Haemoglobin, albumin, lymphocyte, and platelet score as an independent predictor for renal prognosis in IgA nephropathy.

Objective: The haemoglobin, albumin, lymphocyte, and platelet (HALP) score, a convenient and composite laboratory biomarker, can reflect inflammation and systemic nutritional status. This study was performed to investigate the effect of the HALP score on the prognosis of patients with IgA nephropathy (IgAN). Methods: This is a retrospective single centre study that enrolled 895 biopsy-confirmed IgAN patients from June 2019 to June 2022 who were followed for more than 1 year. Kaplan-Meier curves and Cox regression analyses were performed to determine the relationship between HALP and adverse outcomes. The restricted cubic splines was used to identify the possible associations. The optimal cut-off value of HALP for renal poor outcome was identified by the area under the receiver operating characteristic curve (AUC). Results: A total of 895 patients finally participated in the study and were divided into three groups (tertial 1-3) according to the baseline HALP score. More severe clinicopathologic features were observed in the lower HALP group, and Kaplan-Meier analysis showed patients in tertial 1 had a higher risk of kidney failure than the other groups (log-rank=11.02, P= 0.004). Multivariate Cox regression revealed that HALP score was an independent risk factor for renal prognosis in IgAN (adjusted HR: 0.967, 95% CI: 0.945-0.990, P = 0.006). The results of subgroup analysis suggested that HALP was more important in patients under the age of 50, BMI ≤ 23.9 and eGFR ≤ 90 mL/min/1.73 m2. The best cut-off HALP for renal survival was 38.83, sensitivity 72.1%, and specificity 55.9% (AUC: 0.662). Patients were further grouped according to HALP cut-off values and propensity matched. Multivariate Cox regression analysis revealed that HALP remained an independent predictor of IgAN in the matched cohort (HR 0.222, CI: 0.084-0.588, P=0.002). Conclusion: HALP is a novel and potent composite parameter to predict kidney outcome in patients with IgAN.

Association of time-averaged serum uric acid level with clinicopathological information and long-term outcomes in patients with IgA nephropathy.

Objective: Whether serum uric acid (SUA) at baseline could been identiûed as a risk factor for progression in IgA nephropathy (IgAN) patients remains unclear, therefore, long- term SUA control levels must be monitored. We aimed to investigate the relevant factors affecting time-averaged SUA (TA-SUA) and to assess the prognostic value of TA-SUA in IgAN. Methods: This retrospective study included 152 patients with IgAN. The relationships between TA-SUA and clinicopathological features and renal outcomes (defined as the doubling of the baseline serum creatinine level or end-stage renal disease) were analyzed in groups divided by quartiles of TA-SUA levels, the presence of hyperuricemia, and sex. Results: Patients with high TA-SUA levels had higher levels of baseline SUA, blood urea nitrogen (BUN), triglycerides, serum C3 and serum C4 and were more likely to be male and have hypertension, proteinuria, poor renal function, and pathological injuries including high grades of tubular atrophy/interstitial fibrosis (T1-T2). These patients had a poorer prognosis compared with patients with low TA-SUA levels. The TA-SUA level was positively correlated with baseline age and BUN, triglycerides, serum C3, and serum C4 levels, and negatively correlated with baseline eGFR. Survival curve analysis indicated that persistent hyperuricemia was associated with significantly poorer renal outcomes than normo-uricemia in both men and women. The TA-SUA level also was an independent predictor of renal outcome in patients with IgAN, with optimal cutoû values of 451.38 µmol/L (area under the curve (AUC) = 0.934) for men and 492.83 µmol/L (AUC = 0.768) for women. Conclusions: The TA-SUA level is associated with triglyceride level, complement component levels, renal function, and pathological severity of IgAN, and it may be a prognostic indicator in male and female patients with IgAN.

Unveiling biomarkers and therapeutic targets in IgA nephropathy through large-scale blood transcriptome analysis.

INTRODUCTION: IgA nephropathy (IgAN) is the most prevalent form of glomerulonephritis. Unfortunately, molecular biomarkers for IgAN derived from omics studies are still lacking. This research aims to identify critical genes associated with IgAN through large-scale blood transcriptome analysis. METHODS: We constructed novel blood transcriptome profiles from peripheral blood mononuclear cells (PBMCs) of 53 Chinese IgAN patients and 28 healthy individuals. Our analysis included GO, KEGG, and GSEA for biological pathways. We analyzed immune cell profiles with CIBERSORT and constructed PPI networks with STRING, visualized in Cytoscape. Key differentially expressed genes (DEGs) were identified using CytoHubba and MCODE. We assessed the correlation between gene expressions and clinical data to evaluate clinical significance and identified hub genes through machine learning, validated with an open-access dataset. Potential drugs were explored using the CMap database. RESULTS: We identified 333 DEGs between IgAN patients and healthy controls, mainly related to immune response and inflammation. Key pathways included NK cell mediated cytotoxicity, complement and coagulation cascades, antigen processing, and B cell receptor signaling. Cytoscape revealed 16 clinically significant genes (including KIR2DL1, KIR2DL3, VISIG4, C1QB, and C1QC, associated with sub-phenotype and prognosis). Machine learning identified two hub genes (KLRC1 and C1QB) for a diagnostic model of IgAN with 0.92 accuracy, validated at 1.00 against the GSE125818 dataset. Sirolimus, calcifediol, and efaproxiral were suggested as potential therapeutic agents. CONCLUSION: Key DEGs, particularly VISIG4, KLRC1, and C1QB, emerge as potential specific markers for IgAN, paving the way for future targeted personalized treatment options.

Combined Effects of the Serum IgA/C3 Ratio and Glomerular C3 Staining on the Renal Outcome in Adult Immunoglobulin A Nephropathy.

INTRODUCTION: The aim of this study was to evaluate the predictive value of the serum IgA/C3 ratio and glomerular C3 deposits in kidney biopsy in adult IgA nephropathy. METHODS: The study included 718 adult IgAN patients diagnosed based on kidney biopsy. Patients without corticosteroids or immunosuppressive drugs >1 month were regularly followed up for at least 1 year or until the study endpoint. The optimum serum IgA/C3 ratio was calculated by the AUROC-based cutoff ratio. Proteinuria, creatinine, eGFR, serum IgA, and serum C3 were evaluated at baseline. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The degree of glomerular C3 staining was semiquantitatively determined (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) by immunofluorescence microscopy. The patients were divided into four groups by the serum IgA/C3 ratio and glomerular C3 staining. RESULTS: The baseline data suggested that when the serum IgA/C3 ratio was at the same level, patients with a high glomerular C3 staining score (≥2) always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis (group 1 vs. group 2; group 3 vs. group 4). When glomerular C3 staining was at the same level, proteinuria was significantly higher in patients with serum IgA/C3<2.806 (group 1 vs. group 3; group 2 vs. group 4), which was contrary to previous studies that have suggested that the serum level of IgA/C3 was associated with disease severity. Hence, this study set out to investigate the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in adult IgA nephropathy. Renal survival analysis indicated that serum IgA/C3 ≥2.806 and glomerular C3 staining ≥2 (group 1) may be correlated with a poorer prognosis, especially in different clinicopathological characteristics of IgAN patients based on the subgroup analysis. Multivariate Cox analysis demonstrated that hypertension, serum creatinine, CKD stage, T1/2 and C3 staining were independent predictive factors of renal survival. CONCLUSIONS: The combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease. However, further study is required for validation in the future.

Treatment and outcome of IgA nephropathy in children from one single center experience.

BACKGROUND: There is no standard recommendation for IgA nephropathy treatment in children. METHODS: This is a retrospective study. From 2012 to 2020, newly diagnosed primary IgAN followed up for at least 1 year were enrolled. The correlation of MESTC scores and clinical index including proteinuria, gross hematuria and renal dysfunction was analyzed. Treatment and clinical response of 6 month, 1year and 3 year at follow up were also analyzed. Complete renal remission was calculated with Kaplan-Meier analysis. RESULTS: The median follow up was 36 months, from 12 months to 87months in 40 IgAN children. Angiotensin-converting enzyme inhibitor (ACEI) was applied to all patients. 30% received ACEI alone; 15% received glucocorticoids; 37.5% received glucocorticoids plus cyclophosphamide, 17.5% received glucocorticoids plus mycophenolate mofetil. Individuals with diffuse mesangial hypercellularity (M1) were more likely to have nephrotic range proteinuria compared to patients with M0 (80% vs. 20%, P < 0.01). Complete renal remission at 6-month, 1-year and 3-year follow up is 50.25%, 70% and 87.5% respectively. Five-year complete renal remission calculated by Kaplan-Meier analysis is 58.4%. Although without significant difference, there is trend of better survival with complete renal remission in group of nephrotic range proteinuria onset. There is no severe adverse effect. CONCLUSION: This study supports the use of glucocorticoids plus immunosuppressive in addition to ACEI in IgA nephrology pediatric patients with proteinuria. We suggest proactive immunosuppressive treatment in IgA nephropathy in children. This is from a single center in China as may not same results in other population.

IgA nephropathy in adults with epidermolysis bullosa.

Epidermolysis bullosa (EB) is a devastating genetic condition caused by mutations in genes that give rise to aberrant proteins. There are 16 different such proteins implicated in EB that are important in maintaining the integrity of the dermoepidermal junction. It is classified into four major subtypes: (i) EB simplex; (ii) junctional EB (JEB); (iii) dystrophic EB (DEB); and (iv) Kindler EB. Renal disease is a recognized complication of EB and the aetiology is complex. We describe our experience of managing five patients with EB and IgA nephropathy. We recommend that patients with recessive DEB and JEB routinely have the following monitored: renal function, urinary albumin/creatinine ratio, urine analysis, serum albumin levels and immunoglobulins; specifically serum IgA. Management of IgA nephropathy in the context of EB should be tailored to the individual and be carried out within a specialist multidisciplinary team. Our case series provides important insights into the treatment of IgA nephropathy in patients with EB and will help inform treatment in this rare genetic disease. Case series and reports like ours are key in gaining real-life data to quantify the actual risk of morbidity and mortality from each of the treatment modalities discussed.

Serum homocysteine is associated with tubular interstitial lesions at the early stage of IgA nephropathy.

BACKGROUND: The association between homocysteine (Hcy) and IgA nephropathy (IgAN) is not well understood. We aimed to investigate the relationship between Hcy and clinicopathologic features in IgAN patients. METHODS: A total of 337 IgAN patients and 150 sex- and age- matched healthy controls were enrolled in this single-center retrospective study. According to Hcy ≤ 10 µmol/L or > 10 µmol/L, patients were divided into low and high Hcy groups. Multivariate logistic regression was performed to explore the risk factors for elevated Hcy. RESULTS: Serum Hcy was higher in IgAN patients than in healthy controls [11.6 (9.1,15.3) vs. 8.8 (7.5,10.6) µmol/L, P < 0.001], unanimously in the subgroup of 156 patients with a normal estimated glomerular filtration rate (eGFR) (≥ 90 ml/min/1.73 m2) [9.9 (7.6,12.4) vs. 8.8 (7.5,10.6) µmol/L, P < 0.001]. Compared to the low Hcy group, serum creatinine (Scr), blood urine nitrogen (BUN), uric acid (UA), endocapillary hypercellularity (E) and tubular atrophy/interstitial fibrosis lesion (T) were higher in the high Hcy group. Hcy levels were positively correlated with Scr, BUN, UA, 24-h urine protein, and E and T lesions, but negatively correlated with eGFR and superoxide dismutase (SOD). In the subgroup with normal eGFR, patients with higher Hcy were persistent with higher Scr, BUN and T lesions. A multivariate logistic regression model showed that the risk of elevated Hcy in patients with pathological T increased by 2.87-fold. T lesions could better predict high Hcy, with an odds ratio (OR) of 14.20 in the subgroup with normal eGFR. CONCLUSIONS: Pathologic T was an independent risk factor associated with elevated Hcy, especially at the early stage of IgAN.

Is hyperuricemia an independent prognostic factor for IgA nephropathy: a systematic review and meta-analysis of observational cohort studies.

BACKGROUND: Hyperuricemia has been reported to be correlated with IgA nephropathy (IgAN). However, whether hyperuricemia or elevated serum uric acid (SUA) is an independent prognostic factor of IgAN remains unknown. Therefore, this systematic review and meta-analysis evaluated the prognostic value of hyperuricemia and elevated SUA in IgAN. METHODS: Databases including PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Open Gray were reviewed systematically. The kidney failure events of IgAN were defined as a doubling of serum creatinine, halving of eGFR, end-stage renal disease (ESRD), or death. The risk ratio (RR) between hyperuricemia and IgAN-caused kidney failure was evaluated before and after adjustment for relevant covariates. The RR between elevated SUA and IgAN-caused kidney failure was evaluated after adjustment for relevant covariates. RESULTS: A total of 11 548 patients from 14 studies were included in this meta-analysis. Hyperuricemia was found to be an independent prognostic factor of IgAN (unadjusted RR = 2.79, 95% CI = 1.93-4.03, p for heterogeneity <0.00001, I2 = 91%; adjusted RR = 2.12, 95% CI = 1.64-2.73, p for heterogeneity = 0.86, I2 = 0%). Subgroup and sensitivity analyses confirmed the stability of these results. Similarly, elevated SUA was positively correlated with kidney failure events of IgAN (adjusted RR = 1.25, 95% CI = 1.19-1.31, p for heterogeneity = 0.6, I2 = 0%). CONCLUSION: Our meta-analysis showed that hyperuricemia and elevated SUA were both independently associated with an increased incidence of kidney failure events in IgAN patients.

Clinical diagnostic performance of common laboratory indicators in primary glomerulonephritis.

OBJECTIVE: Immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) are common types of primary glomerulonephritis (PGD). A lack of specific clinical features makes diagnosis difficult. Kidney function indicators have been used for their diagnosis. However, the diagnostic performance of these indicators is undetermined. The purpose of this paper is to evaluate their diagnostic potential. PATIENTS AND METHODS: 101 patients with PGD were enrolled, including 50 with MN and 51 with IgAN. The healthy controls included 110 volunteers. The indicators related to kidney function, including TP, ALB, Cre, CysC, eGFR, C1q, Ure, Anti-PLA2R, complement C3, and complement C4 in serum, ACR in urine, and antinuclear antibody profile, IgG staining, IgA staining, IgM staining, C3 staining and C1q staining in tissue samples were evaluated. RESULTS: Statistical differences were found in TP, ALB, Ure, CysC, eGFR, C1q, Anti-PLA2R, complement C3, complement C4 and ACR among the three groups of subjects. ROC analysis showed that Anti-PLA2R and ACR had the highest specificity for identifying IgAN and/or MN from the healthy controls, ACR had the highest sensitivity. The Sp and Se of IgA and IgG in tissue samples for the identification of IgAN and MN were both high. Both IgAN and MN were predicted by anti-PLA2R, especially MN. In tissue samples, MN patients were more likely to be IgG positive and IgAN patients were more likely to be IgA positive. CONCLUSIONS: IgAN and MN may be differentiated using serum Anti-PLA2R, tissue IgG, and tissue IgA. Cre is only useful in middle and late stages of GPDs, ACR is an exclusion marker, and CysC and C1q cannot be used to identify MN.

Complement Activation Is Associated With Crescents in IgA Nephropathy.

Introduction: Crescents, especially those found at a percentage greater than 50%, are often associated with rapid progression of kidney disease in IgA nephropathy (IgAN). The mechanism of crescents forming in IgAN is still unclear. In this study, we aimed to evaluate whether excess complement activation participates in the formation of crescents in IgAN. Methods: One hundred IgAN patients with various proportions of crescents-24 with 1%-24%, 27 with 25%-49%, 21 with 50%-74% 12 with more than 75%, and 16 without crescents-were included. Urinary concentrations of mannose-binding lectin (MBL), Bb, C4d, C3a, C5a, and soluble C5b-9 (sC5b-9) were measured at the time of biopsy. Receiver operating characteristic (ROC) curves were performed to evaluate predictive ability of renal survival for urine complement activation. In addition, historical C4d, C5b-9, and C3d were stained by immunohistochemistry. Results: IgAN patients with more than 50% crescent formation showed higher complement activation levels than the other patients (urinary C3a/creatinine (C3a/Cr): 6.7295 ng/mg, interquartile range (IQR) 1.4652-62.1086 ng/mg vs. 0.1055 ng/mg, IQR 0-1.4089 ng/mg; urinary C5a/Cr: 15.6202 ng/mg, 4.3127-66.7347 ng/mg vs. 0.3280 ng/mg, IQR 0.0859-2.4439 ng/mg; urinary sC5b-9/Cr: 98.6357 ng/mg, 8.8058-1,087.4578 ng/mg vs. 1.4262 ng/mg, 0.0916-11.0858 ng/mg, all p-values <0.001). The levels of urinary MBL and C4d representing lectin complement pathway showed a linear association with the proportion of crescents (r = 0.457 and 0.562, respectively, both p-values <0.001). Combined urine complement products could increase the predictive ability compared with crescents alone from 0.904 to 0.944 (p = 0.062) with borderline significance. Moreover, the glomerular C4d deposition rate elevated with the increase of proportions of crescents. Conclusion: Excess complement activation may be involved in the formation of crescents, especially diffuse crescent formation, in patients with IgAN. Urinary C4d correlated with the proportion of crescents and was a potential biomarker for disease monitoring in crescentic IgAN.

Poly-IgA Complexes and Disease Severity in IgA Nephropathy.

BACKGROUND AND OBJECTIVES: Poly-IgA immune complex formation and glomerular deposition play a key role in IgA nephropathy. Our study sought to develop a new methodology for one-step serologic detection of poly-IgA levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A novel ELISA method using recombinant CD89 as a "capturing" probe was established for detecting poly-IgA immune complex in plasma. We applied semiquantitative measurements of these poly-IgA indices in patients recruited at Peking University First Hospital who had IgA nephropathy or other kidney disease types, as compared with healthy controls. The longitudinal trend of the poly-IgA index and the association with pathologic parameters and treatment responses were evaluated. Finally, we analyzed the molecular composition of poly-IgA complexes in patients by mass spectrometry. RESULTS: Recombinant CD89-mounted ELISA plates specifically captured plasma poly-IgA. The levels of poly-IgA immune complex (26.7 [interquartile range (IQR) 17.1-42.6] U/ml) in IgA nephropathy were significantly higher than those in healthy controls (15.5 [IQR 10.7-20.0] U/ml; P<0.001) or in controls with non-IgA nephropathy disease (14.8 [IQR 10.5-21.9] U/ml; P<0.001). Higher levels of poly-IgA immune complex were associated with lower eGFR and worse kidney outcome. Accuracy parameters and concordant statistics showed good discrimination between IgA nephropathy and healthy controls based on poly-IgA index levels (area under the curve [AUC], 0.78; 95% confidence interval [95% CI], 0.72 to 0.83; P<0.001), significantly outperforming galactose-deficient IgA1 levels (AUC, 0.70; P=0.05). Corticosteroid and immunosuppressant treatments lowered poly-IgA indices. After a recombinant CD89-directed workflow in conjunction with mass spectrometry, we also analyzed the molecular composition of IgA immune complex in patients with IgA nephropathy. CONCLUSIONS: Higher level of recombinant CD89-bound poly-IgA immune complex was associated with the severity of the disease and with treatment response to steroids and immunosuppressants.

Lower serum bilirubin is associated with poor renal outcome in IgA nephropathy patients.

Aims: IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. We conducted this study to explore the relationship between serum bilirubin and renal outcome of patients with IgAN. Methods: A total of 1492 biopsy proven IgAN patients were recruited and divided into two groups according to their median serum bilirubin concentration: the low bilirubin group (serum bilirubin≤9.7umol/L, n=753) and high bilirubin group (serum bilirubin>9.7umol/L, n=739). Basic clinical characteristics were assessed at the time of renal biopsy and the relationships between serum bilirubin and the combined endpoints were analyzed. The combined endpoints were defined as a 50% decline in estimate glomerular filtration rate (e-GFR), end-stage kidney disease (ESKD), renal transplantation and/or death. In addition, propensity score matching (PSM) was then performed to improve balance and simulate randomization between patients in different groups. Kaplan-Meier survival analysis was applied to explore the role of serum bilirubin in the progression of IgAN. Three clinicopathological models of multivariate Cox regression analysis were established to evaluate the association of serum bilirubin and renal prognosis of IgAN. Results: During median 5-year follow-up period, significant differences were shown in Kaplan-Meier analysis. In the unmatched group, 189 (12.7%) patients progressed to the renal combined endpoints. Among this, 122 in 753 patients (16.2%) were in low bilirubin group and 67 in 739 patients (9.1%) were in high bilirubin group (p<0.001). After PSM, there were 134 (11.8%) patients reached the combined endpoints, which included 77 in 566 patients (14.6%) in low bilirubin group and 57 in 566 patients (10.1%) in high bilirubin group (p=0.039). The results of three models (including demographics, pathological, clinical indicators and serum bilirubin) demonstrated that a lower basic serum bilirubin level was significantly associated with a higher risk of reaching combined endpoints in IgAN patients both in unmatched and matched cohort. Conclusion: Serum bilirubin level may be negatively associated with the progression of IgAN.

Identification of key miRNAs and their targets in peripheral blood mononuclear cells of IgA nephropathy using bioinformatics analysis.

BACKGROUND: Currently, renal biopsy is the gold standard for clinical diagnosis and evaluation the degrees of IgA nephropathy. However, renal biopsy is an invasive examination and not suitable for long-term follow-up IgA nephropathy. The activation of peripheral blood mononuclear cells (PBMCs) are related to IgA nephropathy, but the key molecular marker and target of PBMCs for evaluating the progression and prognosis of IgA nephropathy is still unclear. METHODS: We downloaded gene expression omnibus series 25590 (GSE25590) datasets, of which PBMCs from IgA nephrology (IgAN) and healthy patients, from the gene expression omnibus (GEO) database. Differentially expressed miRNAs (DEMs) between IgAN and healthy patients were identified. The Funrich software was used to predict the differentially expressed genes (DEGs). Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyzes of overlapping genes were analyzed at the function level on DAVID 6.8. We used search Tool for the retrieval of interacting genes (STRING) online database constructed the protein-protein interaction (PPI) network. Then we further analyzed the hub genes by Cytoscape software and the hub miRNA by TargetScan. RESULTS: We identified 418 DEMs from the GSE25590 datasets. The upstream transcription factors SP1 regulates most DEMs. According to the GO and KEGG results, the DEGs were enriched in the MAPK signaling pathway and small GTPase mediated signal transduction. SYN1, SYT4, RBFOX1, KCNC1, VAMP2, FBXO11, ASB9, SYT9, KLHL5, and KRAS were identified as hub genes. Hsa-miR-532-5p, hsa-miR-92a, hsa-miR-328, hsa-miR-137, hsa-miR-153, hsa-miR-9-5p, hsa-miR-140-5p, hsa-miR-217, hsa-miR-155, and hsa-miR-212 were predicted as hub miRNAs. CONCLUSIONS: The DEMs and DEGs re-analysis provided potential key genes and hub miRNA of PMBCs, which may help to monitor the happening and prognosis of IgAN.

O- and N-Glycosylation of Serum Immunoglobulin A is Associated with IgA Nephropathy and Glomerular Function.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN. METHODS: To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls. RESULTS: Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. CONCLUSIONS: Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.

Shared genetic study gives insights into the shared and distinct pathogenic immunity components of IgA nephropathy and SLE.

An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r2 ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.

Relationship between blood neutrophil-lymphocyte ratio and renal tubular atrophy/interstitial fibrosis in IgA nephropathy patients.

BACKGROUND: The study aimed to explore the relationship between neutrophil-lymphocyte ratio(NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. METHODS: A Total of 263 IgAN patients were included. The participants were categorized into four groups based on quartile of NLR. The clinical data, pathological features, and 2-year renal survival rates were compared among the four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. RESULTS: The percentage of renal tubular atrophy/interstitial fibrosis increased with the increase of NLR level (p=0.003). The tubular atrophy/interstitial fibrosis score T1 and T2 in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%, p=0.033) and Group Q3 (22.39%, p=0.029). NLR [ß=1.230, 95%CI (0.081, 2.379), p=0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN. The area under curve predicted by NLR was 0.596 (95%CI 0.534~0.656, p=0.007) with the specificity 88.24% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end-stage renal disease within 2 years, and the 2-year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%, p=0.029). CONCLUSION: NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be a significant factor for predicting the prognosis in the IgAN. BACKGROUND: IgA nephropathy (IgAN) is an important cause of the end stage renal disease (ESRD). The study aimed to explore the relationship between neutrophil-lymphocyte ratio (NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis, and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. METHODS: Total 263 IgAN patients confirmed by renal biopsy pathology were included from January 2013 to May 2018 in Ningbo Hwamei Hospital, University of Chinese Academy of Sciences. The peripheral blood samples were taken from these participants and the NLR was analyzed. The participants were categorized into four groups based on the median and upper and lower quartile of NLR, which were Group Q1 (NLR<1.64), Group Q2 (1.64≤NLR<2.19), Group Q3 (2.19≤NLR<3.00), and Group Q4 (NLR≥3.00), respectively. The clinical data and pathological features were compared among four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. The diagnostic ability of NLR for renal tubular atrophy/interstitial fibrosis was evaluated by the area under receiver operating characteristic curve (AUC). The 2-year renal survival rates were compared among the four groups. RESULTS: The levels of white blood cell count, neutrophil count, highly sensitive C-reactive protein, and the percentage of renal tubular atrophy/interstitial fibrosis were increased while lymphocyte count and estimated glomerular filtration rate were decreased with the increase of NLR level (P < 0.05). The percentage of tubular atrophy/interstitial fibrosis 26%-50% (T1) and >50% (T2) in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%) and Group Q3 (22.39%), with significant difference (P < 0.05). NLR [ß = 1.230, 95%CI (0.081, 2.379), P = 0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN according to multivariate linear regression analysis results. The AUC predicted by NLR was 0.596 (95%CI 0.534~0.656, P = 0.007) with the specificity 88.24%, the sensitivity 30.00% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end-stage renal disease within 2 years; and the 2-year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%), with significant difference (P < 0.05). CONCLUSION: NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be an significant factor for predicting the prognosis in IgAN.

IgA nephropathy with serum ANCA positivity: case series and literature review.

The co-occurrence of IgA nephropathy (IgAN) and positive anti-neutrophil cytoplasmic autoantibodies (ANCA) serology is uncommon. In the present case series and literature review, we aimed to clarify the impact of ANCA on pathogenesis, clinical and histopathology presentation, and outcome in IgAN patients. We report four patients with an overlap lesion of IgAN-ANCA positive. Also, we performed a narrative review of all biopsy-proven published case series. Only 1.2% patients had ANCA in our 330-biopsy-proven IgAN cohort. We compared our data with previous reports-6 case series and 3 small retrospective studies-a total of 103 patients. All patients but one had eGFR below 15 mL/min at diagnosis. Besides rapidly decreasing eGFR, all presented with proteinuria around 1.5 g/day and dysmorphic microhematuria, suggesting glomerular inflammation. Systemic symptoms suggestive for ANCA vasculitis were seen in half of our patients, but only one patient had hemorrhagic alveolitis. Patients from our cohort responded to the intensive immunosuppressive regimens used in ANCA-positive vasculitis with renal involvement. However, in the follow-up, one patient had a relapse followed by septic shock related to immunosuppression and one patient started hemodialysis. In the review, we found that IgAN-ANCA -positive patients are characterized by vasculitis-like lesions and clinically by a rapidly progressive decline in kidney function, which was reversed by an aggressive induction immunosuppressive protocol used in ANCA vasculitis. Checking ANCA serology seems useful in patients with rapidly progressive IgAN for therapeutic and prognostic reasons.

Increased Tim-3+ monocytes/macrophages are associated with disease severity in patients with IgA nephropathy.

T-cell immunoglobulin and mucin-domain-containing protein-3 (Tim-3) plays multiple important roles in immune response and participates in the pathogenesis of various inflammatory diseases by regulating macrophage polarization. However, its functions in the development of IgA nephropathy (IgAN) are still unclear. In this study, changes in the relative levels of Tim-3+ monocytes/macrophages in peripheral blood and renal tissue, and their clinical significance in patients with IgAN were investigated. The expression of CD68 and Tim-3 in macrophages from patients with IgAN was determined via immunohistochemistry and immunofluorescence staining assays. Peripheral blood of 48 patients with biopsy-proven IgAN and 18 healthy controls (HCs) was collected to determine the frequency of circulating CD14+Tim-3+ cells using flow cytometry, before and after 24 weeks of prednisolone treatment. Serum interleukin (IL)-10 and tumor necrosis factor α (TNF-α) levels were measured using enzyme-linked immunosorbent assays. The potential association between clinical signs and Tim-3+ monocytes/macrophages was analyzed. The percentages of circulating CD14+Tim-3+ monocytes were higher in samples from patients with IgAN than in those from HCs and were positively associated with the pathological features (segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis) of IgAN, according to the Oxford classification. Tissue staining assays revealed cells positive for both CD68 and Tim-3 in tubulointerstitial lesions of IgAN patients. In addition, elevated levels of serum IL-10 and TNF-α were detected in these patients in comparison to HCs. Furthermore, the frequency of circulating CD14+Tim-3+ monocytes had a positive correlation with levels of 24-h urinary protein and serum IL-10, and was negatively associated with renal function. After 24 weeks of treatment with prednisolone, the percentages of CD14+Tim-3+ cells were significantly reduced. In summary, our findings indicate that Tim-3+ monocytes/macrophages might be involved in the pathogenesisof IgAN and could be used as a potential indicator to evaluate disease severity.

Correlation analysis between expression of histone deacetylase 6 and clinical parameters in IgA nephropathy patients.

BACKGROUND: It has been demonstrated that histone deacetylase 6 (HDAC6) is involved in various kidney diseases in experimental study. However, correlation between HDAC6 and clinical parameters in IgA nephropathy (IgAN) patients is still unknown. METHODS: A total of 46 human kidney biopsy specimens with IgAN were selected as observation group, specimens of normal renal cortex tissue that was not affected by the tumor from patients with renal carcinoma (n = 7) served as control. We investigated the relationship between HDAC6 and clinical parameters in IgAN. RESULTS: HDAC6 was highly expressed in human kidney biopsy specimens with IgAN compared with control group, while the number of acetyl histone H3 positive cells were significantly decreased. There was a statistical difference in the indexes of albumin, estimated glomerular filtration rate (eGFR), serum urea, serum creatinine, serum uric acid, ß2-microglobulin, cystatin C, cholesterol, high-density lipoprotein, low-density lipoprotein, and HDAC6 positive area among the different Oxford Classification (p < 0.05). The expression of HDAC6 was different in various eGFR levels, the expression of HDAC6 increased with the decreasing of eGFR level, the expression of acetyl histone H3 decreased with the decreasing of eGFR level. In addition, the expression of HDAC6 positively correlated with Masson trichrome positive area, serum urea, serum creatinine, ß2 macroglobulin, and cystatin C, while negatively correlated with eGFR and acetyl histone H3. Multivariate linear regression analysis demonstrated that eGFR and cystatin C were independently associated with HDAC6, respectively (p < 0.05). CONCLUSIONS: These results suggested that high level of HDAC6 expression in IgAN is correlated with renal dysfunction.