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Caihong Zeng - Top 30 Publications

Therapeutic Mechanism of Glucocorticoids on Cellular Crescent Formation in Patients With Antiglomerular Basement Membrane Disease.

This study aimed to explore the therapeutic mechanism of glucocorticoids (GCs) in antiglomerular basement membrane disease.

Multitarget Therapy for Maintenance Treatment of Lupus Nephritis.

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; P=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; P<0.01), and the multitarget group had a lower withdrawal rate due to adverse events (1.7% versus 8.9% for azathioprine; P=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.

A haplotype in CFH family genes confers high risk of rare glomerular nephropathies.

Despite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11 complement genes from 91 patients with atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and membranoproliferative glomerulonephritis type I (MPGN I), and identified the concomitant presence of three missense variations located within the human complement Factor H (CFH) gene cluster. The three variations, rs55807605, rs61737525 and rs57960694, have strong linkage disequilibrium; subsequent haplotype analysis indicated that ATA increased the susceptibility of these renal diseases. In silico analysis, the CFHR3 rs61737525-T risk allele altered the physical and structural properties and generated a reduction in binding affinity of the CFHR3/C3b complex. Surface plasmon resonance (SPR) binding analysis further demonstrated the substitution induced a decrease of two orders of magnitude in C3b-binding properties, with a declined cofactor activity in fluid phase. These data suggest that the haplotype carrying the causative allele behaves as a partial C3 convertase deficiency, predisposing individuals to diverse pathologic lesions underlying complement overactivation. Such genotype-phenotype discrepancies allow better understanding about these nephropathies mediated by genetic complement disorders.

Digital pathology imaging as a novel platform for standardization and globalization of quantitative nephropathology.

The introduction of digital pathology to nephrology provides a platform for the development of new methodologies and protocols for visual, morphometric and computer-aided assessment of renal biopsies. Application of digital imaging to pathology made substantial progress over the past decade; it is now in use for education, clinical trials and translational research. Digital pathology evolved as a valuable tool to generate comprehensive structural information in digital form, a key prerequisite for achieving precision pathology for computational biology. The application of this new technology on an international scale is driving novel methods for collaborations, providing unique opportunities but also challenges. Standardization of methods needs to be rigorously evaluated and applied at each step, from specimen processing to scanning, uploading into digital repositories, morphologic, morphometric and computer-aided assessment, data collection and analysis. In this review, we discuss the status and opportunities created by the application of digital imaging to precision nephropathology, and present a vision for the near future.

Clinical and pathological characteristics of Fabry disease combined with IgA nephropathy in Chinese patients

To improve diagnosis and treatment, we characterized Fabry disease combined with IgA nephropathy and its response to treatment clinically and pathologically in Chinese patients.

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

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

Membranous nephropathy occurring with type 2 diabetes mellitus

The incidence of type 2 diabetes mellitus (T2DM) is increasing, and membranous nephropathy (MN) occurs frequently with T2DM. We investigated the clinicopathological features and outcomes of patients with T2DM and MN.

Identification of G8969>A in mitochondrial ATP6 gene that severely compromises ATP synthase function in a patient with IgA nephropathy.

Here we elucidated the pathogenesis of a 14-year-old Chinese female who initially developed an isolated nephropathy followed by a complex clinical presentation with brain and muscle problems, which indicated that the disease process was possibly due to a mitochondrial dysfunction. Careful evaluation of renal biopsy samples revealed a decreased staining of cells induced by COX and NADH dehydrogenase activities, and a strong fragmentation of the mitochondrial network. These anomalies were due to the presence of a mutation in the mitochondrial ATP6 gene, G8969>A. This mutation leads to replacement of a highly conserved serine residue at position 148 of the a-subunit of ATP synthase. Increasing the mutation load in cybrid cell lines was paralleled by the appearance of abnormal mitochondrial morphologies, diminished respiration and enhanced production of reactive oxygen species. An equivalent of the G8969>A mutation in yeast had dramatic consequences on ATP synthase, with a block in proton translocation. The mutation was particularly abundant (89%) in the kidney compared to blood and urine, which is likely the reason why this organ was affected first. Based on these findings, we suggest that nephrologists should pay more attention to the possibility of a mitochondrial dysfunction when evaluating patients suffering from kidney problems.

Ultrastructural characterization of the pronephric glomerulus development in zebrafish.

The zebrafish pronephros is a valuable model for studying kidney development and diseases. Ultrastructural studies have revealed that zebrafish and mammals share similarities in nephron structures such as podocytes, slit diaphragms, glomerular basement membrane, and endothelium. However, the basic ultrastructural features of the pronephric glomerulus during glomerulogenesis have not been characterized. To understand these features, it is instructive to consider the developmental process of the pronephros glomerulus. Here, we describe the ultrastructural features of pronephric glomerulus in detail from 24 h hours post-fertilization (hpf) to 144 hpf, the period during which the pronephric glomerulus develops from initiation to its mature morphology. The pronephric glomerulus underwent progressive morphogenesis from 24 to 72 hpf, and presumptive glomerular cells were observed ventral to the aorta region at 24 hpf. The nascent glomerular basement membrane and initial lumen were formed at 36 hpf. A lumen was clearly visible in the region of the pronephros at 48 hpf. At 60 hpf, the pronephric glomerulus contained more patches of capillaries. After these transformations, the complex capillary vessel networks had formed inside the glomerulus, which was surrounded by podocyte bodies with elaborate foot processes as well as well-formed glomerular basement membrane by 72 hpf. The number of renal glomerular cells rapidly increased, and the glomerulus presented its delicate structural features by 96 hpf. Morphogenesis was completed at 120 hpf with the final formation of the pronephric glomerulus. J. Morphol. 277:1104-1112, 2016. © 2016 Wiley Periodicals, Inc.

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

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.

Clinicopathological features and prognosis of Kimura's disease with renal involvement in Chinese patients.

Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.

Clinico-pathological characteristics and outcomes of patients with biopsy-proven hypertensive nephrosclerosis: a retrospective cohort study.

This study aimed to investigate renal outcomes and their predictors in biopsy-proven hypertensive nephrosclerosis (HN) patients and to compare clinico-pathological characteristics and prognoses between benign nephrosclerosis (BN) and malignant nephrosclerosis (MN) patients.

Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome.

Genetic defects in complement proteins reportedly contribute to the atypical hemolytic uremic syndrome (aHUS). Numerous genetic studies have been published in recent years, but limited data have been gathered from Asian countries.

Clinical-Morphological Features and Outcomes of Lupus Podocytopathy.

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.

Regulation of MUTYH, a DNA Repair Enzyme, in Renal Proximal Tubular Epithelial Cells.

MUTYH is a DNA repair enzyme that initiates a base excision repair (BER) by recognizing and removing 8-Oxoguanine (8-oxoG) and its paired adenine. We demonstrated that both TGF-β1 and H2O2 treatment led to an increased 8-oxoG in cultured human proximal tubule epithelial (HK-2) cells, while the former induced epithelial-mesenchymal transition and the latter caused cell apoptosis. Without stimulation, HK-2 cells showed MUTYH expression in mitochondria. TGF-β1 triggered a transient upregulation of mitochondrial MUTYH and induced the expression of nuclear isoforms, while H2O2 showed no role on MUTYH expression. Ureteral obstruction (UUO) mice exhibited high 8-oxoG reactivity with tubulointerstitial lesions. After obstruction, the MUTYH expression was increased only in tubules at day 3 and decreased with obvious tubular atrophy at day 10. Particularly, MUTYH was primarily located in normal tubular cytoplasm with a dominant mitochondrial form. A few cells with nuclear MUTYH expression were observed in the fibrotic interstitium. We confirmed that increased MUTYH expression was upregulated and positively correlated with the severity of kidney fibrosis. Thus, renal fibrosis caused a cell-type-specific and time-dependent response of oxidative DNA repairs, even within the same tissues. It suggests that intervention of MUTYH might be effective for therapies.

Increased miR-374b promotes cell proliferation and the production of aberrant glycosylated IgA1 in B cells of IgA nephropathy.

The number of B cells is increased and the O-glycans of IgA1 are incompletely galactosylated in IgA nephropathy (IgAN). Here we report that expression of phosphatase and tensin homolog (PTEN) and Cosmc is decreased in B cells, and correlates with B cell number and the aberrant glycosylation of IgA1 in IgAN. Patients with IgAN exhibit higher miR-374b in B cells compared to controls. We show that miR-374b targets PTEN and Cosmc by luciferase assays and western blot analysis. Inhibition of miR-374b increased PTEN and Cosmc expression, and prevented cell proliferation and aberrant glycosylation of IgA1, thus representing a new therapeutic approach for IgAN.

Etiology and Outcome of Crescentic Glomerulonephritis From a Single Center in China: A 10-Year Review.

The disease spectrum of crescentic glomerulonephritis (GN) has been described in only a few previous studies, and detailed epidemiologic data from China are unavailable to date.

The evolution of morphological variants of focal segmental glomerulosclerosis: a repeat biopsy-based observation.

The Columbia classification employs a systematic, hierarchical approach to define five mutually exclusive variants. Studies have demonstrated differences in baseline clinical characteristics and outcomes among the Columbia classification variants. However, the evolution of the Columbia classification variants of primary focal segmental glomerulosclerosis (FSGS) is unclear. We assessed the evolution of morphological variants in FSGS based on repeat native renal biopsies.

CD47 deficiency ameliorates autoimmune nephritis in Fas(lpr) mice by suppressing IgG autoantibody production.

CD47, a self-recognition marker, plays an important role in both innate and adaptive immune responses. To explore the potential role of CD47 in activation of autoreactive T and B cells and the production of autoantibodies in autoimmune disease, especially systemic lupus erythematosus (SLE), we have generated CD47 knockout Fas(lpr) (CD47(-/-) -Fas(lpr) ) mice and examined histopathological changes in the kidneys, cumulative survival rates, proteinuria, extent of splenomegaly and autoantibodies, serum chemistry and immunological parameters. In comparison with Fas(lpr) mice, CD47(-/-) -Fas(lpr) mice exhibit a prolonged lifespan and delayed autoimmune nephritis, including glomerular cell proliferation, basement membrane thickening, acute tubular atrophy and vacuolization. CD47(-/-) -Fas(lpr) mice have lower levels of proteinuria, associated with reduced deposition of complement C3 and C1q, and IgG but not IgM in the glomeruli, compared to age-matched Fas(lpr) mice. Serum levels of antinuclear antibodies and anti-double-stranded DNA antibodies are significantly lower in CD47(-/-) -Fas(lpr) than in Fas(lpr) mice. CD47(-/-) -Fas(lpr) mice also display less pronounced splenomegaly than Fas(lpr) mice. The mechanistic studies further suggest that CD47 deficiency impairs the antigenic challenge-induced production of IgG but not IgM, and that this effect is associated with reduction of T follicular cells and impairment of germinal centre development in lymphoid tissues. In conclusion, our results demonstrate that CD47 deficiency ameliorates lupus nephritis in Fas(lpr) mice via suppression of IgG autoantibody production.

Clinical and morphological features of collagen type III glomerulopathy: a report of nine cases from a single institution.

We report nine Chinese patients with collagen type III glomerulopathy.

The clinical features and outcomes of systemic AL amyloidosis: a cohort of 231 Chinese patients.

Few data are available on the clinical features and outcomes of Chinese patients with systemic immunoglobulin light-chain (AL) amyloidosis. The aim of this study is to reveal the clinical picture and risk factors of disease progression in a large cohort of Chinese patients with AL amyloidosis.

Clinical and morphological features of fibronectin glomerulopathy: a report of ten patients from a single institution.

Fibronectin glomerulopathy is a rare glomerular disease caused by the progressive deposition of fibronectin. We report 10 Chinese patients with fibronectin glomerulopathy.

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

Treatment of lupus nephritis (LN) remains challenging.

A non-invasive laboratory panel as a diagnostic and prognostic biomarker for thrombotic microangiopathy: development and application in a Chinese cohort study.

Thrombotic microangiopathy (TMA) in the kidney is a histopathologic lesion that occurs in a number of clinical settings and is often associated with poor renal prognosis. The standard test for the diagnosis of TMA is the renal biopsy; noninvasive parameters such as potential biomarkers have not been developed.

Relationship between serum soluble urokinase plasminogen activator receptor level and steroid responsiveness in FSGS.

Soluble urokinase plasminogen activator receptor (suPAR) was initially proposed as a pathogenic and predictive biomarker of primary FSGS, but the findings were controversial. This study aimed to clarify the clinical implications of suPAR.

Renal histologic changes and the outcome in patients with diabetic nephropathy.

The progression of diabetic nephropathy (DN) is frequently determined by clinical parameters; however, the predictive value of histologic lesions remains largely unknown. Our aim was to evaluate the relationship between histologic changes and renal outcome in patients with type 2 diabetes mellitus (T2DM).

The spectrum of biopsy-proven kidney diseases in elderly Chinese patients.

Studies on biopsy-proven renal disease in the elderly (age ≥65 years) are extremely limited in China. The aim of this study was to examine the spectrum of renal diseases and their clinical presentations in elderly patients undergoing renal biopsy.

Clinicopathological characteristics and outcomes of pediatric patients with systemic small blood vessel vasculitis.

Systemic small blood vessel vasculitis (SSV) is uncommon among pediatric patients, and the predictive value of the new histopathological classification for SSV in terms of renal outcomes in these patients is unknown.

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

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.

Podocyte autophagic activity plays a protective role in renal injury and delays the progression of podocytopathies.

The progression of podocytopathies is quite variable among patients and the underlying reason for this remains unclear. Here, we report that autophagic activity in podocytes plays a critical role in controlling the progression of podocytopathies. Morphological and biochemical studies on renal biopsies from patients with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) showed that glomeruli, and in particular podocytes, from MCD patients had higher levels of Beclin1-mediated autophagic activity than glomeruli from FSGS patients. Repeat renal biopsies of MCD patients enabled tracking of podocyte autophagic activity and confirmed that patients maintaining high podocyte autophagic activity retained MCD status, whereas patients with decreased podocyte autophagic activity progressed to FSGS. Inhibition of autophagic activity, by knocking down Beclin1 or by treating with 3-methyladenine (3-MA) or chloroquine, enhanced puromycin aminonucleoside (PAN)-induced apoptosis of podocytes. In contrast, rapamycin-mediated promotion of autophagic activity decreased this apoptosis. In PAN-treated rats, inhibition of autophagy with 3-MA or chloroquine resulted in earlier onset and greater proteinuria, more extensive foot-process effacement, and reduction in podocyte markers, whereas rapamycin-mediated stimulation of autophagy led to decreased proteinuria and less severe foot-process effacement, but higher expression of podocyte markers. This study demonstrates that podocyte autophagic activity plays a critical protective role in renal injury and that maintaining podocyte autophagic activity represents a potential therapeutic strategy for controlling the progression of podocytopathies.