Focal segmental glomerulosclerosis(FSGS)is a histological pattern of glomerular damage that significantly contributes to chronic kidney disease and end-stage renal disease.Its incidence is rising globally,necessitatin...Focal segmental glomerulosclerosis(FSGS)is a histological pattern of glomerular damage that significantly contributes to chronic kidney disease and end-stage renal disease.Its incidence is rising globally,necessitating timely and personalized management strategies.This paper aims to provide an updated overview of the pathophysiology,diagnosis,and therapeutic strategies for FSGS,emphasizing the importance of early interventions and tailored treatments.This editorial synthesizes key findings from recent literature to highlight advancements in understanding and managing FSGS.Emerging evidence supports the role of targeted therapies and personalized approaches in improving outcomes for FSGS patients.Advances include novel biomarkers,genetic testing,and innovative therapeutics such as transient receptor potential ion channel blockers and antisense oligonucleotides for apolipoprotein 1-related FSGS.Effective mana-gement of FSGS requires a combination of timely diagnosis,evidence-based therapeutic strategies,and ongoing research to optimize patient outcomes and address gaps in the current understanding of the disease.展开更多
Background:Reliable animal models are crucial to drug development for focal segmental glomerulosclerosis(FSGS),a rare kidney disease.Variability in success rates in literature and significant ethical concerns with ani...Background:Reliable animal models are crucial to drug development for focal segmental glomerulosclerosis(FSGS),a rare kidney disease.Variability in success rates in literature and significant ethical concerns with animal welfare necessitate further optimization of adriamycin(ADR)-induced FSGS model developed on BALB/c mice.Methods:High-performance liquid chromatography(HPLC)was used to assess ADR stability in water and upon light exposure.To identify the optimal ADR level,single intravenous ADR injections with dosing levels from 10 to 17 mg/kg body weight were administered to BALB/c mice to induce FSGS-like pathology.Body weight and proteinuria of FSGS mice were monitored and analyzed for FSGS model-associated morbidity.Animals were euthanized for hematological and kidney histological assessments 8 weeks post induction.To identify the suitable experiment time frame of the ADR-induced FSGS mouse model,a longitudinal study was performed,with an 11-week continuous monitoring of the symptoms.Results:ADR was found to be unstable in aqueous media and light sensitive.A dosing level of 10.5 mg/kg of ADR was optimal for consistent FSGS mouse model induction on BALB/c strain,characterized by minimal mortality and sustained FSGS-like symptoms.Findings from the longitudinal study suggest that 6 weeks post ADR induction may represent the peak of FSGS pathology severity in this mouse model.This time frame may be used for FSGS drug development projects.Conclusion:Based on the outcome from this study,we identified the optimal ADR dosing level and model testing duration.A standard operating procedure(SOP)for the ADR-induced FSGS mouse model was established to facilitate FSGS basic research and drug development.展开更多
BACKGROUND Kidney function loss or renal insufficiency indicated by elevated creatinine levels and/or an estimated glomerular filtration rate(eGFR)<60 mL/minute/1.73 m²at presentation in patients with primary ...BACKGROUND Kidney function loss or renal insufficiency indicated by elevated creatinine levels and/or an estimated glomerular filtration rate(eGFR)<60 mL/minute/1.73 m²at presentation in patients with primary focal segmental glomerulosclerosis(FSGS)is commonly seen as a poor prognostic marker for kidney survival.However,a pre>vious study from our center suggested this may be due to hemodynamic factors.AIM To observe the clinical and biochemical parameters,treatment response,kidney survival,and overall outcomes of adult patients with primary FSGS presenting with kidney function insufficiency.METHODS This retrospective observational study was conducted at the Department of Nephrology,Sindh Institute of Urology and Transplantation,Karachi,Pakistan,from January 1995 to December 2017.During this period,401 biopsy-proven primary FSGS patients were identified,of which 98(24.4%)presented with kidney function loss or renal insufficiency defined as eGFR<60 mL/minute/1.73 m²at presentation and were studied in detail.RESULTS Among the 98 patients with renal function loss on presentation,the mean age was 30.9 years±13.6 years with a male-to-female ratio of 2.5:1.The mean serum creatinine level was 2.2 mg/dL±1.3 mg/dL and mean eGFR 37.1 mL/minute/1.73 m2±12.8 mL/minute/1.73 m2.The mean 24-hour urinary protein excretion was 5.9 g/day±4.0 g/day,and the mean serum albumin was 2.1 g/dL±1.0 g/dL(median:1.5 g/dL).The mean systolic blood pressure(BP)was 132.7 mmHg±19.8 mmHg,and the mean diastolic BP was 87.4 mmHg±12.7 mmHg.Steroid treatment was given to 81(82.6%)of 98 patients for an average duration of 19.9 weeks±14.4 weeks,with a mean total steroid dose of 4.4 g±1.5 g.Treatment response showed that 20(24.6%)patients achieved complete remission,9(11.1%)achieved partial remission,and 52(64.1%)did not respond.The baseline eGFR was significantly lower in the non-responsive group(P=0.006).The distribution of FSGS variants was also significantly different among steroid-responsive and non-responsive groups(P=0.012).CONCLUSION Renal function loss in FSGS patients at presentation does not necessarily indicate irreversible kidney function loss and a significant number of patients respond to appropriate treatment of the underlying disease.展开更多
BACKGROUND The Columbia classification identified five histological variants of focal segmental glomerulosclerosis(FSGS).The prognostic significance of these variants remains controversial.AIM To evaluate the relative...BACKGROUND The Columbia classification identified five histological variants of focal segmental glomerulosclerosis(FSGS).The prognostic significance of these variants remains controversial.AIM To evaluate the relative frequency,clinicopathologic characteristics,and medium-term outcomes of FSGS variants at a single center in Pakistan.METHODS This retrospective study was conducted at the Department of Nephrology,Sindh Institute of Urology and Transplantation,Karachi,Pakistan on all consecutive adults(≥16 years)with biopsy-proven primary FSGS from January 1995 to December 2017.Studied subjects were treated with steroids as a first-line therapy.The response rates,doubling of serum creatinine,and kidney failure(KF)with replacement therapy were compared between histological variants using ANOVA or Kruskal Wallis,and Chi-square tests as appropriate.Data were analyzed by SPSS version 22.0.P-value≤0.05 was considered significant.RESULTS A total of 401 patients were diagnosed with primary FSGS during the study period.Among these,352(87.7%)had a designated histological variant.The not otherwise specified(NOS)variant was the commonest,being found in 185(53.9%)patients,followed by the tip variant in 100(29.1%)patients.Collapsing(COL),cellular(CEL),and perihilar(PHI)variants were seen in 58(16.9%),6(1.5%),and 3(0.7%)patients,respectively.CEL and PHI variants were excluded from further analysis due to small patient numbers.The mean follow-up period was 36.5±29.2 months.Regarding response rates of variants,patients with TIP lesions achieved remission more frequently(59.5%)than patients with NOS(41.8%)and COL(24.52%)variants(P<0.001).The hazard ratio of complete response among patients with the COL variant was 0.163[95%confidence interval(CI):0.039-0.67]as compared to patients with NOS.The TIP variant showed a hazard ratio of 2.5(95%CI:1.61-3.89)for complete remission compared to the NOS variant.Overall,progressive KF was observed more frequently in patients with the COL variant,43.4%(P<0.001).Among these,24.53%of patients required kidney replacement therapy(P<0.001).The hazard ratio of doubling of serum creatinine among patients with the COL variant was 14.57(95%CI:1.87-113.49)as compared to patients with the TIP variant.CONCLUSION In conclusion,histological variants of FSGS are predictive of response to treatment with immunosuppressants and progressive KF in adults in our setup.展开更多
BACKGROUND Focal segmental glomerulosclerosis(FSGS)often recurs after transplantation,leading to graft dysfunction and graft loss.Patients who have lost prior grafts due to recurrence are at particularly high risk of ...BACKGROUND Focal segmental glomerulosclerosis(FSGS)often recurs after transplantation,leading to graft dysfunction and graft loss.Patients who have lost prior grafts due to recurrence are at particularly high risk of re-recurrence in subsequent grafts.Rituximab and plasma exchange have been used pre-emptively to prevent post-transplant recurrence.However,the efficacy of such preventative measures remains unclear.AIM To investigate the outcomes of preventative rituximab and plasma exchange for recurrent FSGS in transplant recipients after prior graft loss.METHODS We conducted a systematic review of 11 studies with 32 patients who had experienced prior graft loss due to post-transplant FSGS recurrence and were treated with either pre-emptive plasma exchange alone,rituximab alone,or a combination of both.RESULTS Overall,47%of the 32 patients experienced recurrence despite prophylactic treatment.Re-recurrence was seen in 25%(1/4)with pre-emptive rituximab alone,and 45%recurrence(9/20)with plasma exchange alone.Re-recurrence was noted in 63%with the use of combined plasma exchange and rituximab.CONCLUSION There is a paucity of available evidence in the literature to draw clear conclusions on the benefits of pre-emptive measures to prevent FSGS re-recurrence.The small sample sizes and variations in protocols call for larger and controlled studies to serve this patient population at high risk of recurrence and graft loss.展开更多
Background: Previous studies suggested that the focal and segmental nature of focal segmental glomerulosclerosis (FSGS) may lead to sample error or diagnosis error that results in minimal change disease (MCD) misdiagn...Background: Previous studies suggested that the focal and segmental nature of focal segmental glomerulosclerosis (FSGS) may lead to sample error or diagnosis error that results in minimal change disease (MCD) misdiagnosis, or FSGS being missed especially in patients with early lesions or limited glomeruli in the biopsy specimens. Patients and methods: Over the past 5 years, patients were included in the study if they had (a) relapse of nephrotic syndrome (NS), (b) biopsy-proven FSGS without immune deposits, (c) long-remission (years) after biopsy-proven Corticosteroid-refractory NS due to MCD, (c) negative history, clinical examination, radiological scans as well as laboratory and serological tests for autoimmune diseases, infections, malignancy and drugs-side effect. Results: After 3 months of therapy with Losartan alone;Proteinuria decreased only by 22% improvement with a mild decrease in Creatinine clearance (ClCr) by 1.5%. However, the addition of Mycophenolate mofetil (MMF) resulted in a further significant decrease in Pr to 72% compared to Losartan alone. Moreover, there were no significant changes in CrCl after 1- and 2 years of follow up. Our data indicates that such a transition may not be due to inadequate sampling but a new lesion. Initial hemodynamic therapy with Losartan was not adequate and immunosuppressive therapy with MMF significantly improved proteinuria and stabilized their kidney function. The data is promising with regard to the management of patients with such relentless disease. In conclusion, a true transition from MCD to FSGS is amenable to therapy with MMF.展开更多
Focal segmental glomerulosclerosis(FSGS) represents one of the most severe glomerular diseases, with frequent progression to end-stage renal disease and a high rate of recurrence in renal allografts(30%-50%). Recurren...Focal segmental glomerulosclerosis(FSGS) represents one of the most severe glomerular diseases, with frequent progression to end-stage renal disease and a high rate of recurrence in renal allografts(30%-50%). Recurrent FSGS portends a negative outcome, with the hazard ratio of graft failure being two-fold higher then that of other glomerulonephritis. Two patterns of clinical presentations are observed: Early recurrence, which is characterized by massive proteinuria within hours to days after implantation of the renal graft, and late recurrence, which occurs several months or years after the transplantation. Many clinical conditions have been recognized as risk factors for recurrence, including younger age, rapid progression of the disease to end-stage renal disease on native kidneys, and loss of previous renal allografts due to recurrence. However, much less is known about the incidence and risk factors of the so-called "de novo " type of FSGS, for which sufferers are transplanted patients without disease on native kidneys; but, rapid development of allograft failure is frequently observed. Management of both forms is challenging, and none of the approaches proposed to date have been demonstrated as consistently beneficial or effective. In the present review we report an update on the available therapeutic strategies for FSGS in renal transplantation within the context of a critical overview of the current literature.展开更多
OBJECTIVE: To observe the effects and mechanisms of Bushenhuoxue on desmin and nephrin expression in mice podocytes, and to investigate its effects on wt1 expression in Wilms' tumor.METHODS: Adriamycin(ADR) was us...OBJECTIVE: To observe the effects and mechanisms of Bushenhuoxue on desmin and nephrin expression in mice podocytes, and to investigate its effects on wt1 expression in Wilms' tumor.METHODS: Adriamycin(ADR) was used to induce focal segmental glomerulous sclerosis(FSGS) in mice. Bushenhuoxue was used to treat FSGS for 6 weeks. We measured body mass and right renal mass, and determined serum albumin(ALB) levels,protein content in urine, and urinary protein and albumin creatinine ratio(UACR). Changes in renal tissue morphology were evaluated by microscopy.wt1 and nephrin expression in podocytes were detected using immunofluorescence. Expression levels of desmin, wt1 and nephrin m RNAs in renal tissue were determined using reverse transcription polymerase chain reaction assays.RESULTS: Protein levels in urine and UACR were significantly increased in FSGS model mice compared with Bushenhuoxue-treated and control mice.Body mass and ALB levels were decreased in FSGS mice compared with control and Bushenhuoxue-treated mice. Expression of the wt1 protein was observed in control mice. Compared with controls,wt1 expression levels were reduced in Bushenhuoxue-treated mice, and to a greater extent in FSGS mice. Nephrin protein expression was widespread in FSGS mice, and significantly reduced in control and Bushenhuoxue mice. Expression levels of wt1 and nephrin m RNAs in FSGS mice were lower compared with those in control and Bushenhuoxue-treated mice. Desmin m RNA levels in FSGS mice were reduced compared with those in control and Bushenhuoxue-treated mice.CONCLUSION: Bushenhuoxue ameliorated albuminuria in FSGS mice; this was possibly related to the up-regulation of wt1 and nephrin, and down-regulation of desmin.展开更多
BACKGROUND Focal segmental glomerulosclerosis(FSGS)is one of the most common glomerular diseases leading to renal failure.FSGS has a high risk of recurrence after kidney transplantation.Prevention of recurrent FSGS us...BACKGROUND Focal segmental glomerulosclerosis(FSGS)is one of the most common glomerular diseases leading to renal failure.FSGS has a high risk of recurrence after kidney transplantation.Prevention of recurrent FSGS using rituximab and/or plasmapheresis has been evaluated in multiple small studies with conflicting results.AIM To assess the risk of recurrence of FSGS after transplantation using prophylactic rituximab with or without plasmapheresis,and plasmapheresis alone compared to the standard treatment group without preventive therapy.METHODS This meta-analysis and systematic review were performed by first conducting a literature search of the MEDLINE,EMBASE,and Cochrane databases,from inception through March 2021;search terms included‘FSGS,’’steroid-resistant nephrotic syndrome’,‘rituximab,’and‘plasmapheresis,’.We identified studies that assessed the risk of post-transplant FSGS after use of rituximab with or without plasmapheresis,or plasmapheresis alone.Inclusion criteria were:Original,published,randomized controlled trials or cohort studies(either prospective or retrospective),case-control,or cross-sectional studies;inclusion of odds ratio,relative risk,and standardized incidence ratio with 95%confidence intervals(CI),or sufficient raw data to calculate these ratios;and subjects without interventions(controls)being used as comparators in cohort and cross-sectional studies.Effect estimates from individual studies were extracted and combined using a random effects model.RESULTS Eleven studies,with a total of 399 kidney transplant recipients with FSGS,evaluated the use of rituximab with or without plasmapheresis;thirteen studies,with a total of 571 kidney transplant recipients with FSGS,evaluated plasmapheresis alone.Post-transplant FSGS recurred relatively early.There was no significant difference in recurrence between the group that received rituximab(with or without plasmapheresis)and the standard treatment group,with a pooled risk ratio of 0.82(95%CI:0.47-1.45,I2=65%).Similarly,plasmapheresis alone was not associated with any significant difference in FSGS recurrence when compared with no plasmapheresis;the pooled risk ratio was 0.85(95%CI:0.60-1.21,I2=23%).Subgroup analyses in the pediatric and adult groups did not yield a significant difference in recurrence risk.We also reviewed and analyzed posttransplant outcomes including timing of recurrence and graft survival.CONCLUSION Overall,the use of rituximab with or without plasmapheresis,or plasmapheresis alone,is not associated with a lower risk of FSGS recurrence after kidney transplantation.Future studies are required to assess the effectiveness of rituximab with or without plasmapheresis among specific patient subgroups with high-risk for FSGS recurrence.展开更多
Accumulating evidence suggests that the small G protein Rho and its downstream effec-tor Rho kinase may play important roles in kidney biology. The present study examined the effects of a Rho-kinase inhibitor, fasudil...Accumulating evidence suggests that the small G protein Rho and its downstream effec-tor Rho kinase may play important roles in kidney biology. The present study examined the effects of a Rho-kinase inhibitor, fasudil, on daunorubicin-induced progressive glomerulosclerosis and explored the underlying mechanism by which fasudil ameliorates glomerulosclerosis. Thirty-six male SD rats were randomly allocated into sham-operation group （sham group, n=12）, unilateral nephrectomy （UNX）＋daunorubicin （DRB） group （model group, n=12）, UNX＋DRB＋Fasudil group （treatment group, n=12）. Two to four weeks after the establishment of the animal model, 6 rats in each group were taken randomly for the detection of 24-h urine protein excretion. Kidney sections were exam-ined by HE and PAS staining, immunohistochemistry and transmission electric microscopy （TEM）. The expression of Rho-kinase mRNA and P27 mRNA in kidney were detected by RT-PCR. It was found that the 24-h urine protein excretion in model group was increased significantly as compared with sham group （P〈0.01）. But this increase was significantly suppressed by fasudil （P〈0.05）. At 4 week, the foot process effacement in podocytes, mesangial proliferation and ECM accumulation were observed in model group, presenting as focal segmental glomerulosclerosis. But in the treatment group, the fasudil alleviated glomerular injury, with proliferating cell nuclear antigen （PCNA）-positive cell infiltration ameliorated and the expression of P27 increased. The expression of Rho-kinase mRNA was significantly enhanced in model group and was suppressed in treatment group. Moreover, fasudil up-regulated the mRNA expression of P27. Our study demonstrated that the glomerulosclerosis was substantially ameliorated by inhibiting the expression of Rho-kinase. It is suggested that Rho-kinase pathway is involved in the renal injury and the inhibition of Rho-kinase may constitute a therapeutic strategy for the treatment of renal injury.展开更多
BACKGROUND Bone marrow-derived mesenchymal stem cells(MSCs)show podocyte-protective effects in chronic kidney disease.Calycosin(CA),a phytoestrogen,is isolated from Astragalus membranaceus with a kidney-tonifying effe...BACKGROUND Bone marrow-derived mesenchymal stem cells(MSCs)show podocyte-protective effects in chronic kidney disease.Calycosin(CA),a phytoestrogen,is isolated from Astragalus membranaceus with a kidney-tonifying effect.CA preconditioning enhances the protective effect of MSCs against renal fibrosis in mice with unilateral ureteral occlusion.However,the protective effect and underlying mechanism of CA-pretreated MSCs(MSCsCA)on podocytes in adriamycin(ADR)-induced focal segmental glomerulosclerosis(FSGS)mice remain unclear.AIM To investigate whether CA enhances the role of MSCs in protecting against podocyte injury induced by ADR and the possible mechanism involved.METHODS ADR was used to induce FSGS in mice,and MSCs,CA,or MSCsCA were administered to mice.Their protective effect and possible mechanism of action on podocytes were observed by Western blot,immunohistochemistry,immunofluorescence,and real-time polymerase chain reaction.In vitro,ADR was used to stimulate mouse podocytes(MPC5)to induce injury,and the supernatants from MSC-,CA-,or MSCsCA-treated cells were collected to observe their protective effects on podocytes.Subsequently,the apoptosis of podocytes was detected in vivo and in vitro by Western blot,TUNEL assay,and immunofluorescence.Overexpression of Smad3,which is involved in apoptosis,was then induced to evaluate whether the MSCsCA-mediated podocyte protective effect is associated with Smad3 inhibition in MPC5 cells.RESULTS CA-pretreated MSCs enhanced the protective effect of MSCs against podocyte injury and the ability to inhibit podocyte apoptosis in ADR-induced FSGS mice and MPC5 cells.Expression of p-Smad3 was upregulated in mice with ADR-induced FSGS and MPC5 cells,which was reversed by MSCCA treatment more significantly than by MSCs or CA alone.When Smad3 was overexpressed in MPC5 cells,MSCsCA could not fulfill their potential to inhibit podocyte apoptosis.CONCLUSION MSCsCA enhance the protection of MSCs against ADR-induced podocyte apoptosis.The underlying mechanism may be related to MSCsCA-targeted inhibition of p-Smad3 in podocytes.展开更多
Collapsing focal segmental glomerulosclerosis （cFSGS）, also known as collapsing glomerulopathy is currently classified under the rubric of FSGS. However, its de-fining morphological features are in stark contrast to...Collapsing focal segmental glomerulosclerosis （cFSGS）, also known as collapsing glomerulopathy is currently classified under the rubric of FSGS. However, its de-fining morphological features are in stark contrast to those observed in most other variants of FSGS. During the early stage of the disease, the lesion is character-ized pathologically by an implosive segmental and/or global collapse of the glomerular capillary tufts, marked hypertrophy and hyperplasia of podocytes, and severe tubulointerstitial disease. With advancement of the disease, segmental and/or global glomerulosclerosis is also observed in association with the collapsing le-sions. The etiology of this enigmatic disorder is still elusive, but a growing list of diseases/conditions is being reported in association with this morphological pattern of renal parenchymal injury. The pathogenesis of cFSGS involves discreet epithelial cell injury leadingto cell cycle dysregulation and a proliferative cellularphenotype. From the clinical perspective, cFSGS is no-torious for its propensity to affect black people, a highincidence and severity of nephrotic syndrome, markedresistance to empirical therapy, and rapid progressionto end-stage renal disease. The lesion has also beenreported in transplanted kidneys either as recurrent orde novo disease, frequently leading to graft loss. Mostcases have been reported in western countries, but the lesion is also being increasingly recognized in the tropi-cal regions. The recent increase in reporting of cFSGS partly refects a true increase in the incidence and part-ly a detection bias. There is no specifc treatment for the disorder at present. Newer insights into the patho-genesis may lead to the development of targeted and specifc therapy in near future. There is an urgent need to increase awareness of the lesion among pathologists and nephrologists, especially those from developing countries, to ensure accurate diagnosis and appropriate managment. With the accumulation of more and more data, it is hoped that the prevailing confusion about the nosological identity of the lesion will also be resolved in a more logical way.展开更多
Primary focal and segmental glomerulosclerosis(FSGS) may be due to genetic or acquired etiologies and is a common cause of nephrotic syndrome with high morbidity that often leads to end-stage renal failure. The differ...Primary focal and segmental glomerulosclerosis(FSGS) may be due to genetic or acquired etiologies and is a common cause of nephrotic syndrome with high morbidity that often leads to end-stage renal failure. The different available therapeutic approaches are unsuccessful, in part due to partially deciphered heterogeneous and complex pathophysiological mechanisms. Moreover, the term FSGS, even in its primary form, comprises a histological description shared by a number of different causes with completely different molecular pathways of disease. This review focuses on the latest developments regarding the pathophysiology of primary acquired FSGS caused by soluble factor urokinase type plasminogen activator receptor, a circulating permeability factor involved in proteinuria and edema formation, and describes recent advances with potential success in therapy.展开更多
BACKGROUND Although minimal change disease(MCD)and focal segmental glomerulosclerosis(FSGS)have been described as two separate forms of nephrotic syndrome(NS),they are not completely independent.We report a case of a ...BACKGROUND Although minimal change disease(MCD)and focal segmental glomerulosclerosis(FSGS)have been described as two separate forms of nephrotic syndrome(NS),they are not completely independent.We report a case of a patient transitioning from MCD to FSGS,review the literature,and explore the relationship between the two diseases.CASE SUMMARY A 42-year-old male welder,presenting with lower extremity edema and elevated serum creatinine,was diagnosed with NS and end-stage kidney disease(ESKD)based on laboratory test results.The patient had undergone a kidney biopsy for NS 20 years previously,which indicated MCD,and a second recent kidney biopsy suggested FSGS.The patient was an electric welder with excessive levels of cadmium and lead in his blood.Consequently,we suspect that his aggravated pathology and occurrence of ESKD were related to metal nephrotoxicity.The patient eventually received kidney replacement therapy and quit his job which involved long-term exposure to metals.During the 1-year follow-up period,the patient was negative for metal elements in the blood and urine and recovered partial kidney function.CONCLUSION MCD and FSGS may be different stages of the same disease.The transition from MCD to FSGS in this case indicates disease progression,which may be related to excessive metal contaminants caused by the patient’s occupation.展开更多
Objective To assess the significance of focal segmental glomerulosclerosis(FSGS)variants on clinicopathological characteristics and short-term outcomes in idiopathic membranous nephropathy(IMN)patients.Methods The cli...Objective To assess the significance of focal segmental glomerulosclerosis(FSGS)variants on clinicopathological characteristics and short-term outcomes in idiopathic membranous nephropathy(IMN)patients.Methods The clinicopathological data of 146 IMN patients diagnosed between December 2016 and March 2019 in our center were collected and analyzed.These patients were divided into the pure IMN group,IMN with glomerular tip lesion(GTL)group,and IMN with non-GTL FSGS group.Results The IMN with non-GTL FSGS and IMN with GTL groups both had higher proportions of patients with hypertension,lower serum albumin,and severe proteinuria,while the IMN with non-GTL FSGS group additionally showed higher blood pressure and serum cholesterol,and lower serum IgG than the IMN group(all P<0.05).As for pathology,the IMN with non-GTL FSGS group had higher proportions of patients with acute tubular injury and moderate to severe chronic injuries than the IMN group(all P<0.05).In the IMN,IMN with GTL,and IMN with non-GTL FSGS groups,the overall one-year remission rates were 81.6%,76%,and 58.8%,respectively.Furthermore,the IMN with non-GTL FSGS group showed the lowest cumulative incidence to reach remission within one year.Multivariate Cox logistic analysis demonstrated that higher level of serum anti-M-type phospholipase A2 receptor antibody and the existence of non-GTL FSGS lesion were independent predictors for no remission in IMN patients.Conclusion The non-GTL FSGS lesion was a novel negative predictor in IMN and should be taken into account in the management of IMN.展开更多
The incidence of the collapsing variant of focal segmental glomerulosclerosis(FSGS)as a human immunodeficiency virus(HIV)-associated nephropathy has reduced since the introduction of antiretroviral therapy(ART).Howeve...The incidence of the collapsing variant of focal segmental glomerulosclerosis(FSGS)as a human immunodeficiency virus(HIV)-associated nephropathy has reduced since the introduction of antiretroviral therapy(ART).However,the incidence of other variants of FSGS,except for the collapsing variant,is increasing,and its therapeutic strategies remain uncertain.A 60-year-old HIV infected man in remission with ART was admitted for progressive renal insufficiency and nephrotic-ranged proteinuria.Renal biopsy revealed a tip variant of FSGS and his clinical manifestations resolved with corticosteroid therapy.HIV infected patients might develop non-collapsing FSGS,including tip variant of FSGS and corticosteroid therapy might be effective for them.A renal biopsy might be essential to determine the renal histology and to decide on corticosteroid therapy.展开更多
Introduction: Focal Segmental Glomerulosclerosis (FSGS) corresponds to a clinicopathological syndrome, manifested by generally abundant proteinuria associated with hyaline deposits on part of certain glomeruli and spa...Introduction: Focal Segmental Glomerulosclerosis (FSGS) corresponds to a clinicopathological syndrome, manifested by generally abundant proteinuria associated with hyaline deposits on part of certain glomeruli and sparing other glomeruli, with effacement of the pedicels. The general objective was to determine the prevalence of FSGS, and to give its profiles;epidemiological, clinical, biological, pathological, etiological, therapeutic and evolutionary of FSGS. Materials and Methods: This is a retrospective analytical study over a period of six years extending from January 1, 2010 to December 31, 2015 patients aged 16 or over who were hospitalized or received consultations during the study period for primary or secondary segmental and focal hyalinosis. Patients whose records were incomplete or unusable were not included in the study. Results: We have 16.54% with 158 cases of FSGS out of 6945 patients received and/or hospitalized. Of the 955 kidney biopsies distributed, the incidences of HSF were;10.15%;14.04%;15%;17.64%;20.11%;19.58% respectively in 2010;2011;2012;2013;2014 and 2015, i.e. an annual increase of around 1.25%. Renal-type edemas were found in 93.3%, the first reason for hospitalization. And ninety-six people had impaired kidney function, or 61%. The average of 24-hour proteinuria was 6.4 ± 3.69 g/24 hours. The extremes were 0.37 and 18.50 g/24h. Patients had nephrotic proteinuria in 84.86%. Non-specific FSGS or NOS (Not Other Specificities) was found in 62 cases or 39.24%, collapsing FSGS in 48 cases or 30.40%. FSGS with found causes was associated with fibrosis in 5/35 cases. Collapsing FSGSs followed by NOS FSGSs were the most corticosteroid-resistant. The evolution of the FSGS reveals that every 8 months the proteinuria decreases by half. Conclusion: Segmental and focal hyalinosis requires histological confirmation and the epidemiological, clinico-biological, etiological, therapeutic and evolutionary profiles depend on the histological (pathological) type. Other works on the risk factors for occurrence and the contribution of electron microscopy in the primary and secondary diagnosis of segmental and focal hyalinosis are desired.展开更多
Objective To analyze the target signaling pathway of histone H3K27 methylation-induced podocyte injury,verify the regulatory effect of histone H3K27 methylation on podocyte injury in focal segmental glomerulosclerosis...Objective To analyze the target signaling pathway of histone H3K27 methylation-induced podocyte injury,verify the regulatory effect of histone H3K27 methylation on podocyte injury in focal segmental glomerulosclerosis(FSGS)mice through target signaling pathway,and explore the mechanism of abnormal methylation of histone H3K27-induced podocyte injury in FSCS mice.Methods(1)Cell experiments:primary cultured immortalized mouse podocytes MPC5 were cultured in vitro,and divided into control group,adriamycin(ADR)group,ADR+GSK-J4(histone demethylase,KDM6B inhibitor)group,ADR+coumarin A1(C-Al,JAK2 agonist)group and ADR+GSK-J4+C-A1 group.The transmission electron microscope was used to observe ultrastructure of podocytes.Immunofluorescence was used to detect the protein expression of H3K27me3and nephrinin podocytes.The whole genome sequence of podocytes was obtained,the differentially expressed genes were screened,and Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)were used for enrichment analysis.Real time-quantitative PCR and Western blotting were used to detect the gene and protein expression of JAK2-STAT3 signaling pathway in podocytes respectively.Enzyme-linked immunosorbent assay was used to detect interleukin 6(IL-6),monocyte chemotactic protein 1(MCP-1),α-smooth muscle actin(α-SMA)and transforming growth factorβ1(TGF-β1).(2)Animal experiments:EZH2 gene knock out(EZH2^(podko))-FSCS(tail vein injection of ADR)mousenmodels were established,and divided into EZH2^(ctrl)+,control group(n=20),EZH2^(ctrl)+FSGS(n=20),EZH2^(podko)control group(n=30)and EZH2^(podko)+FSCS group(n=30).HE staining was used to observe the morphology of kidney tissues.Immunohistochemistry was used to detect the H3K27me3 protein expression in podocytes.Real time-quantitative PCR and Western blotting were used to verify the gene and protein expression of JAK2-STAT3 signaling pathway respectively.Enzyme-linked immunosorbent assay was used to detect IL-6,MCP-1,α-SMA and TGF-β1 of kidney tissues.Results(1)Cell experiments:Compared with control group,the nucleus shrank and ruptured,the cytoplasm showed vacuole,and mitochondria and endoplasmic reticulum swelled in ADR group,which verified that the podocyte injury model of ADR nephropathy was successfully established.Compared with control group,the protein expression level of H3K27me3 in ADR group was significantly lower(P<0.05).Compared with ADR group,the protein expression level of H3K27me3 in podocytes in ADR+GSK-J4 group was significantly higher(P<0.05),and there were 502 increased genes and 443 decreased genes.GO enrichment analysis showed that the differentially enriched peaks were mainly in ribonucleoprotein complex biogenesis,ribosome biogenesis,establishment of protein localization to organelle,and involved in regulation of receptor signaling pathway via JAK-STAT and receptor signaling pathway via JAK-STAT.Differential expressed genes were Irfl,Tnfrsfla,Socsl,Notch1,Gadd45a,Hesl and Socs3,involving in the regulation of JAK-STAT signaling pathway.KECG enrichment analysis showed that the differentially enriched peaks were mainly in amyotrophic lateral sclerosis,and the target genes were Mcll,Egfr,Socsl,Cdknla,Pdgfa and Socs3,involving in the regulation of JAK-STAT signaling pathway.Compared with ADR group,the mRNA and protein expression levels of JAK2 and STAT3 in the ADR+GSK-J4 group were significantly lower,and thedownstream inflammatory factors of IL-6,MCP-1 andα-SMA were significantly higher(all P<0.05).Compared with ADR group,the protein expression level of nephrin in ADR+GSK-J4 group was higher(P<0.05),and the protein expression level of nephrin in ADR+C-A1 group was lower(P<0.05).Compared with ADR+GSK-J4 group,the protein expression level of nephrin in ADR+GSK-J4+C-A1 group was lower(P<0.05).(2)Animal experiments:Compared with EZH2^(ctrl)+FSGSSgroup,EZH2^(podko)+FSCS group showed obvious renal tssue damage,matrix hyperplasia inmesangia1l area with massive homogeneous substance ddeposition,apoptosis and necrosis of renal tubular epithelial cells,obvious thickening and extensive fusion of glomerular epithelial cells,basement membrane collapse,and compression and narrowing of capillary structure.Compared with EZH2^(ctrl)+FSGS group,the protein expression level of.H3K27me3 in EZH2^(podko)+FSCS group was significantly lower,and the mRNA and protein expression levels of JAK2 and STAT3,and the levels of IL-6,MCP-1,α-SMA and TCF-β1 were higher(all P<0.05).Conclusion Abnormal methylation modificationn of H3K27 leads to changee of target gene expression,activation of JAK2-STAT3 signaling pathway,podocyte injury,glomerulosclerosis and renal tubular injury,participating in the development of FSGS.展开更多
BACKGROUND Renal tubular acidosis(RTA)refers to a group of kidney disorders characterized by defective acid excretion or bicarbonate reabsorption,leading to metabolic acidosis.This case series presents three cases of ...BACKGROUND Renal tubular acidosis(RTA)refers to a group of kidney disorders characterized by defective acid excretion or bicarbonate reabsorption,leading to metabolic acidosis.This case series presents three cases of RTA with distinct etiologies and clinical manifestations.These cases emphasize the necessity of a comprehensive evaluation of RTA,considering both renal and systemic origins.CASE SUMMARY The first case describes a female patient with osteopetrosis-related RTA,diagnosed with Guibaud-Vainsel syndrome,emphasizing the importance of genetic assessment.The second case delineates RTA secondary to focal segmental glomerulosclerosis,associating tubular dysfunction with glomerular pathology.In the first two cases whole exome sequencing confirmed genetic diagnosis.The third case illuminates RTA as a complication of Graves’disease,highlighting autoimmune implications.CONCLUSION These cases underscore the interdisciplinary approach essential in RTA management.Understanding the diverse pathophysiology of RTA aids in tailored therapeutic strategies and improved patient outcomes.展开更多
To investigate the protective effects of blocking rennin-angiotensin system(RAS)on the progression of renal injury in glomerulosclerosis,a glomerulosclerosis model was made for SD rats by unilateral nephrectomy and be...To investigate the protective effects of blocking rennin-angiotensin system(RAS)on the progression of renal injury in glomerulosclerosis,a glomerulosclerosis model was made for SD rats by unilateral nephrectomy and being injected with Adriamycin into caudal vein.The rats with glomerulosclerosis were randomly divided as ten per group into those without further treatment(group D)and those treated with Benazepril(group DB),Losartan (group DL),or sham-operation(group C),respectively.After 6 weeks of administration of Benazepril or Losartan, the mRNA expressions of TGF-β_1,Col Ⅳ,Fn,ET-1 and iNOS in renal cortex were measured by RT-PCR.Besides, the expressions of TGF-β_1,ET-1 and iNOS at protein level were detected by Western blotting and the concentrations of Col Ⅳ and Fn were analyzed with immunohistochemistry respectively.Results showed that the rats in group D appeared as obvious proteinuria,hypoalbuminemia and hypercholesterolemia,which had a significant difference compared with group C(p<0.05),and most of their mesangiums were detected with cellular proliferation and significant increasing for extracellular matrix.Renal cortex TGF-β_1,Col Ⅳ,Fn,ET-1 and iNOS in rats of group D were increased by 3.59,2.57,2.21,2.58 and 3.28 times at mRNA level,and by 2.60,1.40,0.75,1.83 and 2.15 times at protein level,respectively,compared with group C.When the animals were treated with Benazepril(group DB)or Losartan(group DL),however,the biochemical and pathological damages were significantly recovered,and protein expressions of TGF-β_1,Col Ⅳ,Fn,ET-1 and iNOS were also significantly diminished(p<0.05).This study suggested that blocking RAS using Benazepril or Losartan can have protective effects on the renal injury in glomerulosclerosis by down-regulating the expressions of TGF-β_1, Col Ⅳ,Fn,ET-1 and iNOS.Cellular & Molecular Immunology.2005;2(2):150-154.展开更多
文摘Focal segmental glomerulosclerosis(FSGS)is a histological pattern of glomerular damage that significantly contributes to chronic kidney disease and end-stage renal disease.Its incidence is rising globally,necessitating timely and personalized management strategies.This paper aims to provide an updated overview of the pathophysiology,diagnosis,and therapeutic strategies for FSGS,emphasizing the importance of early interventions and tailored treatments.This editorial synthesizes key findings from recent literature to highlight advancements in understanding and managing FSGS.Emerging evidence supports the role of targeted therapies and personalized approaches in improving outcomes for FSGS patients.Advances include novel biomarkers,genetic testing,and innovative therapeutics such as transient receptor potential ion channel blockers and antisense oligonucleotides for apolipoprotein 1-related FSGS.Effective mana-gement of FSGS requires a combination of timely diagnosis,evidence-based therapeutic strategies,and ongoing research to optimize patient outcomes and address gaps in the current understanding of the disease.
基金United States Department of Defense Office of the Congressionally Directed Medical Research Programs(CDMRP),Grant/Award Number:W81XWH-22-1-0176。
文摘Background:Reliable animal models are crucial to drug development for focal segmental glomerulosclerosis(FSGS),a rare kidney disease.Variability in success rates in literature and significant ethical concerns with animal welfare necessitate further optimization of adriamycin(ADR)-induced FSGS model developed on BALB/c mice.Methods:High-performance liquid chromatography(HPLC)was used to assess ADR stability in water and upon light exposure.To identify the optimal ADR level,single intravenous ADR injections with dosing levels from 10 to 17 mg/kg body weight were administered to BALB/c mice to induce FSGS-like pathology.Body weight and proteinuria of FSGS mice were monitored and analyzed for FSGS model-associated morbidity.Animals were euthanized for hematological and kidney histological assessments 8 weeks post induction.To identify the suitable experiment time frame of the ADR-induced FSGS mouse model,a longitudinal study was performed,with an 11-week continuous monitoring of the symptoms.Results:ADR was found to be unstable in aqueous media and light sensitive.A dosing level of 10.5 mg/kg of ADR was optimal for consistent FSGS mouse model induction on BALB/c strain,characterized by minimal mortality and sustained FSGS-like symptoms.Findings from the longitudinal study suggest that 6 weeks post ADR induction may represent the peak of FSGS pathology severity in this mouse model.This time frame may be used for FSGS drug development projects.Conclusion:Based on the outcome from this study,we identified the optimal ADR dosing level and model testing duration.A standard operating procedure(SOP)for the ADR-induced FSGS mouse model was established to facilitate FSGS basic research and drug development.
文摘BACKGROUND Kidney function loss or renal insufficiency indicated by elevated creatinine levels and/or an estimated glomerular filtration rate(eGFR)<60 mL/minute/1.73 m²at presentation in patients with primary focal segmental glomerulosclerosis(FSGS)is commonly seen as a poor prognostic marker for kidney survival.However,a pre>vious study from our center suggested this may be due to hemodynamic factors.AIM To observe the clinical and biochemical parameters,treatment response,kidney survival,and overall outcomes of adult patients with primary FSGS presenting with kidney function insufficiency.METHODS This retrospective observational study was conducted at the Department of Nephrology,Sindh Institute of Urology and Transplantation,Karachi,Pakistan,from January 1995 to December 2017.During this period,401 biopsy-proven primary FSGS patients were identified,of which 98(24.4%)presented with kidney function loss or renal insufficiency defined as eGFR<60 mL/minute/1.73 m²at presentation and were studied in detail.RESULTS Among the 98 patients with renal function loss on presentation,the mean age was 30.9 years±13.6 years with a male-to-female ratio of 2.5:1.The mean serum creatinine level was 2.2 mg/dL±1.3 mg/dL and mean eGFR 37.1 mL/minute/1.73 m2±12.8 mL/minute/1.73 m2.The mean 24-hour urinary protein excretion was 5.9 g/day±4.0 g/day,and the mean serum albumin was 2.1 g/dL±1.0 g/dL(median:1.5 g/dL).The mean systolic blood pressure(BP)was 132.7 mmHg±19.8 mmHg,and the mean diastolic BP was 87.4 mmHg±12.7 mmHg.Steroid treatment was given to 81(82.6%)of 98 patients for an average duration of 19.9 weeks±14.4 weeks,with a mean total steroid dose of 4.4 g±1.5 g.Treatment response showed that 20(24.6%)patients achieved complete remission,9(11.1%)achieved partial remission,and 52(64.1%)did not respond.The baseline eGFR was significantly lower in the non-responsive group(P=0.006).The distribution of FSGS variants was also significantly different among steroid-responsive and non-responsive groups(P=0.012).CONCLUSION Renal function loss in FSGS patients at presentation does not necessarily indicate irreversible kidney function loss and a significant number of patients respond to appropriate treatment of the underlying disease.
文摘BACKGROUND The Columbia classification identified five histological variants of focal segmental glomerulosclerosis(FSGS).The prognostic significance of these variants remains controversial.AIM To evaluate the relative frequency,clinicopathologic characteristics,and medium-term outcomes of FSGS variants at a single center in Pakistan.METHODS This retrospective study was conducted at the Department of Nephrology,Sindh Institute of Urology and Transplantation,Karachi,Pakistan on all consecutive adults(≥16 years)with biopsy-proven primary FSGS from January 1995 to December 2017.Studied subjects were treated with steroids as a first-line therapy.The response rates,doubling of serum creatinine,and kidney failure(KF)with replacement therapy were compared between histological variants using ANOVA or Kruskal Wallis,and Chi-square tests as appropriate.Data were analyzed by SPSS version 22.0.P-value≤0.05 was considered significant.RESULTS A total of 401 patients were diagnosed with primary FSGS during the study period.Among these,352(87.7%)had a designated histological variant.The not otherwise specified(NOS)variant was the commonest,being found in 185(53.9%)patients,followed by the tip variant in 100(29.1%)patients.Collapsing(COL),cellular(CEL),and perihilar(PHI)variants were seen in 58(16.9%),6(1.5%),and 3(0.7%)patients,respectively.CEL and PHI variants were excluded from further analysis due to small patient numbers.The mean follow-up period was 36.5±29.2 months.Regarding response rates of variants,patients with TIP lesions achieved remission more frequently(59.5%)than patients with NOS(41.8%)and COL(24.52%)variants(P<0.001).The hazard ratio of complete response among patients with the COL variant was 0.163[95%confidence interval(CI):0.039-0.67]as compared to patients with NOS.The TIP variant showed a hazard ratio of 2.5(95%CI:1.61-3.89)for complete remission compared to the NOS variant.Overall,progressive KF was observed more frequently in patients with the COL variant,43.4%(P<0.001).Among these,24.53%of patients required kidney replacement therapy(P<0.001).The hazard ratio of doubling of serum creatinine among patients with the COL variant was 14.57(95%CI:1.87-113.49)as compared to patients with the TIP variant.CONCLUSION In conclusion,histological variants of FSGS are predictive of response to treatment with immunosuppressants and progressive KF in adults in our setup.
文摘BACKGROUND Focal segmental glomerulosclerosis(FSGS)often recurs after transplantation,leading to graft dysfunction and graft loss.Patients who have lost prior grafts due to recurrence are at particularly high risk of re-recurrence in subsequent grafts.Rituximab and plasma exchange have been used pre-emptively to prevent post-transplant recurrence.However,the efficacy of such preventative measures remains unclear.AIM To investigate the outcomes of preventative rituximab and plasma exchange for recurrent FSGS in transplant recipients after prior graft loss.METHODS We conducted a systematic review of 11 studies with 32 patients who had experienced prior graft loss due to post-transplant FSGS recurrence and were treated with either pre-emptive plasma exchange alone,rituximab alone,or a combination of both.RESULTS Overall,47%of the 32 patients experienced recurrence despite prophylactic treatment.Re-recurrence was seen in 25%(1/4)with pre-emptive rituximab alone,and 45%recurrence(9/20)with plasma exchange alone.Re-recurrence was noted in 63%with the use of combined plasma exchange and rituximab.CONCLUSION There is a paucity of available evidence in the literature to draw clear conclusions on the benefits of pre-emptive measures to prevent FSGS re-recurrence.The small sample sizes and variations in protocols call for larger and controlled studies to serve this patient population at high risk of recurrence and graft loss.
文摘Background: Previous studies suggested that the focal and segmental nature of focal segmental glomerulosclerosis (FSGS) may lead to sample error or diagnosis error that results in minimal change disease (MCD) misdiagnosis, or FSGS being missed especially in patients with early lesions or limited glomeruli in the biopsy specimens. Patients and methods: Over the past 5 years, patients were included in the study if they had (a) relapse of nephrotic syndrome (NS), (b) biopsy-proven FSGS without immune deposits, (c) long-remission (years) after biopsy-proven Corticosteroid-refractory NS due to MCD, (c) negative history, clinical examination, radiological scans as well as laboratory and serological tests for autoimmune diseases, infections, malignancy and drugs-side effect. Results: After 3 months of therapy with Losartan alone;Proteinuria decreased only by 22% improvement with a mild decrease in Creatinine clearance (ClCr) by 1.5%. However, the addition of Mycophenolate mofetil (MMF) resulted in a further significant decrease in Pr to 72% compared to Losartan alone. Moreover, there were no significant changes in CrCl after 1- and 2 years of follow up. Our data indicates that such a transition may not be due to inadequate sampling but a new lesion. Initial hemodynamic therapy with Losartan was not adequate and immunosuppressive therapy with MMF significantly improved proteinuria and stabilized their kidney function. The data is promising with regard to the management of patients with such relentless disease. In conclusion, a true transition from MCD to FSGS is amenable to therapy with MMF.
文摘Focal segmental glomerulosclerosis(FSGS) represents one of the most severe glomerular diseases, with frequent progression to end-stage renal disease and a high rate of recurrence in renal allografts(30%-50%). Recurrent FSGS portends a negative outcome, with the hazard ratio of graft failure being two-fold higher then that of other glomerulonephritis. Two patterns of clinical presentations are observed: Early recurrence, which is characterized by massive proteinuria within hours to days after implantation of the renal graft, and late recurrence, which occurs several months or years after the transplantation. Many clinical conditions have been recognized as risk factors for recurrence, including younger age, rapid progression of the disease to end-stage renal disease on native kidneys, and loss of previous renal allografts due to recurrence. However, much less is known about the incidence and risk factors of the so-called "de novo " type of FSGS, for which sufferers are transplanted patients without disease on native kidneys; but, rapid development of allograft failure is frequently observed. Management of both forms is challenging, and none of the approaches proposed to date have been demonstrated as consistently beneficial or effective. In the present review we report an update on the available therapeutic strategies for FSGS in renal transplantation within the context of a critical overview of the current literature.
基金Supported by Protective Effect of Extract of Fructus Schisandrae Chinensis on Fibrosis of Diabetic Nephropathy among C57BL/6 Mice of National Natural Science Foundation of China(No.81150012)
文摘OBJECTIVE: To observe the effects and mechanisms of Bushenhuoxue on desmin and nephrin expression in mice podocytes, and to investigate its effects on wt1 expression in Wilms' tumor.METHODS: Adriamycin(ADR) was used to induce focal segmental glomerulous sclerosis(FSGS) in mice. Bushenhuoxue was used to treat FSGS for 6 weeks. We measured body mass and right renal mass, and determined serum albumin(ALB) levels,protein content in urine, and urinary protein and albumin creatinine ratio(UACR). Changes in renal tissue morphology were evaluated by microscopy.wt1 and nephrin expression in podocytes were detected using immunofluorescence. Expression levels of desmin, wt1 and nephrin m RNAs in renal tissue were determined using reverse transcription polymerase chain reaction assays.RESULTS: Protein levels in urine and UACR were significantly increased in FSGS model mice compared with Bushenhuoxue-treated and control mice.Body mass and ALB levels were decreased in FSGS mice compared with control and Bushenhuoxue-treated mice. Expression of the wt1 protein was observed in control mice. Compared with controls,wt1 expression levels were reduced in Bushenhuoxue-treated mice, and to a greater extent in FSGS mice. Nephrin protein expression was widespread in FSGS mice, and significantly reduced in control and Bushenhuoxue mice. Expression levels of wt1 and nephrin m RNAs in FSGS mice were lower compared with those in control and Bushenhuoxue-treated mice. Desmin m RNA levels in FSGS mice were reduced compared with those in control and Bushenhuoxue-treated mice.CONCLUSION: Bushenhuoxue ameliorated albuminuria in FSGS mice; this was possibly related to the up-regulation of wt1 and nephrin, and down-regulation of desmin.
文摘BACKGROUND Focal segmental glomerulosclerosis(FSGS)is one of the most common glomerular diseases leading to renal failure.FSGS has a high risk of recurrence after kidney transplantation.Prevention of recurrent FSGS using rituximab and/or plasmapheresis has been evaluated in multiple small studies with conflicting results.AIM To assess the risk of recurrence of FSGS after transplantation using prophylactic rituximab with or without plasmapheresis,and plasmapheresis alone compared to the standard treatment group without preventive therapy.METHODS This meta-analysis and systematic review were performed by first conducting a literature search of the MEDLINE,EMBASE,and Cochrane databases,from inception through March 2021;search terms included‘FSGS,’’steroid-resistant nephrotic syndrome’,‘rituximab,’and‘plasmapheresis,’.We identified studies that assessed the risk of post-transplant FSGS after use of rituximab with or without plasmapheresis,or plasmapheresis alone.Inclusion criteria were:Original,published,randomized controlled trials or cohort studies(either prospective or retrospective),case-control,or cross-sectional studies;inclusion of odds ratio,relative risk,and standardized incidence ratio with 95%confidence intervals(CI),or sufficient raw data to calculate these ratios;and subjects without interventions(controls)being used as comparators in cohort and cross-sectional studies.Effect estimates from individual studies were extracted and combined using a random effects model.RESULTS Eleven studies,with a total of 399 kidney transplant recipients with FSGS,evaluated the use of rituximab with or without plasmapheresis;thirteen studies,with a total of 571 kidney transplant recipients with FSGS,evaluated plasmapheresis alone.Post-transplant FSGS recurred relatively early.There was no significant difference in recurrence between the group that received rituximab(with or without plasmapheresis)and the standard treatment group,with a pooled risk ratio of 0.82(95%CI:0.47-1.45,I2=65%).Similarly,plasmapheresis alone was not associated with any significant difference in FSGS recurrence when compared with no plasmapheresis;the pooled risk ratio was 0.85(95%CI:0.60-1.21,I2=23%).Subgroup analyses in the pediatric and adult groups did not yield a significant difference in recurrence risk.We also reviewed and analyzed posttransplant outcomes including timing of recurrence and graft survival.CONCLUSION Overall,the use of rituximab with or without plasmapheresis,or plasmapheresis alone,is not associated with a lower risk of FSGS recurrence after kidney transplantation.Future studies are required to assess the effectiveness of rituximab with or without plasmapheresis among specific patient subgroups with high-risk for FSGS recurrence.
文摘Accumulating evidence suggests that the small G protein Rho and its downstream effec-tor Rho kinase may play important roles in kidney biology. The present study examined the effects of a Rho-kinase inhibitor, fasudil, on daunorubicin-induced progressive glomerulosclerosis and explored the underlying mechanism by which fasudil ameliorates glomerulosclerosis. Thirty-six male SD rats were randomly allocated into sham-operation group （sham group, n=12）, unilateral nephrectomy （UNX）＋daunorubicin （DRB） group （model group, n=12）, UNX＋DRB＋Fasudil group （treatment group, n=12）. Two to four weeks after the establishment of the animal model, 6 rats in each group were taken randomly for the detection of 24-h urine protein excretion. Kidney sections were exam-ined by HE and PAS staining, immunohistochemistry and transmission electric microscopy （TEM）. The expression of Rho-kinase mRNA and P27 mRNA in kidney were detected by RT-PCR. It was found that the 24-h urine protein excretion in model group was increased significantly as compared with sham group （P〈0.01）. But this increase was significantly suppressed by fasudil （P〈0.05）. At 4 week, the foot process effacement in podocytes, mesangial proliferation and ECM accumulation were observed in model group, presenting as focal segmental glomerulosclerosis. But in the treatment group, the fasudil alleviated glomerular injury, with proliferating cell nuclear antigen （PCNA）-positive cell infiltration ameliorated and the expression of P27 increased. The expression of Rho-kinase mRNA was significantly enhanced in model group and was suppressed in treatment group. Moreover, fasudil up-regulated the mRNA expression of P27. Our study demonstrated that the glomerulosclerosis was substantially ameliorated by inhibiting the expression of Rho-kinase. It is suggested that Rho-kinase pathway is involved in the renal injury and the inhibition of Rho-kinase may constitute a therapeutic strategy for the treatment of renal injury.
基金the National Natural Science Foundation of China(General Program),No.82205002Science and Technology Project of Sichuan Province,No.2022YFS0621,No.21ZDYF0348,and No.2022NSFSC1459+1 种基金Luzhou-Southwest Medical University Science and Technology Strategic Cooperation Project,No.2021LZXNYD-P04Southwest Medical University of Affiliated Traditional Medicine Hospital Project,No.2022-CXTD-03.
文摘BACKGROUND Bone marrow-derived mesenchymal stem cells(MSCs)show podocyte-protective effects in chronic kidney disease.Calycosin(CA),a phytoestrogen,is isolated from Astragalus membranaceus with a kidney-tonifying effect.CA preconditioning enhances the protective effect of MSCs against renal fibrosis in mice with unilateral ureteral occlusion.However,the protective effect and underlying mechanism of CA-pretreated MSCs(MSCsCA)on podocytes in adriamycin(ADR)-induced focal segmental glomerulosclerosis(FSGS)mice remain unclear.AIM To investigate whether CA enhances the role of MSCs in protecting against podocyte injury induced by ADR and the possible mechanism involved.METHODS ADR was used to induce FSGS in mice,and MSCs,CA,or MSCsCA were administered to mice.Their protective effect and possible mechanism of action on podocytes were observed by Western blot,immunohistochemistry,immunofluorescence,and real-time polymerase chain reaction.In vitro,ADR was used to stimulate mouse podocytes(MPC5)to induce injury,and the supernatants from MSC-,CA-,or MSCsCA-treated cells were collected to observe their protective effects on podocytes.Subsequently,the apoptosis of podocytes was detected in vivo and in vitro by Western blot,TUNEL assay,and immunofluorescence.Overexpression of Smad3,which is involved in apoptosis,was then induced to evaluate whether the MSCsCA-mediated podocyte protective effect is associated with Smad3 inhibition in MPC5 cells.RESULTS CA-pretreated MSCs enhanced the protective effect of MSCs against podocyte injury and the ability to inhibit podocyte apoptosis in ADR-induced FSGS mice and MPC5 cells.Expression of p-Smad3 was upregulated in mice with ADR-induced FSGS and MPC5 cells,which was reversed by MSCCA treatment more significantly than by MSCs or CA alone.When Smad3 was overexpressed in MPC5 cells,MSCsCA could not fulfill their potential to inhibit podocyte apoptosis.CONCLUSION MSCsCA enhance the protection of MSCs against ADR-induced podocyte apoptosis.The underlying mechanism may be related to MSCsCA-targeted inhibition of p-Smad3 in podocytes.
文摘Collapsing focal segmental glomerulosclerosis （cFSGS）, also known as collapsing glomerulopathy is currently classified under the rubric of FSGS. However, its de-fining morphological features are in stark contrast to those observed in most other variants of FSGS. During the early stage of the disease, the lesion is character-ized pathologically by an implosive segmental and/or global collapse of the glomerular capillary tufts, marked hypertrophy and hyperplasia of podocytes, and severe tubulointerstitial disease. With advancement of the disease, segmental and/or global glomerulosclerosis is also observed in association with the collapsing le-sions. The etiology of this enigmatic disorder is still elusive, but a growing list of diseases/conditions is being reported in association with this morphological pattern of renal parenchymal injury. The pathogenesis of cFSGS involves discreet epithelial cell injury leadingto cell cycle dysregulation and a proliferative cellularphenotype. From the clinical perspective, cFSGS is no-torious for its propensity to affect black people, a highincidence and severity of nephrotic syndrome, markedresistance to empirical therapy, and rapid progressionto end-stage renal disease. The lesion has also beenreported in transplanted kidneys either as recurrent orde novo disease, frequently leading to graft loss. Mostcases have been reported in western countries, but the lesion is also being increasingly recognized in the tropi-cal regions. The recent increase in reporting of cFSGS partly refects a true increase in the incidence and part-ly a detection bias. There is no specifc treatment for the disorder at present. Newer insights into the patho-genesis may lead to the development of targeted and specifc therapy in near future. There is an urgent need to increase awareness of the lesion among pathologists and nephrologists, especially those from developing countries, to ensure accurate diagnosis and appropriate managment. With the accumulation of more and more data, it is hoped that the prevailing confusion about the nosological identity of the lesion will also be resolved in a more logical way.
文摘Primary focal and segmental glomerulosclerosis(FSGS) may be due to genetic or acquired etiologies and is a common cause of nephrotic syndrome with high morbidity that often leads to end-stage renal failure. The different available therapeutic approaches are unsuccessful, in part due to partially deciphered heterogeneous and complex pathophysiological mechanisms. Moreover, the term FSGS, even in its primary form, comprises a histological description shared by a number of different causes with completely different molecular pathways of disease. This review focuses on the latest developments regarding the pathophysiology of primary acquired FSGS caused by soluble factor urokinase type plasminogen activator receptor, a circulating permeability factor involved in proteinuria and edema formation, and describes recent advances with potential success in therapy.
文摘BACKGROUND Although minimal change disease(MCD)and focal segmental glomerulosclerosis(FSGS)have been described as two separate forms of nephrotic syndrome(NS),they are not completely independent.We report a case of a patient transitioning from MCD to FSGS,review the literature,and explore the relationship between the two diseases.CASE SUMMARY A 42-year-old male welder,presenting with lower extremity edema and elevated serum creatinine,was diagnosed with NS and end-stage kidney disease(ESKD)based on laboratory test results.The patient had undergone a kidney biopsy for NS 20 years previously,which indicated MCD,and a second recent kidney biopsy suggested FSGS.The patient was an electric welder with excessive levels of cadmium and lead in his blood.Consequently,we suspect that his aggravated pathology and occurrence of ESKD were related to metal nephrotoxicity.The patient eventually received kidney replacement therapy and quit his job which involved long-term exposure to metals.During the 1-year follow-up period,the patient was negative for metal elements in the blood and urine and recovered partial kidney function.CONCLUSION MCD and FSGS may be different stages of the same disease.The transition from MCD to FSGS in this case indicates disease progression,which may be related to excessive metal contaminants caused by the patient’s occupation.
基金financially supported by grants from the National Natural Science Foundation of China(No.81961138007,No.81974096 and No.81770711)the National Key Research and Development Program(No.2020YFC0845800 and No.2018YFC1314000)+1 种基金the Program for HUST Academic Frontier Youth Team(No.2017QYTD20)the Natural Science Foundation of Hubei Province(No.2017CKB899).
文摘Objective To assess the significance of focal segmental glomerulosclerosis(FSGS)variants on clinicopathological characteristics and short-term outcomes in idiopathic membranous nephropathy(IMN)patients.Methods The clinicopathological data of 146 IMN patients diagnosed between December 2016 and March 2019 in our center were collected and analyzed.These patients were divided into the pure IMN group,IMN with glomerular tip lesion(GTL)group,and IMN with non-GTL FSGS group.Results The IMN with non-GTL FSGS and IMN with GTL groups both had higher proportions of patients with hypertension,lower serum albumin,and severe proteinuria,while the IMN with non-GTL FSGS group additionally showed higher blood pressure and serum cholesterol,and lower serum IgG than the IMN group(all P<0.05).As for pathology,the IMN with non-GTL FSGS group had higher proportions of patients with acute tubular injury and moderate to severe chronic injuries than the IMN group(all P<0.05).In the IMN,IMN with GTL,and IMN with non-GTL FSGS groups,the overall one-year remission rates were 81.6%,76%,and 58.8%,respectively.Furthermore,the IMN with non-GTL FSGS group showed the lowest cumulative incidence to reach remission within one year.Multivariate Cox logistic analysis demonstrated that higher level of serum anti-M-type phospholipase A2 receptor antibody and the existence of non-GTL FSGS lesion were independent predictors for no remission in IMN patients.Conclusion The non-GTL FSGS lesion was a novel negative predictor in IMN and should be taken into account in the management of IMN.
文摘The incidence of the collapsing variant of focal segmental glomerulosclerosis(FSGS)as a human immunodeficiency virus(HIV)-associated nephropathy has reduced since the introduction of antiretroviral therapy(ART).However,the incidence of other variants of FSGS,except for the collapsing variant,is increasing,and its therapeutic strategies remain uncertain.A 60-year-old HIV infected man in remission with ART was admitted for progressive renal insufficiency and nephrotic-ranged proteinuria.Renal biopsy revealed a tip variant of FSGS and his clinical manifestations resolved with corticosteroid therapy.HIV infected patients might develop non-collapsing FSGS,including tip variant of FSGS and corticosteroid therapy might be effective for them.A renal biopsy might be essential to determine the renal histology and to decide on corticosteroid therapy.
文摘Introduction: Focal Segmental Glomerulosclerosis (FSGS) corresponds to a clinicopathological syndrome, manifested by generally abundant proteinuria associated with hyaline deposits on part of certain glomeruli and sparing other glomeruli, with effacement of the pedicels. The general objective was to determine the prevalence of FSGS, and to give its profiles;epidemiological, clinical, biological, pathological, etiological, therapeutic and evolutionary of FSGS. Materials and Methods: This is a retrospective analytical study over a period of six years extending from January 1, 2010 to December 31, 2015 patients aged 16 or over who were hospitalized or received consultations during the study period for primary or secondary segmental and focal hyalinosis. Patients whose records were incomplete or unusable were not included in the study. Results: We have 16.54% with 158 cases of FSGS out of 6945 patients received and/or hospitalized. Of the 955 kidney biopsies distributed, the incidences of HSF were;10.15%;14.04%;15%;17.64%;20.11%;19.58% respectively in 2010;2011;2012;2013;2014 and 2015, i.e. an annual increase of around 1.25%. Renal-type edemas were found in 93.3%, the first reason for hospitalization. And ninety-six people had impaired kidney function, or 61%. The average of 24-hour proteinuria was 6.4 ± 3.69 g/24 hours. The extremes were 0.37 and 18.50 g/24h. Patients had nephrotic proteinuria in 84.86%. Non-specific FSGS or NOS (Not Other Specificities) was found in 62 cases or 39.24%, collapsing FSGS in 48 cases or 30.40%. FSGS with found causes was associated with fibrosis in 5/35 cases. Collapsing FSGSs followed by NOS FSGSs were the most corticosteroid-resistant. The evolution of the FSGS reveals that every 8 months the proteinuria decreases by half. Conclusion: Segmental and focal hyalinosis requires histological confirmation and the epidemiological, clinico-biological, etiological, therapeutic and evolutionary profiles depend on the histological (pathological) type. Other works on the risk factors for occurrence and the contribution of electron microscopy in the primary and secondary diagnosis of segmental and focal hyalinosis are desired.
文摘Objective To analyze the target signaling pathway of histone H3K27 methylation-induced podocyte injury,verify the regulatory effect of histone H3K27 methylation on podocyte injury in focal segmental glomerulosclerosis(FSGS)mice through target signaling pathway,and explore the mechanism of abnormal methylation of histone H3K27-induced podocyte injury in FSCS mice.Methods(1)Cell experiments:primary cultured immortalized mouse podocytes MPC5 were cultured in vitro,and divided into control group,adriamycin(ADR)group,ADR+GSK-J4(histone demethylase,KDM6B inhibitor)group,ADR+coumarin A1(C-Al,JAK2 agonist)group and ADR+GSK-J4+C-A1 group.The transmission electron microscope was used to observe ultrastructure of podocytes.Immunofluorescence was used to detect the protein expression of H3K27me3and nephrinin podocytes.The whole genome sequence of podocytes was obtained,the differentially expressed genes were screened,and Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)were used for enrichment analysis.Real time-quantitative PCR and Western blotting were used to detect the gene and protein expression of JAK2-STAT3 signaling pathway in podocytes respectively.Enzyme-linked immunosorbent assay was used to detect interleukin 6(IL-6),monocyte chemotactic protein 1(MCP-1),α-smooth muscle actin(α-SMA)and transforming growth factorβ1(TGF-β1).(2)Animal experiments:EZH2 gene knock out(EZH2^(podko))-FSCS(tail vein injection of ADR)mousenmodels were established,and divided into EZH2^(ctrl)+,control group(n=20),EZH2^(ctrl)+FSGS(n=20),EZH2^(podko)control group(n=30)and EZH2^(podko)+FSCS group(n=30).HE staining was used to observe the morphology of kidney tissues.Immunohistochemistry was used to detect the H3K27me3 protein expression in podocytes.Real time-quantitative PCR and Western blotting were used to verify the gene and protein expression of JAK2-STAT3 signaling pathway respectively.Enzyme-linked immunosorbent assay was used to detect IL-6,MCP-1,α-SMA and TGF-β1 of kidney tissues.Results(1)Cell experiments:Compared with control group,the nucleus shrank and ruptured,the cytoplasm showed vacuole,and mitochondria and endoplasmic reticulum swelled in ADR group,which verified that the podocyte injury model of ADR nephropathy was successfully established.Compared with control group,the protein expression level of H3K27me3 in ADR group was significantly lower(P<0.05).Compared with ADR group,the protein expression level of H3K27me3 in podocytes in ADR+GSK-J4 group was significantly higher(P<0.05),and there were 502 increased genes and 443 decreased genes.GO enrichment analysis showed that the differentially enriched peaks were mainly in ribonucleoprotein complex biogenesis,ribosome biogenesis,establishment of protein localization to organelle,and involved in regulation of receptor signaling pathway via JAK-STAT and receptor signaling pathway via JAK-STAT.Differential expressed genes were Irfl,Tnfrsfla,Socsl,Notch1,Gadd45a,Hesl and Socs3,involving in the regulation of JAK-STAT signaling pathway.KECG enrichment analysis showed that the differentially enriched peaks were mainly in amyotrophic lateral sclerosis,and the target genes were Mcll,Egfr,Socsl,Cdknla,Pdgfa and Socs3,involving in the regulation of JAK-STAT signaling pathway.Compared with ADR group,the mRNA and protein expression levels of JAK2 and STAT3 in the ADR+GSK-J4 group were significantly lower,and thedownstream inflammatory factors of IL-6,MCP-1 andα-SMA were significantly higher(all P<0.05).Compared with ADR group,the protein expression level of nephrin in ADR+GSK-J4 group was higher(P<0.05),and the protein expression level of nephrin in ADR+C-A1 group was lower(P<0.05).Compared with ADR+GSK-J4 group,the protein expression level of nephrin in ADR+GSK-J4+C-A1 group was lower(P<0.05).(2)Animal experiments:Compared with EZH2^(ctrl)+FSGSSgroup,EZH2^(podko)+FSCS group showed obvious renal tssue damage,matrix hyperplasia inmesangia1l area with massive homogeneous substance ddeposition,apoptosis and necrosis of renal tubular epithelial cells,obvious thickening and extensive fusion of glomerular epithelial cells,basement membrane collapse,and compression and narrowing of capillary structure.Compared with EZH2^(ctrl)+FSGS group,the protein expression level of.H3K27me3 in EZH2^(podko)+FSCS group was significantly lower,and the mRNA and protein expression levels of JAK2 and STAT3,and the levels of IL-6,MCP-1,α-SMA and TCF-β1 were higher(all P<0.05).Conclusion Abnormal methylation modificationn of H3K27 leads to changee of target gene expression,activation of JAK2-STAT3 signaling pathway,podocyte injury,glomerulosclerosis and renal tubular injury,participating in the development of FSGS.
文摘BACKGROUND Renal tubular acidosis(RTA)refers to a group of kidney disorders characterized by defective acid excretion or bicarbonate reabsorption,leading to metabolic acidosis.This case series presents three cases of RTA with distinct etiologies and clinical manifestations.These cases emphasize the necessity of a comprehensive evaluation of RTA,considering both renal and systemic origins.CASE SUMMARY The first case describes a female patient with osteopetrosis-related RTA,diagnosed with Guibaud-Vainsel syndrome,emphasizing the importance of genetic assessment.The second case delineates RTA secondary to focal segmental glomerulosclerosis,associating tubular dysfunction with glomerular pathology.In the first two cases whole exome sequencing confirmed genetic diagnosis.The third case illuminates RTA as a complication of Graves’disease,highlighting autoimmune implications.CONCLUSION These cases underscore the interdisciplinary approach essential in RTA management.Understanding the diverse pathophysiology of RTA aids in tailored therapeutic strategies and improved patient outcomes.
文摘To investigate the protective effects of blocking rennin-angiotensin system(RAS)on the progression of renal injury in glomerulosclerosis,a glomerulosclerosis model was made for SD rats by unilateral nephrectomy and being injected with Adriamycin into caudal vein.The rats with glomerulosclerosis were randomly divided as ten per group into those without further treatment(group D)and those treated with Benazepril(group DB),Losartan (group DL),or sham-operation(group C),respectively.After 6 weeks of administration of Benazepril or Losartan, the mRNA expressions of TGF-β_1,Col Ⅳ,Fn,ET-1 and iNOS in renal cortex were measured by RT-PCR.Besides, the expressions of TGF-β_1,ET-1 and iNOS at protein level were detected by Western blotting and the concentrations of Col Ⅳ and Fn were analyzed with immunohistochemistry respectively.Results showed that the rats in group D appeared as obvious proteinuria,hypoalbuminemia and hypercholesterolemia,which had a significant difference compared with group C(p<0.05),and most of their mesangiums were detected with cellular proliferation and significant increasing for extracellular matrix.Renal cortex TGF-β_1,Col Ⅳ,Fn,ET-1 and iNOS in rats of group D were increased by 3.59,2.57,2.21,2.58 and 3.28 times at mRNA level,and by 2.60,1.40,0.75,1.83 and 2.15 times at protein level,respectively,compared with group C.When the animals were treated with Benazepril(group DB)or Losartan(group DL),however,the biochemical and pathological damages were significantly recovered,and protein expressions of TGF-β_1,Col Ⅳ,Fn,ET-1 and iNOS were also significantly diminished(p<0.05).This study suggested that blocking RAS using Benazepril or Losartan can have protective effects on the renal injury in glomerulosclerosis by down-regulating the expressions of TGF-β_1, Col Ⅳ,Fn,ET-1 and iNOS.Cellular & Molecular Immunology.2005;2(2):150-154.
