laboratory examination

Inflammatory biomarkers

Chan et al.16revealed that a white blood count of>15×109cells/L, platelet level of >500＞109cells/L, elevated antistreptolysin O level,and low complement C3 level are significant risk factors associated with renal involvement in HSP.Early interventions for these risk factors can help to prevent renal disease.

The neutrophil-to-lymphocyte ratio(NLR)is an inflammatory marker that is used to assess systemic inflammation in various diseases.Nagy et al.31conducted a retrospective review on adult patients diagnosed with HSP between 2004 and 2016,and their data suggest that the C-reactive protein level (P=0.002) and NLR (P<0.001) were each significantly higher among the HSP patients who developed gastrointestinal and/or renal manifestations,and that the NLR provided the strongest diagnostic value. The optimal cutoff NLR value for predicting systemic involvement was 3.34, with a specificity of 95% and a sensitivity of 85%. Additionally, the pretreatment NLR was found to be significantly correlated with the severity of the systemic manifestations of HSP(P=0.022).This study suggests that the NLR is a potential indicator for predicting systemic involvement in adult HSP.

Yuan et al.32found that the concentrations of TNF-a,IL-8, and IL-10 in the serum were significantly higher in the patients with HSP than those in the control group(all P<0.05). TNF-a in the HSPN group was significantly higher than that in the HSP group(P<0.05).Additionally,the TNF-a, IL-8, and IL-10 levels in the acute nephritis,chronic nephritis, and nephrotic syndrome subgroups were all higher than those in the simple proteinuria subgroup.Furthermore,the levels of these three factors in the acute nephritis subgroup were all higher than those of the chronic nephritis and nephrotic syndrome subgroups(P<0.05).The IL-8,IL-10,and TNF-a serum levels were positively correlated with the urinary protein levels.Together, these results indicate that the levels of serum TNF-a,IL-8,and IL-10 are correlated with HSPN and that the serum TNF-a concentration can be used as an indicator of the severity of HSPN.

Immune indexes

Antineutrophil cytoplasmic antibodies(ANCA),which are a group of autoantibodies directed against proteins in the granules of neutrophils and in peroxidase-positive lysosomes of peripheral blood monocytes,have been detected in HSP patients but with unclear clinical significance.Cytoplasmic (c)-ANCA and perinuclear (p)-ANCA are characteristic for pauci-immune small vessel vasculitis,whereas the presence of ANCA in immune-complexmediated vasculitis, especially HSP, remains controversial.33-35IgA ANCA was detected during the acute phase in 82% of HSP children with a high sensitivity, and was proposed to be a good marker for confirming an HSP diagnosis despite having a low specificity and positive likelihood ratio.36The presence of c-ANCA in HSP is very unusual.Kim and Shin37-39suggested that the presence of c-ANCA in patients diagnosed with HSP may relate to TNF-a and defective T-regulatory cells. It has been reported that ANCA of the IgG isotype may be associated with rapidly progressive glomerulonephritis.However,the clinical and pathological significance of IgG c-ANCA in the setting of HSP and whether these antibodies could be used as potential markers for aggressive HSP need to be further studied.33

Berthelot et al.40revealed that serum galactose-deficient IgA1 and urinary IgA, IgG, IgM, neutrophil gelatinaseassociated lipocalin,IL-1b,IL-6,IL-8,IL-10,and IgA-IgG and IgA-sCD89 complexes were associated with nephritis in HSP patients.The urinary IgA level may improve patient risk stratification for poor outcome.

Ho?evar et al.41found that the presence of aPL was not associated with any distinct clinical manifestation in the HSP cohort. However, a significant association between the IgA isotypes of antibodies against the phosphatidylserine-prothrombin complex (IgA aPS/PT)and kidney involvement in acute HSP was found, with a relative risk of 2.4 (95% confidence interval: 1.6–3.7).IgA aPS/PT-positive patients also more frequently developed nephrotic syndrome and/or acute renal failure.There was a trend toward more frequent relapses in the persistently aPL-positive group than those without. The findings suggest that patients with aPLs have higher markers of inflammation than those without. The subset of HSP patients with IgA aPS/PT more commonly had renal involvement.

Other biomarkers

He et al.42conducted a comparative proteomic analysis in patients with HSP(n=6),patients with HSPN(n=6),and healthy subjects (n=7). Their results show that the angiotensinogen concentration is correlated with HSPN,and could be used as a potential marker for the progression of HSP.

Conclusion

Overall,the prognosis of patients with HSPN is favorable.However, some patients (1%–7%) have a high risk of progressing to end-stage renal disease. Additionally,HSPN is increasingly seen as the main reason for chronic renal failure among pediatric patients. Therefore, early diagnosis and differentiation of nephritis play an important role in avoiding or delaying the occurrence of endstage renal disease. Although some genetic factors,epidemiological factors, and clinical features, as well as some abnormal laboratory findings,are considered to have a predictive effect, the full set of risk factors associated with renal involvement remains unclear.4Therefore,further studies are needed to establish a risk evaluation model for HSPN, which is more practical, quantifiable,and simple than the currently available options.