Deep learning-based framework for the distinction of membranous nephropathy: a new approach through hyperspectral imagery.

BACKGROUND: Common subtypes seen in Chinese patients with membranous nephropathy (MN) include idiopathic membranous nephropathy (IMN) and hepatitis B virus-related membranous nephropathy (HBV-MN). However, the morphologic differences are not visible under the light microscope in certain renal biopsy tissues. METHODS: We propose here a deep learning-based framework for processing hyperspectral images of renal biopsy tissue to define the difference between IMN and HBV-MN based on the component of their immune complex deposition. RESULTS: The proposed framework can achieve an overall accuracy of 95.04% in classification, which also leads to better performance than support vector machine (SVM)-based algorithms. CONCLUSION: IMN and HBV-MN can be correctly separated via the deep learning framework using hyperspectral imagery. Our results suggest the potential of the deep learning algorithm as a new method to aid in the diagnosis of MN.

Membranous nephropathy associated with thrombospondin type-1 domain-containing 7A (THSD7A) in an adult woman with eosinophilia.

A 30-year-old woman on steroid therapy for eosinophilia presented with nephrotic syndrome during steroid tapering. She was diagnosed with membranous nephropathy (MN) stage II-III (positive for IgG1 and IgG4) by renal biopsy. There was no evidence of secondary MN. Her urinary protein level was controlled to 0.5 g/day or less, and her eosinophil count in white blood cell differential was stabilized at less than 10% without increasing the steroid dosage. The renal specimen did not show any enhanced granular expression of PLA2R along the glomerular basement membrane, and PLA2R was not detected in the patient's serum. On retrospective analysis, enhanced granular staining for thrombospondin type-1 domain-containing 7A (THSD7A) in the glomeruli was detected in the biopsy, and anti-THSD7A IgG was detected in the serum using a commercial indirect immunofluorescence test (IFT). Based on these, the case was considered as THSD7A-associated MN with comorbid eosinophilia. The causal relationship between THSD7A-related MN and eosinophilia was unclear. However, a few cases of THSD7A-associated MN with eosinophilia have been reported, and further clarification on the relationship between THSD7A-related MN and eosinophilia is warranted.

Antibody-mediated rejection in the Banff classifications of 2007 and 2017: A comparison of renal graft loss prediction capability.

BACKGROUND: Antibody-mediated rejection (ABMR) is the leading cause of kidney graft loss worldwide. Criteria for acute humoral rejection (currently labeled active humoral rejection) established by the 2007 Banff classification are highly specific but lack sensitivity. Modifications to the Banff classification were introduced for its 2013 and 2017 versions in order to identify more cases of this entity. PURPOSE: We intend to demonstrate that, compared to its 2007 version, the 2017 Banff classification bears an improved capacity for graft loss prediction when histologic criteria for active ABMR are met. PATIENTS AND METHODS: Single-center retrospective cohort study. A random sample of 201 kidney recipients who underwent a graft biopsy since January 2004 was analyzed. Patients were classified as ever developing histologic characteristics of acute ABMR (2007 Banff) or not and renal survival between groups was compared. The same patients were then classified as ever developing histologic characteristics of active ABMR (2017 Banff) or not and renal survival was again compared. Presence of circulating donor-specific antibodies (DSA) was not taken into consideration. RESULTS: Patients were followed for a median 13.9 ±â€¯7.9 years, during which grafts were biopsied on 537 occasions (2.7 ±â€¯1.6 biopsies per graft). Baseline eGFR was 73.26 ±â€¯17.6 ml/min and baseline creatinine 1.14 ±â€¯0.25 mg/dl. Graft loss occurred in 38 recipients (18.9%) mainly due to ABMR (60.5%). Acute ABMR (2007 Banff) was identified in 11 recipients (5.5%) and graft survival did not differ between groups with and without active ABMR occurrence (log-rank p = 0.939). Active ABMR (2017 Banff) was found in 59 recipients (29%) and graft survival was better from the second post-transplant year onward in the group of patients without active ABMR occurrence (log-rank p = 0.001). Moderate microvascular inflammation was present in 89.6% of the 48 additional patients with active ABMR. CONCLUSION: The 2017 Banff classification identifies more patients who develop active ABMR and stratifies graft loss risk better than the 2007 version.

[Membranous nephropathy in a Russian population]. / Membranoznaia nefropatiia v rossiiskoi populiatsii.

AIM: To analyze the clinical and morphological manifestations of membranous nephropathy (MN) and to evaluate the efficiency of its therapy. MATERIAL AND METHODS: MN cases in 2009 to 2016 were retrospectively detected with a subsequent analysis of patients with primary MN (PMN). The titer of IgG-autoantibodies to phospholipase A2 receptor (anti-PLA2R Ab) was determined by an indirect immunofluorescence assay. Treatment outcomes, such as the time course of changes in proteinuria, nephrotic syndrome (NS), and the development of complete and partial remissions (CR and PR), were assessed. RESULTS: MN was detected in 201 cases; the secondary etiology of the disease was established in 24.9%. The prevalence of MN among morphologically confirmed glomerulopathies was 14%; that of PMN was 10.4%. The median period to diagnosis PMN was 8 (5; 19) months. 150 patients with PMN (66.7% were men; age was 50±15 years) were distributed according to the following morphological stages: Stages I (23.9%), II (48.5%), III (26.1%), and IV (1.5%). Elevated anti-PLA2R Ab levels were found in 51.6% of cases; NS in the presence of proteinuria was detected in 85.6% of patients. An estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m2 was seen in 25% of cases. Treatment outcomes were evaluated in 80 cases; the median follow-up period was 19 (8; 40) months. 68% of cases had CR (32%) or PR (36%) with a median follow-up of 26 (13; 44) months. Spontaneous CRs or PRs were observed in 7.5% of the patients. Multivariate analysis showed that the probability of CR or PR increased 3.2-fold in the use of cyclophosphamide and/or cyclosporine and decreased as eGFR dropped. CONCLUSION: In Russia, PMN is a common type of glomerulopathy, the specific features of which should include the low rates of spontaneous remissions and detection of anti-PLA2R Abs. For renal protection, the majority of patients with PMN require timely diagnosis and treatment; individualization of the choice of treatment and its enhanced efficiency call for further investigations.

[Diagnostic value of renal phospholipase A2 receptor and serum anti-phospholipase A2 receptor antibody in membranous nephropathy].

OBJECTIVE: To examine the expression of phospholipase A2 receptor (PLA2R) in renal tissues and the level of anti-PLA2R antibody in serum in patients with idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy (SMN), and to evaluate their diagnostic value in IMN.
 Methods: A total of 73 patients, who were diagnosed between May, 2014 and February, 2015 in the Department of Nephrology of the Second Xiangya Hospital, Central South University, were divided into three groups: an IMN group (n=48), an SMN group (n=17) and a minimal change disease group (n=8) according to the renal biopsy. PLA2R expression in renal tissues and the level of anti-PLA2R antibody in serum were detected by indirect immunofluorescence technique.
 Results: The positive rate and fluorescence intensity for PLA2R in the renal tissues in the IMN group were higher than those in the SMN group (91.7% in the IMN group vs 29.4% in the SMN group, P<0.05), while the positive rate and serum level for anti-PLA2R antibody in the IMN group were higher than those in the SMN group (85.4% in the IMN group vs 29.4% in the SMN group, P<0.05); the expression of PLA2R in renal tissues and the serum level for anti-PLA2R antibody were not detected in the minimal change disease group. The serum level of anti-PLA2R antibody was positively correlated with 24 h urine protein (r=0.432, P<0.01) and negatively correlated with serum albumin (r=-0.307, P<0.05).
 Conclusion: The expression of PLA2R in renal tissues and the serum level of anti-PLA2R antibody might be potential markers for diagnosis of IMN.

Association of podocyte autophagosome numbers with idiopathic membranous nephropathy and secondary membranous nephropathy.

PURPOSE: This study was to investigate the relation between the number of autophagosomes in podocytes and the syndromes of idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy (sMN). METHODS: The pathological changes in the kidney tissues of patients were detected with the hematoxylin and eosin staining, the periodic acid-Schiff reagent treatment, the Masson's trichrome staining and the immunofluorescence detection (IF). Meanwhile, the autophagosomes in podocyte were analyzed by transmission electron microscopy and the IF assay pointing to LC3-II, an autophagic marker. Clinical data, including age, sex, edema, serum creatinine, estimated glomerular filtration rate, hematuria, urine protein excretion and serum albumin, were collected from in-patient medical records. Finally, the association of podocyte autophagosome numbers with idiopathic membranous nephropathy and secondary membranous nephropathy was studied. RESULTS: Fewer autophagosomes were observed in podocytes of nephropathy group compared with the control group. Moreover, there was a significant difference in the autophagosome number between the two types of MN and each kind of nephropathy demonstrated distinct characteristics. Although the reduced autophagosome number in the IMN cases was not related to sex, this trend was exacerbated along with the progression from pathological stage I to II. In contrast, fewer autophagosomes were observed in class II and V LN patients compared with the controls, while greater numbers were detected in class III and IV LN patients. CONCLUSIONS: The results indicated that the autophagy participated in the podocyte injury in IMN and sMN and the number of autophagosomes in podocytes was related to the pathological classification.

[Anti-NEP and anti-PLA2R antibodies in membranous nephropathy: an update]. / Anticorps anti-EPN et anti-PLA2R dans les glomerulopathies extramembraneuses: le point en 2014.

Membranous nephropathy (MN) is the most common cause for nephrotic syndrome in adults and occurs as an idiopathic (primary) or secondary disease. Since the early 2000's, substantial advances have been made in the understanding of the molecular bases of MN. The neutral endopeptidase (NEP) and the receptor for secretory phospholipase A2 (PLA2R) have been identified as target antigens for circulating and deposited antibodies in allo-immune neonatal and adult " idiopathic " MN, respectively. These antibodies recognize specific antigens of podocytes, precipitate as subepithelial immune complexes and activate complement leading to proteinuria. Anti-PLA2R antibodies are of particular clinical importance. Indeed, they are detected in approximately 70% of primary MN in adults, demonstrating that MN actually is an autoimmune condition specific to the kidney. In Europeans, genome-wide studies have shown an association between alleles of PLA2R1 and HLA DQA1 (class II genes of tissue histocompatibility complex) genes and idiopathic MN. Newly developed diagnostic tests detecting circulating anti-PLA2R antibody and PLA2R antigen in glomerular deposits have induced a change in paradigm in the diagnostic approach of idiopathic MN. Measurement of circulating anti-PLA2R antibody is also very useful for the monitoring of MN activity. However, the mechanisms responsible for the formation of anti-PLA2R antibodies as well as those involved in the progression of MN to end-stage renal disease remain to be defined.

Membranous-like glomerulopathy with masked IgG kappa deposits.

The diagnostic classification of glomerulonephritis is determined by the interplay of changes seen using light, immunofluorescence, and electron microscopy of the renal biopsy. Routine direct immunofluorescence on fresh tissue is currently considered the gold standard for the detection and characterization of immune deposits. We recently found a peculiar form of glomerular immune complex deposition in which masked deposits required an antigen-retrieval step to be visualized. Over a 2-year period, 14 cases were characterized by numerous, large subepithelial deposits visualized by electron microscopy and C3-predominant staining by routine immunofluorescence on fresh tissue with weak to negative immunoglobulin staining. Repeat immunofluorescence after digestion of the formalin-fixed paraffin-embedded tissue with pronase elicited strong IgG-κ staining restricted within the deposits. The patients were often young with a mean age of 26 years and commonly had clinical evidence of vague autoimmune phenomenon. The clinicopathologic findings in this unusual form of glomerulopathy do not fit neatly into any currently existing diagnostic category. We have termed this unique form of glomerulopathy membranous-like glomerulopathy with masked IgG-κ deposits.

Study of nephrotic syndrome in children: importance of light, immunoflourescence and electron microscopic observations to a correct classification of glomerulopathies.

OBJECTIVE: To evaluate the contribution of electron microscopy (EM) to the accurate diagnosis of glomerulopathies in childhood nephrotic syndrome (NS) in a developing country. METHODS: The study was carried out at the Histopathology Department, Sindh Institute of Urology and Transplantation (SIUT) from April 2007 to March 2008. All children (≤18 years) presenting with NS were included. Patients' demographic, clinical, laboratory, and biopsy data were retrieved from case records and biopsy reports. Renal biopsies were studied by light microscopy, immunoflourescence, and EM. RESULTS: The mean age of 74 children was 11.34, 4.85 years, EM was useful in 97.2% of cases, being essential in 31% and helpful in 66.2% cases. CONCLUSION: The results demonstrate that the ultrastructural study is both helpful and essential to a correct classification of glomerular diseases underlying NS in children in nearly all cases and whenever feasible this should be used in the pathologic evaluation of renal biopsies.

Membranous (class V) renal disease in systemic lupus erythematosus may be more common than previously reported: results of a 6-year retrospective analysis.

BACKGROUND: The actual incidence and prevalence of the various histological classes (based on World Health Organization classification) of lupus nephritis (LN) are not known but seem to vary with sex, age, and ethnicity. We have analyzed renal biopsies in patients with systemic lupus erythematosus (SLE) at our center, and hereby report our experience. METHODS: All renal biopsies performed at the University of Mississippi between January 1999 and December 2004 in patients with SLE were retrospectively analyzed. Results were validated by a detailed review of renal biopsy reports and additional records were reviewed for data specific to LN disease activity. RESULTS: There were 92 renal biopsies performed in patients with SLE during a 6-year period. These included 84 African Americans (72 women and 12 men), 5 whites (4 women and 1 man), and 3 unknown race (1 F, 2 M) subjects. The prevalence of LN classes in our cohort was as follows: class I (0%), class II (9.8%), class III (8.7%), class IV (36.9%), class V (40.2%), and class VI (4.3%). Prevalence of class V LN among males was high at 40%. CONCLUSION: In contrast to previous literature, isolated membranous lupus nephritis (MLN) was much more prevalent in this series-40% versus 14%. Also, no sex difference in the prevalence of MLN was seen. This biopsy cohort suggests that MLN/class V disease may be more common than previously reported especially in African American population.

Mycophenolate mofetil as the primary treatment of membranous lupus nephritis with and without concurrent proliferative disease: a retrospective study of 29 cases.

Studies of immunosuppressive therapy, particularly mycophenolate mofetil (MMF), in membranous lupus nephritis (MLN) are limited. We report on our experience with primary (first-line) MMF therapy to induce and sustain renal remission in MLN with and without a concurrent proliferative lesion. Systemic lupus erythematosus (SLE) patients were studied, retrospectively, if treated with MMF for newly diagnosed MLN. Complete remission was defined as proteinuria less than 0.5 g/24 h, inactive urine sediment and normal estimated glomerular filtration rate. Response in pure MLN (Group I, n=10) was compared with mixed MLN and proliferative lupus nephritis (Group II, n=19). By 12 months, 4 (40%) patients in Group I and 7 (36.8%) in Group II achieved complete remission (P=0.87). One (10%) patient in Group I and 2 (10.5%) in Group II had worsening renal disease (P=0.97). Mean time to remission was more than seven months in both groups. The remaining patients had stable disease without improvement or worsening. Only 2 of 11 achieving initial remission had a relapse with an average of 28 months of follow-up after remission. Self-limited gastrointestinal symptoms occurred in 12 patients, none requiring withdrawal of the drug. Mycophenolate mofetil as a primary therapy in MLN was successful in inducing complete remission in about 40% of MLN, particularly in patients with mild proteinuria. However, 12 months of therapy was necessary for best outcomes. Response rate was not different in the presence or absence of a proliferative lesion.

Idiopathic membranous nephropathy in children.

Idiopathic membranous nephropathy (MN) is a rare cause of asymptomatic proteinuria (AP) or nephrotic syndrome (NS) in childhood. To improve our understanding of its clinical course, we retrospectively reviewed 19 cases of idiopathic MN seen in our hospital over a period of 28.5 years, i.e., from January 1977 to July 2005. Eight patients (39%) had AP and 11 (61%) presented with NS. All eight AP patients achieved remission, regardless of treatment modality. Oral corticosteroid was given to all 11 NS patients, but only three of them responded to corticosteroid. Of the eight steroid non-responders, three achieved remissions with the addition of cyclosporine, and the five who were not administered additional immunosuppressive drugs had persistent NS. At the latest evaluation, all six NS patients that achieved remission remained free of proteinuria and had a normal renal function. Moreover, two of the 5 steroid non-responders showed persistent nephrotic-range proteinuria but a stable renal function. The remaining three steroid non-responders progressed into chronic renal insufficiency, and this progression was preceded by renal vein thrombosis (RVT) in two of the three patients. Presentation with NS (P=0.045) and the development of RVT (P=0.010) were identified as poor prognostic factors.

Segmental membranous glomerulonephritis in children: comparison with global membranous glomerulonephritis.

Generally, idiopathic membranous glomerulonephritis (MGN) is a global glomerular disease that affects the whole of the glomerulus. However, idiopathic segmental MGN (SMGN) that shows IgG deposits in a portion of the glomerulus is encountered often. For clarification of whether SMGN is the same entity as idiopathic global MGN (GMGN), the two diseases were compared. From 1978 to 2004, 38 children (11 with SMGN and 27 with GMGN) received a diagnosis of idiopathic MGN. Immunofluorescence microscopy showed segmental granular IgG staining along the capillary loops in SMGN, whereas GMGN showed global staining. On light microscopy, SMGN showed segmental thickening of the glomerular basement membrane, with spike formation, whereas GMGN showed global lesions. The frequency of C1q deposits in SMGN was significantly higher than that in GMGN (91 versus 41%; P < 0.01). On electron microscopy, mesangial electron-dense deposits were detected in 10 (91%) cases of SMGN and also were found in the subepithelial and intramembranous area, whereas only six (22%) cases of GMGN had mesangial electron-dense deposits (P < 0.001). There were no significant differences in clinical features between the groups. Two children with SMGN underwent a repeat biopsy 3 yr after the first biopsy, and both patients again showed SMGN. At the final observation (mean observation time 7.5 yr in SMGN and 12.4 yr in GMGN), all children of both groups had a good outcome. In conclusion, these findings as a whole suggest that SMGN may be another glomerular disease entity with child predominance that is distinctive from GMGN.

[Membranous nephropathy].

Membranous nephropathy (MN) is a frequent cause of nephrotic syndrome in adults. A considerable diversity of prognosis is seen with idiopathic MN. We overview the recent progress of clinicopathological research, especially the initial factors affecting the longterm outcome of idiopathic MN. We studied retrospectively 105 patients with idiopathic MN and could assign the patients to two different groups based on the electron microscopic (EM) findings. In the homogeneous type only one patient developed end-stage renal failure, and earlier remission occurred in this group. With regard to secondary outcome, increased age, focal segmental glomerular sclerosis, arteriolosclerosis, heterogeneous type of EM findings were independent risk factors. Our results suggest that a new EM classification at initial biopsy is an independent indicator of prognosis in human idiopathic MN.

Class V lupus nephritis: a clinicopathologic study in 152 patients.

BACKGROUND: Class V lupus nephritis (LN) can be divided into two subgroups according to the 1995 WHO modified classification, but the difference in clinical characteristics between these subgroups is not well known. METHODS: We classified 152 patients with Class V LN, confirmed by renal biopsy, into two subgroups (61 Class Va, 91 Class Vb), and enrolled 488 patients with Class IV as controls. The clinical manifestations, serologic results and prognosis were compared for Classes Va and Vb. RESULTS: The incidence of hypertension and anemia in Class Vb patients was significantly higher than in Class Va (38.5% vs 21.3%, 72.5% vs 52.5%, p<0.05). The incidence of hematuria and renal insufficiency in Class Vb was 64.8%and 15.4%, which was higher than Class Va (44.2% and 3.3%), but lower than Class IV (89.1% and 35%), p<0.05. The percentage of patients with positive anti-dsDNA antibody and hypocomplementemia in Class Vb tended to be higher than Class Va (35.2% vs 26.2%, 50.6% vs 31.2%). Repeated renal biopsies in 24 patients (11 Class Va, 13 Class Vb) showed that eight Class Vb patients had "transformed" to Class IV LN, while only two Class Va patients did (p<0.05). In three Class Va patients serum creatinine doubled during follow-up, but none of them progressed to end-stage renal disease (ESRD). In Class Vb serum creatinine doubled in ten patients, and three progressed to ESRD. CONCLUSIONS: The renal injury and extrarenal manifestations of Class Vb patients were severer than Class Va. Class Vb patients were more likely to shift to Class IV LN, and the prognosis was poorer than for Class Va.

Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis.

BACKGROUND: Patients with systemic lupus erythematosus have a spectrum of glomerular disease, but the different patterns of glomerular injury identified within the general category of "severe" lupus glomerulonephritis are responsible for much of the morbidity and mortality in this disease. The glomerular injury patterns seen with severe lupus glomerulonephritis have been separated into distinct histopathologic groups to determine whether they can predict long-term patient outcome. METHODS: We analyzed the clinical follow-up of 85 patients participating in a controlled prospective therapeutic trial for the treatment of severe lupus glomerulonephritis conducted from April 1981 to December 1988, with an average follow-up of 10 years. Patients were classified according to the 1982 World Health Organization classification for lupus glomerulonephritis. RESULTS: During the course of follow-up [120 +/- 65 (SD) months], 60% of patients with category IV (diffuse proliferative glomerulonephritis) lesions entered a remission compared with only 38% of patients with category III (> or =50%, focal and segmental glomerulonephritis) lesions and 27% of patients with category Vc (> or =50%) and Vd (P < 0.05). Renal survival at 10 years was 75% for those with category IV lesions, 47% for patients with category Vc (> or =50%) and Vd, and 52% for patients with category III (> or =50%) lesions (P < 0.05). Based on multivariate analysis, patients with category III (> or =50%) or Vc (> or =50%) and Vd lesions had a relative risk of progression to end-stage renal disease 2.9 times that of category IV patients (P < 0.01), while the likelihood of entering a remission was 8.2 times greater for category IV patients (P = 0.0001). CONCLUSION: The histopathologic categorization among patients with severe lupus glomerulonephritis provides information relevant to their long-term outcome.

Treatment and long-term follow-up of patients with stage II to III idiopathic membranous nephropathy.

Many important aspects of the therapeutic approach to patients with idiopathic membranous nephropathy are still controversial. There are several reports that the effectiveness of therapy depends on histological staging and severity of interstitial mononuclear cell infiltration. We used several different treatments in 39 patients with stage II to III primary membranous nephropathy with proteinuria more than 2.5 g/d, without hypertension and chronic renal failure at biopsy. Ten patients were not treated, 13 were treated with only steroids, 13 with alternate use of steroids and chlorambucil, and three with cyclosporine A. The follow-up period was 5 to 10 years. Statistics included Kruskall-Wallis and one-way ANOVA analysis. A significant decrease in proteinuria was noted in patients treated with steroids (P < 0.01), from 8.45 +/- 1.04 g/d (mean +/- SEM) to 1. 42 +/- 0.45 g/d after follow-up of 5 years and in patients treated with steroids and chlorambucil (12.9 +/- 2.4 g/d [mean +/- SEM] to 2. 46 +/- 1.38 g/d). Compared with patients treated with steroids (15. 3%) and patients treated with steroids and chlorambucil (15.3%), untreated patients had a high frequency of chronic renal failure after 5 years of follow-up (70%) and had a significant increase in mean serum creatinine (P = 0.008). We conclude that steroid therapy alone, or associated with chlorambucil, is effective in patients with stage II to III membranous nephropathy. Patients responded with a decrease of proteinuria and stable renal function during the long-term follow-up period. The group of patients treated with cyclosporine A was too small to analyze.