Immunotherapy has significantly improved the treatment of metastatic solid tumors; however, detecting early signs of response to enable timely intervention for resistant tumors remains challenging. A blood-only circulating tumor DNA (ctDNA) test may provide a rapid assessment of tumor response without reliance on matched tumor tissue. We applied a tissue-agnostic, genome-wide methylation enrichment assay, based on cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq), to plasma samples from patients in a phase 2 trial evaluating pembrolizumab across multiple solid tumors (NCT02644369). A decrease in ctDNA from baseline to pre-cycle 3 was significantly associated with higher objective response and clinical benefit rates and longer progression-free and overall survival in univariate analyses, with these associations remaining significant in multivariable models except for overall survival. These results validate a commercial-grade, tissue-agnostic plasma cfDNA methylation platform for immunotherapy response monitoring, which may facilitate earlier, more informed treatment decisions and improve patient outcomes.

Objective:Acute kidney injury (AKI) is a common clinical syndrome with poor prognosis and limited targeted therapies. This study aimed to systematically identify genetically supported candidate proteins associated with AKI and to explore potential biological pathways and phenotypic associations. Methods:Using data from the UK Biobank Pharma Proteomics Project (UKB-PPP), FinnGen, IEU Open GWAS, and other large-scale databases, we applied summary-data Mendelian randomization (SMR), Bayesian colocalization analysis, two-sample Mendelian randomization (MR), mediation analysis, and phenome-wide association study (PheWAS) to assess the causal relationships and mechanisms linking plasma proteins to AKI risk.We collected blood samples undergoing cardiac surgery with cardiopulmonary bypass to measure the levels of CX3CL1 and UMOD in the plasma and compare them with indicators such as serum creatinine and urinary [TIMP2]*[IGFBP7], to evaluate the efficacy of CX3CL1 and UMOD in diagnosing AKI. Results:Two plasma proteins, CX3CL1 and uromodulin (UMOD), were identified as significantly and positively causally associated with AKI risk, supported by genetic colocalization evidence. Mediation analysis indicated that CX3CL1's effect on AKI may be partially mediated by metabolites such as 1,6-anhydroglucose and Mannitol. PheWAS revealed associations of these proteins with hypertension, carbohydrate metabolism disorders, and infections, suggesting potential off-target effects that should be considered in drug development. The associations of these two proteins were further evaluated in human plasma samples.we found that patients with I/R-induced AKI exhibited significantly elevated plasma levels of CX3CL1 and UMOD compared to those who underwent ischemia-reperfusion without developing AKI (P< 0.05). Spearman's test demonstrated a significant correlation between serum creatinine and plasma CX3CL1 and UMOD in patients with I/R induced AKI (r = 0.848, P < 0.001; r = 0.794, P< 0.001, respectively). Plasma CX3CL1 and UMOD showed high specificity but low sensitivity in diagnosing AKI (sensitivity 68.0% and 60%;specificity 92.0% and 88%,respectively). Conclusion:This study systematically elucidates the genetic evidence and possible pathogenic mechanisms of CX3CL1 and UMOD as candidate proteins for AKI, CX3CL1 and UMOD demonstrated potential associations with I/R-induced AKI risk in the present cohort., enriching our understanding of AKI pathogenesis and providing theoretical and safety considerations for future targeted drug development.

2545 Background: Recent work from the INSPIRE study (PMID38393391) suggests that kinetics of cell-free DNA (cfDNA) methylation profiles reflect immunotherapy treatment response in solid tumors. Here we provide validation data of a tissue-agnostic, genome-wide methylation enrichment assay based on cell free methylated DNA immunoprecipitation and high throughput sequencing (cfMeDIP-seq) designed for clinical use, to determine response to immunotherapy. Methods: This study utilizes samples and clinical data from the INSPIRE study, a single-institution investigator-initiated phase II study of pembrolizumab in multiple solid tumors given every 3 weeks (NCT02644369). A prior published analysis of cfMeDIP used TCGA to develop a classifier and demonstrated an association of response to immunotherapy. In contrast, in this analysis, a novel quantitative and highly specific measurement of ctDNA was estimated using a generative machine learning model trained on differentially methylated regions identified from a large cfMeDIP methylome atlas from individuals with and without cancer. In a blinded validation analysis, Firth’s logistic regressions were used to test differences in objective response (ORR) and clinical benefit rate (CBR) defined as complete or partial response or stable disease > / = 6 cycles between patients with a decrease in ctDNA from baseline to cycle 3 of treatment, and those with an increase in ctDNA. Sensitivity for no objective response, specificity for objective response, and positive and negative predictive values (PPV and NPV) were summarized. Cox regressions and log-rank tests were used to evaluate differences in progression-free survival (PFS) and overall survival (OS) between the two groups. Results: The analysis included 64 unique patients with a median follow up of 18.43 months (a total of 128 samples), including head & neck (n = 9), triple negative breast (n = 10), ovarian (n = 11), melanoma (n = 7), and other mixed solid tumor types (n = 27). A decrease in ctDNA was associated with significantly better objective response than an increase [odds ratio (OR) 33.89 (4.07, 44426.47), p = 0.0001], 58% sensitivity, 100% specificity, 100% PPV and 35% NPV. Significantly better CBR [OR 10.17 (2.74, 55.74), p = 0.0002] was also observed. A decrease in ctDNA was associated with significantly better PFS [hazard ratios (HR) 0.28 (0.15, 0.49) p < 0.0001] and OS [HR 0.42 (0.24, 0.76) p < 0.003]. Conclusions: A clinical tissue-agnostic, genome-wide methylome enrichment approach using cfMeDIP-seq accurately predicts clinical outcomes in patients treated with pembrolizumab in multiple advanced solid tumors. This test provides relative quantification of methylated ctDNA to predict response to immmunotherapy and does not require tumor tissue. This analysis highlights potential generalizability across tumor types in response monitoring. Clinical trial information: NCT02644369 .

Abstract Background: Plasma-based tests to quantify circulating cell-free DNA cancer signal have emerged as viable applications across the cancer continuum, from early detection to optimal disease management. Here we demonstrate the feasibility of a tissue-agnostic, genome-wide methylome enrichment platform based on cell-free methylated DNA immunoprecipitation and high throughput sequencing (cfMEDIP-seq) for cancer detection, cancer signal quantification, and prognostication in head and neck cancer (HNC). Methods: Pre-treatment plasma samples from individuals with newly diagnosed stage I-IV HPV+ or HPV- HNC were analyzed with a bisulfite-free, non-degradative, genome-wide methylome enrichment platform using 5-10 ng of cell-free DNA. For cancer detection, a machine learning classifier used differentially methylated regions to distinguish cancers from non-cancer controls. The area under the receiver operating characteristic curve (AUC) and 95% confidence intervals were calculated. Cancer signals were quantified from average normalized counts across informative methylated regions and a 95% specificity threshold. For prognostication, events were defined as recurrence, progression, or death due to HNC, whichever occurred earliest. Time to event was compared for samples with cancer signal quantities above versus below the threshold. Post-treatment and longitudinal plasma samples from individuals with Stage I-IVB HNC (HPV+ and HPV- included) will be analyzed for recurrence prediction and detection of relapse. More than 100 patients and 300 samples will be analyzed. Results: For cancer detection, 92 pre-treatment plasma samples from HNC cases were distinguished from 674 controls with an AUC of 0.96 (0.94, 0.98). The AUC was 0.93 (0.86, 1.0) for Stage I, 0.93 (0.83, 1.0) for Stage II, 0.96 (0.94, 0.99) for Stage III, and 0.97 (0.96, 0.99) for Stage IV. For prognostication, 91 pre-treatment samples were included (7 stage I, 16 stage II, 23 stage III, 45 stage IV). Median follow-up time was 50.6 months with 27 events. Likelihood of recurrence or progression was significantly higher in samples with cancer signal above the threshold [hazard ratio 5.4 (95% CI 2.25, 12.95), log-rank P<0.001]. In the upcoming analysis, data will be reported on the ability to predict recurrence and relapse in post-treatment samples. Conclusions: The cfMeDIP-seq approach demonstrated robust detection of HNC, across all stages and subtypes, and the ability to predict recurrence and progression from pre-treatment samples. We will report training data with cross validation to predict recurrence and relapse using post-treatment and longitudinal sampling. Collectively, data from these studies indicate that genome wide methylome enrichment has multiple use cases across the care continuum for patients with HNC. Citation Format: Geoffrey Liu, Jun Min, Yarong Wang, Justin Burgener, Ben Brown, Karen Budhraja, Junjun Zhang, Owen Hall, Shu Yi Shen, Martha Pienkowski, Shao Hui Huang, Laurie Ailles, Katrina Rey-McIntyre, Jeremy B. Provance, Eduardo Sosa, Cynthia Frye, Scott Bratman, Brian Allen, Joshua T. Jones, Abel Licon, Jing Zhang, Anne-Renee Hartman, Daniel D. De Carvalho. The development of a tissue-agnostic genome-wide methylome enrichment MRD assay for applications across the cancer care continuum for head and neck malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2427.

Hyperuricemia is a crucial feature of metabolic syndrome, characterized by elevated uric acid that causes urate crystal deposits in joints, kidneys, and subcutaneous tissues, resulting in gout and hyperuricemic nephropathy. The primary causes of uric acid metabolism disorder include overproduction and reduced excretion. The majority of uric acid in human body is derived from the breakdown of purine nucleotides. Overproduction of uric acid can result from increased concentration or activity of xanthine oxidase, the key enzyme responsible for uric acid synthesis. Alterations in the activity of proteins responsible for uric acid reabsorption and excretion can also affect serum uric acid. Many bioactive compounds derived from natural plants have been shown to inhibit xanthine oxidase activity to reduce uric acid production, modulate the activity of transport proteins to promote uric acid excretion, or alleviate oxidative stress and inflammation through various signaling pathways. These properties have garnered significant attention from researchers. In this paper, we first introduce the pathophysiological mechanisms of hyperuricemia, then summarize bioactive compounds with urate-lowering effects, and discuss their potential applications in treating hyperuricemia and its complications.

To investigate the relationship between serum uric acid level and glomerular ischemic lesions (GIL) in patients with primary membranous nephropathy (PMN) and identify relevant risk factors. A total of 201 patients with PMN but normal renal function confirmed by renal biopsy executed in the Liaocheng People’s Hospital, China, during January 2020-January 2023 were analyzed retrospectively. The enrolled patients were divided into a hyperuricemia group and a normal serum uric acid group (control group) according to their serum uric acid levels. Then, the participants were further divided into a non-GIL group or a GIL group based on the patient’s renal biopsy results. The two groups’ clinical and pathological data and meaningful indicators for differences were analyzed by binary logistic regression analysis. Additionally, the serum uric acid level prediction value on GIL was investigated using receiver operating characteristic (ROC) curves. Compared with the control group, the hyperuricemia group exhibited high serum uric acid, the prevalence of GIL, serum albumin, the prevalence of hypertension, and low-density lipoprotein cholesterol (LDL) levels (P < 0.05). Compared with the non-GIL group, the GIL group exhibited were older, had enhanced serum uric acid, serum albumin, and an increased prevalence of tubular atrophy/interstitial fibrosis (TA/IF), arteriolosclerosis, and low eGFR levels (P < 0.05). The binary logistic regression analysis revealed that the serum uric acid and the TA/IF are independent risk factors of GIL (P < 0.05). The AUC of ROC of GIL of PMN patients, predicted based on the serum uric acid concentration, was 0.736 (P < 0.05), wherein the threshold = 426.5 μmol/L and the Youden’s index = 0.41. Serum uric acid concentration and the TA/IF are independent risk factors of GIL in patients with PMN, and the former exhibits prediction value on GIL in patients with PMN.

Abstract Background and Aims Anti-CD20 monoclonal antibody has become one of the first-line therapies for the treatment of moderate and high-risk primary membranous nephropathy (pMN). A novel glycoengineered type Ⅱ anti-CD20 antibody, MIL62 with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of MIL62 in pMN, we conducted a multicenter, randomized, controlled, open-label, phase Ib/Ⅱ study (NCT05398653). Method This study aims to investigated MIL62 or Cyclosporine for the treatment of Chinese pMN. Eligible patients with pMN diagnosed by kidney biopsy, proteinuria of at least 3.5 g per 24 hours received intravenous MIL62 (two infusions, 600 or 1000 mg each, administered 14 days apart; repeated at 6 months) or Cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed up for up to 104 weeks. The primary outcome was a composite of complete or partial remission of proteinuria and stable eGFR at 76 weeks. Laboratory variables and safety were also assessed. Results From February 23th, 2022 to December 21th, 2022, 85 patients were randomly enrolled from 19 centers in China, and received at least one dose of MIL62 or Cyclosporine. At the data cut-off date (January 30th, 2023), 60 patients were followed up for at least 12 weeks, 24/40 (60%) patients in the MIL62 group and 7/20 (35%) patients in the Cyclosporine group achieved complete or partial remission; 26 patients were followed up for at least 24 weeks, 11/18 (61.1%) patients in the MIL62 group and 2/8 (25%) patients in the Cyclosporine group achieved partial remission. In the 56 patients who were positive for anti-PLA2R antibodies (≥14RU/mL) at baseline and followed up for at least 12 weeks, 29/38 (76.3%) patients in the MIL62 group achieved immunological remission (PLA2R Abs<14RU/mL), which was superior to the Cyclosporine group where 8/18 (44.4%) patients achieved immunological remission (P< 0.05). The remission to MIL62 in our study was rapid because 61.1% of patients achieved complete or partial remission at 24 weeks compared with the 35% 6-month response rate reported in the Membranous Nephropathy Trial of Rituximab study [1]. Among the 85 safety-evaluable patients, treatment emergent adverse events (TEAEs) occurred in 23/30 (76.7%) patients in the MIL62 600 mg group, 26/30 (86.7%) patients in the MIL62 1000 mg group and 24/25 (96.0%) patients in the Cyclosporine group; treatment-related AEs (TRAEs) occurred in 21/30 (70.0%), 23/30 (76.7%) and 18/25 (72.0%) in the MIL62 600 mg, MIL62 1000 mg and Cyclosporine group respectively; Grade 3 or above TEAEs were observed in 5 (16.7%), 1 (3.3%) and 2 (8.0%) patients in the MIL62 600 mg, MIL62 1000 mg and Cyclosporine group respectively; Serious adverse events (SAEs) occurred in 5 (16.7%), 0 (0.0%) and 2 (8.0%) patients in the MIL62 600 mg, MIL62 1000 mg and Cyclosporine group respectively. Only one patient in the MIL62 600 mg group experienced serious treatment-related thrombocytopenia and has recovered so far; Other SAEs are not related to treatment. B cell depletion occurred within 24 hours after MIL62 infusion and could last for 24 weeks. Conclusion The 12-week immunological remission rate in the MIL62 group was significantly higher than the Cyclosporine group. MIL62 had a manageable safety profile. This phase Ib/II preliminary data warrant further phase III clinical trials of MIL62 in pMN.

IgAN is the most common primary glomerulonephritis worldwide. However, the pathogenesis of IgAN remains unknown. Currently, there is evidence that C3 deposition plays a role in disease development. This study aimed to investigate clinical, pathological features, and prognosis of adult IgAN patients with C3 deposition, as well as explore the role of complement activation in disease progression. A total of 821 patients with biopsy-proven IgAN were included in this study. Patients were divided into three different groups according to their C3 deposition intensity. Clinical and pathological characteristics were compared between groups. Logistic analysis was used to estimate the relationship between C3 deposition and the Oxford scoring system. Univariate and multivariate Cox proportional hazard regression models were used to analyze the effect of the presence of C3 deposits on the prognosis of patients with IgA nephropathy. Kaplan–Meier survival analysis was used to evaluate the cumulative incidence of renal progression between groups. Patients with C3 deposition exhibited more severe clinical and pathological features and had a higher score according to the Oxford scoring system. With the increasing intensity of C3 deposition, patients present more hematuria, crescents, heavier interstitial inflammatory cell infiltration and a higher score on segmental sclerosis lesions. Logistic regression identified a positive relationship between C3 deposition and histopathology. Univariate and multivariate Cox regression indicated that C3 deposition was an independent risk factor for IgAN severity. The Kaplan–Meier survival curves indicated that patients with positive C3 deposition had a worse prognosis compared to those without C3 deposition. Patients with positive glomerular C3 deposition presented with more severe clinical and histopathological characteristics and a higher score on the Oxford scoring system. With the increasing intensity of C3 deposition, IgAN patients were more likely to present with high level of microscopic hematuria, fibrous crescents, interstitial inflammatory cell infiltration, and a higher score on segmental sclerosis lesions. C3 deposition at the time of renal biopsy is likely an independent risk factor for IgA nephropathy severity and progression.

Objective. To construct a novel nomogram model that predicts the risk of hyperuricemia incidence in IgA nephropathy (IgAN) . Methods. Demographic and clinicopathological characteristics of 1184 IgAN patients in the First Affiliated Hospital of Zhengzhou University Hospital were collected. Univariate analysis and multivariate logistic regression were used to screen out hyperuricemia risk factors. The risk factors were used to establish a predictive nomogram model. The performance of the nomogram model was evaluated using an area under the receiver operating characteristic curve (AUC), calibration plots, and a decision curve analysis. Results. Independent predictors for hyperuricemia incidence risk included sex, hypoalbuminemia, hypertriglyceridemia, blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), 24-hour urinaryprotein (24h TP), Gross and tubular atrophy/interstitial fibrosis (T). The nomogram model exhibited moderate prediction ability with an AUC of 0.834 ((95% CI 0.804–0.864)). The AUC from validation reached 0.787 (95% CI 0.736-0.839). The decision curve analysis displayed that the hyperuricemia risk nomogram was clinically applicable.Conclusion. Our novel and simple nomogram containing 8 factors may be useful in predicting hyperuricemia incidence risk in IgAN.

BackgroundThyroid dysfunction is common in patients with kidney disease. However, the relationship between thyroid dysfunction and idiopathic membranous nephropathy (IMN) remains unclear. This retrospective study aimed to investigate the clinicopathological characteristics and prognosis of patients with IMN and thyroid dysfunction compared to patients with IMN and without thyroid dysfunction.MethodsA total of 1052 patients with IMN diagnosed by renal biopsy were enrolled in this study, including 736 (70%) with normal thyroid function and 316 (30%) with abnormal thyroid function. We analyzed the clinicopathological features and prognostic data between the two groups, using propensity score matching (PSM) to reduce the bias. Logistic regression analysis was performed to investigate the risk factors for IMN combined with thyroid dysfunction. Kaplan-Meier curves and Cox regression analysis were used to evaluate the association between thyroid dysfunction and IMN.ResultsPatients with IMN and thyroid dysfunction exhibited more severe clinical features. Female sex, lower albumin level, higher D-dimer level, severe proteinuria, and decreased estimated glomerular filtration rate were predictors of thyroid dysfunction in patients with IMN. After PSM, 282 pairs were successfully matched. Results from the Kaplan-Meier curves indicated that the thyroid dysfunction group had a lower complete remission rate (P = 0.044), higher relapse rate (P < 0.001), and lower renal survival rate (P = 0.004). The multivariate Cox regression analysis revealed that thyroid dysfunction was an independent risk factor for complete remission [hazard ratio (HR) = 0.810, P = 0.045], relapse (HR = 1.721, P = 0.001), and composite endpoint event (HR = 2.113, P = 0.014) in IMN.ConclusionsThyroid dysfunction is relatively common in patients with IMN, and the clinical indicators are more severe in these patients. Thyroid dysfunction is an independent risk factor for poor prognosis in patients with IMN. More attention should be paid to thyroid function in patients with IMN.

Mild mesangial proliferative IgA nephropathy with minimal change disease (MCD-IgAN) and mild mesangial proliferative IgA nephropathy without minimal change disease (Non-MCD-IgAN) have similar characteristics on light microscopy. Nevertheless, their discrepancies in clinicopathological features and prognosis remain unknown. A total of 589 patients with biopsy-proven mild mesangial proliferative IgA nephropathy (M-IgAN) combined with light microscopy and immunofluorescence were enrolled. Firstly, the diagnoses of the patients by electron microscopy were recorded and used as the gold standard. We calculated the sensitivity and specificity using nephrotic syndrome (NS) as the diagnostic criteria to identify MCD-IgAN. Then, excluding patients with a 24-h urinary total protein less than 0.5 g/day, incomplete clinical data, or less than the six-month follow-up, we included 184 cases of non-MCD-IgAN and 98 cases of MCD-IgAN. The patients' clinicopathological and outcome data were collected and compared. Among the 589 patients, according to electron microscopy, 381 were diagnosed with non-MCD-IgAN, 167 with MCD-IgAN, and 41 with M-IgAN complicated by other glomerular diseases. Using NS as the diagnostic criteria to distinguish non-MCD-IgAN and MCD-IgAN, the sensitivity and specificity were 83.8% and 99.5%, respectively. The patients in the MCD-IgAN group tended to be younger, hypotensive, with lower urinary erythrocytes, and more likely to achieve complete remission, and fewer patients progressed to the endpoint than those in the non-MCD-IgAN group (all P < 0 .05). NS appears to be an objective indicator for differentiating MCD-IgAN from non-MCD-IgAN. Non-MCD-IgAN varies greatly from MCD-IgAN in clinicopathology and treatment response, with a poorer prognosis.

The relationship between hyperuricemia and IgA nephropathy (IgAN) was evaluated systematically in this research. The Preferred Reporting Items for Systematic Review and Meta-analysis statement was employed to design and report the study. Twenty-five studies were included in this meta-analysis with a total of 6048 IgAN patients. The clinical indicators indicated that blood urea nitrogen (BUN) (p < 0.00001, mean difference (MD) = 2.60, 95% confidence interval (CI) 1.74–3.46), serum creatinine (Scr) (p < 0.00001, MD = 44.56, 95% CI 31.15–57.98), diastolic blood pressure(DBP) (p < 0.00001, MD = 3.86, 95% CI 2.84–4.88), systolic blood pressure(SBP) (p < 0.00001, MD = 6.71, 95% CI 4.70–8.71), and 24-h urine protein(24 h TP) (p < 0.00001, MD = 0.76, 95% CI 0.58–0.94) were significantly increased in IgAN with hyperuricemia group than that in normouricemic IgAN group. The pathological analysis indicated that mesangial proliferation (p < 0.00001, MD = 0.12, 95% CI 0.07–0.17), vascular lesion (p < 0.00001, MD = 0.17, 95% CI 0.13–0.20), segmental lesion (p < 0.00001, MD = 0.15, 95% CI 0.03–0.26), tubulointerstitial damage (p < 0.00001, MD = 1.27, 95% CI 1.06–1.48), and glomerulosclerosis (p < 0.00001, MD = 0.56, 95% CI 0.40–0.72) were considerably climbed in IgAN patients with hyperuricemia compared without hyperuricemia group. Additionally, the estimated glomerular filtration rate (p < 0.00001, MD = − 29.03, 95% CI − 36.83 to − 21.23) was decreased in IgAN patients with hyperuricemia compared with normouricemic group. Hyperuricemia exacerbates IgAN prognosis through aggravating the clinical outcomes and pathological results of IgAN.

Introduction:Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. However, biomarkers for predicting the progression or regression of IgAN remain a clinical challenge. In the present study, we aim to identify promising prognostic markers of IgAN. Methods:Using the cytokine antibody array, we detected serum and urinary levels of 9 common cytokines selected from 23 IgAN-related biomarkers in 32 patients with IgAN and 16 healthy controls. The best biomarkers for distinguishing IgAN patients from healthy controls were identified and confirmed in a multicenter cohort with 222 patients with IgAN and 159 age- and sex-matched healthy controls. Their associations with IgAN progression were further explored in 762 patients with IgAN with a median follow-up of 65 months. Results:Among the 9 candidate markers, urinary interleukin-6 (IL-6) and transforming growth factor-β1 (TGF-β1) levels were the best for distinguishing patients with IgAN from healthy controls. In the diagnostic cohort, both urinary IL-6 and TGF-β1 levels were elevated in patients with IgAN and showed good discriminatory power, with an area under curve (AUC) of 0.9725 (95% confidence interval: 0.9593-0.9858). Elevated urinary IL-6 level was independently and significantly correlated with the high risk of composite renal outcome (hazard ratio per log-transformed IL-6:1.420 [1.139-1.769]), but no statistical significance was observed between urinary TGF-β1 level and IgAN progression after adjusting for multiple confounders. Conclusions:Elevated urinary IL-6 and TGF-β1 levels predict the progression of IgAN. Urinary IL-6 is an independent risk factor and a promising noninvasive predictor for IgAN progression.

Background: The clinical manifestations and prognosis of IgA nephropathy (IgAN) are diverse. Some patients may present with kidney dysfunction lasting shorter than 3 months and meet the acute kidney disease (AKD) criteria. This study aimed to investigate the clinicopathological features, causes and prognosis of newly diagnosed cases of IgAN with AKD. Methods: 1320 IgAN patients diagnosed via kidney biopsy between January 2012 and June 2018 were included in this retrospective study, with a median follow-up period of 35 months. We analyzed the clinicopathological, etiological variables, as well as short-term and long-term prognosis. The main outcome was a composite event of 40% decline in eGFR, kidney failure or death. Results: Incidence of AKD was 8.8% in the newly diagnosed IgAN patients, and was found to be an independent risk factor affecting the short-term (HR, 7.1; 95% CI, 2.3-22.2; P = 0.001) and long-term (HR, 1.8; 95% CI, 1.2-2.6; P = 0.006) prognosis, respectively. The most common cause of AKD was malignant hypertension-related AKD (MHT-AKD; 24.1%), followed by hematuria-related AKD (H-AKD; 12.9%), nephrotoxic-drug-exposurerelated AKD (NTDE-AKD; 12.1%) and crescents-related AKD (C-AKD; 11.2%). The patients in AKD group had more severe clinicopathological characteristics and poor short-term and long-term prognosis than non-AKD group. In subgroup analysis, the MHT-AKD had the worst 5 years survival rate, followed by NTDE-AKD and C-AKD, whereas H-AKD had the best survival rate. Conclusions: AKD is not rare among IgAN patients, and is an independent risk factor for short-term and long-term prognosis. IgAN patients with AKD resulting from different causes have different prognosis.

Objective:To study the clinicopathological characteristics, treatment and prognosis in lupus nephritis (LN) patients with renal thrombotic microangiopathy (TMA), so as to provide more theoretical basis for clinicians to recognize and treat this disease.Methods:The clinical data of LN patients who underwent renal biopsy in the First Affiliated Hospital of Zhengzhou University from January 1, 2012 to May 31, 2019 were retrospectively collected and analyzed. According to renal clinicopathological examination, the patients were divided into renal TMA group and non-renal TMA group. The clinical data, laboratory examination, renal pathological examination, therapeutic measures and prognostic between the two groups were compared. Follow-up end points were defined as composite ends, including all-cause death, entry into end-stage renal disease, and estimated glomerular filtration rate decrease>50% of baseline. Kaplan-Meier survival curve and log-rank test were used to compare the difference of survival rate between the two groups, and multivariate Cox regression equation was used to analyze the risk factors of endpoint events in LN patients.Results:A total of 1 133 patients with LN were enrolled in this study. Patients with renal TMA were more likely to have hypertension ( χ2=16.310, P<0.001), higher baseline serum creatinine ( Z=-6.918, P<0.001) and 24-hour urine protein ( Z=-2.232, P=0.026), and higher renal pathology activity index (AI) score ( Z=1.957, P=0.001)and chronic index (CI) score ( Z=1.836, P=0.002). The proportions of hormone shock ( P<0.001) and plasma exchange ( P<0.001) in the renal TMA group were higher than those in non-renal TMA group. After treatment of (12±2) months, patients in the renal TMA group had a lower complete response rate ( χ2=10.455, P=0.001) and a higher non-response rate ( χ2=6.047, P=0.014) than those in non-renal TMA group, and were associated with worse prognosis (Log-rank test χ2=26.490, P<0.001). Renal TMA was an independent risk factor for poor prognosis ( HR=2.347, 95% CI 1.210-4.553, P=0.012). Conclusions:Compared with LN patients without renal TMA, LN patients with renal TMA are more likely to have hypertension, with higher serum creatinine, 24-hour urinary protein, AI and CI, suggesting poorer treatment response and renal prognosis. Moreover, renal TMA is an independent risk factor for poor prognosis in patients with LN.