Fibrocellular Crescents Research Articles

A case of de novo glomerulonephritis following COVID-19 in a patient with preexistent IgA vasculitis.

During the unprecedented COVID-19 outbreak, new-onset or relapsing glomerulonephritis, such as ANCA-associated glomerulonephritis and Immunoglobulin A (IgA) nephropathy, following COVID-19 has been reported. However, to date, the association of COVID-19 with preexistent IgA vasculitis (IgAV) remains unclear. Here, we present the case of a 20-something old Japanese woman with preexistent IgAV who newly developed glomerulonephritis following COVID-19. At the diagnosis of IgAV, she had cutaneous purpura, joint pains, and gastrointestinal symptoms, but no signs of kidney involvement. Three months ago, she was tested positive for COVID-19 and subsequently developed hematuria and proteinuria. She was then admitted to our hospital and renal biopsy showed glomerular mesangial expansion and hypercellularity and cellular and fibrocellular crescents, accompanied by diffuse IgA and C3 deposits. With the diagnosis of de novo IgAV nephritis, the patient was treated with intravenous methylprednisolone followed by oral prednisolone. She had favorable responses to this treatment and has achieved and maintained the remission of hematuria and proteinuria after initiation of glucocorticoid therapy. Our case highlights that immune response to SARS-CoV-2 infection could trigger the onset of glomerulonephritis in the IgAV patients who have no renal involvement.

Comparison of Histomorphological Indices Between Adult and Pediatric Patients in Response to Induction Therapy.

Renal involvement, known as lupus nephritis (LN), is a common and serious complication of systemic lupus erythematosus (SLE), linked to significant morbidity and mortality. Histomorphological indices, such as the activity index (AI) and chronicity index (CI), are critical in predicting treatment responses and outcomes. This study aims to compare these histomorphological indices between adult and pediatric patients with LN and evaluate their impact on post-induction therapy outcomes. A cross-sectional analysis was conducted at a single nephrology department from 2005 to 2019, including patients with biopsy-confirmed LN. Data on demographic characteristics, histomorphological indices, and clinical outcomes post-induction therapy were collected. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 20.0 (Released 2011; IBM Corp., Armonk, New York, United States) to identify significant correlations and differences. Pediatric patients exhibited significantly lower AI (p=0.042) and CI scores compared to adults. Lower frequencies of hyaline thrombi (p=0.005) and tubular atrophy (p=0.028) were observed in the pediatric group. Key predictors of a complete response to induction therapy included interstitial inflammation <0.65 and tubular atrophy <0.63. Significant correlations were found between post-induction renal function tests (RFT) and indices such as AI (p=0.035), CI (p<0.001), cellular and fibrocellular crescents (p<0.001), and tubular atrophy (p<0.001). Proteinuria outcomes were significantly associated with CI (p=0.040), interstitial inflammation (p=0.006), and tubular atrophy (p=0.026). The conclusion aligns with the established understanding that pediatric patients with LN often have a different disease trajectory compared to adults. Pediatric patients generally presented with less severe histomorphological damage, contributing to better responses to induction therapy. Detailed histopathological assessments are essential for guiding treatment strategies and improving patient prognosis in both adult and pediatric LN populations.

Podocyte injury as a potential therapeutic target in IgA nephropathy: should pathology guide us?

The Oxford histopathologic classification (MEST-C: scores for lesions indicating active glomerular inflammation, mesangial [M] and endocapillary [E] hypercellularity as well as cellular or fibrocellular crescents [C], and for segmental glomerulosclerosis [S] and interstitial fibrosis and/or tubular atrophy [T]) is useful in helping assess prognosis in patients with IgA nephropathy. Elements of this classification indicative of active glomerular inflammation, endocapillary hypercellularity and crescents, also have been found to be responsive to immunosuppressive therapy, potentially including newer agents specifically targeting mediators of such inflammation. In this issue of Kidney International, Bellur and coworkers identify histopathologic subtypes of segmental glomerulosclerosis in IgA nephropathy showing podocyte injury that also behave like active lesions, including showing improved outcomes with immunosuppression. This podocyte injury, identifiable only by kidney biopsy, may represent a potential therapeutic target in some patients with IgA nephropathy.

#3033 IgA vasculitis: a unexpected diagnosis of pulmonary renal syndrome

Abstract Background IgA vasculitis is an inflammatory condition affecting blood vessels that poses a significant diagnostic and therapeutic challenge in clinical practice. Characterized by the deposition of immunoglobulin A (IgA) on vessel walls, this pathology can manifest in various ways, presenting a broad and sometimes complex clinical spectrum. Ninety percent of cases occur in the pediatric age group. Severe lung involvement, such as pulmonary hemorrhage, is rare in patients with IgAV. We present a case of a 33-year-old patient with pulmonary renal syndrome and without purpura, an atypical presentation of IgA vasculitis. Case Report We describe the case of a 33-year-old patient with no relevant medical history or regular medication, who presented to the emergency department in November 2022 with symptoms of hemoptysis, fatigue, myalgias, and pallor. On physical examination, the patient was conscious, cooperative, normotensive, tachycardic, afebrile, with bilateral axillary adenopathies, and scattered crackles on lung auscultation. Laboratory tests revealed anemia with a hemoglobin level of 5.8 g/dL, non-oliguric acute kidney injury with a creatinine level of 2.25 mg/dL, microscopic hematuria (&amp;gt;50/hpf), and proteinuria (UPCR of 2.8 mg/mg and UACR of 1.6 mg/mg). A chest CT scan showed bilateral and scattered ground-glass opacities consistent with alveolar hemorrhage. The patient was admitted to the Nephrology service, underwent 3 sessions of plasma exchange, and started therapy with methylprednisolone 1000 mg for 3 days. A renal biopsy revealed 24 glomeruli, with 3 showing segmental sclerosis and 1 with fibrocellular crescents, mild interstitial nephritis; immunofluorescence showed IgA+++, C3++, IgM, and IgG+- Oxford Classification: M1 E0 S1 T0 C1. Bronchofibroscopy showed a rosy bronchoalveolar lavage and macrophages with hemosiderin pigment deposition. The patient continued with prednisolone at 1 mg/kg. In January 2023 (after two months), there was a &amp;gt;25% reduction in albuminuria with resolution of acute kidney injury. A gradual reduction of prednisolone was initiated, and it was definitively discontinued in October 2023. In the last outpatient visit in January 2024, the patient maintained normal renal function, with no hematuria, UPCR of 100 mg/g, UACR of 70 mg/g, and no further episodes of alveolar hemorrhage. Conclusion This case stands out for its atypical presentation: an adult with alveolar hemorrhage and without other more classical manifestations of IgA vasculitis, such as purpura. This is yet another case that emphasizes the importance of the broad spectrum of diagnoses that a nephrologist should consider in the face of acute kidney injury.

#2837 Novel therapeutic for crescentic glomerulonephritis through targeting CLDN1 in parietal epithelial cells

Abstract Background and Aims Crescentic glomerulonephritis (CrGN) is the final mode of kidney injury common to several immune-mediated kidney diseases. CrGN is characterized by extensive glomerular parietal epithelial cells (PECs) proliferation forming crescents. The destructive crescent is then progressively replaced by fibrosis. Currents therapies for CrGN do not directly target the deleterious response of resident kidney cells. In a pathological context, claudin-1 (CLDN1), a transmembrane protein involved in epithelial tight junctions, can be exposed outside the tight junctions and mediate pro-fibrotic pathways and extracellular matrix (ECM) remodelling. Lixudebart (formerly ALE.F02) is a first-in-class monoclonal antibody that specifically targets and blocks exposed CLDN1 in injured epithelial cells. A phase II clinical trial is under way for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with rapidly progressive glomerulonephritis which induces kidney fibrosis (RENAL-F02, NCT06047171). CLDN1 is highly expressed by glomerular PECs. This study investigated the functional role of CLDN1 in CrGN and the potential benefit to target CLDN1 in CrGN. Method CLDN1 expression in renal tissues of CrGN patients was analyzed using kidney multicolor immunofluorescence staining and spatial transcriptomics. Correlation between CLDN1 expression and clinical endpoints (eGFR, proteinuria), disease biomarkers and crescent evolution were studied. A spatially resolved molecular roadmap from CLDN1+ crescentic glomeruli was conducted. Proof-of-concept studies using anti-CLDN1 mAb were performed in preclinical models of CrGN. Results In tissues (n = 150) of patients with AAV and IgAN, multicolor immunofluorescence revealed up-regulated CLDN1 expression by cellular and fibrocellular crescents. At the time of diagnostic kidney biopsy, glomerular CLDN-1 expression was correlated with podocyte loss (as measured with P57 staining) and fibronectin area. The extent of dual expression of CLDN1 and CD44 at the surface of active PECs was associated with poor renal outcome (eGFR &amp;lt; 30 ml/min) in AAV and IgAN patients with a median follow-up of 2.5 and 3.7 years respectively. Spatial transcriptomics analysis highlighted the association between CLDN1+ crescentic glomeruli and ECM genes. Treatment with anti-CLDN1 mAb reduced albuminuria, improved kidney function and decreased fibrosis biomarkers in nephrotoxic serum-induced CrGN in mice. Conclusion Our results suggest a functional role of CLDN1 in the pathogenesis of CrGN, providing preclinical proof-of-concept for anti-CLDN1 antibodies as a novel therapeutic approach in patients with CrGN.

OA21 Clinical outcomes and predictors of difficult-to-treat lupus nephritis: observations from a single center retrospective cohort

Abstract Background/Aims Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE). About 14-33% of LN patients fail to respond to standard treatment. In this study we evaluated the treatment outcomes of LN patients who failed to respond to standard first-line immunosuppressives and attempted to define the clinical characteristics of ‘difficult-to-treat’ (DTT) LN. Methods Records of all SLE patients from the lupus clinic in our center who underwent renal biopsy were reviewed. Those with class III, IV, and V LN were included. Demographic, clinical, laboratory and histopathological features were recorded. Any patient with inadequate response to first-line induction which, according to the ACR, is disease worsening at three months or treatment failure by six months or who did not have partial or complete response as per EULAR/ERA-EDTA definition, were classified as DTT LN. Those who achieved complete response but developed flares within 24 months of therapy warranting second induction were also considered DTT. All of these patients received a second induction therapy. The outcome of interest was a composite outcome of worsening creatinine, end-stage renal disease (ESRD) or death. Secondary outcomes included response rates, time to achieve response, progression to ESRD, mortality, and adverse events. Results We identified 181 SLE patients (91.7% female) with biopsy-proven LN with complete records who had at least 2-year follow-up from 2004 to 2022. Their age (median, IQR) was 29 (24-32) years, median duration of disease 48 (24-84) months, median SLEDAI-2K was 12 (8-16). Among the initial kidney biopsies, 71 (39.2%) were class III, 74 (40.8%) class IV, 23 (12.7%) pure class V and 13 (7.1%) class III/IV + V. Fifty-seven of 181 (31.4%) were identified as DTT. Among these, 28/57 (49.1%) received second induction treatment, 22/57 (38.6%) received three induction, and 7/57 (12.3%) received &amp;gt;3 induction. Being of male sex, presence of constitutional symptoms, serositis, hypertension, leucopenia, active sediments in the initial urinalysis, anti-Ro-60, anti-U1RNP, any antiphospholipid antibodies (aPLs), low C3, wire loop lesions, interstitial inflammation, fibrinoid necrosis, cellular or fibrocellular crescents, and glomerulosclerosis were significantly associated with DTT LN (Table 1). On multivariate logistic regression, only the presence of aPLs and active urinary sediments remained as independent predictors of DTT LN(table 1). A Kaplan-Meier plot showed the cumulative incidence of the composite outcome to be significantly high in the DTT group. After follow up of 250 months, 24/57 (42.1%) DTT patients were in complete remission and 11/57 (19.3%) in partial remission, while 22/57 (38.6%) remained non-responsive to treatment. Conclusion The burden of DTT LN was 30% in our cohort, of whom 65% responded completely to second or third inductions, while a significant proportion failed to achieve remission even with repeat induction. Presence of active sediments at initial diagnosis and co-existence of aPLs were independent predictors of DTT LN. Disclosure J.B. K l: None. A. Jose: None. V. G: None. B. Mashetty: None. G. M s: None. M. Gorijavolu: None. C. Kavadichanda: None. A. Gopal: None. C. Mariaselvam: None. M.M. Thabah: None. V.S. Negi: None.

The Clinicopathological Correlation and Outcome of Glomerulonephritis With Crescent: A Single-Center Study.

There is a lack of standardized treatments for patients with less than 50% crescents observed in their renal biopsies. This study aimed to analyze the crescent percentage, clinicopathological characteristics, and renal prognosis of glomerulonephritis (GN) cases with at least one crescentic lesion. This retrospective cohort study was conducted at the Indira Gandhi Institute of Medical Sciences, Patna, from January 2016 to December 2020. Consecutive patients (aged between 18 and 65 years) with renal biopsy findings suggestive of GN and at least one crescent were included in the study. Demographic details and clinical presentation were collected from the medical records. A total of 145 patients were included. The mean (standard deviation (SD)) age was 33.06 (11.739) years. Hemoptysis was significantly higher in the ≥50% crescentgroup (P=0.011). Rapidly progressive glomerulonephritis (RPGN) was significantly higher in the ≥50% crescent group (P<0.001). There was a significant difference observed in mean creatinine (P=0.001), mean crescents (P<0.001), and mean urine polymerase chain reaction (PCR) (P=0.031). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis was significantly higher in the ≥50% crescent group (P<0.001). Complete remission decreased as crescents increased. In GN with crescent, the presence of fibrous crescents (≥50%) is associated with a higher rate of treatment resistance (100%) compared to fibrocellular (58.33%) and cellular crescents (6.25%).In the ≥50% crescentgroup, death was significantly higher in patients with fibrous crescentage (57.14%). Crescentpercentage and crescentage were found to be significantly related to greater risk of renal failure and resistance to treatment.

Glomerular Exostosin-Positivity is Associated With Disease Activity and Outcomes in Patients With Membranous Lupus Nephritis

IntroductionThe relationship of Exostosin 1 and Exostosin 2 (EXT1/EXT2) expression and outcomes in membranous lupus nephritis (MLN) was controversial. MethodsEXT1/EXT2 was performed by immunohistochemistry in 283 consecutive MLN patients. Clinicopathological characteristics and outcomes of EXT1/EXT2-positive patients were compared with EXT1/EXT2-negative patients.The primary endpoints were adverse renal events include death, dialysis and renal transplantation. Results29.3% MLN patients were positive for EXT1/EXT2. The prevalence of EXT1/2 positive MLN was significantly higher in pure class V MLN than those for mixed class V MLN (44.2% vs. 19.4%, P<0.001). For EXT1/EXT2-positive patients, For EXT1/EXT2-positive patients, the median time between onset of lupus and renal biopsy, and lupus nephritis and renal biopsy is shorter [6 (IQR, 2-25) months vs. 12 (IQR, 3-49) months, P=0.008 and 3 (IQR, 2-18) months vs. 6 (IQR, 2-23) months, P=0.039].) and they had significantly lower Systemic Lupus Erythematosus Disease Activity Index scores (P=0.015) and lower serum creatinine levels (P<0.001), higher hemoglobin (P=0.006) as well as lower blood pressure. The EXT1/EXT2-positive patients had significantly fewer chronicity features (glomerulosclerosis, P<0.001, interstitial fibrosis, P=0.006, and tubular atrophy, P=0.002) and fewer activity indicators (endocapillary hypercellularity, P=0.012, fibrocellular crescents, P=0.007 and cellular crescents, P<0.001) on renal biopsy. After a Median follow-up of 65 (28-126) months, EXT1/EXT2-positive patients were less likely to experience adverse renal events (2.4% vs. 16.0%, P=0.001). ConclusionCompared with EXT1/EXT2-negative patients, the EXT1/EXT2-positive patients presented with lower disease activity and were less likely to experience adverse renal events in relationship with the chronicity index.

Development of a Kidney Prognostic Score in a Japanese Cohort of Patients With Antineutrophil Cytoplasmic Autoantibody Vasculitis

Glomerulonephritis is frequent in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and crucial to disease outcomes. We conducted a detailed assessment of renal pathology in Japanese patients with AAV, and developed a new score that would predict renal outcome. Two hundred twenty-one patients who were diagnosed with AAV and underwent a kidney biopsy were enrolled. Data on glomerular, tubular, interstitial, and vascular lesions from kidney biopsies were analyzed; the 3 established classification and prognostic scoring systems (Berden Classification, Mayo Clinic/RPS Chronicity Score [MCCS], and ANCA Renal Risk Score [ARRS]) were validated. Further, we developed a new prognostic score by including variables relevant for Japanese patients with ANCA-glomerulonephritis. Median follow-up was 60 months (interquartile range: 6-60). End-stage kidney disease (ESKD) risk prediction by the MCCS and the ARRS was confirmed. Moreover, our analysis identified 4 items with significant ESKD risk prediction capacity, namely percentage of cellular, fibrocellular, and fibrous crescents; and sclerotic glomeruli. Based on our findings, we created a score evaluating the percentage of these lesions to total glomeruli, the Percentage of ANCA Crescentic Score (PACS). The area under the receiver operating characteristic (ROC) curve evaluating PACS was 0.783. The PACS had a comparable performance as the ARRS in predicting ESKD. The optimal PACS cut-off for ESKD risk over 60 months was 43%. In addition, the percentage of cellular crescents and presence of interstitial inflammation were independent predictors of kidney function recovery. We developed a new score predicting renal prognosis using histopathological data of Japanese patients with ANCA-glomerulonephritis. Studies are needed to validate our results in international cohorts.

Renal tubular and glomerular estrogen receptor ß levels are lower in lupus nephritis than in familial Mediterranean fever-associated renal amyloidosis.

Estrogen has been thought to play an essential role in the disease pathogenesis of systemic lupus erythematosus, which is 9-10 times more prevalent in the female population. It has been shown that irregular estrogen/estrogen receptor signaling pathways may contribute to the pathophysiology of various renal diseases. In this study, we compared renal estrogen receptors between lupus nephritis, familial Mediterranean fever-associated renal amyloidosis, ANCA-associated nephritis, and intact kidney to investigate their role in the pathophysiology of renal diseases. This study was designed as a retrospective cohort study. Thirty systemic lupus erythematosus patients with lupus nephritis, 12 familial Mediterranean fever amyloidosis and 10 ANCA-associated glomerulonephrites, and 14 individuals with normal renal histology were included in the study. Tubular estrogen receptor ß expression score was found to be significantly higher in the familial Mediterranean fever [5 (1-8)] group than in the lupus nephritis [0 (0-1)] (B = 1.385, OR = 3.996, CI %95 = 1.805-8.846, p = .001) and ANCA [4 (1-6.5)] (B = -1.431, OR = 0.239, CI 95% = 0.093-0.614, p = .003) groups. A significant correlation was found between serum creatinine values and tubular estrogen receptor ß expression score (OR = 0.565, CI 95% = 0.622-1.402, p < .0001). In ANCA-associated glomerulonephritis, a significant relationship was found between fibro cellular crescents in renal biopsy and glomerular estrogen receptor ß expression score (OR = 0.247, CI 95% = 0.11-0.999, p = .045) and tubular estrogen receptor ß expression score (OR = 0.282, CI 95% = -0.180-2.812, p = .026). This study showed that tubular estrogen receptor ß expression score was elevated in familial Mediterranean fever amyloidosis and correlated with serum creatinine levels and renal crescents.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits and atypical pathological findings treated with corticosteroid and rituximab

A 16-year-old girl with fever that appeared after taking the second COVID-19 vaccine presented to the clinic with a serum creatinine of 0.89 mg/dL and C-reactive protein of 6.9 mg/dL. She had proteinuria and microscopic hematuria, with slowly worsening kidney function. Her kidney biopsy showed fibrocellular crescents in seven of nine glomeruli that were observed under light microscopy. Another glomerulus showed endocapillary hypercellularity and mesangial cell proliferation. Electron-dense deposits were significant in the mesangial area, with monoclonal IgG1-κ and C3 deposition by immunofluorescence. The patient was diagnosed with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and atypical pathological finding of diffuse crescent formation. The treatment regimen for PGNMID has not yet been established, and the appropriate duration of treatment is unknown. In our case, considering that rituximab acts by binding to CD20 on the surface of B cells through its crystallizable fragment, it was administered in addition to prednisolone, which successfully decreased the proteinuria over time.

#5207 CENTRAL NERVOUS SYSTEM INVOLVEMENT IN EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS: A DIAGNOSTIC DILEMMA

Abstract Background Central nervous system involvement is extremely rare in eosinophilic granulomatosis with polyangiitis, and associated with very poor prognosis. A high index of suspicion is needed to diagnose this entity and initiate prompt treatment for this life-threatening condition. Case presentation A 71-year-old man was admitted to our hospital with lower limb weakness, loss of vision in the left eye and diplopia for four weeks. Four months prior to admission he reported unintentional weight loss and wheezing. Laboratory studies revealed anemia, eosinophilia and high antineutrophil cytoplasmic antibodies (ANCA) anti myeloperoxidase (MPO) levels. Brain computerized tomography (CT) was normal. Although corticosteroids were started, addition of other immunosupressants was delayed due to ongoing infection. During the next three days, the patient presented with worsening kidney function and was disoriented, agitated and combative. Lumbar puncture and brain CT scan showed no acute abnormalities. Therefore, plasmapheresis was started. During the third session of plasmapheresis, the patient became drowsy and non-responsive. Brain CT scan revealed subdural hematoma with uncal herniation. Trepanation and initiation of hemodialysis were required. Kidney biopsy revealed focal proliferative glomerulonephritis with fibrocellular crescents. Magnetic resonance imaging and ophthalmological evaluation showed abnormalities compatible with vasculitic disease. Cyclophosphamide was added to prednisolone, with renal and extra renal manifestations improvement. One year later, the patient is autonomous, with right hand paresis, stable kidney function (serum creatinine 2.5 mg/dL) and negative ANCA MPO serology. Conclusion Neurological involvement in GEPA is heterogeneous and requires differential diagnosis with central nervous system infections, adverse effects of corticosteroids and complication of plasmapheresis. The diagnosis is challenging and demands a high level of suspicion. Otherwise, it may lead to delayed, erroneous diagnosis and worse survival.

#5924 LATE DIAGNOSIS OF IGA NEPHROPATHY IN LOWER SAXONY (GERMANY) – CLINICAL AND HISTOPATHOLOGICAL DATA FROM 246 PATIENTS AT TIME OF INITIAL RENAL BIOPSY

Abstract Background and Aims IgA Nephropathy (IgAN) is the most frequent glomerulonephritis and contributes significantly to the burden of dialysis dependence. If not detected in the context of screening health examinations e.g. for the military service, decline in renal function is usually unnoticed due to the lack of specific symptoms. After decades of limited pharmacological options, the advent of new therapies provides opportunities for early intervention. Age and renal function as well as proteinuria at the time of renal biopsy varies depending on healthcare systems but might influence the use of novel interventions. Publications from outside Germany report that eGFR at the time of first renal biopsy in IgAN varies between 73.8 and 94.9ml/min/1,73 m2. The age at the time of diagnosis is between 27 and 40 years. The aim of our study was to investigate renal function, degree of proteinuria as well as histological parameters at the time of first renal biopsy in patients with IgA nephropathy. Method This retrospective study evaluated data from two different tertiary care hospitals in Germany that that sent their renal biopsies to the Nephropathology Department at the Hannover Medical School from January 2012 – October 2022. Only initial biopsies from native kidneys were included. Histopathological parameters and clinical as well as laboratory parameters at the month of biopsy were obtained. eGFR was calculated according to the CKD-EPI formula. Results First time diagnosis of IgA nephropathy was made in 246 patients at a median age at of 45 (range 4–79) years, 76.8% were male. The median serum creatinine level was 1.44mg/dl, corresponding to a median eGFR of 43.0 (3.8–132) ml/min/1.73 m2. Surprisingly 49.5% of all patients were at CKD KDIGO GFR stage 3B or higher at the time of first biopsy (Figure 1). Median proteinuria was 1.84 (0.08 – 16.5) g/d in those patients where 24h urine collection was performed. 156 of 246 patients had microhematuria at the time of biopsy. Based on the Oxford classification &amp;gt;50% had hypercellularity. Endocapillary hypercellularity was present in 24%. Segmental glomerulosclerosis was almost evenly distributed (S0:116 | S1:112). Tubular atrophy and interstitial fibrosis were visible in most biopsies in 0-25% of cortical area (T0:153 | T1:59 | T2:16). In 27.2% the C-score was analyzed, showing cellular and/or fibrocellular crescent in 26.8% of those patients. Thrombosis and necrosis were rather uncommon in initial biopsies of IgA Nephropathy. Conclusion The study shows that an IgA Nephropathy shows severe renal impairment at the time of diagnosis i.e. first renal biopsy, suggesting that patients are referred rather late for this diagnostic procedure. These regional data have to be validated in larger cohorts. If confirmed, measures for earlier screening and referral should be implemented to allow timely intervention thus lowering need for renal replacement therapy.

#5076 MONOCLONAL GAMMOPATHY IN C3 GLOMERULOPATHY: DOES THE BUCKET STOP THERE?

Abstract Background and Aims C3 glomerulopathy (C3G) is a rare diagnosis, characterized by dysregulation of the alternative pathway of complement, classically presenting in children and young adults. Recently, it has been reported the association between the production of a monoclonal protein and the development of C3G, affecting a larger age span. Method We report the case of a 53-year-old male patient, that attended the emergency department due to persistent holocranial headache. He was an IV drug abuser with a history of treated Hepatitis C infection and free lambda light chain monoclonal protein, being studied by the Haematology Department. On admission, he was hypertensive (187/98 mmHg), and labs showed an acute on chronic kidney disease (serum creatinine 2.35 mg/dL from a basal of 1.5 mg/dL) with an active urinary sediment (38 erythrocytes/field, with dysmorphia), a urinary protein/creatinine ratio of 626 mg/g, and C3 consumption (0.52 g/L). The patient was admitted, and a kidney biopsy was performed. Results Further lab results confirmed a serum IgG Lambda monoclonal protein. Autoantibodies screening (ANCAs, ANAs, Anti-GBM), ASLO and Rheumatoid Factor were negative. Cryoglobulinemia was detected, and the cryoprecipitate's immunofixation revealed monoclonal proteins IgG Lambda and IgM Kappa. HCV viral load was negative. Bone marrow biopsy revealed a small population (&amp;lt; 3%) of plasma cells with Lambda light chain restriction. Kidney biopsy's light microscopy showed increased mesangial matrix and cells, endocapillary hypercellularity, and some glomeruli with lobulated appearance. Five out of 15 glomeruli presented fibrocellular crescents. Immunofluorescence showed C3 dominant staining on capillary walls and in the mesangium, with absent IgG and light chain deposits. A presumptive diagnosis of C3 glomerulopathy was made and the patient was empirically started on corticosteroids (3 pulses of intravenous methylprednisolone, followed by oral prednisolone 1mg/Kg/day), which was followed by paraprotein-directed chemotherapy with bortezomib, cyclophosphamide and dexamethasone (VCD). The patient is currently on the third VCD cycle, presenting both renal and haematological responses: recovery of serum creatinine to basal levels (1.54 mg/dL), resolution of haematuria and proteinuria, normalisation of C3 levels. Serum immunofixation is currently negative for monoclonal protein, with normal serum immunoglobulin levels. Electron microscopy revealed electron-dense deposits in the mesangium, and mesangium-capillary transition, supporting the diagnosis of C3 glomerulonephritis. Genetic testing of complement-related genes revealed a rare missense variation of unknown significance (c.4855A&amp;gt;C) on the C3 gene, that has been previously reported in association with C3 glomerulopathy and atypical Haemolytic-Uremic syndrome. Conclusion This case represents a monoclonal gammopathy associated-C3 glomerulonephritis with a favourable response to paraprotein-directed chemotherapy. Although the association between monoclonal gammopathy and C3G rests on epidemiologic findings, experimental evidence suggests that several monoclonal proteins have complement dysregulation features, which may enhance alternate complement pathway activation. Our patient's response is in line with observational data that have shown improved renal outcomes in patients who achieve a haematological response following clone-directed chemotherapy, which further supports the role of monoclonal gammopathy in C3G pathogenesis [1]. Interestingly, the genetic variation identified in our patient might have provided a favourable genetic background for the development of C3G, which is thought to rely upon a complex interaction of triggering events, such as a monoclonal gammopathy, and underlying complement abnormalities, such as genetic variants in complement genes.

IgA-dominant glomerulonephritis with DNAJB9-negative fibrillar polytypic immunoglobulin deposits in the subepithelium.

Fibrillary glomerulonephritis (FGN), a rare disease is pathologically characterized by glomerular fibril accumulation ranging from 12 to 24nm in diameter with negative Congo red staining. Recently, the identification of DnaJ homolog subfamily B member 9 (DNAJB9) as a highly sensitive and specific marker for FGN has revolutionized diagnosis of this disease. However, few recent studies have reported DNAJB9-negative glomerulonephritis with fibrillar deposits. As such, it remains unclear whether DNAJB9-negative cases can be considered equivalent to FGN. Here, we report the case of a 70-year-old woman who developed renal impairment and nephrotic-range proteinuria. Renal biopsy and pathological examination revealed focal glomerulonephritis with fibrocellular crescents. Immunofluorescence microscopy showed IgA-dominant deposition of polytypic IgG in the glomerulus. Electron microscopy revealed hump-like subepithelial electron dense deposits with fibrils of 15-25nm in diameter. These findings were consistent with FGN; thus, Congo red and direct fast scarlet (DFS) staining, and immunohistochemistry for DNAJB9 were performed. In addition to negative Congo red/DFS/DNAJB9 staining, laser microdissection (LMD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) resulted negative for DNAJB9, which is a highly sensitive and specific marker for FGN. The patient's renal function further declined, prompting administration of rituximab weekly for 2weeks, similar to the treatment for FGN. This is a unique case of IgA-dominant glomerulonephritis with DNAJB9-negative fibrillar polytypic immunoglobulin deposits in the subepithelium, unlike previous DNAJB9-negative cases. Thus, DNAJB9-negative cases diagnosed based on accurate electron microscopic evaluation must be gathered, and LMD and LC-MS/MS must be used to analyze the organized fibrillar deposits to reveal the disease entity.

Rare Presentation of Crescentic Glomerulonephritis in a 4-Week-Old Infant

Abstract Introduction/Objective Rapidly progressive glomerulonephritis is characterized by sudden decline in renal function and glomerular crescents. Crescentic glomerulonephritis develops along three pathways: glomerular basement membrane antibody in situ deposition , circulating immune complex glomerular deposition, or pauci-immune (typically ANCA-associated). For the latter, histopathologic diagnosis is more frequently obtained in adults than in children. Therefore, tissue examination opportunities in infants and neonates is exceptionally rare. Methods/Case Report Here we report the autopsy findings from a 4-week-old infant who was part of dichorionic, diamniotic twin pregnancy and born prematurely at 34 weeks to a 30-year-old G6P4 mother. The infant initially presented with labored breathing and poor oral intake, but subsequently developed Enterobactor meningoencephalitis and sepsis, leading to extensive strokes andstatus epilepticus. An infectious source was not identified clinically, and evaluation for an underlying immunodeficiency was indeterminant. The mother had no known autoimmune diseases or antenatal infections. At autopsy, kidney histology showed focal fibrinoid necrosis and/or cellular and fibrocellular crescents (~5%), especially mid to deep cortex. Intracapillary hypercellularity was minimal to absent. Mesangial matrix was not expanded. The interstitium contained patchy inflammatory infiltrates (mononuclear &amp;gt; polymorphonuclear). Direct immunofluorescence (IF) on pronase-treated paraffin sections did not show glomerular deposition of IgG, IgA, or IgM. Electron microscopy (EM) did not show electron dense deposits despite autolysis. Results (if a Case Study enter NA) NA. Conclusion The absence of immune complex deposition by IF and dense deposits by EM favors the rare diagnosis of pauci-immune glomerulonephritis in this case of neonatal crescentic glomerulonephritis associated with Enterobactor meningoencephalitis and sepsis, with no associated maternal autoimmune disease or antenatal infections.

Crescents and IgA Nephropathy: A Delicate Marriage.

IgA nephropathy (IgAN) is a progressive disease with great variability in the clinical course. Among the clinical and pathologic features contributing to variable outcomes, the presence of crescents has attracted particular interest as a distinct pathological feature associated with severity. Several uncontrolled observations have led to the general thought that the presence and extent of crescents was a prognostic indicator associated with poor outcomes. However, KDIGO 2021 guidelines concluded that either the presence or the relative number of crescents should not be used to determine the progression of IgAN nor should they suggest the choice of immunosuppression. Our aim is to report and discuss recent data on the debated issue of the value of active (cellular and fibrocellular) crescents in the pathogenesis and clinical progression of IgAN, their predictive value, and the impact of immunosuppression on renal function. We conclude that the value of crescents should not be disregarded, although this feature does not have an independent predictive value for progression in IgAN, particularly when considering immunosuppressed patients. An integrated overall evaluation of crescents with other active MEST scores, clinical data, and novel biomarkers must be considered in achieving a personalized therapeutic approach to IgAN patients.

Rare Case of Renal Limited Dual Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: Double Trouble!

Dual anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) characterized by the presence of both anti-proteinase-3 (PR3-ANCA) and anti-myeloperoxidase (MPO-ANCA) antibodies is a rare clinical entity. Only few cases have been reported previously, most of which were associated with infections, drugs, autoimmune diseases and malignancies. Herein, we describe a young woman who presented with rapidly progressive glomerulonephritis with hypocomplementemia and markedly elevated anti-PR3 and anti-MPO titres. Meticulous work-up ruled out all possible secondary causes. Renal biopsy showed the presence of focal fibrocellular crescents with focal mesangial hypercellularity. Immunofluorescence and electron microscopy showed pauci-immune deposits. The patient was treated with an induction regimen comprising oral prednisolone and cyclophosphamide. She attained both clinical and serological remission at 3 months and is currently on an azathioprine-based maintenance regimen. We have extensively reviewed all previous cases of dual AAV and have formulated an approach to diagnose and treat this rare entity.LEARNING POINTSDual anti-neutrophil cytoplasmic antibody-associated vasculitis characterized by both PR3-ANCA and MPO-ANCA antibodies is a rare clinical entity.Prior to treating with immunosuppression, we need to rule out secondary aetiologies such as drugs, certain infections, autoimmune diseases and haematological malignancies.Atypical presentations such as hypocomplementemia, other serological abnormalities like positive ANA, cryoglobulins, anti-histone antibody and histology showing mesangial hypercellularity, interstitial inflammation and lack of pauci-immunity, may create a diagnostic dilemma.

Lupus nephritis correlates with B cell interferon-\u03b2, anti-Smith, and anti-DNA: a retrospective study

BackgroundIn systemic lupus erythematosus (SLE), detection of interferon-β (IFNβ) in B cells was found to be most prominent in patients with high anti-Smith (Sm) and renal disease, but a mechanistic connection was not clear. The objective of the present study is to determine the association of IFNβ in peripheral blood naïve B cells with the histopathological features of lupus nephritis (LN).MethodsThe percentage of IFNβ+ cells in IgD+CD27− naïve CD19+ B cells (B cell IFNβ) among peripheral blood mononuclear cells (PBMCs) from 80 SLE patients were analyzed using flow cytometry. Serological and clinical data were collected. The correlations of B cell IFNβ with LN classification and with histopathological findings (light, electron, and immunofluorescence [IF] microscopic analyses for deposition of IgM, IgG, IgA, C1q, and C3) were determined in 23 available biopsy specimens.ResultsB cell IFNβ is positively associated with anti-Sm (p = 0.001), anti-DNA (p = 0.013), and LN (p < 0.001) but was negatively associated with oral/nasal ulcer (p = 0.003) and photosensitivity (p = 0.045). B cell IFNβ positively correlated with immune complex (IC) deposit in the glomerular basement membrane (GBM) (p = 0.002) but not in the mesangial (p = 0.107) or tubular region (p = 0.313). Patients with high B cell IFNβ had statistically increased development of the proliferative LN (Classes III, IV and/or V), compared to patients with low B cell IFNβ (p < 0.0001). Histopathological features positively associated with increased B cell IFNβ included active glomerular lesions as determined by fibrocellular crescents (p = 0.023), chronic glomerular lesions indicated by segmental sclerosis (p = 0.033), and a membranous pattern of renal damage indicated by spike/holes (p = 0.015).ConclusionB cell IFNβ correlates with history of severe LN, glomerular basement membrane (GBM) IC deposition, and anatomical features of both active and chronic glomerular lesions.

Иммуноглобулин-А-нефропатия у детей: обзор литературы и собственные данные

Актуальность. IgA-нефропатия (IgAN) — наиболее распространенная форма первичной хронической гломерулопатии (ГП) как у взрослых, так и у детей. Считается, что в детском возрасте она имеет доброкачественное течение, однако у взрослых занимает 1-е место среди ГП как причина терминальной стадии хронической болезни почек (ХБП) в молодом возрасте. Цель исследования: анализ литературных данных, клинических, иммунопатологических и морфологических изменений при IgA-нефропатии у детей для выявления пациентов с высоким риском прогрессирования заболевания. Материалы и методы. В исследование вошли 53 пациента с IgAN (36 мальчиков, 17 девочек) в возрасте от 6 до 17 лет, находившихся под наблюдением в Республиканском центре детской нефрологии и почечной заместительной терапии г. Минска. Критерий включения: преобладание доминантных/кодоминантных мезангиальных депозитов IgA при иммуногистологии нефробиоптата с использованием классификации MEST+C 2016 г. Длительность наблюдения составила от 13 месяцев до 6 лет. Результаты. У детей с IgAN концентрация аберрантного deGal-IgA1 оказалась значимо выше в сравнении с пациентами с нефритом Шенлейна — Геноха и здоровыми лицами (р &lt; 0,001). Риск быстрого прогрессирования и наступления терминальной стадии ХБП повышается у пациентов с артериальной гипертензией, протеинурией свыше 0,5 г/сут, снижением рСКФ менее 60 мл/мин, наличием сегментарного склероза, тубулярной атрофии, интерстициального фиброза, фиброзных и фиброклеточных полулуний, большого количества депозитов IgA в комбинации с С3 в биоптате. Выводы. В детском возрасте в большинстве случаев IgAN имеет низкую скорость прогрессирования и не приводит к полной утрате функции почек.