Metastatic Non-Small-Cell Lung Cancer Presenting as Renal Failure From IgA Nephropathy.

Studies have highlighted a potential link between malignancies and immunoglobulin A nephropathy (IgAN). In such studies, the treatment of malignancy improved the symptoms of IgAN. Here, we report a patient case involving a history of hypertension, tobacco use disorder, and chronic kidney disease (CKD) presenting with hematuria with acute renal failure secondary to IgAN per renal biopsy. Prompted by this association, a malignancy workup was performed including computed tomography (CT) body imaging and biopsies of mediastinal and cervical lymph nodes which revealed a metastatic adenocarcinoma. Current knowledge includes a general mechanism behind the development of IgAN that points toward glomerular deposition of tumor-specific immunoglobulin A (IgA) immunoglobulins. However, the association of IgAN and malignancy has no definitive management guidelines. This clinical case serves as an important contribution in the hopes of future development of guidelines regarding the surveillance and management of IgAN in the setting of malignancy.

Correlation of Serum Bilirubin with Clinical and Pathological Characteristics of Patients with IgA Nephropathy.

OBJECTIVE: To investigate the correlations of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) with various clinical indicators and pathological features of patients with IgA nephropathy (IgAN). METHODS: Patients diagnosed with IgAN were included and divided into low and high TBIL/DBIL/IBIL groups. Correlation analysis was performed to assess the relationships between the bilirubin indices and other clinical and pathological variables. Logistic regression was applied to identify the independent risk factors of mesangial cell proliferation (corresponding to M1 in the Oxford classification of IgAN). RESULTS: Totally 192 patients with IgAN were included, and the patient clinical indicators were compared between the different bilirubin subgroups. Compared to the groups with higher TBIL, DBIL, and IBIL levels, groups with lower values of these bilirubin indices exhibited a higher 24-hour urine protein (24hUP) concentration but a lower proportion of males as well as reduced total protein, albumin, haemoglobin, and glutamic-pyruvic transaminase levels (p < 0.05). Moreover, the low-DBIL group displayed higher total cholesterol, triglyceride, and low-density lipoprotein (LDL) concentrations (p < 0.05) than those in the high DBIL group. Spearman analysis further revealed that TBIL, DBIL, and IBIL were negatively correlated with 24hUP and positively correlated with haemoglobin, total protein, and albumin (p < 0.05). Additionally, DBIL exhibited negative correlations with total cholesterol, triglyceride, and LDL (p < 0.05). From a pathological perspective, M1 incidence was higher in the low TBIL and IBIL groups (both p < 0.05). Furthermore, the high IBIL group showed a lower occurrence of cellular/fibrocellular crescents (C1 (in at least one glomerulus) and C2 (in >25% of glomeruli) in the Oxford classification, p < 0.05). Lastly, the multivariate regression model suggested that IBIL was an independent protective factor for M1 (odds ratio = 0.563, 95% confidence interval = 0.344-0.921, p = 0.022). CONCLUSIONS: Patients with IgAN accompanied by low values of bilirubin indices exhibit worsened disease-related clinical indicators (24hUP, total protein, albumin, and haemoglobin levels). Reduced TBIL and IBIL concentrations are indicative of severe renal pathology, with IBIL being a protective factor against M1.

Changes in the spectrum of biopsy-proven renal diseases over 11 years: a single-center study in China.

BACKGROUND: There have been some shifts in the frequency and distribution of biopsy-proven renal diseases in China over recent years. The aim of the study was to investigate the changing spectrum of renal diseases from the view of kidney biopsy data in a single center of China. METHODS AND RESULTS: A total of 10,996 cases of native renal biopsies from patients aged ≥15 years old in Huashan Hospital, Fudan University, between 2008 and 2018 were analyzed retrospectively. The results showed that primary glomerular nephropathy (PGN) remained the most common biopsy-proven renal disease (69.42% of total), with IgA nephropathy (IgAN) accounting for 44.40% of PGN, membranous nephropathy (MN) for 28.55%, minimal change disease (MCD) for 13.26% and focal segmental glomerulosclerosis (FSGS) for 8.00%. During the study period, the proportion of MN in PGN appeared an increasing tendency, while that of IgAN and MCD remained stable and that of FSGS showed a decline. Secondary glomerular nephropathy (SGN) constituted 21.54% of total cases, among which the leading two diseases were lupus nephritis (LN) and Henoch-Schonlein purpura nephritis (HSN) which accounted for 41.08% and 19.11% respectively. CONCLUSIONS: The 11-year retrospective study revealed that PGN was the predominant histologic diagnosis among patients undergoing renal biopsy and the most frequent type of PGN remained to be IgAN, followed by MN which increased dramatically.

The prognostic value of the systemic immune inflammation index in patients with IgA nephropathy.

BACKGROUND: Immune and inflammatory factors are considered the basic underlying mechanisms of IgA nephropathy (IgAN). The systemic immune inflammation index (SII) is a new inflammatory biomarker and has been identified as a prognostic indicator for various diseases. However, limited studies have been conducted on the prognostic value of the SII in patients with IgAN, and we aimed to address this gap. METHODS: A total of 374 patients with IgAN confirmed by renal biopsy performed from 1 January 2015 to 1 April 2019, were retrospectively included. The follow-up period of all patients was at least 12 months after diagnosis, and the endpoint was defined as end-stage kidney disease (ESKD). Patients were further divided into a high-risk group (SII ≥ 456.21) and a low-risk group (SII < 456.21) based on the optimal cutoff value of the SII determined by receiver operating characteristic (ROC) curve analysis. Baseline clinicopathological parameters were compared between the groups, and Cox proportional hazards analyses and Kaplan-Meier analysis were performed to assess renal survival in IgAN patients. RESULTS: After a median follow-up period of 32.5 months, a total of 53 patients eventually reached ESKD. Patients in the high-SII group tended to have a lower hemoglobin level (p = 0.032) and eGFR (p < 0.001), a higher serum creatinine level (p = 0.023) and 24-hour total protein level (p = 0.004), more severe tubular atrophy and interstitial fibrosis (p = 0.002) and more crescents (p = 0.030) than did those in the low-SII group. Univariate and multivariate Cox regression analyses demonstrated that an SII ≥456.21 was an independent risk factor for poor renal survival in IgAN patients (HR 3.028; 95% CI 1.486-6.170; p = 0.002). Kaplan-Meier analysis revealed that a high SII was significantly associated with poor renal prognosis (p < 0.001) and consistently exhibited remarkable discriminatory ability across different subgroups in terms of renal survival. CONCLUSION: A high SII was associated with more severe baseline clinical and pathological features, and an SII ≥456.21 was an independent risk factor for progression to ESKD in IgAN patients.

A preliminary probabilistic nomogram model for predicting renal arteriolar damage in IgA nephropathy from clinical parameters.

Background: IgA nephropathy (IgAN) is a significant contributor to chronic kidney disease (CKD). Renal arteriolar damage is associated with IgAN prognosis. However, simple tools for predicting arteriolar damage of IgAN remain limited. We aim to develop and validate a nomogram model for predicting renal arteriolar damage in IgAN patients. Methods: We retrospectively analyzed 547 cases of biopsy-proven IgAN patients. Least absolute shrinkage and selection operator (LASSO) regression and logistic regression were applied to screen for factors associated with renal arteriolar damage in patients with IgAN. A nomogram was developed to evaluate the renal arteriolar damage in patients with IgAN. The performance of the proposed nomogram was evaluated based on a calibration plot, ROC curve (AUC) and Harrell's concordance index (C-index). Results: In this study, patients in the arteriolar damage group had higher levels of age, mean arterial pressure (MAP), serum creatinine, serum urea nitrogen, serum uric acid, triglycerides, proteinuria, tubular atrophy/interstitial fibrosis (T1-2) and decreased eGFR than those without arteriolar damage. Predictors contained in the prediction nomogram included age, MAP, eGFR and serum uric acid. Then, a nomogram model for predicting renal arteriolar damage was established combining the above indicators. Our model achieved well-fitted calibration curves and the C-indices of this model were 0.722 (95%CI 0.670-0.774) and 0.784 (95%CI 0.716-0.852) in the development and validation groups, respectively. Conclusion: With excellent predictive abilities, the nomogram may be a simple and reliable tool to predict the risk of renal arteriolar damage in patients with IgAN.

Podocyte injury as a potential therapeutic target in IgA nephropathy: should pathology guide us?

The Oxford histopathologic classification (MEST-C: scores for lesions indicating active glomerular inflammation, mesangial [M] and endocapillary [E] hypercellularity as well as cellular or fibrocellular crescents [C], and for segmental glomerulosclerosis [S] and interstitial fibrosis and/or tubular atrophy [T]) is useful in helping assess prognosis in patients with IgA nephropathy. Elements of this classification indicative of active glomerular inflammation, endocapillary hypercellularity and crescents, also have been found to be responsive to immunosuppressive therapy, potentially including newer agents specifically targeting mediators of such inflammation. In this issue of Kidney International, Bellur and coworkers identify histopathologic subtypes of segmental glomerulosclerosis in IgA nephropathy showing podocyte injury that also behave like active lesions, including showing improved outcomes with immunosuppression. This podocyte injury, identifiable only by kidney biopsy, may represent a potential therapeutic target in some patients with IgA nephropathy.

Immune checkpoint activity exacerbate renal interstitial fibrosis progression by enhancing PD-L1 expression in renal tubular epithelial cells.

Renal interstitial fibrosis (RIF) is often associated with inflammatory cell infiltration and no effective therapy. Programmed death cell-1 (PD-1) and its ligand PD-L1 were playing critical roles in T cell coinhibition and exhaustion, but the role in RIF is unclear. Here the data analyses of serum from 122 IgA nephrology (IgAN) patients showed that high level of soluble PD-1(sPD-1) was an independent risk factor for RIF and renal function progression. PD-L1 was also overexpressed in renal interstitial tissues from both IgAN patients with high level of sPD-1 and the unilateral ureteral obstruction (UUO) mouse. PD-L1 was significantly overexpressed in HK-2 cells with upregulated collagen and α-SMA when stimulated by inflammation or hypoxia in vitro. Additionally, matrix metalloproteinases (MMP-2) could increase the level of sPD-1 in culture supernatant when added in co-culture system of HK-2 and jurkat cells, which implied serum sPD-1 of IgAN might be cleaved by MMP-2 from T cells infiltrated into the tubulointerstitial inflammatory microenvironment. Crucially, injection of PD-L1 fusion protein, the blocker of sPD-1, could ameliorate kidney fibrosis in UUO mice by increasing T cell coinhibition and exhaustion, suggesting the therapeutic potential of PD-L1 fusion targeting for renal fibrosis. Take together, it reveals a novel causal role of sPD-1 in serum and PD-L1 of renal interstitial tissues in the development of renal fibrosis of IgAN, and targeting sPD-1 in serum by PD-L1 fusion protein is a potential therapeutic approach to prevent renal fibrosis of IgAN.

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.

Molecular characterization of m6A RNA methylation regulators with features of immune dysregulation in IgA nephropathy.

The role of RNA N6-methyladenosine (m6A) modification in immunity is being elucidated. This study aimed to explore the potential association between m6A regulators and the immune microenvironment in IgA nephropathy (IgAN). The expression profiles of 24 m6A regulators in 107 IgAN patients were obtained from the Gene Expression Omnibus (GEO) database. The least absolute shrinkage and selection operator (LASSO) regression and logistic regression analysis were utilized to construct a model for distinguishing IgAN from control samples. Based on the expression levels of m6A regulators, unsupervised clustering was used to identify m6A-induced molecular clusters in IgAN. Gene set enrichment analysis (GSEA) and immunocyte infiltration among different clusters were examined. The gene modules with the highest correlation for each of the three clusters were identified by weighted gene co-expression network analysis (WGCNA). A model containing 10 m6A regulators was developed using LASSO and logistic regression analyses. Three molecular clusters were determined using consensus clustering of 24 m6A regulators. A decrease in the expression level of YTHDF2 in IgAN samples was significantly negatively correlated with an increase in resting natural killer (NK) cell infiltration and was positively correlated with the abundance of M2 macrophage infiltration. The risk scores calculated by the nomogram were significantly higher for cluster-3, and the expression levels of m6A regulators in this cluster were generally low. Immunocyte infiltration and pathway enrichment results for cluster-3 differed significantly from those for the other two clusters. Finally, the expression of YTHDF2 was significantly decreased in IgAN based on immunohistochemical staining. This study demonstrated that m6A methylation regulators play a significant role in the regulation of the immune microenvironment in IgAN. Based on m6A regulator expression patterns, IgAN can be classified into multiple subtypes, which might provide additional insights into novel therapeutic methods for IgAN.

The predictive value of free thyroxine combined with tubular atrophy/interstitial fibrosis for poor prognosis in patients with IgA nephropathy.

Background: IgA nephropathy (IgAN), the most common type of glomerulonephritis, has great individual differences in prognosis. Many studies showed the relationship between thyroid hormones and chronic kidney disease. However, the relationship between free thyroxine (FT4), as a thyroid hormone, and IgAN is still unclear. This study aimed to evaluate the impact of FT4 on IgAN prognosis. Methods: This retrospective study involved 223 patients with biopsy-proven IgAN. The renal composite outcomes were defined as: (1) ESRD, defined as eGFR < 15 ml/(min·1.73 m2) or initiation of renal replacement therapy (hemodialysis, peritoneal dialysis, renal transplantation); (2) serum creatinine doubled from baseline; (3) eGFR decreased by more than 50% from baseline. The predictive value was determined by the area under the curve (AUC). Kaplan-Meier and Cox proportional hazards analyses assessed renal progression and prognosis. Results: After 38 (26-54) months of follow-up, 23 patients (10.3%) experienced renal composite outcomes. Kaplan-Meier survival curve analysis showed that the renal survival rate of the IgAN patients with FT4<15.18pmol/L was lower than that with FT4≥15.18pmol/L (P < 0. 001). Multivariate Cox regression model analysis showed that FT4 was a protective factor for poor prognosis of IgAN patients, whether as a continuous variable or a categorical variable (HR 0.68, 95%CI 0.51-0.90, P =0.007; HR 0.04, 95%CI 0.01-0.20, P <0.001). ROC curve analysis showed that FT4 combined with t score had a high predictive value for poor prognosis of IgAN patients (AUC=0.881, P<0.001). Conclusion: FT4 was a protective factor for IgAN. In addition, FT4 combined with tubular atrophy/interstitial fibrosis had a high predictive value for poor prognosis of IgAN.

Accelerated involution of germinal center in palatine tonsils in IgA nephropathy.

BACKGROUND: Altered immunological responses in the palatine tonsils may be involved in the pathogenesis of IgA nephropathy (IgAN). The germinal center serves as the site for antigen-specific humoral immune responses in the palatine tonsils. Germinal center involution is frequently observed in the palatine tonsils of IgAN (IgAN tonsils). However, the pathogenic significance of these characteristic changes remains unclear. This study aimed to investigate the morphological changes in secondary lymphoid follicles in IgAN tonsils and to evaluate the correlation between the morphometric results and the clinicopathological severity of IgAN. METHODS: The tonsils of age-matched patients with recurrent tonsillitis (RT tonsils) were used as controls. The correlation between the degree of lymphoid follicular involution and histopathological severities in clinical or kidney biopsy was evaluated. RESULTS: In total, 87 patients with IgAN were included (48% male, median age 35 years, median estimated glomerular filtration rate: 74 mL/min/1.73 m2). Compared to RT tonsils, IgAN tonsils showed smaller median sizes of lymphoid follicles and germinal centers (P < 0.001). The relative areas of lymphoid follicles (%LFA) and germinal centers (%GCA) in the total tonsillar tissue were smaller in the IgAN tonsils than in the RT tonsils (P < 0.001). In contrast, the median proportion of mantle zones in the total tonsillar tissue was comparable between the groups. A lower %LFA was associated with a longer period from the onset of urinary abnormalities to biopsy diagnosis and higher urinary protein excretion (P = 0.01). %LFA showed significant negative correlations with frequencies of glomeruli with both global and segmental sclerosis. CONCLUSIONS: The present study confirmed accelerated germinal center involution in the tonsils of patients with IgAN. This characteristic change in the IgAN tonsil correlates with heavy proteinuria and advanced chronic histopathological changes in the kidneys, thereby suggesting the involvement of repeated tonsillar immunoreactions during IgAN progression.

Medullary sponge kidney with IgA nephropathy: a case report and literature review.

BACKGROUND: Medullary sponge kidney (MSK)is rare in association with glomerulonephritis. We report a patient with medullary sponge kidney, and the kidney biopsy revealed a diagnosis of IgA nephropathy. CASE PRESENTATION: A 27-year-old female presented with hematuria and proteinuria, and imaging studies indicated the presence of medullary spongy kidney. With appropriate preparation, a kidney biopsy was performed. Considering the patient's clinical and pathological characteristics, the final diagnosis was determined to be medullary sponge kidney associated by IgA nephropathy. The combination of corticosteroids and angiotensin receptor blockers (ARBs) proved to be significantly effective in reducing proteinuria in the current case. To the best of our knowledge, this is the first reported case that demonstrates the coexistence of MSK and IgA nephropathy. CONCLUSIONS: Administering precise therapy based on renal pathology can potentially enhance outcomes for patients with renal conditions, necessitating the need for clinicians to be vigilant about differential diagnosis in order to reduce the rates of missed diagnoses and misdiagnosis.

Genome-wide analysis of long noncoding RNAs as cis-acting regulators of transcription factor-encoding genes in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world, but the disease pathogenesis noncoding is yet to be elucidated. Previous studies have revealed regulatory functions for long noncoding RNA (lncRNA) in various diseases; however, the roles of lncRNA in IgAN and regulation of transcription factors (TFs) have been scarcely investigated. METHODS: Renal tissue samples (n = 5) from patients with IgAN and control samples (n = 4) were collected and RNA sequencing (RNA-seq) was performed. Four software programs were employed for lncRNA prediction. GO (Gene Ontology)/KEGG (Kyoto Encyclopedia of Genes and Genomes) were employed for analysis of the identified differentially expressed genes (DEGs). A regulatory network model of DE lncRNA-TF-DEG was developed, and the levels of expression of key lncRNAs, TFs, and corresponding target genes were assessed using qRT-PCR and immunofluorescence. RESULTS: The current study identified 674 upregulated and 1,011 downregulated DE mRNAs and 260 upregulated and 232 downregulated DE lncRNAs in IgAN samples compared with control samples. The upregulated DE mRNAs showed enrichment in cell adhesion and collagen glial fiber organization pathways. The DE lncRNAs-DE mRNAs showing co-expression are associated with transmembrane transport. A novel regulatory network model of lncRNA-TF-DEG has been developed. This study identified seven TFs that are cis-regulated by 6 DE lncRNAs, and show co-expression with 132 DEGs (correlation coefficient ≥ 0.8, P ≤ 0.01), generating 158 pairs that showed co-expression. The lncRNAs NQO1-DT and RP5-1057120.6 were found to be highly expressed in IgAN samples. The TFs vitamin D Receptor (VDR) and NFAT5, along with their target genes were also aberrantly expressed. CONCLUSION: Key lncRNAs and TFs centrally associated with IgAN have been identified in this study. A regulatory network model of lncRNA-TF-mRNA was constructed. Further studies on the genes identified herewith could provide insight into the pathogenesis of IgAN.

Characterizing Glomerular Barrier Dysfunction with Patient-Derived Serum in Glomerulus-on-a-Chip Models: Unveiling New Insights into Glomerulonephritis.

Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy.

Histological Correlation between Tonsillar and Glomerular Lesions in Patients with IgA Nephropathy Justifying Tonsillectomy: A Retrospective Cohort Study.

Tonsillectomy with steroid pulse therapy (SPT) has been established as an effective treatment for immunoglobulin A nephropathy (IgAN) in Japan. However, the underlying mechanisms supporting tonsillectomy remain unclear. This study assessed palatine tonsils from 77 patients with IgAN, including 14 and 63 who received SPT before and after tonsillectomy, respectively. Tonsils from 21 patients with chronic tonsillitis were analyzed as controls. Specific tonsillar lesions were confirmed in patients with IgAN, correlating with active or chronic renal glomerular lesions and SPT. T-nodule and involution of lymphoepithelial symbiosis scores in tonsils correlated with the incidence of active crescents and segmental sclerosis in the glomeruli, respectively. The study revealed an essential role of the tonsil-glomerular axis in early active and late chronic phases. Moreover, the SPT-preceding group demonstrated no changes in the T-nodule score, which correlated with active crescent formation, but exhibited a considerable shrinkage of lymphatic follicles that produced aberrant IgA1. The study underscores the involvement of innate and cellular immunity in IgAN and advocates for tonsillectomy as a necessary treatment alongside SPT for IgAN, based on a stepwise process.

Protocol for a systematic review of the application of the kidney failure risk equation and Oxford classification in estimating prognosis in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is a common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Outcomes are highly variable and predicting risk of disease progression at an individual level is challenging. Accurate risk stratification is important to identify individuals most likely to benefit from treatment. The Kidney Failure Risk Equation (KFRE) has been extensively validated in CKD populations and predicts the risk of ESRD at 2 and 5 years using non-invasive tests; however, its predictive performance in IgAN is unknown. The Oxford classification (OC) describes pathological features demonstrated on renal biopsy that are associated with adverse clinical outcomes that may also inform prognosis. The objective of this systematic review is to compare the KFRE with the OC in determining prognosis in IgAN. METHODS: A systematic review will be conducted and reported in line with PRISMA guidelines (PRISMA-P checklist attached as Additional file 1). Inclusion criteria will be cohort studies that apply the KFRE or OC to determine the risk of CKD progression or ESRD in individuals with IgAN. Multiple databases will be searched in duplicate to identify relevant studies, which will be screened first by title, then by abstract and then by full-text analysis. Results will be collated for comparison. Risk of bias and confidence assessments will be conducted independently by two reviewers, with a third reviewer available if required. DISCUSSION: Identifying individuals at the highest risk of progression to ESRD is challenging in IgAN, due to the heterogeneity of clinical outcomes. Risk prediction tools have been developed to guide clinicians; however, it is imperative that these aids are accurate and reproducible. The OC is based on observations made by specialist renal pathologists and may be open to observer bias, therefore the utility of prediction models incorporating this classification may be diminished, particularly as in the future novel biomarkers may be incorporated into clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022364569.

Cross-species single-cell analysis uncovers the immunopathological mechanisms associated with IgA nephropathy progression.

IgA nephropathy (IgAN) represents the main cause of renal failure, while the precise pathogenetic mechanisms have not been fully determined. Herein, we conducted a cross-species single-cell survey on human IgAN and mouse and rat IgAN models to explore the pathogenic programs. Cross-species single-cell RNA sequencing (scRNA-Seq) revealed that the IgAN mesangial cells (MCs) expressed high levels of inflammatory signatures CXCL12, CCL2, CSF1, and IL-34 and specifically interacted with IgAN macrophages via the CXCL12/CXCR4, CSF1/IL-34/CSF1 receptor, and integrin subunit alpha X/integrin subunit alpha M/complement C3 (C3) axes. IgAN macrophages expressed high levels of CXCR4, PDGFB, triggering receptor expressed on myeloid cells 2, TNF, and C3, and the trajectory analysis suggested that these cells derived from the differentiation of infiltrating blood monocytes. Additionally, protein profiling of 21 progression and 28 nonprogression IgAN samples revealed that proteins CXCL12, C3, mannose receptor C-type 1, and CD163 were negatively correlated with estimated glomerular filtration rate (eGFR) value and poor prognosis (30% eGFR as composite end point). Last, a functional experiment revealed that specific blockade of the Cxcl12/Cxcr4 pathway substantially attenuated the glomerulus and tubule inflammatory injury, fibrosis, and renal function decline in the mouse IgAN model. This study provides insights into IgAN progression and may aid in the refinement of IgAN diagnosis and the optimization of treatment strategies.

Machine learning-based diagnostic prediction of IgA nephropathy: model development and validation study.

IgA nephropathy progresses to kidney failure, making early detection important. However, definitive diagnosis depends on invasive kidney biopsy. This study aimed to develop non-invasive prediction models for IgA nephropathy using machine learning. We collected retrospective data on demographic characteristics, blood tests, and urine tests of the patients who underwent kidney biopsy. The dataset was divided into derivation and validation cohorts, with temporal validation. We employed five machine learning models-eXtreme Gradient Boosting (XGBoost), LightGBM, Random Forest, Artificial Neural Networks, and 1 Dimentional-Convolutional Neural Network (1D-CNN)-and logistic regression, evaluating performance via the area under the receiver operating characteristic curve (AUROC) and explored variable importance through SHapley Additive exPlanations method. The study included 1268 participants, with 353 (28%) diagnosed with IgA nephropathy. In the derivation cohort, LightGBM achieved the highest AUROC of 0.913 (95% CI 0.906-0.919), significantly higher than logistic regression, Artificial Neural Network, and 1D-CNN, not significantly different from XGBoost and Random Forest. In the validation cohort, XGBoost demonstrated the highest AUROC of 0.894 (95% CI 0.850-0.935), maintaining its robust performance. Key predictors identified were age, serum albumin, IgA/C3, and urine red blood cells, aligning with existing clinical insights. Machine learning can be a valuable non-invasive tool for IgA nephropathy.

Nefropatía por IgA con microangiopatía trombótica / IgA nephropathy with thrombotic microangiopathy

INTRODUCTION: IgA nephropathy is the most common glomerulopathy in the world, it has a wide clinical expression, from asymptomatic to rapidly progressive glomerulonephritis. The definitive diagnosis is renal biopsy, within which the IgA pattern can be identified, including thrombotic microangiopathy. CLINICAL CASE: 28-year-old female patient, with a history of preeclampsia in the last pregnancy, presents high blood pressure, hematuria and proteinuria. Study begins with initially negative results. Renal biopsy confirms IgA nephropathy with thrombotic microangiopathy. DISCUSSION: Vascular damage is underestimated in IgA nephropathy. Thrombotic microangiopathy can be associated with various clinical manifestations, however when it is associated with IgA Nephropathy it is usually associated with proteinuria, arterial hypertension and elevation of creatinine. In the presence of microangiopathy, secondary causes must be ruled out. In general, there is no pathognomonic serological marker. Eventually patients could benefit from the use of eculizumab. CONCLUSION: IgA nephropathy is the most common glomerulopathy worldwide; there is a wide range of clinical presentations, among which thrombotic microangiopathy can be found. This presentation is associated with a higher risk of progression to end-stage renal disease.

INTRODUCCIÓN: La nefropatía por IgA es la glomerulopatía más frecuente en el mundo, tiene una amplia expresión clínica, desde asintomática hasta glomerulonefritis rápidamente progresivas. El diagnóstico definitivo es la biopsia renal, dentro de las cuales se puede identificar el patrón de la IgA, dentro de los cuales está la microangiopatía trombótica. CASO CLÍNICO: Paciente femenina 28 años, con antecedentes de preeclampsia en último embarazo, presenta hipertensión arterial, hematuria y proteinuria. Se inicia estudio con resultados inicialmente negativos. Biopsia renal confirma nefropatía por IgA con microangiopatía trombótica. DISCUSIÓN: En la nefropatía por IgA se subestima el daño vascular. La microangiopatía trombótica se puede asociar con varias manifestaciones clínicas, sin embargo, cuando está asociada a NIgA suele estar asociado con proteinuria, hipertensión arterial y elevación y creatinina. Ante la presencia de microangiopatía, se deben descartar causas secundarias de la misma. En general no existe un marcador serológico patognomónico. Eventualmente los pacientes se podrían beneficiar del uso de eculizumab. CONCLUSIÓN: La nefropatía por IgA es la glomerulopatía más frecuente a nivel mundial, existe una gran gama de presentaciones clínicas, dentro de las cuales se puede encontrar microangiopatía trombótica. Esta última presentación se asocia con mayor riesgo de progresión a enfermedad renal en etapa terminal.