Focal Segmental Glomerulosclerosis Group Research Articles

Aberrant localization of β1 integrin in podocyte cytoplasm of primary FSGS with cellular lesion.

Podocyte detachment is a major trigger in pathogenesis of focal segmental glomerulosclerosis (FSGS). Detachment via β1 integrin (ITGB1) endocytosis, associated with endothelial cell injury, has been reported in animal models but remains unknown in human kidneys. The objectives of our study were to examine the difference in ITGB1 dynamics between primary FSGS and minimal change nephrotic syndrome (MCNS), among variants of FSGS, as well as between the presence or absence of cellular lesions (CEL-L) in human kidneys, and to elucidate the pathogenesis of FSGS. Thirty-one patients with primary FSGS and 14 with MCNS were recruited. FSGS cases were categorized into two groups: those with CEL-L, defined by segmental endocapillary hypercellularity occluding lumina, and those without CEL-L. The podocyte cytoplasmic ITGB1 levels, ITGB1 expression, and degrees of podocyte detachment and subendothelial widening were compared between FSGS and MCNS, FSGS variants, and FSGS groups with and without CEL-L (CEL-L( +)/CEL-L( -)). ITGB1 distribution in podocyte cytoplasm was significantly greater in CEL-L( +) group than that in MCNS and CEL-L( -) groups. ITGB1 expression was similar in CEL-L( +) and MCNS, but lower in CEL-L( -) compared with others. Podocyte detachment levels were comparable in CEL-L( +) and CEL-L( -) groups, both exhibiting significantly higher detachment than the MCNS group. Subendothelial widening was significantly greater in CEL-L( +) compared with CEL-L( -) and MCNS groups. The findings of this study imply the existence of distinct pathological mechanisms associated with ITGB1 dynamics between CEL-L( +) and CEL-L( -) groups, and suggest a potential role of endothelial cell injury in the pathogenesis of cellular lesions in FSGS.

Value of urinary CD80 in differentiating minimal change disease from focal segmental glomerulosclerosis

Background. Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are two common forms of childhood nephrotic syndrome (NS). Separating MCD from FSGS is essential to determine the treatment therapy and the prognosis. Cluster of differentiation 80 (CD80) in urine is now considered a valuable marker for detecting MCD. Therefore, we conducted this research to evaluate the role of urinary CD80 concentrations in differentiating MCD from FSGS. Methods. A cross-sectional descriptive study was performed on 67 children with NS who underwent kidney biopsy and 67 children in the control group. Results. MCD accounted for the majority (61.2%), while FSGS accounted for 38.8% with an MCD/FSGS ratio of 1.6:1. There were no significant differences in age, gender, hematuria, hypertension, urinary protein-creatinine ratio, and albumin concentrations between the two study groups (p>0.05). There were statistically significant differences in glomerular filtration rate (GFR) between the two study groups with p<0.05. The urinary CD80/creatinine ratio in the MCD group was 25.6 (5.4-38.3) pg/µmol, which was significantly higher than that of the FSGS group (3.6 (1.9-6.5) pg/µmol) with p<0.05. The area under the ROC curve for urinary CD80/creatinine ratio in the diagnosis of MCD with FSGS was 0.87 (95% CI 0.79-0.95) at a cut-off value of 4.6 pg/µmol, with a sensitivity of 85.4% and specificity of 73.1%, p<0.05. Conclusion. The urinary CD80/creatinine ratio was useful in differentiating between nephrotic syndrome with MCD and FSGS.

Risk factors for acute kidney injury and kidney relapse in patients with lupus podocytopathy.

Patients with lupus podocytopathy show a high incidence of acute kidney injury (AKI) and relapse, but the risk factors and mechanisms were unclear. This study analysed the clinicopathological features and risk factors for AKI and relapse in lupus podocytopathy patients. The cohort of lupus podocytopathy was generated by screening the biopsies of patients with lupus nephritis (LN) from 2002 to 2022 and was divided into the mild glomerular lesion (MGL) and focal segmental glomerulosclerosis (FSGS) groups based on glomerular morphological characteristics. The acute (ATI) and chronic (CTI) tubulointerstitial lesions were semi-quantitatively scored. Logistic and Cox regressions were employed to identify the risk factors for AKI and relapse, respectively. Among 6052 LN cases, 98 (1.6%) were diagnosed as lupus podocytopathy, with 71 in the MGL group and 27 in the FSGS group. All patients presented with nephrotic syndrome and 33 (34.7%) of them had AKI. Seventy-seven (78.6%) patients achieved complete renal response (CRR) within 12weeks of induction treatment, in which there was no difference in the CRR rate between glucocorticoid monotherapy and combination therapy with glucocorticoids plus immunosuppressants. Compared with the MGL group, patients in the FSGS group had significantly higher incidences of hypertension and haematuria; in addition, they had higher Systemic Lupus Erythematosus Disease Activity Index 2000, ATI and CTI scores but a significantly lower CRR rate. Urinary protein ≥7.0g/24h and serum C3 ≤0.750g/l were independent risk factors for AKI. During a median follow-up of 78months, 57 cases (60.0%) had relapse and none reached the kidney endpoint. Failure to achieve CRR within 12weeks, maintenance with glucocorticoid monotherapy and AKI at onset were independent risk factors for kidney relapse. In this study, histological subtypes of lupus podocytopathy were found to be associated with clinical features and treatment response. In addition, several risk factors associated with AKI occurrence and kidney relapse were identified.

Analysis of glomerular deposition of IgM and C3 in patients with podocytopathies

Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are the main causes of nephrotic syndrome in the world. The complement system appears to play an important role in the pathogenesis of these diseases. To evaluate the deposition of immunoglobulins and particles of the complement system in renal biopsies of patients with FSGS and MCD and relate to laboratory data, we selected 59 renal biopsies from patients with podocytopathies, 31 from patients with FSGS and 28 with MCD. Epidemiological, clinical, laboratory information and the prognosis of these patients were evaluated. Analysis of the deposition of IgM, IgG, C3, C1q and C4d in renal biopsies was performed. We related IgM and C3 deposition with laboratory parameters. Statistical analysis was performed using GraphPad Prism version 7.0. Glomerular deposition of IgM was significantly higher in the FSGS group, as was codeposition of IgM and C3. The clinical course of patients and laboratory data were also worse in cases of FSGS, with a higher percentage progressing to chronic kidney disease and death. Patients with C3 deposition had significantly higher mean serum creatinine and significantly lower eGFR, regardless of disease. Patients with FSGS had more IgM and C3 deposition in renal biopsies, worse laboratory data and prognosis than patients with MCD. C3 deposition, both in FSGS and MCD, appears to be related to worsening renal function.

The utility of biomarkers to predict steroid response in idiopathic nephrotic syndrome

Objective: The most common form of nephrotic syndrome (NS) is minimal change disease (MCD) in children and focal segmental glomerulosclerosis (FSGS) following it. As, it is important to predict corticosteroid (CS) response at the beginning of the disease, we aimed to evaluate the efficacy of some biomarkers in terms of predicting steroid response in patients with NS. Patients and Methods: Twenty patients who met the inclusion criteria for the study were divided into 3 groups and 6 healthy control participants were included in the analysis as the 4th group. Group-1 included 10 patients at the first episode of idiopathic NS (INS), group-2 included the same 10 patients in remission, group-3 included 10 patients with steroid resistant NS (SRNS) diagnosed as FSGS by renal biopsy, and group-4 included six healthy children as controls. Urinary and serum cluster of differentiation (CD) CD80, IL-17, IL-23, IL-10, TGF-β, CD86, CD28, CTLA-4 levels were measured for all groups. Results: Urinary CD80 level in INS-relapse group was significantly higher than the levels of the INS-remission, FSGS and control groups (p

Analysis of the alleviating effect of modified Huangqi Chifeng decoction on rats with focal segmental glomerulosclerosis based on gut microbiota and fecal metabolomics.

To investigate the reno-protective effects of modified Huangqi Chifeng decoction (MHCD) on focal segmental glomerulosclerosis (FSGS) rats, and the underlying mechanisms of systemic regulation of gut microbiota and metabolite profiles. A rat FSGS model was established via unilateral nephrectomy plus doxorubicin injections. Rats were divided into sham, FSGS, and MHCD groups from which urine, blood, and histological tests were conducted. Fecal microbiotas were identified via 16S rRNA gene sequencing. Fecal metabolomics allowed for metabolic pathways analysis. Biochemical indices and pathological examination revealed that MHCD treatment improved the symptoms of FSGS, and corrected dysbiosis of gut microbiota, enriched the abundance of Bifidobacterium, Odoribacter, Christensella, Oscillospira, and reduced that of harmful bacteria such as Collinsella and Coprobacterilus at the genus level. Fecal metabolomic profiles revealed 152 different metabolites between the FSGS and sham groups, which are mainly enriched in signaling pathways like arachidonic acid, serotonergic synapse, and oxytocin. Besides, 93 differential metabolites between MHCD and FSGS groups were identified, which are mainly enriched in signaling pathways like steroid hormone biosynthesis, prostate cancer, and linoleic acid metabolism. Spearman's correlation analysis showed a correlation between differential fecal metabolites and enriched gut microbiota or serum biochemical parameters. MHCD may exert a reno-protective effect by regulating the gut microbiome and metabolite profiles in FSGS rats.

Immunoglobulin G deposition on proximal tubules and the tubular basement membrane in acute tubular injury complicated with focal segmental glomerulosclerosis (FSGS): A possible prediction tool for subclinical FSGS

Immunofluorescent deposition of immunoglobulin G (IgG) in the tubular basement membrane (TBM) has been evaluated in the diagnosis of various diseases; however, few studies have investigated the immunofluorescence of acute tubular injury (ATI). Herein, we attempted to clarify IgG expression in the proximal tubular epithelium and TBM in ATI due to various causes. Patients with ATI with nephrotic-range proteinuria, including focal segmental glomerulosclerosis (FSGS, n = 18) and minimal change nephrotic syndrome (MCNS, n = 8), ATI with ischemia (n = 6), and drug-induced ATI (n = 7), were enrolled. ATI was evaluated by light microscopy. CD15 and IgG double staining and IgG subclass staining were performed to evaluate immunoglobulin deposition in the proximal tubular epithelium and TBM. IgG deposition was identified in the proximal tubules only in the FSGS group. Furthermore, IgG deposition in the TBM was observed in the FSGS group showing severe ATI. IgG3 was predominantly deposited by the IgG subclass study. Our results indicate that IgG deposition in the proximal tubular epithelium and TBM suggests the leaking of IgG from the glomerular filtration barrier and its reabsorption by proximal tubules, which may predict disruption of the glomerular size barrier, including subclinical FSGS. FSGS with ATI should be included as a differential diagnosis when IgG deposition in TBM is observed.

In situ assessment of Mindin as a biomarker of podocyte lesions in diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal failure worldwide. Several mechanisms are involved in the pathogenesis of this disease, which culminate in morphological changes such as podocyte injury. Despite the complex diagnosis and pathogenesis, limited attempts have been made to establish new biomarkers for DN. The higher concentration of Mindin protein in the urine of patients with type 2 diabetes mellitus suggests that it plays a role in DN. Therefore, this study investigated whether in situ protein expression of Mindin can be considered a potential DN biomarker. Fifty renal biopsies from patients diagnosed with DN, 57 with nondiabetic glomerular diseases, including 17 with focal segmental glomerulosclerosis (FSGS), 14 with minimal lesion disease (MLD) and 27 with immunoglobulin A nephropathy (IgAN), and 23 adult kidney samples from autopsies (control group) were evaluated for Mindin expression by immunohistochemistry. Podocyte density was inferred by Wilms' tumor 1 (WT1) immunostaining, while foot process effacement was assessed by transmission electron microscopy. Receiver operative characteristic (ROC) analysis was performed to determine the biomarker sensitivity/specificity. Low podocyte density and increased Mindin expression were observed in all cases of DN, regardless of their class. In the DN group, Mindin expression was significantly higher than that in the FSGS, MCD, IgAN and control groups. Higher Mindin expression was significantly positively correlated with foot process effacement only in class III DN cases. Furthermore, Mindin protein presented high specificity in the biopsies of patients with DN (p < 0.0001). Our data suggest that Mindin may play a role in DN pathogenesis and is a promising biomarker of podocyte lesions.

Urinary CD80 and Serum suPAR as Biomarkers of Glomerular Disease among Adults in Brazil.

Urinary CD80 has been shown to have good specificity for minimal change disease (MCD) in children. However, the investigation of circulating factors such as soluble urokinase plasminogen activator receptor (suPAR) as biomarkers of focal segmental glomerulosclerosis (FSGS) is quite controversial. The objective of this study was to determine whether urinary CD80 and serum suPAR can be used for the diagnosis of MCD and FSGS, respectively, in the adult population of Brazil. We also attempted to determine whether those biomarkers assess the response to immunosuppressive treatment. This was a prospective study in which urine and blood samples were collected for analysis of CD80 and suPAR, respectively, only in the moment of renal biopsy, from patients undergoing to diagnostic renal biopsy. At and six months after biopsy, we analyzed serum creatinine, serum albumin, and proteinuria in order to evaluate the use of the CD80 and suPAR collected in diagnosis as markers of response to immunosuppressive treatment. In healthy controls were collected urinary CD80 and proteinuria, serum suPAR, and creatinine. The results of 70 renal biopsies were grouped, by diagnosis, as follows: FSGS (n = 18); membranous nephropathy (n = 14); MCD (n = 5); and other glomerulopathies (n = 33). There was no significant difference among the groups in terms of the urinary CD80 levels, and serum suPAR was not significantly higher in the FSGS group, as would have been expected. Urinary CD80 correlated positively with nephrotic syndrome, regardless of the type of glomerular disease. Neither biomarker correlated with proteinuria at six months after biopsy. In adults, urinary CD80 can serve as a marker of nephrotic syndrome but is not specific for MCD, whereas serum suPAR does not appear to be useful as a diagnostic or treatment response marker.

Expression of Wilms’ Tumor 1 Antigen, Vimentin, and Corticotropin-Releasing Factor in the Human Kidney with Focal Segmental Glomerulosclerosis and Effect of Oxidative Stress on These Markers in HEK 293 Cells

Introduction: Wilms’ tumor 1 antigen (WT1) expression in podocytes has the important role of maintaining their integrity and glomerular function. Vimentin also plays a role in preserving podocyte function and in morphological changes observed after injury. Corticotropin-releasing factor (CRF) is important in stress and in maintaining homeostasis. According to our previous studies, tyrosine (Tyr) isoforms (meta- and ortho-Tyr) may play a role in the development of many diseases. Methods: Our aim was to investigate the expression of WT1, vimentin, and CRF in the human kidney and in HEK 293 cell cultures. Histological and clinical features of 42 focal segmental glomerulosclerosis (FSGS) patients were evaluated and compared to those of patients with thin basement membrane as a control group. Cells were cultured in medium containing para-, meta-, and ortho-Tyr, and their expression of WT1, vimentin, and CRF were determined by immunocytochemistry. Podocyte foot process effacement was investigated by electron microscope. Results: The intensity of WT1 staining in glomeruli was the same in FSGS and control groups, but it was lower in the tubulointerstitium of FSGS patients. Vimentin was lower in glomeruli of FSGS patients (p = 0.009), and it was higher in the tubulointerstitium compared to the control group (p = 0.003). CRF intensity was lower in the glomeruli (p = 0.002). Podocyte foot process effacement determined by electron microscope showed correlation with vimentin and CRF in glomeruli. WT1 staining intensity was lower in meta- and ortho-Tyr group (p = 0.001; p = 0.009). Vimentin was lower in the meta-Tyr group (p = 0.001). Discussion: Our observations on kidney biopsy samples support that the reduction of WT1 and vimentin could be characteristic for FSGS. Our results on HEK cells suggest that meta- and ortho-Tyr may play a role in the development of FSGS.

Extracellular vesicles from focal segmental glomerulosclerosis pediatric patients induce STAT3 activation and mesangial cell proliferation.

Primary focal segmental glomerulosclerosis (FSGS), a major cause of end-stage kidney disease (ESKD) in adolescents and young adults, is attributable to recognized genetic mutations in a minority of cases. For the majority with idiopathic primary FSGS, the cause of the disease is unknown. We hypothesize that extracellular vesicle (EVs), that carry information between podocytes and mesangial cells, may play a key role in disease progression. A total of 30 participants (20 primary nephrotic syndrome/ 10 healthy controls) were enrolled in this study. Primary nephrotic syndrome subjects were grouped based on pathologic diagnosis. The FSGS group was compared to healthy control subjects based on demographic and clinical findings. EVs were isolated from the urine of each group before being characterized by Western blotting, transmission electron microscopy, and nanoparticle tracking analysis. The effects of the EVs from each group on normal human mesangial cells and activation of certain pathways were then investigated. Based on demographic and clinical findings, mean serum creatinine was significantly higher in the FSGS group than the normal healthy control group. The mean size of the EVs in the FSGS group was significantly higher than the healthy control group. The mesangial cells that were challenged with EVs isolated from FSGS patients showed significant upregulation of STAT-3, PCNA, Ki67, and cell proliferation. Our data demonstrate that EVs from FSGS patients stimulate mesangial cell proliferation in association with upregulation of the phospho-STAT-3 pathway. Additional studies are planned to identify the molecular cargo within the EVs from FSGS patients that contribute to the pathogenesis of FSGS.

Potential Urine Proteomic Biomarkers for Focal Segmental Glomerulosclerosis and Minimal Change Disease.

Primary focal segmental glomerulosclerosis (FSGS), along with minimal change disease (MCD), are diseases with primary podocyte damage that are clinically manifested by the nephrotic syndrome. The pathogenesis of these podocytopathies is still unknown, and therefore, the search for biomarkers of these diseases is ongoing. Our aim was to determine of the proteomic profile of urine from patients with FSGS and MCD. Patients with a confirmed diagnosis of FSGS (n = 30) and MCD (n = 9) were recruited for the study. For a comprehensive assessment of the severity of FSGS a special index was introduced, which was calculated as follows: the first score was assigned depending on the level of eGFR, the second score—depending on the proteinuria level, the third score—resistance to steroid therapy. Patients with the sum of these scores of less than 3 were included in group 1, with 3 or more—in group 2. The urinary proteome was analyzed using liquid chromatography/mass spectrometry. The proteome profiles of patients with severe progressive FSGS from group 2, mild FSGS from group 1 and MCD were compared. Results of the label free analysis were validated using targeted LC-MS based on multiple reaction monitoring (MRM) with stable isotope labelled peptide standards (SIS) available for 47 of the 76 proteins identified as differentiating between at least one pair of groups. Quantitative MRM SIS validation measurements for these 47 proteins revealed 22 proteins with significant differences between at least one of the two group pairs and 14 proteins were validated for both comparisons. In addition, all of the 22 proteins validated by MRM SIS analysis showed the same direction of change as at the discovery stage with label-free LC-MS analysis, i.e., up or down regulation in MCD and FSGS1 against FSGS2. Patients from the FSGS group 2 showed a significantly different profile from both FSGS group 1 and MCD. Among the 47 significantly differentiating proteins, the most significant were apolipoprotein A-IV, hemopexin, vitronectin, gelsolin, components of the complement system (C4b, factors B and I), retinol- and vitamin D-binding proteins. Patients with mild form of FSGS and MCD showed lower levels of Cystatin C, gelsolin and complement factor I.

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

ObjectiveTo assess the significance of focal segmental glomerulosclerosis (FSGS) variants on clinicopathological characteristics and short-term outcomes in idiopathic membranous nephropathy (IMN) patients.MethodsThe 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.ResultsThe 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.ConclusionThe non-GTL FSGS lesion was a novel negative predictor in IMN and should be taken into account in the management of IMN.

Long-term Rituximab Therapy in Adult Patients with Idiopathic Nephrotic Syndrome

Patients with refractory idiopathic nephrotic syndrome (INS) are at risk of infections, renal failure, and the inherent side effects of immunosuppressive therapy. In the present study, we investigated the efficacy of yearly rituximab therapy in adult patients with this syndrome over 5–10 years. In the minimal change disease group, 14 of the 15 patients had complete remission (CR) and one had partial remission (PR). Of those who achieved CR, eight patients did not require rituximab 4 years later. The patient with PR was treated in the same way as those with focal segmental glomerulosclerosis (FSGS) group and remained stable by the end of the study. In the FSGS group, rituximab therapy resulted in the amelioration of INS in nine patients, although two were non-responders (NR) and developed end-stage renal disease (ESRD). In the membranous glomerulopathy group, 36 patients had CR but two were NR and developed ESRD. Twenty (55%) of those did not require treatment after 4 years, whereas the rest maintained CR with yearly rituximab. Nine women received rituximab after the third month of pregnancy without significant adverse effects on the fetus or subsequent conception. In conclusion, rituximab is a safe, practical, and effective long-term therapy for adult patients in these three groups of INS.

Expression profile of miR-15 and miR-16 in peripheral blood mononuclear cells of patients with steroid-resistant nephrotic syndrome

Introduction: Steroids are considered first-line therapeutic opportunities in cases with idiopathic nephrotic syndrome (INS). The trustworthy biomarkers for steroid-resistant NS (SRNS) would permit more precise decisions in the treatment of INS. Objectives: This study aimed to evaluate the miR-15 and miR-16 levels in NS cases. Patients and Methods: Adult cases with primary NS (n=60) including 30 FSGS (Focal segmental glomerulosclerosis) and 30 membranous glomerulonephritis (MGN) patients and 24 healthy individuals were included. The evaluation of miR-15 and miR-16 expression in blood cells was performed using real-time polymerase chain reaction (qPCR). Moreover, gene ontology analysis and prediction of the miRNA targets were completed to recognize the biological procedures and signaling pathways involved in the pathophysiology of NS. Results: A significant increase was observed in miR-15a-5p expression in cases with primary MGN and FSGS compared with healthy subjects. Conversely, the miR-16-5p expression was significantly decreased in both conditions compared with healthy controls. In the clinical subdivision of FSGS group to steroid-resistant-FSGS and steroid-responsive-FSGS, significant elevated levels of miR-15a-5p and diminished levels of miR-16-5p were observed in both groups compared to normal controls. Gene annotation demonstrated that these miRNAs contribute to cell cycle, ion transport, biological adhesion, cation transport, cellular response to endogenous stimulus, and regulation of small GTPase-related signal transduction. Conclusion: Dysregulated levels of miR-15 and miR-16 may be involved in the pathogenesis and response to steroid therapy in patients with INS.

Kidney transplantation outcomes in patients with IgA nephropathy and other glomerular and non-glomerular primary diseases in the new era of immunosuppression.

ObjectivesKidney transplant (KTx) recipients with IgAN as primary disease, were compared with recipients with other causes of renal failure, in terms of long-term outcomes.MethodsNinety-nine KTx recipients with end-stage kidney disease (ESKD) due to IgAN, were retrospectively compared to; i/ a matched case-control group of patients with non-glomerular causes of ESKD, and ii/ four control groups with ESKD due to glomerular diseases; 44 patients with primary focal segmental glomerulosclerosis (FSGS), 19 with idiopathic membranous nephropathy (IMN), 22 with lupus nephritis (LN) and 21 with pauci-immune glomerulonephritis (PIGN).ResultsAt end of the observation period, graft function and survival, were similar between KTx recipients with IgAN and all other groups, but the rate of disease recurrence in the graft differed significantly across groups. The rate of IgAN recurrence in the graft was 23.2%, compared to 59.1% (p<0.0001) in the FSGS group, 42.1% (p = 0.17) in the IMN group, and 0% in the LN and PIGN groups (p = 0.01). IgAN recipients, who were maintained with a regimen containing tacrolimus, experienced recurrence less frequently, compared to those maintained with cyclosporine (p = 0.01). Graft loss attributed to recurrence was significantly higher in patients with FSGS versus all others.ConclusionRecipients with IgAN as primary disease, experienced outcomes comparable to those of recipients with other causes of ESKD. The rate of IgAN recurrence in the graft was significantly lower than the rate of FSGS recurrence, but higher than the one recorded in recipients with LN or PIGN. Tacrolimus, as part of the KTx maintenance therapy, was associated with lower rates of IgAN recurrence in the graft, compared to the rate cyclosporine.

Dysregulated levels of glycogen synthase kinase-3β (GSK-3β) and miR-135 in peripheral blood samples of cases with nephrotic syndrome.

BackgroundGlycogen synthase kinase-3 (GSK-3β) is a serine/threonine kinase with multifunctions in various physiological procedures. Aberrant level of GSK-3β in kidney cells has a harmful role in podocyte injury.MethodsIn this article, the expression levels of GSK-3β and one of its upstream regulators, miR-135a-5p, were measured in peripheral blood mononuclear cells (PBMCs) of cases with the most common types of nephrotic syndrome (NS); focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN). In so doing, fifty-two cases along with twenty-four healthy controls were included based on the strict criteria.ResultsLevels of GSK-3β mRNA and miR-135 were measured with quantitative real-time PCR. There were statistically significant increases in GSK-3β expression level in NS (P = 0.001), MGN (P = 0.002), and FSGS (P = 0.015) groups compared to the control group. Dysregulated levels of miR-135a-5p in PBMCs was not significant between the studied groups. Moreover, a significant decrease was observed in the expression level of miR-135a-5p in the plasma of patients with NS (P = 0.020), MGN (P = 0.040), and FSGS (P = 0.046) compared to the control group. ROC curve analysis approved a diagnostic power of GSK-3β in discriminating patients from healthy controls (AUC: 0.72, P = 0.002) with high sensitivity and specificity.ConclusionsDysregulated levels of GSK-3β and its regulator miR-135a may participate in the pathogenesis of NS with different etiology. Therefore, more research is needed for understanding the relationship between them.

In situ evaluation of podocytes in patients with focal segmental glomerulosclerosis and minimal change disease.

Podocyte injury in focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) results from the imbalance between adaptive responses that maintain homeostasis and cellular dysfunction that can culminate in cell death. Therefore, an in situ analysis was performed to detect morphological changes related to cell death and autophagy in renal biopsies from adult patients with podocytopathies. Forty-nine renal biopsies from patients with FSGS (n = 22) and MCD (n = 27) were selected. In situ expression of Wilms Tumor 1 protein (WT1), light chain microtubule 1-associated protein (LC3) and caspase-3 protein were evaluated by immunohistochemistry. The foot process effacement and morphological alterations related to podocyte cell death and autophagy were analyzed with transmission electronic microscopy. Reduction in the density of WT1-labeled podocytes was observed for FSGS and MCD cases as compared to controls. Foot process width (FPW) in control group was lower than in cases of podocytopathies. In FSGS group, FPW was significantly higher than in MCD group and correlated with proteinuria. A density of LC3-labeled podocytes and the number of autophagosomes in podocytes/ pedicels were higher in the MCD group than in the FSGS group. The number of autophagosomes correlated positively with the estimated glomerular filtration rate in cases of MCD. The density of caspase-3-labeled podocytes in FSGS and MCD was higher than control group, and a higher number of podocytes with an evidence of necrosis was detected in FSGS cases than in MCD and control cases. Podocytes from patients diagnosed with FSGS showed more morphological and functional alterations resulting from a larger number of lesions and reduced cell adaptation.

Circulating and cellular levels of miR-193 and miR-217 in patients with common glomerular diseases

Introduction: The definitive diagnosis of the common types of glomerular disease including FSGS (focal segmental glomerulosclerosis) and MN (membranous nephropathy) is still performed by biopsy studies, which has high risks and complications. MicroRNAs (miRNAs) can open a new horizon for the treatment and diagnosis of glomerular diseases. Objectives: In the present study, we focused on miR-217, miR-193-3p, and miR-124 expression in patients with FSGS and MN. Patients and Methods: Sixty cases (30 FSGS and 30 MN) were included based on strict criteria. A group of healthy controls were also included. The relative expression of the microRNAs was evaluated in the plasma and peripheral blood mononuclear cells (PBMCs) by quantitative real-time PCR. The association between the expression levels of microRNAs and clinicopathological parameters were also assessed. Results: There were significant differences in miR-193-3p levels between FSGS and MN group in plasma samples (P = 0.036). Furthermore, significantly decreased levels of miR-217 were observed in plasma samples of patients with NS (P = 0.026) and MN (P = 0.036) groups. Conclusion: The studied miRNAs are dysregulated in clinical samples of patients with nephrotic syndrome and they may be involved in the pathogenesis of FSGS and MN. More research is needed for understanding the relationship between these microRNAs and the pathogenesis of FSGS and MGN.

Baseline characteristics and long-term outcomes of steroid-resistant nephrotic syndrome in children: impact of initial kidney histology.

Although many pediatric nephrologists consider focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) as separate clinical entities, whether the initial histology could affect clinical courses in children with steroid-resistant nephrotic syndrome (SRNS) suspected of having an immune-based etiology remains unknown, especially for long-term outcomes. We retrospectively reviewed long-term outcomes (> 3years; median follow-up, 9.1years) of 21 children with initial SRNS (FSGS, N = 9; MCD, N = 12) who achieved complete remission with immunosuppressive agents, including cyclosporine. At NS onset, incidence of acute kidney injury (67% vs. 8%, P < 0.05) and proportion of patients with non-selective proteinuria (56% vs. 0%, P < 0.01) were significantly higher in the FSGS group than the MCD group. Furthermore, median days until complete remission after treatment was significantly longer in the FSGS group than the MCD group (116days vs. 45days, P < 0.001). Although subsequent biopsy histology of the 12 patients in the MCD group was still identical in all MCD, three of nine patients in the FSGS group were reclassified from FSGS to MCD at second biopsy. At last visit, all patients maintained complete remission, and none developed chronic kidney disease. Initial presentation in the FSGS group was characterized by more severe clinical manifestations than the MCD group. If complete remission is achieved, FSGS and MCD in children with immune-mediated SRNS may constitute a single disease spectrum because the long-term outcomes are favorable, irrespective of initial histology.