Electron-dense Deposits Research Articles

Immunoglobulin A-dominant membranoproliferative glomerulonephritis-like pattern of injury as a possible paraneoplastic nephropathy in a breast cancer patient.

A middle-aged woman was found to have proteinuria during a health check-up. About sixteen months later, she was diagnosed with stage IIA invasive ductal carcinoma of the right breast. Her proteinuria progressed to nephrotic syndrome with significant hematuria. Hormone therapy was initiated for her estrogen and progesterone receptor-positive breast cancer. A kidney biopsy performed 47days after starting the therapy revealed an IgA-dominant membranoproliferative glomerulonephritis-like pattern of injury. Electron microscopy showed subendothelial-dominant electron-dense deposits (EDD), with small amounts of mesangial EDD and a single occurrence of subepithelial hump-like EDD, along with occasional mesangial interpositions. Similar pathology can be caused by IgA vasculitis with nephritis, IgA-dominant infection-associated glomerulonephritis, and liver disease-associated glomerulopathy, but all of these were ruled out. The deposited IgA was found to be galactose-deficient IgA1. Thus, IgA nephropathy with glomerular capillary IgA deposition was considered. She underwent a right partial mastectomy and sentinel lymph node biopsy in the right axilla 75days after starting hormone therapy, followed by adjuvant radiation. Proteinuria and hematuria tended to decrease after the treatment, and this trend continued even after corticosteroid therapy for glomerulonephritis, which was administered 156days after starting hormone therapy. Approximately 15months after starting hormone therapy, her proteinuria had reduced to around 1.0g/g of creatinine, and her hematuria was negative. IgA nephropathy with glomerular capillary IgA deposition is known to be resistant to corticosteroid therapy. The favorable clinical course of the rare glomerulopathy following breast cancer treatment suggested a diagnosis of paraneoplastic glomerulopathy secondary to breast cancer in our patient.

Metallic and metallic oxide nanoparticles toxicity primarily targets the mitochondria of hepatocytes and renal cells.

Nanoparticles (NPs) are utilized in various applications, posing potential risks to human health, tissues, cells, and macromolecules. This study aimed to investigate the ultrastructural alterations in hepatocytes and renal tubular cells induced by metallic and metal oxide NPs. Adult healthy male Wistar albino rats (Rattus norvegicus) were divided into 6 (n = 7) control and 6 treated groups (n = 7). The rats in the treated groups exposed daily to silver NPs, gold NPs, zinc oxide NPs, silicon dioxide NPs, copper oxide NPs, and ferric oxide NPs for 35 days. The members of the control group for each corresponding NPs received the respective vehicle. Liver and kidney tissue blocks from all rats were processed for Transmission Electron Microscopy (TEM) examinations. The hepatocytes and renal tubular cells of all NPs-treated rats demonstrated mitochondrial ultrastructural alterations mainly cristolysis, swelling, membrane disruption, lucent matrices, matrices lysis, and electron-dense deposits. However, other organelles demonstrated injury but to a lesser extent in the form of shrunken nuclei, nuclear membrane indentation, endoplasmic reticulum fragmentation, cellular membranes enfolding, brush border microvilli disruption, lysosomal hyperplasia, ribosomes dropping, and peroxisome formation. One may conclude from the findings that the hepatocytes and the renal tubular cells mitochondria are the main targets for nanoparticles toxicity ending in mitochondrial disruption and cell injury. Further studies taking into account the relation of mitochondrial ultrastructural damage with a weakened antioxidant defense system induced by chronic exposure to nanomaterials are needed.

Contribution of collagen-binding protein Cnm of Streptococcus mutans to induced IgA nephropathy-like nephritis in rats

IgA nephropathy (IgAN), the most common primary glomerulonephritis, is considered an intractable disease with unknown pathogenic factors. In our previous study, Streptococcus mutans, the major causative bacteria of dental caries, which expresses Cnm, was related to the induction of IgAN-like nephritis. In the present study, the Cnm-positive S. mutans parental strain, a Cnm-defective isogenic mutant strain, its complementation strain, and recombinant Cnm (rCnm) protein were administered intravenously to Sprague Dawley rats, and the condition of their kidneys was evaluated focusing on the pathogenicity of Cnm. Rats treated with parental and complement bacterial strains and rCnm protein developed IgAN-like nephritis with mesangial proliferation and IgA and C3 mesangial deposition. Scanning immunoelectron microscopy revealed that rCnm was present in the electron-dense deposition area of the mesangial region in the rCnm protein group. These results demonstrated that the Cnm protein itself is an important factor in the induction of IgAN in rats.

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a clinicopathological study of three cases

AimsTo explore the clinical and pathological features of light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID-LC).MethodsFrom January 2010 to December 2022, patients who were diagnosed with...

Monoclonal immunoglobulin deposition disease a spectrum? The treatment of an unusual biopsy presentation

Introduction: Monoclonal gammopathy of renal significance (MGRS) is characterized by clonal cell deposition of monoclonal immunoglobulin causing renal manifestations without overt malignancy. MIDD is a subtype of MGRS characterized by deposition of monoclonal light (LCDD), heavy chains (HCDD), or both (LHCDD) along the renal glomerular and tubular basement membranes. Virtually all organs can be involved, and if left untreated, MIDD can progress to MM and end stage renal disease. Although these patients classically did not receive treatment, current MIDD management is primarily focused on controlling the underlying clonal plasma cell disorder. Case description: We present a 56-year-old male with atypical MIDD treated successfully with plasma cell directed therapy consisting of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (DARA-CYBOR-D). Despite a primary diagnosis of diabetic kidney disease, renal biopsy suggested myeloma-related MIDD based on linear immunofluorescent staining for IgG and kappa light chains along the tubular and glomerular basement membranes. Notably there were no electron dense deposits in the mesangium or tubular basement membranes typical to MIDD electron microscopy. Despite the presentation of MIDD on IF only, DARA-CYBOR-D treatment led to hematologic and renal improvement and remission from MIDD, with a GFR increase from 22 to 59 mL/min/BSA and a drop in urine protein from up to 9 to 0.6 g/dL. Conclusions: In conclusion, our case illustrates the efficacy of the DARA-CYBOR-D regimen in a patient with IF-only MIDD. We highlight the importance of obtaining a kidney biopsy when there are other potential causes for real decline and enhance our understanding of pathological and clinical spectrum of MIDD.

#2108 Secondary amyloidosis in a cancer patient on pembrolizumab—an unusual finding

Abstract Background and Aims With the widening horizon of ICPIs in the management of oncological disorders, we require to remain vigilant of the possible iRAEs. We present a case report of secondary amyloidosis in at metastatic non-small cell lung carcinoma (NSCLC) patient treated with Pembrolizumab. We aim to describe the clinic-biological & histopathological characteristics of ICPI-related kidney injury which may be beyond interstitial nephritis & its response to treatment & the role of kidney biopsy to define ICPI-related kidney injury. Treatment is challenging due to a paucity of relevant data, implicating further studies. Treatment with colchicine and steroids, tocilizumab in the setting of elevated interleukin-6 (IL6) levels have been reported in case series; unfortunately no appreciable renal benefit were noted. Method 77 year male, diabetic & hypertensive on regular medication for >15 yr, reformed smoker (≈50 pack-years of cigarette) diagnosed with NSCLC (EGFR–wild type, PDL1–70%), received Pembrolizumab (13 cycles) & Paclitaxel + Carboplatin & was in remission. Follow up PET showed partial response—new lesions in brain. Gemcitabine added to the treatment & had received 2 cycles, till hospitalization with febrile episode, decreased oral intake & progressive edema. Clinical evaluation was non-contributory. Hematology & biochemical evaluation (Table 1) showed raised serum creatinine 1.1 mg/dL (baseline 1 mg/dL), urinalysis—2+ protein, quantification showed 2.9295 g/24 h → 6.38 g/24 h (baseline uPCR-0.19 g/g). Abdominal ultrasound & ECHO finding were not conclusive. Fundoscopy showed no evidence of proliferative diabetic or hypertensive retinopathy. Results Kidney Biopsy (Figure) was done. LM showed, few of 8 gloms with mild segmental mesangial expansion due to amorphous extracellular deposits which was PAS & silver negative but showed congophilia (Fig. A,B,C,D). If negative for albumin, IgG, IgA, C3, C1q & had 1+ granularity in the mesangium on IgM staining & showed no light chain restriction in glomeruli & tubular cast for kappa & lambda. IHC (Fig. E) was positive for serum amyloid associated proteins. EM revealed minimal subendothelial & mesangial expansion due to extracellular material organized into randomly arranged fine fibrils, & no significant foot process effacement, electron dense deposits along the capillary basement membrane or within mesangium, glomerular basement membrane, thereby excluding possibility of light chain deposition disease. Conclusion Secondary amyloidosis with ICPI use has uncommonly & with Pembrolizumab rarely been reported. Treatment is challenging due to paucity of literature. Hassan Izzedine et al. in their case series, on Pembrolizumab treated cancer patient [N = 676], showed 12 patients (7 men) (Incidence 1.77%) developed AKI (n = 10) &/or Proteinuria (n = 2), median duration of use 9 months. All (n = 12) underwent renal biopsy, which showed AIN in 4, ATI in 5, MCD in 2. Recovery happened with withdrawal of drug coupled with corticosteroid. Reintroduction resulted in more severe recurrence of AIN in 1 patient only. Lapman et al. reported 1 case of secondary amyloidosis in cancer patients treated with Pembrolizumab. 42yr male Caucasian, had no reported chronic illness, except Asthma. Similarly developed significant proteinuria (Urine Pro 3+) & AKI (Sr. Creat 1.58 mg/dl; Baseline 1.0 mg/dl) after 90 days of Pembrolizumab therapy. Under went 2 Kidney Biopsy–1st Biopsy revealed AA amyloid. AA amyloidosis was attributed to Pembrolizumab as repeat Bx revealed progressive deposits despite remission of malignancy, but his kidney disease progressed, and had to be initiation on maintenance hemodialysis. Stopping Pembrolizumab & corticosteroids led to resolution of proteinuria in our patient too.

#1273 Rapidly progressive glomerulonephritis with anti-neutrophil cytoplasmic antibodies, in a patient on golimumab

Abstract Background 73-year-old Chinese lady presented with fever, gross hematuria, and dysuria of 1-week duration. She has seronegative arthritis and was treated with human anti-tumor necrosis factor alpha monoclonal antibody (TNF-alpha inhibitor), golimumab injection 50 mg monthly, as she had previous adverse reaction with sulfasalazine and methotrexate. She suffered from severe osteoporosis and was treated with oral alendronic acid. At presentation, her blood pressure was 172/76 mmHg and pulse rate 100 beats per minute. The highest recorded temperature was 38.1 degrees Celsius. Clinical examination was unremarkable. She was diagnosed with rapidly progressive glomerulonephritis (RPGN). Creatinine at presentation was 252 µmol/L, estimated glomerular filtration rate (eGFR) 16 mL/min/1.73 m2. Two months ago, her creatinine was 68 µmol/L, eGFR 66 mL/min/1.73 m2. Urinalysis showed dysmorphic red blood cells of more than 2250 per high power field, few white blood cells, and no epithelial cells. Urine protein/creatine ratio (UPCR) was 2.3 g/g and serum albumin level was 30 g/L. ANA was borderline raised at 1:160 titer with homogeneous pattern. Anti-double stranded DNA (anti-dsDNA) was indeterminate at 29.34 IU. Anti-myeloperoxidase (MPO) antibody was positive at 162 RU/mL (Normal < 20 RU/mL). Anti-proteinase-3 (PR3) antibody was negative. Serum complement levels (C3 and C4) were normal. Screening for hepatitis B, hepatitis C, and HIV was negative. Ultrasound imaging of the kidneys showed raised renal echoes and resistive index. Percutaneous kidney biopsy was performed. On light microscopy, 19 glomeruli were seen. Some displayed segmental increase in mesangial cells and expansion of mesangial matrix. 4 glomeruli showed cellular crescents (Fig. 1). Immunofluorescence showed dominant 2+ staining for Immunoglobulin A (IgA) in the mesangium and electron microscopy revealed electron dense deposits in the mesangial and para-mesangial region. An occasional tubuloreticular structure was found. Diagnosis of IgA nephropathy was made and Oxford classification was M0 E1 S0 T0 C1. Results Our patient presented with rapidly progressive glomerulonephritis (RPGN) with positive MPO antibody, as well as ANA and anti-dsDNA at indeterminate levels. TNF-alpha inhibitors may lead to autoantibody formation and kidney biopsy was the key in clinching the diagnosis for our patient. Diagnosis of IgA nephropathy was made on the basis of dominant mesangial IgA on immunofluorescence and ultrastructural electron dense deposits within the mesangial and para-mesangial area. To our best knowledge, there has been only one case of IgA nephropathy reported with golimumab that occurred after 3 years and with mild albuminuria and no decline in renal function. Golimumab was promptly discontinued for our patient and she was inducted with pulsed methylprednisolone and high dose oral prednisolone 1 mg/kg/day. As she had history of severe osteoporosis, oral mycophenolate mofetil at 750 mg twice a day was commenced as steroid sparing agent. Prednisolone dose was then tapered to 0.5 mg/kg/day. She achieved full clinical remission after 3 months of immunosuppressive therapy. MPO antibody level decreased to normal after 5 months. Arthritis activity remained quiescent and she was maintained on low dose prednisolone. Conclusion We report a case of IgA nephropathy with crescents associated with golimumab. Treatment was successful with withdrawal of drug, oral prednisolone and mycophenolate mofetil.

#2984 SLE associated fibrillary glomerulonephritis vs SLE nephritis with fibrils: can a straightforward distinction always be made?

Abstract Background and Aims Fibrillary glomerulonephritis (FGN) is an uncommon but serious kidney disease with unclear aetiology, variable prognosis, and a not well-established treatment. FGN has been associated with autoimmune diseases including SLE. Other aetiologies comprise diabetes, malignancies, HCV and chronic infections. Our goal is to discuss the pathologic and clinical differential diagnosis conundrums that a patient with a suspected SLE presented. Method We present the case of a 53-year-old woman evaluated for proteinuria (1 g/24 h), and glomerular haematuria. Renal function was normal. She referred mild arthralgias for the past two years. Her medical history was unremarkable for diabetes and hypertension. ANA and anti-dsDNA were positive. The rest of the immunological work-up was normal as well as protein immunofixation/free light chains. HCV, HBV, and HIV serology was negative. A thorough evaluation for malignancy was negative. A renal biopsy was performed. Results The renal biopsy showed enlarged glomeruli with mesangial matrix expansion (Congo-red negative), mild mesangial hypercellularity and focal endocapillary hypercellularity without hyaline deposits, fibrinoid necrosis or crescents, without significant chronic lesions (Fig. 1). A probable diagnosis based on light microscope could be that of a lupus nephritis class III with low activity and low chronicity indices. Immunofluorescence demonstrated weak or moderate immunofixation of IgG (2+), IgA(1+), C3(2+), C1q(1+), κ(1+) and λ(1+) in the mesangium and segmentally in the capillary walls with a smudgy appearance. IgM, C4, fibrinogen and albumin were negative. The lack of a full-house pattern and, more significantly, the low C1q intensity raised some questions about the validity of a lupus nephritis diagnosis. Ultrastructural evaluation revealed abundant fibrils that occupied the mesangium and permeated the glomerular basement membranes (GBMs). Fibrils were non branching and randomly oriented with a mean diameter of ∼15 nm (range: 11,87 nm -18,84 nm) (Fig. 2). No electron dense deposits, fingerprint deposits or tubuloreticular inclusions were detected. Immunohistochemical staining for DNA-J heat-shock protein family member B9 (DNAJB9) was then performed showing strong positivity in the mesangial matrix and GBMs. Interestingly, C4d was also strongly positive with the same pattern as DNAJB9. The diagnosis of fibrillary glomerulonephritis was suggested, mostly based on ultrastructural evaluation and immunohistochemical findings. Conclusion It is well known that the characteristic features of lupus nephritis (intense C1q staining, full-house staining, extraglomerular deposits, tubuloreticular inclusions, and combined subendothelial and subepithelial deposits) are, in some cases, neither universally present nor specific for lupus nephritis. Of special interest is the identification of fibrils in the renal biopsy of an SLE patient. The crucial importance of distinguishing between SLE associated FGN and SLE nephritis with fibrils is based on the generally poor renal prognosis of FGN as well as the unsatisfactory performance of immunosuppression. The differential diagnosis can be very challenging especially when DNAJB9 is not available.

#735 The clinicopathologic prognostic factors to estimate ESRD in patients with FSGS from national wide cohort of renal biopsy

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is one of the leading causes of glomerulonephritis in Korea. FSGS can be caused by heterogenous aetiologies with subdivided by primary, secondary, and genetical forms. The proposed clinicopathologic classification is dependent on amount of proteinuria, laboratory findings of possible secondary causes, and genetic profiles, however, that may not provide definite subtypes of FSGS. Therefore, it is important to search for prognostic markers of any form of FSGS. Method We enrolled a total of 20,404 adult patients who underwent native renal biopsy from 1979 to 2018 in 18 hospitals in Korea. Clinical, demographic, and laboratory data were collected in conjunction with pathologic findings. Among diagnosis of FSGS by pathologists of each hospital, we selected patients with definite segmental sclerosis by light microscopic examination including ≥10 glomeruli and without electron dense deposits by electron microscopic examination. We excluded patients with other forms of pathologic diagnosis except FSGS, with diabetes mellitus, or with follow-up period < 6 months after renal biopsy. We evaluated prognostic factors to estimate the risk of ESRD which event was found from ESRD registry of the Korean Society of Nephrology or the data from each hospital. Results Among 511 selected FSGS patients, 314 (61.4%) men were included. Mean age was 45.0 ± 17.9 years at biopsy. The laboratory finding of serum creatinine, estimated GFR, and urine protein to creatinine ratio (UPCR) was 1.38 ± 0.85 mg/dl, 71.8 ± 36.6 ml/min/1.73 m2, and 4.32 ±4.84 g/g creatinine, respectively (there were no missing data). GFR <60 ml/min/1.73 m2 was found in 41.5 % of patients and UPCR ≥ 3.0 g/g creatinine in 41.1 % of patients. During 117.5 ± 100.1 months of follow-up period, there were 97 (19.0%) patients with incident ESRD. Clinical prognostic factors to incident ESRD were estimated GFR, diastolic blood pressure, and year of renal biopsy. Pathologic prognostic factors were glomerular size, amount of global sclerosis and segmental sclerosis, severity of increase in glomerular matrix, interstitial fibrosis, interstitial inflammation, and tubular atrophy, and presence of artherosclerosis of intrarenal vessels. Adjusted with clinicopathologic factors related to incident ESRD, Cox's proportional hazard models revealed only pathologic findings of amount of glomerular global sclerosis and segmental sclerosis and presence of tubular atrophy were the independent prognostic factors (Model with 3.5 % of missing cases and -2 log likelihood ratio is 956.9, p < 0.001). GFR and UPCR showed significant relationship with incidence of ESRD, however, the significance was gone in the model adjusted with pathologic findings. AUC by ROC to estimate the event of ESRD by percentage of global sclerosis (GS) was 0.601 (range; 0.538-0.663, p = 0.002) and, by percentage of segmental sclerosis (SS), 0.679 (range; 0.616-0.743, p < 0.001). We grouped patients with three pathology categorical variables of a criterion of GS 30.9%, SS 10.5 %, and moderate degree in severity of tubular atrophy (TA), resulted in 8 groups, and summarized into 4 groups according to the relative risk to develop ESRD (Fig. 1). UPCR was a significant risk factor to estimate ESRD only in Group 4 with the criterion of 2 g/g creatinine by the Kaplan-Meier test (p = 0.034). GFR was not a prognostic factor in any pathology subgroup. Conclusion Important prognostic factors to estimate incident ESRD were pathologic findings of global sclerosis, segmental sclerosis, and tubular atrophy in FSGS patients. Significance of UPCR and GFR as prognostic factors was varied according to pathologic findings. We need to reconsider the criterion of UPCR to initiate immunosuppressive treatment and to break down the effect of immunosuppressive treatments for FSGS according to pathologic findings at renal biopsy.

#1517 Glomerular immune complex deposits on electron microscopy in ANCA associated vasculitis: clinical and outcomes features

Abstract Background and Aims Glomerulonephritis related to antineutrophil cytoplasmic autoantibodies (ANCA) is typically referred to as “pauci-immune”, however, it is not unusual for kidney biopsies to exhibit some immune complex deposition within glomeruli on electron microscopic study. Such deposits in ANCA-glomerulonephritis have not been widely studied, and their potential pathologic and clinical significance is not clear, although a possible synergistic effect between immune complexes and ANCA in producing more severe glomerulonephritis is suggested in the literature. Method An observational retrospective study was conducted using a dataset comprising all patients with ANCA associated vasculitis diagnosis from a Portuguese Center between march 2011 and march 2023. Demographic and clinical data were collected from medical records. Electron microscopy reports from kidney biopsies were examined for the presence of electron-dense deposits. Descriptive statistics were used to describe all reports. The objective of this study was to explore associations between the presence or absence of such deposits and clinical data, including serum creatinine, urine protein-creatinine ratio levels (PCR) at the time of biopsy as well as overall survival and renal outcomes at follow-up. Non-parametric Mann-Whitney U test and the Chi-squared test were used for continuous and categorical variables respectively. Kaplan-Meier curves were used for assessing time to event data. All analyses were two-tailed and a p value ≤ 0.05 was considered significant. Results From a total of 39 patients with ANCA associated vasculitis diagnosis, 33 underwent at least one kidney biopsy, and among them, 17 were analysed by electron microscopy. 8 (47%) of biopsies showed glomerular immune complex deposits by electron microscopy; Table 1 describes demographic data of both groups (immune complex deposits—D; no-immune complex deposits—ND). The median numbers of glomeruli examined by electron microscopy were identical between the two groups. In group D there was less patients with positive titers for ANCA (p = 0.034) and serum creatinine levels were higher at admission (mean 7.1 mg/dL IQR: 5.6-8.1 versus 4.2 IQR 3.2-7.1), despite the lack of definitive statistical significance (p = 0.123). Urine protein-to-creatinine ratio did not differ between groups. The need for renal replacement therapy at admission was greater for patients with dense deposits on kidney biopsy (p = 0.008). At the end of follow-up (median 48, IQR 24-48 months), death and progression to end stage kidney disease occurred in 25.0% and 37.5% of group D patients versus 11.1% and 22.2% of ND patients, respectively (Fig. 1). Conclusion Immune complex deposits were found on electron microscopy in nearly half of kidney biopsies. Our data suggest that these immune complex deposits are common and might play a role in clinical presentation, overall survival and renal prognosis. The small sample size of our cohort is a limitation, as well as the retrospective nature of the study. Larger cohorts and more comprehensive electron microscopic studies are warranted to better characterize this population.

#2864 IgA dominant post-infectious glomerulonephritis secondary to the infected left ankle joint in a non-diabetic patient, a case report

Abstract Introduction Post-infectious glomerulonephritis (PIGN) is an immune complex glomerulonephritis that commonly affects children and young adults following beta haemolytic Streptococcal throat or skin infections. Kidney biopsy is characterised by Segmental or global endocapillary hypercellularity, and crescents may be present. In immunofluorescence, post-infectious glomerulonephritis typically shows IgG and C3 deposition. A rare type of PIGN is IgA-dominant post-infection glomerulonephritis. It commonly occurs in the setting of active infection. It usually presents in patients > 60 years old with diabetes mellitus, alcohol consumption, and Staphylococcal infections. It can present with RPGN, AKI, and nephrotic syndrome. Hypocomplementemia can be present, and immunofluorescence is characterised by IgA dominance with C3 co-dominance and no IgG. Despite the strong association with Staph aureus, however, it has been reported with other types of infections. The main line of treatment is antibiotic eradication of the infection. Steroids can be used based on the severity of the lesion and the presence of crescents. Its prognosis is worse than that of the traditional PIGN. In this case, we report a case of IgA-dominant post-infectious glomerulonephritis secondary to left ankle osteomyelitis with Staph aureus infection. Case Presentation A 65-year-old lady had open reduction and internal fixation of a left trimalleolar ankle fracture in June 2023 at a district general hospital. Unfortunately, the post-operative course was complicated by wound infection. The wound swab showed Heavy growth of Staphylococcus aureus. This was followed by Acute Kidney Injury (AKI) stage 3; therefore, she was transferred from her hospital to our renal ward. On admission to the ward, her creatinine was 388 μmol/L(baseline creatinine was 73 μmol/L one month before admission), urine dipstick was positive for blood and protein, and urine protein creatinine ratio was 480 mg/mmol. She had only a medical background of bronchial asthma for which she was only on Inhalers (Beta Agonist) as a regular medication. CT scan of the left ankle revealed appearances consistent with osteomyelitis of both the lateral and medial malleoli. This finding was discussed with microbiology and orthopaedic teams, and the patient was started on intravenous antibiotics (Vancomycin followed by doxycycline). A kidney biopsy was done. Mesangial electron-dense deposits were identified. Immunohistochemistry revealed IgA dominant, predominantly mesangial positivity, with associated C3. The picture was consistent with IgA acute glomerulonephritis associated with S. aureus, which is a post-infectious Glomerulonephritis with dominant IgA staining (rather than conventional IgA nephropathy). With proper intravenous hydration and antibiotics, her inflammatory markers started to improve, and her renal chemistry followed the inflammatory markers, and her last creatinine improved to 146 μmol/L, eGFR 31 ml/min and UPCR was 40 mg/mmol. Discussion IgA-dominant post-infectious glomerulonephritis is now a distinct form of PIGN, which usually presents with acute kidney injury, haematuria, and proteinuria and is typically related to Staph aureus infection. In contrast to typical IgA nephropathy, there is no role for steroid or immunosuppression in the treatment of IgA-dominant post-infectious glomerulonephritis, and the treatment is mainly dependent on the treatment of infection.

#1305 Analysis of clinicopathological characteristics of membranous nephropathy with concomitant malignancy and literature review

Abstract Background and Aims In recent years, the incidence of membranous nephropathy (MN) with malignancy has gradually increased, but the clinical and pathological characteristics of these patients are still unclear. Method Patients diagnosed with renal biopsy-proven MN and comorbid malignancy detected within 5 years before and after MN diagnosis were included. The control group were diagnosed with renal biopsy-proven IMN with no malignancy and no other clear secondary cause for MN. We present a comprehensive analysis of MN with concomitant malignancy in our cohort and literature review. Results A total of 19 MN patients with concomitant malignancy were evaluated at our center; among them, 13 (68.4%) were male, and the median age was 57.0 (45.0, 69.0) years. Malignancy occurred after the onset of renal disease in 61.1% of patients, with digestive system malignancy (36.8%) ranking as the predominant type. 8 (8/11) patients achieved either PR or CR during the follow-up period. Most patients had pathology typical of IMN. IF showed strong positivity for IgG (100%), whereas only 13 (68.4%) patients were positive for C3. IEM showed electron-dense deposits predominantly located in subepithelial. Specific MN antigen staining of renal tissues from 19 patients showed that the highest percentage was 68.4% (13/19) for PLA2R-only positivity followed by 15.8% (3/19) for THSD7A-only positivity. Specific MN antigen staining of malignant tissue was performed in 5 patients whose tumor samples were available. Only 2 patients expressed the same antigen on kidney and tumor. Screening 17 articles encompassing a total of 21 patients in whom MN-specific antigen staining was performed on both renal and tumor tissues simultaneously. Among these patients, 71.4% (15/21) were male, with a median age of 61.0 years (56.3, 72.8). In this cohort, malignancy was diagnosed before or simultaneously with MN in 15 patients (75.0%), with digestive system malignancy constituting the most prevalent comorbid malignancy, at 33.3%. Notably, THSD7A accounted for the highest proportion of MN antigens, at 66.7% (14/21); among these patients, 78.6% (11/14) also exhibited positive tumor THSD7A staining. Of the 21 patients, 72.2% (13/18) achieved CR or PR. No significant difference between the baseline characteristics was observed between the 19 patients from our center and 21 patients documented in the literature. Therefore, the clinicopathological data of these 40 patients were pooled and compared with 101 IMN patients without malignancy at our center. Compared to patients without malignancy, MN patients with malignancy were older at the time of renal biopsy (P = 0.017), had a lower eGFR (P = 0.035) and demonstrated a lower rate of CR or PR after treatment (P < 0.001). The rate of PLA2R positivity in the glomeruli of MN patients with concomitant malignancy was significantly lower (40.0% vs. 92.1%, P < 0.001), while the rate of THSD7A positivity was significantly higher (42.5% vs. 2.0%, P < 0.001). Renal tissue IgG subclass staining showed that the rate of IgG4 positivity was significantly decreased compared with that in IMN patients (59.3% vs. 90.1%, P < 0.001), and the rate of IgG2 positivity was significantly increased (36.0% vs. 16.5%, P = 0.033). Conclusion To conclude, malignancy screening should be more actively performed for MN patients presenting with the above characteristics.

Pediatric early-phase anorexia nervosa without hypokalemia exhibiting acute tubular injury: a case report.

Anorexia nervosa can lead to kidney complications. Few studies reported kidney biopsy results in young adults, most of whom had chronic anorexia nervosa, and kidney biopsy findings in pediatric patients with early-phase anorexia nervosa are rarely reported. A 14-year-old girl who lost weight due to excessive exercise and reduced diet was admitted for kidney dysfunction. She was 147cm tall and weighed 32.9kg, with a body mass index of 15.2kg/m2. She was 39kg about a year earlier. Her heart rate and blood pressure were 30-40 beats/min and 108/68mmHg, respectively. She had kidney dysfunction (estimated glomerular filtration rate, 56.6mL/min/1.73 m2). Urine β2-microglobulin was slightly elevated (393μg/L), and percent tubular phosphate reabsorption was low (75.2%), suggesting tubular damage; however, hypokalemia was absent. Kidney dysfunction did not improve with fluid loading. Kidney biopsy revealed that all glomeruli were intact, with no vasculitis, interstitial inflammation or fibrosis on light microscopy. However, proximal tubular epithelial walls were flattened and the brush border was absent, suggesting acute tubular injury. Immunofluorescent staining was negative for immunoglobulins and complement proteins, and electron microscopy showed no significant electron-dense deposition. The patient's serum creatinine gradually declined, normalizing on the 17th day of admission. Unlike previous reports in young adults, kidney dysfunction was observed even in the absence of hypokalemia in the current pediatric patient with early-phase anorexia nervosa. Proximal tubular injury in early-phase anorexia nervosa may be caused by bradycardia without hypokalemia, leading to subsequent kidney dysfunction.

De novo posttransplant membranous nephropathy after COVID-19 vaccination 9years after renal transplantation in a patient with polycystic kidney disease.

A 63-year-old man with polycystic kidney disease underwent kidney transplantation from his wife. Nine years later, after the first and second doses of the COVID-19 vaccination, he developed proteinuria, hematuria, and elevated C-reactive protein. Kidney biopsy 7months after the initial appearance of proteinuria showed immunoglobulin (Ig)-G granular stain, predominantly IgG1, and spike formation in the glomerular basement membrane. Electron microscopy revealed mainly subepithelial deposits, which corresponds to membranous nephropathy (MN) stage 3 of the Ehrenreich-Churg classification indicating chronic disease, but it also showed electron-dense deposits and endothelial damage. Because a kidney biopsy was performed 1h after renal transplantation and a biopsy of the patient's native kidney showed intact glomeruli, atypical de novo posttransplant membranous nephropathy (MN) was diagnosed, and a close relationship with COVID-19 vaccination was assumed. Clinicians should consider the involvement of COVID-19 vaccination in de novo posttransplant MN with unclear pathogenesis.

Bi-allelic NIT1 variants cause a brain small vessel disease characterized by movement disorders, massively dilated perivascular spaces, and intracerebral hemorrhage

PurposeTo describe a recessively inherited cerebral small vessel disease, caused by loss-of-function variants in Nitrilase1 (NIT1). MethodsWe performed exome sequencing, brain magnetic resonance imaging, neuropathology, electron microscopy, western blotting, and transcriptomic and metabolic analyses in 7 NIT1-small vessel disease patients from 5 unrelated pedigrees. ResultsThe first identified patients were 3 siblings, compound heterozygous for the NIT1 c.727C>T; (p.Arg243Trp) variant and the NIT1 c.198_199del; p.(Ala68∗) variant. The 4 additional patients were single cases from 4 unrelated pedigrees and were all homozygous for the NIT1 c.727C>T; p.(Arg243Trp) variant. Patients presented in mid-adulthood with movement disorders. All patients had striking abnormalities on brain magnetic resonance imaging, with numerous and massively dilated basal ganglia perivascular spaces. Three patients had non-lobar intracerebral hemorrhage between age 45 and 60, which was fatal in 2 cases. Western blotting on patient fibroblasts showed absence of NIT1 protein, and metabolic analysis in urine confirmed loss of NIT1 enzymatic function. Brain autopsy revealed large electron-dense deposits in the vessel walls of small and medium sized cerebral arteries. ConclusionNIT1-small vessel disease is a novel, autosomal recessively inherited cerebral small vessel disease characterized by a triad of movement disorders, massively dilated basal ganglia perivascular spaces, and intracerebral hemorrhage.

Optimal treatment targets for lupus nephritis using per-protocol repeat kidney biopsy findings at 2 years and clinical data up to 5 years: a single-center observational study.

The criteria for remission in both clinical and pathological contexts for lupus nephritis (LN) remain controversial. To identify optimal short-term goals (remission criteria) for LN predicting long-term success at 5 years, using repeat kidney biopsy (Biopsy 2) and clinical data. Single-center observational study. Twenty-three consecutive LN patients undergoing Biopsy 2 2 years post-induction therapy were evaluated. Two ideal long-term goals at 5 years were defined as: "A," Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) = 0 and prednisolone (PSL) ⩽5 mg/day, and "B," proteinuria ⩽0.2 g/day with a normal serum creatinine level and PSL ⩽5 mg/day. Histologically, the electron-dense deposit (EDD) score grades immune deposits based on their intensity, amount, and location. A score of ⩽1 was defined as "electron microscopy remission (ER)." Conventional renal indices failed to predict long-term goals. The short-term goals with an accuracy (area under the curve: 95% confidence interval) of ⩾0.8 predicted long-term goals: "A at 5 years" (A-5y), A-2y (0.91: 0.79-1.00), DORIS-R-2y (0.87: 0.72-1.00), EDD score (0.85: 0.70-1.00), B-2y (0.83: 0.66-0.99), and SLEDAI-R-2y (0.82: 0.66-0.98) as well as "B at 5 years" (B-5y), A-2y (0.87: 0.73-1.00), B-2y (0.87: 0.73-1.00), EDD score (0.85: 0.69-1.00), and DORIS-R-2y (0.83: 0.67-0.99). EDD scores predicted A-5y, B-5y, and PSL dose at 5 years in proportion to the score. The clinical and histological goals aligned. The best predictive short-term goal was A-2y. Concordance between clinical remission (A-2y, B-2y, and DORIS-R-2y) and histological remission (ER) at 2 years suggests optimal short-term goals for LN.

The fate of immune complexes in membranous nephropathy.

The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane. There have been great advances in the understanding of the destiny of immune complexes in MN by the benefit of experimental models represented by Heymann nephritis. Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively. The nascent immune complexes would not be pathogenic until they develop into immune deposits. Podocytes are the major source of autoantigens in idiopathic membranous nephropathy. They also participate in the modulation and removal of the immune complexes to a large extent. The balance between deposition and clearance is regulated by a wide range of factors such as the composition and physicochemical properties of the immune complexes and the complement system. Complement components such as C3 and C1q have been reported to be precipitated with the deposits whereas a complement regulatory protein CR1 expressed by podocytes is involved in the phagocytosis of immune complexes by podocytes. Podocytes regulate the dynamic change of immune complexes which is disturbed in membranous nephropathy. To elucidate the precise fate of the immune complexes is essential for developing more rational and novel therapies for membranous nephropathy.

Scaffold protein SH3BP2 signalosome is pivotal for immune activation in nephrotic syndrome.

Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune signaling complex (signalosome) with 17 other proteins, including phospholipase Cγ2 (PLCγ2) and Rho-guanine nucleotide exchange factor VAV2 (VAV2). Bioinformatic analysis of human glomerular transcriptome (Nephrotic Syndrome Study Network cohort) revealed upregulated SH3BP2 in MCD and FSGS. The SH3BP2 signalosome score and downstream MyD88, TRIF, and NFATc1 were significantly upregulated in MCD and FSGS. Immune pathway activation scores for Toll-like receptors, cytokine-cytokine receptor, and NOD-like receptors were increased in FSGS. Lower SH3BP2 signalosome score was associated with MCD, higher estimated glomerular filtration rate, and remission. Further work using Sh3bp2KI/KI transgenic mice with a gain-in-function mutation showed ~6-fold and ~25-fold increases in albuminuria at 4 and 12 weeks, respectively. Decreased serum albumin and unchanged serum creatinine were observed at 12 weeks. Sh3bp2KI/KI kidney morphology appeared normal except for increased mesangial cellularity and patchy foot process fusion without electron-dense deposits. SH3BP2 co-immunoprecipitated with PLCγ2 and VAV2 in human podocytes, underscoring the importance of SH3BP2 in immune activation. SH3BP2 and its binding partners may determine the immune activation pathways resulting in podocyte injury leading to loss of the glomerular filtration barrier.

Segmentation and thickness calculation of glomerular basement membrane using RADS-Net in glomerular microscopic images

Glomerular ultrastructure needs to be observed under transmission electron microscopy during pathological diagnosis of renal biopsies. Evaluating the glomerular basement membranes (GBM) is necessary for the renal pathological diagnosis. There is little work that performs well for full-flow automated analysis of GBM in whole-glomerular electron microscopy images, including GBM segmentation, location, and thickness calculation. To address this problem, we propose a network architecture, RADS-Net, whose segmentation module combines the advantages of ViT and CNN to achieve better performance in GBM and electron dense deposit (EDD) segmentation tasks. It also contains an uncertainty evaluation module and a location module to exclude unsuitable regions for measurement and extract accurate GBM contours. We propose a GBM thickness calculation method based on statistical learning method, skeletonization algorithm, and improved region growth method. Systematic experiments demonstrate that our proposed segmentation network achieves superior accuracy compared to other competing methods. Additionally, the computed GBM thickness, after an automatic screening of suitable fields of view, meets the requirements for pathology evaluation.

Anti-Glomerular Basement Membrane Disease in a Six-year-old Child: A Rare Presentation

Antiglomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis caused by auto-antibodies targeting auto-antigen expressed in basement membranes of capillary beds in lungs and kidneys. A six-year-old male presented with fever, cough, and generalized weakness for three days with respiratory distress for one day. The child had three prior admissions with similar complaints and was treated as a case of lower respiratory tract infection with severe iron deficiency anemia in the past. Multiple packed red cell transfusions were required in these past admissions. In this current admission, he had tachycardia, tachypnea, severe pallor, right-sided lung crepitations & bronchial breath sounds. The hemogram showed severe anemia and leukocytosis. Urine examination showed mild proteinuria and microscopic hematuria. Chest X-ray (current admission) showed right middle and lower zone consolidation. HRCT of the chest revealed an interstitial pattern. A lung biopsy showed pulmonary hemorrhage and positive Prussian blue staining. Raised anti-GBM titers confirmed diagnosis of anti-GBM disease. Renal biopsy revealed normal glomerular morphology on histopathology; with immune fluorescence showing linear positivity for IgG (3+), Kappa (3+), and Lambda (3+). Electron microscopy reported mild effacement of visceral epithelial foot processes and subepithelial/intramembranous electron-dense deposits. He was treated with intravenous methylprednisone for 5 days followed by oral prednisolone for one month, which was thereafter tapered to a lower maintenance dose for 18 months. The child received six cycles of intravenous cyclophosphamide along with a daily low dose of steroids. Currently, the child is asymptomatic after one year of follow-up with seroconversion (antiGBM titers decreased) and normalization of the chest radiograph.