Progression Of IgA Nephropathy Research Articles

The clinical significance of circulating microRNA-21 in patients with IgA nephropathy

Background: Urinary microRNA-21 (miR-21) has been reported to correlate with the histologic lesions of IgA nephropathy (IgAN). We investigated whether urinary or circulating miR-21 could serve as a biomarker for detecting the renal progression of IgAN.Methods: Forty patients with biopsy-proven IgAN were enrolled in this study. Serum and urinary sediment miRs were extracted, and the expression of miR-21 was quantified by real-time quantitative polymerase chain reaction. Renal progression was defined as end-stage renal disease, a sustained doubling of serum creatinine, or a 50% decrease in estimated glomerular filtration rate (eGFR) from baseline.Results: Six patients experienced renal progression during the follow-up period. The baseline eGFR was lower in the progression group (49±11 mL/min/1.73 m2 vs. 90±23 mL/min/1.73 m2, p<0.05) than in the non-progression group. The level of circulating miR-21 on kidney biopsy was higher in the progression group than in the non-progression group (40.0±0.6 vs. 38.2±1.1 ΔCt value of miR-21, p<0.01), whereas there was no significant difference in urinary miR-21 (38.1±2.1 vs. 37.8±1.4 ΔCt value of miR-21, p=0.687) between the two groups. Receiver operating characteristic curve analysis demonstrated that circulating miR-21 had good discriminative power for diagnosing renal progression of IgAN, with an area under the curve of 0.975.Conclusions: The level of circulating miR-21 was higher in the progression group than in the non-progression group at the time of kidney biopsy. Therefore, circulating miR-21 could be a surrogate marker of renal progression in patients with IgAN.

Complement factor H variants are associated with microangiopathy lesions in IgA nephropathy

BackgroundThrombotic microangiopathy (TMA) occurs in immunoglobulin A nephropathy (IgAN), and the pathogenesis is not known behind the endothelium injury. The genetic studies have indicated that complement factor H (CFH) and complement factor H-related protein genes (CFHRs)play a key role in IgAN. We perform a study to investigate the CFH /CFHRs gene variants and their roles in IgAN with microangiopathy based on a previous genome-wide association study (GWAS). MethodsWe re-review microangiopathic lesions in 2055 IgAN patients by light microscopy. And 204 IgAN patients with MA and 1851 IgAN without MA are confirmed in this study. Nineteen single nucleotide polymorphisms (SNPs) across CFH and CFHRs genes information are extracted from GWAS data. ResultsThe results show that 204 out of 2055(9.93 %) MA patients are screened from our IgAN cohort. Patients with MA lesions are strongly associated with more severe clinical conditions and higher serum complement factor H (FH) levels than IgAN without MA(MA vs IgAN-non MA:428.16 ± 141.05 vs 364.62 ± 139.06ug/mL, p = 0.004). The genetic association study indicates the frequency of rs800292-G in CFH was significantly higher in the MA group (0.441 vs 0.374, odds ratio1.37[1.07–1.62], p = 0.010) compared with IgAN without MA. In addition, patients with the rs412852-G allele in CFH become an independent risk factor for end-stage renal disease (ESRD)in MA patients (Hazard Ratio 2.77[1.17–6.65], p = 0.021). However, the gene variants did not correlate with serum FH, serum C3, and C3 deposits in the renal specimens. ConclusionOur results indicated that variants in CFH are associated with the development and progression of IgAN with microangiopathy.

Visit-to-visit variability in blood pressure and kidney disease progression in IgA nephropathy.

The visit-to-visit variability (VVV) in blood pressure (BP) is an important risk factor for stroke and coronary heart disease and may also be associated with kidney damage and the development of chronic kidney disease (CKD). Data on the association between VVV in BP and the risk of CKD progression among patients with immunoglobulin A nephropathy (IgAN) are limited. We aimed to evaluate the relationships of VVV in BP with the progression of IgAN. We assessed 1376 patients with IgAN at Peking University First Hospital. The main VVV in BP was expressed as the standard deviation (SD), coefficient of variation (CV) and average real variability (ARV). The associations of variability in BP with composite kidney disease progression events, defined as a 50% decline in estimated glomerular filtration rate (eGFR) and kidney failure, were examined using Cox models. During a median follow-up of 44.1months (interquartile range 23.0-76.7), 247 (18.0%) patients experienced composite kidney disease progression events. With a higher SD in systolic BP (SBP) values, the risk of kidney disease progression events increased {hazard ratio [HR] 1.07 [95% confidence interval (CI) 1.03-1.11]; P<.001} after maximal adjustment, including baseline SBP and mean SBP during the first 12-month period. Using the first quartile of SD SBP values as the reference, the risk of composite kidney disease progression events was higher among patients with higher SD SBP values; the HR was 2.12 (95% CI 1.31-3.44) in the highest quartile (P for trend<.001). A similar trend could be observed when analysing the SD of diastolic BP, but the risk was not significantly increased. The associations were similar when analysed with the CV and ARV. SBP variability was significantly associated with kidney disease progression in IgAN.

Immunosuppressive therapy versus supportive care in IgA nephropathy patients with stage 3 and 4 chronic kidney disease.

The use of immunosuppressive therapy for immunoglobulin A nephropathy (IgAN) patients with stage 3 or 4 chronic kidney disease (CKD) is controversial. We performed a monocentric retrospective study on 83 consecutive IgAN patients with stage 3 or 4 CKD and proteinuria ≥0.75 g/d (age 41 [33-56] years, 72% male, estimated glomerular filtration rate 36.1 [25.4-47.5] mL/min/1.73 m2) who received uncontrolled supportive care (Supp) (n = 36), corticosteroids/corticotherapy (CS) (n = 14), or CS combined with monthly pulses of cyclophosphamide (CS + CFM) (n = 33) between 2010 and 2017. Patients were followed until composite endpoint (doubling of serum creatinine, end-stage kidney disease (dialysis or kidney transplant) or death, whichever came first) or end of study (January 2020). Patients were followed for a median of 29 (95% confidence interval = 25.2-32.7) months, and 12 (15%) patients experienced the composite endpoint. Within the limitation of a retrospective study, our results suggest no benefit from immunosuppressive therapy in patients with IgAN with stage 3 and 4 CKD as compared with supportive care. There were no differences between the 3 studied groups regarding age, estimated glomerular filtration rate, proteinuria, Oxford classification score, arterial hypertension, and therapy with renin-angiotensin system inhibitors. Mean kidney survival time for the entire cohort was 81.0 (95% confidence interval = 73.1-89.0) months, without significant differences between the 3 groups. In univariate and multivariate Cox regression analysis adjusted for IgAN progression factors, immunosuppressive therapy was not associated with better kidney survival when compared with supportive therapy.

Particulate matter of air pollution may increase risk of kidney failure in IgA nephropathy

IgA nephropathy (IgAN) is characterized by deposition of galactose-deficient IgA1 (Gd-IgA1) in glomerular mesangium associated with mucosal immune disorders. Since environmental pollution has been associated with the progression of chronic kidney disease in the general population, we specifically investigated the influence of exposure to fine particulate matter less than 2.5 μm in diameter (PM2.5) on IgAN progression. Patients with biopsy-proven primary IgAN were recruited from seven Chinese kidney centers. PM2.5 exposure from 1998 to 2016 was derived from satellite aerosol optical depth data and a total of 1,979 patients with IgAN, including 994 males were enrolled. The PM2.5 exposure levels for patients from different provinces varied but, in general, the PM2.5 exposure levels among patients from the north were higher than those among patients from the south. The severity of PM2.5 exposure in different regions was correlated with regional kidney failure burden. In addition, each 10 μg/m3 increase in annual average concentration of PM2.5 exposure before study entry (Hazard Ratio, 1.14; 95% confidence interval, 1.06-1.22) or time-varying PM2.5 exposure after study entry (1.10; 1.01-1.18) were associated with increased kidney failure risk after adjustment for age, gender, estimated glomerular filtration rate, urine protein, uric acid, hemoglobin, mean arterial pressure, Oxford classification, glucocorticoid and renin-angiotensin system blocker therapy. The associations were robust when the time period, risk factors of cardiovascular diseases or city size were further adjusted on the basis of the above model. Thus, our results suggest that PM2.5 is an independent risk factor for kidney failure in patients with IgAN, but these findings will require validation in more diverse populations and other geographic regions.

Triglyceride-Glucose Index May Predict Renal Survival in Patients with IgA Nephropathy.

Background: The triglyceride–glucose (TyG) index is a simple, novel and reliable surrogate marker of insulin resistance. However, evidence for the prognostic impact of an elevated TyG index on IgA nephropathy (IgAN) is limited. Therefore, we evaluated the relationship between the TyG index and the risk of renal progression in IgAN. Method: This cohort study involved biopsy-proven IgAN between January 2009 and December 2018 in West China Hospital, in which patients were assigned to two groups based on the cut-off value of TyG using receiver operating characteristic (ROC) curves. A 1:1 matched-pair analysis was established to optimize the bias in IgAN by propensity score matching (PSM). The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The composite endpoint was defined by eGFR decreased ≥50% of the baseline level, end-stage kidney disease (ESKD), renal transplantation and/or death. Univariable and multivariable Cox proportional hazard models were applied to confirm the predictive value of the optimal marker. Results: Before PSM, a total of 1210 participants were ultimately included. During a median follow-up period of 55.8 months (range 37.20–79.09 months), 129 participants progressed to the composite endpoint (10.7%). After PSM, 366 patients were enrolled in the matched cohort, of whom 34 (9.3%) patients reached the endpoints. Based on the cut-off value of the TyG index, patients were divided into the low TyG index group (TyG ≤ 8.72, n = 690) and the high TyG index group (TyG > 8.72, n = 520). Further analysis demonstrated that a higher TyG index was significantly associated with a higher risk of reaching composite endpoints in IgAN patients in both the unmatched and matched cohorts (before PSM: HR 2.509, 95% CI 1.396–4.511, p = 0.002; after PSM: HR 2.654, 95% CI 1.299–5.423, p = 0.007). Conclusion: A high TyG index is associated with a higher risk of renal progression.

Identification of key candidate genes for IgA nephropathy using machine learning and statistics based bioinformatics models

Immunoglobulin-A-nephropathy (IgAN) is a kidney disease caused by the accumulation of IgAN deposits in the kidneys, which causes inflammation and damage to the kidney tissues. Various bioinformatics analysis-based approaches are widely used to predict novel candidate genes and pathways associated with IgAN. However, there is still some scope to clearly explore the molecular mechanisms and causes of IgAN development and progression. Therefore, the present study aimed to identify key candidate genes for IgAN using machine learning (ML) and statistics-based bioinformatics models. First, differentially expressed genes (DEGs) were identified using limma, and then enrichment analysis was performed on DEGs using DAVID. Protein-protein interaction (PPI) was constructed using STRING and Cytoscape was used to determine hub genes based on connectivity and hub modules based on MCODE scores and their associated genes from DEGs. Furthermore, ML-based algorithms, namely support vector machine (SVM), least absolute shrinkage and selection operator (LASSO), and partial least square discriminant analysis (PLS-DA) were applied to identify the discriminative genes of IgAN from DEGs. Finally, the key candidate genes (FOS, JUN, EGR1, FOSB, and DUSP1) were identified as overlapping genes among the selected hub genes, hub module genes, and discriminative genes from SVM, LASSO, and PLS-DA, respectively which can be used for the diagnosis and treatment of IgAN.

Increased proportion of follicular helper T cells is associated with B cell activation and disease severity in IgA nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis, characterized by glomerular deposition of IgA immune complexes, mainly produced by B cells under the regulation of CD4+T cells. However, the alterations of specific CD4+T cell subsets and the mechanism of B cells activation in IgAN remain unclear. Therefore, we aimed to investigate the landscape characteristics and role of CD4+T cells in the progression of IgAN. We identified that the proportion of Th2, Th17 and Tfh (follicular helper T) cells in patients with IgAN was significantly higher than that of healthy controls (P < 0.05). Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) showed that Th cells and B cells in patients with IgAN were more activated. Correspondingly, multiplex immunohistochemistry staining of renal biopsy showed increased infiltration of CD4+T and B cells in the kidneys of patients with IgAN. The degree of infiltration was positively correlated with the degree of renal damage. Interestingly, the proportion of Tfh cells in peripheral blood was positively correlated with the severity of proteinuria. Moreover, the proximity position of Tfh cells and B cells suggested that cell-cell interactions between Tfh and B cells were happening in situ. Intercellular communication analysis also showed enhanced interaction between Tfh cells and B cells in IgAN. Our findings suggested that Tfh cells of patients possibly contributed to the progression of IgAN by activating B cells via cell-cell interactions and TNFSF14-TNFRSF14 may be an underlying signaling pathway.

Relationship between Traditional Chinese Medicine Syndrome Elements and Prognosis of Patients with IgA Nephropathy.

Objective It is not clear which Traditional Chinese Medicine- (TCM-) related elements affect primary IgA nephropathy (IgAN) progression. Here, we explored the risk factors, based on TCM syndrome elements, related to the prognosis of primary IgAN patients. Methods We analyzed patients with newly diagnosed, biopsy-proven IgAN at a single institution from December 2013 to September 2021. Basic clinical and pathological characteristics were assessed at the time of renal biopsy. The study endpoint was end-stage renal disease (ESRD: eGFR <15 ml/min per 1.73 m2, dialysis, or kidney transplantation) and/or eGFR decreased by >30% from baseline. Kaplan‒Meier survival analysis was used to explore the role of TCM syndrome elements in IgAN progression. Multivariate Cox regression analysis with adjustment for traditional risk factors was performed to explore TCM syndrome elements that may influence patient prognosis. The factors correlated with TCM syndrome elements in IgAN patients were further evaluated by logistic regression analysis. Results During a median follow-up of 22.0 months, 53 (12.5%) of the 423 included IgAN patients reached the study endpoint. The main IgAN disease location elements were the kidney, liver, and spleen. The main IgAN disease nature elements were Yin-deficiency and Qi-deficiency, dampness, Yang-deficiency, phlegm, and Blood-deficiency. Kaplan‒Meier analysis identified three disease locations (liver, spleen, and kidney) and four disease natures (Qi-deficiency, Yang-deficiency, phlegm, and dampness) as elements associated with poor renal survival in IgAN patients. In multivariate Cox regression analysis, baseline Yang-deficiency was an independent risk predictor of poor prognosis in primary IgAN patients (hazard ratio 2.338; 95% confidence interval [CI]: 1.208–4.525; P=0.012) after adjustment for traditional risk factors. Furthermore, logistic regression analysis identified being female (odds ratio [OR] 2.518; 95% CI: 1.538–4.122; P < 0.001), older age (OR 1.043; 95% CI: 1.022–1.065; P < 0.001), low hemoglobin levels (OR 0.984; 95% CI: 0.971–0.996; P=0.013), and cellular/fibrocellular crescents (OR 1.706; 95% CI: 1.068–2.728; P=0.026) as factors affecting Yang-deficiency in IgAN patients. Conclusions Yang-deficiency independently predicts the risk of poor prognosis in primary IgAN patients. Being female, older age, low hemoglobin levels, and cellular/fibrocellular crescents were independently associated with Yang-deficiency in IgAN patients.

Protective effects of budesonide on LPS-induced podocyte injury by modulating macrophage M1/M2 polarization: Evidence from in vitro and in silico studies.

Budesonide (Bud), one of the most widely used lung medicines, is currently used as a repurposing medicine for immunoglobulin A nephropathy (IgAN) treatment. The progression of IgAN is related to inflammation involving macrophages and podocytes. The present study aimed to explore the effects of Bud on classically activated (M1)/alternatively activated (M2) macrophage polarization and podocyte injury under lipopolysaccharide (LPS)-induced inflammatory stress in vitro. Anti-inflammatory bioinformation of Bud was identified based on the Gene Expression Omnibus database. RAW264.7 cells were treated with normal medium, LPS, curcumin (Cur, positive control), or Bud 5, 10, or 20 µM. The expression levels of inducible nitric oxide synthase (iNOS), TNF-α, mannose receptor (CD206) and arginase (Arg)-1 were quantified by western blotting. The collected supernatants from macrophages were termed (Nor)MS, (LPS)MS, (Cur)MS and (Bud)MS. The TNF-α, IL-1β and nitric oxide (NO) levels in the supernatants were evaluated by ELISA and Griess assay. The podocytes were cultured in different supernatants and their survival rates were assessed by bromodeoxyuridine assay. TNF signaling is an important pathway by which Bud exerts anti-inflammatory activities. Compared with the LPS group, 5, 10 and 20 µM Bud significantly increased Arg-1 and decreased iNOS expression (Six: P<0.05) and 20 µM Bud significantly increased Arg-1 and CD206 and decreased iNOS and TNF-α expression (Four: P<0.05). Cur significantly decreased iNOS and TNF-α expression (Two: P<0.05). Compared with LPS, 5, 10 and 20 µM Bud and Cur significantly decreased TNF-α, IL-1β and NO levels (All: P<0.05). The podocyte survival rates of (Bud)MS and (Cur)MS were significantly higher than those of (LPS)MS (Four: P<0.05). The protective effect of Bud on podocyte injury is related to its modulation of M1/M2 polarization.

PSTAT1 Is Activated during the Progression of IgA Nephropathy

Introduction: IgA nephropathy is the most common primary glomerular disease. Its pathogenesis is still poorly understood. Alterations of the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway may play an important role in IgA nephropathy. Methods: We evaluated the clinical features, pathology, and tissue staining for lymphocytes and phosphorylated STAT1 (pSTAT1) in 43 patients with biopsy proven IgA nephropathy. They were followed to determine their disease outcomes. All had biopsy tissue and multiple laboratory measurements to assess their kidney disease progression. Sixteen patients underwent repeat kidney biopsy to further assess their clinical status. Results: The median eGFR at baseline was 61 mL/min/1.73 m² and the median proteinuria was 2,600 mg/d. The median follow-up was 5 years with an average annual decline in eGFR of 2.25 mL/min/1.73 m². There was significant inflammation and atrophy seen in the first biopsy, which progressed among those who undertook a 2nd biopsy. Compared to healthy kidney tissue, glomeruli and tubulointerstitium demonstrated increased lymphocyte (CD3+) infiltrates and increased pSTAT1 staining by immunohistochemistry. Increased CD3 (p = 0.001) staining and increased pSTAT1 (p = 0.03) correlated with reduced eGFR levels. In repeat biopsy samples, increasing pSTAT1 staining correlated with loss of eGFR over time (p = 0.02). Conclusion: These findings support the hypothesis that pSTAT1 is activated in IgA nephropathy and may play a role in the progression toward kidney failure.

The relationship between serum uric acid levels and glomerular ischemic lesions in patients with Immunoglobin A nephropathy-a analytical cross-sectional study

BackgroundTo investigate the relationship between serum uric acid levels and glomerular ischemic lesions in patients with immunoglobulin A nephropathy (IgAN) and the relevant risk factors.MethodsA total of 86 patients with IgAN and normal renal functions were divided into a hyperuricemia group and a normal serum uric acid group (control group). These patients were further divided into a glomerular ischemic lesions group and a non-glomerular ischemic lesions group (control group) based on the renal biopsy results. The relationship between serum uric acid levels and glomerular ischemic lesions was analysed.ResultsIn patients with IgAN, the prevalence or occurrence of glomerular ischemic lesions was significantly higher in the hyperuricemia group compared with the normal serum uric acid group. Elevated serum uric acid levels are independently associated with glomerular ischemic disease.ConclusionHyperuricemia in patients with IgAN may lead to glomerular ischemic lesions, and lowering serum uric acid levels may delay the progression of IgAN.

The Dual Role of Endothelin-1 and Angiotensin II in Disease Progression of Focal Segmental Glomerulosclerosis and IgA Nephropathy

IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) are rare primary glomerulopathies, though the incidence of IgAN is greater. Endothelin 1 (ET-1) and angiotensin II (Ang II) are implicated in the development and progression of IgAN and FSGS. Both conditions impact health-related quality of life (HRQoL) and may lead to kidney failure. IgAN and FSGS are both evidenced clinically by proteinuria, with a greater degree of such associated with more progressive disease and shorter times to kidney failure. Accordingly, the reduction of proteinuria in patients with these conditions is a key target. Currently, IgAN and FSGS treatments are unsuccessful or only partially successful in a number of patients. Immunosuppressant therapy is first-line for primary FSGS and utilised for patients with IgAN who remain at high risk of progression despite maximal supportive care; however, while effective, there is a significant risk of toxicity and relapse is frequent. A number of clinical trials are ongoing to investigate the use of non-immunosuppressive agents in the management of these conditions. The dual endothelin Type A receptor/Ang II subtype 1 receptor (ETAR/AT1R) antagonist (DEARA) sparsentan is currently being assessed as a means to control kidney disease progression. Interim study results show that sparsentan can lead to greater reductions in proteinuria than AT1R antagonism alone in IgAN and more patients reaching partial remission (PR) in FSGS. Herein, a symposium by leading experts at the European Renal Association (ERA) 59th Congress in Paris, 19th−22nd May 2022, is presented. It highlights IgAN and FSGS and the role of proteinuria in these conditions, and how targeting ET-1 and Ang II can lead to a reduction in proteinuria in IgAN and potential FSGS PR.

Crescents and IgA Nephropathy: A Delicate Marriage.

IgA nephropathy (IgAN) is a progressive disease with great variability in the clinical course. Among the clinical and pathologic features contributing to variable outcomes, the presence of crescents has attracted particular interest as a distinct pathological feature associated with severity. Several uncontrolled observations have led to the general thought that the presence and extent of crescents was a prognostic indicator associated with poor outcomes. However, KDIGO 2021 guidelines concluded that either the presence or the relative number of crescents should not be used to determine the progression of IgAN nor should they suggest the choice of immunosuppression. Our aim is to report and discuss recent data on the debated issue of the value of active (cellular and fibrocellular) crescents in the pathogenesis and clinical progression of IgAN, their predictive value, and the impact of immunosuppression on renal function. We conclude that the value of crescents should not be disregarded, although this feature does not have an independent predictive value for progression in IgAN, particularly when considering immunosuppressed patients. An integrated overall evaluation of crescents with other active MEST scores, clinical data, and novel biomarkers must be considered in achieving a personalized therapeutic approach to IgAN patients.

Prognostic Value of Triglyceride to High-Density Lipoprotein Cholesterol Ratio (TG/HDL-C) in IgA Nephropathy Patients.

BackgroundThe triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio is an easy-to-use atherogenic and prognostic marker which has attracted increasing attention these days. However, whether TG/HDL-C correlate with outcomes in IgA nephropathy (IgAN) patients remains unknown. To clarify these issues, we conducted this study.MethodsA total of 1146 patients from West China Hospital of Sichuan University were retrospectively analysed between 2008 and 2018.The demographic, clinical and pathological data of all patients at the time of biopsy were collected. Then, patients were divided into the high TG/HDL group (TG/HDL ≥ 1.495, N=382) and the low TG/HDL group (TG/HDL-C < 1.495, N=764) based on the optimal cut-off value of the TG/HDL-C using receive operating curve. Cox proportional hazard models and Kaplan–Meier curves were used to evaluate the renal outcomes of IgAN.ResultsThe median age of the patients was 33 (26-42) years, and 44.5% were men. By correlation analysis, we found that the TG/HDL-C ratio was negatively correlated with the eGFR (r = 0.250, P < 0.001) but positively correlated with proteinuria (r = 0.230, P< 0.001), BMI (r=0.380, P<0.001) and serum uric (r =0.308, P< 0.001). Patients with a higher TG/HDL-C ratio tended to have hypertension [odds ratio (OR), 1.987; 95% CI, 1.527-2.587; P<0.001] and more severe pathologic lesions with tubular atrophy/interstitial fibrosis (OR, 1.610; 95% CI, 1.203-2.154; P=0.001). During a median follow-up period of 54.1 (35.6-73.2) months, a high TG/HDL ratio was strongly associated with worse renal survival in IgAN patients (log-rank: P <0.001). Multivariate Cox analysis demonstrated that a high TG/HDL-C ratio (HR 1.775, 95% CI 1.056-2.798; P=0.029) was an independent predictive marker to ESRD.ConclusionIn this study, we addressed the importance of TG/HDL-C ratio as a predictive marker for IgAN progression.

ICAM-1 related long noncoding RNA is associated with progression of IgA nephropathy and fibrotic changes in proximal tubular cells

Intercellular adhesion molecule 1 (ICAM-1) related long noncoding RNA (ICR) is on the antisense strand of ICAM-1 and regulates ICAM-1 expression. ICAM-1 is involved in renal tubulointerstitial injury; however, the expression and clinical implication of ICR are not determined in IgA nephropathy (IgAN). We compared renal ICR levels in 337 IgAN patients with those of 89 biopsy controls, and a markedly increased ICR level was observed in IgAN patients. By Cox proportional hazards models, higher levels of renal ICR were independently associated with disease progression event defined as end-stage renal disease or ≥ 40% decline in estimated glomerular filtration rate. Patients in the highest tertile of renal ICR had a 3.5-fold higher risk for disease progression compared with those in the lowest tertile. The addition of renal ICR to a model with traditional risk factors improved risk prediction of disease progression (net reclassification index: 0.31 [95% CI 0.01–0.50]; integrated discrimination index: 0.10 [95% CI 0.04–0.16]). Inhibition of ICR by transfection with plasmids containing ICR shRNA significantly reduced expression of collagen I and α-SMA, and phosphorylation of Akt and mTOR in TGF-β1- treated HK-2 cells. Our findings suggest that renal ICR might be an independent predictor of IgAN progression and contribute to renal fibrosis.

Renal Megalin mRNA Downregulation Is Associated with CKD Progression in IgA Nephropathy

Introduction: Megalin plays an important role in proximal tubule uptake of filtered proteins. Downregulation and dysfunction of megalin were previously demonstrated in IgA nephropathy (IgAN); however, its relationship to IgAN progression remains unclear. Methods: We measured renal megalin mRNA and miR-148b, previously identified as a regulator of megalin, in a retrospective cohort of 417 IgAN patients at the time of biopsy, and evaluated their associations with chronic kidney disease (CKD) progression event, defined as end-stage renal disease or ≥40% decline in estimated glomerular filtration rate, using Cox proportional hazard models. Risk classification statistics were calculated for CKD progression. Results: During a median follow-up of 43 months, 121 (29.0%) patients reached the CKD progression event. Patients in the highest tertile of renal megalin mRNA had a lower risk for CKD progression than in the lowest tertile (hazard ratio (HR): 0.407, 95% confidence interval (CI) 0.231–0.719; p = 0.002). Log megalin mRNA was independent and negatively associated with CKD progression in IgAN (HR: 0.529, 95% CI 0.377–0.742; p < 0.001). The addition of renal megalin mRNA to a model with traditional risk factors improved risk prediction of disease progression (C statistic from 0.76 to 0.80; integrated discrimination index: 0.04 [95% CI: 0.02–0.07]). Moreover, patients in the highest tertile of renal miR-148b had a 2.3-fold higher risk for CKD progression compared with those in the lowest tertile. Conclusions: Lower renal megalin mRNA levels were associated with a greater risk of CKD progression in IgAN independent of clinical and pathological characteristics, suggesting that renal megalin could be an important prognostic factor for IgAN.

Platelet-to-Albumin Ratio: A Novel IgA Nephropathy Prognosis Predictor.

BackgroundChronic inflammation is related to the development of IgA nephropathy (IgAN). Emerging studies have reported that platelet-related parameters including platelet (PLT), platelet-to-albumin ratio (PAR), and platelet-to-lymphocyte ratio (PLR) are proved to be novel prognostic indicators for several inflammatory diseases. Whether platelet-related parameters could serve as predictors for IgAN remains unknown.MethodsA total of 966 IgAN patients were enrolled in this retrospective study and were divided into several groups based on the optimal cut-off value of the platelet-related parameters. End-stage renal disease was used as the renal endpoint. A 1:2 propensity score (PS) match was then carried out to eliminate significant differences at baseline. The area under the receiver operating characteristic curve (AUROC), Kaplan–Meier (K-M) curve, and Cox proportional hazards analyses were performed to evaluate their predictive effect.ResultsWithout considering the effect of covariates, the K-M curve showed that PLT, PLR, and PAR were strongly correlated with the renal outcomes of IgAN. However, the AUROC revealed that the PAR and PLR had better predictive power than the PLT. Multivariate Cox regression adjusting for demographic data, pathological findings, treatment, and laboratory results indicated that compared with PLR, albumin and PLT, PAR seemed to be a better marker of adverse renal outcome, implying that PAR was the only platelet-related parameter that could be used as an independent risk factor. Notably, high PAR patients seemed to have more severe clinical manifestations and pathological lesions. However, after eliminating the influence of different baselines on outcome variables, the PAR could still predict the poor prognosis of IgAN. To more accurately evaluate the predictive power of the PAR, we analyzed the predictive effect of the PAR on patients with different clinicopathological characteristics through subgroup analysis. It was indicated that the PAR might better predict the prognosis and outcome of patients whose disease was already very severe.ConclusionPAR might be used as an independent risk factor for IgAN progression.

Identification and Validation of Prognostic Biomarkers Specifically Expressed in Macrophage in IgA Nephropathy Patients Based on Integrated Bioinformatics Analyses.

Background: Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and a frequent cause of end-stage renal disease. The inflammation cascade due to the infiltration and activation of immune cells in glomeruli plays an essential role in the progression of IgAN. In this study, we aimed to identify hub genes involved in immune infiltration and explore potential prognostic biomarkers and therapeutic targets in IgAN. Methods: We combined the single-cell and bulk transcriptome profiles of IgAN patients and controls with clinical data. Through single-cell analysis and weighted gene co-expression network analysis (WGCNA), Gene Ontology (GO) enrichment analysis, and differentially expressed gene (DEG) analysis in the bulk profile, we identified cell-type-specific potential hub genes in IgAN. Real hub genes were extracted via validation analysis and clinical significance analysis of the correlation between the expression levels of genes and the estimated glomerular filtration rate (eGFR) in the external dataset. Gene set enrichment analysis was performed to predict the probable roles of the real hub genes in IgAN. Results: A total of eleven cell clusters were classified via single-cell analysis, among which macrophages showed a variable proportion between the IgAN and normal control samples. We recognized six functional co-expression gene modules through WGCNA, among which the black module was deemed an IgAN-related and immune-involving module via GO enrichment analysis. DEG analysis identified 45 potential hub genes from genes enriched in GO terms. A total of twenty-three potential hub genes were specifically expressed in macrophages. Furthermore, we validated the differential expression of the 23 potential hub genes in the external dataset and identified nine genes with prognostic significance as real hub genes, viz., CSF1R, CYBB, FPR3, GPR65, HCLS1, IL10RA, PLA2G7, TYROBP, and VSIG4. The real hub gens are thought to contribute to immune cell regulation, immunoreaction, and regulation of oxidative stress, cell proliferation, and material metabolism. Conclusion: In this study, we demonstrated that macrophages infiltrated the glomeruli and contributed to the inflammatory response in IgAN. Based on integrated bioinformatics analyses of single-cell and bulk transcriptome data, we highlighted nine genes as novel prognostic biomarkers, which may enable the development of innovative prognostic and therapeutic strategies for IgAN.

MO268: Use of Corticosteroids in a Norwegian Cohort of Patients with IGA Nephropathy and Rapid Progression to End-Stage Renal Disease

Abstract BACKGROUND AND AIMS Despite several clinical trials, treatment with corticosteroids in patients with Immunoglobulin A nephropathy (IgAN) remains controversial [1, 2]. The recently updated KDIGO guidelines suggests that treatment with corticosteroids could be considered in patients with persistent proteinuria above 0.75 to 1.0 g per day in patients with estimated glomerular filtration rate (eGFR) above 30 mL/min/1.73 m2 despite intensive supportive care [3]. This is a more liberal approach compared with the 2012 guidelines, which suggested that patients selected for treatment with steroids should have eGFR above 50 mL/min/1.73 m2 [4]. It could be valuable to identify clinicians decision on when to initiate immunosuppressive treatment, since this could have implication on how future therapeutics might be used in patients with IgAN [5]. Our aim is to describe the use of corticosteroids and evaluate the effect of this treatment using a Norwegian cohort of patients with IgAN. METHOD We identified patients with biopsy-proven IgAN from the Norwegian Kidney Biopsy Registry and the Norwegian Renal Registry, who all had progressed to end-stage renal disease (ESRD) and collected clinical, treatment and biochemical data from patient records. RESULTS A total of 151 patients with a diagnostic kidney biopsy performed between 1988 and 2010 were included. The median time from biopsy to ESRD was 5 years. A majority of 94% of the patients received supportive treatment with Renin–Angiotensin–Aldosterone System blockade. A total of 40 patients (27%) received treatment with corticosteroids, with a median eGFR and proteinuria at time of biopsy at 49.5 mL/min/1.73 m2 and 5.1 g per day, respectively. Median time from biopsy to steroid treatment was 12 months. Patients treated with corticosteroids had a significant decrease in proteinuria from 5.6 to 3 g per day (P = .02), but there was no difference in time to progression to ESRD between the two groups (P = .58). The vast majority (87.5%) of the patients treated with corticosteroids reported on adverse events. CONCLUSION We found that the use of corticosteroids had significant impact on proteinuria but did not delay progression to ESRD. Adverse events were common in patients treated with corticosteroids. The patients were treated according to the current guidelines