Minimal Change Nephrotic Syndrome Patients Research Articles

Decreased GM3 correlates with proteinuria inminimal change nephrotic syndrome and focal segmental glomerulosclerosis.

Glycolipids on cell membrane rafts play various roles by interacting with glycoproteins. Recently, it was reported that the glycolipid GM3 is expressed in podocytes and may play a role in podocyte protection. In this report, we describe the correlation between changes in GM3 expression in glomeruli and proteinuria in minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) patients. We performed a case-control study of the correlation between nephrin/GM3 expression levels and proteinuria in MCNS and FSGS patients who underwent renal biopsy at our institution between 2009 and 2014. Normal renal tissue sites were used from patients who had undergone nephrectomy at our institution and gave informed consent. Both MCNS and FSGS had decreased GM3 and Nephrin expression compared with the normal (normal vs. MCNS, FSGS; all p < 0.01). Furthermore, in both MCNS and FSGS, GM3 expression was negatively correlated with proteinuria (MCNS: r = -0.61, p < 0.01, FSGS: r = -0.56, p < 0.05). However, nephrin expression had a trend to correlate with proteinuria in FSGS (MCNS: r = 0.19, p = 0.58, FSGS: r = -0.48, p = 0.06). Furthermore, in a simple linear regression analysis, GM3 expression also correlated with proteinuric change after 12months of treatment (MCNS: r = 0.40, p = 0.38, FSGS: r = 0. 68, p < 0.05). We showed for the first time that decreased GM3 expression correlates with proteinuria in MCNS and FSGS patients. Further studies are needed on the podocyte-protective effects of GM3.

Clinical and histopathological features related to time to complete remission in adult-onset minimal change nephrotic syndrome patients with corticosteroid treatment.

Minimal change nephrotic syndrome (MCNS) is a common type of nephrotic syndrome in adults, though evidence regarding its clinical and histopathological features related to time to complete remission (CR) is limited. This was a retrospective study of biopsy-proven, first-onset, adult MCNS patients who achieved CR after undergoing corticosteroid treatment. Body weight (BW) change rate was calculated as follows: (BW at admission - BW at discharge)/BW at discharge × 100. Histopathological examinations were performed, with particular attention given to tubulointerstitial lesions. Fifty-seven patients (median 41years old, range 22-63years; 37 males) were diagnosed with MCNS from 2007 to 2020. Time to CR was a median 11 (8-21) days. In addition to serum creatinine and urinary protein, BW change rate also showed a positive correlation with time to CR (rs = 0.438, p < 0.001; rs = 0.280, p = 0.035; rs = 0.544, p < 0.001; respectively), while multivariate Cox proportional hazards models also revealed those factors as significant predictors for longer time to CR. In MCNS patients with a higher BW change rate (n = 28), serum creatinine, urinary protein, histopathological score, and time to CR were significantly greater as compared to those with a lower BW change rate (n =29). Also, in those patients, histopathological interstitial edema was significantly associated with longer time to CR after adjustments for serum creatinine and urinary protein. The present results indicate that BW change rate can predict time to CR in adult-onset MCNS patients. Histopathologically, interstitial edema is also an important factor for time to CR in MCNS patients with greater BW increase.

Lupus nephritis with corticosteroid responsiveness: molecular changes of CD46-mediated type 1 regulatory T cells.

The engagement of the complement regulatory proteins CD46 and CD3 in human CD4+ T cells induces the type 1 regulatory T cells (Tr1) and interleukin-10 (IL-10) secretion. This study aimed to elucidate the molecular changes of Tr1 cells through CD46 cytoplasmic Cyt1 tail in lupus nephritis (LN) respond to intravenous methylprednisolone (ivMP) therapy. We enrolled 40 pediatric patients with LN and 30 healthy controls. Clinical characteristics and peripheral blood mononuclear cells were collected before and 3 days after the administration of ivMP. Kidney specimens were taken from five LN and five minimal-change nephrotic syndrome patients. We found that defective CD46-mediated T-helper type 1 contraction (IL-10 switching) is present in active LN patients. The ivMP therapy enhanced LN remission, restored the production of IL-10, increased the CD46-Cyt1/Cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation, and induced migration with the expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells. Pharmacologic interventions that alter the patterns of CD46-Cyt1/Cyt2 expression and the secretion of IL-10 by CD3/CD46-activated Tr1 cells can be used in patients with active LN. In patients with LN, ivMP was associated with increased IL-10 production and increased CD46-Cyt1/Cyt2 ratio and AKT phosphorylation by Tr1 cells, with enhanced potential to migration in response to CCL17. These results suggest that expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4 + CD46 + Tr1 cells differ in patients with active LN but can be corrected by corticosteroid treatment. Enhancing the expression of functional CD4 + CD46 + Tr1 cells may be a useful therapeutic approach for LN.

Association between anti-complement factor H antibodies and renal outcome in primary membranous nephropathy.

The complement factor H (CFH) is a regulator for the alternative complement pathway. The prevalence and roles of anti-CFH antibodies in the clinical outcome of primary membranous nephropathy (MN) patients remain unclear. A total of 106 biopsy-proven kidney disease patients and 18 healthy controls were retrospectively investigated in this study. 36 patients had primary MN and 70 patients were diseased controls (31 minimal change nephrotic syndrome (MCNS), 19 rapidly progressive glomerulonephritis (RPGN), and 20 IgA glomerulonephritis (IgAGN)). Serum anti-CFH antibody titers were measured by enzyme-linked immunosorbent assay. 77.8% of MN patients were positive for anti-CFH antibodies. However, only 27.1% of diseased control patients and 5.6% of healthy controls were positive for anti-CFH antibodies. Moreover, median anti-CFH antibody titers were significantly higher in MN patients (4.69 AU/mL) than in diseased control patients (MCNS patients (0 AU/mL, p<0.01), RPGN patients (0 AU/mL, p<0.05), IgAGN patients (0 AU/mL, p<0.01)), and healthy controls (0 AU/mL, p<0.01). Anti-CFH antibody titer was selected as an independent unfavorable predictor of renal dysfunction by Cox proportional hazards analysis. These data suggest that anti-CFH antibodies may be involved in the deterioration of renal function in primary MN.

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.

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.

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.

Unique proximal tubular cell injury and the development of acute kidney injury in adult patients with minimal change nephrotic syndrome

BackgroundAdult patients with minimal change nephrotic syndrome (MCNS) are often associated with acute kidney injury (AKI). To assess the mechanisms of AKI, we examined whether tubular cell injuries unique to MCNS patients exist.MethodsWe performed a retrospective analysis of clinical data and tubular cell changes using the immunohistochemical expression of vimentin as a marker of tubular injury and dedifferentiation at kidney biopsy in 37 adult MCNS patients. AKI was defined by the criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI.ResultsThirteen patients (35.1%) were designated with AKI at kidney biopsy. No significant differences in age, history of hypertension, chronic kidney disease, diuretics use, proteinuria, and serum albumin were noted between the AKI and non-AKI groups. Urinary N-acetyl-β-D-glucosaminidase (uNAG) and urinary alpha1-microglobulin (uA1MG) as markers of tubular injury were increased in both groups, but the levels were significantly increased in the AKI group compared with the non-AKI group. The incidence of vimentin-positive tubules was comparable between AKI (84.6%) and non-AKI (58.3%) groups, but vimentin-positive tubular area per interstitial area was significantly increased in the AKI group (19.8%) compared with the non-AKI group (6.8%) (p = 0.011). Vimentin-positive injured tubules with tubular simplification (loss of brush-border of the proximal tubule/dilated tubule with flattening of tubular epithelium) were observed in the vicinity of glomeruli in both groups, suggesting that the proximal convoluted tubules were specifically injured. Two patients exhibited relatively severe tubular injuries with vimentin positivity and required dialysis within 2 weeks after kidney biopsy. The percentage of the vimentin-positive tubular area was positively correlated with uNAG but not with uA1MG in the non-AKI group.ConclusionsProximal tubular injuries with increased uNAG exist in MCNS patients without renal dysfunction and were more severe in the AKI group than they were in the non-AKI group. The unique tubular injuries probably due to massive proteinuria might be a predisposing factor for the development of severe AKI in adult MCNS patients.

Changes in DNA methylation in na\xefve T helper cells regulate the pathophysiological state in minimal-change nephrotic syndrome

BackgroundDNA methylation plays a crucial role in regulating transcription, and changes in DNA methylation affect gene expression and disease development. Minimal change nephrotic syndrome (MCNS) has been reported to involve immunological disturbances. Since the characteristic features of the disease include recurrent relapse and sex and age preference, the disease pathogenesis may be partly related to epigenetic changes. However, little is known about these changes.MethodsWe analyzed genome-wide DNA methylation using the microarray-based integrated analysis of methylation by isoschizomers method. This method was used to evaluate methylation in monocytes (patient number; n = 6) and naïve T helper cells (n = 4) from the peripheral blood of MCNS patients both in relapse and following remission and that of healthy controls (n = 5).ResultsIn total, 85 co-occurring genes were identified in naïve T helper cells, while 4 such genes were identified in monocytes, which were common among the 3 following comparisons for changes in DNA methylation using sample pairs: (1) relapse versus remission, (2) relapse versus controls, and (3) remission versus controls. In 82 of 85 co-occurring genes (96.5%) in naïve T helper cells, the level of DNA methylation was altered according to disease activity, but was not related to disease activity in the 4 genes detected in monocytes.ConclusionsTherefore, in 82 co-occurring genes in naïve T helper cells, the regulation of DNA methylation was well correlated with the clinical and pathophysiological state. Our genome-wide approach to analyze DNA methylation provides further insight into the pathogenesis of MCNS and indicates potential prediction and diagnostic tool for the disease.

Influence of acute kidney injury on the time to complete remission in adult minimal change nephrotic syndrome: a single-centre study.

Acute kidney injury (AKI) is a common complication of minimal change nephrotic syndrome (MCNS), particularly in adults. We evaluated the prevalence of AKI at the onset of adult MCNS and analyzed the influence of AKI on the duration of achieving complete remission (CR). A retrospective, single-centre, dynamic cohort study was conducted with biopsy-proven, first-onset, adult MCNS patients treated with corticosteroids. Fifty-three consecutive patients diagnosed with MCNS from January 2000 to April 2014 were enrolled. Age, gender, daily urinary protein excretion, and serum creatinine levels were measured. To evaluate AKI during induction, we used the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI and judged AKI stage according to the fluctuations in serum creatinine levels during the first 4 weeks of starting corticosteroid therapy. Twenty patients (37.7%) met the AKI criteria and all 53 patients achieved CR within 1 year. Kaplan-Meier analysis showed that the median time to CR was significantly longer in patients with AKI than in patients without AKI. Cox proportional hazard analysis showed that the hazard ratio (HR) associated with the presence of AKI for achieving CR within 4 weeks was 0.36 after adjustment for age, gender, serum albumin, daily urinary protein excretion, hypertension, administration of 25% albumin, and methylprednisolone pulse therapy. A graded association was also observed between AKI stage and HR for achieving CR. The prevalence of AKI is high in adult patients with MCNS during induction therapy. AKI is an independent factor that delays the time to CR.

The Expression and Effect of Helper IL-10- Producing B Cells in Human Minimal Change Nephrotic Syndrome

This study is aimed at determining the putative contribution of B cell types in patients with newly diagnosed minimal change nephrotic syndrome (MCNS) before treatment and 8-12 weeks post-treatment. Significantly higher percentages of CD19+CD27+, CD19+CD38+, and CD19+CD86+ B cells were observed compared to healthy controls. Importantly, lower levels of Breg cells and intracellular expression of IL-10 protein were detected in MCNS patients. 24-h urinary proteins were positively correlated with the percentage of CD19+CD27+ B cells and negatively correlated with the percentage of Breg cells. A positive correlation between the percentage of CD19+CD5+CD1d+ cells and the levels of serum albumin was observed in these patients. Treatment with prednisone (PDN) significantly reduced the frequency of CD19+CD27+, CD19+CD38+, and CD19+CD86+ B cells, and elevated the levels of Breg cells and Breg cell-derived IL-10. This data indicates that several of the CD19+ B cell subtypes and IL-10+ Breg cells have a potentially crucial role in the MCNS patients.

Urinary proteins induce lysosomal membrane permeabilization and lysosomal dysfunction in renal tubular epithelial cells.

Lysosomal membrane permeabilization (LMP) has been shown to cause the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol and initiate a cell death pathway. Whether proteinuria triggers LMP in renal tubular epithelial cells (TECs) to accelerate the progression of renal tubulointerstitial injury remains unclear. In the present study, we evaluated TEC injury as well as changes in lysosomal number, volume, activity, and membrane integrity after urinary protein overload in vivo and in vitro. Our results revealed that neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels were significantly increased in the urine of patients with minimal change nephrotic syndrome (MCNS) and the culture supernatant of HK-2 cells treated by urinary proteins extracted from MCNS patients. Urinary protein overload also induced apoptotic cell death in HK-2 cells. Importantly, we found that lysosomal volume and number were markedly increased in TECs of patients with MCNS and HK-2 cells overloaded with urinary proteins. However, lysosome function, as assessed by proteolytic degradation of DQ-ovalbumin and cathepsin-B and cathepsin-L activities, was decreased in HK-2 cells overloaded with urinary proteins. Furthermore, urinary protein overload led to a diffuse cytoplasmic immunostaining pattern of cathepsin-B and irregular immunostaining of lysosome-associated membrane protein-1, accompanying a reduction in intracellular acidic components, which could be improved by pretreatment with antioxidant. Taken together, our results indicate that overloading of urinary proteins caused LMP and lysosomal dysfunction at least partly via oxidative stress in TECs.

Outcomes of primary nephrotic syndrome in elderly Japanese: retrospective analysis of the Japan Renal Biopsy Registry (J-RBR).

There are very little data available regarding nephrotic syndrome (NS) in elderly (aged ≥65 years) Japanese. The aim of this study was to examine the causes and outcomes of NS in elderly patients who underwent renal biopsies between 2007 and 2010. From July 2007 to June 2010, all of the elderly (aged ≥65 years) Japanese primary NS patients who underwent native renal biopsies and were registered in the Japan renal biopsy registry (J-RBR; 438 patients including 226 males and 212 females) were identified. From this cohort, 61 patients [28 males and 33 females including 29, 19, 6, 4, and 3 patients with membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), and other conditions, respectively] were registered from the representative multi-centers over all districts of Japan, and analyzed retrospectively. The treatment outcome was assessed using proteinuria-based criteria; i.e., complete remission (CR) was defined as urinary protein level of <0.3 g/day or g/g Cr, and incomplete remission type I (ICR-I) was defined as urinary protein level of <1.0-0.3 g/day or g/g Cr, and renal dysfunction was defined as a serum creatinine (Cr) level of 1.5 times the baseline level. In this elderly primary NS cohort, MN was the most common histological type of NS (54.8 %), followed by MCNS (19.4 %), FSGS (17.4 %), and MPGN (8.4 %). Of the patients with MN, MCNS, or FSGS, immunosuppressive therapy involving oral prednisolone was performed in 25 MN patients (86.2 %), 18 MCNS patients (94.7 %), and all 6 FSGS patients (100 %). CR was achieved in all 19 (100 %) MCNS patients. In addition, CR and ICR-I were achieved in 16 (55.2 %) and 18 (62.1 %) MN patients and 4 (66.7 %) and 5 (83.3 %) FSGS patients, respectively. There were significant differences in the median time to CR among the MCNS, FSGS, and MN patients (median: 26 vs. 271 vs. 461 days, respectively, p < 0.001), and between the elderly (65-74 years, n = 7) and very elderly (aged ≥75 years, n = 12) MCNS patients (7 vs. 22 days, p = 0.037). Relapse occurred in two (6.9 %) of the MN and nine (47.4 %) of the MCNS patients. Renal dysfunction was observed in five (7.2 %) of the MN patients. Serious complications developed in eight (14.8 %) patients, i.e., two (3.7 %) patients died, four (7.4 %, including three MCNS patients) were hospitalized due to infectious disease, and two (3.7 %) developed malignancies. The initiation of diabetic therapy was necessary in 14 of the 61 patients (23.0 %) with much higher initial steroid dosage. Renal biopsy is a valuable diagnostic tool for elderly Japanese NS patients. In this study, most of elderly primary NS patients respond to immunosuppressive therapy with favorable clinical outcomes. On the other hand, infectious disease is a harmful complication among elderly NS patients, especially those with MCNS. In future, modified clinical guidelines for elderly NS patients should be developed.

Urinary MMP-9/NGAL Ratio as a Potential Marker of FSGS in Nephrotic Children

BACKGROUND: The study was undertaken to develop a potential new markers for distinguishing minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) in children. We hypothesized that matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin (MMP-9/NGAL) is a better marker of focal sclerosis in the glomerulus then matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) and matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-2 MMP2/TIMP-2.METHODS: The present study used a sample of 36 children and adolescents subdivided into two groups: I – 20 children with MCNS, subjected to examination twice: A – in relapse of nephrotic syndrome, before treatment and B – after regression of proteinuria; II – 16 children with FSGS. MMPs and TIMPs and NGAL levels were measured in the urine using ELISA kit. MMP-9/TIMP-1, MMP-2/TIMP-2 and MMP-9/NGAL ratios were calculated.RESULTS: Median NGAL/cr. was significantly higher in MCNS and FSGS patients when compared to healthy controls. Both, NGAL and MMP-9 urinary levels were significantly elevated in FSGS subjects, as compared with control subjects. Contrary to FSGS children, in MCNS group, before treatment only NGAL/cr., but not MMP-9/cr. was increased. Urinary concentrations of NGAL and MMP-9 were highly associated with each other (NGAL/cr. vs. MMP-9/cr.,r= 0.485,p&lt; 0.01). Median urine MMP-9/NGAL ratio in FSGS patients was significantly higher than in patients with MCNS. We also found that significant increase in MMP-9/NGAL was associated with FSGS [odds ratio (OR) – 9.0; confidence interval (CI) 1.97–41.07].CONCLUSION: MMP-9/NGAL ratio may serve as differentiation marker between MCNS and FSGS in nephrotic children.

Urinary MMP-9/NGAL ratio as a potential marker of FSGS in nephrotic children.

BACKGROUND: The study was undertaken to develop a potential new markers for distinguishing minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) in children. We hypothesized that matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin (MMP-9/NGAL) is a better marker of focal sclerosis in the glomerulus then matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) and matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-2 MMP2/TIMP-2.METHODS: The present study used a sample of 36 children and adolescents subdivided into two groups: I – 20 children with MCNS, subjected to examination twice: A – in relapse of nephrotic syndrome, before treatment and B – after regression of proteinuria; II – 16 children with FSGS. MMPs and TIMPs and NGAL levels were measured in the urine using ELISA kit. MMP-9/TIMP-1, MMP-2/TIMP-2 and MMP-9/NGAL ratios were calculated.RESULTS: Median NGAL/cr. was significantly higher in MCNS and FSGS patients when compared to healthy controls. Both, NGAL and MMP-9 urinary levels were significantly elevated in FSGS subjects, as compared with control subjects. Contrary to FSGS children, in MCNS group, before treatment only NGAL/cr., but not MMP-9/cr. was increased. Urinary concentrations of NGAL and MMP-9 were highly associated with each other (NGAL/cr. vs. MMP-9/cr., r = 0.485, p < 0.01). Median urine MMP-9/NGAL ratio in FSGS patients was significantly higher than in patients with MCNS. We also found that significant increase in MMP-9/NGAL was associated with FSGS [odds ratio (OR) – 9.0; confidence interval (CI) 1.97–41.07].CONCLUSION: MMP-9/NGAL ratio may serve as differentiation marker between MCNS and FSGS in nephrotic children.

Effect of single-dose rituximab on steroid-dependent minimal-change nephrotic syndrome in adults

Steroid-dependent minimal-change nephrotic syndrome (MCNS) requires administration of prolonged courses of prednisolone (PSL); therefore, a paradigm shift from such toxic 'non-specific' therapies to selective immunomodulating regimens is necessary for these cases. To assess the therapeutic effects of rituximab (an anti-CD20 antibody) in adult patients with steroid-dependent MCNS, we performed a prospective trial of the effects of a single dose of rituximab administered twice at an interval of 6 months in 25 MCNS patients. We evaluated the biochemical parameters and compared the clinical findings between the 12-month period before and 12-month period after the first rituximab infusion. A significant reduction in the number of relapses and the total dose and the maintenance dose of PSL administered was observed during the 12-month period after the first rituximab infusion when compared with the findings during the 12-month period before the first rituximab infusion [25 (100%) versus 4 (16%), P < 0.001; 8.2 versus 3.3 g, P < 0.001; 26.4 mg/day at baseline versus 1.1 mg/day at 12-month, P < 0.0001]. Complete remission was achieved/maintained in all patients undergoing B-cell depletion. Four of 17 patients with B-cell repletion developed relapse. Our results revealed that rituximab therapy was associated with a reduction in the number of relapses and in the total dose of PSL needed. Therefore, rituximab appears to be a useful therapeutic agent for adult patients with steroid-dependent MCNS. These results suggest that this treatment is rational and should be considered as an important option in the management of adult patients with steroid-dependent MCNS.

GSTT1 gene abnormality in minimal change nephrotic syndrome with elevated serum immunoglobulin E

Imbalance between T-helper 1 (Th1) and 2 (Th2) lymphocytes and effects of reactive oxygen species (ROS) upon glomerular capillary walls have been implicated in minimal change nephrotic syndrome (MCNS). By polymerase chain reaction and comparative genomic hybridization, we evaluated mutations of the GSTT1 gene (GSTT1), a member of the glutathione S-transferase (GST) supergene family associated with both protection of cells from ROS and control of allergic reactions and serum immunoglobulin (Ig) E. Among 15 children with MCNS, IgE elevation (over 2,000 IU/l) and GSTT1 deletion was found in 2 who showed severe allergic symptoms. Serum ROS concentrations in these 2 patients were significantly higher than in healthy controls or other MCNS patients. In addition, a Th2 shift caused by increased serum interleukin (IL)- 4 was observed. These results suggest presence of a GSTT1 abnormality in some children with MCNS having marked serum IgE elevations and various allergic complications. Defective ROS degradation and Th1/Th2 imbalance caused by GSTT1 abnormality could initiate proteinuria leading to MCNS.

Serial Tc-99m MAG3 Renography Evaluating the Recovery of Acute Kidney Injury Associated with Minimal Change Nephrotic Syndrome

Acute kidney injury (AKI) is a well-recognized complication of minimal change nephrotic syndrome (MCNS). Previous reports support the concept that AKI associated with MCNS is reversible; however, information regarding the hemodynamic basis of AKI in MCNS is insufficient. We herein describe a case of AKI in a man with MCNS. In this case, monitoring the longitudinal changes in renal perfusion using serial Tc-99m-MAG3 renal scanning was beneficial for evaluating the pathophysiological background associated with the development of AKI. The potential impact of serial renal scanning in MCNS patients with AKI will also be discussed.

Comparison of the effects of intravenous methylprednisolone pulse versus oral prednisolone therapies on the first attack of minimal‐change nephrotic syndrome in adults

Minimal-change nephrotic syndrome (MCNS) is characterized by a good response to corticosteroid, but a high incidence of relapse. We compared the effect of intravenous methylprednisolone pulse plus oral prednisolone therapy (pulse group) with that of conventional oral prednisolone alone therapy (oral group) on the responsiveness and relapse in the first attack of adult-onset MCNS patients. Eighty-one adult patients with biopsy-proven MCNS, who were previously untreated and admitted to our hospital with their first attack of nephrotic syndrome, were analyzed retrospectively. They were arbitrarily assigned to either pulse group (n = 29, 1000 mg of methylprednisolone intravenously for 3 days, and then oral prednisolone 30 to 40 mg daily for 4 to 8 weeks) or oral group (n = 52, oral prednisolone 1 mg/kg daily for 4 to 8 weeks). We compared the time to response and relapse between the two groups. Time to steroid response was significantly shorter in the pulse group compared with the oral group (15.2 ± 10.2 vs 26.7 ± 17.6 days, P = 0.03). In 74 patients who reached remission within 12 weeks (pulse vs oral groups; 86.2% vs 96.2%, ns), the time to relapse was not different between two groups but the relapse rate was significantly higher in the pulse group (pulse vs oral groups; 60% vs 35%, P = 0.038). Kaplan-Meier analyses revealed that both complete remission rates within 4 weeks of the initial steroid therapy and relapse rate within 12 months after attaining remission were significantly higher in the pulse group than the oral group. In the Cox regression model, intravenous methylprednisolone pulse therapy had a significant effect on relapse (hazard ratio, 2.39 (95% confidence interval 1.11-5.15), P = 0.026). Intravenous methylprednisolone pulse followed by oral prednisolone therapy shows an earlier responsiveness but a much more frequent relapse compared with conventional oral prednisolone alone therapy for the first attack of adult-onset MCNS.