Therapeutic apheresis in kidney diseases: an updated review.

Besides conventional medical therapies, therapeutic apheresis has become an important adjunctive or alternative therapeutic option to immunosuppressive agents for primary or secondary kidney diseases and kidney transplantation. The available therapeutic apheresis techniques used in kidney diseases, including plasma exchange, double-filtration plasmapheresis, immunoadsorption, and low-density lipoprotein apheresis. Plasma exchange is still the leading extracorporeal therapy. Recently, growing evidence supports the potential benefits of double-filtration plasmapheresis and immunoadsorption for more specific and effective clearance of pathogenic antibodies with fewer side effects. However, more randomized controlled trials are still needed. Low-density lipoprotein apheresis is also an important supplementary therapy used in patients with recurrent focal segmental glomerulosclerosis. This review collects the latest evidence from recent studies, focuses on the specific advantages and disadvantages of these techniques, and compares the discrepancy among them to determine the optimal therapeutic regimens for certain kidney diseases.

Recent Advances in the Emerging Therapeutic Strategies for Diabetic Kidney Diseases.

Diabetic kidney disease (DKD) is one of the most common causes of end-stage renal disease worldwide. The treatment of DKD is strongly associated with clinical outcomes in patients with diabetes mellitus. Traditional therapeutic strategies focus on the control of major risk factors, such as blood glucose, blood lipids, and blood pressure. Renin-angiotensin-aldosterone system inhibitors have been the main therapeutic measures in the past, but the emergence of sodium-glucose cotransporter 2 inhibitors, incretin mimetics, and endothelin-1 receptor antagonists has provided more options for the management of DKD. Simultaneously, with advances in research on the pathogenesis of DKD, some new therapies targeting renal inflammation, fibrosis, and oxidative stress have gradually entered clinical application. In addition, some recently discovered therapeutic targets and signaling pathways, mainly in preclinical and early clinical trial stages, are expected to provide benefits for patients with DKD in the future. This review summarizes the traditional treatments and emerging management options for DKD, demonstrating recent advances in the therapeutic strategies for DKD.

Association between chronic kidney disease and Alzheimer's disease: an update.

It has been accepted that kidney function is connected with brain activity. In clinical studies, chronic kidney disease (CKD) patients have been found to be prone to suffering cognitive decline and Alzheimer's disease (AD). The cognitive function of CKD patients may improve after kidney transplantation. All these indicators show a possible link between kidney function and dementia. However, little is known about the mechanism behind the relation of CKD and AD. This review discusses the associations between CKD and AD from the perspective of the pathophysiology of the kidney and complications and/or concomitants of CKD that may lead to cognitive decline in the progression of CKD and AD. Potential preventive and therapeutic strategies for AD are also presented. Further studies are warranted in order to confirm whether the setting of CKD is a possible new determinant for cognitive impairment in AD.

The classic signalling and trans-signalling of interleukin-6 are both injurious in podocyte under high glucose exposure.

Interleukin-6 (IL-6) is a multifunctional cytokine that employs IL-6 classic and trans-signalling pathways, and these two signal channels execute different or even opposite effects in certain diseases. As a cardinal event of diabetic kidney disease (DKD), whether the podocyte abnormalities are associated with IL-6 signalling, especially classic or trans-signalling respectively, remains unclear. In this study, we identified that the circulatory IL-6, soluble IL-6R (sIL-6R) and soluble glycoprotein 130 (sgp130) levels are elevated in patients with DKD. The expressions of membrane-bound IL-6R (mIL-6R), sIL-6R and gp130 are enhanced in kidney cortex of diabetic mice accompanying with activated STAT3 by tyrosine 705 residue phosphorylation, while not serine 727. Above data infer both classic signalling and trans-signalling of IL-6 are activated during DKD. In cultured podocyte, high glucose (HG) up-regulates the expression of mIL-6R and gp130, as well as STAT3 tyrosine 705 phosphorylation, in a time-dependent manner. Entirely blocking IL-6 signalling by gp130 shRNA, gp130 or IL-6 neutralizing antibodies attenuates HG-induced podocyte injury. Interestingly, either inhibiting IL-6 classic signalling by mIL-6R shRNA or suppressing its trans-signalling using sgp130 protein dramatically alleviates HG-induced podocyte injury, suggesting both IL-6 classic signalling and trans-signalling play a detrimental role in HG-induced podocyte injury. Additionally, activation of IL-6 classic or trans-signalling aggravates podocyte damage in vitro. In summary, our observations demonstrate that the activation of either IL-6 classic or trans-signalling advances podocyte harming under hyperglycaemia. Thus, suppressing IL-6 classic and trans-signalling simultaneously may be more beneficial in podocyte protection and presents a novel therapeutic target for DKD.

IL-6 increases podocyte motility via MLC-mediated focal adhesion impairment and cytoskeleton disassembly.

The disturbance of podocyte motility is an essential pathogenic mechanisms of foot process effacement during proteinuric diseases, and myosin light chain (MLC) is a pivotal component in regulating the motility of podocytes. Inflammatory cytokine interleukin-6 (IL-6) has been reported to induce podocyte abnormalities by various mechanisms, however, whether aberrant cell motility contributes to the IL-6-induced podocyte injury remains unknown. Here, by wound healing, transwell, and cell migration assays, we confirmed that IL-6 accelerates the motility of podocyte. Simultaneously, the phosphorylation of MLC is elevated along with perturbed focal adhesion (FAs) and cytoskeleton. Next, via genetic and pharmacologic interruption of MLC or its phosphorylation we revealed that the activation of MLC is implicated in IL-6-mediated podocyte hypermotility as well as the disassembly of FAs and F-actin. By using stattic, an inhibitor for STAT3 phosphorylation, we uncovered that STAT3 activation is the upstream event for MLC phosphorylation and the following aberrant motility of podocytes. Additionally, we found that calcitriol markedly attenuates podocyte hypermotility via blocking STAT3-MLC. In conclusion, our study demonstrated that IL-6 interrupts FAs dynamic, cytoskeleton organization, and eventually leads to podocyte hypermotility via STAT3/MLC, whereas calcitriol exerts its protective role by inhibiting this pathway. These findings enrich the mechanisms accounting for IL-6-mediated podocyte injury from the standpoint of cell motility and provide a novel therapeutic target for podocyte disorders.

A New Pathogenesis of Albuminuria: Role of Transcytosis.

Transcytosis is an important intracellular transport process by which multicellular organisms selectively move cargoes from apical to basolateral membranes without disrupting cellular homeostasis. In kidney, macromolecular components in the serum, such as albumin, low-density lipoprotein and immunoglobulins, pass through the glomerular filtration barrier (GFB) and proximal tubular cells (PTCs) by transcytosis. Protein transcytosis plays a vital role in the pathology of albuminuria, which causes progressive destruction of the GFB structure and function. However, the pathophysiological consequences of protein transcytosis in the kidney remain largely unknown. This article summarizes recent researches on the regulation of albumin transcytosis across the GFB and PTCs in both physiological and pathological conditions. Understanding the mechanism of albumin transcytosis may reveal potential therapeutic targets for prevention or alleviation of the pathological consequences of albuminuria.

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2.

BACKGROUND/AIMS: Renal tubular epithelial cells and fibroblasts are the main sources of myofibroblasts, and these cells produce the extracellular matrix during tubulointerstitial fibrosis (TIF). Histone deacetylases (HDAC) inhibitors exert an antifibrogenic effect in the skin, liver and lung. Sirtuin 2 (SIRT2), which is a class III HDAC, is an important member of NAD+-dependent protein deacetylases. The current study evaluated the role of SIRT2 in renal TIF. METHODS: Immunohistochemical staining and Western blot were performed to evaluate SIRT2 expression in TIF patients and unilateral urethral obstruction (UUO) mice. Western blot was used to assess the protein levels of SIRT2, α-SMA, collagen III, fibronectin, and MDM2 in tubular epithelial cells and fibroblasts. The specific inhibitor AGK2 was used to inhibit SIRT2 activity, and targeted siRNA was used to suppress SIRT2 expression. RESULTS: SIRT2 expression increased in the tubulointerstitium of TIF patients and UUO mice. SIRT2 inhibition ameliorated TIF in UUO mice. SIRT2 expression in tubular cells was unchanged after exposure to TGF-ß1. The SIRT2-specifc inhibitor AGK2 did not attenuate TGF-ß1-induced tubular epithelial-mesenchymal transition. However, SIRT2 was upregulated in fibroblasts, and fibroblasts were activated after TGF-ß1 treatment. Genetic knockdown and chemical inhibition of SIRT2 attenuated TGF-ß1-induced fibroblast activation. We also explored the downstream signaling of SIRT2 during fibroblast activation. Genetic knockdown and chemical inhibition of SIRT2 suppressed TGF-ß1-induced increase in MDM2 expression, and inhibition of the MDM2-p53 interaction using Nutlin-3 did not suppress SIRT2 upregulation. CONCLUSION: Our results suggest that SIRT2 participates in the activation of fibroblasts and TIF, which is mediated via regulation of the MDM2 pathway, and the downregulation of SIRT2 may be a therapeutic strategy for renal fibrosis.

MDM2 is implicated in high-glucose-induced podocyte mitotic catastrophe via Notch1 signalling.

Podocyte injury and depletion are essential events involved in the pathogenesis of diabetic nephropathy (DN). As a terminally differentiated cell, podocyte is restricted in 'post-mitosis' state and unable to regenerate. Re-entering mitotic phase will cause podocyte disastrous death which is defined as mitotic catastrophe (MC). Murine double minute 2 (MDM2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM2 is involved in podocyte MC during hyperglycaemia. We found aberrant mitotic podocytes with multi-nucleation in DN patients. In vitro, cultured podocytes treated by high glucose (HG) also showed an up-regulation of mitotic markers and abnormal mitotic status, accompanied by elevated expression of MDM2. HG exposure forced podocytes to enter into S phase and bypass G2/M checkpoint with enhanced expression of Ki67, cyclin B1, Aurora B and p-H3. Genetic deletion of MDM2 partly reversed HG-induced mitotic phase re-entering of podocytes. Moreover, HG-induced podocyte injury was alleviated by MDM2 knocking down but not by nutlin-3a, an inhibitor of MDM2-p53 interaction. Interestingly, knocking down MDM2 or MDM2 overexpression showed inhibition or activation of Notch1 signalling, respectively. In addition, genetic silencing of Notch1 prevented HG-mediated podocyte MC. In conclusion, high glucose up-regulates MDM2 expression and leads to podocyte MC. Notch1 signalling is an essential downstream pathway of MDM2 in mediating HG-induced MC in podocytes.

MDM2 mediates fibroblast activation and renal tubulointerstitial fibrosis via a p53-independent pathway.

It is well recognized that murine double minute gene 2 (MDM2) plays a critical role in cell proliferation and inflammatory processes during tumorigenesis. It is also reported that MDM2 is expressed in glomeruli and involved in podocyte injury. However, whether MDM2 is implicated in renal fibrosis remains unclear. Here we investigated the role of MDM2 in tubulointerstitial fibrosis (TIF). By immunohistochemical staining and Western blotting we confirmed that MDM2 is upregulated in the tubulointerstitial compartment in patients with TIF and unilateral urethral obstruction (UUO) mice, which mainly originates from myofibroblasts. Consistently, in vitro MDM2 is increased in TGF-ß1-treated fibroblasts, one of the major sources of collagen-producing myofibroblasts during TIF, along with fibroblast activation. Importantly, genetic deletion of MDM2 significantly attenuates fibroblast activation. We then analyzed the possible downstream signaling of MDM2 during fibroblast activation. p53-dependent pathway is the classic downstream signaling of MDM2, and Nutlin-3 is a small molecular inhibitor of MDM2-p53 interaction. To our surprise, Nutlin-3 could not ameliorate fibroblast activation in vitro and TIF in UUO mice. However, we found that Notch1 signaling is attenuated during fibroblast activation, which could be markedly rescued by MDM2 knockdown. Overexpression of intracellular domain of Notch1 (NICD) by plasmid could obviously minimize fibroblast activation induced by TGF-ß1. In addition, the degradation of NICD is strikingly suppressed by PYR-41, an inhibitor of ubiquitin-activating enzyme E1, and proteasome inhibitor MG132. Taken together, our findings provide the first evidence that MDM2 is involved in fibroblast activation and TIF, which associates with Notch1 ubiquitination and proteasome degradation.

Evaluation of Mental Disorders Using Proton Magnetic Resonance Spectroscopy in Dialysis and Predialysis Patients.

BACKGROUND/AIMS: Psychological complications are prevalent in patients with chronic kidney disease (CKD). This study aimed to investigate mental disorders in stage 4-5 CKD patients, to detect metabolite concentrations in the brain by proton magnetic resonance spectroscopy (1H-MRS) and to compare the effects of different dialysis therapies on mental disorders in end-stage renal disease (ESRD). METHODS: The sample population was made up of predialysis (13), hemodialysis (HD) (13), and peritoneal dialysis (PD) patients (12). We collected the baseline data of patients' age, sex, hemoglobin (Hb) and parathyroid hormone（PTH） levels. The predialysis patients served as the control group. The psychological status of the three groups was assessed using three psychological scales. 1H-MRS was used to evaluate the relative metabolite concentrations in the bilateral amygdala, hippocampus and unilateral anterior cingulated cortex (ACC). RESULTS: The psychological status was better in HD patients than in predialysis and PD patients. 1H-MRS alterations were predominantly found in the ACC. Choline-containing compounds relative to creatine (Cho/Cr), myo-inositol relative to creatine (MI/Cr) and glutamate and glutamine relative to creatine (Glx/Cr) in the ACC were higher in HD patients. 1H-MRS results were correlated with the baseline data and the scores of psychological scales. CONCLUSIONS: CKD patients showed different types of mental disorders as well as metabolite disturbances in the brain. The metabolite concentrations correlated with the psychological status which was better in HD than in predialytic and PD patients.

MAD2B-mediated SnoN downregulation is implicated in fibroblast activation and tubulointerstitial fibrosis.

MAD2B, an anaphase-promoting complex/cyclosome (APC/C) inhibitor and a small subunit of DNA polymerase ζ, is indispensible for mitotic checkpoint control and DNA repair. Previously, we established that MAD2B is expressed in glomerular and tubulointerstitial compartments and participates in high glucose-induced podocyte injury. However, its role in other renal diseases remains elusive. In the present study, we aim to illustrate the potential role of MAD2B in the pathogenesis of renal fibrosis. By immunofluorescence and Western blotting, we found MAD2B expression is obviously increased in tubulointerstitial fibrosis (TIF) patients and unilateral ureteral obstruction (UUO) mice. It is widely accepted that resident fibroblasts are the major source of collagen-producing myofibroblasts during TIF. Therefore, we evaluated the level of MAD2B in fibroblasts (NRK-49F) exposed to transforming growth factor (TGF)-ß1 by immunoblotting and revealed that MAD2B is upregulated in a time-dependent manner. Intriguingly, SnoN, a transcriptional repressor of the TGF-ß1/Smad signaling pathway, is decreased in TGF-ß1-treated fibroblasts as well as the kidney cortex from TIF patients and UUO mice. Either in vitro or in vivo, local genetic depletion of MAD2B by lentiviral transfection could preserve SnoN abundance and suppress Smad3 phosphorylation, which finally dampens fibroblast activation, ECM accumulation, and alleviates the severity of TIF. However, the ubiquitin ligase APC/C is not involved in the MAD2B-mediated SnoN decline, although this process is ubiquitination dependent. In conclusion, our observation proposes that besides cell cycle management, MAD2B has a profibrotic role during fibroblast activation and TIF by suppressing SnoN expression. Targeting the MAD2B-SnoN pathway is a promising intervention for TIF.

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B.

BACKGROUND/AIMS: Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion. METHODS: Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH) in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. RESULTS: Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R). The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. CONCLUSION: Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R.

Thioredoxin-interacting protein mediates NALP3 inflammasome activation in podocytes during diabetic nephropathy.

Numerous studies have shown that the NALP3 inflammasome plays an important role in various immune and inflammatory diseases. However, whether the NALP3 inflammasome is involved in the pathogenesis of diabetic nephropathy (DN) is unclear. In our study, we confirmed that high glucose (HG) concentrations induced NALP3 inflammasome activation both in vivo and in vitro. Blocking NALP3 inflammasome activation by NALP3/ASC shRNA and caspase-1 inhibition prevented IL-1ß production and eventually attenuated podocyte and glomerular injury under HG conditions. We also found that thioredoxin (TRX)-interacting protein (TXNIP), which is a pro-oxidative stress and pro-inflammatory factor, activated NALP3 inflammasome by interacting with NALP3 in HG-exposed podocytes. Knocking down TXNIP impeded NALP3 inflammasome activation and alleviated podocyte injury caused by HG. In summary, the NALP3 inflammasome mediates podocyte and glomerular injury in DN, moreover, TXNIP participates in the formation and activation of the NALP3 inflammasome in podocytes during DN, which represents a novel mechanism of podocyte and glomerular injury under diabetic conditions.

MAD2B contributes to podocyte injury of diabetic nephropathy via inducing cyclin B1 and Skp2 accumulation.

It is well documented that mitotic arrest deficiency (MAD)2B can inhibit the anaphase-promoting complex/cyclosome (APC/C) via cadherin (Cdh)1 and, consequently, can destroy the effective mitotic spindle checkpoint control. Podocytes have been observed to rapidly detach and die when being forced to bypass cell cycle checkpoints. However, the role of MAD2B, a cell cycle regulator, in podocyte impairment of diabetic nephropathy (DN) is unclear. In the present study, we investigated the significance of MAD2B in the pathogenesis of DN in patients, an animal model, and in vitro podocyte cultures. By Western blot and immunohistochemistry analyses, we found that MAD2B was evidently upregulated under high glucose milieu in vivo and in vitro, whereas Cdh1 was inhibited with high glucose exposure. Overexpression of MAD2B in podocytes by plasmid DNA transfection suppressed expression of Cdh1 and triggered the accumulation of cyclin B1 and S phase kinase-associated protein (Skp)2, two key molecules involving in cell cycle regulation, and the subsequent podocyte insult. In contrast, MAD2B deletion alleviated the high glucose-induced reduction of Cdh1 as well as the elevation of cyclin B1 and Skp2, which rescued the podocyte from damage. Taken together, our data demonstrate that MAD2B may play an important role in high glucose-mediated podocyte injury of DN via modulation of Cdh1, cyclin B1, and Skp2 expression.

Attenuation of glomerular endothelial cells from high glucose-induced injury by blockade of MAD2B.

BACKGROUND/AIMS: To assess the role of mitotic arrest-deficient 2-like protein 2 (MAD2B) in high glucose-induced injury in mouse glomerular endothelial cells (GEnCs). METHODS: GEnCs were cultured in vitro, and MAD2B protein levels were measured by Western blot in cells stimulated with high glucose (30 mM) for various periods of time. MAD2B and scrambled shRNA were introduced into GEnCs by liposomal transfection. Cell proliferation, apoptosis, nitric oxide (NO) production, and monolayer permeability were then measured in cells grown in the following conditions: control, high glucose treatment, MAD2B shRNA transfection with high glucose treatment, and scrambled shRNA transfection with high glucose treatment. RESULTS: High glucose increased the protein levels of MAD2B in GEnCs. Compared with control cells, apoptosis was increased by high glucose treatment, which was attenuated by transfection with MAD2B shRNA transfection. Cells treated with high glucose produced less NO than control cells, whereas MAD2B shRNA transfection increased NO production. Cell monolayer permeability was enhanced in high glucose treated cells, but MAD2B shRNA transfection reduced permeability. CONCLUSION: High glucose levels induced the expression of MAD2B in GEnCs, whereas suppressing its expression reduced high glucose-induced endothelial cell apoptosis and high permeability, and promoted cell proliferation and NO production.

Tumor Necrosis Factor-Alpha and 8-Hydroxy-2'-Deoxyguanosine are Associated with Elevated Urinary Angiopoietin-2 Level in Type 2 Diabetic Patients with Albuminuria.

BACKGROUND/AIMS: We previously showed that urine and serum Angiopoietin-2 (Ang-2) levels increased significantly with the degree of albuminuria in diabetes patients, but the reasons remain unclear. Consequently we aimed to determine whether there was an association between Ang-2, inflammatory cytokines (TNF-α and IL-18) and reactive oxygen species (8-OHdG and SOD) in type 2 diabetes patients with albuminuria. METHODS: This retrospective study evaluated 113 patients with type 2 diabetes and normoalbuminuria, microalbuminuria, or macroalbuminuria and 30 healthy controls. Serum and urine TNF-α, IL-18 and 8-OHdG levels were measured by ELISA. Superoxide dismutase (SOD) activity was determined by spectrophotometry. RESULTS: Serum and urine TNF-α, IL-18 and 8-OHdG levels increased significantly with the degree of albuminuria, and were positively correlated with increased Ang-2. In contrast, SOD activity decreased with the degree of albuminuria and was negatively correlated with Ang-2. Multivariable linear regression analysis revealed that serum Ang-2 level was independently associated with serum levels of TNF-α (P<0.001), 8-OHdG (P=0.001), and IL-18 (P=0.003). Urinary Ang-2 level was independently associated with urinary TNF-α (P<0.001) and 8-OHdG (P=0.004) levels. CONCLUSION: TNF-α and 8-OHdG are associated with elevated urinary Angiopoietin-2 levels in type 2 diabetic patients with albuminuria.

Revolutionizing nephrology research: expanding horizons with kidney-on-a-chip and beyond.

Organs-on-a-chip (OoC) is a microengineered three-dimensional cell culture system developed for decades. Utilizing microfluidic technology, OoC cultivates cells on perfusable channels to construct in vitro organ models, enabling the simulation of organ-level functions under physiological and pathophysiological conditions. The superior simulation capabilities compared to traditional animal experiments and two-dimensional cell cultures, making OoC a valuable tool for in vitro research. Recently, the application of OoC has extended to the field of nephrology, where it replicates various functional units, including glomerulus-on-a-chip, proximal tubule-on-a-chip, distal tubule-on-a-chip, collecting duct-on-a-chip, and even the entire nephron-on-a-chip to precisely emulate the structure and function of nephrons. Moreover, researchers have integrated kidney models into multi-organ systems, establishing human body-on-a-chip platforms. In this review, the diverse functional kidney units-on-a-chip and their versatile applications are outlined, such as drug nephrotoxicity screening, renal development studies, and investigations into the pathophysiological mechanisms of kidney diseases. The inherent advantages and current limitations of these OoC models are also examined. Finally, the synergy of kidney-on-a-chip with other emerging biomedical technologies are explored, such as bioengineered kidney and bioprinting, and a new insight for chip-based renal replacement therapy in the future are prospected.

Actin-associated Proteins in the Pathogenesis of Podocyte Injury.

Podocytes have a complex cellular architecture with interdigitating processes maintained by a precise organization of actin filaments. The actin-based foot processes of podocytes and the interposed slit diaphragm form the final barrier to proteinuria. The function of podocytes is largely based on the maintenance of the normal foot process structure with actin cytoskeleton. Cytoskeletal dynamics play important roles during normal podocyte development, in maintenance of the healthy glomerular filtration barrier, and in the pathogenesis of glomerular diseases. In this review, we focused on recent findings on the mechanisms of organization and reorganization of these actin-related molecules in the pathogenesis of podocyte injury and potential therapeutics targeting the regulation of actin cytoskeleton in podocytopathies.

[Pregnant rate and pregnancy-relating factors of patients with early endometrial carcinoma and severe atypical hyperplasia of endometrium after fertility-preserving treatment by progestin].

OBJECTIVE: To summarize the pregnant rate of patients with early endometrial carcinoma and severe atypical hyperplasia after fertility-preserving treatment and analyze their pregnancy-relating factors. METHODS: Endometrial curettage was used to evaluate the therapy response of endometrium after every 3 months of administration of high-dose progestin as fertility-sparing treatment for 51 patients with stage I endometrial carcinoma or severe endometrial atypical hyperplasia from Jun. 1996 to Jan. 2010. Individualized maintained treatment was given to patients after achieving complete remission of the endometrium. Pregnant results and pregnancy-relating factors were analyzed retrospectively. RESULTS: The median age of all the 51 patients was 29 years old. Forty-five (88%, 45/51) achieved complete response. Of the 34 cases who desired to conceive after complete response, 16 of them had 22 pregnancies, the pregnant rate was 47% (16/34); and 12 women obtained healthy live birth baby, the fertility rate was 35% (12/34). The pregnant rate of patients at age >35 or ≤ 35 was 0/2 and 50% (16/32) respectively (P > 0.05). The pregnant rate of patients with or without infertility was 40% (8/20) and 8/14, with endometrial cancer or severe atypical hyperplasia was 40% (10/25) and 6/9, respectively (all P > 0.05). The pregnant rate of patients who received in vitro fertilization-embryo transfer, ovulation promotion, or no treatment was 7/7, 6/16 and 3/11 respectively (P < 0.01). CONCLUSIONS: Fertility-preserving treatment for early endometrial cancer and severe atypical hyperplasia with high-dose progestin could achieve higher response rate. Assisted reproductive technologies could significantly increase the chance of conception.

Triggering of ovulation for GnRH-antagonist cycles in normal and low ovarian responders undergoing IVF/ICSI: A systematic review and meta-analysis of randomized trials.

OBJECTIVE: To conduct a systematic review andmeta-analysis of all randomized controlled trials (RCTs) that investigated whether dual triggering [a combination of gonadotropin-releasing hormone (GnRH) agonist and human chorionic gonadotropin (hCG)] of final oocyte maturation can improve the number of oocytes retrieved and clinical pregnancy rate in low or normal responders undergoing in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles using a GnRH-antagonist protocol. STUDY DESIGN: Studies up to October 2022 were identified from PubMed, Scopus, Cochrane Library and Web of Science. The risk of bias of included studies was assessed. Dichotomous outcomes were reported as relative risks (RR), and continuous outcomes were reported as weighted mean differences (WMD) with 95% confidence intervals (CI). The primary outcomes were number of oocytes retrieved, number of mature [metaphase II (MII)] oocytes, clinical pregnancy rate and ongoing pregnancy rate; other IVF outcomes were considered as secondary outcomes. RESULTS: Seven studies were identified, and 898 patients were eligible for inclusion in this meta-analysis. The results showed that the number of oocytes retrieved [WMD = 1.38 (95% CI 0.47-2.28), I2 = 66%, p = 0.003, low evidence], number of MII oocytes [WMD = 0.7 (95% CI 0.35-1.05), I2 = 42%, p < 0.0001, moderate evidence], number of embryos [WMD = 0.68 (95% CI 0.07-1.3), I2 = 67%, p = 0.03, low evidence] and number of good-quality embryos [WMD = 1.14 (95% CI 0.35-1.93), I2 = 0%, p = 0.005, moderate evidence] in the dual trigger group were significantly higher than in the hCG trigger group. The results of the ovarian response subgroup analysis showed significant differences in all of these outcomes in normal responders, and no differences in any of the outcomes in low responders, except for the number of MII oocytes. In low responders, clinical pregnancy rates may be improved in the dual trigger group [RR = 2.2 (95% CI 1.05-4.61), I2 = 28%, p = 0.04, low evidence]. CONCLUSION: Dual triggering by GnRH agonist and hCG improved oocyte maturity and embryo grading for normal responders in GnRH-antagonist cycles. Dual triggering for final oocyte maturation may improve clinical pregnancy rates in low responders.