Automatic classification of immune-mediated glomerular diseases based on multi-modal multi-instance learning

Histologic classification of glomerular diseases: clinicopathologic correlations, limitations exposed by validation studies, and suggestions for modification

B-cell oligoclonal expansions in renal tissue of patients with immune-mediated glomerular disease

Advances in Understanding of Pathogenesis and Treatment of Immune-Mediated Kidney Disease: A Review

Targeted therapy in glomerular diseases

Background: The presence of tubuloreticular inclusions (TRIs) in endothelial cells (ECs) always evokes suspicion of an association with underlying viral infections or autoimmune diseases. However, other underlying diseases can be associated with TRI expression. Since identification of the underlying disease is of primary consideration for management of glomerulonephritis (GN), it is important to clarify the clinical significance of TRI expression.Methods: The authors studied 104 renal biopsy cases having TRI. They investigated their clinicopathological profiles and focused on potential connections with underlying diseases.Results: Among 104 renal biopsy cases, 62 cases (59.6%) were associated with lupus nephritis (LN) and 20 cases (19.2%) were associated with a viral infection (hepatitis B virus (13), hepatits C virus (4), and human immunodeficiency virus (3)). Other underlying disease groups included membranous GN (MGN) (7), IgA nephropathy (7), Henoch-Schoenlein purpura (HSP) nephritis (2), and others (6). The incidence of TRIs in both LN and viral infections was significantly higher than for other diseases (p < 0.0001). Among 7 MGN cases, 2 cases were diabetes, 1 case was associated with lung cancer, another case with antineutrophilic cytoplasmic antibody (ANCA), and the others showed no evidence of systemic disease. On immunofluorescence (IF) study, 2 MGN cases, 2 IgA nephropathy cases, and 1 HSP nephritis case showed C1q deposition, with no evidence of SLE.Conclusions: TRIs were identified in MGN and other glomerular diseases, including IgA nephropathy and HSP nephritis. However, a diagnosis of LN should be considered because TRIs associated with a full-house IF pattern are usually found in LN.

Outcomes-based research rarely focuses on patients with ESRD caused by GN. The hypotheses were that the GN subtype would clinically discriminate patient groups and independently associate with survival after ESRD therapy initiation. Data were extracted from the US Renal Data System for adult patients with incident (1996-2011) ESRD attributed to six GN subtypes: FSGS, IgA nephropathy (IgAN), membranous nephropathy, membranoproliferative glomeruonephritis, lupus nephritis (LN), and vasculitis. ESRD attributed to diabetes and autosomal dominant polycystic kidney disease served as non-GN comparators. Unadjusted and adjusted mortality hazard ratios (aHRs) with 95% confidence intervals (95% CIs) were estimated using Cox regression (reference, IgAN). Models sequentially adjusted for sociodemographic (model 2), comorbidity/laboratory (model 3), and ESRD treatment modality (model 4) variables. Among 84,301 patients with ESRD attributed to GN, the median age ranged from 39 (LN) to 66 (vasculitis) years, male sex ranged from 18% (LN) to 68% (IgAN), and black race ranged from 7% (IgAN) to 49% (LN). Patients with IgAN had the fewest comorbidities and lowest use of hemodialysis (70.1%). After a median follow-up of 2.5 (interquartile range, 1.0-4.9) years, crude mortality was lowest in IgAN (3.7 deaths/100 person years). Compared to IgAN, adjusted mortality was highest in LN (model 4 aHR=1.75; 95% CI, 1.68 to 1.83) and in diabetes (aHR=1.73; 95% CI, 1.67 to 1.79), and was also higher in all other GN subtypes (membranous nephropathy: aHR=1.23; 95% CI, 1.17 to 1.29; FSGS: aHR=1.37; 95% CI, 1.32 to 1.42; membranoproliferative GN: aHR=1.38; 95% CI, 1.31 to 1.45; vasculitis: aHR=1.51; 95% CI, 1.45 to 1.58) and in autosomal dominant polycystic kidney disease (aHR=1.22; 95% CI, 1.18 to 1.27). This study exposes substantial heterogeneity across GN subtypes at ESRD therapy initiation and identifies independent associations between GN subtype and post-ESRD mortality. These survival discrepancies warrant further study, and the utility of current research practice to group GN subtypes together when evaluating ESRD outcomes should be questioned.

Microstructural information acquired from image analysis can be used in cell modeling. In order to obtain more precise Solid Oxide Fuel Cell (SOFC) microstructure parameters, an adaptive fuzzy approach is developed for three-phase identification of YSZ/Ni anode Optical Microscopic (OM) images. A new quantum-inspired clique potential Markov random field (MRF) function is proposed to considerate spatial information in fuzzy logic model, where the space distance based weight is introduced to reflect the influence of neighborhood pixels. Simulated images and real SOFC anode OM images are used to compare the effectiveness and practicability of the proposed algorithm with others. Experiment results demonstrate that the proposed methods can accurately separate there-phase of SOFC OM images, which lays the foundation of subsequent microstructural parameters extracting.

C4d is a well-known biomarker of the complement cascade. It is derived from cleavage of the labile thioester bond of C4b. This was a retrospective and prospective cross-sectional study, done at our tertiary care hospital. Methods: We evaluated 50 cases and 10 controls to adjudge the significance of C4d deposits in native renal diseases. Majority of the patients (44%) were in the age group of 10-20 years followed by 20% in the age group of 31-40 years. 62% of study population were male. Results: Majority of patients were diagnosed with FSGS (16%), followed by membranous nephropathy (14%), Lupus nephropathy (14%) and IgA nephropathy (12%). All patients diagnosed with Membranous nephropathy, IgA nephropathy and hypertensive nephropathy showed glomerular C4d deposits. All patients diagnosed with IgA Nephropathy, post infectious glomerulonephritis, Lupus Nephritis, minimal change disease, acute/ chronic tubulointerstitial nephritis, diabetic nephropathy, hypertensive nephropathy showed tubular C4d deposits. All patients diagnosed with Diabetic nephropathy and hypertensive nephropathy showed arterial C4d deposits. There was correlation of intensity expression of glomerular C4d deposits with presenting 24 hours urinary protein level at the time of biopsy ( p value=0.027) but no correlation with urea/creatinine. There was significant association (p value 0.019) of tubular C4d positivity with 24 hour protein at the time of biopsy. Tubular C4d deposits showed no significant presenting serum urea and creatinine at the time of biopsy. Conclusion: There was also no correlation noted between presenting 24 hours urinary protein and serum urea and creatinine levels with arterial C4d deposit in diabetic and hypertensive nephropathy patients.

SAT-366 RITUXIMAB IN IMMUNE-MEDIATED GLOMERULAR DISEASE

Acquired glomerular lesions in patients with Down syndrome

BACKGROUND AND AIMS Although C1q nephropathy (C1QN) was introduced three decades ago, the clinical significance and renal outcomes of C1QN remain unclear. Furthermore, it is uncertain whether the diagnosis of C1QN could be a new pathologic entity with clinical meanings. This study aimed to compare the clinical characteristics of the GN reclassified into C1QN based on the criteria described by Jennette and Falk (Pediatr Nephrol 2010: 25: 1385–1396) and corresponding GN not included in C1QN. METHOD We enrolled 21 212 patients with native kidney biopsy between 1979 and 2018 from 18 hospitals throughout Korea, retrospectively. We primarily adopted the findings and diagnosis by the pathologist in each hospital and then reclassified into C1q nephropathy (C1QN) on the basis of the criteria as follows: (i) presence of ≥ 2 + C1q in the mesangium on immunofluorescence (IF), (ii) corresponding mesangial or para-mesangial electron dense deposits on electron microscopy (EM), and (iii) lack of clinical and pathological evidence of systemic lupus erythematosus. Among 21212 patients, 77 patients were selected as C1QN with the criteria; however, six patients were excluded because of presence of primary diseases, such as renal amyloidosis, Henoch-Schölein Nephritis and systemic vasculitis, and myeloma cast nephropathy. The data of final outcomes, incidences of end-stage renal disease (ESRD) and death, were gathered from each hospital’s data registry, from the ESRD registry of the Korean Society of Nephrology, and from the Statistics of Korea, and were merged based on the identifier of Koreans. The follow-up duration for ESRD was 69.1 ± 67.8 months and, for mortality, 77.9 ± 65.5 months. RESULTS There were pathologic findings of 71 patients reclassified into C1QN including 41 (57.7%) males. Mean age of patients were 42.9 ± 18.9 years. There were 9 (12.7%) patients with DM and 39 (54.9%) hypertensive patients. The levels of creatinine, eGFR, and UPCR were 1.24 ± 0.92 mg/dL, 84 ± 43 mL/min/1.73 m2 and 2.58 ± 2.80 g/g creatinine, respectively. There were 22 (31.0%) patients with eGFR &amp;lt; 60 mL/min/1.73 m2 and 22 (31.0%) patients with UPCR ≥ 3.5 g/g creatinine. There were various pathologic diagnoses classified into C1QN, such as, original C1QN (21), IgA nephropathy (IGAN) (21), membranous nephropathies (MN) (11), focal segmental glomerulosclerosis (7), mesangial glomerulopathy (6), diabetic nephropathy (3), minimal change lesion (1), and acute tubulointerstitial nephritis (1). We compared the characteristics among the pathologic finding classified into C1QN, the pathologic finding without C1q stain, and the pathologic finding with non-dominant C1q stain which did not fulfill the criteria of C1QN. The identified GNs, which included enough number of patients to compare, were FSGS, IGAN and MN. Some differences of clinico-pathologic findings and incidence of ESRD were not evident after re-analysis with groups matched age and gender with 1:3 manner between the GN re-categorized into C1QN and the corresponding GN without C1q staining. The only difference was lesser amount of proteinuria in MN patients re-classified into C1QN compared with MN patients without C1q staining. Immunoglobulins showed higher intensity in IF staining of C1QN compared with non-C1QN of the corresponding GN. Intensity of C3 was also higher in IGAN and MN re-categorized into C1QN compared with the corresponding IGAN and MN not included in C1QN, respectively. CONCLUSION Reclassification into C1QN with the pre-defined criteria did not indicate a different clinico-pathologic identity based on comparison with the original diagnosis of GN. Activation of C1q, presumed activation of classical complement pathway in kidney tissues, in so-called C1QN could not be classified into new disease entity. Further studies on this topic are needed.

Inverse dynamical photon scattering (IDPS), an artificial neural network based algorithm for three-dimensional quantitative imaging in optical microscopy, is introduced. Because the inverse problem entails numerical minimization of an explicit error metric, it becomes possible to freely choose a more robust metric, to introduce regularization of the solution, and to retrieve unknown experimental settings or microscope values, while the starting guess is simply set to zero. The regularization is accomplished through an alternate directions augmented Lagrangian approach, implemented on a graphics processing unit. These improvements are demonstrated on open source experimental data, retrieving three-dimensional amplitude and phase for a thick specimen.

Background and Aims Membranous nephropathy, focal segmental glomerulosclerosis (FSGS) and IgA nephropathy are the most frequent types of primary glomerulonephrites in the adulthood. Glomerulonephritides may progress into end-stage renal disease despite appropriate treatment. Both the manifestations of the glomerulonephritides and medications for treatment might yield cardiovascular events such as venous thromboembolism, coronary artery disease and stroke. The purpose of this study is to compare three different types of primary glomerulonephritides in terms of all-cause mortality, kidney-related and cardiovascular outcomes. Method All patients who underwent kidney biopsy between 01.01.2000 and 01.06.2022 in Hacettepe University Hospital were screened and cases with primary glomerulonephritis and follow-up data were enrolled. Data regarding baseline demographics, laboratory and kidney pathology reports and outcomes were obtained. The primary end-point was defined as all-cause mortality. Kidney related and cardiovascular outcomes were determined as secondary end-points. Results population was 39 (18-81) years. Membranous nephropathy was present in 36.5% (n = 172), focal segmental glomerulosclerosis was present in 25.9% (n = 122) and IgA nephropathy was present in 37.6% (n = 177) of the cases. Age (p &amp;lt; 0.001), frequency of diabetes (p = 0.004) and smoking history (p = 0.020) were significantly higher in patients with membranous nephropathy than both FSGS and IgA nephropathy. Serum albumin levels were lower (p &amp;lt; 0.001), while total cholesterol (p &amp;lt; 0.001), LDL cholesterol (p &amp;lt; 0.001) and proteinuria levels (p &amp;lt; 0.001) were higher both in patients with membranous nephropathy than the other two groups and in patients with FSGS than IgA nephropathy. Median duration of follow-up was 120.2 (1.7-273.3) months (Table 1). All-cause mortality rate was significantly higher in patients with membranous nephropathy than the other two groups (p = 0.005); however the type of glomerulonephritides was not found to be related to all-cause mortality (HR: 1.07; 95% CI: 0.65-1.77; p = 0.770). Age (HR: 1.079; 95% CI: 1.05-1.10; p &amp;lt; 0.001), serum creatinine (HR: 1.35; 95% CI: 1.10-1.66; p = 0.003) and serum albumin (HR: 0.60; 95% CI: 0.38-0.95; p = 0.030) levels were found to be associated with all-cause mortality in patients with primary glomerulonephritides. The rates of ischemic stroke, atrial fibrillation and steroid induced diabetes were similar between all of the glomerulonephritides subgroups. Acute coronary syndrome (p = 0.015), coronary revascularization (p = 0.021) and venous thromboembolic events were more frequent in patients with membranous nephropathy than IgA nephropathy. There was no difference in terms of cardiovascular outcomes between the patients with FSGS and IgA nephropathy (Table 1). Although the remission rate was significantly higher in patients with membranous nephropathy than the other two groups (p &amp;lt; 0.001); there was not a distinct difference in relapse rates. Progression to end-stage renal disease was prominently lower in patients with membranous nephropathy than the other groups (p = 0.003) and loss of glomerular filtration rate per year was significantly higher in cases with FSGS compared to other groups (p = 0.021). Conclusion All-cause mortality risk was higher in patients with membranous nephropathy because of higher age at diagnosis and accompanying higher burden of comorbidities including diabetes and dyslipidemia. FSGS had a worse prognosis in terms of kidney related outcomes compared to other glomerulonephritides due to higher loss of glomerular filtration rate per year and increased rates of progression to end-stage renal disease. Intensive cardiovascular risk reduction strategies should be applied especially in patients with membranous nephropathy due to increased mortality rates.

The management of steroid-resistant glomerulopathies remains a clinical problem. In this trial, we report a clinical observation of 43 patients treated with mycophenolate mofetil (MMF) for steroid-resistant glomerulopathies. All patients underwent renal biopsies, and immunofluorescence and light microscopy examinations were conducted in all cases. All patients had been treated with prednisone at a dose of 1 mg/kg per day for at least 8 weeks. Of the 43 patients, 16 were treated with cyclophosphamide and five were treated with cyclosporine A before MMF started. The primary study outcomes were the change in the urinary protein excretion, serum creatinine, comparing the levels at the start of MMF treatment with those at the end of the MMF treatment period. Changes in renal function were also estimated with Modification of Diet in Renal Failure calculation. Wilcoxon signed-ranks test was used as appropriate to compare data from the start with data at the end of the treatment period. The primary glomerular diseases represented included membranoproliferative glomerulonephritis in 23.2%, membranous glomerulonephritis in 18.6%, IgA nephropathy in 13.9%, focal segmental glomerulosclerosis in 9.3%, lupus nephritis (systemic lupus erythematosus) in 25.6% and pauci-immune glomerulopathy in 9.3% of patients. The mean follow-up time was 28.9+/-12 months. Before MMF treatment, 16 patients (37%) had nephrotic range proteinuria and 11 (26%) had renal insufficiency. The urinary protein before MMF treatment was 3.3+/-2.6 g/dL (0.6-9.6) and decreased significantly to 0.87+/-1.1 g/dL (0-5.5) at the end of the MMF treatment period (P=0.02). During treatment, complete remission was seen in 27 patients, partial remission in 10 patients and MMF failure in six patients. The serum creatinine level decreased significantly from 1.29+/-0.55 mg/dL (0.6-3.0) to 1.14+/-0.38 mg/dL (0.5-2.4) post MMF therapy (P=0.046). Using the four-variable Modification of Diet in Renal Failure formula, the glomerular filtration rate increased from 71.5+/-28 mL/min per 1.73 m2 to 78.1+/-27 mL/min per 1.73 m2 (P=0.021). Renal insufficiency resolved in seven of the 11 (63.6%) patients with renal insufficiency initially, two with membranoproliferative glomerulonephritis, two with membranous glomerulonephritis, one with focal segmental glomerulosclerosis, four with pauci-immune glomerulopathy, two with systemic lupus erythematosus nephritis, and in two patients de novo renal insufficiency developed. In general, MMF was well tolerated, and most of the patients achieved remission and improvement of renal functions. MMF treatment appeared to offer benefits to problematic patients refractory to conventional therapies for glomerulopathies.

Since the introduction of the SLICC criteria in 2012, biopsy-proven lupus nephritis (LN) has been the only independent diagnostic criterion for systemic lupus erythematosus (SLE). This was reaffirmed by the EULAR/ACR in 2019, emphasizing the importance of renal biopsy in LN. However, the current classification lacks specific histopathological criteria for defining LN. This study describes the histological findings of patients with LN, compares them with those of other glomerular diseases, and evaluates their diagnostic accuracy in a large Latin American population. This retrospective cohort included 731 kidney biopsies from two distinct academic centers. The patients were divided into two groups as follows: a LN group and a control group comprising patients with membranous nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, pauci-immune glomerulonephritis, and proliferative glomerulonephritis. Sensitivity and specificity analyses were conducted for various histopathological features. We identified the following five features strongly correlated with LN: mesangial proliferation, subendothelial deposits, C1q staining ≥1+, dominant IgG, and ≥4 positive immunofluorescence elements. Combined, these features yielded an area under the ROC curve of 0.94 (95% CI: 0.91-0.95). These results were validated in a diverse population. In membranous nephropathy, histological features such as mesangial deposits, C1q positivity, and ≥4 positive immunofluorescence elements effectively distinguished class V LN from non-lupus membranous nephropathy, with an area under the ROC curve of 0.85 (95% CI: 0.76-0.93). The combination of mesangial proliferation, subendothelial deposits, C1q staining ≥1+, dominant IgG, and ≥4 positive immunofluorescence elements offer good accuracy for diagnosing renal involvement in SLE in a large Latin American population. In the absence of pathognomonic features, combined criteria are valuable diagnostic tools, particularly when other SLE criteria are lacking.