Clinicopathological features and medium-term outcomes of histologic variants of primary focal segmental glomerulosclerosis in adults:A retrospective study

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.

Review of plasma exchange and rituximab for prevention of recurrent focal segmental glomerulosclerosis after a prior graft loss

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.

Synergism of calycosin and bone marrow-derived mesenchymal stem cells to combat podocyte apoptosis to alleviate adriamycininduced focal segmental glomerulosclerosis

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.

Focal Segmantal Glomerulosclerosis: Epidemiological, Clinico-Biological, Pathological, Etiological, Therapeutic and Evolutionary Profiles in Dakar

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.

Update on the treatment of focal segmental glomerulosclerosis in renal transplantation

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.

A Rho-kinase Inhibitor, Fasudil, Attenuates Progressive Glomerulosclerosis Induced by Daunorubicin in Rats

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.

Rituximab or plasmapheresis for prevention of recurrent focal segmental glomerulosclerosis after kidney transplantation:A systematic review and meta-analysis

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.

Collapsing focal segmental glomerulosclerosis: Current concepts

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.

Primary focal and segmental glomerulosclerosis and soluble factor urokinase-type plasminogen activator receptor

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.

Transition from minimal change disease to focal segmental glomerulosclerosis related to occupational exposure:A case report

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.

Non-glomerular Tip Lesion Focal Segmental Glomerulosclerosis as a Negative Predictor in Idiopathic Membranous Nephropathy

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.

Case of human immunodeficiency virus infection presenting as a tip variant of focal segmental glomerulosclerosis: A case report and review of the literature

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.

Long-term prognosis of focal segmental glomerulosclerosis treated with therapeutic low-density lipoprotein-apheresis in patients with severe kidney dysfunction and proteinuria

Background:The prognosis of focal segmental glomerulosclerosis patients with nephrotic syndrome is estimated to be 10%-20%in 5 years and 30%-50%in 10 years,leading to end-stage kidney disease.The response rate with steroid therapy is 40%-60%.Therapeutic low-density lipoprotein-apheresis(LDL-A)may be effective in patients with steroid resistance.Information regarding the long-term prognosis of patients with focal segmental glomerulosclerosis receiving this therapy is scarce.Methods:We investigated the effectiveness of treatment in 50 patients with primary focal segmental glomerulosclerosis diagnosed between 1961 and 2017 at Kanazawa University Hospital and related facilities.The patients were observed at least 12 months after biopsy or until end-stage kidney disease occurrence or death.Results:LDL-A was performed in four patients who presented with steroidresistant nephrotic syndrome(two patients had concurrent acute renal failure for which hemodialysis was performed).In comparison with 17 patients who did not receive LDL-A after 1989,the LDL-A group had higher urinary protein excretion(13.7 vs.5.2 g/day,P=0.053)and serum creatinine(4.11 vs.1.65 mg/dL)levels at onset,and a numerically higher remission rate(75.0%vs.58.7%)compared with the nonlipoprotein-apheresis group.Conclusion:Therapeutic LDL-A can be performed for critical cases and may improve the remission rate.

Exploring kidney biopsy findings in congenital heart diseases:Insights beyond cyanotic nephropathy

BACKGROUND The association between congenital heart disease and chronic kidney disease is well known.Various mechanisms of kidney damage associated with congenital heart disease have been established.The etiology of kidneydisease has commonly been considered to be secondary to focal segmental glomerulosclerosis(FSGS),however,this has only been demonstrated in case reports and not in observational or clinical trials.AIM To identify baseline and clinical characteristics,as well as the findings in kidney biopsies of patients with congenital heart disease in our hospital.METHODS This is a retrospective observational study conducted at the Nephrology Depart-ment of the National Institute of Cardiology“Ignacio Chávez”.All patients over 16 years old who underwent percutaneous kidney biopsy from January 2000 to January 2023 with congenital heart disease were included in the study.RESULTS Ten patients with congenital heart disease and kidney biopsy were found.The average age was 29.00 years±15.87 years with pre-biopsy proteinuria of 6193 mg/24 h±6165 mg/24 h.The most common congenital heart disease was Fallot’s tetralogy with 2 cases(20%)and ventricular septal defect with 2(20%)cases.Among the 10 cases,one case of IgA nephropathy and one case of membranoproliferative glomerulonephritis associated with immune complexes were found,receiving specific treatment after histopathological diagnosis,delaying the initiation of kidney replacement therapy.Among remaining 8 cases(80%),one case of FSGS with perihilar variety was found,while the other 7 cases were non-specific FSGS.CONCLUSION Determining the cause of chronic kidney disease can help in delaying the need for kidney replacement therapy.In 2 out of 10 patients in our study,interventions were performed,and initiation of kidney replacement therapy was delayed.Prospective studies are needed to determine the usefulness of kidney biopsy in patients with congenital heart disease.

Protective Effects of Blocking Renin-Angiotensin System on the Progression of Renal Injury in Glomerulosclerosis

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.

New Mutation of Coenzyme Q10 Monooxygenase 6 Causing Podocyte Injury in a Focal Segmental Glomerulosclerosis Patient

Background:Focal segmental glomerulosclerosis (FSGS)is a kidney disease that is commonly associated with proteinuria and the progressive loss of renal function,which is characterized by podocyte injury and the depletion and collapse of glomerular capillary segments.The pathogenesis of FSGS has not been completely elucidated;however,recent advances in molecular genetics have provided increasing evidence that podocyte structural and functional disruption is central to FSGS pathogenesis.Here,we identified a patient with FSGS and aimed to characterize the pathogenic gene and verify its mechanism. Methods:Using next-generation sequencing and Sanger sequencing,we screened the causative gene that was linked to FSGS in this study.The patient's total blood RNA was extracted to validate the messenger RNA (mRNA)expression of coenzyme Q10 monooxygenase 6(COQ6)and validated it by immunohistochemistry.COQ6 knockdown in podocytes was performed in vitro with small interfering RNA, and then,F-actin was determined using immunofluorescence staining.Cell apoptosis was evaluated by flow cytometry,the expression of active caspase-3was determined by Western blot,and mitochondrial function was detected by MitoSOX. Results:Using whole-exome sequencing and Sanger sequencing,we screened a new causative gene,COQ6,NM_182480:exonl:c.G41A: p.W14X.The mRNA expression of COQ6 in the proband showed decreased.Moreover,the expression of COQ6,which was validated by immunohistochemistry,also had the same change in the proband.Finally,we focused on the COQ6 gene to clarify the mechanism of podocyte injury.Flow cytometry showed significantly increased in apoptotic podocytes,and Western blotting showed increases in active caspase-3in si-COQ6 podocytes.Meanwhile,reactive oxygen species (ROS)levels were increased and F-actin immunofluorescence was irregularly distributed in the si-COQ6 group. Conclusions:This study reported a possible mechanism for FSGS and suggested that a new mutation in COQ6,which could cause respiratory chain defect,increase the generation of ROS,destroy the podocyte cytoskeleton,and induce apoptosis.It provides basic theoretical basis for the screening of FSGS in the future.

Genetic basis of adult-onset nephrotic syndrome and focal segmental glomerulosclerosis

Nephrotic syndrome （NS） is one of the most common glomerular diseases with signs of nephrosis, heavy proteinuria, hypoalbuminemia, and edema. Dysfunction of glomerular filtration barrier causes protein loss through the kidneys. Focal segmental glomerulosclerosis （FSGS） accounts for nearly 20% of NS among children and adults. Adult-onset FSGS/NS is often associated with low response to steroid treatment and immunosup- pressive medication and poor renal survival. Several genes involved in NS and FSGS have been identified by linkage analysis and next-generation sequencing. Most of these genes encode proteins and are highly expressed in glomerular podocytes, which play crucial roles in slit-diaphragm signaling, regulation of actin cytoskeleton dynamics and maintenance of podocyte integrity, and cell-matrix interactions. In this review, we focus on the recently identified genes in the adult-onset NS and FSGS and discuss clinical significance of screening of these genes.

Efficacy of tacrolimus in the treatment of children with focal segmental glomerulosclerosis

Background:Focal segmental glomerulosclerosis(FSGS)is the most common glomerular condition leading to end-stage renal disease(ESRD)and the third most common cause of ESRD in pediatric patients.Methods:This is a retrospective study consisting of 22 pediatric patients with FSGS and heavy proteinuria.After demonstrating steroids resistance,the patients were treated with tacrolimus,targeting a trough level 5-8 ng/mL.The primary outcome is the induction of remission with tacrolimus.Results:Thirteen patients(59%)achieved remission(complete in 31.8%and partial in 27.2%)and 12 patients showed stable or improved renal function over an average follow-up of 2.9 years(range:0.5-7 years).There was no significant difference in response rate between African American and Caucasian patients.None of the patients had significant side-effect to tacrolimus and none of the repeat biopsies showed an increase in interstitial fibrosis compared to baseline.The best renal outcome was for patients who achieved complete remission.Partially responsive patients had improved renal function compared with resistant patients.Conclusion:Tacrolimus is a viable option in the treatment of children with idiopathic steroid resistant FSGS.

Influence of Bushenhuoxue on podocytes of focal segmental glomerulosclerosis mice

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.

Effects of Shikonin on Proliferation, Apoptosis, and Extracellular Matrix of Human Mesangial Cells

Objective:To investigate the effect of shikonin on the proliferation, apoptosis and extracellular matrix (ECM) of human mesangial cells (MC). Methods: MC was cultured in vitro with different concentrations of glucose (30, 50, 80 mmol/L). The cell growth was observed by using MTT method and apoptosis by using an aunexin-V-Fluos. Immunohistochemical studies for Laminin (LN), Fibronectin (FN) and type Ⅳ Collagens (Col Ⅳ) were measured. Results: Shikonin inhibited their growth (P<0.05) and apoptosis in the glycated cultured cells. Shikonin 0.05 mmol/L significantly reduced the secretion of LN, FN and Col Ⅳ from MC (P<0.05) cultured in 30, 50 and 80 mmol/L glucose. Conclusion: Shikonin could prevent or treat diabetic nephropathy (DN) and glomerulosclerosis (GS).