Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Heterozygous mutations in factor H aggravate pathological damage in a stable IgA deposition model induced by Lactobacillus casei cell wall extract.

Introduction: Activation of complement through the alternative pathway (AP) has a key role in the pathogenesis of IgA nephropathy (IgAN). We previously showed, by intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE), C57BL/6 mice develop mild kidney damage in association with glomerular IgA deposition. To further address complement activity in causing glomerular histological alterations as suggested in the pathogenesis of IgAN, here we used mice with factor H mutation (FHW/R) to render AP overactivation in conjunction with LCWE injection to stimulate intestinal production of IgA. Methods: Dose response to LCWE were examined between two groups of FHW/R mice. Wild type (FHW/W) mice stimulated with LCWE were used as model control. Results: The FHW/R mice primed with high dose LCWE showed elevated IgA and IgA-IgG complex levels in serum. In addition to 100% positive rate of IgA and C3, they display elevated biomarkers of kidney dysfunction, coincided with severe pathological lesions, resembling those of IgAN. As compared to wild type controls stimulated by the same high dose LCWE, these FHW/R mice exhibited stronger complement activation in the kidney and in circulation. Discussion: The new mouse model shares many disease features with IgAN. The severity of glomerular lesions and the decline of kidney functions are further aggravated through complement overactivation. The model may be a useful tool for preclinical evaluation of treatment response to complement-inhibitors.

A cluster of type I interferon-regulated genes associates with disease activity and prognosis in patients with IgA nephropathy.

The exact pathogenesis of IgA nephropathy (IgAN) is complex and so far, not well defined. Since it has been shown that microbial infections could induce high levels of type I interferon (IFN-I) and there is an evident link between mucosal infection and gross hematuria in IgAN, we hypothesized that IFN-I may play a role in the pathogenic process. In this study, we investigated the type I interferon status in IgAN based on the expression of 17 IFN-regulated genes (IRGs) in whole blood from 59 IgAN patients in a cross-sectional study, of which 34 patients followed longitudinally. Analysis of the IFN-score showed that there was a significant elevated IFN-score in the IgAN patients compared with healthy controls (n = 28, p = 9.80 × 10-3), and we observed an elevated IFN-score in the group with less tubular atrophy/interstitial fibrosis (p = 1.07 × 10-2) and with a lower proportion of mesangial hypercellularity (p = 1.23 × 10-2). In the longitudinal analysis, Cox regression analysis revealed that a higher IFN level was associated with a better renal outcome in IgAN after adjustments for gender and age (hazard ratio, 0.90; 95 % confidence interval, 0.81 to 0.97; p = 4.20 × 10-2). In conclusion, our finding suggested that IFN score may represent a novel type of biomarker in IgAN, which requires further exploration on its mechanism and therapeutic targeting.

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

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

Distinct characteristics and prognosis of IgA nephropathy patients with nephrotic syndrome: a propensity score-matched cohort study.

Introduction: IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally. While nephrotic syndrome (NS) is uncommon in IgAN, its significance remains unclear. Methods: We conducted a retrospective analysis of 170 IgAN patients, classifying them into NS (n = 85) and non-NS (n = 5) groups. Our study aims to compare their clinical characteristics, treatment responses, and prognoses. Patients were selected based on renal biopsy from 2003 to 2020. Propensity score matching ensured comparability. Clinical, pathological, and immunological data were analyzed. Composite endpoints were defined as end-stage kidney disease (ESKD) or a 30% decline in estimated glomerular filtration rate (eGFR). Results: NS patients showed higher eGFR (74.3 ± 36.8 vs. 61.5 ± 33.6 mL/min.1.73 m2, p = 0.02), severe hematuria (35.0 (4.7,147.5) vs. 4.0 (1.8,45,0) cells/µl, p < 0.001), severe foot process effacement (p = 0.01), and lower C3 levels (1.0 ± 0.3 vs. 1.1 ± 0.2 g/L, p = 0.03). In contrast, the non-NS group had higher BMI (24.3 ± 4.0 vs. 26.8 ± 3.7 kg/m2, p < 0.001) and elevated serum uric acid levels (376 (316,417) vs. 400 (362, 501) mmol/L, p = 0.001), suggesting metabolic factors might contribute to their condition. Both groups exhibited similar MESTC scores. NS patients had higher complete remission rates (26.2% vs. 14.1%, p = 0.04). Cox regression revealed NS independently associated with a higher risk of composite endpoints (HR = 1.97, 95% CI 1.05-3.72, p = 0.04). Linear mixed models did not show significant eGFR trajectory differences. Discussion: This study has established that IgAN patients with NS exhibit distinct characteristics, including active disease and increased complement activation. NS is independently associated with a poorer prognosis, emphasizing the need for targeted interventions in this subgroup.

Time-Varying Proteinuria and Progression of IgA Nephropathy: A Cohort Study.

RATIONALE & OBJECTIVE: Proteinuria is a surrogate end point for predicting long-term kidney outcomes in IgA nephropathy (IgAN) with levels<1g/day identified as a therapeutic target. However, this threshold has not been sufficiently studied. We quantified the associations of progression of IgAN with various levels of proteinuria. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 1,530 patients with IgAN and at least 12 months of follow-up at Peking University First Hospital. EXPOSURE: Proteinuria levels updated over time (time-varying proteinuria, TVP). OUTCOME: A composite kidney outcome of a 50% reduction in the estimated glomerular filtration rate or end-stage kidney disease. ANALYTICAL APPROACH: Marginal structural models. RESULTS: After a median follow-up period of 43.5 (IQR, 27.2-72.8) months, 254 patients (16.6%) developed the composite kidney outcome. A graded association was observed between TVP and composite kidney outcomes with higher risk among those with proteinuria of≥0.5g/day. Compared with TVP<0.3g/day, the HRs for proteinuria levels of 0.3 to<0.5g/day, 0.5 to<1.0g/day, 1.0 to<2.0g/day, and≥2.0g/day were 2.22 (95% CI, 0.88-5.58), 4.04 (95% CI, 1.93-8.46), 8.46 (95% CI, 3.80-18.83), and 38.00 (95% CI, 17.62-81.95), respectively. The trend was more pronounced in patients with baseline proteinuria of≥1.0g/day, among whom a higher risk was observed with TVP of 0.3 to<0.5g/day compared with TVP<0.3g/day (HR, 3.26 [95% CI, 1.07-9.92], P=0.04). However, in patients with baseline proteinuria levels of<1g/day, the risk of composite kidney outcome only began to increase when TVP was≥1.0g/day (HR, 3.25 [95% CI, 1.06-9.90]). LIMITATIONS: Single-center observational study, selection bias, and unmeasured confounders. CONCLUSIONS: This study showed that patients with IgAN and proteinuria levels of>0.5g/day, have an elevated risk of kidney failure especially among patients with proteinuria levels≥1.0g/day before initiating treatment. These data may serve to inform the selection of proteinuria targets in the treatment of IgAN. PLAIN-LANGUAGE SUMMARY: The presence of proteinuria has often been considered a surrogate end point and a possible therapeutic target in clinical trials in IgA nephropathy (IgAN). Some guidelines recommend a reduction in proteinuria to<1g/day as a treatment goal based on the results of previous longitudinal studies. However, these findings may have been biased because they did not properly adjust for time-dependent confounders. Using marginal structural models to appropriately account for these confounding influences, we observed that patients with IgAN and proteinuria levels≥0.5g/day have an elevated risk of kidney failure, especially among patients who had proteinuria levels of≥1.0g/day before initiating treatment. These data may serve to inform the selection of proteinuria targets in the treatment of IgAN.

Digital Health Interventions for Quality Improvements in Chronic Kidney Disease Primary Care: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Chronic kidney disease (CKD) is a significant public health issue globally. The importance of its timely identification and early intervention is paramount. However, a systematic approach for early CKD management in the primary care setting is currently lacking, receiving less attention compared to upstream risk factors such as diabetes and hypertension. This oversight may lead to a failure in meeting quality-of-care indicators. Digital health interventions (DHIs), which leverage digital tools to enhance healthcare delivery, have shown effectiveness in managing chronic diseases and improving the quality, safety, and efficiency of primary care. Our research aimed to evaluate the effectiveness of DHIs in the care process, focusing on their reach, uptake, and feasibility. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for randomized controlled trials (RCTs) assessing DHIs' effectiveness in CKD patient care among adults in primary care settings. The search, conducted on 30 June 2023, included studies published in English from 1 January 2009. Screening was conducted using Covidence, adhering to Cochrane's guidelines for data extraction. We primarily evaluated changes in care processes (testing, documentation, medication use, etc.) and the use of renin-angiotensin-aldosterone system inhibitors (RAASi), referrals, among others. Multilevel meta-analysis was employed to address within-study clustering, and meta-regression analyzed the impact of study characteristics on heterogeneity in effect sizes. Clinical endpoints were recorded where available. Bias risk was assessed using the Cochrane Risk of Bias 2 tool. Data on reach, uptake, and feasibility were narratively summarized. The study is registered with PROSPERO (CRD42023449098). RESULTS: From 679 records, 12 RCTs were included in the narrative synthesis, and 6 studies (encompassing 7 trials) in the meta-analysis. The trials indicated a -0.85% change (95%CI, -5.82% to 4.11%) in the proportion of patients receiving desired care. This result showed considerable heterogeneity (I2 = 91.9%). One study characteristic (co-intervention, education) correlated with larger effects. Although including co-intervention in multivariable meta-regression was significant, it did not diminish heterogeneity. The reported reach varied and was not high, while the uptake was relatively high. Most studies did not explicitly address feasibility, though some statements implied its evaluation. CONCLUSIONS: The current literature on the impact of DHIs in community-based CKD care is limited. The studies suggest a non-significant effect of DHIs on enhancing CKD management in community settings, marked by significant heterogeneity. Future research should focus on rigorous, methodologically sound implementations to better assess the effectiveness of DHIs in the primary care management of CKD.

Association between urinary C4d levels and disease progression in IgA nephropathy.

BACKGROUND: C4d mesangial deposition, a hallmark of lectin pathway activation in IgA nephropathy (IgAN), has been shown to be associated with risk of kidney failure. To date, the relationship between urinary C4d and renal outcome remain unelucidated. METHODS: A total of 508 patients with biopsy-proven IgAN were enrolled in this study, whose baseline urine samples at the time of biopsy were collected and the levels of urinary C4d were quantified by enzyme-linked immunosorbent assay. The time-averaged C4d (TA-C4d) and the change in proteinuria were measured in sequential urine samples obtained from IgAN patients. The kidney progression event was defined as a 50% estimated glomerular filtration rate (eGFR) decline or end-stage kidney disease (ESKD) or death. RESULTS: After a median follow-up of 36 months, 70 (13.8%) of the participants reached the kidney progression event. Higher levels of urinary C4d/creatinine were found to be associated with decreased eGFR, massive proteinuria, lower serum albumin levels, hypertension, and severe Oxford E and T scores. Upon adjusting for traditional risk factors (including demographics, eGFR, proteinuria, hypertension, Oxford pathologic score, and immunosuppressive therapy), elevated levels of urinary C4d/creatinine were independently associated with an increased risk of CKD progression (adjusted HR per standard deviation increment of log-transformed C4d/creatinine: 1.46; 95% CI: 1.04 to 2.06; P=0.030). In reference to the low C4d group, the risk of poor renal outcome increased for the high C4d group (adjusted HR: 1.93; 95% CI: 1.05 to 3.54; P=0.033). Additionally, a low baseline C4d level was independently assosicated with a favorable proteinuria response to immunosuppressive therapy at three months (adjusted relative risk: 2.20; 95% CI: 1.04-4.63, P=0.038). CONCLUSION: The urinary C4d, serving as a non-invasive biomarker, is associated with the progression of IgAN and holds the potential to predict proteinuria response in this disease.

Graph-guided deep hashing networks for similar patient retrieval.

With the rapid growth and widespread application of electronic health records (EHRs), similar patient retrieval has become an important task for downstream clinical decision support such as diagnostic reference, treatment planning, etc. However, the high dimensionality, large volume, and heterogeneity of EHRs pose challenges to the efficient and accurate retrieval of patients with similar medical conditions to the current case. Several previous studies have attempted to alleviate these issues by using hash coding techniques, improving retrieval efficiency but merely exploring underlying characteristics among instances to preserve retrieval accuracy. In this paper, drug categories of instances recorded in EHRs are regarded as the ground truth to determine the pairwise similarity, and we consider the abundant semantic information within such multi-labels and propose a novel framework named Graph-guided Deep Hashing Networks (GDHN). To capture correlation dependencies among the multi-labels, we first construct a label graph where each node represents a drug category, then a graph convolution network (GCN) is employed to derive the multi-label embedding of each instance. Thus, we can utilize the learned multi-label embeddings to guide the patient hashing process to obtain more informative and discriminative hash codes. Extensive experiments have been conducted on two datasets, including a real-world dataset concerning IgA nephropathy from Peking University First Hospital, and a publicly available dataset from MIMIC-III, compared with traditional hashing methods and state-of-the-art deep hashing methods using three evaluation metrics. The results demonstrate that GDHN outperforms the competitors at different hash code lengths, validating the superiority of our proposal.

The predictive value and response to immunosuppressive therapy of IgA nephropathy patients with crescents in a large retrospective Chinese cohort.

Background: The prognostic value and response to immunosuppressive therapy (IST) of patients with crescents in the different backgrounds of pathological presentations in immunoglobulin A nephropathy (IgAN) is unclear. Methods: A total of 1262 IgAN patients were enrolled. Crescents (C, 0/1/2), fibrinoid necrosis (FN, 0/1) and endocapillary hypercellularity (E, 0/1) were integrated into different degrees of glomerular activity (0-4 points): mild (0), moderate (1-2) and severe (≥3). The effect of IST on patients with different glomerular activity scores and chronic tubular and interstitial lesions (T, 0/1/2) were analysed using Cox regression analysis. The kidney outcome was defined as an estimated glomerular filtration rate decrease ≥30% or end-stage kidney disease. Results: C2 was an independent risk factor for kidney outcomes {overall cohort: hazard ratio [HR] 1.85 [95% confidence interval (CI) 1.03-3.31], P = .040; T0 patients: HR 6.52 [95% CI 2.92-14.54], P < .001; reference to C0} in those without IST, while the HR decreased to 0.83 (95% CI 0.54-1.27; P = .396) in the overall cohort and 2.39 (95% CI 1.00-5.67; P = .049) in T0 patients with IST. For patients with severe glomerular activity, IST decreased the risk of kidney outcomes by 70% in the overall cohort [HR 0.30 (95% CI 0.12-0.74), P = .009; reference to those without IST] and 86% in T0 patients [HR 0.14 (95% CI 0.04-0.54), P = 0.005; reference to those without IST]. Conclusions: IST could reduce the risk for kidney outcomes in IgAN patients with C2 and T0 lesions together, as well as in those with crescents and at least one other active lesion, including FN and E1 lesions.

Clinical and pathological characteristics in elderly patients with IgA nephropathy.

Background: Immunoglobulin A nephropathy (IgAN) is the most common cause of primary glomerulonephritis, with highly variable manifestations. Although the peak incidence of IgAN is in young adults, the diagnosis among elderly people is increasing. Here we explored the effect of aging on IgAN features, as well as cellular senescence in the kidney of IgAN. Methods: A total of 910 patients with IgAN were enrolled, which contained 182 individuals in each age stage (aged ≥60, 50-59, 40-49, 30-39 and 20-29 years). Clinical and pathological manifestations at the time of renal biopsy were compared. Additionally, 38 patients with IgAN (19 aged over or equal to 60 years and 19 aged below 60 years) were randomly selected for p16INK4a staining by immunohistochemistry. The percentage of p16INK4a-positive cells in glomeruli, renal tubule and interstitium were separately quantified. Results: Compared with young IgAN patients, elderly patients presented with higher levels of circulating IgA, uric acid and proteinuria, but lower estimated glomerular filtration rates (eGFR), as well as lower red blood cell counts, platelet counts and lymphocyte counts. Moreover, elderly IgAN patients showed higher incidence of hypertension, and lower incidence of prodromic infection. Regarding histological lesions in the kidney, young IgAN patients had higher degree of IgA and C3 deposits, while elderly IgAN patients had more severe Oxford-E lesions, but less severe Oxford-S lesions. The percentage of glomerular and tubular p16INK4a-positive cells in elderly patients showed an increasing trend, but statistical significance was not reached. The percentage of p16INK4a-positive nuclei in renal interstitium was positively associated with T score, while increased percentage of p16INK4a-positive nuclei in renal tubule was associated with eGFR and 24-h urinary protein level. Conclusion: In our IgAN cohort, elderly IgAN patients presented with some aging-related features, and both aging- and IgAN-induced pathological injury contributed to the kidney lesions in patients with IgAN.

A biosensing array for multiplex clinical evaluation of glucose, creatinine, and uric acid.

The multiplex and simultaneous determination of blood glucose, creatinine and uric acid is essential for the early screening of chronic diseases or regular disease monitoring. Here, we report for the first time a biosensing array for the multiplex and simultaneous determination of plasma glucose, creatinine and uric acid. The sensing electrodes are fabricated on a PET surface, including three working electrodes, one reference electrode, and one counter electrode. Each specific enzyme is immobilized on its corresponding working electrode. The biosensing array can exhibit high sensitivity and selectivity for the simultaneous determination of blood glucose, creatinine and uric acid in real blood samples, and the measurement results are accurate and consistent with those from the clinical biochemistry analyzer in the hospital. It is expected that this work could provide new avenues for the fundamental study of biosensing device construction, as well as practical applications of the detection of biomarkers in chronic diseases.

Twenty-four-hour proteinuria levels are associated with adverse pregnancy outcomes among women with CKD.

Background: Proteinuria is commonly measured to assess the renal status of chronic kidney disease (CKD) patients before the 20th week of gestation during pregnancy. High levels of proteiuria have been associated with adverse pregnancy outcomes. However, researchers have not clearly determined what baseline proteinuria levels would be associated with adverse pregnancy outcomes. This study aimed to analyse associations between proteinuria levels and adverse pregnancy outcomes among CKD patients treated with or without steroids/immunosuppressive therapy in early pregnancy. Methods: This retrospective study included the clinical information of 557 pregnant patients with CKD from 1 January 2009 to 31 December 2021. A multivariable logistic regression analysis was conducted to evaluate the risk of adverse pregnancy outcomes across various proteinuria ranges, which were further stratified by whether the patients were receiving steroids/immunosuppressive therapy. Results: (i) Proteinuria was assessed on 24-h urine collection. The median (quartile) baseline proteinuria levels were 0.83 g (0.20, 1.92) and 0.25 g (0.06, 0.80) in the steroids/immunosuppressive therapy and therapy-free groups, respectively. (ii) CKD patients with adverse pregnancy outcomes had significantly higher proteinuria levels in the first trimester than patients without adverse pregnancy outcomes. (iii) The risk of adverse pregnancy outcomes increased with increasing baseline proteinuria levels (P < .001). (iv) In the early-pregnancy steroids/immunosuppressive therapy group, the risk of severe preeclampsia was higher in patients with higher baseline proteinuria levels (P < .007) [odds ratio (OR) 30.86 for proteinuria ≥5.00 g/24 h]; in the therapy-free group, the risks of severe preeclampsia, very-low-birth-weight infants, early preterm birth and foetal-neonatal death were higher in patients with higher baseline proteinuria levels (OR 53.16 for proteinuria ≥5.00 g/24 h; OR 37.83 for proteinuria ≥5.00 g/24 h; OR 15.30 for proteinuria ≥5.00 g/24 h; and OR 18.83 for proteinuria ≥5.00 g/24 h, respectively; P < .001, P < .001, P < .001 and P = .006, respectively). Conclusions: As shown in the present study, a baseline 24-h proteinuria level >1.00 g was associated with adverse maternal outcomes. Furthermore, a 24-h proteinuria level >2.00 g increased the incidence of adverse foetal events among CKD patients.

Long-term renal outcomes of patients with COVID-19: a meta-analysis of observational studies.

BACKGROUND: Kidney involvement is common in hospitalized coronavirus disease 2019 (COVID-19) patients during the acute phase, little is known about the long-term impact of COVID-19 on the kidney. METHODS: This is a systematic review and meta-analysis on long-term renal outcomes among COVID-19 patients. We carried out a systematic literature search in PUBMED, EMBASE, SCOPUS, and Cochrane COVID-19 study register and performed the random-effects meta-analysis of rates. The search was last updated on November 23, 2022. RESULTS: The study included 12 moderate to high-quality cohort studies involving 6976 patients with COVID-19-associated acute kidney injury and 5223 COVID-19 patients without acute kidney injury. The summarized long-term renal non-recovery rate, dialysis-dependent rate, and complete recovery rate among patients with COVID-19-associated AKI was 22% (12-33%), 6% (2-12%), and 63% (44-81%) during a follow-up of 90-326.5 days. Heterogeneity could be explained by differences in the prevalence of chronic kidney disease and proportion of acute kidney injury requiring renal replacement therapy using meta-regression; patients with more comorbidities or higher renal replacement therapy rate had higher non-recovery rates. The summarized long-term kidney function decrease rate among patients without acute kidney injury was 22% (3-51%) in 90-199 days, with heterogeneity partially explained by severity of infection. CONCLUSION: Patients with more comorbidities tend to have a higher renal non recovery rate after COVID-19-associated acute kidney injury; for COVID-19 patients without acute kidney injury, decrease in kidney function may occur during long-term follow-up. Regular evaluation of kidney function during the post-COVID-19 follow-up among high-risk patients may be necessary.

Effect of SGLT2 inhibitors on the proteinuria reduction in patients with IgA nephropathy.

Backgroud: Recent trials suggest sodium-glucose cotransporter 2 inhibitors (SGLT2i) significantly reduced proteinuria in patients with IgA nephropathy (IgAN). While little was known its efficacy in clinical practice especially in those already received full dose reninangiotensin-aldosterone system (RAAS) inhibitors. Methods: A cohort of 93 Chinese patients with biopsy-proven IgAN and persistent proteinuria underwent full supportive therapy, including optimal blood pressure control and full dose angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy. Proteinuria reduction at three and six months after initiating SGLT2i therapy was analyzed. Results: A total of 93 patients were enrolled in this study and 62 of them completed the six-month follow-up. After SGLT2i administration, a significant reduction in proteinuria was observed, with a decrease of 22.9% (p < 0.001) at three months and 27.1% (p < 0.001) at six months. During the six-month follow-up period, a decline of 3.0 mL/min/1.73m2 in estimated glomerular filtration rate (eGFR) (p = 0.012) and an increase of 0.8 g/L in albumin (p = 0.017) were observed. The anti-hypertensive effect of SGLT2i was not significant (p > 0.05). Notably, a consistent antiproteinuric effect of SGLT2i was observed across various settings, including different age groups, baseline levels of proteinuria/eGFR, use of immunosuppressive agents, and the presence of comorbid diabetes and hypertension (all p values >0.05). Conclusion: The proteinuria was significantly reduced after SGLT2i administration in IgAN patients with full dose angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy. Importantly, the antiproteinuric effect of SGLT2i was observed independently of immunosuppressive agent therapy, age, baseline eGFR and proteinuria levels, as well as the history of hypertension and diabetes.

Machine learning in predicting T-score in the Oxford classification system of IgA nephropathy.

Background: Immunoglobulin A nephropathy (IgAN) is one of the leading causes of end-stage kidney disease (ESKD). Many studies have shown the significance of pathological manifestations in predicting the outcome of patients with IgAN, especially T-score of Oxford classification. Evaluating prognosis may be hampered in patients without renal biopsy. Methods: A baseline dataset of 690 patients with IgAN and an independent follow-up dataset of 1,168 patients were used as training and testing sets to develop the pathology T-score prediction (T pre) model based on the stacking algorithm, respectively. The 5-year ESKD prediction models using clinical variables (base model), clinical variables and real pathological T-score (base model plus T bio), and clinical variables and T pre (base model plus T pre) were developed separately in 1,168 patients with regular follow-up to evaluate whether T pre could assist in predicting ESKD. In addition, an external validation set consisting of 355 patients was used to evaluate the performance of the 5-year ESKD prediction model using T pre. Results: The features selected by AUCRF for the T pre model included age, systolic arterial pressure, diastolic arterial pressure, proteinuria, eGFR, serum IgA, and uric acid. The AUC of the T pre was 0.82 (95% CI: 0.80-0.85) in an independent testing set. For the 5-year ESKD prediction model, the AUC of the base model was 0.86 (95% CI: 0.75-0.97). When the T bio was added to the base model, there was an increase in AUC [from 0.86 (95% CI: 0.75-0.97) to 0.92 (95% CI: 0.85-0.98); P = 0.03]. There was no difference in AUC between the base model plus T pre and the base model plus T bio [0.90 (95% CI: 0.82-0.99) vs. 0.92 (95% CI: 0.85-0.98), P = 0.52]. The AUC of the 5-year ESKD prediction model using T pre was 0.93 (95% CI: 0.87-0.99) in the external validation set. Conclusion: A pathology T-score prediction (T pre) model using routine clinical characteristics was constructed, which could predict the pathological severity and assist clinicians to predict the prognosis of IgAN patients lacking kidney pathology scores.

Mesangial C3 Deposition, Complement-Associated Variant, and Disease Progression in IgA Nephropathy.

BACKGROUND: IgA nephropathy is the most common primary GN worldwide, with dominant deposition of IgA and co-deposits of complement component 3 (C3). Phenotypes and progression of IgA nephropathy varies among different ethnic populations, while patients with IgA nephropathy from Asia showed more severe clinical phenotypes, active kidney lesions, and rapid progression. Our previous genome-wide association study identified complement factor H ( CFH ) variant rs6677604, tightly linked with the deletion of CFH -related protein 3 and CFH -related protein 1 genes ( ΔCFHR3-1 ), as IgA nephropathy susceptible variant, and additionally revealed its effect on complement regulation in IgA nephropathy. METHODS: To further explore the effect of rs6677604 on IgA nephropathy progression, here we enrolled a Chinese IgA nephropathy cohort of 1781 patients with regular follow-up for analysis. The rs6677604 genotype was measured, and the genotype-phenotype correlation was analyzed using the t test, the chi-squared test, or the nonparametric test, and the association between rs6677604 genotype or mesangial C3 deposition and IgA nephropathy prognosis was analyzed using Kaplan-Meier analysis and Cox regression. RESULTS: We found that patients with rs6677604-GG genotype had a stronger intensity of mesangial C3 deposition than those with the rs6677604-AA/AG genotype. Patients with IgA nephropathy who had stronger intensity of C3 deposition manifested with more severe clinical and pathological manifestations, including lower eGFR and higher Oxford-M/S/T/C (mesangial hypercellularity, endocapillary cellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and crescent) scores. In the survival analysis, stronger intensity of mesangial C3 deposition, but not rs6677604-GG genotypes, was associated with poor long-term kidney outcome in IgA nephropathy. CONCLUSIONS: We found that in Chinese patients with IgA nephropathy, variant rs6677604 was associated with mesangial C3 deposition, and mesangial C3 deposition, but not rs6677604, was associated with IgA nephropathy severity and progression.

MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy.

Multiple genome-wide association studies (GWASs) have reproducibly identified the MTMR3/HORMAD2/LIF/OSM locus to be associated with IgA nephropathy (IgAN). However, the causal variant(s), implicated gene(s), and altered mechanisms remain poorly understood. Here, we performed fine-mapping analyses based on GWAS datasets encompassing 2762 IgAN cases and 5803 control individuals, and identified rs4823074 as the candidate causal variant that intersects the MTMR3 promoter in B-lymphoblastoid cells. Mendelian randomization studies suggested the risk allele may modulate disease susceptibility by affecting serum IgA levels through increased MTMR3 expression. Consistently, elevated MTMR3 expression in peripheral blood mononuclear cells was observed in patients with IgAN. Further mechanistic studies in vitro demonstrated that MTMR3 increased IgA production dependent upon its phosphatidylinositol 3-phosphate binding domain. Moreover, our study provided the in vivo functional evidence that Mtmr3-/- mice exhibited defective Toll Like Receptor 9-induced IgA production, glomerular IgA deposition, as well as mesangial cell proliferation. RNA-seq and pathway analyses showed that MTMR3 deficiency resulted in an impaired intestinal immune network for IgA production. Thus, our results support the role of MTMR3 in IgAN pathogenesis by enhancing Toll Like Receptor 9-induced IgA immunity.

Clinicopathological and immunological features of new onset kidney disease: a rare event after SARS-CoV-2 vaccination.

The onset of various kidney diseases has been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. However, detailed clinical and pathological features are lacking. We screened and analyzed patients with newly diagnosed kidney diseases after inactivated SARS-CoV-2 vaccination in Peking University First Hospital from January 2021 to August 2021, and compared them with the reported cases in the literature. We obtained samples of blood, urine and renal biopsy tissues. Clinical and laboratory information, as well as light microscopy, immunostaining and ultrastructural observations, were described. The SARS-CoV-2 spike protein and nucleoprotein were stained using the immunofluorescence technique in the kidney biopsy samples. SARS-CoV-2 specific antibodies were tested using magnetic particle chemiluminescence immunoassay. The study group included 17 patients with a range of conditions including immune-complex-mediated kidney diseases (IgA nephropathy, membranous nephropathy and lupus nephritis), podocytopathy (minimal change disease and focal segmental glomerulosclerosis) and others (antineutrophil-cytoplasmic-antibody-associated vasculitis, anti-glomerular basement membrane nephritis, acute tubulointerstitial nephritis and thrombotic microangiopathy). Seven patients (41.18%) developed renal disease after the first dose and ten (58.82%) after the second dose. The kidney disease spectrum as well as clinicopathological features are similar across different types of SARS-CoV-2 vaccines. We found no definitive evidence of SARS-CoV-2 spike protein or nucleoprotein deposition in the kidney biopsy samples. Seropositive markers implicated abnormal immune responses in predisposed individuals. Treatment and follow-up (median = 86 days) showed that biopsy diagnosis informed treatment and prognosis in all patients. In conclusion, we observed various kidney diseases following SARS-CoV-2 vaccine administration, which show a high consistency across different types of SARS-CoV-2 vaccines. Our findings provide evidence against direct vaccine protein deposition as the major pathomechanism, but implicate abnormal immune responses in predisposed individuals. These findings expand our understanding of SARS-CoV-2 vaccine renal safety.