Minimal Change Nephrotic Syndrome Research Articles

Mechanism and restoration strategy of lysosomal abnormalities induced by urinary protein overload in proximal tubule epithelial cells.

Persistent elevated concentrations of urinary protein can destroy proximal tubule epithelial cells (PTECs) by inducing lysosomal abnormalities, thereby aggravating PTEC damage and renal fibrosis. However, the specific mechanisms of these serial biochemical events and methods for treating or preventing PTEC damage upon proteinuria need further investigation. In this study, electron microscopy and dual-labeled immunofluorescence analysis for identifying lysosome type revealed inadequate primary lysosome biogenesis and secondary lysosome accumulation in the PTECs of patients with minimal change nephrotic syndrome or membranous nephropathy who suffered from proteinuria. In vitro studies on HK-2 cells indicated that this abnormality was associated with decreased expression of transcription factor EB (TFEB). In contrast, TFEB overexpressing HK-2 cells under urinary protein overload exhibited significantly reduced accumulation of secondary lysosomes and increased proportion and quantity of primary lysosomes as indicated by dual-labeled immunofluorescence. Further, these cells could upregulate lysosomal degradation functions, as determined using Cathepsin L activity assays and flow cytometry for dye quenched-albumin. These results indicate that abnormal TFEB expression is a key mechanism of lysosomal dyshomeostasis caused by protein overload in PTECs. TFEB is thus a potential therapeutic target for the treatment of urinary protein-related kidney disease.

Epidemiological study of nephrotic syndrome in pediatrics in Menoufia University Hospitals

ObjectivesTo study the epidemiology of nephrotic syndrome in pediatric patients.BackgroundNephrotic syndrome is a common renal problem in pediatrics, with great variation in patients' characteristics in different regions of the world. The aim of this study was to define these characteristics in Egyptian children with nephrotic syndrome.Patients and methodsThis study is an observational cross-sectional study in which records of 170 patients with nephrotic syndrome were reviewed. Demographic, clinical, and histopathological data and response to therapy were statistically analyzed.ResultsThe mean age of onset was 4.66 ± 2.64 years. Overall, 23.5% of patients were steroid resistant, and 76.5% showed initial steroid response; 50 (29.4%) of the latter were steroid dependent. A total of 58 (34.1%) patients underwent a renal biopsy with minimal change nephrotic syndrome occurring in 69%, membranoproliferative glomerulonephritis in 13.8%, and focal segmental glomerulosclerosis in 17.2%. Overall, 1.8% of cases developed chronic renal insufficiency. Complete remission on cyclosporine occurred in 90% of steroid-resistant patients with nephrotic syndrome. Complete remission on mycophenolate mofetil occurred in 40% of steroid-dependent patients.ConclusionMinimal change nephrotic syndrome was the main pathology found in our patients. Response to immunosuppressive was different from other studies, probably owing to differences in the priority of selection for immunosuppressive therapy in our unit.

Clinicopathological Impact of Gene Polymorphism of Nephrin and Glucocorticoid Receptor Genes in Egyptian Children with Nonfamilial Nephrotic Syndrome.

Idiopathic nephrotic syndrome (NS) is one of the most common primary glomerular diseases in children. In this study, we investigate the association of single-nucleotide polymorphisms of nephrin gene and glucocorticoid receptor gene (NR3C1) and susceptibility to develop NS and the response to steroid therapy in 100 Egyptian children with NS using polymerase chain reaction-restriction fragment length polymorphism. We also analyzed the correlation between the genotypes and clinicopathologic features of the patients. Thirty-four patients (34%) were initial steroid nonresponders, renal biopsy findings of those patients were available, of which 22 (64.7%) showed minimal change NS and 12 (35.3%) had focal segmental glomerulosclerosis. The distribution of the genotypes was comparable between the patient and control groups, allele frequencies showed no significant difference between the patient's group and the control group. The genotypes showed no correlation with the age of onset of NS, initial steroid responsiveness, renal pathologic findings, estimated glomerular filtration rate (eGFR), and serum albumin. However, 24-h protein in urine showed a significant association with the NR3C1 gene. These data suggested that the nephrin gene and NR3C1 gene SNPs do not affect the development of NS, initial steroid responsiveness, renal pathological lesion, eGFR, and serum albumin. However, 24-h protein in urine showed a significant association with the NR3C1 gene in Egyptian children with NS.

MicroRNAs as Biomarkers for Nephrotic Syndrome.

Nephrotic syndrome represents the clinical situation characterized by presence of massive proteinuria and low serum protein caused by a variety of diseases, including minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephropathy. Differentiating between diagnoses requires invasive renal biopsies in general. Even with the biopsy, we encounter difficulties to differentiate MCNS and FSGS in some cases. There is no other better option currently available for the diagnosis other than renal biopsy. MicroRNAs (miRNAs) are no-coding RNAs of approximately 20 nucleotides in length, which regulate target genes in the post-transcriptional processes and have essential roles in many diseases. MiRNAs in serum and urine have been shown as non-invasive biomarkers in multiple diseases, including renal diseases. In this article, we summarize the current knowledge of miRNAs as the promising biomarkers for nephrotic syndrome.

Circulating plasmablasts and high level of BAFF are hallmarks of minimal change nephrotic syndrome in adults.

The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis. We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN). Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = -0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = -0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively). An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells.

Clinical and histopathological features of acute kidney injury in adult-onset minimal change nephrotic syndrome.

Acute kidney injury (AKI) is a common complication of minimal change nephrotic syndrome (MCNS), particularly in adults. To predict development of AKI, as defined by the Kidney Disease Improving Global Outcomes classification, we investigated clinical and histopathological features of adult-onset MCNS patients. A retrospective study was conducted with biopsy-proven adult-onset MCNS patients treated with corticosteroids. A total of 58 MCNS patients [49 (24-71) years old, 38 males] were diagnosed using kidney biopsy findings from 2005 to 2018 at Osaka City University Hospital, of whom 24 (41.4%) were found to be complicated with AKI. Age, urinary protein, increased body weight (difference from admission to discharge), and histopathological scores were significantly greater in patients with as compared to without AKI, while urinary protein, increased body weight, and interstitial edema score were significantly associated with AKI development [OR 1.55 (95% CI 1.04-2.31), 1.37 (95% CI 1.03-1.81), 20.7 (95% CI 1.76-243), respectively]. Of the 24 MCNS patients with AKI, 10 underwent transient hemodialysis treatment. Although histopathological features were not different, the time interval between disease onset and kidney biopsy was significantly longer for MCNS patients complicated with AKI requiring hemodialysis as compared to those for whom that was not required [32 (24-46) vs. 13 (10-23) days, p = 0.034]. These results indicate that urinary protein, increased body weight, and interstitial edema score are important information for predicting development of AKI in adult-onset MCNS patients.

Significance of urinary fatty acid-binding protein 4 level as a possible biomarker for the identification of minimal change disease in patents with nephrotic-range proteinuria

BackgroundFatty acid-binding protein 4 (FABP4), but not FABP1 (liver-type FABP), is ectopically induced in injured glomerular endothelial cells, and urinary FABP4 (U-FABP4) level is associated with proteinuria and renal dysfunction in a general population.MethodsThe clinical significance of U-FABP4 was investigated in 81 patients (male/female: 43/38, age: 57 ± 17 years) who underwent kidney biopsy.ResultsU-FABP4 was negatively correlated with estimated glomerular filtration rate (eGFR) (r = − 0.56, P < 0.01) and was positively correlated with age, blood pressure, triglycerides, proteinuria (r = 0.58, P < 0.01), plasma FABP4 and urinary FABP1 (U-FABP1) (r = 0.52, P < 0.01). Multivariable regression analysis showed that eGFR, proteinuria and U-FABP1 were independent predictors of U-FABP4. The level of U-FABP4, but not that of proteinuria, eGFR or U-FABP1, in minimal change nephrotic syndrome (MCNS) was significantly lower than the level in membranous nephropathy (MN) and that in diabetic nephropathy. Receiver operating characteristic curve analysis indicated that U-FABP4 level ≤ 0.78 μg/gCr predicted MCNS in patients who had nephrotic-range proteinuria with a high level of accuracy. When divided by the median value of U-FABP4 at baseline in 33 of the 81 patients who could be followed up, the yearly change (post–pre) in eGFR in the low U-FABP4 group was significantly greater than that in the high U-FABP4 group (median: 11.0 vs. -5.0 mL/min/1.73m2/year).ConclusionsU-FABP4 level is independently associated with proteinuria and renal dysfunction in patients with glomerular kidney disease. A low U-FABP4 level may predict MCNS in patients with nephrotic syndrome and would be a useful biomarker for differential diagnosis of MCNS and MN, which are common causes of nephrotic syndrome.

Retrospective single-arm cohort study of steroid-dependent minimal change nephrotic syndrome treated with very low-dose rituximab.

Conclusions regarding the best rituximab (RTX) dose to maintain remission and reduce immunosuppressant dependence in adult patients with steroid-dependent minimal change nephrotic syndrome (MCNS) are inconsistent. We report the first low-dose (&lt; 375 mg/m2 BSA) RTX therapy, administered once every 6 months. In this retrospective single-arm cohort study, we investigated the safety and efficacy of low-dose RTX therapy to reduce and ultimately stop prednisolone (PSL) and cyclosporine (CyA) treatment. 13 patients (8 men and 5 women; aged 16 - 65 years; 8-year median treatment history; 12 patients concurrently taking CyA) with steroid-dependent MCNS were chosen to maintain remission following low-dose RTX (200 mg/body) administration. The median period of subject observation following the first RTX dosing was 34 months (cumulative RTX dose: 400 - 1,400 mg). RTX significantly reduced PSL and CyA doses during the final observation in each subject (median dose: PSL 15→0 mg/day, p = 0.0002; CyA 80→0 mg/day, p = 0.0005). All patients maintained complete remission after discontinuing both drugs for a median complete remission (CR) maintenance period of 25 months. One patient showed relapse following the first RTX dose, but a temporary increase in PSL and CyA dose restored the remission. No serious RTX-related adverse effects were observed. Even with MCNS remission, peripheral CD19-positive cell count was not depleted in 90.5% of all cases. Low-dose RTX therapy appears to be effective in maintaining remission and reducing immunosuppressant doses in patients with steroid-dependent MCNS, which might involve a B-cell-independent mechanism.

Concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report

BackgroundConcurrent type 1 diabetes mellitus (T1DM) and idiopathic nephrotic syndrome is rare, and most previously reported cases were in children. We report the case of an adult woman who developed T1DM and minimal change nephrotic syndrome (MCNS) nearly simultaneously.Case presentationA 24-year-old woman had first presented to another hospital with nausea, vomiting, and fatigue. She was diagnosed with diabetic ketoacidosis and T1DM on the basis of her hyperglycemia, ketoacidosis, and positive anti-glutamic acid decarboxylase antibody test result. Rapid infusion of normal saline and insulin administration alleviated hyperglycemia and ketoacidosis. Two weeks after admission, however, she developed nephrotic syndrome (NS) with rapidly decreasing urine volume. She was referred to our hospital with a diagnosis of acute kidney injury. Although she temporarily required dialysis and high doses of insulin, within 1 month NS and acute kidney injury had been alleviated by oral prednisolone and low-density lipoprotein apheresis. Renal biopsy showed minor glomerular abnormalities without diabetic nephropathy, so we diagnosed her with MCNS. Seven weeks after the discharge, NS relapsed, and cyclosporine was added to prednisolone. However, NS relapsed twice within the next 4 months, so we started her on rituximab. At 6 months after initiating rituximab therapy, she remained in complete remission.Her mother also had T1DM but not MCNS. The patient had HLA-DRB1*09:01/09:01, DQB1*03:03/03:03, and her mother had HLA-DRB1*04:05/09:01, DQB1*03:03/04:01.ConclusionsConcurrent T1DM and MCNS is rare and their coexistence might be coincidental. Alternatively, they might have been caused by an underlying, unidentified genetic predisposition. Previous reports and our patient’s findings suggest that specific HLA alleles and haplotypes or a Th1/Th2 imbalance might be associated with T1DM and MCNS that occurred nearly simultaneously.

Profile of Minimal and Non-Minimal Change Nephrotic Syndrome in Children: A Cross-Sectional Study

Introduction: Idiopathic nephrotic syndrome (INS) is the most common kidney disease in children. Histopathological features classify the disease into minimal change nephrotic syndrome (MCNS) and non-minimal change nephrotic syndrome (NMCNS). Clinical and laboratory characteristics are considered to be useful in estimating the underlying pathological changes. This study aimed to assess the spectrum of clinical and laboratory profiles in children suffering from MCNS and NMCNS.&#x0D; Methods: This was a cross-sectional study using medical records of patients hospitalized at Dr. Wahidin Sudirohusodo Central General Hospital and Hasanuddin University Teaching Hospital from January 2016 to August 2018. Subjects were classified into MCNS and NMCNS groups and evaluated for age, sex, hypertension, degree of edema, degree of hematuria, proteinuria level, cholesterol level, albumin level, urea level, and creatinine level. Data were analyzed by using chi-square, fisher's exact test Mann Whitney analysis, multivariate by logistic multiple regression analysis, and diagnostic test.&#x0D; Results: Of the 36 subjects enrolled, 10 (27.8%) had MCNS, and 26 (72.2%) had NMCNS. Bivariate analysis showed significant differences in hypertension (p=0.020; OR=12.3; 95% CI 1.35-111.61) and hematuria (p=0.018; OR=7.7 ; 95% CI 1.52-39.75). Multivariate analysis indicated that only hematuria is a significant predictor (p=0.014; OR=7.778; 95% CI 1.522 – 39.754). The diagnostic test of NMCNS showed hematuria sensitivity at 77% and specificity at 70% with a positive predictive value of 87% and a negative predictive value of 46%.&#x0D; Conclusion: Our study showed that hematuria is a sensitive predictor of NMCNS.

Kidney–Targeted drug delivery systems based on tailor-made nanocapsules

Podocyte damage plays a central role in the pathogenesis of idiopathic nephrotic syndrome, as well as in the progression of many chronic glomerular diseases. Targeted therapy in these diseases still represents a challenge. We have previously shown that c-mip (c-maf inducing protein) plays a pivotal role in podocyte diseases in minimal change nephrotic syndrome patients. In this context, we implement a non-viral approach targeting the expression of c-mip in podocytes to reduce proteinuria. This therapeutic approach is based on nanovectors composed by chitosan and plasmids coding for micro-Ribonucleic Acid (miRNA) against c-mip. The overall elaboration process, monitored by absorbance and zeta potential measurements, relies on the alternate deposition of these biopolymers with opposite charges onto gold colloidal nanoparticles used as solid template (characterized by transmission electron microscopy TEM and Small-angle X-ray scattering SAXS measurements). Their hydrolysis lead to hollow nanostructures, also called nanocapsules (evidenced by TEM analysis). From this approach, crucial parameters impacting the biological assay can be easily investigated in particular (i) the size, (ii) the number of plasmid layers and (iii) the presence of the solid template. The efficiency of the synthesized nanomaterial will be tested in different conditions on Human Embryonic Kidney cells (HEK), immortalized podocytes and in vivo on a mouse podocyte damage model. To our knowledge, this is the first experiment including designed Deoxyribonucleic acid (DNA) derived nanocapsules to reach podocytes.

Nephrotic syndrome due to minimal-change disease superimposed on anti-glomerular basement membrane antibody positive glomerulonephritis; a case report

BackgroundThe prognosis for renal function in anti-GBM glomerulonephritis (anti-GBM GN) is extremely poor, and when renal impairment progresses severely, it is difficult to expect improvement. In addition, it is also known that once the disease activity can be controlled by aggressive treatment, its recurrence is rare. We experienced an anti-GBM GN that improved from severe renal dysfunction and relapsed. A possible cause was the superimpose of nephrotic syndrome due to minimal change disease (MCD).Case presentationA 30-year-old man was admitted to our hospital because of general malaise, fever, oliguria and renal dysfunction. The patient’s laboratory data showed serum creatinine as high as 6.6 mg/dl, and severe inflammation (C-reactive protein 20.6 mg/dl). Anti-glomerular basement membrane antibody (anti-GBM Ab) was detected in his serum, which led to the diagnosis of anti-GBM GN. Treatment was initiated with high-dose glucocorticoid (GC) and plasma exchange therapy (PE), and the patient’s renal function and oliguria improved rapidly and he was discharged 40 days after admission. Renal biopsy findings showed cellular crescents associated with linear IgG depositions along the glomerular tufts compatible with anti-GBM GN, but only about one-third of the glomeruli was involved, suggesting that it still remains an early stage of the disease. However, 2 months after discharge, he had a relapse and was readmitted due to severe proteinuria with positive anti-GBM Ab. On the second admission, after high-dose GC and PE combined with intravenous cyclophosphamide, and remission was achieved. Despite the relatively minor renal biopsy findings, the patient showed rapid renal dysfunction and relatively rapid improvement with our treatment. Electron microscopy of the renal biopsy tissue showed significant foot process effacement on podocytes in the apparently normal glomeruli, without electron dense deposits.ConclusionOn the basis of clinical course and renal pathology, it is suggested that the present case was a rare complication of an early stage of anti-GBM GN and minimal change nephrotic syndrome. Although the simultaneous development of anti-GBM GN and MCD with anti-GBM antibody is unclear, it might have been precipitated by influenza infection or some unknown factor.

Relation between plasma lipids and relapse of idiopathic nephrotic syndrome in children

Background: Nephrotic syndrome (NS) is one of the most common renal diseases in children. It is a chronicchildhood disorder with a course of relapse and remission. Hyperlipidemia is a constant feature (95% cases)of minimal change nephrotic syndrome (MCNS) having serum cholesterol &gt;250 mg/dl. Both increased synthesisand decreased clearance of lipoproteins may contribute to the hyperlipoproteinemia which frequently complicatesthe NS. Persistent hyperlipidemia can lead to relapse of NS which is a potential risk factor for progression ofglomerular injury. Persistent hyperlipidemia and frequent relapse of NS are further responsible forcardiovascular disease and progressive glomerular damage leading to renal failure. This study was done todetermine relationship between plasma lipids and relapse of idiopathic NS in children.&#x0D; Methods: This prospective study was carried out from July 2015 to June 2017 at the Department of Paediatricsin Sylhet MAG Osmani Medical College Hospital. Patients with the diagnosis of NS fulfilling the inclusioncriteria were included in this study purposively. A total of 50 children were included into this study. Theprimary end point was to determine plasma lipids level in children having idiopathic NS at acute phase, inremission and at 6 months after completion of treatment. The secondary end point was to evaluate the relationshipbetween persistent hyperlipidemia in remission phase and relapse of NS.&#x0D; Results: Among 50 children with clinical diagnosis of NS, 35 were first episode and 15 were in relapse cases.Among the first episode NS cases serum lipids level were decreased significantly during remission but HDLwas increased, whereas in relapse cases even during remission serum lipids level were significantly higher.After six months of follow up, out of 50 patients 28 patients had persistent remission and 22 patients hadrelapsed. The relationship between plasma lipids level and the incidence of relapse showed that acute lipidfraction levels were not risk factor in relapsing NS. Only the triglyceride level during remission was a riskfactor in relapsing NS (p&lt;0.035) with OR 5.4 and 95% CI [1.06, 25.4].&#x0D; Conclusion: Persistent hypertriglyceridemia and hypercholesterolemia in remission phase is a risk factor forrelapse of idiopathic NS in children.&#x0D; Birdem Med J 2020; 10(2): 97-102

Malaria, Collapsing Glomerulopathy, and Focal and Segmental Glomerulosclerosis.

Malaria, a potentially life-threatening disease, is the most prevalent endemic infectious disease worldwide. In the modern era, the spectrum of glomerular involvement observed in patients after malarial infections remains poorly described. We therefore performed a retrospective multicenter study to assess the clinical, biologic, pathologic, and therapeutic characteristics of patients with glomerular disease demonstrated by kidney biopsy in France within 3 months of an acute malaria episode. We identified 23 patients (12 men), all but 1 of African ancestry and including 10 patients with concomitant HIV infection. All of the imported cases were in French citizens living in France who had recently traveled back to France from an endemic area and developed malaria after their return to France. Eleven patients had to be admitted to an intensive care unit at presentation. Plasmodium falciparum was detected in 22 patients, and Plasmodium malariae was detected in 1 patient. Kidney biopsy was performed after the successful treatment of malaria, a mean of 24 days after initial presentation. At this time, all patients displayed AKI, requiring KRT in 12 patients. Nephrotic syndrome was diagnosed in 17 patients. Pathologic findings included FSGS in 21 patients and minimal change nephrotic syndrome in 2 patients. Among patients with FSGS, 18 had collapsing glomerulopathy (including 9 patients with HIV-associated nephropathy). In four patients, immunohistochemistry with an antibody targeting P. falciparum histidine-rich protein-2 demonstrated the presence of the malaria antigen in tubular cells but not in podocytes or parietal epithelial cells. An analysis of the apoL1 risk genotype showed that high-risk variants were present in all seven patients tested. After a mean follow-up of 23 months, eight patients required KRT (kidney transplantation in two patients), and mean eGFR for the other patients was 51 ml/min per 1.73 m2. In patients of African ancestry, imported Plasmodium infection may be a new causal factor for secondary FSGS, particularly for collapsing glomerulopathy variants in an APOL1 high-risk variant background.

IL-17 aggravates renal injury by promoting podocyte injury in children with primary nephrotic syndrome.

Primary nephrotic syndrome (PNS) is the most common chronic kidney disease in childhood, where podocyte injury is a key factor in the occurrence of kidney disease. In the present study, the expression of IL-17 in renal tissues of patients with PNS and its relationship with podocyte injury were examined. Reverse transcription-quantitative PCR (RT-qPCR), western blot analysis and immunochemistry were used to measure the expression of IL-17 in renal biopsies of patients with ONS, including 9 patients with minimal change nephrotic syndrome (MCNS), 15 patients with mesangial proliferative glomerulonephritis (MsPGN) and 9 patients with focal segmental glomerulosclerosis (FSGS), in addition to 15 normal kidney tissues. IL-17 was found to be highly expressed in the renal tissues from patients with PNS, with the highest expression levels found in tissues from patients with FSGS and the lowest in those from MCNS. A negative correlation was observed between the levels of IL-17 mRNA and PCX mRNA in renal tissues, whereas a positive correlation between IL-17 mRNA levels and the number of urinary podocytes in patients with PNS was found. In vitro, IL-17 induced podocyte apoptosis and reduced the expression of markers associated with podocytes, including Wilm's tumor 1, nephrin, synaptopodin and podocalyxin, whilst increasing the levels of Fas, Fas ligand (FasL), active-caspase-8, active-caspase-3 and phosphorylated-p65. However, treatment with helenalin, a NF-κB inhibitor, decreased p65 phosphorylation, attenuated IL-17-induced podocyte apoptosis and suppressed the IL-17-activated Fas/FasL/caspase-8/caspase-3 apoptotic pathway. Taken together, these observations suggest that IL-17 was highly expressed in renal tissues from patients with PNS, where it induced podocyte apoptosis by activating the Fas/FasL/caspase-8/caspase-3 apoptotic pathway in a NF-κB-dependent manner.

Role of cathepsin L in idiopathic nephrotic syndrome in children

Nephrotic syndrome (NS) is one of the most common glomerular diseases in children. Glomerular podocyte dysfunction can result in proteinuria, the presence of a large amount of protein in the urine. Podocytes are unique epithelial cells that divide into 3 separate structural and functional segments: a cell body, major processes, and foot processes. Since synaptopodin, dynamin, and actin are crucial components of the podocyte cytoskeleton, degradation of these proteins is associated with cytoskeleton instability, resulting in the development of proteinuria. Cathepsin L (CatL), a cysteine proteinase, plays a crucial role in various renal diseases. CatL expression is elevated in rats with puromycin aminonucleoside-induced nephropathy, which is used as a model of minimal change NS. In CatL-deficient mice, which do not develop proteinuria, dynamin is retained through the escape of CatL-mediated decomposition, resulting in no changes in the filtration barrier of podocytes. However, there is limited information on the roles of CatL in NS. Based on these data, CatL might play an important role in the development of proteinuria. Furthermore, identifying the functions of CatL may contribute to a better understanding of the pathogenesis of childhood-onset NS. We hypothesize that high levels of CatL can lead to cytoskeletal instability of podocytes, resulting in proteinuria in childhood-onset NS.

Corticosteroid reduction by addition of cetirizine and montelukast in biopsy-proven minimal-change nephrotic syndrome concomitant with allergic disorders

Recent reports suggest helper T-cell abnormalities in minimal-change nephrotic syndrome (MCNS), which often complicate allergic disorders that show a similar helper T-cell profile with Th2/Th17 predominance. However, the effect of anti-allergy therapy on MCNS remains unknown. This retrospective study included 51 patients with biopsy-proven MCNS recruited between November 2012 and October 2015, with follow-up through November 2017. We analyzed relapse and temporal daily corticosteroid dose with and without co-administration of histamine H1 receptor antagonist, cetirizine, and cysteinyl-leukotriene receptor antagonist, montelukast, as well as between baseline and after follow-up. Thirteen patients were treated with cetirizine and montelukast in addition to conventional therapy, whereas 38 patients were treated by conventional therapy only, consisting of corticosteroids and immunosuppressants. To adjust for baseline clinical characteristics, a 1:1 propensity score–matched model was applied. The clinical characteristics of the two groups after matching were similar at baseline. The treatment group showed a significant reduction in the lowest daily dose of oral prednisolone throughout the entire treatment course after the study compared to that of baseline (p < 0.025), which was not observed in the control group (p = 0.37), and showed significantly higher percentage of patients establishing corticosteroid-free state for the first time throughout the entire treatment course by addition of cetirizine and montelukast compared to the control group (p < 0.025). The study shows, for the first time, the steroid sparing effect of cetirizine and montelukast in addition to conventional treatment in MCNS patients with concomitant allergies.

Podocyte autophagy is associated with foot process effacement and proteinuria in patients with minimal change nephrotic syndrome.

Autophagy is a cellular mechanism involved in the bulk degradation of proteins and turnover of organelle. Several studies have shown the significance of autophagy of the renal tubular epithelium in rodent models of tubulointerstitial disorder. However, the role of autophagy in the regulation of human glomerular diseases is largely unknown. The current study aimed to demonstrate morphological evidence of autophagy and its association with the ultrastructural changes of podocytes and clinical data in patients with idiopathic nephrotic syndrome, a disease in which patients exhibit podocyte injury. The study population included 95 patients, including patients with glomerular disease (minimal change nephrotic syndrome [MCNS], n = 41; idiopathic membranous nephropathy [IMN], n = 37) and 17 control subjects who underwent percutaneous renal biopsy. The number of autophagic vacuoles and the grade of foot process effacement (FPE) in podocytes were examined by electron microscopy (EM). The relationships among the expression of autophagic vacuoles, the grade of FPE, and the clinical data were determined. Autophagic vacuoles were mainly detected in podocytes by EM. The microtubule-associated protein 1 light chain 3 (LC3)-positive area was co-localized with the Wilms tumor 1 (WT1)-positive area on immunofluorescence microscopy, which suggested that autophagy occurred in the podocytes of patients with MCNS. The number of autophagic vacuoles in the podocytes was significantly correlated with the podocyte FPE score (r = -0.443, p = 0.004), the amount of proteinuria (r = 0.334, p = 0.033), and the level of serum albumin (r = -0.317, p = 0.043) in patients with MCNS. The FPE score was a significant determinant for autophagy after adjusting for the age in a multiple regression analysis in MCNS patients (p = 0.0456). However, such correlations were not observed in patients with IMN or in control subjects. In conclusion, the results indicated that the autophagy of podocytes is associated with FPE and severe proteinuria in patients with MCNS. The mechanisms underlying the activation of autophagy in association with FPE in podocytes should be further investigated in order to elucidate the pathophysiology of MCNS.

Efficacy of a mitochondrion-targeting agent for reducing the level of urinary protein in rats with puromycin aminonucleoside-induced minimal-change nephrotic syndrome.

BackgroundOxidative stress is a major factor responsible for minimal-change nephrotic syndrome (MCNS), which occurs most commonly in children. However, the influence of oxidative stress localized to mitochondria remains unclear. We examined the effect of a mitochondrion-targeting antioxidant, MitoTEMPO, in rats with puromycin aminonucleoside (PAN)-induced MCNS to clarify the degree to which mitochondrial oxidative stress affects MCNS.Materials and methodsThirty Wistar rats were divided into three groups: normal saline group (n = 7), PAN group (n = 12), and PAN + MitoTEMPO group (n = 11). Rats in the PAN and PAN + MitoTEMPO groups received PAN on day 1, and those in the PAN + MitoTEMPO group received MitoTEMPO on days 0 to 9. Whole-day urine samples were collected on days 3 and 9, and samples of glomeruli and blood were taken for measurement of lipid peroxidation products. We also estimated the mitochondrial damage score in podocytes in all 3 groups using electron microscopy.ResultsUrinary protein excretion on day 9 and the levels of lipid peroxidation products in urine, glomeruli, and blood were significantly lower in the PAN + MitoTEMPO group than in the PAN group (p = 0.0019, p = 0.011, p = 0.039, p = 0.030). The mitochondrial damage score in podocytes was significantly lower in the PAN + MitoTEMPO group than in the PAN group (p <0.0001).ConclusionsThis mitochondrion-targeting agent was shown to reduce oxidative stress and mitochondrial damage in a MCNS model. A radical scavenger targeting mitochondria could be a promising drug for treatment of MCNS.

Advances in pathogenesis of minimal change nephrotic syndrome

Minimal change nephrotic syndrome (MCNS) is the most common nephrotic syndrome among children.Although the details of pathogenesis remain unknown, it is widely considered that upregulated expression of T lymphocyte cell cytokines contributes to the initiation of MCNS.Moreover, studies had revealed that altered number and function of B lymphocyte cells could change the functions of antigen presentation, participating in the onset of MCNS by affecting the function of T lymphocyte cells.Recently, CD80 has emerged as popular research topic which exerts its effects via the change of podocytes morphology, thereby affecting the glomerular permeability.However, neither immune nor podocyte dysfunction is poorly demonstrated to be associated with the pathogenesis of MCNS, the hypothesis such as a 'two hit disorder and γδT cells exacerbate podocyte injury via the CD28/B7-1-phosphor-SRC kinase pathway are raised.In the current review, we summarized the related investigations to help us to understand the mechanisms and pathogenesis of MCNS. Key words: Minimal change nephrotic syndrome; Pathogenesis; T lymphocyte cells; B lymphocyte cells; CD80