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Abstract Gestational diabetes mellitus (GDM), a common pregnancy disease, has long-term negative effects on offspring health. Epigenetic changes may have important contributions to that, but the underlying mechanisms are not well understood. Here, we report the influence of GDM on DNA methylation of offspring (GDF1) oocytes and the possible mechanisms. Our results show that GDM induces genomic hyper-methylation of offspring oocytes, and at least a part of the altered methylation is inherited by F2 oocytes, which may be a reason for the inheritance of metabolic disorders. We further find that GDM exposure increases the expression of Ezh2 in oocytes. Ezh2 regulates DNA methylation via DNMT1, and Ezh2 knockdown reduces the genomic methylation level of GDF1 oocytes. These results suggest that GDM may induce oocyte genomic hyper-methylation of offspring via enhancing the Ezh2 expression recruiting more DNMT1 into nucleus.

Abstract Objective Pulmonary infection is one of the leading causes of death in patients with ANCA-associated vasculitis (AAV). It is sometimes difficult to differentiate pulmonary infection from pulmonary involvement of vasculitis in AAV patients. Fiberoptic bronchoscopy and bronchoalveolar lavage fluid (BALF) assays are useful diagnostic methods. In addition to conventional microbiological tests (CMTs), metagenomic next-generation sequencing (mNGS) facilitates rapid and sensitive detection of various pathogens. The current study aimed to evaluate the advantages of additional BALF mNGS in the management of pulmonary infection in AAV patients. Methods 27 patients with active AAV and suspected pulmonary infection whose BALF samples were tested by mNGS and CMTs and 17 active AAV patients whose BALF were tested by CMTs alone were retrospectively recruited. The results of microbiological tests, and adjustments of treatment following BALF mNGS, were described. The durations of antimicrobial treatment and in-hospital mortality in patients were compared. Results Among the 27 patients whose BALF samples were tested by mNGS, 25.9% of patients did not have evidence of pathogenic microorganism in their BALF samples, 55.6% had polymicrobial infections, including bacteria, fungi and viruses. Of these 27 patients, 40.7% did not have evidence of pathogenic microorganism in their BALF or serum samples according to CMTs. Patients in the BALF mNGS/CMT group received a significantly shorter duration of antibacterial and total antimicrobial treatment than patients in the CMT alone group (17.3 ± 14.7 vs. 27.9 ± 19.0 days, P = 0.044; 18.9 ± 15.0 vs. 29.5 ± 17.7 days, P = 0.040, respectively). Fewer patients in the BALF mNGS/CMT group died than in the CMT alone group (4/27 vs. 7/17, P = 0.049). Conclusion Compared with CMT alone, additional mNGS tests may shorten the duration of antimicrobial treatment and possibly decrease death from severe infection by providing precise and quick diagnosis of infection.

Maternal obesity has deleterious effects on the process of establishing oocyte DNA methylation; yet the underlying mechanisms remain unclear. Here, we found that maternal obesity disrupted the genomic methylation of oocytes using a high-fat diet (HFD) induced mouse model, at least a part of which was transmitted to the F2 oocytes and livers via females. We further examined the metabolome of serum and found that the serum concentration of melatonin was reduced. Exogenous melatonin treatment significantly reduced the hyper-methylation of HFD oocytes, and the increased expression of DNMT3a and DNMT1 in HFD oocytes was also decreased. These suggest that melatonin may play a key role in the disrupted genomic methylation in the oocytes of obese mice. To address how melatonin regulates the expression of DNMTs, the function of melatonin was inhibited or activated upon oocytes. Results revealed that melatonin may regulate the expression of DNMTs via the cAMP/PKA/CREB pathway. These results suggest that maternal obesity induces genomic methylation alterations in oocytes, which can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of HFD oocytes by increasing the expression of DNMTs via the cAMP/PKA/CREB pathway.

Background Light-chain proximal tubulopathy (LCPT) is a rare disease characterized by the accumulation of monoclonal light chains within proximal tubular cells. This study aimed to investigate the clinical characteristics of LCPT from a single Chinese nephrology referral center.Methods Patients with kidney biopsy-proven isolated LCPT between 2016 and 2022 at Peking University First Hospital were retrospectively included. Clinical data, kidney pathological type, treatment, and prognosis were analyzed.Results Nineteen patients were enrolled, the mean age at diagnosis was 57 ± 11 and the sex ratio was 6/13 (female/male). Mean proteinuria was 2.44 ± 1.89 g/24 hr and the mean estimated glomerular filtration rate (eGFR) at the point of biopsy was 59.640 ± 27.449 ml/min/1.73 m2. κ-restriction (84%) was dominant among LCPTs. An abnormal free light chain ratio was observed in 86% of the patients. Proximal tubulopathy with cytoplasmic inclusions accounted for the majority (53%), followed by tubulopathy associated with interstitial inflammation reaction (26%), proximal tubulopathy without cytoplasmic inclusions (16%), and proximal tubulopathy with lysosomal indigestion/constipation (5%). One patient presented with acute kidney injury and 16 patients presented with chronic kidney disease. Regarding follow-up, patients received bortezomib-based or R-CHOP chemotherapy or supportive treatment only. The mean follow-up time was 22 ± 16 months, and the mean eGFR was 63.098 ± 27.439 ml/min/1.73 m2 at the end of follow-up. These patients showed improved or stable kidney function.Conclusions This is the first case series report of LCPT in four different pathological types in northern China. Clone-targeted chemotherapy may help preserve the kidney function in these patients.

Objective Lipoprotein glomerulopathy (LPG) is a rare disorder characterized by the development of glomerular lipoprotein thrombosis. LPG exhibits familial aggregation, with mutations in the apolipoprotein E (APOE) gene identified as the leading cause of this disease. This study aimed to investigate APOE gene mutations and the clinicopathological features in eleven LPG patients.Methods Clinicopathological and follow-up data were obtained by extracting DNA, followed by APOE coding region sequencing analysis. This study analyzed clinical and pathological manifestations, gene mutations, treatment and prognosis.Results The mean age of the eleven patients was 33.82 years. Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria. Dyslipidemia was identified in ten patients. In all renal specimens, there was evident dilation of glomerular capillary lumens containing lipoprotein thrombi, and positive oil red O staining was observed in frozen sections of all samples. APOE gene testing revealed that one patient had no mutations, while the remaining ten patients exhibited mutations in the APOE gene, with three patients presenting with multiple mutations simultaneously. Following the confirmation of LPG diagnosis, treatment with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) was initiated, and the disease progressed slowly.Conclusion LPG is histologically characterized by lamellated lipoprotein thrombi in glomeruli, and kidney biopsy is essential for diagnosis. Mutations in the APOE gene are the leading cause of LPG. This study revealed clinicopathological characteristics and APOE gene mutations in patients with LPG, which helps us better understand the disease.

BackgroundParkinson’s disease (PD) is an age-related neurodegenerative disease characterized by the death of dopamine neurons in the substantia nigra. A large number of studies have focused on dopamine neurons themselves, but so far, the pathogenesis of PD has not been fully elucidated.ResultsHere, we explored the significance of oligodendrocyte precursor cells (OPCs)/oligodendrocytes in the pathogenesis of PD using a bioinformatic approach. WGCNA analysis suggested that abnormal development of oligodendrocytes may play a key role in early PD. To verify the transcriptional dynamics of OPCs/oligodendrocytes, we performed differential analysis, cell trajectory construction, cell communication analysis and hdWGCNA analysis using single-cell data from PD patients. Interestingly, the results indicated that there was overlap between hub genes and differentially expressed genes (DEGs) in OPCs not in oligodendrocytes, suggesting that OPCs may be more sensitive to PD drivers. Then, we used ROC binary analysis model to identify five potential biomarkers, including AGPAT4, DNM3, PPP1R12B, PPP2R2B, and LINC00486.ConclusionIn conclusion, our work highlights the potential role of OPCs in driving PD.

Abstract Objective It has been reported that in western countries malignancy risk was higher in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with that in the general population. In the current study, we investigated the incidence, spectrum and risk factors of malignancy in Chinese AAV patients. Methods AAV patients diagnosed from 1995 to 2021 in Peking University First Hospital with a follow-up more than 12 months were recruited. Standardized incidence ratios (SIR) were calculated to describe the risk of malignancy, adjusted for sex, age and follow-up time. Results A total of 552 AAV patients were recruited, among which 23 patients had malignancies either preceding or concurrent with AAV diagnosis, and 43 of the remaining 529 patients developed malignancies within 4.3 ± 4.2 years post AAV diagnosis (SIR: 2.24; 95% CI: 1.68–2.99; p

Rationale & Objective: The Kidney Failure Risk Equations have been proven to perform well in multinational databases, whereas validation in Asian populations is lacking. This study sought to externally validate the equations in a community-based chronic kidney disease cohort in China. Study Design: A retrospective cohort study. Setting & Participants: Patients with and estimated glomerular filtration rate (eGFR)

Our 2022 published working definition of disease modification in systemic lupus erythematosus (SLE) was ‘minimising disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression’. The objective of this review was to classify current SLE treatments according to the proposed non-renal disease modification criteria excluding toxicities. Based on a review of select clinical trial (n=32) and observational study (n=54) publications for 14 SLE medications across different therapeutic classes, and the authors’ clinical experience, we evaluated disease modification potential as per the proposed framework at three time points. Specific criteria used to determine disease modification potential included a drug’s capacity to reduce: (1) non-renal disease activity, (2) severe flares, (3) use of steroids/immunosuppressants and (4) organ damage accrual. Criteria 1–3 were assessed at 1 year and 2–5 years and, when positive, were considered evidence for disease modification potential; criterion 4 was used to confirm disease modification at >5 years. Each treatment received one of four mutually exclusive designations at each time point: (a) criterion met, (b) indications of criterion met despite insufficient evidence in the literature, (c) inconclusive and (d) no available supportive data. This review excludes an assessment of potential toxicities. Eight of the 14 SLE treatments met ≥1 disease modification criteria up to year 5. Hydroxychloroquine improved overall survival at >5 years, suggesting long-term disease modification, but no data on specific organ systems were reported. Belimumab was the only treatment to meet all criteria. Belimumab and hydroxychloroquine met disease modification definitions across three time points. Evidence for other SLE therapies was incomplete, particularly at >5 years. Future studies are warranted for other treatments to meet the disease modification criteria. We discuss challenges to classification and possible updates to our published criteria.

Background: Increasing evidence indicates that clinicopathologic phenotypes and ANCA serotypes may differ ethnically and geographically. This review highlights the progress in the prevalence, pathogenesis, management, and outcomes of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in China. Summary: AAV is not rare in China. Cumulative evidence has demonstrated a significant preponderance of microscopic polyangiitis (MPA) and myeloperoxidase (MPO)-ANCA AAV in China. Even in patients with granulomatosis with polyangiitis (GPA), there is a predominance of MPO-ANCA over proteinase 3 (PR3)-ANCA, presenting a unique subset. The pathogenesis of AAV is multifactorial, with the role of complement activation being highlighted during recent years. Treatment strategies for AAV in China have also been refined recently. A rapid tapering of glucocorticoids to minimize exposure has been recommended by the Chinese guidelines. Along with a better understanding of the disease, B cell-targeted therapy and complement-targeted therapy are developing. A considerable number of patients in China received rituximab treatment and achieved remission. However, infection risk and associated mortality still remain concerns. Therefore, less rituximab exposure should be considered and evaluated in Chinese AAV patients. Prognostic factors have been reviewed. Of note, along with improved outcomes, there is an increase of cardiovascular and malignant-related death, warranting specific care. Recently, a modified renal risk score model has been validated for early risk prediction in Chinese AAV patients. Moreover, emerging biomarkers for AAV, including complement components, have been identified in Chinese patients. Key Messages: There is a preponderance of MPA and MPO-ANCA in China. Treatment strategies for Chinese AAV patients generally align with those in western countries, and to some extent, less aggressive. Prognostic factors and emerging biomarkers for AAV in China have been identified. Further challenges include optimizing interventions, minimizing treatment-related comorbidities, improving disease monitoring, and enhancing life qualities of AAV patients.

Abstract Background Climate change profoundly shapes the population health at the global scale. However, there was still insufficient and inconsistent evidence for the association between heat exposure and chronic kidney disease (CKD). Methods In the present study, we studied the association of heat exposure with hospitalizations for cause-specific CKD using a national inpatient database in China during the study period of hot season from 2015 to 2018. Standard time-series regression models and random-effects meta-analysis were developed to estimate the city-specific and national averaged associations at a 7 lag-day span, respectively. Results A total of 768,129 hospitalizations for CKD was recorded during the study period. The results showed that higher temperature was associated with elevated risk of hospitalizations for CKD, especially in sub-tropical cities. With a 1 °C increase in daily mean temperature, the cumulative relative risks (RR) over lag 0–7 d were 1.008 [95% confidence interval (CI) 1.003–1.012] for nationwide. The attributable fraction of CKD hospitalizations due to high temperatures was 5.50%. Stronger associations were observed among younger patients and those with obstructive nephropathy. Our study also found that exposure to heatwaves was associated with added risk of hospitalizations for CKD compared to non-heatwave days (RR = 1.116, 95% CI 1.069–1.166) above the effect of daily mean temperature. Conclusions Short-term heat exposure may increase the risk of hospitalization for CKD. Our findings provide insights into the health effects of climate change and suggest the necessity of guided protection strategies against the adverse effects of high temperatures.

Background: Hyperoxaluria is a major cause of oxalate nephropathy, which can lead to impaired renal function presenting as acute kidney injury, acute on chronic kidney disease, or chronic kidney disease. The Chronic Renal Insufficiency Cohort study showed that higher urinary oxalate is associated with renal outcome in patients with chronic kidney disease, supporting the nephrotoxicity of oxalate. Therefore, a better understanding of the role of oxalate in kidney injury is needed. This review describes the metabolism of oxalate and the clinical and pathology presentation of oxalate nephropathy. It also summarizes the available evidence for the underlying pathogenic mechanism and the development of treatments for oxalate-induced kidney injury. Summary: Disruption to any key step in the oxalate pathway including abnormal endogenous generation, ingestion of abnormally high dose of oxalate, increased absorption or attenuation of oxalate degradation in the gut, and reduced excretion through the kidney may lead to disrupted oxalate homeostasis. Oxalate nephropathy is mainly caused by hyperoxaluria. Oxalate crystal deposition in the kidney is usually accompanied with tubular toxicity, obstruction, interstitial fibrosis, and tubular atrophy. The mechanism of oxalate-induced renal injury has not been fully clarified. Evidence from both in vivo and in vitro studies shows that NLRP3 inflammasome activation and macrophage infiltration are involved in the processes of crystal adhesion, aggregation, and elimination and promote intrarenal inflammation and renal fibrosis. Novel treatment strategies have been developed and targeted therapies tested for oxalate nephropathy. Key Messages: Prompt diagnosis and management may help to reduce the deposition of calcium oxalate crystals in the kidney. Further studies are needed to clarify the underlying mechanisms to help develop more targeted therapies for oxalate nephropathy.

Abstract Background The phospholipase A2 receptor (PLA2R) associated with membranous nephropathy (MN) is an organ-specific autoimmune disease associated with PLA2R and human leukocyte antigen (HLA) genes. Familial PLA2R-related MN is rarely reported. The combination of anti-GBM disease and MN has been well documented, though the mechanism behind it remains unclear. Case presentation We describe two siblings diagnosed with pathology-confirmed PLA2R-related MN 1 year apart. And one of the two siblings developed an anti-GBM disease. The high-resolution HLA typing showed identical alleles in both siblings, specifically heterozygotes of DRB1*15:01/*03:01. Conclusion We describe a familial case of PLA2R-related MN supporting the role of genetic factors that HLA-DRB1*15:01 and DRB1*03:01 predispose patients in the development of PLA2R-related MN in the Han Chinese population. The combination of MN and anti-GBM disease may also partially be associated with the same susceptible HLA allele DRB1*15:01.

Abstract Purpose To investigate the distribution and changes in ocular biometry in 4-to to 9-year-old Chinese children and to compare the differences between age and genders in these parameters. Methods This was a school-based cross-sectional study. A total of 1,528 Chinese children, aged 4–9 years, from one primary school and 12 kindergartens, were included in the study. Axial length, corneal curvature, anterior chamber depth, and corneal diameter were measured for each child. Results AL and anterior chamber depth gradually increased with age in both genders. No significant changes in corneal curvature or corneal diameter were detected at different ages in either genders group. The mean ALs of males and females were 22.94 ± 0.80 mm and 22.38 ± 0.79 mm, respectively. The mean corneal curvatures of males and females were 43.05 ± 1.37 D and 43.75 ± 1.48 D, respectively. The mean anterior chamber depth of males and females were 3.47 ± 0.24 mm and 3.38 ± 0.25 mm, respectively. The mean corneal diameter of males and females were 12.08 ± 0.43 mm and 11.94 ± 0.44 mm, respectively. Females had consistently shorter ALs, shorter anterior chamber depth, smaller corneal diameter, and steeper corneal curvatures than males at any age. Conclusions Boys had larger dimensions than girls for all ocular parameters except corneal curvature (flatter). Boys and girls showed similar trends for all parameters. Axial length and anterior chamber depth increased from 4 to 9 years of age, whereas corneal diameter and curvature did not change with age in either genders.

Objectives This study was initiated to establish a renal thrombotic microangiopathy (TMA) scoring system based on clinical needs and investigate its predictive value for patients’ long-term outcomes.Methods Kidney biopsy-proven Complement-mediated TMA (C-TMA) patients from January 2000 to December 2017 in Peking University First Hospital were retrospectively studied. Both acute and chronic TMA-related lesions, including 15 pathologic indices, were semiquantitatively scored. The interobserver and intraobserver reproducibility and correlation between the pathologic indices and clinical parameters were analyzed. Furthermore, the patients were divided into 2 groups by dialysis use at baseline, and the association of these pathologic indices with their prognostic outcomes was assessed between the two groups.Results Ninety-two patients with renal biopsy-proven C-TMA were enrolled. All fifteen included pathology indices showed good or moderate interobserver and intraobserver reproducibility and correlated well with several clinical parameters. Several clinicopathological indices were worse in the dialysis group than in the nondialysis group, such as serum creatinine, hemoglobin, platelet count, and estimated glomerular filtration rate. Moreover, morphologic features in the dialysis group presented with more severe vascular lesions. Interstitial fibrosis and chronic tubulointerstitial lesions were related to a trend of high risk of continuous dialysis in the dialysis group. Based on univariate and multivariable Cox regression analysis, more severe glomerular lesions, including glomerular mesangiolysis, glomerular basement membrane double contours and glomerular mesangial proliferation, were identified as risk factors predicting worse prognosis.Conclusions Our renal C-TMA semiquantitative scoring system is reliable with good reproducibility and prognostic value in clinical practice, which needs further validation.

Objectives Evidence linking dietary potassium and serum potassium is virtually scarce and inconclusive. The aim of the study was to investigate the association between serum potassium level and potassium intake measured by 24-hour urine. We also explored whether the association differed across health conditions.Design A cross-sectional study conducted from September 2017 to March 2018.Setting 48 residential elderly care facilities in northern China.Participants Participants aged 55 years and older and with both serum potassium and 24-hour urinary potassium measured were classified as having a low (apparently healthy), moderate (with ≥1 health condition but normal renal function) and high (with ≥1 health condition and abnormal renal function) risk of hyperkalaemia.Exposure Potassium intake is measured by 24-hour urinary potassium.Outcomes Serum potassium in association with potassium intake after adjustment for age, sex, region and accounting for the cluster effect.Results Of 962 eligible participants (mean age 69.1 years, 86.8% men), 17.3% were at low risk, 48.4% at moderate risk and 34.3% at high risk of hyperkalaemia. Serum potassium was weakly associated with 24-hour urinary potassium among individuals with moderate (adjusted β=0.0040/L; p=0.017) and high (adjusted β=0.0078/L; p=0.003) but not low (adjusted β=0.0018/L; p=0.311) risk of hyperkalaemia.Conclusions A weak association between dietary potassium intake and serum potassium level existed only among individuals with impaired renal function or other health conditions but not among apparently healthy individuals. The results imply that increasing dietary potassium intake may slightly increase the risk of hyperkalaemia but may also decrease the risk of hypokalaemia in unhealthy individuals, both of which have important health concerns.Trial registration number NCT03290716; Post-results.

Abstract Background Most primary membranous nephropathy (MN) is mediated by anti-phospholipase A2 receptor (PLA2R) antibodies. Recently, these antibodies have been revealed months to years before the disease's onset. Their production and pathogenicity need further investigation. Methods Anti-PLA2R antibodies were purified from plasma of eight healthy individuals, 12 patients with PLA2R-related MN and negative circulating antibody (Ab-), and 18 patients with positive anti-PLA2R antibodies (Ab +), using affinity column coupled with recombinant human PLA2R. The antigen specificity, antibody amount, titer, IgG subclass, and affinity were assessed by Western blot, immunofluorescence, ELISA, and surface plasmon resonance. Results The natural anti-PLA2R antibodies recognized the conformational structure of PLA2R which locates on the cell membrane of podocytes. The amount of natural IgG was 0.12 ± 0.04 g/L, which accounted for 0.80% of total IgG and was lower than that of patients (2.36%, P

Abstract Background The renal risk score (RRS) is a useful tool to predict end-stage renal disease (ESRD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to validate the predictive performance of RRS and to further modify this model in Chinese AAV patients. Methods Two hundred and seventy-two patients diagnosed with AAV confirmed by renal biopsies were retrospectively enrolled from a single center. The RRS was calculated based on 3 categorical variables, i.e., the proportion of normal glomeruli, the proportion of interstitial fibrosis and tubular atrophy (IF/TA), and eGFR at biopsy, classifying these patients into low-, medium-, and high-risk groups. In addition, a modified model was developed based on the RRS and was further validated in another independent cohort of 117 AAV patients. The predictive performance of each model was evaluated according to discrimination and calibration. Results Patients were classified by the RRS into low- (26.5%), medium- (46.7%), and high-risk (26.8%) groups, with 120-month renal survival rates of 93.3%, 57.2%, and 18.4%, respectively (P 50%) included. Internal and external validation of the modified model were performed. Finally, an online risk prediction tool was developed based on the modified model. Conclusions The RRS was an independent predictor of ESRD of AAV patients. The modified model could predict the probability of ESRD for AAV patients with improved performance in Chinese AAV patients.

Background The pathogenesis of primary membranous nephropathy (MN) involves the antibodies against antigens on the cell surface of podocytes, with the majority of M-type phospholipase A2 receptor (PLA2R), and a profound podocyte dysfunction. The effects of anti-PLA2R antibodies directly to the podocytes remain unclear.Methods Anti-PLA2R antibodies from patients with PLA2R-associated MN were affinity-purified using a column coupled with recombinant human PLA2R protein. Their effects on conditionally immortalized human podocytes were assessed by apoptosis assays, cellular calcium detection, wound healing assay, and immunofluorescent staining. Proteomics analysis was performed by LC-MS/MS and on PANTHER database.Results The stimulation by anti-PLA2R antibodies could induce early-stage apoptosis of podocytes (MFI of Annexin V = 104.3 ± 19.2 vs. 36.7 ± 7.6, p = 0.004). The increase of calcium concentration in podocytes (MFI = 3309.3 ± 363.6 vs. 1776.3 ± 212.7, p = 0.015) might attribute to the endoplasmic reticulum calcium efflux. The expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) was also increased (MFI = 134.4 ± 9.8 vs. 105.3 ± 10.1, p = 0.011). Proteomics results suggested that anti-PLA2R antibody treatment led to damage on cellular structure, and produced functional disorders on protein binding, actin filament binding, and microtubule motor activity. The staining of F-actin on foot process was reduced (MFI = 27.3 ± 2.8 vs. 47.5 ± 1.0, p = 0.001) and the motility and adherence capacity of podocytes were reduced (number of migrated cells = 44.7 ± 3.1 vs. 53.3 ± 4.9, p = 0.001) after incubation with anti-PLA2R antibodies.Conclusion These data indicate that anti-PLA2R antibodies may directly induce podocyte damage independent of the complement system, which expands the mechanism of anti-PLA2R antibodies on MN.

Background Anti-glomerular basement membrane (anti-GBM) disease is a rare but severe autoantibody-mediated immune disorder. The typical clinical presentation includes rapidly progressive glomerulonephritis and often concurrent pulmonary hemorrhage. The present study is aimed to investigate the therapeutic effects of rituximab either used alone or with other immunosuppressants.Methods Eight patients diagnosed with anti-GBM disease and treated with rituximab from 2014 to 2020 were retrospectively reviewed.Results Eight patients included 5 males and 3 females with a median age of 58.5 years. They all presented severe kidney injuries and 1 patient had lung hemorrhage. At diagnosis, the median of serum creatinine was 246 µmol/L (ranging from 91 to 850 µmol/L), with 3 patients requiring dialysis. All of them received corticosteroids and plasmapheresis. Rituximab was given as either standard four weekly doses or one pulse ranging from 100 to 600 mg. After a median follow-up of 34.5 months, kidney function was partially recovered or stabilized in 5/8 (62.5%) patients, free of dialysis. Anti-GBM antibodies remained undetected in all patients during follow-up. No severe adverse effect associated with rituximab was observed.Conclusion Rituximab may be an alternative therapy in the treatment of patient with severe or refractory anti-GBM disease.

Background Patients with persistent nephrotic-range proteinuria have a high risk of kidney dysfunction and cardiovascular events. Recently, the maintenance of proteinuria remission has been demonstrated to reduce the risk of kidney endpoint. However, the effect of remission duration on cardiovascular outcomes remains unclear.Methods This study enrolled 982 patients with primary nephrotic syndrome who had achieved clinical remission. Remission duration was defined as the maintenance time (months) of the first remission. Arteriosclerotic cardiovascular disease (ASCVD) and kidney dysfunction (ESKD or eGFR reduction >50%) were the endpoints. Survival curves, Cox regression models, restricted cubic spline analysis were used and the cutoff time points were determined.Results During the 38.3 months of follow-up, 161 (16.4%) patients developed ASCVD (51.3 per 1000 patient-years) and 52 (5.3%) patients developed kidney dysfunction (15.3 per 1000 patient-years). Multivariate analysis showed that remission duration was an independently protective factor to ASCVD, in which each one-year extension associated with a 15% reduction of the risk (HR, 0.854; 95% CI, 0.776 ∼ 0.940, p = .001). The initial time point was seven months for remission to present the protective effect to ASCVD and the maximum time point was 36 months. Remission duration was also an independently protective factor to kidney dysfunction. This effect was shown from the beginning of remission and reached the maximum at 26 months.Conclusions The maintenance of proteinuria remission was crucial for the improvement of cardiovascular and kidney outcomes in nephrotic syndrome patients.

BackgroundThe alkaline phosphatase-to-albumin ratio (APAR) has been demonstrated to be a promising non-invasive biomarker for predicting prognosis in certain diseases. However, the relationship between APAR and prognosis in non-dialysis chronic kidney disease (CKD) patients remains unclear. This study aims to identify the association between APAR and prognosis among CKD stages 1–4 in China.MethodsPatients with CKD stages 1–4 were consecutively recruited from 39 clinical centers in China from 2011 to 2016. New occurrences of end-stage kidney disease (ESKD), major adverse cardiovascular and cerebrovascular events, and all-cause deaths were the outcome events of this study. Subdistribution hazard competing risk and Cox proportional hazards regression models were adopted.ResultsA total of 2,180 participants with baseline APAR values were included in the analysis. In the primary adjusted analyses, higher APAR level [per 1-standard deviation (SD) increase in natural logarithm transformed (ln-transformed) APAR] was associated with 33.5% higher risk for all-cause deaths [adjusted hazard ratio (HR) 1.335, 95% confidence interval (CI) 1.068–1.670]. In addition, there was evidence for effect modification of the association between APAR and ESKD by baseline estimated glomerular filtration rate (eGFR) (P interaction < 0.001). A higher APAR level (per 1-SD increase in ln-transformed APAR) was associated with a greater risk of ESKD among participants with eGFR ≥ 60 ml/min/1.73 m2 (adjusted SHR 1.880, 95% CI 1.260–2.810) but not in eGFR < 60 ml/min/1.73 m2.ConclusionHigher APAR levels in patients with CKD stages 1–4 seemed to be associated with an increased risk of all-cause death. Thus, APAR appears to be used in risk assessment for all-cause death among patients with CKD stages 1–4.

Introduction: Renal vein thromboembolism is a severe complication of nephrotic syndrome. Small thrombus in the intra-kidney venous system cannot be recognized by ultrasonography. The current study was to investigate the kidney pathological features of intra-kidney venous thrombus and their values in clinical practice. Methods: Kidney pathological features of glomerular capillary dilatation and congestion, peritubular capillary dilatation and congestion, and intraglomerular neutrophil infiltration were screened and scored during kidney biopsy information interpretation. Eighty-four consecutive patients with these features and primary glomerulonephritis were analyzed, comparing to another 84 control patients without these features who were matched according to the pathological types of glomerulonephritis. Results: In the patients with pathological features of suspected intra-kidney venous thrombus, the levels of proteinuria (5.2 vs. 3.2 g/24 h, p = 0.005), serum creatinine (80.9 vs. 71.2 μmol/L, p < 0.001), platelet count (274.0 vs. 254.5 ×109/L, p = 0.020), D-dimer (0.2 vs. 0.2 mg/L, p = 0.002), and fibrin degradation products (1.9 vs. 1.0 mg/L, p = 0.003) were significantly higher than those in control patients. The levels of serum albumin (24.2 vs. 28.6 g/L, p = 0.003) and eGFR (92.1 vs. 103.9 mL/min/1.73 m2, p < 0.001) were significantly lower. The scores of these pathological features were positively correlated with the levels of D-dimer (r = 0.21, p = 0.05). During follow-up, 9 (10.7%) patients with pathological features of suspected intra-kidney venous thrombus developed venous thromboembolism, which was significantly more than that of control patients (0%, p = 0.006). Conclusions: Kidney pathological features could indicate intra-kidney venous thromboembolism, and their scores represent the possibility of thrombus. The notice of these features may provide clinical alerts for venous thromboembolism possibility.

A 3D laser scanning strategy based on cascaded deep neural network is proposed for the scanning system converted from 2D Lidar with a pitching motion device. The strategy is aimed at moving target detection and monitoring. Combining the device characteristics, the strategy first proposes a cascaded deep neural network, which inputs 2D point cloud, color image and pitching angle. The outputs are target distance and speed classification. And the cross-entropy loss function of network is modified by using focal loss and uniform distribution to improve the recognition accuracy. Then a pitching range and speed model are proposed to determine pitching motion parameters. Finally, the adaptive scanning is realized by integral separate speed PID. The experimental results show that the accuracies of the improved network target detection box, distance and speed classification are 90.17%, 96.87% and 96.97%, respectively. The average speed error of the improved PID is 0.4239°/s, and the average strategy execution time is 0.1521 s. The range and speed model can effectively reduce the collection of useless information and the deformation of the target point cloud. Conclusively, the experimental of overall scanning strategy show that it can improve target point cloud integrity and density while ensuring the capture of target.

Abstract Background The phenomenon of medical migration is common in China. Due to the limited capacity and substantial geographical variation in medical practice, patients with chronic kidney disease (CKD) travel more frequently to seek medical care. We aimed to assess the cost-effectiveness of medical migration for CKD patients in China and provide real-world evidence for the allocation of CKD resources. Methods Records of patients with CKD between January 2014 and December 2018 were extracted from a large national database. A patient is defined as a medical migrant if she travelled across the provincial border to a non-residential province to be admitted for inpatient care. The propensity score matching method is used to estimate the effect of medical migration on medical expenditure, length of hospital stay, and in-hospital mortality. The cost-effectiveness is evaluated by comparing the estimated cost per life saved with contemporaneous estimates of the value of a statistical life. Results Among 4,392,650 hospitalizations with CKD, medical migrants accounted for 4.9% in 2018. Migrant patients were estimated to incur a 26.35% increase in total medical expenditure, experience a 0.24-percentage-points reduction in in-hospital mortality rates, and a 0.49-days reduction in length of hospital stay compared to non-migrant patients. Overall, medical migration among CKD patients incurred an average of 1 million yuan per life saved, which accounted for 20–40% of contemporaneous estimates of the value of a statistical life. Compared with migrant patients with self-payment and commercial insurance, migrant patients with public health insurance (urban basic medical insurance and new rural co-operative medical care) incurred lower cost per life saved. Cost per life saved for CKD patients was similar between female and male, lower among older population, and varied substantially across regions. Conclusions The medical care seeking behaviors of CKD patients was prominent and medical resources of kidney care were unevenly allocated across regions. Medical migration led to a reduction in mortality, but was associated with higher medical expenditure. It is imperative to reduce the regional disparity of medical resources and improve the clinical capacity. Our study shows that it is imperative to prioritize resource allocation toward improving kidney health and regional health care planning.

Abstract Background Primary membranous nephropathy (MN) is a kidney-specific autoimmune disease. Human embryonic stem cells-derived immunity-and-matrix regulatory cells (hESC-IMRCs) have immunoregulatory functions. We hypothesized that hESC-IMRCs might have therapeutic effects on MN and be a potential treatment in clinical practice. Methods Rats of Heymann nephritis were injected with sheep anti-rat Fx1A serum. hESC-IMRCs were intravenously administrated upon the detection of proteinuria, with 6 × 106 cells (high-dose) or 3 × 106 cells (low-dose) in 1 ml every other day. Splenocytes and IMRCs were co-cultured at different times and ratios. Cell types and cytokines were detected by flow cytometry and enzyme-linked immunosorbent assay. Results The urinary protein of rats with Heymann nephritis was reduced remarkably to a level comparable to negative controls, in both low-dose (45.6 vs. 282.3 mg/d, P

Abstract Background Although extensive efforts have been paid to identify reliable predictors for renal outcomes of diabetic kidney disease (DKD) patients in type 2 diabetes mellitus (T2DM), there are still only a limited number of predictive factors for DKD progression. Increasing evidence reported the role of the overactivated complement system in the pathogenesis of DKD. Whether renal complement depositions are associated with renal outcomes of DKD in T2DM is of interest. Methods A total of 213 biopsy‐proven DKD patients with T2DM were retrospectively recruited. Clinical and pathological data of the patients were analyzed. Kaplan‐Meier analysis and Cox regression analysis were performed to explore predictors of end‐stage renal disease (ESRD). Results During a median follow‐up of 23.0 (12.0, 39.0) months, 100/213 (46.9%) patients progressed to ESRD. C3c and C1q deposition were observed in 133/213 (62.4%) and 45/213 (21.1%) patients, respectively. Kaplan‐Meier analysis revealed patients with C3c or C1q deposition had significantly worse renal outcomes compared with those without C3c or C1q deposition (p = .001 and p

Background: Cryoglobulinemic glomerulonephritis (Cryo-GN), caused by circulating cryoglobulins, has varied etiology and clinical-pathologic manifestations. This study aimed to investigate the clinicopathological spectrum and outcome of patients with various Cryo-GN in China. Methods: A retrospective review of 74 Chinese patients with biopsy-proven cryoglobulin-related renal lesions in Peking University First Hospital from 2010 to 2020 was performed. Results: The mean age at diagnosis was 52.9 ± 15.0 years, and the female-to-male ratio was about 2/5. For the etiology screening, serum/urine monoclonal immunoglobulin could be detected on immunofixation electrophoresis in 34% of patients, including 6 patients who had hematological malignancies. Fifty-seven percent of patients had HBV infection, far more than HCV infection (5%). Ten percent of patients had other infections, and 27% of patients were classified as essential or idiopathic. Eleven out of the 15 patients with type II cryoglobulinemia had a consistent monotype of serum monoclonal immunoglobulins and monoclonal cryoprecipitate. The clinical manifestations were similar between various types of cryoglobulinemia. Hematuria, proteinuria, hypertension, anemia, and chronic renal insufficiency were the most common features. Fifty-three percent of patients presented with nephrotic syndrome, and 32% experienced acute kidney injury. Hypocomplementemia, serum-positive rheumatoid factor activity, and skin lesions were reported in 45%, 29%, and 28% of patients, respectively. After a median of 24 months follow-up, 18 patients reached end-stage kidney disease. The clone-targeted treatment could retard the renal deterioration compared with immunosuppressive therapy. Conclusions: This was the largest single-center, clinicopathological retrospective study of Cryo-GN in China. Our data strongly support the association between monoclonal gammopathy and type II Cryo-GN. The renal responsive rate of immunosuppressant therapy is still suboptimal. The clone-targeted treatment shows promising effects in patients with type I or II Cryo-GN.

ObjectiveThe aim of this study is to explore the prevalence and clinicopathological associations between anti-C1qA08 antibodies and anti-monomeric CRP (mCRP) a.a.35-47 antibodies and to explore the interaction between C1q and mCRP.MethodsNinety patients with biopsy-proven lupus nephritis were included from a Chinese cohort. Plasma samples collected on the day of renal biopsy were tested for anti-C1qA08 antibodies and anti-mCRP a.a.35-47 antibodies. The associations between these two autoantibodies and clinicopathologic features and long-term prognosis were analyzed. The interaction between C1q and mCRP was further investigated by ELISA, and the key linear epitopes of the combination of cholesterol binding sequence (CBS; a.a.35-47) and C1qA08 were tested by competitive inhibition assays. The surface plasmon resonance (SPR) was used to further verify the results.ResultsThe prevalence of anti-C1qA08 antibodies and anti-mCRP a.a.35-47 antibodies were 50/90 (61.1%) and 45/90 (50.0%), respectively. Levels of anti-C1qA08 antibodies and anti-mCRP a.a.35-47 antibodies were negatively correlated with serum C3 concentrations ((0.5(0.22-1.19) g/L vs. 0.39(0.15-1.38) g/L, P=0.002) and (0.48(0.44-0.88) g/L vs. 0.41(0.15-1.38) g/L, P=0.028), respectively. Levels of anti-C1qA08 antibodies were correlated with the score of fibrous crescents and tubular atrophy (r=-0.256, P=0.014 and r=-0.25, P=0.016, respectively). The patients with double positive antibodies showed worse renal prognosis than that of the double negative group (HR 0.899 (95% CI: 0.739-1.059), P=0.0336). The binding of mCRP to C1q was confirmed by ELISA. The key linear epitopes of the combination were a.a.35-47 and C1qA08, which were confirmed by competitive inhibition experiments and SPR.ConclusionThe combination of anti-C1qA08 and anti-mCRP a.a.35-47 autoantibodies could predict a poor renal outcome. The key linear epitopes of the combination of C1q and mCRP were C1qA08 and a.a.35-47. A08 was an important epitope for the classical pathway complement activation and a.a.35-47 could inhibit this process.

Accumulating evidence suggests the pathogenic role of immunity and metabolism in diabetic kidney disease (DKD). Herein, we aimed to investigate the effect of complement factor B (CFB) on lipid metabolism in the development of DKD. We found that in patients with diabetic nephropathy, the staining of Bb, CFB, C3a, C5a, and C5b-9 was markedly elevated in renal tubulointerstitium. Cfb-knockout diabetic mice had substantially milder tubulointerstitial injury and less ceramide biosynthesis. The in vitro study demonstrated that cytokine secretion, endoplasmic reticulum stress, oxidative stress, and cell apoptosis were ameliorated in HK-2 cells transfected with siRNA of CFB under high-glucose conditions. Exogenous ceramide supplementation attenuated the protective effect of CFB knockdown in HK-2 cells, while inhibiting ceramide synthases (CERS) with fumonisin B1 in CFB-overexpressing cells rescued the cell injury. CFB knockdown could downregulate the expression of NF-κB p65, which initiates the transcription of CERS3. Furthermore, C3 knockdown abolished CFB-mediated cytokine secretion, NF-κB signaling activation, and subsequently ceramide biosynthesis. Thus, CFB deficiency inhibited activation of the complement alternative pathway and attenuated kidney damage in DKD, especially tubulointerstitial injury, by inhibiting the NF-κB signaling pathway, further blocking the transcription of CERS, which regulates the biosynthesis of ceramide. CFB may be a promising therapeutic target of DKD.

National strategies for addressing chronic kidney disease (CKD) are crucial to improving kidney health. We sought to describe country-level variations in non-communicable disease (NCD) strategies and CKD-specific policies across different regions and income levels worldwide. The International Society of Nephrology Global Kidney Health Atlas (GKHA) was a multinational cross-sectional survey conducted between July and October 2018. Responses from key opinion leaders in each country regarding national NCD strategies, the presence and scope of CKD-specific policies, and government recognition of CKD as a health priority were described overall and according to region and income level. 160 countries participated in the GKHA survey, comprising 97.8% of the world’s population. Seventy-four (47%) countries had an established national NCD strategy, and 53 (34%) countries reported the existence of CKD-specific policies, with substantial variation across regions and income levels. Where CKD-specific policies existed, non-dialysis CKD care was variably addressed. 79 (51%) countries identified government recognition of CKD as a health priority. Low- and low-middle income countries were less likely to have strategies and policies for addressing CKD and have governments which recognise it as a health priority. The existence of CKD-specific policies, and a national NCD strategy more broadly, varied substantially across different regions around the world but was overall suboptimal, with major discrepancies between the burden of CKD in many countries and governmental recognition of CKD as a health priority. Greater recognition of CKD within national health policy is critical to improving kidney healthcare globally.

Objective. Modified C-reactive protein (mCRP) is known to be involved in the upregulation and amplification of the local inflammatory response. This study investigated the circulating and local levels of mCRP and their relevance to clinicopathological features in patients with lupus nephritis. Methods. Ninety-five patients with renal biopsy-proven lupus nephritis and 30 normal controls were enrolled in this study. Plasma and urinary mCRP were screened by enzyme-linked immunosorbent assay (ELISA). The renal deposition of mCRP was detected by immunohistochemistry and immunofluorescence staining. A human proximal tubular epithelial cell line (HK2 cells) was incubated with purified IgG from lupus nephritis, and the production of CRP by HK2 cells was further evaluated. Results. Plasma and urinary levels of mCRP increased significantly in patients with lupus nephritis compared with normal controls (P=0.013, P

Introduction: Previous studies suggested that sevelamer carbonate is well tolerated with a favorable efficacy and safety profile in both dialysis and nondialysis patients in Europe; however, the efficacy remains controversial, and few studies have examined sevelamer carbonate therapy in other ethnic nondialysis CKD patients. This study assessed the efficacy and safety of sevelamer carbonate in Chinese nondialysis CKD patients with hyperphosphatemia. Methods: The multicenter, randomized, double-blind, parallel group, placebo-controlled, and phase 3 clinical trial enrolled 202 Chinese nondialysis CKD patients with serum phosphorus ≥1.78 mmol/L. Patients were randomly assigned 1:1 to receive sevelamer carbonate (2.4-12 g per day) or placebo for 8 weeks. The primary outcome was the change in serum phosphorous between baseline and week 8. Results: Totally 482 Chinese patients were screened and 202 were randomized (sevelamer carbonate, n=101; placebo, n=101). The mean serum phosphorous decreased significantly in patients treated with sevelamer carbonate compared with placebo (-0.22±0.47 vs. 0.05±0.44 mmol/L, p

Introduction To explore the chronological trends in clinical features and utilization of healthcare resources for hospitalized patients with urolithiasis in China. Methods Patients with urolithiasis were extracted from the Hospital Quality Monitoring System, a national database of hospitalized patients in China, based on International Classification of Diseases, Tenth Revision, codes. Variables including demographic characteristics, comorbidities, treatment modalities for urolithiasis, length of hospital stay, and expenditures were collected and analyzed. Results Among 79.8 million hospitalized patients, 3.5 million were diagnosed with urolithiasis with an increasing trend (from 3.0% in 2013 to 4.0% in 2018). Most of these patients had upper urinary tract calculi (76.6% in 2013 and 81.7% in 2018). Middle-aged patients (46–65 years) constituted the largest proportion with a stable trend (from 46.9% in 2013 to 48.8% in 2018), while the proportion of older patients (>65 years) showed an increasing trend (from 23.7% in 2013 to 27.4% in 2018). The percentages of gout/hyperuricemia, hypertension, diabetes, and cardiovascular disease among the hospitalized patients with urolithiasis increased steadily, with the sharpest increases in patients from rural areas. Overall, 656,952 patients (18.9%) received surgical interventions for urolithiasis. The proportions of ureteroscopy and extracorporeal shockwave lithotripsy increased steadily during the 6-year study period, with simultaneous decreases in open surgery and percutaneous nephrolithotomy. The median length of hospital stay decreased from 10 days to 8 days. The cost for urolithiasis intervention accounted for 2.0% of the total hospitalization fee in 2013, and increased to 2.7% in 2018. Conclusions The analysis showed an increasing trend in the percentage of hospitalized patients with urolithiasis, accompanied by an increased percentage of the total hospitalization fee for urolithiasis intervention during the 6-year study period. Based on the increasing trends in the proportion of older patients (>65 years) and percentages of metabolic comorbidities among patients with urolithiasis, an increased burden of urolithiasis on the healthcare system in China is anticipated.

Introduction: Understanding heterogeneity in the prognosis of chronic kidney disease (CKD) has implications in management of patients. We aimed to evaluate the comparative risk of end-stage kidney disease (ESKD), cardiovascular (CV) events, and death among patients with CKD in China. Methods: In total, 3,700 patients with CKD stage 1–4 were recruited from 39 clinical centers in China between 2011 and 2016. New occurrence of ESKD, CV events, and all-cause mortality was recorded until the end of 2017. The crude incidence rate was calculated for each outcome. Ratios of incidence between different outcomes were generated with 95% confidence interval (CI) estimated by 1,000 times of bootstrapping. Multivariable adjusted Cox regression models accounting for competing risk between the outcomes were used to evaluate the association of risk factors with the outcomes. Results: The population mean age was 50 ± 14 years, with 58.2% male and 60.3% of glomerulonephritis. After a median follow-up of 4.65 years (interquartile range [IQR]: 3.71–5.60 years) for ESKD, 4.76 years (IQR: 3.97–5.76 years) for CV events, and 4.84 years (IQR: 3.97–5.76 years) for death, the incidence rates of the 3 outcomes were 3.1, 1.5, and 0.92/100 patient-years, respectively. The ratio for the incidence of ESKD and CV events was 2.15 (95% CI: 1.87, 2.53) and that for incidence of ESKD and death was 3.41 (95% CI: 2.88, 4.08). Significant differences regarding the ratios were detected through levels of age, history of CV disease, the estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (uACR), and etiology of CKD. In the Cox regression model adjusting for traditional CV and kidney-specific risk factors, older age was associated with a higher risk of CV events and death but a lower risk of ESKD (hazard ratios [HRs] = 1.45 [95% CI: 1.29, 1.64], 1.48 [95% CI: 1.29, 1.70], and 0.78 [95% CI: 0.73, 0.84] per 10 year increase, respectively). By comparison, reduced eGFR was associated with a higher risk of ESKD and death, rather than CV events (HRs = 3.62 [95% CI: 2.96, 4.43], 1.30 [95% CI: 1.02, 1.66], and 1.22 [95% CI: 0.99, 1.49] per 30.26 mL/min/1.73 m2 increase, respectively). Similar patterns were seen for increased uACR (HRs = 1.42 [95% CI: 1.30, 1.55], 1.17 [95% CI: 1.05, 1.30], and 1.07 [95% CI: 0.99, 1.17] per 1 natural log-transformed value increase, respectively). Conclusion: ESKD was more likely to occur than CV events and death in the population with CKD stage 1–4 in China. Traditional risk factors contributed differently to the comparative risk of the outcomes.

Abstract. Background:. Whether there is an association between serum uric acid (SUA) level and risk of mortality in the general population remains unclear. Based on the China National Survey of Chronic Kidney Disease linked to mortality data, a population-based cohort study was performed to investigate the association between SUA level and all-cause mortality, cardiovascular disease (CVD) mortality, and cancer mortality in China. Methods:. The survival status of participants in the cross-sectional survey was identified from January 1, 2006 to December 31, 2017. Only 33,268 individuals with complete SUA data among the 47,204 participants were included in the analysis. We determined the rates of all-cause mortality, CVD mortality, and cancer mortality. We used Cox proportional hazards regression models to evaluate the effect of the SUA level on mortality. Results:. During a total of 297,538.4 person-years of follow-up, 1282 deaths occurred. In the Cox proportional hazards regression model, the rate of all-cause mortality, CVD mortality, and cancer mortality had a U-shaped association with SUA levels only in men, whereas no significant associations were detected in women. For all-cause mortality in men, the multivariable-adjusted hazard ratios (HRs) in the first, second, and fourth quartiles compared with the third quartile were 1.31 (95% confidence interval [CI] 1.04–1.67), 1.17 (95% CI 0.92–1.47), and 1.55 (95% CI 1.24–1.93), respectively. For CVD mortality, the corresponding HRs were 1.47 (95% CI 1.00–2.18), 1.17 (95% CI 0.79–1.75), and 1.67 (95% CI 1.16–2.43), respectively. For the cancer mortality rate, only a marginally significant association was detected in the fourth quartile compared with the third quartile with an HR of 1.43 (95% CI 0.99–2.08). Conclusions:. The association between SUA and mortality differed by sex. We demonstrated a U-shaped association with SUA levels for all-cause and CVD mortalities among men in China.

Background:Aedes albopictus is an indigenous primary vector of dengue and Zika viruses in China. Wolbachia is a gram-negative and common intracellular bacteria, which is maternally inherited endosymbionts and could expand their propagation in host populations by means of various manipulations. Compared with research on the dispersion of Ae. albopictus at the macrospatial level (mainly at the country or continent level), little is known about its variation and Wolbachia infection at the microspatial level, which is essential for its management. Meanwhile, no local cases of dengue fever have been recorded in the history of Nanjing, which implies that few adulticides have been applied in the city. Thus, the present study examines how the Ae. albopictus population varies and the Wolbachia infection status of each population among microspatial regions of Nanjing City.Methods: The genetic structure of 17 Aedes albopictus populations collected from urban, urban fringe, and rural regions of Nanjing City was investigated based on 9 microsatellite loci and the mitochondrial coxI gene. The Wolbachia infection status of each population was also assessed with Wolbachia A- and Wolbachia B-specific primers.Results: Nine out of 58 tested pairs of microsatellite markers were highly polymorphic, with a mean PIC value of 0.560, and these markers were therefore chosen for microsatellite genotyping analysis. The Na value of each Ae. albopictus population was very high, and the urban area populations (7.353 ± 4.975) showed a lower mean value than the urban fringe region populations (7.866 ± 5.010). A total of 19 coxI haplotypes were observed among 329 Ae. albopictus individuals via haplotype genotyping, with the highest diversity observed among the urban fringe Ae. albopictus populations (Hd = 0.456) and the lowest among the urban populations (Hd = 0.277). Each Ae. albopictus population showed significant departure from HWE, and significant population expansion was observed in only three populations from the urban (ZSL), urban fringe (HAJY), and rural areas (HSZY) (p < 0.05). Combined with DAPC analysis, all the Ae. albopictus populations were adequately allocated to two clades with significant genetic differences according to population structure analysis, and the best K value was equal to two. AMOVA results showed that most (96.18%) of the genetic variation detected in Ae. albopictus occurred within individuals (FIT = 0.22238, p < 0.0001), while no significant positive correlation was observed via isolation by distance (IBD) analysis (R2 = 0.03262, p = 0.584). The TCS network of all haplotypes showed that haplotype 1 (H1) and haplotype 4 (H4) were the most frequent haplotypes among all populations, and the haplotype frequency significantly increased from urban regions (36.84%) to rural regions (68.42%). Frequent migration was observed among Ae. albopictus populations from rural to urban regions via the urban fringe region, with four direct migration routes between rural and urban regions. Furthermore, Wolbachia genotyping results showed that most of the individuals of each population were coinfected with Wolbachia A and Wolbachia B. The independent infection rate of Wolbachia A was slightly higher than that of Wolbachia B, and no significant differences were observed among different regions.Conclusion: In the microspatial environment of Nanjing City, the urban fringe region is an important region for the dispersion of Ae. albopictus populations between rural and urban areas, and Wolbachia A and Wolbachia B coinfection is the most common Wolbachia infection status in all Ae. albopictus populations among different regions.

Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE.We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on ‘disease manifestations’ (ie, signs, symptoms and patient-reported outcomes) and on ‘disease outcomes’ (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested.Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE.

Background: Lupus nephritis is characterized by multiple autoantibodies production. However, there are few autoantibodies associated with disease activity and prognosis. CRP exists in at least two conformationally distinct forms: native pentameric C-reactive protein (pCRP) and modified/monomeric CRP (mCRP). Autoantibodies against mCRP are prevalent in sera of patients with lupus nephritis and are reported to be pathogenic. Summary: The levels of serum anti-mCRP autoantibodies are associated with clinical disease activity, tubulointerstitial lesions, treatment response, and prognosis in patients with lupus nephritis. The key epitope of mCRP was amino acid 35–47. Furthermore, emerging evidence indicated that anti-mCRP autoantibodies could participate in the pathogenesis of lupus nephritis by forming in situ immune complexes or interfering with the biological functions of mCRP, such as binding to complement C1q and factor H. Key Messages: Here, we review the recent advances in the prevalence, clinical-pathological associations, and potential pathogenesis of anti-mCRP autoantibodies in lupus nephritis, which may provide a promising novel therapeutic strategy for lupus nephritis.

Abstract Background Anemia is one of the common complications in patients with chronic kidney disease (CKD). However, there is no systematic investigation on the prevalence of anemia in CKD patients and its relationship with the quality of life in China. Methods The data for this study comes from baseline data from the Chinese Chronic Kidney Disease Cohort Study (C-STRIDE), which recruited predialysis CKD patients in China. The kidney disease quality of life summary (KDQOL-TM) was used to assess health-related quality of life (HRQoL). Use linear regression model to estimate the relationship between hemoglobin level and quality of life. Results A total of 2921 patients were included in this study. The adjusted prevalence of hemoglobin (Hb) less than 100 g/L was 10.3% (95% confidence interval [CI]: 9.9,11.4%), and showed an increased trend through reduced eGFR levels from 4.0% (95%CI:2.3,5.9%) in the 45-60 ml/min/1.73m2 group to 23.4% (95%CI:20.5,26.2%) in the 15–29 ml/min/1.73m2 group. The prevalence of anti-anemia treatment was 34.0% (95%CI: 28.7,39.3%) and it is shown by reducing eGFR levels from 15.8% (95%CI:0,36.7%) in the 45-60 ml/min/1.73m2 group to 38.2% (95%CI: 30.7,45.2%) in the 15–29 ml/min/1.73m2 group. All five dimensions of the KDQOL scores in patients with CKD decreased as hemoglobin declined. After multivariable adjustments,the degrees of decrease became somewhat blunted. For example, compared with hemoglobin of ≥130 g/L, regression coefficients in the hemoglobin of

BackgroundIncreasing studies demonstrated the importance of activation of neutrophils in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Previous studies showed that annexin A1 (ANXA1) inhibited the recruitment, transendothelial migration and respiratory burst of neutrophils and induced apoptosis of neutrophils. The current study aimed to investigate the plasma and renal levels of ANXA1 as well as their association with the disease severity in AAV patients.MethodsThirty-one AAV patients in active stage and 35 AAV patients in remission stage were recruited. The expression of ANXA1 in renal specimens was assessed by immunohistochemistry. The co-localization of ANXA1 with renal intrinsic and infiltrating cells was detected by double immunofluorescence. The plasma levels of ANXA1 were determined by ELISA. The association of plasma and renal levels of ANXA1 with clinicopathological parameters was further analyzed.ResultsPlasma levels of ANXA1 were significantly higher in active AAV patients than those in AAV patients in remission as well as healthy controls. The renal expression of ANXA1 was significantly higher in active AAV patients than in healthy controls and disease controls. Double immunofluorescence assay showed that ANXA1 was expressed in glomerular endothelial cells, mesangial cells, podocytes, proximal tubular epithelial cells, neutrophils, monocytes/macrophages and T cells in AAV patients. The mean optical density of ANXA1 in glomeruli was correlated with serum creatinine levels (r = −0.491, P = 0.005) and eGFR (r = 0.492, P = 0.005) at renal biopsy and the proportion of crescents (r = −0.423, P = 0.018) in renal specimens of AAV patients. The expression of ANXA1 in glomeruli of AAV patients achieving complete renal recovery was significantly higher than those achieving partial renal recovery.ConclusionIn AAV patients, the renal expression of ANXA1 was associated with the severity of renal injury.

BackgroundChronic kidney disease (CKD) is a global public health issue. Red blood cell distribution width (RDW) is a recently recognized potential inflammatory marker, which mirrors the variability in erythrocyte volume. Studies indicate that elevated RDW is associated with increased risk of mortality in CKD patients, while evidence regarding the impact of RDW on kidney outcome is limited.MethodsAltogether 523 patients with CKD stage 1–4 from a single center were enrolled. We identified the cutoff point for RDW level using maximally selected log-rank statistics. The time-averaged estimated glomerular filtration rate (eGFR) slope was determined using linear mixed effects models. Rapid CKD progression was defined by an eGFR decline >5 ml/min/1.73 m2/year. The composite endpoints were defined as doubling of serum creatinine, a 30% decline in initial eGFR or incidence of eGFR < 15 ml/min/1.73 m2, whichever occurred first. Multivariable logistic regression or Cox proportional hazards regression was performed, as appropriate.ResultsDuring a median follow-up of 26 [interquartile range (IQR): 12, 36] months, 65 (12.43%) patients suffered a rapid CKD progression and 172 (32.89%) composite kidney events occurred at a rate of 32.3/100 patient-years in the high RDW group, compared with 14.7/100 patient-years of the remainder. The annual eGFR change was clearly steeper in high RDW group {−3.48 [95% confidence interval (CI): −4.84, −2.12] ml/min/1.73 m2/year vs. −1.86 [95% CI: −2.27, −1.45] ml/min/1.73 m2/year among those with RDW of >14.5% and ≤14.5%, respectively, P for between-group difference

Objective To investigate the demographic and clinicopathological features and renal outcomes of Chinese patients with C3 glomerulonephritis in the setting of monoclonal gammopathy. Methods Patients with renal biopsy-proven C3 glomerulonephritis and detectable serum and/or urine monoclonal immunoglobulin from 2006 to 2018 in Peking University First Hospital were included, their clinical data, renal pathology type, treatment, and prognosis were collected and analyzed. Results Nineteen patients were enrolled, accounting for 24% of C3GN patients in the study period. The mean age of onset was 55 years old and the gender ratio was 4/15 (female/male). The mean eGFR at biopsy was 49.55 ± 29.81 ml/min/1.73m2. The prominent clinical manifestations included nephrotic syndrome (58%), anemia (68%), microscopic hematuria and leukocyturia (58%), and hypocomplementemia (13, 68%). The IgG was the most common isotype of monoclonal Ig on immunofixation electrophoresis. Kidney biopsies revealed a relatively prominent MPGN pattern. Only two patients had direct evidence of monocle immunoglobulins acting as C3GN pathogenic factors. Two patients had concurrent TMA-like renal injuries. The median renal survival was 12 and 15 months, respectively in patients receiving conservative therapy and immunosuppressant therapy, without statistical significance. The efficacy of clone-targeted therapy needed further investigation. Plasma exchange therapy only improved one patient’s renal outcome. Conclusions This is the first case series report of C3GN combined with monoclonal Ig in northern China. The renal prognosis of these patients is poor, and immunosuppressant therapies show no advantage over supportive therapy in renal prognosis, while the benefit of clone-targeted chemotherapy is still requiring investigation.

Abstract Background Multiple myeloma (MM) is a plasma-cell derived hematologic malignant disease. The malignant proliferating plasma cells secrete massive monoclonal immunoglobulins which lead to various pathologic types of renal injury. Myeloma cast nephropathy (MCN) is the most common histopathologic lesion with the worst renal prognosis. Rarely, the free light chains in the protein casts can form amyloid fibrils. Here, we reported two rare cases of MCN with diffuse amyloid casts. Case presentation Case 1: A 54-year-old Chinese man presented with a 4-year history of multiple myeloma, proteinuria and hematuria. He had monoclonal IgAλ plus free λ spike in both serum and urine. He had been on chemotherapy for 4 years and maintained normal serum creatinine until 11 months ago. Then, his renal function deteriorated and he went on hemodialysis 4 months before admission. Renal biopsy showed diffuse amyloid casts in the tubular lumens, without any obvious amyloid deposits in other kidney compartments or signs of extra-renal amyloidosis. The amyloid fibrils formed around mononuclear cells which were CD68 negative. According to the morphology and location, these mononuclear cells were considered as tubular epithelial cells. The patient was maintained on chemotherapy and hemodialysis. He died 8 months after renal biopsy. Case 2: A 58-year-old Chinese man presented with a one-and-a-half-year history of proteinuria and slowly rising serum creatinine. He had monoclonal IgDλ spike in both serum and urine. Amyloid casts were observed in the tubular lumens and mononuclear cells could be identified in the center of some casts. There were no amyloid deposits in other kidney compartments and no sign of systemic amyloidosis. The patient also had fine granular deposits along the tubular basement membrane with λ linear staining along tubular basement membrane suggesting light chain deposition disease. He was treated with bortezomib-based chemotherapy followed by lenalidomide-based chemotherapy and achieved very good partial remission (VGPR). After 27 months of follow-up, the patient still showed no signs of systemic amyloidosis. Conclusions These 2 cases of MCN with diffuse amyloid casts have different histopathologic characteristics from the usual myeloma casts and tubular epithelial cells might play important roles in the pathogenesis.

Abstract Background Anti-glomerular basement membrane disease (GBM) is an autoimmune disease caused by the deposition of circulating anti-GBM antibodies. Non-collagen region of α3 chain of type IV collagen (α3(IV)NC1) is one of the main target antigens, in which EA and EB are the most classical antigen epitopes. It has been reported that anti-GBM antibodies can be detected in HIV patients; however, its immunological characteristics are still unclear. Objectives In this study, the positive rate of the anti-GBM antibodies in HIV and the immunological characteristics of the target antigens were clarified. Methods A total of 93 HIV patients diagnosed in Beijing Youan Hospital from November 2017 to January 2018 were included. Enzyme-linked immunosorbent assay was used to measure the serum IgG autoantibodies specifically against GBM in these patients, as well as their subtypes and antigen spectra. Results It was found that five out of the 93 patients with HIV had low to moderate levels of anti-GBM antibodies. However, these patients presented with no clinical manifestation of any kidney injury or pulmonary hemorrhages. Compared with HIV patients with negative antibodies, there were no significant differences in gender, age, CD4+T cell count and HIV viral load. All sera of five patients recognized non-collagenous domain1 (NC1) of alpha 3 chain of type IV collagen [(α3(IV)NC1] as classic anti-GBM patients, followed by α5(IV)NC1. The antibodies against α3(IV)NC1 were IgG3 predominant, while these antibodies did not react with either of the classic epitopes on α3 (EA and EB). Conclusion These data suggest a distinct immunological profile of anti-GBM antibodies in patients with HIV, and might explain the non-pathogenic features of HIV associated anti-GBM antibodies.

Introduction: Long-term exposure to mercury can cause minimal change disease. However, the current understanding of mercury-associated minimal change disease (M-MCD) is inadequate. To improve the understanding of M-MCD, this study retrospectively analyzed the clinicopathological, ultrastructural, and prognostic features of M-MCD, in comparison with primary minimal change disease (P-MCD). Methods: We retrospectively analyzed the clinicopathological data of 21 M-MCD patients and 21 P-MCD patients. Electron micrographs of glomerular capillaries were taken, and the foot process width (FPW) was measured. A receiver operating characteristics (ROC) curve analysis was performed to determine the optimum cutoff value of FPW that can differentiate the M-MCD from P-MCD. Results: M-MCD patients presented similar clinical and routine pathological characteristics with P-MCD patients but had lower levels of FPW (935.0 [interquartile range (IQR) 853.7–1,176.7] nm vs. 1,403.2 [IQR 1,089.2–1,841.8] nm, p = 0.002). ROC curve analysis showed that FPW value below 1,385 nm might help to differentiate M-MCD from P-MCD (area under the curve of 0.787, sensitivity of 94.7%, and specificity of 52.4%). For patients with M-MCD, 77.8% achieved complete remission after mercury detoxification monotherapy. Patients with M-MCD had a lower relapse rate than patients with P-MCD (0 vs. 47.1%, p = 0.003). In addition, there was no significant difference in remission time between M-MCD patients treated with mercury detoxification monotherapy and those initially treated with immunosuppressive therapy (2.0 [IQR 1.0–6.0] months vs. 2.0 [IQR 1.5–2.5] months, p = 0.606). Conclusions: M-MCD patients showed similar clinicopathological features with P-MCD patients, but with less severe foot process effacement, suggesting different pathogenesis of these 2 disease entities. The treatment of mercury detoxification was highly effective for patients with M-MCD and can be considered as a primary choice in clinical practice.

Abstract Background The roots of Salvia miltiorrhiza are used in traditional Chinese medicine (TCM) and have high medicinal value. Tanshinone IIA (Tan IIA) is the active ingredient of Salvia miltiorrhiza which can inhibit the growth of acute leukemia cell lines in vitro, although the mechanism remains unclear. Methods CCK-8 assays and BrdU stain were used to evaluate cell proliferation ability. Western blot analysis was used to detect protein expression. miR-497-5p expression level was detected by using qRT-PCR, and Annexin V-FITC/propidium iodide (PI) was used to detect cell apoptosis. Results Here we reported that Tan IIA could inhibit cell proliferation, induce cell cycle arrest, and promote cell apoptosis in acute myeloid leukemia (AML) cells. Thus, Tan IIA had the anti-cancer activity in AML cell lines, which was likely mediated by up-regulation of miR-497-5p expression. Our data further showed that in AML cells, the same effects were observed with overexpression of miR-497-5p by a miR-497-5p mimic. We demonstrated that Tan IIA could inhibit the expression of AKT3 by up-regulating the expression of miR-497-5p. We subsequently identified that AKT3 was the direct target of miR-497-5p, and that treatment with Tan IIA obviously reversed the effect of treatment with an miR-497-5p inhibitor under harsh conditions. In turn, PCNA expression was increased and cleaved Caspase-3 was suppressed, which contributed to the growth of AML cells. Conclusions Our results showed that Tan IIA could inhibit cell proliferation in AML cells through miR-497-5p-mediated AKT3 downregulation pathway.

Heat stress negatively affects wheat production in many regions of the world. At present, sensitivity to heat stress remains one of the least understood aspects of wheat genetics and breeding, and measures for preventing heat stress are understudied. In this study, we used three cultivars of winter wheat (GY2018, SL02-1 and SY20) to evaluate the effect of heat stress at different days after anthesis (DAA) on yield and quality. Heat stability of the cultivars were analyzed and evaluated for the effects of two kinds of regulators on wheat under heat stress conditions. Heat treatment at 7 DAA led to the most substantial reduction in yield while GY2018 had the best heat stability with respect to yield, and demonstrated the most positive effects on several quality traits including protein content, sedimentation volume and glutenin and gliadin contents. Heat treatment at 14 DAA had the least reduction in yield, while SY20 had the best heat stability with respect to yield and heat treatment had minimal effects on quality. Heat treatment at 21 DAA had only a limited effect on yield, while SL02-1 had the best heat stability with respect to yield, but it showed the most negative effects on quality. Stable time at 14 DAA and protein content at 21 DAA can be used as indicators for detecting the stability of quality under heat stress. Among the three studied cultivars, SY20 was the most sensitive to heat stress with the stable time decreasing from 26.4 to 9.1 min, a higher sedimentation volume at 7 DAA, and a lower γ-gliadin content which increased 2.4-fold under high-temperature treatment. The addition of various regulators had different effects: potassium dihydrogen phosphate (KDP) was more protective of yield with heat stress at 7 DAA, while Duntianbao (DTB) had better effects on quality with heat stress at 21 DAA.