A membranous nephropathy variant mimicking minimal change disease

Mechanisms of hypercoagulability in nephrotic syndrome associated with membranous nephropathy as assessed by thromboelastography

Tubular NF-κB and AP-1 activation in human proteinuric renal disease

The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and nephrotic syndrome has long been recognized. Minimal change disease and membranous nephropathy have been the most common findings in those patients in whom a kidney biopsy was performed (1–6). Regarding NSAIDs-related minimal change disease, it is a peculiar type of nephrotic syndrome in which most of reported patients present with a severe AKI accompanying nephrotic syndrome manifestations (edema, proteinuria >3.5 g/d, and hypoalbuminemia). Kidney biopsies typically show the characteristic pattern of drug-induced acute interstitial nephritis (AIN): a diffuse interstitial infiltrate composed predominantly of T lymphocytes, although eosinophils, macrophages, and plasma cells can also be observed (7). The glomeruli are normal in light microscopy, but a diffuse effacement of podocyte foot processes is observed in electron microscopy (1–4). NSAIDs-related minimal change disease could be, therefore, categorized as a complication of NSAIDs-induced AIN. However, a "pure" nephrotic syndrome has been described in some patients taking NSAIDs, with diffuse fusion of foot processes but no accompanying interstitial infiltrates. In some patients, tubular necrosis without interstitial infiltrates has been the most salient histopathologic finding. Patients with AIN accompanied by minimal change disease have been reported with a variety of conventional NSAIDs and selective COX-2 inhibitors. As usual in NSAIDs-induced AIN, the extrarenal manifestations (low-grade fever, skin rash, and eosinophilia) that frequently accompany AIN induced by antibiotics and other drugs are characteristically absent (7). Although NSAIDs are one of the most frequent causes of drug-induced AIN, the incidence of nephrotic syndrome seems to be low. In two patient series of drug-induced AIN, only three patients of a total of 121 showed nephrotic-range proteinuria, although NSAIDs were the offending drug in 40% of the patients (7). However, patients with NSAIDs-related AIN tend to present higher proteinuria values than other types of drug-induced AIN, although they rarely reach the nephrotic range (7,8). Notably, nephrotic syndrome and nephrotic-range proteinuria seem to be a specific complication of NSAIDs, because they have been only exceptionally reported with other types of drug-induced AIN. To explain this susceptibility for proteinuria, it has been suggested that a decrease in the synthesis of prostaglandins induced by NSAIDs could result in an increased conversion of arachidonic acid to leukotrienes, which could activate T-helper cells and induce a diffuse podocyte damage. However, no studies have confirmed this hypothesis. In most patients, NSAIDs-related minimal change disease resolves after drug discontinuation, which is accompanied in some patients by a short course of corticosteroids (1–4). It has been reported that early treatment with corticosteroids can induce a more rapid and efficient recovery of kidney function in NSAIDs-induced AIN accompanied or not by nephrotic proteinuria (8). Paradoxically, NSAIDs induce a marked reduction of proteinuria in different types of nondiabetic glomerular nephropathies and can potentiate the antiproteinuric effect of renin-angiotensin blockers (9). Changes in glomerular hemodynamic through a preglomerular vasoconstriction and an improvement of the glomerular protein permselectivity have been invoked to explain this effect. However, the frequent side effects of NSAIDs have prevented their clinical use for the treatment of glomerular diseases. Nephrotic syndrome with a histopathologic pattern of membranous nephropathy, a paradigmatic type of immune complex glomerular disease, is another side effect of NSAIDs, and different types of conventional and selective NSAIDs have been reported as causatives of this complication (1,5,6). The presence of electron-dense subepithelial deposits along the glomerular capillary loops and a complete effacement of foot processes were the most characteristic findings in kidney biopsies (5,6). Unlike NSAIDs-related minimal change disease, inflammatory interstitial infiltrates were absent in most reported patients. This histologic difference explains why most of the patients with NSAIDs-induced minimal change disease present with nephrotic syndrome accompanied by severe AKI, whereas nephrotic syndrome with normal kidney function is the most frequent presentation in NSAIDs-induced membranous nephropathy. Immunostaining for the different subclasses of IgG can help to differentiate NSAIDs-induced membranous nephropathy from primary forms of the disease. As in other types of secondary membranous nephropathy, deposition of IgG1 has been reported in patients with cases associated with NSAIDs (5), whereas deposition of IgG4 is characteristic of primary forms. The pathogenesis of membranous nephropathy associated with NSAIDs is unknown. Glomerular deposition of antigens bound to NSAIDs could elicit an immune response, although these drugs could also exacerbate or trigger autoimmune reactions against podocyte antigens. Intriguingly, positive immunostaining for PLA2R has been reported in a patient with membranous nephropathy precipitated by piroxicam, although serum anti-PLA2R was not available (5). The incidence of NSAIDs-related membranous nephropathy could be greater than suspected according with the study of Radford et al. (6). They reported 125 patients with early membranous nephropathy (stages 1 and 2 membranous nephropathy with small subepithelial deposits). Twenty-nine of them were taking NSAIDs at the time of diagnosis, of which 13 (10%) fulfilled the criteria defined by the authors to establish the diagnosis of NSAIDs-related membranous nephropathy: onset of the nephrotic syndrome while taking NSAIDs, exclusion of other causes of secondary membranous nephropathy, and rapid disappearance of proteinuria after NSAIDs withdrawal (6). Interestingly and reinforcing the causal association between NSAIDs and nephrotic syndrome, relapses of proteinuria have been reported after re-exposure to NSAIDs, and in some patients, re-exposure was to a type of NSAIDs different from the one causing the first episode of nephrotic syndrome (5). In this issue of CJASN, Bakhriansyah et al. (10) describe the results of a systematic observational matched patient-control study about the association between NSAIDs and nephrotic syndrome. The study used data from the Clinical Practice Research Datalink, a general practitioner database of the United Kingdom National Health Service. Patients had a diagnosis of nephrotic syndrome established in the period 1989–2017, and controls were patients without nephrotic syndrome before and at the date of diagnosis of nephrotic syndrome in matching cases. Exposure to NSAIDs was divided into current use (NSAIDs prescription within the last month before the date of diagnosis), recent use (prescription within 1–2 months before), or past use (prescription >2 months before). According to the duration of NSAIDs exposure, current use was divided into use of 1–14, 15–28, or >28 days. Patients with past use were divided into those in whom NSAIDs had been discontinued between 2 months and 2 years before the date of diagnosis and those with an NSAIDs discontinuation >2 years. NSAIDs were classified as acetic acid derivatives (such as indomethacin, ketorolac, and diclofenac), propionic acid derivatives (such as naproxen, ibuprofen, and ketoprofen), selective COX-2 inhibitors (coxibs), fenamates, and oxicams, and other NSAIDs. A total of 2620 patients and 10,454 matched controls were included in the analysis. The results show that current use for >2 weeks, recent use, and past use (discontinuation >2 months to 2 years) of conventional NSAIDs (acetic acid and propionic acid derivatives) were associated with a significantly higher risk of nephrotic syndrome (adjusted odds ratio, 1.34; 95% confidence interval, 1.06 to 1.70; adjusted odds ratio, 1.55; 95% confidence interval, 1.11 to 2.15; and adjusted odds ratio, 1.24; 95% confidence interval, 1.07 to 1.43, respectively) compared with nonuse and that the risk disappeared after 2 years of discontinuation. The use of selective COX-2 inhibitors was not associated with a higher risk of nephrotic syndrome, although there was not a statistically significant trend among patients with a past use (>2 months to 2 years). This study is the first systematic analysis of the association between NSAIDs consumption and the risk of developing a nephrotic syndrome. Its conclusions are clinically relevant, although several important caveats should be taken into account. One of them is the inevitable chronological imprecision when analyzing drugs, like conventional NSAIDs, that are frequently available over the counter and consumed in a discontinuous manner by a large number of normal subjects. Additionally, the accuracy of the diagnosis of nephrotic syndrome using pre-established codes should be taken with caution in studies like this that involve a large number of patients over a long period of time. The criteria used to establish the diagnosis of nephrotic syndrome are not reported, and therefore, we do not know if all included patients presented a proteinuria >3.5 g/d accompanied by hypoalbuminemia. A major constraint of the study is the low percentage of patients with histologic confirmation of kidney disease. Although patients 18 years old or younger were excluded (another limitation of the study), a kidney biopsy was performed in only 11% of the patients, despite the fact that kidney biopsy is considered a central tool in the diagnostic workup of most adult patients presenting with nephrotic syndrome. The list of histologic diagnoses is somewhat surprising, because only a minority of patients (15 of 167) taking NSAIDs and presenting a nephrotic syndrome received the diagnosis of minimal change disease or AIN, and other diagnoses (for instance, crescentic or mesangiocapillary GN) have no apparent pathogenic relationship with these drugs. The study of Bakhriansyah et al. (10) raises questions of great clinical importance for the clinician. Are we overlooking patients with NSAIDs-induced nephrotic syndrome? If so, are we prescribing long courses of immunosuppressive treatments to patients with minimal change disease or membranous nephropathy caused by NSAIDs that would have resolved with the discontinuation of the drug accompanied perhaps by a short course of corticosteroids? Considering that the existing literature on this topic is in general old and scarce, with only patient reports or short series of patients published, data from this study should encourage nephrologists to, on one hand, carefully review the current or recent intake of NSAIDs in any patient with nephrotic syndrome, particularly when minimal change disease or membranous nephropathy is found in kidney biopsies, and on the other hand, perform collaborative studies to collect large series of patients with unequivocal diagnosis of NSAIDs-induced nephrotic syndrome to identify their differential clinical and histopathologic characteristics and delineate their more efficient treatment. Basic research about the pathogenic mechanisms through which NSAIDs cause glomerular damage is also needed. Disclosures Dr. Praga has received personal fees for lectures from Alexion, Fresenius, Otsuka, and Retrophin and grant support and personal fees from Alexion, outside of the submitted work. Dr. Mérida has nothing to disclose.

Objective To investigate the expression and significance of Toll-like receptor 4 (TLR4) in renal tissue and peripheral blood of children with idiopathic nephrotic syndrome(INS). Methods The renal biopsy tissues of 78 children with INS diagnosed in the First Affiliated Hospital of Xinxiang Medical University from October 2015 to June 2018 and normal renal tissues of 21 children (control group 1) were collected, and the expressions of TLR4 in the renal tissue was detected by using immunohistochemical method.The expression of TLR4 in different renal pathological types and clinical types of INS was compared, and the correlation of TLR4 with 24-hour urinary protein and serum albumin was analyzed.The expression levels of TLR4 in peripheral blood of children with INS before and after treatment (active stage and remission stage) and 23 healthy children (control group 2) were detected by enzyme linked immunosorbent assay(ELISA). The serum expression levels of TLR4 in different renal pathological types and clinical types of INS were compared, and the correlation of TLR4 with 24-hour urinary protein and serum albumin was analyzed; The correlation between TLR4 expression in renal tubules and in the serum of children with INS was also analyzed. Results (1)Compared with the expression of TLR4 in normal renal tissues[(0.93±0.26)%], the expression of TLR4 in glomeruli and interstitium of all pathological types of INS [mesangial proliferative glomerulonephritis (MsPGN): (0.93 ± 0.21)%, focal segmental glomerulosclerosis (FSGS): (1.02±0.25)%, membranous glomerulonephritis(MN): (1.03±0.09)%, minimal change disease(MCD): (1.02±0.27)%]was not significantly different (F=0.741, P=0.562), but the expression of TLR4 in renal tubules[MCD: (82.94±4.62)%, MN: (63.54±1.98)%, MsPGN(42.32±2.97)%, FSGS: (22.60±2.07)%] was significantly increased (F=1 929.842, P<0.01), Especially, the expression of TLR4 in renal tubules of MCD type INS was significantly higher than that of MN, MsPG N and FSGS [MCD: (82.94±4.62)%, MN: (63.54±1.98)%, MsPGN: (42.32±2.97)%, FSGS: (22.60±2.07)%], and the differences were statistically significant(all P<0.01). TLR4 expression in renal tubules was the highest in steroid-sensitive nephrotic syndrome (SSNS) type and the lowest in INS patients with steroid-resistant nephrotic syndrome (SRNS) type, and the differences were statistically significant(F=220.951, P<0.01). (2)The expression of serum TLR4 in INS children at the active stage [MsPNG: (143.36±12.99) ng/L, FSGS(75.94±7.29) ng/L, MN(210.22±14.66) ng/L, MCD(283.93±21.58) ng/L]was significantly higher than that in INS children at remission stage [MsPNG: (29.51±4.93) ng/L, FSGS(15.66±3.78) ng/L, MN(45.40±5.73) ng/L, MCD(62.29±7.90) ng/L]and control group 2[(0.69 ± 0.33) ng/L], and the differences were statistically significant(all P<0.01); the expression of serum TLR4 in INS children at remission stage was significantly higher than that in the control group 2 (F=286.287, P<0.01). TLR4 had the highest expression level in serum of MCD type INS children at active and remission stages, followed by MN and FSGS successively.The expression of serum TLR4 was highest in SSNS and lowest in SRNS, and the differences were statistically significant (F=147.438, P<0.01). (3)The expression of TLR4 in renal tubules of children with INS[(62.82 ±20.94)%]was positively correlated with the expression of TLR4 in serum[(213.26±73.33) ng/L] (r=0.852, P< 0.05). The expression levels of TLR4 in renal tubules and serum of INS patients at active stage were positively correlated with 24-hour urinary protein level[(123.05±33.55) mg/kg] (r=0.401, 0.427, all P<0.05), and negatively correlated with serum albumin level[(19.54±3.55)g/L] (r=-0.602, -0.617, all P<0.05). Conclusions The expression of TLR4 in renal tubules and serum of children with INS increases, and may be related to different renal pathological types and clinical types of children with INS, as well as disease activity. Key words: Toll-like receptor 4; Kidney tissue; Serum; Idiopathic nephrotic syndrome; Child

Membranous nephropathy (MN) and minimal change disease (MCD) are two common causes leading to nephrotic syndrome (NS). They have similar clinical features but different treatment strategies and prognoses. M-type phospholipase A2 receptor (PLA2R) is considered as a specific marker of membranous nephropathy. However, its sensitivity is only about 70%. Therefore, there is a lack of effective and noninvasive tools to distinguish PLA2R-negative MN and MCD patients without renal biopsy. A total 949 patients who were pathologically diagnosed as idiopathic MN or MCD were enrolled in this study, including 805 idiopathic MN and 144 MCD. Based on the basic information and laboratory examination of 200 PLA2R-negative MN and 144 MCD, we used a univariate and multivariate logistic regression to select the relevant variables and develop a discrimination model. A novel model including age, albumin, urea, high density lipoprotein, C3 levels and red blood cell count was established for PLA2R-negative MN and MCD. The discrimination model has great differential capability (with an AUC of 0.904 in training group and an AUC of 0.886 in test group) and calibration capability. When testing in all 949 patients, our model also showed good discrimination ability for all idiopathic MN and MCD.

B Cell Suppression in Primary Glomerular Disease

Objective To detect the M-type phospholipase A2 receptor (PLA2R), and thrombospondin type-1 domain-containing 7A (THSD7A) expression in renal tissue and the levels of their antibodies in adult idiopathic membranous nephropathy (IMN). Also to determine the value of the two markers in the diagnosis of IMN. Methods One hundred and sixteen patients with biopsy-proven MN at the Second Hospital of Hebei Medical University from December 2014 to August 2015 were enrolled, including 86 patients with IMN, 10 patients with HBV-MN and 10 patients with stage V lupus nephritis (LN-V). Twenty patients with minimal change disease (MCD) were regarded as control group. We conducted immunohistochemical analysis of the presence of THSD7A and PLA2R the Paraffin section and enzyme linked immunosorbent assay (ELISA) detecting serum PLA2R-AB and THSD7A-AB concentration to investigate whether there was a correlation between them and clinical indicators. Results Compared with the SMN and MCD groups, the positive rates of PLA2R and PLA2R-AB were significantly higher in IMN groups. Expression PLA2R was detected in 88.4%, 47.4%, 10% and 0% and PLA2R-AB in 82.6%, 15%, 10%, 0%, respectively, of the patients with IMN, HBV-MN, LN-V and MCD. Expression THSD7A was detected in 2.3% of the patients with IMN while not detected in SMN and MCD. THSD7A-AB antibody was negative in all patients. Compared with serum PLA2R-Ab negative individuals, patients with serum PLA2R-Ab positive had lower serum albumin (P <0.001), higher urine protein excretion (P=0.01). The sensitivity of PLA2R-AB, PLA2R, THSD7A and PLA2R+THSD7A in the diagnosis of IMN were 82.6%, 88.4%, 2.3%, 88.6%, and the specificity was 92%, 66.7%, 100%, 66.7%, respectively. Conclusions PLA2R in renal tissue and serum PLA2R-AB are specific markers for the diagnosis of IMN, which are closely related with the severity of IMN. Expression of THSD7A is only positive in some of IMN patients with negative PLA2R, which can be used as a supplementary examination of IMN patients with negative PLA2R. Key words: Receptors, phospholipase A2; Glomerulonephritis, membranous; Diagnosis, differential; Thrombospondin type-1 domain-containing; Idiopathic membranous nephropathy

Background and Aims In recent years, progress has been made in studying the immunological mechanisms of primary podocytopathies, such as membranous nephropathy (MN). However, in minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), these mechanisms are still not well understood. Nephrin is a structural component of the filtration slit, and mutations in its gene are responsible for congenital Finnish nephrotic síndrome. Recently, the presence of anti-nephrin antibodies has been described in a cohort of patients with minimal change disease and in recurrent cases of focal segmental glomerulosclerosis. The aim of this study is to investigate the presence of anti-nephrin antibodies in the serum of patients with MCD and primary FSGS and determine whether they are found at a similar percentage to what has been reported in the literature. Method We evaluated serum samples from patients with MCD and FSGS in an active disease state from hospitals within the GLOSEN network, searching for circulating autoantibodies against nephrin. These were compared to a control group of healthy patients and another group with MN. The presence of these antibodies in serum was determined using ELISA techniques, and the measurement was normalized by protein levels. Results A total of 136 serum samples were studied: 56 from MCD patients, 33 from FSGS patients, 21 from MN patients, and 15 from controls. The threshold for considering anti-nephrin autoantibody levels as positive was 3,872, the highest value observed in the control cohort without renal pathology (n = 15). Based on this threshold, the presence of anti-nephrin antibodies was confirmed in 18% of MCD samples and 12.1% of FSGS samples. However, in the MN group, they were found in one case (4.8%). It was also observed that the maximum levels of autoantibodies were higher in MCD and FSGS than in MN (MCD: 38,181; FSGS: 31,279; MN: 5,740). No significant differences were found in biochemical parameters between patients with and without anti-nephrin antibodies. Conclusion We confirm the presence of anti-nephrin antibodies in MCD, although at a slightly lower percentage than previously reported in the literature (18% vs. 29%). In FSGS, we also found the presence of anti-nephrin antibodies, but at a lower percentage than in minimal change disease (12% vs. 18%).

BackgroundImmunosuppressive treatment will predispose an idiopathic membranous nephropathy (iMN) patient to opportunistic infections. Disease severity is one of the main concerns for making the treatment decision. Urinary angiotensinogen (UAGT) level has been shown highly correlated with intrarenal renin-angiotensin system (RAS) activity and severity of chronic kidney diseases (CKD). We aimed to test the relationship between the UAGT level and the severity of iMN.MethodsThis cross-sectional study included a total of 48 biopsy-proven iMN patients, 46 minimal change disease (MCD) patients, and 44 healthy volunteers. The clinical and laboratory data and urine samples were collected from all subjects before the use of RAS inhibitors. We determined the UAGT levels with a method of enzyme-linked immunosorbent assay.ResultsThe UAGT levels were not different between the iMN (277.05 ± 61.25, μg/g.Cr) and MCD patients (244.19 ± 40.24, μg/g.Cr), but both of them were significantly higher than those of healthy controls (6.85 ± 1.10, μg/g.Cr). UAGT levels were correlated negatively with serum albumin (r = − 0.393, p = 0.006) and estimated glomerular filtration rate (eGFR) (r = − 0.352, p = 0.014) and positively with 24-h proteinuria (r = 0.614, p < 0.001) in iMN patients but not in MCD patients. Multivariate linear regression analysis revealed that only proteinuria independently determinate the levels of UAGT (β = 0.649, p < 0.001) in iMN patients.ConclusionsUAGT levels were correlated negatively with serum albumin and glomerular filtration rate and positively with proteinuria in iMN patients at the onset. This suggests that elevated levels of UAGT are associated with the severity of iMN. The UAGT level may be used as a cofactor for deciding immunosuppressive therapy in iMN patient.

IgA nephropathy (IgAN) is the most prevalent form of primary glomerular disease. However, its diagnosis is contingent on kidney biopsy. Therefore, noninvasive biomarkers are urgently needed for diagnosis. This study aims to identify novel urinary biomarkers that differentiate IgAN from other common primary glomerular diseases, specifically membranous nephropathy (MN) and minimal change disease (MCD). The peripheral blood mononuclear cell (PBMC) transcriptome dataset GSE73953 was obtained from the GEO database. Differential gene expression, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Gene Ontology (GO) enrichment, and immune infiltration analyses were performed. Protein-protein interaction (PPI) analysis and lysosome-related genes were used to identify hub genes. The expression of the hub gene ATP6V1D in urine and kidney tissues from individuals with IgAN, healthy controls, MCD and MN patients was assessed using enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunostaining techniques. Spearman's correlation analysis was employed to investigate the relationships between the concentration of ATP6V1D in urine, the concentration of galactose-deficient IgA1(GD-IgA1), and the clinical data of patients. The receiver operating characteristic (ROC) curve was used to assess the role of urine ATP6V1D levels in distinguishing IgAN from MN and MCD. ATPase was identified as the principal intracellular structure associated with differentially expressed genes (DEGs) between IgAN patients and healthy controls in PBMCs. ATP6V1D was identified as a hub gene at the intersection of lysosome-related and differential genes. ATP6V1D levels were lower in PBMCs, urine, and kidney samples from IgAN patients than in those from healthy individuals, MCD and MN patients. The decreased urinary ATP6V1D levels and increased GD-IgA1 levels in IgAN patients were further validated. These changes were positively correlated with 24-h urine protein levels. Notably, a negative correlation was observed between ATP6V1D and GD-IgA1 levels. ROC curve analysis demonstrated that urinary ATP6V1D (AUC = 0.972) and GD-IgA1 (AUC = 0.952) had significant discriminative power in distinguishing IgAN patients from MCD and MN patients, with no significant difference in predictive performance between the two biomarkers (P > 0.05). The findings underscore the potential utility of the urine ATP6V1D concentration as a biomarker to distinguish IgAN from MN and MCD.

Differential chemokine expression in tubular cells in response to urinary proteins from patients with nephrotic syndrome

Rituximab as Initial Therapy in Adult Patients With Minimal Change Disease

The urinary excretion of N-acetyl-beta-glucosamynidase (NAG) is increased in subjects exposed to substances toxic for renal tubular cells. In experimental and human glomerular diseases, its increased excretion is probably due to the dysfunction of tubular epithelial cells induced by increased traffic of proteins in the tubular lumen. The first aim of this study was to evaluate whether NAG excretion is correlated not only with the amount of proteinuria but also with some proteinuric components which reflect both glomerular capillary wall damage (IgG) and an impairment of tubular reabsorption of microproteins (alpha(1) microglobulin). The second aim was to assess whether NAG excretion has a predictive value on functional outcome and response to therapy. In 136 patients with primary glomerulonephritis [74 with idiopathic membranous nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and 18 with minimal change disease (MCD)] urinary NAG excretion was measured by a colorimetric method and expressed in units per gram of urinary creatinine. Using univariate linear regression analysis NAG excretion in all 136 patients was significantly dependent on IgG excretion, 24-h proteinuria, fractional excretion of alpha(1) microglobulin (FE alpha(1)m) and diagnosis. Using multiple linear regression analysis, NAG excretion was significantly dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67 patients with nephrotic syndrome (NS) and baseline normal renal function, by multiple linear regression, NAG excretion was significantly dependent on IgG excretion (P=0.0004), 24-h proteinuria (P=0.0067) and FE alpha(1)-m (P=0.0032) (R(2)=0.63). In 66 patients with NS and normal baseline renal function (MCD 10 patients; FSGS 20 patients; IMN 36 patients), according to values below or above defined cut-offs (IMN, </= or >18 U/g urinary Cr; FSGS and MCD, </= or >24 U/g urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients (P=0.0002) and 77 vs 14% of FSGS patients (P=0.005). Progression to chronic renal failure (CRF) was 0 vs 47% in IMN patients (P=0.001) and 8 vs 57% in FSGS patients (P=0.03). Using Cox model, in IMN patients only NAG excretion (P=0.01, RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients had NAG excretion values below the chosen cut-off, and 90% of them developed remission. Response to immunosuppressive therapy was significantly different in patients with NAG excretion values below or above the cut-offs. Urinary NAG excretion can be considered as a reliable marker of the tubulo-toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion values show a significant relationship with 24-h proteinuria, IgG excretion and FE alpha(1)m. Its determination may be a non-invasive, useful test for the early identification of patients who will subsequently develop CRF or clinical remission and responsiveness to therapy.

AIM: To investigate vascular endothelial growth factor (VEGF) mRNA expression in glomerular disease in the context of heavy proteinuria. METHODS: Non-radioisotopic in situ hybridisation was performed using a cocktail of...

The lack of high-quality clinical evidences hindered broad consensus on optimal therapies for primary nephrotic syndromes. The aim of the present study was to compare prevalence of immunosuppressive drug use in patients with primary nephrotic syndrome across 6 regions in Japan. Between 2009 and 2010, 380 patients with primary nephrotic syndrome in 56 hospitals were enrolled in a prospective cohort study [Japan Nephrotic Syndrome Cohort Study (JNSCS)], including 141, 151, and 38 adult patients with minimal change disease (MCD), membranous nephropathy (MN), and focal segmental glomerulosclerosis (FSGS), respectively. Their clinical characteristics were compared with those of patients registered in a large nationwide registry of kidney biopsies [Japan Renal Biopsy Registry (J-RBR)]. The regional prevalence of use of each immunosuppressive drug was assessed among adult MCD, MN, and FSGS patients who underwent immunosuppressive therapy in the JNSCS (n = 139, 127, and 34, respectively). Predictors of its use were identified using multivariable-adjusted logistic regression models. The clinical characteristics of JNSCS patients were comparable to those of J-RBR patients, suggesting that the JNSCS included the representatives in the J-RBR. The secondary major immunosuppressive drugs were intravenous methylprednisolone [n = 33 (24.6%), 24 (19.7%), and 9 (28.1%) in MCD, MN, and FSGS, respectively] and cyclosporine [n = 25 (18.7%), 62 (50.8%), and 16 (50.0%), respectively]. The region was identified as a significant predictor of use of intravenous methylprednisolone in MCD and MN patients. Use of intravenous methylprednisolone for MCD and MN differed geographically in Japan. Its efficacy should be further evaluated in a well-designed trial.