Prognosis Of Immunoglobulin A Nephropathy Research Articles

#1425 Anemia in patients with IgA nephropathy: an impact on the prognosis of IgA nephropathy

Abstract Background and Aims Immunoglobulin A Nephropathy (IgAN) has several well-known predictors of renal outcomes, including persistent proteinuria, hypertension, and baseline eGFR at the time of diagnosis. However, the effect of hemoglobin (Hb) levels on the progression of IgAN is rarely reported. This study aims to evaluate the impact of Hb levels on the prognosis of IgAN and to identify risk factors for anemia in patients with IgAN. Method A retrospective analysis of the data of 855 patients diagnosed with IgAN at Kyungpook National University Hospital between January 2002 and December 2021 was performed. We obtained the data on clinical parameters and pathological findings according to the Oxford classification at the time of the kidney biopsy. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors for anemia, and a Cox proportional hazard model was used to estimate the effects of anemia on the development of end-stage kidney disease (ESKD). Results Lower serum albumin, lower eGFR, severe interstitial fibrosis, and tubular atrophy were associated with anemia in patients with IgAN. The Kaplan-Meier survival curve revealed that patients with anemia had worse renal survival than those without anemia. The multivariable Cox analysis showed that anemia was an independent risk for the progression to ESKD (HR 2.86, confidence interval 1.58–5.17, p = 0.001). In a sex-specific analysis, only the female sex showed a significant and higher risk for ESKD (hazard ratio 4.07, confidence interval 1.53–10.8, p = 0.005). Conclusion A low Hb level at the time of biopsy, even if subclinical, was an independent risk factor for the development of ESKD in patients with IgAN. Therefore, it is necessary to monitor Hb levels at the time of diagnosis and take proactive measures to reduce the risk of disease progression.

Renal thrombotic microangiopathy is associated with poor renal survival in children with immunoglobulin A nephropathy.

The aim of this study was to examine the clinical and pathological characteristics as well as the prognosis of immunoglobulin A nephropathy (IgAN) accompanied by renal thrombotic microangiopathy (rTMA) in paediatric patients. After balancing epidemiological characteristics and pathological types between groups, 427 patients (rTMA group: 23, non-rTMA group: 46) were included. The clinical and pathological features, prognosis and clinical risk factors of the two groups were analysed. IgAN-rTMA children showed more severe clinical and pathological manifestations. The findings from the logistic regression analysis indicated that hypercellularity 1 (E1) (HR: 0.805, 95% CI: 0.763 ~ 1.452, P = .016), endocapillary proliferation (HR: 1.214, 95% CI: 0.093 ~ 4.815, P = .025) and C3 staining (HR: 7.554, 95% CI: 2.563 ~ 15.729, P = .037) were the risk factors for rTMA in children with IgAN. The renal survival in rTMA group was lower than non-rTMA group (χ2 = 18.467, P = .000). Cox regression analysis showed that E1 (HR: 7.441, 95% CI: 1.095 ~ 10.768, P = .037), C3 disposition (HR: 3.414, 95% CI: 0.834 ~ 11.578, P = .027) and rTMA (HR: 8.918, 95% CI: 1.032 ~ 16.754, P = .041) were identified as independent risk factors for the development of end-stage renal disease (ESRD). The presence of rTMA had a significant impact on the severity and prognosis of IgAN. And rTMA has been identified as an independent risk factor for the development of renal failure in children diagnosed with IgAN.

Ethnicity and IgA nephropathy: worldwide differences in epidemiology, timing of diagnosis, clinical manifestations, management and prognosis.

Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis, is one of the major causes of end-stage renal disease. Significant variances in epidemiology, clinical manifestation, timing of diagnosis, management and renal prognosis of IgAN have been reported worldwide. The incidence of IgAN is the most frequent in Asia, followed by Europe, and lower in Africa. Moreover, Asian patients show more frequent acute lesions in renal histology and present poorer renal outcomes compared with Caucasians. The comorbidities also show the difference between Asians and Caucasians. Although the frequency of gross hematuria with upper respiratory tract infection is not different, comorbidities with gastrointestinal diseases are reported to be higher in Europe. Recently, genetic studies for variant ethnic patients revealed widely ranging genetic risks in each ethnicity. A genetic risk score is most elevated in Asians, intermediate in Europeans and lowest in Africans, consistent with the disease prevalence of IgAN globally. Ethnic variance might be highly affected by the difference in genetic background. However, it is also essential to mention that the different timing of diagnosis due to variant urinary screening systems and the indication for renal biopsy in different countries may also contribute to these variances. The management of IgAN also varies internationally. Currently, several novel therapies based on the pathogenesis of IgAN are being assessed and are expected to become available soon. Further understanding the ethnic variance of IgAN might help establish individualized care for this disease. Here, we review the issues of ethnic heterogeneities of IgAN.

Clinical significance of urinary exosomal microRNAs in patients with IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. The clinical relevance of 11 urinary exosomal microRNAs (miRNAs) was evaluated in patients with IgAN. From January 2009 to November 2018, IgAN (n = 93), disease control (n = 11), and normal control (n = 19) groups were enrolled. We evaluated the expression levels of urinary exosomal miRNAs at the baseline and their relationship with clinical and pathologic features. This study aimed to discriminate statistically powerful urinary exosomal miRNAs for the prognosis of IgAN. Urinary miRNA levels of miR-16-5p, miR-29a-3p, miR-124-3p, miR-126-3p, miR-199a-3p, miR-199b-5p, and miR-335-3p showed significant correlation with both estimated glomerular filtration rate (eGFR) and urine protein-to-creatinine ratio (uPCR). In univariate regression analysis, age, body mass index, hypertension, eGFR, uPCR, Oxford classification E, and three miRNAs (miR-16-5p, miR-199a-3p, and miR-335-3p) were associated with disease progression in patients with IgAN. The area under the curve (AUC) of miR-199a-3p was high enough (0.749) without any other clinical or pathologic factors, considering that the AUC of the International IgAN Risk Prediction Tool was 0.853. Urinary exosomal miRNAs may serve as alternative prognostic biomarkers of IgAN with further research.

The Effects of Specific Gut Microbiota and Metabolites on IgA Nephropathy-Based on Mendelian Randomization and Clinical Validation.

Although recent research suggests that alterations in gut microbiota and metabolites play a critical role in the pathophysiology of immunoglobulin A nephropathy (IgAN), the causal relationship between specific intestinal flora and metabolites and the risk of IgAN remains unclear. This study employed Mendelian randomization (MR) to investigate the causal association between gut microbiota and IgAN. To explore potential associations between gut microbiota and various outcomes, four MR methods were applied: inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. If the results of the four methods are inconclusive, we prefer the IVW as the primary outcome. Additionally, MR-Egger, MR-PRESSO-Global, and Cochrane's Q tests were used to detect heterogeneity and pleiotropy. The stability of MR findings was assessed using the leave-one-out approach, and the strength of the causal relationship between exposure and outcome was tested using Bonferroni correction. Additional clinical samples were utilized to validate the results of Mendelian randomization, and the outcomes were visualized through an ROC curve, confusion matrix, and correlation analysis. This study examined a total of 15 metabolites and 211 microorganisms. Among them, eight bacteria and one metabolite were found to be associated with the risk of IgAN (p < 0.05). The Bonferroni-corrected test reveals that only Class. Actinobacteria (OR: 1.20, 95% CI: 1.07-1.36, p = 0.0029) have a significant causal relationship with IgAN. According to Cochrane's Q test, there is no substantial heterogeneity across different single-nucleotide polymorphisms (p > 0.05). Furthermore, MR-Egger and MR-PRESSO-Global tests (p > 0.05) showed no evidence of pleiotropy. No reverse causal association was found between the risk of IgAN and microbiota or metabolites (p > 0.05). Clinical specimens demonstrated the effectiveness and accuracy of Actinobacteria in distinguishing IgAN patients from those with other glomerular diseases (AUC = 0.9, 95% CI: 0.78-1.00). Additionally, our correlation analysis revealed a potential association between Actinobacteria abundance and increased albuminuria (r = 0.85) and poorer prognosis in IgAN patients (p = 0.01). Through MR analysis, we established a causal link between Actinobacteria and the incidence of IgAN. Moreover, clinical validation using fecal samples indicated that Actinobacteria might be associated with the onset and poorer prognosis of IgAN. This finding could provide valuable biomarkers for early, noninvasive detection of the disease and potential therapeutic targets in IgAN.

Polymorphisms of CARD9 Gene Predict Disease Progression and Renal Survival of Immunoglobulin A Nephropathy

Introduction: A previous genome-wide association study has identified CARD9 (caspase recruitment domain family member 9) as a susceptibility gene for immunoglobulin A nephropathy (IgAN), which encodes an adapter protein and is related to mucosal immunity. This study aimed to investigate the association of CARD9 variants with the clinicopathological phenotypes and prognosis of IgAN. Methods: Eight single nucleotide polymorphisms within CARD9 were genotyped using Sequenom MassARRAY iPLEX for 986 IgAN patients in this study. Logistic and linear regression analyses adjusted for age and gender were performed to evaluate the effects of CARD9 gene polymorphisms on clinicopathological phenotypes. The Kaplan-Meier method and Cox proportional hazard models were applied to analyze the associations between genetic variants and renal survival. Results: The T allele of rs10747047 was strongly associated with higher levels of serum creatinine (p = 0.005) and lower levels of estimated glomerular filtration rate (p = 0.005). The rs10870149-G and rs10870077-C alleles were associated with elevated 24-h urine protein excretion (p = 0.041 and 0.022, respectively) and more serious segmental glomerulosclerosis lesions (p = 0.005 and 0.041, respectively) in IgAN patients. Carriers with the T allele of rs10781533 and the C allele of rs3812552 also presented with severe segmental glomerulosclerosis lesions (p = 0.001 and 0.010, respectively). Additionally, rs10747047-C and rs10870077-C alleles were independently related to the poor prognosis of IgAN patients after adjustments for covariates (TT vs. CC hazard ratio [HR] = 0.138, 95% confidence interval [95% CI] = 0.022–0.871, p = 0.035; GG vs. CC HR = 0.321, 95% CI = 0.123, 0.836, p = 0.020, respectively). Conclusion: CARD9 variants are associated with disease severity and rapid disease progression for IgAN in a Chinese Han population.

Clinicopathological Characteristics and Outcomes of Immunoglobulin A Nephropathy with Different Types of Dyslipidemia: A Retrospective Single-Center Study

Introduction: Immunoglobulin A nephropathy (IgAN) is one of the most common glomerulonephritic diseases in the world. Several lines of evidence have suggested that dyslipidemia is related to the disease progression and prognosis of IgAN. However, the study is scarce on the clinicopathological characteristics and outcomes of IgAN with dyslipidemia. Methods: This study retrospectively analyzed 234 patients with biopsy-proven idiopathic IgAN at the Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, between January 2015 and June 2021. The participants were divided into dyslipidemia (n = 119) and non-dyslipidemia (n = 115), and the dyslipidemia group was also divided into the following 4 groups: hypertriglyceridemia group, hypercholesterolemia group, mixed hyperlipidemia group, and low high-density lipoprotein cholesterol group. The estimated glomerular filtration rate (eGFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Results: The prevalence of dyslipidemia in IgAN patients in our center was 50.9% (119/234). The patients with dyslipidemia presented with higher systolic blood pressure (BP), diastolic BP, serum creatinine, uric acid, hemoglobin, proteinuria, and eGFR (p < 0.05). Proportions of males, hypertension, and chronic kidney disease stage 2∼5 were also higher in the dyslipidemia group (p < 0.05). Similarly, the pathological characteristics performed were worse in the dyslipidemia group. Most dyslipidemia patients had a higher percentage of mesangial hypercellularity (M1) and tubular atrophy/interstitial fibrosis (T1∼2) in the Oxford Classification’s scoring system (p < 0.05). Multivariate logistic regression analysis revealed that male gender (odds ratio [OR] = 2.397, 95% confidence interval [CI]: 1.051–5.469, p = 0.038) and proteinuria (OR = 1.000, 95% CI: 1.000–1.001, p = 0.035) were possible risk factors for dyslipidemia. A total of 13 patients (13.8%) in the dyslipidemia group had an endpoint event, of which 6 patients (6.4%) had a ≥50% decrease in eGFR from baseline and 7 patients (7.4%) reached the end-stage renal disease stage. Kaplan-Meier survival curve analysis showed that patients in the dyslipidemia group had a worse outcome than those in the non-dyslipidemia group (log-rank test, p = 0.048). Conclusions: IgAN patients with dyslipidemia presented more severe clinicopathological characteristics. Male gender and proteinuria are significantly associated with the occurrence of dyslipidemia in IgAN patients. Patients in the dyslipidemia group had a worse prognosis than those in the non-dyslipidemia group, which may be essential for the disease management of IgAN and help identify the high-risk patients.

Noninvasive Assessment of the Renal Function, Oxford Classification and Prognostic Risk Stratification of IgAN by Using Intravoxel Incoherent Motion Diffusion-Weighted Imaging and Blood Oxygenation Level-Dependent MRI.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Oxford classification including mesangial hypercellularity (M), endothelial hypercellularity (E), segmental sclerosis (S), interstitial fibrosis/tubular atrophy (T), and crescent (C) were recommended to predict the prognosis of IgAN. To explore whether multiparametric magnetic resonance imaging (MRI) can be applied to assess the renal function, Oxford classification, and risk of progression to end-stage kidney disease within 5 years of IgAN. Prospective. A total of 46 patients with pathologically confirmed IgAN and 20 healthy volunteers. A 3-T, blood oxygenation level-dependent (BOLD)-MRI, intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). Two radiologists measured the cortex and medulla T2*, apparent diffusion coefficient (ADC), true diffusion (Dt), pseudo-diffusion (Dp), perfusion fraction (fp). All participants were divided into three groups: group 1, healthy volunteers; group 2, patients with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 ; group 3, patients with eGFR <60 mL/min/1.73 m2 . Or two groups: group A, 5-year risk scores ≤10% and group B, 5-year risk scores >10%. Intraclass correlation coefficient, one-way analysis of variance, least-significant difference, Student's t-test, Pearson product-moment correlation, Spearman's rank correlation, and receiver operating characteristics (ROC) with the area under the curve (AUC). A P value <0.05 was considered statistically significant. Except for cortical Dp, all other MRI parameters showed significant differences between group 1 and group 2. None of the MRI parameters showed a significant correlation with M, E, or C scores. Cortical T2*, Dt, fp, and medullary Dt and fp showed low-to-moderate significant correlations with S scores. Except for cortical and medullary Dp, all other MRI parameters were significantly correlated with T scores. Cortical Dt showed the largest AUC for differentiating group A from group B (AUC=0.927) and T0 from T1/T2 (AUC=0.963). Imaging by IVIM-DWI and BOLD-MRI could facilitate noninvasive assessment of the renal function, Oxford classification, and prognostic risk of IgAN patients. 2. Stage 3.

Significance of Mannan Binding Lectin-Associated Serine Protease 2 in Urinary Extracellular Vesicles in IgA Nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is a common chronic glomerulonephritis and the main cause of end-stage renal diseases. Recent evidence suggests that mannan binding lectin associated serine proteases 2 (MASP2) is related to IgAN; therefore, we investigated the expression and significance of MASP2 in serum and urinary extracellular vesicles (UEVs) in patients with IgAN. Thirty-eight patients with IgAN and 17 healthy controls were enrolled in this study. UEVs were extracted by ultracentrifugation. The separation by ultra-high-speed centrifuge was verified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Candidate internal references (TSG101, CD9, flotillin, β-actin and GAPDH) were identified by western blotting in the control group, and the expression of MASP2 in the UEVs was compared. The levels of MASP2 in the serum and UEVs in the IgAN and control groups were determined by enzyme-linked immunosorbent assay (ELISA). TEM and NTA results demonstrated that UEVs were successfully extracted. Western blotting results confirmed that TSG101 was suitable as an internal reference for this study. Compared with the control group, the IgAN group showed positive expression of MASP2. MASP2 levels in the UEVs, determined by ELISA, showed significant differences between IgAN and control groups, which were significantly positively correlated with the level of urinary microalbumin. The level of MASP2 in UEVs was related to IgAN and shows promise as a biomarker for evaluating the severity of renal injury and prognosis of IgAN, thereby helping to elucidate the role of MASP2 in the mannan-binding lectin pathway.

Arterial-Arteriolar Sclerosis Is Independently Associated With Poor Renal Outcome in IgA Nephropathy Patients.

Aim: This study aimed to investigate the clinicopathological features and prognosis of immunoglobulin A nephropathy (IgAN) with arterial-arteriolar sclerosis (AS).Methods: Patients with biopsy-proven IgAN from the West China Hospital of Sichuan University were retrospectively enrolled. Clinicopathological features were collected. Patients were categorized based on the presence and the severity of the AS. All the patients were regularly followed-up until a composite end point. The correlation between AS and prognosis of IgAN was assessed.Results: A total of 1,424 patients were recruited and followed for 60.0 ± 28.7 months. Patients with AS tended to have older age, higher blood pressure, heavier proteinuria, higher serum creatinine, uric acid, and total triglyceride (TG). Meanwhile, they were more likely to have a lower estimated glomerular filtration rate (eGFR), hemoglobin, and albumin. At the end of follow-up, 126 patients in the AS group and 47 patients in the non-AS group had reached the composite end point (p < 0.001). AS was associated with the renal outcome (log-rank p < 0.001) and was an independent risk factor for the progression of IgAN (p = 0.049). The severity of AS was associated with renal outcomes (log-rank p < 0.001) and there was a trend that it might serve as an independent risk marker for progression of IgAN. In the subgroup analysis, patients presenting with AS and lower eGFR, albumin, and hemoglobin or higher proteinuria, uric acid, and TG had a significant trend for a shorter time to reach the end point (log-rank p < 0.001).Conclusion: AS was commonly seen in patients with IgAN and was independently associated with the poor prognosis.

HLA-DQB1 and HLA-DRB1 expression is associated with disease severity in IgAN.

Several genome-wide association studies have found that HLA class II histocompatibility antigen, DQ beta1 (HLA-DQB1) and HLA class II histocompatibility antigen, DR beta1 (HLA-DRB1) were associated with immunoglobulin A nephropathy (IgAN). However, few studies have explored the association between HLA-DQB1 and HLA-DRB1 expression and IgAN. This is the first study to investigate the relationship between HLA-DQB1 and HLA-DRB1 expression and clinical pathological characteristics. A total of 113 patients with biopsy-proven IgAN and 71 healthy control patients participated in this study. HLA-DQB1 and HLA-DRB1 expression in peripheral blood lymphocytes was measured by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and flow cytometry. Serum galactose-deficient IgA1 (Gd-IgA1) level was measured by an enzyme-linked immunosorbent assay kit. The clinical and histopathological data of patients with IgAN were collected at the time of renal biopsy. Pearson's or Spearman's correlation coefficients were used to analyze the correlation between the expression of HLA-DQB1 and HLA-DRB1 mRNA and protein and the clinical pathological features of IgAN. HLA-DQB1 and HLA-DRB1 messenger ribonucleic acid expression was decreased in IgAN patients compared to healthy control patients (P<0.01). HLA-DQB1 and HLA-DRB1 protein expression was significantly lower in IgAN patients than healthy control patients (P<0.05). HLA-DQB1 and HLA-DRB1 protein expression was positively correlated with 24-h urinary protein excretion (P<0.05). HLA-DRB1 protein expression was negatively correlated with renal function as measured by an estimated glomerular filtration rate (P<0.05). HLA-DRB1 protein expression was higher in patients with crescentic IgAN than patients without crescent formation (P<0.05). Our study found the expression of HLA-DQB1, HLA-DRB1 were associated with the disease severity of IgAN and abnormal HLA-DQB1 and HLA-DRB1 expression may aggravate the progression of IgAN. We intend to gather further follow-up data to explore the effects of HLA-DQB1 and HLA-DRB1 expression on the prognosis of IgAN.

Comprehensive metabolomic profiling in early IgA nephropathy patients reveals urine glycine as a prognostic biomarker.

Identification of a urinary metabolite biomarker with diagnostic or prognostic significance for early immunoglobulin A nephropathy (IgAN) is needed. We performed nuclear magnetic resonance‐based metabolomic profiling and identified 26 metabolites in urine samples. We collected urine samples from 201, 77, 47, 36 and 136 patients with IgAN, patients with membranous nephropathy, patients with minimal change disease, patients with lupus nephritis and healthy controls, respectively. We determined whether a metabolite level is associated with the prognosis of IgAN through Cox regression and continuous net reclassification improvement (cNRI). Finally, in vitro experiments with human kidney tubular epithelial cells (hTECs) were performed for experimental validation. As the results, the urinary glycine level was higher in the IgAN group than the control groups. A higher urinary glycine level was associated with lower risk of eGFR 30% decline in IgAN patients. The addition of glycine to a predictive model including clinicopathologic information significantly improved the predictive power for the prognosis of IgAN [cNRI 0.72 (0.28‐0.82)]. In hTECs, the addition of glycine ameliorated inflammatory signals induced by tumour necrosis factor‐α. Our study demonstrates that urinary glycine may have diagnostic and prognostic value for IgAN and indicates that urinary glycine is a protective biomarker for IgAN.

Mesangial IgM deposition predicts renal outcome in patients with IgA nephropathy: a multicenter, observational study.

Mesangial IgM deposition is found in patients with immunoglobulin A nephropathy (IgAN). This study aims to investigate the relationships between mesangial IgM deposition and disease progression in IgAN patients. A total of 1239 patients with biopsy-proven primary IgAN were enrolled in this multicenter, observational study between January 2013 and August 2017. According to the degree of IgM deposition, 1239 patients were divided into three groups: Grade 0 (no or trace; n = 713, 57.55%), Grade 1 (mild; n = 414, 33.41%), Grades 2 + 3 (moderate and marked; n = 112, 9.04%). Using a 1:1 propensity score matching (PSM) method identifying age, gender and treatment modality to minimize confounding factors, 1042 matched patients (out of 1239) with different degrees of IgM deposition were enrolled to evaluate the severity of baseline clinicopathological features and renal outcome: Grade 0 (n = 521, 50.00%), Grade 1 (n = 409, 39.25%), Grades 2 + 3 (n = 112, 10.75%). Kaplan-Meier and Cox proportional hazards analyses were performed to determine whether different degrees of mesangial IgM deposition are associated with varying renal outcomes in IgAN. During a mean follow-up of 48.90 ± 23.86 and 49.01 ± 23.73months, before and after adjusting for propensity scores, respectively, the rate of complete remission (CR) was progressively lower with increased IgM deposition in both unmatched (63.39%, 46.14%, 45.54%) and matched cohort (61.80%, 46.45%, 45.54%), whereas the proportion of patients progressing to end-stage renal disease (ESRD) showed reverse correlation (P < 0.001). Kaplan-Meier analysis indicated negative correlation between the intensity of mesangial IgM deposits and cumulative renal survival (all P < 0.05). Moreover, Cox regression analysis revealed that the degree of mesangial IgM deposition predicted renal outcome independent of MESTC score and clinical variables in the unmatched (Grade 1, HR, 1.59; 95% CI, 1.11-2.29; P = 0.01; Grades 2 + 3, HR, 1.69; 95% CI, 1.02-2.08; P = 0.04) and matched cohort (Grade 1, HR, 1.84; 95% CI, 1.19-2.85; P = 0.01; Grades 2 + 3, HR, 1.91; 95% CI, 1.01-3.24; P = 0.04). Mesangial IgM deposition is associated with histological activity, clinical severity and renal outcome and is an independent risk factor for poor renal prognosis in IgAN. TRIAL REGISTRATION: TCTR, TCTR20140515001. Registered May 15, 2014, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=1074 .

Tubular decoy receptor 2 as a predictor of prognosis in patients with immunoglobulin A nephropathy.

BackgroundAccelerated senescence of renal tubular epithelial cells (RTECs) might contribute to immunoglobulin A nephropathy (IgAN) progression. This study aimed to determine whether the RTEC senescence marker, decoy receptor 2 (DcR2), could predict prognosis in IgAN. MethodsWe included a retrospective cohort of 105 patients with biopsy-proven IgAN. Tubular DcR2 expression was assessed at renal biopsy and the Oxford histological MEST-C score [mesangial hypercellularity (M), endocapillary proliferation (E), segmental sclerosis (S), interstitial fibrosis/tubular atrophy (T) and crescents (C)] defined disease severity. IgAN progression was defined as a composite of end-stage renal disease or a 30% decline in the estimated glomerular filtration rate (eGFR), analyzed using Kaplan–Meier and Cox regression analyses. ResultsTubular DcR2 was overexpressed in IgAN. Numbers of DcR2 and p16 double-positive RTECs increased with increasing severity of tubular atrophy/interstitial fibrosis (T lesion). Patients with ≥25% tubular DcR2 expression experienced worse proteinuria, T lesions and a lower eGFR. Cumulative renal survival was significantly lower in patients with ≥25% DcR2 positivity. Multivariate regression analyses showed that ≥25% tubular DcR2 expression was significantly associated with worse eGFR slopes (the rate of renal function decline; P = 0.003) and the incidence of the composite outcome (P = 0.001) in IgAN. The addition of tubular DcR2 to a model with clinical data at biopsy (mean arterial pressure, proteinuria and eGFR) or MEST-C score significantly improved the 5-year risk prediction of IgAN progression, as confirmed by receiver operating characteristic curve analyses.ConclusionsTubular DcR2 expression detected at biopsy was a strong independent predictor for IgAN progression and might have prognostic value in addition to established risk markers.

Increasing prescription of renin-angiotensin-aldosterone system blockers associated with improved kidney prognosis in Korean IgA nephropathy patients.

BackgroundWe aimed to describe the characteristics of immunoglobulin A nephropathy (IgAN) in Korea with assessment for time trends.MethodsWe performed a multicenter retrospective observational cohort study including biopsy-confirmed native IgAN cases from four tertiary hospitals in Korea. Time eras of diagnosis were stratified into 1979–2003, 2004–9 and 2010–17. The prognostic variable was progression to end-stage kidney disease (ESKD) analyzed by multivariable Cox regression analysis.ResultsWe included 1366 (from 1979 to 2003), 1636 (from 2004 to 2009) and 1442 (from 2010 to 2017) IgAN patients in this study. In the recent periods, IgAN had relatively better clinical characteristics, as patients had higher estimated glomerular filtration rates and lower baseline blood pressures than before. The use of renin–angiotensin–aldosterone system (RAAS) blockers increased from 57.7% in 1979–2003 to 80.0% in 2010–17. During a median follow-up duration of 11.3 years, 722 patients progressed to ESKD with an incidence rate of 12.5 per 1000 person-years. The 10-year risk of progression to ESKD was lower in 2010–17 compared with that of 1979–2003 [adjusted hazard ratio 0.692 (95% confidence interval 0.523–0.915)], even after adjustment for multiple clinicopathologic characteristics. The use of RAAS blockers was a significant mediator (P < 0.001) for the association between time trends and lower 10-year ESKD risk.ConclusionsClinicopathologic characteristics of IgAN in Korea have changed over time. Although the limitation of a retrospective observational study remains, the result showed that the prognosis of IgAN has improved over the study period, possibly related to increased prescription of RAAS blockers.

Coagulation parameters are associated with the prognosis of immunoglobulin a nephropathy: a retrospective study

BackgroundInterstitial fibrosis/tubular atrophy (T) score is a known determinant of the progression of immunoglobulin A nephropathy (IgAN). Strong evidence indicates that the components of the coagulation system closely linked with fibrotic events have been highlighted in the kidney. However, whether the coagulation system can affect the renal outcome of IgAN remains unclear. Herein, we investigated the association of coagulation parameters and pathological phenotype of IgAN and their combined effects on the deterioration of renal function.MethodsThis retrospective study included N = 291 patients with biopsy-proven IgAN from May 2009 to April 2013 in the Second Xiangya Hospital. Clinical data, pathological features were collected, and the associations of coagulation parameters at biopsy, T score, and renal outcome were evaluated. T score indicated the degree of tubular atrophy or interstitial fibrosis. The renal outcome was defined as an end-stage renal disease (ESRD) or an irreversible 50% estimated glomerular filtration rate (eGFR) reduction.ResultsShorter prothrombin time (PT) and the activated partial thromboplastin time (APTT) were significantly associated with T (both p < 0.001). PT (< 11.15 s) or APTT (< 29.65 s) had worse cumulative survival rate (p = 0.008, p = 0.027 respectively) and were significantly but not independently associated with a higher risk of renal outcome (p = 0.012, p = 0.032 respectively). In the combined analyses of PT, APTT, and T lesions, the odd ratios for the outcome were significantly higher in the presence of T with PT (< 11.15 s) or APTT (< 29.65 s).ConclusionShorter PT and APTT are associated with an increased incidence of the T lesion and are additional factors that portend a poorer prognosis in IgAN. Monitoring coagulation function might be important when assessing the risk of progression. Additional studies exploring the molecular mechanism between coagulation and IgAN pathology are needed.

Early tonsillectomy for severe immunoglobulin A nephropathy significantly reduces proteinuria.

Early multiple-drug therapy for severe childhood immunoglobulin A (IgA) nephropathy prevents the progression of nephritis and improves the long-term prognosis. Recent studies have focused on the relationship between the pathophysiology of IgA nephropathy and tonsillar focal infection, and the efficacy of tonsillectomy with methylprednisolone pulse therapy in children has been demonstrated. However, no study has reported on the relationship between the period from diagnosis to tonsillectomy and the long-term prognosis of IgA nephropathy. To clarify the long-term effects of an early tonsillectomy, 40 patients who were diagnosed with severe IgA nephropathy in childhood and underwent a tonsillectomy were divided into two groups based on the period from diagnosis to undergoing tonsillectomy: Group A, less than 3years; and Group B, more than 3years. The primary endpoint of this study was the change in the amount of proteinuria. Renal prognosis was evaluated 10years after the diagnosis. This study enrolled 40 patients diagnosed with severe IgA nephropathy in childhood who underwent tonsillectomy after multiple-drug therapy with/without methylprednisolone pulse therapy at Kindai University Hospital; eight patients were excluded based on the exclusion criteria. Group A consisted of 18 patients and Group B, 14 patients. Proteinuria and hematuria levels were significantly reduced in the early surgery group (P < 0.01). No significant differences were found in serum creatinine, uric acid, and IgA/C3 ratio. High proteinuria levels worsen the renal prognosis in IgA nephropathy. Tonsillectomy in less than 3years combined with multiple-drug therapy after the initial diagnosis could improve long-term prognosis.

Clinical Significance of Crescent Formation in IgA Nephropathy – a Multicenter Validation Study

Background/Aims: Additional validation study was warranted to confirm the clinical significance of C score, which was recently added to the Oxford classification for immunoglobulin A nephropathy (IgAN). Methods: We performed a multicenter retrospective cohort study in four hospitals in Korea. Patients who had biopsied glomeruli less than eight or inadequate follow-up information were excluded. Clinicopathologic parameters, including the degree of cellular or fibrocellular crescents, were collected and included in multivariable models for Cox regression analysis. The main outcome was a composite renal outcome, defined as a merge of progression to end-stage renal disease (ESRD) and halving of estimated glomerular filtration rate (eGFR) from baseline. Results: Among included 3,380 biopsy-confirmed IgAN patients, there were 664 (19.6%) patients with C1 and 60 (1.8%) patients with C2 scores in the study population. Although C0 and C1 patients shared similar baseline characteristics, C2 patients frequently had more clinicopathologic risk factors for poor prognosis of IgAN. Both C1 [adjusted HR 1.33 (1.11-1.58), P=0.002] and C2 [adjusted HR 2.24 (1.46-3.43), P< 0.001] scores were associated with an increased risk of the composite outcome. C2 was a strong predictive parameter associated with both progression to ESRD and halving of eGFR, whereas C1 was mainly associated with the increased risk of halving of eGFR. Notably, the proportion of crescent showed a linear association with the risk of adverse renal outcome. Conclusion: The C score in the Oxford classification is a valid predictive parameter for IgAN prognosis. Additional clinical attention is necessary for IgAN patients with identified cellular or fibrocellular crescents.

An update on predicting renal progression in IgA nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is a heterogeneous disease, and predicting individual patient risk of renal progression is challenging. Recent studies provide new evidence regarding the use of clinical, histologic, and biomarker predictors of renal outcome in IgAN. A meta-analysis of clinical trials demonstrated that early change in proteinuria is a valid surrogate outcome measure for longer term decline in renal function, which supports the use of proteinuria to dynamically re-evaluate patient prognosis over time. The MEST histologic classification has been further validated in a large European cohort. An international multiethnic observational study demonstrated that crescents are independently associated with renal outcome, and as a result a crescent score (<25% versus >25% of glomeruli) has been added to MEST. Proteinuria, estimated glomerular filtration rate (GFR), and blood pressure at the time of biopsy can be used to accurately predict prognosis when combined with MEST, instead of using 2 years of follow-up data. Currently, no available risk prediction model that combines clinical and histologic predictors has been sufficiently validated for routine use. There are multiple biomarkers that have been studied in IgAN, however none have been externally validated and shown to improve prediction beyond clinical and histologic risk factors. Proteinuria, estimated GFR, blood pressure, and the MEST-C score are the most readily available risk factors to predict renal prognosis in IgAN. Future research is required to develop and validate methods of integrating these risk factors together to accurately risk stratify individual patients, and provide the framework for evaluating biomarkers capable of further improving risk prediction.

Outcomes of IgA Nephropathy with Segmental Glomerular Necrosis But without Crescent Formation

Background: The significance of segmental glomerular necrosis (SGN) was not evident in immunoglobulin A nephropathy (IgAN) patients. Especially, there were a number of patients who presented with slight histopathological damage except SGN. We, therefore, conducted a study to highlight the occurrence of these cases and to define their clinical characteristics and outcomes at our centre. Methods: The clinical, laboratory and pathological manifestations and outcomes of these IgAN patients were collected and compared with IgAN patients with simily histopathological background but without SGN. Survival curves were constructed according to the Kaplan-Meier method. Multivariate Cox regression analysis was used to identify independent factors for the development of endpoint. Results: Eighty-two patients with SGN but without crescents were found in Haas grades I-III. Macroscopic hematuria and prodromal infection were more popular and the mean daily proteinuria was significantly higher in patients with SGN. More patients had high serum IgA in the ecrotizing IgAN group. At last follow-up, there were no differences in hypertension, proteinuria, serum creatinine, estimated GFR and the incidence of end-point events between 2 groups. SGN was not an independent predictor for the prognosis of IgAN. Corticosteroid treatment could decrease proteinuria significantly. The outcomes of the 2 populations of necrotizing IgAN patients with or without corticosteroid treatment were not different. Conclusions: SGN can be found in mild pathological damage patients and is not always associated with crescent formation. Heavier proteinuria was found in these IgAN patients. SGN was not an independent predictor for the prognosis of IgAN.