Publications by authors named "Zhengzhao Liu"

25 Publications

  • Page 1 of 1

Opposing roles of E3 ligases TRIM23 and TRIM21 in regulation of ion channel ANO1 protein levels.

J Biol Chem 2021 May 3:100738. Epub 2021 May 3.

Division of Life Science, Hong Kong University of Science and Technology, Hong Kong; Department of Chemical and Biological Engineering, Hong Kong University of Science and Technology, Hong Kong; State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong; HKUST Shenzhen Research Institute, Hong Kong University of Science and Technology, Hong Kong; Hong Kong Branch of Guangdong Southern Marine Science and Engineering Laboratory (Guangzhou), Hong Kong University of Science and Technology, Hong Kong. Electronic address:

ANO1 (TMEM16A) is a calcium-activated chloride channel that plays critical roles in diverse physiological processes, such as sensory transduction and epithelial secretion. ANO1 levels have been shown to be altered under physiological and pathological conditions, although the molecular mechanisms that control ANO1 protein levels remain unclear. The ubiquitin-proteasome system is known to regulate the levels of numerous ion channels, but little information is available regarding whether and how ubiquitination regulates levels of ANO1. Here, we showed that two E3 ligases, TRIM23 and TRIM21, physically interact with the C-terminus of ANO1. In vitro and in vivo assays demonstrated that whereas TRIM23 ubiquitinated ANO1 leading to its stabilization, TRIM21 ubiquitinated ANO1 and induced its degradation. Notably, ANO1 regulation by TRIM23 and TRIM21 is involved in chemical-induced pain sensation, salivary secretion, and heart-rate control in mice, and TRIM23 also mediates ANO1 upregulation induced by epidermal growth factor (EGF) treatment. Our results suggest that these two antagonistic E3 ligases act together to control ANO1 expression and function. Our findings reveal a previously unrecognized mechanism for regulating ANO1 protein levels and identify a potential molecular link between ANO1 regulation, EGF, and other signaling pathways.
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http://dx.doi.org/10.1016/j.jbc.2021.100738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191318PMC
May 2021

and osteogenesis up-regulated by two-dimensional nanosheets through a macrophage-mediated pathway.

Biomater Sci 2021 Feb;9(3):780-794

Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China. and Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China and Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha 410008, China and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China and Hunan Key Laboratory of Organ Injury, Aging and Regenerative Medicine, Changsha 410008, China and Hunan Key Laboratory of Bone Joint Degeneration and Injury, Changsha 410008, China.

Two-dimensional (2D) nanomaterials are attracting more and more interest in regenerative medicine due to their unique properties; however 2D biomimetic calcium mineral has not yet been developed and demonstrated application for bone tissue engineering. Here we described a novel calcium phosphate material with a 2D nanostructure that was synthesized using collagen and sodium alginate as the template. In vitro performance of the nanocrystalline material was evaluated, and we found that 2D CaP nanoparticles (NPs) enhanced the in vitro osteogenic differentiation of rat mesenchymal stem cells (rMSCs) through a macrophage-mediated signal pathway, when co-cultured with RAW 264.7 cells, rather than direct NP/stem cell interaction. A 2D topology structured surface was constructed by encapsulating the CaP nanomaterials in a gelatin hydrogel, which was demonstrated to be able to mediate in vivo ossification through a macrophage polarization related pathway in a femur defect rat model, and allowed the optimal therapeutic outcome compared to normal CaP counterparts. Our current work may have enlightened a new mechanism regarding NP-induced stem cell differentiation through immunoregulation, and the 2D CaP encapsulated hydrogel scaffold may serve as a potential alternative to autograft bone for orthopedic applications.
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http://dx.doi.org/10.1039/d0bm01596bDOI Listing
February 2021

Coronavirus disease 2019 in renal transplant recipients: Report of two cases.

Transpl Infect Dis 2020 Oct 31;22(5):e13329. Epub 2020 Jul 31.

Department of Nephrology, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University, Nanjing, China.

Coronavirus disease 2019 (COVID-19) has been a pandemic worldwide. The data about COVID-19 in renal transplant recipient are deficiency. Herein, we report two COVID-19 cases in renal transplant recipients. Both cases were discharged following a treatment regimen including discontinued immunosuppressant and low-dose methylprednisolone-based therapy. There were no signs of rejection during the treatment. These successfully treated cases can provide helpful information about the management of COVID-19 in renal transplant recipients.
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http://dx.doi.org/10.1111/tid.13329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267089PMC
October 2020

Induction of diabetes in cynomolgus monkey with one shot of analytical grade streptozotocin.

Animal Model Exp Med 2020 Mar 20;3(1):79-86. Epub 2020 Mar 20.

Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational Medicine Shenzhen Second People's Hospital The First Affiliated Hospital of Shenzhen University Health Science Center Shenzhen China.

Backgrounds: Streptozotocin (STZ)- induced diabetic monkey is a wide used preclinical animal model for the investigation of diabetes such as islet transplantation and development of diabetic drugs. There are serious side effects of this method, including nausea, emesis, weight loss, liver damage, renal failure, and metabolic acidosis. In order to reduce the side effects, diabetic monkeys were induced using clinical-grade STZ. However, clinical-grade STZ is not available in China. Here, we establised a method by using 100 mg/kg analytical-grade STZ to induce complete diabetes in cynomolgus monkey without generating adverse effects to liver and renal.

Methods: Three cynomolgus monkeys were used in this study. 100 mg/kg STZ dissolved in normal saline and infused through vein line in 5 minutes after indwelling catheter in the carotid artery and jugular vein. After the STZ administration, blood glucose levels were examined every 1 or 2 hours in the first 48 hours. Then, blood glucose levels were examined twice per day during the first week after the STZ injection. Insulin and C-peptide levels were measured by ELISA. Blood chemistry of hepatic and renal function tests were performed. Insulin and glucagon expression in the islet of diabetic monkey and normal monkey were examined by immunohistochemistry assays.

Results: The stimulated C-peptide level (Intravenous glucose tolerance test) which is less than 0.5 ng/mL, the triphasic blood glucose response and the destroyed β cell suggested the complete induction of diabetes model. No apparent adverse effects were observed including no signs of vomiting and toxicity after STZ injection.

Conclusion: In summary, we established a safe and reproducible STZ-induced diabetic cynomolgus monkey model for islet transplantation which will be used to develop novel approaches for the treatment of diabetes.
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http://dx.doi.org/10.1002/ame2.12109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167243PMC
March 2020

Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice.

FASEB J 2019 06 26;33(6):6838-6851. Epub 2019 Feb 26.

Department of Chemical and Biological Engineering, Hong Kong University of Science and Technology (HKUST), Hong Kong, China.

The channel that governs mechanotransduction (MT) by hair cells in the inner ear has been investigated intensively for 4 decades, but its precise molecular composition remains enigmatic. Transmembrane channel-like protein 1 (TMC1) was recently identified as a component of the MT channel, and lipoma HMGIC fusion partner-like 5 (LHFPL5) is considered to be part of the MT complex and may functionally couple the tip link to the MT channel. As components of the MT complex, TMC1 and LHFPL5 are expected to localize at the lower end of the tip link in hair cells, a notion generally supported by previous studies on neonatal mice. However, the localization of these 2 proteins, particularly in the hair cells of adult mice, remains incompletely elucidated. Because determination of TMC1 and LHFPL5 localization at distinct developmental stages is essential for understanding their function and regulation, we used several approaches to examine the localization of these proteins in neonatal and adult hair cells in the mouse. We report several notable findings: ) TMC1 and LHFPL5 predominantly localize at the tip of the shorter rows of stereocilia in neonatal hair cells, which largely verifies the previously published findings in neonatal hair cells; ) LHFPL5 persists in the hair bundle of hair cells after postnatal day (P)7, which clarifies the previously reported unexpected absence of LHFPL5 after P7 and supports the view that LHFPL5 is a permanent component in the MT complex; and ) TMC1 and LHFPL5 remain at the tip of the shorter rows of stereocilia in adult outer hair cells, but in adult inner hair cells, TMC1 is uniformly distributed in both the tallest row and the shorter rows of stereocilia, whereas LHFPL5 is uniformly distributed in the shorter rows of stereocilia. These findings raise intriguing questions regarding the turnover rate, regulation, additional functions, and functional interaction of TMC1 and LHFPL5. Our study confirms the previous findings in neonatal hair cells and reveals several previously unidentified aspects of TMC1 and LHFPL5 localization in more mature hair cells.-Li, X., Yu, X., Chen, X., Liu, Z., Wang, G., Li, C., Wong, E. Y. M., Sham, M. H., Tang, J., He, J., Xiong, W., Liu, Z., Huang, P. Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice.
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http://dx.doi.org/10.1096/fj.201802155RRDOI Listing
June 2019

Distinction between MPO-ANCA and PR3-ANCA-associated glomerulonephritis in Chinese patients: a retrospective single-center study.

Clin Rheumatol 2019 Jun 8;38(6):1665-1673. Epub 2019 Feb 8.

Jinling Clinical Medical College of Nanjing Medical University, Nanjing, China.

Objectives: To retrospectively investigate the clinical and histological features and outcomes of ANCA-associated glomerulonephritis (AAGN) with different ANCA serotypes.

Method: A total of 467 AAGN patients were divided into MPO-AAGN (MPO) and PR3-AAGN (PR3) groups according to ANCA serotype. Clinical and histological features and renal outcomes were compared.

Results: In this study, 429 (91.9%) patients tested positive for MPO-ANCA, and 38 (8.1%) for PR3-ANCA. The median age at diagnosis (P = 0.017) and proportion of females (P = 0.003) were higher in the MPO group. Joint (P < 0.001), ENT (P = 0.000), skin (P = 0.007), and eye (P = 0.014) involvements were more common in the PR3 group. Compared with that in the PR3-group, a higher proportion of patients in the MPO group had microscopic polyangiitis (P = 0.000), and a lower proportion of exhibited granulomatosis with polyangiitis (P = 0.000). Patients in the MPO group also exhibited lower BVAS scores (P = 0.003) and higher serum albumin levels (P = 0.009). Histologically, a lower proportion of MPO patients had crescentic glomerulonephritis (P = 0.028) and acute tubule-interstitial lesion scores (P = 0.007), but a higher proportion of these patients exhibited mixed class glomerulonephritis (P = 0.032) than in the PR3 group. The relapse rate was lower (P = 0.020), and the 5-year relapse-free survival rate (P = 0.003) was higher in the MPO group than in the PR3 group. However, the 5-year renal survival rates (P = 0.106) were not significantly different.

Conclusions: MPO-ANCA was predominant in Chinese patients with ANCA-associated vasculitis and renal disease. The epidemiological characteristics, extra-renal involvement, and histopathological classes and outcomes were different between MPO-positive and PR3-positive patients, implying that they might be two different disease entities.
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http://dx.doi.org/10.1007/s10067-019-04458-9DOI Listing
June 2019

A Method for Islet Transplantation to the Omentum in Mouse.

J Vis Exp 2019 01 7(143). Epub 2019 Jan 7.

Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, Shenzhen University Health Science Center;

Islet transplantation has been proposed to be a potential treatment for type 1 diabetes. Recent compelling evidence indicates that intravascular islet infusion is far from ideal and therefore, the omentum is re-emerging as a potentially valuable site for islet transplantation. This experiment requires the isolation of high quality islets and the implantation of the islets to the diabetic recipients. Transplantation to the omentum requires surgical steps that can be better demonstrated visually. Here, the detailed steps for this procedure are presented. Two methods of mixing the isolated islets with hydrogel before placing the mixture into the omental pouch of diabetic mice are described here. Different hydrogels are used for the different conditions. Blood glucose levels of diabetic mouse recipients of syngeneic islets in the omentum were monitored for up to 35 days. Some animals were sacrificed after 14 days to perform immuno-histochemical analysis. This pre-clinical transplantation approach can be used as preliminary data leading up to translation to clinical transplantation.
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http://dx.doi.org/10.3791/57160DOI Listing
January 2019

ALS-Associated E478G Mutation in Human OPTN (Optineurin) Promotes Inflammation and Induces Neuronal Cell Death.

Front Immunol 2018 14;9:2647. Epub 2018 Nov 14.

State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Shanghai, China.

Amyotrophic Lateral Sclerosis (ALS) is a group of neurodegenerative disorders that featured with the death of motor neurons, which leads to loss of voluntary control on muscles. The etiologies vary among different subtypes of ALS, and no effective management or medication could be provided to the patients, with the underlying mechanisms incompletely understood yet. Mutations in human (Optineurin), particularly E478G, have been found in many ALS patients. In this work, we report that NF-κB activity was increased in knockout () MEF (mouse embryonic fibroblast) cells expressing OPTN of different ALS-associated mutants especially E478G. Inflammation was significantly activated in mice infected with lenti-virus that allowed overexpression of mutation in the motor cortex, with marked increase in the secretion of pro-inflammatory cytokines as well as neuronal cell death. Our work with both cell and animal models strongly suggested that anti-inflammation treatment could represent a powerful strategy to intervene into disease progression in ALS patients who possess the distinctive mutations in gene.
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http://dx.doi.org/10.3389/fimmu.2018.02647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251386PMC
October 2019

Risk factors for infectious complications of ANCA-associated vasculitis: a cohort study.

BMC Nephrol 2018 06 14;19(1):138. Epub 2018 Jun 14.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China.

Background: Severe infections are common complications of immunosuppressive treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with renal involvement. We investigated the clinical characteristics and risk factors of severe infection in Chinese patients with AAV after immunosuppressive therapy.

Methods: A total of 248 patients with a new diagnosis of ANCA-associated vasculitis were included in this study. The incidence, time, site, and risk factors of severe infection by the induction therapies were analysed. Multivariate Cox proportional hazards models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CI).

Results: A total of 103 episodes of severe infection were identified in 86 (34.7%, 86/248) patients during a median follow-up of 15 months. The incidence of infection during induction therapy was 38.5% for corticosteroids (CS), 39.0% for CS+ intravenous cyclophosphamide (IV-CYC), 33.8% for CS+ mycophenolate mofetil and 22.5% for CS + tripterygium glycosides, 76 (73.8%) infection episodes occurred within 6 months, while 66 (64.1%) occurred within 3 months. Pneumonia (71.8%, 74/103) was the most frequent type of infection, and the main pathogenic spectrum included bacteria (78.6%), fungi (12.6%), and viruses (8.7%). The risk factors associated with infection were age at the time of diagnosis (HR = 1.003, 95% CI = 1.000-1.006), smoking (HR = 2.338, 95% CI = 1.236-4.424), baseline secrum creatinine (SCr) ≥5.74 mg/dl (HR = 2.153, 95% CI = 1.323-3.502), CD4 T cell< 281 μl (HR = 1.813, 95% CI = 1.133-2.900), and intravenous cyclophosphamide regimen (HR = 1.951, 95% CI =1.520-2.740). Twelve (13.9%) patients died of severe pneumonia.

Conclusion: The infection rate during induction therapy was high in patients with AAV. Bacterial pneumonia was the main type of infection encountered. Age at the time of diagnosis, smoking, baseline SCr ≥5.74 mg/dl, CD4 T cell< 281 μl, and IV-CYC therapy were identified as risk factors for infection.
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http://dx.doi.org/10.1186/s12882-018-0933-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002994PMC
June 2018

Transcriptomic analysis uncovers novel synergistic mechanisms in combination therapy for lupus nephritis.

Kidney Int 2018 02;93(2):416-429

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China. Electronic address:

A recent clinical study showed that combination therapy consisting of mycophenolate mofetil, tacrolimus and steroids was shown to be more effective in achieving complete remission in patients with severe forms of lupus nephritis than conventional therapy consisting of intravenous cyclophosphamide and steroids. To explore the underlying molecular and cellular mechanisms of increased efficacy of the combination therapy regimen, we employed a mouse model of lupus nephritis, MRL/lpr mice, and treated them with monotherapies of prednisone, mycophenolate mofetil, or tacrolimus, or with their combination. Consistent with previous clinical findings, combination therapy markedly improved renal outcome compared to the monotherapies in mice with lupus nephritis. Transcriptomic analysis of their kidneys revealed distinct molecular pathways that were differentially regulated in combination therapy versus monotherapies. Combination therapy not only provided additive immunosuppressive effects, but also induced gene expression and molecular pathways to confer enhanced renoprotection. Specifically, combination therapy inhibited TLR7 expression in the kidneys of mice with lupus nephritis; combination of tacrolimus and mycophenolate mofetil led to better stabilization of the podocyte actin cytoskeleton through the reciprocal regulation of RhoA and Rac1 activities. Combination therapy strongly suppressed the IL-6/Stat3 pathway. These findings were further validated in renal biopsy samples from patients with lupus nephritis before and after treatments with mycophenolate mofetil, tacrolimus or combination therapy. Thus, our study further supports the earlier clinical finding and further provides insights into the molecular basis for increased efficacy of combination therapy.
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http://dx.doi.org/10.1016/j.kint.2017.08.031DOI Listing
February 2018

Multitarget Therapy for Maintenance Treatment of Lupus Nephritis.

J Am Soc Nephrol 2017 Dec 31;28(12):3671-3678. Epub 2017 Jul 31.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China;

Our previous studies showed that multitarget therapy is superior in efficacy to intravenous cyclophosphamide as an induction treatment for lupus nephritis in Asian populations. We conducted an open label, multicenter study for 18 months as an extension of the prior induction therapy trial in 19 renal centers in China to assess the efficacy and safety of multitarget maintenance therapy in patients who had responded at 24 weeks during the induction phase. Patients who had undergone multitarget induction therapy continued to receive multitarget therapy (tacrolimus, 2-3 mg/d; mycophenolate mofetil, 0.50-0.75 g/d; prednisone, 10 mg/d), and patients who had received intravenous cyclophosphamide induction treatment received azathioprine (2 mg/kg per day) plus prednisone (10 mg/d). We assessed the renal relapse rate during maintenance therapy as the primary outcome. We recruited 116 patients in the multitarget group and 90 patients in the azathioprine group. The multitarget and azathioprine groups had similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67; 0.74), and serum creatinine levels and eGFR remained stable in both groups. The azathioprine group had more adverse events (44.4% versus 16.4% for multitarget therapy; <0.01), and the multitarget group had a lower withdrawal rate due to adverse events (1.7% versus 8.9% for azathioprine; =0.02). In conclusion, multitarget therapy as a maintenance treatment for lupus nephritis resulted in a low renal relapse rate and fewer adverse events, suggesting that multitarget therapy is an effective and safe maintenance treatment for patients with lupus nephritis.
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http://dx.doi.org/10.1681/ASN.2017030263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698076PMC
December 2017

The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms.

Elife 2017 06 28;6. Epub 2017 Jun 28.

Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China.

Adenylyl cyclases (ACs) generate cAMP, a second messenger of utmost importance that regulates a vast array of biological processes in all kingdoms of life. However, almost nothing is known about how AC activity is regulated through protein degradation mediated by ubiquitination or other mechanisms. Here, we show that transcriptional regulator interacting with the PHD-bromodomain 1 (TRIP-Br1, Sertad1), a newly identified protein with poorly characterized functions, acts as an adaptor that bridges the interaction of multiple AC isoforms with X-linked inhibitor of apoptosis protein (XIAP), a RING-domain E3 ubiquitin ligase. XIAP ubiquitinates a highly conserved Lys residue in AC isoforms and thereby accelerates the endocytosis and degradation of multiple AC isoforms in human cell lines and mice. XIAP/TRIP-Br1-mediated degradation of ACs forms part of a negative-feedback loop that controls the homeostasis of cAMP signaling in mice. Our findings reveal a previously unrecognized mechanism for degrading multiple AC isoforms and modulating the homeostasis of cAMP signaling.
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http://dx.doi.org/10.7554/eLife.28021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503512PMC
June 2017

Pig-to-Primate Islet Xenotransplantation: Past, Present, and Future.

Cell Transplant 2017 06 3;26(6):925-947. Epub 2017 Feb 3.

Islet allotransplantation results in increasing success in treating type 1 diabetes, but the shortage of deceased human donor pancreata limits progress. Islet xenotransplantation, using pigs as a source of islets, is a promising approach to overcome this limitation. The greatest obstacle is the primate immune/inflammatory response to the porcine (pig) islets, which may take the form of rapid early graft rejection (the instant blood-mediated inflammatory reaction) or T-cell-mediated rejection. These problems are being resolved by the genetic engineering of the source pigs combined with improved immunosuppressive therapy. The results of pig-to-diabetic nonhuman primate islet xenotransplantation are steadily improving, with insulin independence being achieved for periods >1 year. An alternative approach is to isolate islets within a micro- or macroencapsulation device aimed at protecting them from the human recipient's immune response. Clinical trials using this approach are currently underway. This review focuses on the major aspects of pig-to-primate islet xenotransplantation and its potential for treatment of type 1 diabetes.
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http://dx.doi.org/10.3727/096368917X694859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657750PMC
June 2017

Risk Factors for Renal Survival in Chinese Patients with Myeloperoxidase-ANCA-Associated GN.

Clin J Am Soc Nephrol 2017 Mar 1;12(3):417-425. Epub 2017 Feb 1.

National Clinical Research Centre of Kidney Diseases, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing, China

Background And Objectives: Our study explored the association of histopathologic classification of ANCA-associated GN with renal survival in Chinese patients with myeloperoxidase-ANCA-associated GN.

Design, Setting, Participants, & Measurements: Two hundred fifteen patients with biopsy-proven myeloperoxidase-ANCA-associated GN were included from January of 1996 to December of 2014. The biopsies included focal (=27), mixed (=82), crescentic (=47), and sclerotic (=59) classes. The long-term renal outcome and risk factors of myeloperoxidase-ANCA-associated GN for different histopathologic classes were retrospectively analyzed.

Results: During a median follow-up time of 22 (9-51) months, 88 (40.9%) patients reached ESRD. The 5-year renal survival (overall 58.7%) was highest in the focal class (100.0%) and lowest in the sclerotic class (20.7%), with no difference between the mixed (58.9%) and crescentic (67.4%) classes. Patients in the mixed (hazard ratio, 0.34; 95% confidence interval, 0.20 to 0.57; <0.001) and crescentic (hazard ratio, 0.31; 95% confidence interval, 0.16 to 0.59; <0.001) classes were at lower risk for ESRD compared with patients in the sclerotic class, as were patients who received glucocorticoids plus mycophenolate mofetil (hazard ratio, 0.32; 95% confidence interval, 0.18 to 0.60; <0.001) compared with those receiving glucocorticoids alone. In addition, patients with a serum creatinine level ≥4 mg/dl (hazard ratio, 2.93; 95% confidence interval, 1.77 to 4.85; <0.001) or hypoalbuminemia (hazard ratio, 2.11; 95% confidence interval, 1.32 to 3.34; =0.002) were at higher risk for ESRD. A serum creatinine level ≥4 mg/dl and a percentage of global sclerotic glomeruli ≥60% were the two independent risk factors for ESRD in the sclerotic class.

Conclusions: The histopathologic classification of ANCA-associated GN in combination with serum creatinine and serum albumin levels and treatment regimen is associated with renal outcome in myeloperoxidase-ANCA-associated GN. The evaluation of serum creatinine level and percentage of global sclerotic glomeruli provides additional information on the risk of renal survival in the sclerotic class of myeloperoxidase-ANCA-associated GN.
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http://dx.doi.org/10.2215/CJN.06200616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338707PMC
March 2017

Long-term outcomes in antineutrophil cytoplasmic autoantibody-positive eosinophilic granulomatosis with polyangiitis patients with renal involvement: a retrospective study of 14 Chinese patients.

BMC Nephrol 2016 07 26;17(1):101. Epub 2016 Jul 26.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China.

Background: The clinic-pathological features and outcomes of Chinese patients with antineutrophil cytoplasmic autoantibody (ANCA)-positive eosinophilic granulomatosis with polyangiitis (EGPA) and renal involvement have not been studied.

Methods: Fourteen EGPA patients with renal involvement were included. All patients underwent renal biopsy. Clinic-pathological features and outcomes were retrospectively analyzed.

Results: The most common initial symptom of EGPA was asthma (57.1 %), followed by hemoptysis (21.4 %), gross hematuria (14.3 %), and arthritis (7.1 %). All patients had positive serum ANCA (anti-MPO in 12, anti-PR3 in 2). Elevated eosinophils (median 15 %, range 10-45 %) were found in all patients. The median serum IgE level was 463 g/L (range 200-1000 g/L). All patients presented with renal dysfunction, with a median SCr of 5.4 mg/dL (range 1.47-11 mg/dL), seven patients (50 %) required initial renal replacement therapy. Thirteen patients showed hematuria and proteinuria (median 1.1 g/24 h, range 0.5-7.8 g/24 h). Renal biopsy showed pauci-immune segmental necrotizing glomerulonephritis with crescents in 13 patients and acute interstitial nephritis in one patient. Twelve patients (85.7 %) showed renal interstitial eosinophil infiltration, among whom three had eosinophilic granuloma. Among seven patients (71.4 %) who required initial dialysis, 5 discontinued dialysis, one died, one received maintenance dialysis after glucocorticoids plus immunosuppressive for induction treatment. Twelve patients were followed up for a median of 43.5 months (range 6-83 months), during follow-up, two patients progressed to end-stage renal disease, nine had chronic kidney disease with eGFR < 60 mL/min, and two patients had normal eGFR.

Conclusions: Renal involvement in ANCA-positive EGPA could be severe and showed varied renal histology. Although intensive immunosuppressive therapy effectively improved the renal function, the long-term renal survival was poor. Early diagnosis and treatment are essential to improve long-term renal survival.
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http://dx.doi.org/10.1186/s12882-016-0319-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962371PMC
July 2016

Actinin-1 binds to the C-terminus of A2B adenosine receptor (A2BAR) and enhances A2BAR cell-surface expression.

Biochem J 2016 07 17;473(14):2179-86. Epub 2016 May 17.

Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China Division of Biomedical Engineering, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China

A2BAR (A2B adenosine receptor) has been implicated in several physiological conditions, such as allergic or inflammatory disorders, vasodilation, cell growth and epithelial electrolyte secretion. For mediating the protein-protein interactions of A2BAR, the receptor's C-terminus is recognized to be crucial. In the present study, we unexpectedly found that two point mutations in the A2BAR C-terminus (F297A and R298A) drastically impaired the expression of A2BAR protein by accelerating its degradation. Thus we tested the hypothesis that these two point mutations disrupt A2BAR's interaction with a protein essential for A2BAR stability. Our results show that both mutations disrupted the interaction of A2BAR with actinin-1, an actin-associated protein. Furthermore, actinin-1 binding stabilized the global and cell-surface expression of A2BAR. By contrast, actinin-4, another non-muscle actinin isoform, did not bind to A2BAR. Thus our findings reveal a previously unidentified regulatory mechanism of A2BAR abundance.
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http://dx.doi.org/10.1042/BCJ20160272DOI Listing
July 2016

Long-term outcome of mycophenolate mofetil treatment for patients with microscopic polyangiitis: an observational study in Chinese patients.

Rheumatol Int 2016 Jul 11;36(7):967-74. Epub 2016 May 11.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China.

This study aimed to retrospectively analyze the long-term outcome of mycophenolate mofetil (MMF) therapy for microscopic polyangiitis (MPA) with mild to moderate renal involvement in Chinese patients. Thirty-four MPA patients (24 females, 10 males, aged 44.7 ± 17 years, BVAS score 13.8 ± 3.2, SCr 2.2 ± 1.1 mg/dl) with SCr < 5 mg/dl and who received glucocorticoids plus MMF therapy for inducing and maintaining remission were included in this study. The remission and relapse rates, patient and renal survival rates and adverse events were retrospectively analyzed. We found that 31 (91.2 %) of 34 patients achieved remission and were continuously treated with glucocorticoids plus MMF for maintaining remission. The median duration of MMF treatment was 24 months (IQR 15-53 months) and follow-up time was 86 months (IQR 29-124 months). During the follow-up, 7 (22.6 %) patients relapsed, one patient died, and one patient progressed into end-stage renal disease. The 5-year patient and renal survival rates were 92.8 and 95.2 %, respectively. 11 (32.4 %) patients suffered 16 adverse events, 13 of which were pulmonary infection. In conclusion, glucocorticoids plus MMF regimen as induction and maintenance therapy could achieve high remission rate and good long-term renal survival in MPA patients with mild to moderate renal involvement. Prospective controlled trials with a large sample size are needed to confirm the efficacy of MMF in this population.
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http://dx.doi.org/10.1007/s00296-016-3492-5DOI Listing
July 2016

Clinical-Morphological Features and Outcomes of Lupus Podocytopathy.

Clin J Am Soc Nephrol 2016 Apr 16;11(4):585-92. Epub 2016 Mar 16.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.

Background And Objectives: Lupus podocytopathy, which is characterized by diffuse foot process effacement without peripheral capillary wall immune deposits and glomerular proliferation, has been described in SLE patients with nephrotic syndrome in case reports and small series. This study aimed to better characterize the incidence, clinical-morphologic features, and outcomes of such patients from a large Chinese cohort.

Design, Setting, Participants, & Measurements: Lupus podocytopathy was identified from 3750 biopsies of SLE patients obtained from 2000 to 2013 that showed mild glomerular histology in patients with a clinical sign of nephrotic syndrome. The biopsy results were divided into three groups: glomerular minimal change, mesangial proliferation, and FSGS.

Results: Fifty (1.33%) cases were identified as lupus podocytopathy and included minimal change in 13 cases, mesangial proliferation in 28 cases, and FSGS in nine cases. Extensive foot process effacement appeared in all the biopsies and mesangial electron-dense deposits were present in 47 biopsies. All patients demonstrated nephrotic syndrome, and the median proteinuria was 5.72 g/24 h (interquartile range [IQR], 3.82, 6.92). Seventeen (34%) cases presented with AKI. Forty-seven (94%) patients achieved remission after immunosuppressive therapy for a median time of 4 weeks (IQR, 2, 8). Compared with the patients with minimal change and mesangial proliferation, patients with FSGS showed significantly higher incidence of AKI and severe tubule-interstitial injury and a much lower complete remission rate. During follow-up of a median of 62 (IQR, 36, 84) months, renal relapses occurred in 28 (59.6%) patients. No patient died or developed ESRD.

Conclusions: The findings from this cohort study suggest that lupus podocytopathy may represent a special entity of lupus nephritis with distinct clinical-morphologic features. The differences in AKI incidence, tubular injury severity, and response to treatment between the patients with minimal change/mesangial proliferation and those with FSGS patterns indicate two different subtypes of lupus podocytopathy.
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http://dx.doi.org/10.2215/CJN.06720615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822663PMC
April 2016

Double Filtration Plasmapheresis in the Treatment of Antineutrophil Cytoplasmic Autoantibody Associated Vasculitis With Severe Renal Failure: A Preliminary Study of 15 Patients.

Ther Apher Dial 2016 Apr 7;20(2):183-8. Epub 2016 Mar 7.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.

Our aim was to investigate the clinical efficacy of double filtration plasmapheresis (DFPP) in the treatment of antineutrophil cytoplasmic autoantibody-(ANCA) associated vasculitis (AAV) with severe renal involvement. Fifteen AAV patients who had severe renal failure (median SCr 5.6(IQR 5.2-9.0) mg/dL) and needed initial renal replacement therapy (RRT) were treated with DFPP and immunosuppressive therapy. Two plasma volumes were processed during each DFPP session. The changes of serum ANCA and renal function were investigated. After the DFPP treatment for three to five sessions, serum MPO-ANCA level decreased from 250.0 ± 86.9 RU/mL to 70.5 ± 64.7RU/mL (P = 0.00), with a median reduction rate of 67.6%. Eleven patients (73.3%) no longer needed from RRT 3 months after DFPP treatment, while another four patients remained on dialysis. During the follow up for median 10 (IQR 6-24) months, SCr level decreased to normal in one patient, one patient progressed into ESRD. The 1 year renal survival rate was 62.9%. Five (33.3%) patients were complicated with pulmonary infection. DFPP combined with immunosuppressive therapy could increase the renal recovery rate through rapidly decreasing serum ANCA levels for AAV patients with severe renal failure, but its clinical efficacy and impact on long-term renal survival require further studies.
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http://dx.doi.org/10.1111/1744-9987.12389DOI Listing
April 2016

Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.

Ann Intern Med 2015 Jan;162(1):18-26

Background: Treatment of lupus nephritis (LN) remains challenging.

Objective: To assess the efficacy and safety of a multitarget therapy consisting of tacrolimus, mycophenolate mofetil, and steroid compared with intravenous cyclophosphamide and steroid as induction therapy for LN.

Design: 24-week randomized, open-label, multicenter study. (ClinicalTrials.gov: NCT00876616).

Setting: 26 renal centers in China.

Patients: Adults (aged 18 to 65 years) with biopsy-proven LN.

Intervention: Tacrolimus, 4 mg/d, and mycophenolate mofetil, 1.0 g/d, versus intravenous cyclophosphamide with a starting dose of 0.75 (adjusted to 0.5 to 1.0) g/m2 of body surface area every 4 weeks for 6 months. Both groups received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy.

Measurements: The primary end point was complete remission at 24 weeks. Secondary end points included overall response (complete and partial remission), time to overall response, and adverse events.

Results: After 24 weeks of therapy, more patients in the multitarget group (45.9%) than in the intravenous cyclophosphamide group (25.6%) showed complete remission (difference, 20.3 percentage points [95% CI, 10.0 to 30.6 percentage points]; P < 0.001). The overall response incidence was higher in the multitarget group than in the intravenous cyclophosphamide group (83.5% vs. 63.0%; difference, 20.4 percentage points [CI, 10.3 to 30.6 percentage points]; P < 0.001), and the median time to overall response was shorter in the multitarget group (difference, -4.1 weeks [CI, -7.9 to -2.1 weeks]). Incidence of adverse events did not differ between the multitarget and intravenous cyclophosphamide groups (50.3% [91 of 181] vs. 52.5% [95 of 181]).

Limitation: The study was limited to 24 weeks of follow-up.

Conclusion: Multitarget therapy provides superior efficacy compared with intravenous cyclophosphamide as induction therapy for LN.

Primary Funding Source: National Basic Research Program of China, National Key Technology R&D Program.
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http://dx.doi.org/10.7326/M14-1030DOI Listing
January 2015

Pathological spectrums and renal prognosis of severe lupus patients with rapidly progressive glomerulonephritis.

Rheumatol Int 2015 Apr 4;35(4):709-17. Epub 2014 Oct 4.

National Clinical Research Centre of Kidney Desease, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China.

The objectives of the study were to investigate the pathological features and renal prognosis of severe lupus patients with rapidly progressive glomerulonephritis. One hundred and one cases of biopsy-proven severe LN with rapidly progressive glomerulonephritis (RPGN) were analyzed in this retrospective study. Another 200 severe LN patients without RPGN were randomly enrolled as a control group. Their clinicopathological data and long-term outcome were compared. There were 76 females and 25 males with an average age of 31.9 ± 14.2 years followed for a median period of 4 years. Compared with controls, patients with RPGN had shorter LN duration (p = 0.008), higher level of creatinine (p < 0.001), severe anemia (p = 0.037), heavier hematuria (p < 0.001), severe tubular injury parameters [NAG (p < 0.001), RBP (p < 0.001), C3 (p < 0.001)], higher scores of AI (p = 0.001) and CI (p = 0.004), higher proportions of glomerular sclerosis (0.033) and crescents (p < 0.001), severe tubulointerstitial lesions (p < 0.001) and interstitial inflammation (p < 0.001), lower rate of complete remission (33.9 vs 68.2 %) and higher rate of treatment failure (46.8 vs 7.9 %). The 3-, 5- and 10-year cumulative renal survival rates of RPGN and non-RPGN patients were 65.1 versus 53.9 versus 42.9 and 96.9 versus 94.9 versus 91.7 %, respectively. Multivariate analysis revealed that SCr concentration and the proportion of crescents were the most important risk factors for end-stage renal disease (ESRD) in severe LN with RPGN (p < 0.001). In conclusion, RPGN occurred in 3.6 % of LN and is associated with severe renal manifestations, serious sclerotic and crescentic glomeruli lesions, severe tubulointerstitial inflammation, atrophy and fibrosis, prominent leukocyte infiltration and worse treatment response. Multivariate analysis revealed that SCr concentration and the proportion of crescents were the most important risk factors for ESRD. 57.1 % of severe LN patients with RPGN might progress to ESRD within 10 years.
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http://dx.doi.org/10.1007/s00296-014-3140-xDOI Listing
April 2015

Ubiquitylation of autophagy receptor Optineurin by HACE1 activates selective autophagy for tumor suppression.

Cancer Cell 2014 Jul;26(1):106-20

State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Cancer Research Center, SIBS-Xuhui Central Hospital, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China. Electronic address:

In selective autophagy, receptors are central for cargo selection and delivery. However, it remains yet unclear whether and how multiple autophagy receptors might form complex and function concertedly to control autophagy. Optineurin (OPTN), implicated genetically in glaucoma and amyotrophic lateral sclerosis, was a recently identified autophagy receptor. Here we report that tumor-suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62/SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux. Interestingly, the Lys48-linked polyubiquitin chains that HACE1 conjugates onto OPTN might predominantly target OPTN for autophagic degradation. By demonstrating that the HACE1-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells, our findings may open an avenue for developing autophagy-targeted therapeutic intervention into cancer.
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http://dx.doi.org/10.1016/j.ccr.2014.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166492PMC
July 2014

Diffuse segmental and pure diffuse global proliferative glomerulonephritis: different patterns of class IV lupus nephritis.

Clin Nephrol 2014 Jun;81(6):411-8

Nanjing University School of Medicine, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing, China.

Background: No consensus has been obtained on the differences between class IV-S and IV-G lupus nephritis (LN), especially regarding renal outcome. Our study investigated clinical-pathological features and prognosis of diffuse segmental and pure diffuse global proliferative LN.

Methods: In this retrospective study, a total of 120 patients with biopsy-proven diffuse LN were included, of which 31 patients were class IV-S and 89 were pure class IVG. Class IV-S was defined as segmental lesion involving ≥ 50% of all glomeruli, while pure class IV-G was defined as global lesion involving ≥ 50% of all glomeruli with no segmental necrosis or crescents. The clinical- pathological and prognostic features of the two classes were compared.

Results: There was no difference in levels of urine protein or serum creatinine between the two groups. Higher serological activity was observed in the pure IV-G group with lower complement C3 (p < 0.001) and C4 level (p < 0.001), compared to the IV-S group. Histologically, immune-complex deposits were significantly more common in the pure IV-G group, with higher prevalence of wire loop (42.7% vs. 0%, p < 0.001) and hyaline thrombi (34.8% vs. 3.2%, p < 0.001). However, the complete remission (CR) rate to intravenous cyclophosphamide (IVCY) induction was lower in the IV-S than in the pure IV-G group (16.7% vs. 53.2%, p = 0.023). After 1 year, the pure class IV-G group had a higher CR rate (71.9% vs. 48.4%, p = 0.017). The 10-year renal survival rate (without doubling of serum creatinine or end-stage renal disease) was significantly lower in patients with IV-S than pure IV-G (75.2% vs. 97.4%, p = 0.028).

Conclusion: LN class IV-S and class IV-G without segmental lesion showed different clinical-histological features and prognosis, suggesting that different mechanisms may exist.
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http://dx.doi.org/10.5414/cn108191DOI Listing
June 2014

Clinico-pathological features and outcomes of patients with propylthiouracil-associated ANCA vasculitis with renal involvement.

J Nephrol 2014 Apr 26;27(2):159-64. Epub 2014 Feb 26.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, University School of Medicine, Nanjing, 210002, Jiangsu, China.

Objective: To retrospectively investigate clinico-pathological features and outcomes of patients with renal involvement in propylthiouracil (PTU)-associated antineutrophil cytoplasmic autoantibody (ANCA) vasculitis (PTU-AAV).

Methods: Clinico-pathological features and outcomes of 12 patients (female 11, average age 32.4 ± 13.8 years) who developed AAV after treatment with PTU were collected and analyzed. ANCA was detected by both immunofluorescence (IF) and enzyme linked immunosorbent assay (ELISA). All patients had renal biopsy.

Results: Twelve patients received PTU for 2-264 months (median 42 months) when PTUAAV was diagnosed. All patients had positive serum P-ANCA, 11 of them were MPO-ANCA, 1 was MPO and PR3-ANCA double positive. All patients presented with hematuria and proteinuria, 5 of them had gross hematuria, urine protein was 1.9 ± 1.6 g/24 h, 7 of 12 (58.3%) patients had renal dysfunction, among them 3 needed initial renal replacement therapy. Renal biopsy showed pauci-immune segmental necrotizing crescentic glomerulonephritis in ten patients, segmental necrotizing glomerulonephritis superimposed on membranous nephropathy in two patients. All patients withdrew PTU and received steroid and immunosuppressive therapy. After a median follow-up of 42 months (range 21-86), 3 patients developed to ESRD, 7 patients entered complete renal remission. Serum ANCA turned negative only in 2 patients, 10 patients had persistent positive serum ANCA. Three patients relapsed with the elevation of serum ANCA level.

Conclusion: Renal damage of PTU-AAV could be pauci-immune necrotizing crescentic glomerulonephritis, and necrotizing glomerulonephritis coexisted with membranous nephropathy. Most patients had persistent positive serum ANCA and had a risk of relapse and progression to ESRD even after PTU withdrawal and immunosuppressive therapy.
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http://dx.doi.org/10.1007/s40620-014-0063-2DOI Listing
April 2014

Significance of histological crescent formation in patients with diffuse proliferative lupus nephritis.

Am J Nephrol 2013 13;38(6):445-52. Epub 2013 Nov 13.

Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.

Background: Although crescentic nephritis is not rare in diffuse proliferative lupus nephritis (DPLN), little is known about the clinicopathological features in DPLN with crescents worldwide. This study was undertaken to investigate the clinicopathological features and outcome of Chinese DPLN patients with different degrees of crescents.

Methods: 520 DPLN patients with more than 10% histological crescents (cDPLN) were enrolled in this retrospective study. They were divided into three groups: group 1 (10%≤ crescents <25%, n = 240), group 2 (25%≤ crescents <50%, n = 160), and group 3 (crescents ≥50%, n = 120). Another 100 patients without histological crescents were enrolled as a control group. Clinicopathological features, treatment responses, and outcomes were compared among the four groups.

Results: There were 450 (86.6%) females and 70 (13.4%) males with an average age of 31.7 ± 11.4 years. Compared with the control group, cDPLN patients had shorter lupus nephritis duration (20.7 ± 34.1 vs. 30.4 ± 48.9 months), higher prevalence of rapidly progressive glomerulonephritis syndrome (21.8%), and gross hematuria (26.7%). Laboratory findings indicated more severe hypoproteinemia, hyperlipidemia, and renal insufficiency; heavier proteinuria and microscopic hematuria; higher tubular injury parameters, and lower serological activity in crescentic groups. Histologically, cDPLN patients have severe glomerular and tubulointerstitial lesions as well as extensive leukocyte infiltration together with a lesser degree of immune complex deposition. The proportion of death, end-stage renal disease, and treatment failure correlates positively with the degree of histological crescents.

Conclusions: cDPLN patients with acute onset and short disease duration mostly show severe renal manifestations, less extrarenal organ involvement, lower serological activity, serious capillary necrosis, severe tubulointerstitial inflammation, atrophy and fibrosis, prominent leukocyte infiltration, less glomerular immune complex deposition, poor treatment response, and worse renal outcome.
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http://dx.doi.org/10.1159/000356184DOI Listing
September 2014